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The Pennsylvania State University

The Graduate School

Eberly College of Science

TOTAL SYNTHESES OF (±)-ISOPHELLIBILINE AND (±)-COMMUNESIN F, AND DESIGN, SYNTHESIS AND PHARMACOLOGICAL EVALUATION

OF DIHYDRO-β-ERYTHROIDINE (DHβE) ANALOGS

A Dissertation in

Chemistry

Johannes Belmar

Submitted in Partial Fulfillment of the Requirements

for the Degree of

Doctor of Philosophy

December 2012

The dissertation of Johannes Belmar was reviewed and approved* by the following:

Raymond L. Funk Professor of Chemistry Dissertation Advisor Chair of Committee

Kenneth S. Feldman Professor of Chemistry

Scott T. Phillips Assistant Professor of Chemistry

Robert Rioux Friedrich G. Helfferich Assistant Professor of Chemical Engineering

Barbara J. Garrison Shapiro Professor of Chemistry Head of the Chemistry Department

*Signatures are on file in the Graduate School

iii

ABSTRACT

The intramolecular cycloaddition reactions of 2-amidoacroleins are

discussed in Part I. Application of this methodology in natural product synthesis

resulted in the first total synthesis of a member of the nonaromatic

homoerythrinan class of natural products, (±)-isophellibiline. The synthesis was

completed in 16 linear steps from 2,2-dimethyl-1,3-dioxan-5-one in an overall

yield of 2.3%. In addition, the design, synthesis and pharmacological evaluation

of analogs of the nicotinic acetylcholine receptor (nAChR) antagonist dihydro-β-

erythroidine (DHβE) are described.

In Part II efforts towards the total synthesis of the marine natural product

(±)-communesin F are discussed. First, we describe the reactions of aza-ortho-

xylylenes generated via the Lewis acid catalyzed retrocycloaddition reaction of

3,1-benzoxazin-2-ones. Although, the total synthesis of communesin F was not

realized through application of this methodology, it resulted in the preparation

of an advanced intermediate towards communesin F.

Next, we explore the Diels–Alder cycloaddition reactions of indol-2-one

and detail the successfully applied this methodology in a concise total synthesis

of (±)-communesin F. The synthesis was completed in 15 linear steps from 4-

bromotryptophol in an overall yield of 6.7%.

TABLE OF CONTENTS

LIST OF SCHEMES ................................................................................................... vi

LIST OF FIGURES ..................................................................................................... x

LIST OF TABLES ....................................................................................................... xi

ACKNOWLEDGEMENTS ....................................................................................... xii

Part I: Total Synthesis of (±)-Isophellibiline and Design, Synthesis and Pharmacological Evaluation of Dihydro-β-Erythroidine (DHβE) Analogs ................................................................................................................ 1

Chapter 1. Introduction and Background ...................................................... 2 1.1. The Erythrina alkaloids ...................................................................... 2 1.2. Pharmacology of the Erythrina alkaloids ........................................ 2 1.3. Biosynthesis of the Erythrina alkaloids ............................................ 5 1.4. Previous synthetic efforts towards the Erythrina alkaloids ........... 8

1.4.1. Padwa’s strategy for the synthesis of erythrinan and homoerythrinan alkaloids ........................................................... 9

1.4.2. Tu’s strategy for the synthesis of erythrinan and homoerythrinan alkaloids ........................................................... 10

1.4.3. Tsuda’s syntheses of erythrinan and homoerythrinan alkaloids via a unified synthetic strategy ................................. 11

1.5. Studies towards the erythrinan and homoerythrinan alkaloids in the Funk laboratory: A 2-Amidoacrolein Cycloaddition Route ..................................................................................................... 12 1.5.1. 2-Amidoacroleins ...................................................................... 12 1.5.2. Previous synthetic effort directed toward the Erythrina

alkaloids in the Funk laboratory ................................................ 15 Chapter 2. Total Synthesis of (±)-Isophellibiline ........................................... 18

2.1. Retrosynthetic analysis of isophellibiline ........................................ 18 2.2. Total synthesis of (±)-isophellibiline ................................................. 19 2.3. Concluding remarks ............................................................................ 26

Chapter 3. Preparation of Dihydro-β-Erythroidine (DHβE) Analogs ........ 27 3.1. Background and significance ............................................................. 27

3.1.1. Nicotinic acetylcholine receptors (nAChRs) ......................... 27 3.1.2. Pharmacophore models for nAChR ligands ......................... 29 3.1.3. Dihydro-β-erythroidine (DHβE) ............................................. 32

3.2. Synthesis of DHβE analogs ................................................................ 39 3.3. Results and discussion ........................................................................ 42

Chapter 4. Experimental ................................................................................... 44 4.1. Materials and Methods ....................................................................... 44

4.2. Preparative Procedures ....................................................................... 45 Spectra of Isophellibiline (Authentic and Synthetic) .................................... 72 References ........................................................................................................... 77

Part II: Total Synthesis of (±)-Communesin F ....................................................... 81

Chapter 5. Introduction and Background ...................................................... 82 5.1. Isolation and structural characterization of the communesins

and perophoramidine ......................................................................... 82 5.2. Pharmacology of the communesins and perophoramidine .......... 84 5.3. Biosynthesis of the communesins and perophoramidine ............. 84 5.4. Previous synthetic approaches to the communesins ...................... 88

5.4.1. Stoltz’s approach to the communesin ring system ............... 88 5.4.2. Adlington’s approach to the communesin ring system ....... 89 5.4.3. Qin’s total synthesis of (±)-communesin F ............................ 90 5.4.4. Weinreb’s total synthesis of (±)-communesin F .................... 92 5.4.5. Ma’s total synthesis of (-)-communesin F .............................. 93 5.4.6. Ma’s total synthesis of communesins A and B ...................... 94

Chapter 6. Studies Towards the Communesins in the Funk Laboratory: An Aza-ortho-xylylene Route .............................................. 97 6.1. Introduction .......................................................................................... 97 6.2. Previous synthesis efforts directed towards the communesins

in the Funk laboratory ........................................................................ 100 Chapter 7. An Approach to the Synthesis of Communesin F: An Aza-

ortho-xylylene Route ................................................................................... 103 7.1. Retrosynthetic analysis of communesin F ........................................ 103 7.2. Synthesis of an advanced intermediate towards the synthesis

of communesin F ................................................................................. 104 7.3. Concluding remarks ............................................................................ 110

Chapter 8. Studies Towards the Communesins in the Funk Laboratory: An Indol-2-one Route ........................................................... 111 8.1. Introduction .......................................................................................... 111 8.2. Prior work in the Funk laboratory .................................................... 113

Chapter 9. Total Synthesis of (±)-Communesin F via a Cycloaddition with Indol-2-one ......................................................................................... 118 9.1. Retrosynthetic analysis of communesin F ........................................ 118 9.2. Total synthesis of (±)-communesin F ................................................ 119 9.3. Concluding remarks ............................................................................ 135

Chapter 10. Experimental ................................................................................. 137 10.1. Materials and Methods ..................................................................... 137 10.2. Preparative Procedures ..................................................................... 138

Spectra of 1’’-Deoxocommunesin F and Communesin F ............................. 171 References ........................................................................................................... 176

LIST OF SCHEMES

Scheme 1.3.1. Barton’s proposed biosynthesis of the Erythrina alkaloids ........ 6

Scheme 1.3.2. Zenk’s proposed biosynthesis of the Erythrina alkaloids ........... 7

Scheme 1.4.1. Synthetic strategies for the construction of the erythtinan and homoerythrinan ring system .................................................................... 8

Scheme 1.4.2. Padwa’s approach to the erythrinan and homoerythrinan ring systems ........................................................................................................ 10

Scheme 1.4.3. Tu’s approach to the erythrinan and homoerythrinan ring systems ................................................................................................................ 10

Scheme 1.4.4. Tsuda’s total syntheses of erysotrine and 3-epi-schelhammeridine .............................................................................................. 11

Scheme 1.5.1. Kato’s synthesis of 2-amidoacroleins ............................................ 13

Scheme 1.5.2. Hon’s synthesis of 2-amidoacroleins ............................................ 13

Scheme 1.5.3. Funk’s synthesis of 2-amidoacroleins ........................................... 13

Scheme 1.5.4. Funk’s total syntheses featuring cycloaddition reactions of 2-amidoacroleins ................................................................................................ 14

Scheme 1.5.5. Ishihara’s enantioselective cycloaddition reaction of a 2-imidoacrolein ...................................................................................................... 15

Scheme 1.5.6. He and Funk’s total syntheses of (±)-β-erythroidine and (±)-8-oxo-β-erythroidine .......................................................................................... 16

Scheme 2.1.1. Retrosynthetic analysis of isophellibiline ..................................... 19

Scheme 2.2.1. Preparation of dioxin 1-89 .............................................................. 19

Scheme 2.2.2. Intramolecular amidoacrolein cycloaddition .............................. 20

Scheme 2.2.3. Preparation of Z-enoate 1-84 .......................................................... 21

Scheme 2.2.4. Preparation of vinyl iodide 1-92 .................................................... 22

Scheme 2.2.5. Introduction of the tetrahydroazepine ring ................................. 22

Scheme 2.2.6. Preparation of diene 1-94 ................................................................ 23

vii

Scheme 2.2.7. Introduction of the C(3) hydroxyl substituent ............................ 23

Scheme 2.2.8. Protection of the C(3) hydroxyl group .......................................... 24

Scheme 2.2.9. Attempted reintroduction of the C(6)–C(7) unsaturation .......... 24

Scheme 2.2.10. Reintroduction of the C(6)–C(7) unsaturation ........................... 25

Scheme 2.2.11. Completion of the total synthesis of (±)-isophellibiline ........... 25

Scheme 2.2.12. Attempted conversion of isophellibiline to phellibiline .......... 26

Scheme 3.2.1. Preparation of Type I deslactone-DHβE analogs .......................... 40

Scheme 3.2.2. Preparation of Type II deslactone-DHβE analogs ......................... 41

Scheme 5.3.1. Mantle’s biosynthetic pathway to communesin B ...................... 85

Scheme 5.3.2. Biosynthesis of perophoramidine ................................................. 86

Scheme 5.3.3. Stoltz’s biosynthetic pathway to communesin B ........................ 86

Scheme 5.3.4. Funk’s biosynthetic pathway to communesin B ......................... 87

Scheme 5.4.1. Stoltz’s approach to the communesin ring system ..................... 88

Scheme 5.4.2. Adlington’s initial approach to the communesin ring system .. 89

Scheme 5.4.3. Adlington’s modified approach to the communesin ring system .................................................................................................................. 90

Scheme 5.4.4. Qin’s total synthesis of (±)-communesin F ................................... 91

Scheme 5.4.5. Weinreb’s total synthesis of (±)-communesin F .......................... 92

Scheme 5.4.6. Ma’s total synthesis of (-)-communesin F .................................... 94

Scheme 5.4.7. Ma’s total synthesis of communesins A and B ............................ 95

Scheme 6.1.1. Thermal decarboxylation of 3,1-benzoxazin-2-ones ................... 98

Scheme 6.1.2. Competitive [1,5]-sigmatropic hydrogen shift ............................ 98

Scheme 6.1.3. Palladium catalyzed decarboxylation of 4-vinyl-3,1-benzoxazin-2-ones ............................................................................................. 98

viii

Scheme 6.1.4. Base-mediated elimination of HCl from o-chloromethylanilines ......................................................................................... 99

Scheme 6.1.5. Acid-catalyzed dehydration of 2-aminobenzyl alcohols ........... 99

Scheme 6.2.1. Crawley and Funk’s first-generation synthetic plan .................. 100

Scheme 6.2.2. Crawley and Funk’s second-generation synthetic plan ............. 101

Scheme 6.2.3. Crawley and Funk’s third-generation synthetic plan ................ 102

Scheme 7.1.1. Retrosynthetic analysis for communesin F .................................. 103

Scheme 7.2.1. Preparation of allenyl indole 2-110 ............................................... 105

Scheme 7.2.2. Preparation of N-acyl-4-acyl-3,1-benzoxazin-2-one 2-114 ......... 105

Scheme 7.2.3. Synthesis of aminal 2-103 ............................................................... 106

Scheme 7.2.4. Alkylation of lactam 2-103 .............................................................. 107

Scheme 7.2.5. Attempted transamidation reaction .............................................. 108

Scheme 7.2.6. Crawley’s inadvertent transamidation reaction .......................... 108

Scheme 7.2.7. Crawley’s transamidation reaction of tosylimide 2-120 ............. 109

Scheme 7.2.8. Attempted preparation of a more reactive imide ....................... 110

Scheme 8.1.1. Remote addition of a nucleophile to an indol-2-one intermediate ........................................................................................................ 112

Scheme 8.1.2. Cycloaddition reaction of an indol-2-one intermediate ............. 112

Scheme 8.2.1. Fuchs and Funk’s total synthesis of (±)-perophoramidine ........ 114

Scheme 8.2.2. Crawley and Funk’s intramolecular indol-2-one cycloaddition approach towards the communesins ..................................... 115

Scheme 8.2.3. Crawley and Funk’s planned intermolecular indol-2-one cycloaddition approach towards the communesins ..................................... 116

Scheme 8.2.4. Intermolecular indol-2-one cycloaddition and determination of the stereochemical outcome ......................................................................... 117

Scheme 9.1.1. Retrosynthetic analysis for communesin F .................................. 118

Scheme 9.2.1. Reaction of 3-bromoindol-2-one with 3-methylindole ............... 120

Scheme 9.2.2. Preparation of indolenine 2-157 ..................................................... 120

Scheme 9.2.3. Construction of aminal 2-167 ......................................................... 121

Scheme 9.2.4. Preparation of amide 2-169 ............................................................. 122

Scheme 9.2.5. Attempted Heck reaction ................................................................ 123

Scheme 9.2.6. Deprotection of tosylamide 2-169 .................................................. 123

Scheme 9.2.7. Preparation of bis-Boc allylic alcohol 2-173 ................................. 124

Scheme 9.2.8. Attempted benzazepine formation ............................................... 124

Scheme 9.2.9. Preparation of allylic alcohol 2-177 ............................................... 125

Scheme 9.2.10. Allylic amination with mercuric triflate ..................................... 126

Scheme 9.2.11. Introduction of the benzazepine ring ......................................... 126

Scheme 9.2.12. Possible pathway for the mercuric triflate catalyzed cyclization ........................................................................................................... 127

Scheme 9.2.13. Preparation of bridgehead lactam 2-185 ..................................... 128

Scheme 9.2.14. Attempted alkylation of bridgehead lactam 2-186 ................... 129

Scheme 9.2.15. Preparation of bridgehead lactam 2-188 ..................................... 130

Scheme 9.2.16. Alkylation of bridgehead lactam 2-188 ....................................... 131

Scheme 9.2.17. Synthesis of 1”-deoxocommunesin F .......................................... 132

Scheme 9.2.18. N-Ethylation of indolines with acyloxyborohydrides .............. 133

Scheme 9.2.19. A proposed synthetic pathway to 1”-deoxocommunesin F .... 134

Scheme 9.2.20. Completion of the total synthesis of (±)-communesin F .......... 135

Scheme 9.3.1. Total synthesis of (±)-communesin F ............................................ 136

LIST OF FIGURES

Figure 1.1.1. The Erythrina alkaloids ...................................................................... 3

Figure 1.2.1. Biologically active erythrinan and homoerythrinan alkaloids .... 4

Figure 3.1.1. Structures of acetylcholine and nicotine ......................................... 27

Figure 3.1.2. (1) Beers–Reich pharmacophore, (2) as applied to nicotine ......... 30

Figure 3.1.3. (1) Sheridan pharmacophore, (2) as applied to nicotine .............. 30

Figure 3.1.4. Abbott “four-point” pharmacophore as applied to nicotine ....... 31

Figure 3.1.5. (1) Novo Nordisk pharmacophore, (2) as applied to nicotine ..... 32

Figure 3.1.6. Structures of lead compounds and synthetic analogues .............. 34

Figure 3.1.7. Pharmacophoric elements in β-E as determined by Beers and Reich, and DHβE and strychnine as determined by Sheridan .................... 35

Figure 3.1.8. Conformations of DHβE, protonated-cis and -trans ...................... 36

Figure 3.1.9. Type I and Type II analogs of deslactone-DHβE ............................. 39

Figure 5.1.1. The communesins and perophoramidine ....................................... 83

Figure 9.2.1. X-ray crystal structure of aminal 2-167 ........................................... 121

Figure 9.2.2. Comparison of cyclization precursor conformations.................... 125

Figure 9.2.3. X-ray crystal structure of benzazepine 2-180 ................................. 126

LIST OF TABLES

Table 3.1.1. Structure and binding results for Funk and He’s DHβE analogs ................................................................................................................. 37

Table 3.1.2. Structure and binding results for Wildeboer’s β-E analogs .......... 38

Table 3.3.1. Binding results for Type I and II analogs ......................................... 43

Table 8.2.1. Comparison of 1H NMR and 13C NMR data for synthetic (±)-communesin F and natural communesin F5 in CDCl3 .................................. 170

xii

ACKNOWLEDGEMENTS

Though one name appears on the cover, a dissertation is a far more collaborative

project than that. I owe a debt of gratitude to Professor Raymond Funk, who not

only offered me a place in his lab even though my background was in biology,

but also gave me the guidance and support necessary to get this thing done. I am

also indebted to the members of the Funk laboratory, individually and

collectively, for their willingness to answer my questions and give me

experimental advice. Thanks too to all my friends for the many years of good

company and friendship while in State College. Deep expressions of gratitude,

along with love, are due to my family for a lifetime of support of every kind.

Part I: Total Synthesis of (±)-Isophellibiline and Design, Synthesis and Pharmacological Evaluation of Dihydro-β-

Erythroidine (DHβE) Analogs

Chapter 1. Introduction and Background

1.1. The Erythrina alkaloids

The Erythrina alkaloids,1 which have attracted significant attention due to

their biological activity and their unique structure, are a large class of natural

products isolated from the genus Erythrina. The Erythrina alkaloids can be

categorized into two groups based on their structural features: the erythrinans

which posses a 6-5-6-n tetracyclic core (A-B-C-D) and the homoerythrinans

which posses a 6-5-7-n tetracyclic core (Figure 1.1.1). These groups can be further

subdivided depending on whether the D-ring is aromatic or nonaromatic. To

date, well over 110 erythrinan alkaloids and over 70 homoerythrinan alkaloids

have been isolated.1a,2

1.2. Pharmacology of the Erythrina alkaloids

The Erythrina genus consists of about 110 species that are distributed

throughout tropical and subtropical regions worldwide. Many Erythrina species

have played important roles in indigenous medicines.1b,1c,3 For example, E.

americana was used by Aztec Indians as a purgative, diuretic, sudorific, and

hypnotic.4 The Huastec of Mexico used the aqueous extract of the leaves of E.

americana in the treatment of insomnia and restless anxiety.5 The bark of E. fusca

and E. indica have been used to treat fever, malaria, rheumatism, toothache, and

boils.6

Figure 1.1.1. The Erythrina alkaloids

In the late 1870’s, Altimirano and Dominguez reported that extracts of the

seeds of E. americana produced a curare-like action (i.e., causes paralysis of

smooth muscle).7 However, it was not until 1937 that Folkers and Major8 isolated

a physiologically active crystalline alkaloid, named erythroidine, from the seeds

of E. americana and demonstrated that it caused a curare-like action. Subsequent

analysis showed that the substance isolated was a mixture of two isomeric

alkaloids designated α-erythroidine (1-9, Figure 1.2.1) and β-erythroidine (1-6,

Figure 1.1.1), the latter being the more active isomer.9 β-Erythroidine (1-6) and its

1-8isophellibiline

1-43-epi-schelhammericine

1-3comosine

1-6β-erythroidine

1-7cocculolidine

1-1erythraline

1-5selaginoidine

NO O

1-28-oxo-erymelanthine

NMeO2C

NA B

1 6 8

5 ( )n

n = 1 erythrinan alkaloidsn = 2 homoerythrinan alkaloids

(aromatic erythrinan) (heteroaromatic erythrinan)

(aromatic homoerythrinan) (heteroaromatic homoerythrinan)

(nonaromatic erythrinan) (nonaromatic homoerythrinan)

2 7

Figure 1.2.1. Biologically active erythrinan and homoerythrinan alkaloids

more potent dihydro derivative, 2,7-dihydro-β-erythroidine (DHβE, 1-10), are

antagonists of nicotinic acetylcholine receptors (nAChRs). DHβE is widely used

in functional assays as a nonselective, competitive antagonist for nAChRs.

In contrast to the erythrinan alkaloids, there are few reports on the

pharmacological effects of the homoerythrinan alkaloids. Wilsonine (1-11) has

been found to be a weak antileukemic agent in mice.10 3-epi-12-

hydroxyschelhammericine (1-12) has been found to possess cardioactivity in rat

atrial preparations.11 3-epi-Schelhammericine (1-4, Figure 1.1.1) and

dyshomoerythrine (1-13) have been shown to exhibit potent molluscicidal

activity.12 Dyshomoerythrine has also demonstrated activity against a number of

agricultural pests, including the Australian sheep blowfly L. cuprina.13

1-9α-erythroidine

O1-11

wilsonine

1-102,7-dihydro-β-erythroidine

(DHβE)

1-123-epi-12-hydroxyschelhammericine

1-13dyshomoerythrine

OOH

1.3. Biosynthesis of the Erythrina alkaloids

In 1957, Barton and coworkers proposed the first broadly accepted

biosynthetic pathway for the biosynthesis of the Erythrina alkaloids (Scheme

1.3.1).14 This proposal was supported by feeding studies with young E. crista-galli

plants wherein they observed that the benzylisoquinoline (S)-

norprotsoinomenine (1-14) was incorporated to the extent of 0.25% into the

erythrinan alkaloid erythraline (1-1).15 Thus, it was proposed that (S)-

norprotsoinomenine undergoes cyclization by para-para phenol oxidative

coupling to give dienone 1-15. Ring opening of dienone 1-15 and subsequent

reduction of the imine functionality of 1-16 gives the symmetric bisphenol 1-17.

Oxidation of bisphenol 1-17 provides the bisquinone 1-18. A subsequent

intramolecular conjugate addition reaction completes the erythrinan tetracyclic

ring system to afford erysodienone (1-19), which is transformed into erythraline

(1-1).

However, Zenk’s observation that Barton’s proposed pathway would

have constituted a biosynthetic exception to the multitude of isoquinoline

alkaloids, including the aporphines, pavines, and morphinanes, that are derived

from (S)-reticuline (1-20: N-CH3 instead of N-H, Scheme 1.3.2), and the low

incorporation rate (0.25%) of (S)-norprotsoinomenine (1-14) prompted a

reinvestigation by Zenk and coworkers.16 Thus, following 3H and 13C labeling

studies, it was shown that (S)-[1-13C]norreticuline (1-20) was incorporated at a

rate of 7.9% into erythraline (1-1) with exclusive incorporation of 13C at the C(10)

position, thereby excluding the possibility of a symmetric intermediate such as

Scheme 1.3.1. Barton’s proposed biosynthesis of the Erythrina alkaloids

1-17. A new biosynthetic pathway and mechanism for Erythrina alkaloid

biosynthesis was required in light of these findings (Scheme 1.3.2).

The revised route commences with a para-para phenol coupling of (S)-

norreticuline (1-20) to give, according to model reactions performed by Franck

and Teetz,17 a morphindienone derivative, such as norisosalutaridine (1-21).

Subsequent formation of the methylenedioxy group provides noramurine (1-22),

which after rearrangement and reduction gives asymmetric dibenzazonine 1-25.

The free phenolic ring of dibenzazonine 1-25 is then oxidized in a two-electron

process to the diallylic cation 1-27, which reacts with the nitrogen atom to

produce erythratinone (1-28). Finally, erythratinone (1-28) is transformed into

erythraline (1-1) according to the steps previously proposed by Barton.14

OOH

HNH

OOH

OHO

OOH

OHO

OOH

NH NO

[H]

[O]

1-14(S)-norprotosinomenine

1-19erysodienone

1-15 1-16

1-17 1-18

NOO

1-1erythraline

Scheme 1.3.2. Zenk’s proposed biosynthesis of the Erythrina alkaloids

The biosynthetic pathway proposed for the homoerythrinan alkaloids

based on Barton’s proposal starting from the homolog of (S)-norprotsoinomenine

(1-14)18 would likely require revision in light of the work of Zenk and coworkers.

OHO

OOH

OHO

OOH

NH NO

1-28erythratinone

- e- - e-

1-20(S)-[1-13C]norreticuline

1-21norisosalutaridine

1-22noramurine

1-23

1-24 1-25 1-26

1-27

NOO

1-1erythraline

1.4. Previous synthetic efforts towards the Erythrina alkaloids

The Erythrina alkaloids have attracted considerable attention from the

synthesis community due to their biological activity and unique tetracyclic core.

In many cases, new synthetic methods have been developed and tested in the

course of this synthesis work. The most common strategies for construction of

the erythrinan and homoerythrinan core can be classified into three general

routes based on the last ring formed in the synthetic sequence: (I) formation of

the A-ring by introduction of a four-carbon unit onto the tricyclic B-C-D skeleton,

(II) formation of the B-ring by elaboration of the C(5) spirocyclic ring system,

and, the most prevalent strategy, (III) formation of the C-ring and simultaneous

construction of the C(5) quaternary center (Scheme 1.4.1).1a The aromatic

erythrinans have been the target of the majority of synthetic efforts, resulting in

many successful total syntheses.1 The nonaromatic erythrinans have posed a

greater challenge,19 and accordingly, only three members of this subclass have

Scheme 1.4.1. Synthetic strategies for the construction of the erythtinan and homoerythrinan ring system

NA B

1 6 8

5 ( )n

n = 1 erythrinan alkaloidsn = 2 homoerythrinan alkaloids

2 7

NA B

5 ( )n

NHA

5 ( )n

III

been synthesized: (±)-cocculolidine (1-7),19d β-erythroidine (1-6),19e,19f and (±)-8-

oxo-β-erythroidine.19f The homoerythrinans, in comparison to the erythrinans,

have received little attention and all work has been limited to the aromatic

homoerythrinans.2,20

Surprisingly, in light of the small structural difference between the

erythrinan and homoerythrinan alkaloids, the development of a concise, unified

strategy for the preparation of both groups of natural products has proven

elusive.20e-h,20m Strategies aimed at overcoming this difficult problem have thus far

focused on the synthesis of the aromatic erythrinan and homoerythrinan

alkaloids. The most notable of these efforts are described below.

1.4.1. Padwa’s strategy for the synthesis of erythrinan and homoerythrinan alkaloids

Padwa’s strategy for constructing the core of the aromatic erythrinan and

homoerythrinan alkaloids employed a tandem reaction to construct the B and C

rings in a single operation (a combination of strategies II and III).20k The reaction

proceeds via an initial acid catalyzed Pummer reactions of sulfoxides 1-29 and 1-

30, and subsequent π-cyclization of the thionium ion (Scheme 1.4.2). The newly

generated N-acyliminium ions 1-31 and 1-32 then undergo a Pictet–Spengler

reaction to furnish the core ring system of the erythrinan and homoerythrinan

alkaloids, 1-33 and 1-34, respectively. The authors have yet to report on the

application of this strategy in the context of total syntheses of members of the

erythrinan and homoerythrinan alkaloids.

Scheme 1.4.2. Padwa’s approach to the erythrinan and homoerythrinan ring systems

1.4.2. Tu’s strategy for the synthesis of erythrinan and homoerythrinan alkaloids

Tu utilized a similar disconnection to construct the C ring in their

synthesis of the aromatic erythrinan and homoerythrinan alkaloid core ring

systems (strategy III).20i In this case, the B ring was constructed via an initial

alkylation of 1-35 with either 1-36 or 1-37, which was followed by a subsequent

intramolecular cyclization (Scheme 1.4.3). Upon treatment with TFA, lactams 1-

38 and 1-39 underwent a Pictet–Spengler reaction to give the respective

tetracycles, 1-42 and 1-43.

Scheme 1.4.3. Tu’s approach to the erythrinan and homoerythrinan ring systems

CO2Et

SEt

n NO

EtO2C SEt

1-29 n = 1, R = H1-30 n = 2, R = Et

1-33 n = 1, R = H (76%)1-34 n = 2, R = Et (40%)

EtO2C SEt

1-31 n = 1, R = H1-32 n = 2, R = Et

TFAA, TFA,CH2Cl2, rt,2 h

ORn

OTFA,CH2Cl2,rt, 24 h

O nR

LDA, THF, -78 °C;

1-36 n = 1, R = H1-37 n = 2, R = Me

1-38 n = 1, R = H (84%)1-39 n = 2, R = Me (86%)

1-42 n = 1, R = H (75%)1-43 n = 2, R = Me (83%)

1-40 n = 1, R = H1-41 n = 2, R = Me

1-35

1.4.3. Tsuda’s syntheses of erythrinan and homoerythrinan alkaloids via a unified synthetic strategy

To date, the Tsuda group has reported the only total synthesis of members

of the aromatic homoerythrinan alkaloids. They have reported the total syntheses

of six members of the aromatic homoerythrinan alkaloids, including comosine (1-

3, Figure 1.1.1), 3-epi-schelhammericine (1-4, Figure 1.1.1) and 3-epi-

schelhammeridine (1-51, Scheme 1.4.4). 20a-d While lengthy (22–26 steps), these

syntheses employed a strategy (strategy I) similar to that employed in the

synthesis of the aromatic erythrinan alkaloid erysotrine (1-51).21

Thus, the [2 + 2] photocycloaddition of Danishefsky’s diene and

dioxopyrroloisoquinolines 1-44 and 1-45 provided the respective cyclobutane

adducts 1-46 and 1-47 (Scheme 1.4.4). Reduction of the ketone in 1-46 and 1-47

was followed by a 1,3-anionic rearrangement to complete the construction of the

Scheme 1.4.4. Tsuda’s total syntheses of erysotrine and 3-epi-schelhammeridine

OTMS

OEtO2C

TMSO

ORO

R1O

OEtO2C

R1O

OHEtO2C

R1O

300 W Hg lamp,0 °C, 1 h

NRO

R1O

erysotrine (1-50)n = 1, R = R1 = Me

3-epi-schelhammeridine (1-51) n = 2, R = R1 = -CH2-

n n

1-48 n = 1, R = R1 = Me (60%)1-49 n = 2, R = R1 = -CH2- (89%)

1-44 n = 1, R = R1 = Me 1-45 n = 2, R = R1 = -CH2-

1-46 n = 1, R = R1 = Me (64%)1-47 n = 2, R = R1 = -CH2- (80%)

1. NaBH4, MeOH, 0 °C, 0.3 h

2. TBAF, THF, -30 °C, 1.25 h

A ring in 1-48 and 1-49. Further manipulation of 1-48 and 1-49 led to the total

syntheses of erysotrine (1-50) and 3-epi-schelhammeridine (1-51), respectively,

via a unified synthetic strategy.

Although these syntheses of aromatic Erythrina alkaloids are noteworthy,

it is evident that there certainly remains a need for the further development of

concise, unified routes towards the erythrina and homoerythrina alkaloids. In

particular, approaches that can accommodate the construction of the

nonaromatic erythrina and homoerythrina alkaloids are completely lacking.

1.5. Studies towards the erythrinan and homoerythrinan alkaloids in the Funk laboratory: A 2-Amidoacrolein Cycloaddition Route

1.5.1. 2-Amidoacroleins

A survey of the literature for known methods to access 2-amidoacroleins

uncovered few possibilities, some representative examples of which are

described below. Kato and coworkers have described the oxidation of 2-amido-

1,3-diols to give 2-amidoacroleins (Scheme 1.5.1).22 In their report, they disclosed

that oxidation of diol 1-52 under Swern conditions gives an initial β-hydroxy

aldehyde which was dehydrated under the reaction conditions to give

amidoacrolein 1-53.

Scheme 1.5.1. Kato’s synthesis of 2-amidoacroleins

Additionally, Hon and coworkers have prepared amidoacroleins 1-56 via

methlenylation of the ozonide 1-55 prepared by ozonolysis of allylamide 1-54

(Scheme 1.5.2).23

Scheme 1.5.2. Hon’s synthesis of 2-amidoacroleins

The Funk laboratory has developed a versatile method for the preparation

of 2-amidoacroleins 1-59.24 In practice, condensation of dioxanone 1-57 with an

amine generates the corresponding imine, which following acylation with an

acid chloride gives amidodioxin 1-58 (Scheme 1.5.3). The thermal or Lewis acid

catalyzed retrocycloaddition of amidodioxins 1-58 yields the 2-amidoacrolein 1-

59.

The Funk laboratory has demonstrated the synthetic utility of

amidoacroleins in cycloaddition19f,24b,25 and electrophilic aromatic substitution26

Scheme 1.5.3. Funk’s synthesis of 2-amidoacroleins

OHO

OOH

(COCl)2, DMSO,Et3N, -70 oC

65%

1-52 1-53

O O

O NH

O3,CH2Cl2,

-78 oC

CH2Br2, Et2NH,55 oC, 1.5 h

42%1-54 1-55 1-56

O O

RR'

RNH2

Δ or LA

1-57 1-58 1-59

+ O

PhNEt2

reactions by completing the total syntheses of a number of natural products. The

key cycloaddition reactions of a few representative total syntheses are shown in

Scheme 1.5.4. In the synthesis of FR901483 (1-62), the amidoacrolein, generated

from amidodioxin 1-60, participated in a cycloaddition reaction to give the 1-

alkyl-1-aminocyclohexene 1-61 (eq. 1, Scheme 1.5.4).24b In the key cycloaddition

reaction in the synthesis of fasicularin (1-66), amidoacrolein 1-64 reacted with

diene 1-63 under high-pressure reaction conditions to give 1-alkyl-1-

aminocyclohexene 1-65 (eq. 2, Scheme 1.5.4).25a The synthesis of β-erythroidine (1-

6) featured the intramolecular cycloaddition of an amidoacrolein to prepare

Scheme 1.5.4. Funk’s total syntheses featuring cycloaddition reactions of 2-amidoacroleins

O O

OOMe

OMe

TIPSO TIPSO

OOMe

MeO NO

HNH

HOHO

benzonitrile,120 oC 64%

1-60 1-61 1-62FR901483

OH H

NTf

Ph OH

O N

SCN

12 kbar,CH2Cl2

93%

1-64 1-65 1-66fasicularin

1-67 1-68

1-6β−erythroidine

(eq. 1)

(eq. 2)

(eq. 3)

toluene,110 oC

66% exo(+ 11% endo)

1-63

lactam 1-68 (eq. 3, Scheme 1.5.4).19f Thus, 2-amidoacroleins are competent

dienophiles in intramolecular and intermolecular cycloaddition reactions under

both thermal and high-pressure reaction conditions.

More recently, Ishihara and coworkers have described the enantioselective

cycloaddition reaction of 2-imidoacrolein 1-69 (Scheme 1.5.5).27 They report that

2-imidoacrolein 1-69 undergoes cycloaddition with diene 1-70 in the presence of

the organocatalyst 1-71 to give the 1-alkyl-1-aminocyclohexene 1-72 with 96% ee

in 82% yield.

Scheme 1.5.5. Ishihara’s enantioselective cycloaddition reaction of a 2-imidoacrolein

1.5.2. Previous synthetic effort directed toward the Erythrina alkaloids in the Funk laboratory

To date, work in the Funk laboratory has resulted in the total synthesis of

(±)-β-erythroidine (1-6) and (±)-8-oxo-β-erythroidine (1-79), both members of the

nonaromatic erythrinan subclass of natural products (Scheme 1.5.6).19f The

syntheses of the natural products commenced with the retrocycloaddition of

dioxin 1-67 and concomitant intramolecular cycloaddition of the intermediate

amidoacrolein to afford exo-cycloadduct 1-68 as the major product. Aldehyde 1-

O+ PhthN

NH N

NH2Bn

iBu

C6F5SO3H

82% (96% ee)

1-69 1-70

1-71

1-72

68 was transformed under the Still–Gennari protocol to the Z-enoate 1-73. Heck

cyclization of vinyl bromide 1-73 afforded the E-dienoate, which was hydrolyzed

to give acid 1-74. Upon heating, acid 1-74 underwent a 6π-electrocyclic closure to

the corresponding lactone. The lactone was protected as ortho ester 1-75. The

C(6)–C(7) unsaturation was introduced by selenylation/oxidative deselenylation

to give the diene lactam which was deconjugated to diene 1-76. A

diastereoselective cycloaddition of diene 1-76 with singlet oxygen from the less

hindered face and a reductive workup gave diol 1-77. Subsequent treatment of

diol 1-77 with potassium hydroxide and methyl iodide in the presence of a phase

Scheme 1.5.6. He and Funk’s total syntheses of (±)-β-erythroidine and (±)-8-oxo-β-erythroidine

OBrOO

toluene,110 oC

66% exo(+ 11% endo)

(F3CH2CO)2P O

OMe

18-Crown-6, 95%

1. Pd(OAc)2, PPh3, K2CO3 90%

2. LiOH 95%

O1. toluene, 110 oC 89%

2. CH(OMe)3,HOCH2CH2OH 95%

1. LDA, PhSeSePh; H2O2, pyridine 86%

2. KHMDS, HMPA; AcOH 91%

1O2, hν,rose bengal;NH2CSNH2 73%

KOH, MeI,Et4NBr

88%

1. AlH3•NEt(Me)2 80%

2. H3O+

95%H3O+

96%1-79

8-oxo-β-erythroidine

1-67 1-68 1-73

1-74 1-75 1-76

1-77 1-78 1-6β−erythroidine

6 7

transfer catalyst allowed for simultaneous methylation of the C(3) hydroxyl and

for elimination of the C(6) hydroxyl to provide lactam 1-78. Hydrolysis of the

ortho ester of 1-78 furnished (±)-8-oxo-β-erythroidine (1-79). Reduction of lactam

1-78 with alane–ethyldimethyamine complex, followed by hydrolysis of the

ortho ester functionality completed the total synthesis of (±)-β-erythroidine (1-6).

Chapter 2. Total Synthesis of (±)-Isophellibiline

2.1. Retrosynthetic analysis of isophellibiline

Following He and Funk’s successful total syntheses of two nonaromatic

erythrinan alkaloids, we aimed to demonstrate the versatility of this strategy by

completing the total synthesis of a nonaromatic homoerythrinan alkaloid,

isophellibiline (1-8).28 Isophellibiline was isolated from Phelline billiardieri

(Iliacacées) and its structure was determined from chemical and spectral data. Our

retrosynthetic approach to the synthesis of isophellibiline is illustrated in Scheme

2.1.1. It was proposed that isophellibiline could be prepared by seemingly

straightforward extension of He and Funk’s β-erythroidine synthesis. However,

it was expected that the seven-membered ring, the C(1)–C(6) alkene, and the C(3)

hydroxyl group would make the synthesis of this natural product more

challenging. Thus, 1,6-reduction of diene amide 1-80, reduction of the lactam,

and unmasking of the lactone would give isophellibiline (1-8). Oxidation of the

deconjugated diene derived from diene 1-81 would install the C(3) hydroxyl

substituent in diene amide 1-80. Diene 1-81 would in turn arise from lactam 1-82

following protection of the lactone functionality, and introduction of the diene

functionality. Lactone 1-82 would derive from dieneoate 1-83 via a 6π-

electrocyclic ring closure. Acid 1-83 could arise from an intramolecular Heck

reaction of ester 1-84. Finally, the intramolecular cycloaddition of amidoacrolein

Scheme 2.1.1. Retrosynthetic analysis of isophellibiline

1-85 which possesses the necessary additional carbon within the amide alkenyl

side chain would be followed by Still–Gennari olefination to furnish ester 1-84.

2.2. Total synthesis of (±)-isophellibiline

The total synthesis of isophellibiline commenced with the condensation of

2,2-dimethyl-1,3-dioxan-5-one (1-57) with 4-bromopent-4-ene-1-amine (1-86)29 in

the presence of sodium sulfate to give imine 1-87 (Scheme 2.2.1.). Acylation of

imine 1-87 with hexa-3,5-dienoyl chloride (1-88), prepared in two steps from

sorbic acid,30 gave amidodioxin 1-89.

Scheme 2.2.1. Preparation of dioxin 1-89

O BrH

HON

HOO

1-8isophellibiline

1-80 1-81 1-82

1-83 1-84

1-85

1 67

1-891-57

1-86 1-88

1-87

NClO

H2N

OONa2SO4,benzene,rt, 8 h;

PhNEt2, THF,rt, 12 h63% (2 steps)

Scheme 2.2.2. Intramolecular amidoacrolein cycloaddition

Upon heating, amidodioxin 1-89 underwent a retrocycloaddition and

concomitant cycloaddition to give a 4.5:1 mixture of exo-cycloadduct 1-91 and

endo-cycloadduct 1-90, respectively (Scheme 2.2.2). Presumably, this ratio reflects

the strain energy difference between the cis-cycloadduct 1-91 and the trans-

cycloadduct 1-90 (~3 kcal/mol, PCMODEL, MMX) that is, to some extent, also

present in the respective exo-1-85 and endo-1-85 transition states, thus overriding

any putative stabilization incurred through secondary orbital interactions in

endo-1-85.

At this stage, we attempted to rectify a shortcoming in Funk and He’s β-

erythroidine (1-6) synthesis, namely, the lack of an enantioselective approach.

However, our attempt to address this issue through a classical substrate

controlled approach employing an α-silyloxy substituent on C(2) of the hexa-3,5-

dienoyl moiety was unsuccessful. Moreover, all attempts to catalyze the

N O

exo-1-85endo-1-85

13% 59%

1-89

1-90 1-91

toluene,110 °C,6.5 h

intramolecular cycloaddition of amidoacrolein 1-85 with chiral catalysts such as

Carmona’s rhodium catalyst,31 Kündig’s ruthenium catalyst,32, Nishida’s

ytterbium(III) BINAMIDE complex,33 and Ishihara34 or Yamamoto’s35 chiral

Brønstead acid catalysts, among others also proved unsuccessful.

With racemic cycloadduct 1-91 in hand, we turned our attention towards

the introduction of the key tetrahydroazepine ring. Thus, Still–Gennari

olefination36 of neopentyl aldehyde 1-91 gave Z-enoate 1-84 (Scheme 2.2.3).

However, initial attempts to effect the Heck cyclization of vinyl bromide 1-84

using the conditions (Pd(OAc)2, PPh3, K2CO3) employed in the course of He and

Funk’s β-erythroidine synthesis, as well as several other protocols (e.g.,

Pd(OAc)2, P(o-tol)3, K2CO3; Pd(OAc)2, AsPh3, iPrNEt2; Pd(OAc)2, dppp, Et3N;

Pd(PPh3)4, NaOAc), provided the desired E-dienoate in very low yield (<5%)

along with significant decomposition of the starting material, usually the result

of debromination. Similarly, Heck cyclization of vinyl iodide 1-92, prepared from

the from vinyl bromide 1-84 via halogen exchange (Scheme 2.2.4),37 led mainly to

the deiodination product. Padwa and coworkers noted similar difficulties in

effecting a Heck cyclization to form a tetrahydroazepine ring in their approach

ambiguine38 synthesis gave the desired E-dienoate with clean inversion of

Scheme 2.2.3. Preparation of Z-enoate 1-84

(F3CH2CO)2P O

OMe

OKN

Br18-Crown-6, THF,-78 °C, 1 h 66%

1-91 1-84

Scheme 2.2.4. Preparation of vinyl iodide 1-92

stereochemistry (Scheme 2.2.5).39 The resulting methyl ester was immediately

saponified with LiOH to give dienoic acid 1-83. As noted by Baran and

coworkers, the slow addition of Herrmann’s catalyst40 was necessary to achieve a

consistent yield in the Heck reaction. Interestingly, the reduced product was not

observed. Thus, it can be concluded that even in the highly reducing

environment (excess sodium formate), interception of the intermediate alkyl-

palladium species by hydride ion is slower than the competing β-hydride

elimination.

The next task in the total synthesis involved introduction of the lactone D-

ring (Scheme 2.2.6) and installation of the C(3) hydroxyl substituent. With these

goals in mind, heating dienoic acid 1-83 in refluxing toluene promoted a clean

6π-electrocyclic closure to lactone 1-82. Lactone 1-82 was then protected with 1,2-

ethanediol in the presence trimethyl orthoformate and catalytic acid to give ortho

Scheme 2.2.5. Introduction of the tetrahydroazepine ring

Br1-84

I1-92

HN N

HCuI, KI, dioxane,115 °C, 96 h

95%

PdP

Ar Ar

Ar = o-CH3C6H4

O OPdOO

PAr Ar

NaOCOH, Bu4NBr, Et3N, MeCN, 85 °C, 24 h

2. LiOH, THF, MeOH, H2O, rt, 3 h, 65% (2 steps)

HOO

1-84 1-83

Scheme 2.2.6. Preparation of diene 1-94

ester 1-93. The C(6)–C(7) unsaturation present in 1-81 was introduced via a

selenylation/deselenylation sequence. Treatment of diene amide 1-81 with LDA,

followed by a kinetic quench with acetic acid at low temperature (–78 °C),

yielded the deconjugated diene lactam 1-94.

With diene 1-94 in hand, the C(3) hydroxyl substituent could be installed.

Thus, a stereoselective cycloaddition with singlet oxygen, from the face opposite

to the bulky ortho ester, gave endoperoxide 1-95 (Scheme 2.2.7). Reduction of the

crude endoperoxide with thiourea proceeded smoothly, affording the cis-1,4-diol

1-96 in good yield.

Scheme 2.2.7. Introduction of the C(3) hydroxyl substituent

1. nBuLi, THF, -78 °C, 0.75 h; PhSeSePh, 1 h2. H2O2, pyridine, CH2Cl2, 0 °C, 1 h

81% (2 steps)

1-81 1-94

HOO

1-83 1-82 1-93

toluene,110 °C,12 h

80%

CH(OMe)3, CSAHOCH2CH2OH,CH2Cl2, rt, 12 h

78%

LDA, HMPA,THF, -78 °C, 2.5 h; AcOH 96%

1-94 1-95 1-96

HON

OO1O2, hν,rose bengal,

acetone, 0 oC, 2 h;

H2N NH2

MeOH, rt,12h, 70%

Since isophellibiline (1-8) possesses a C(3) hydroxyl substituent instead of

the C(3) methoxy substituent present in β-erythroidine (1-6), we could not

employ the strategy previously utilized to reintroduce the C(6)–C(7)

unsaturation (1-77à1-78, Scheme 1.5.6). Therefore, after extensive

experimentation, the C(3) hydroxyl of diol 1-96 was protected selectively as its

silyl ether (1-97) with N-(tert-butyldimethylsilyl)-N-methyltrifluoroacetamide

(Scheme 2.2.8).41

Scheme 2.2.8. Protection of the C(3) hydroxyl group

An attempt to implement the aforementioned methylation/elimination

sequence (KOH, MeI, Et4NBr) to install the C(6)–C(7) unsaturation was

hampered by a competitive silyl transfer, resulting in the C(6) silyl ether and

subsequent methylation of the hydroxyl group at C(3) (Scheme 2.2.9). Efforts to

dehydrate 1-97 using either Martin’s sulfurane or the Burgess reagent also were

unsuccessful.

Scheme 2.2.9. Attempted reintroduction of the C(6)–C(7) unsaturation

TBSO

1-97

1-96

F3C

N TBS

MeCN,rt, 12 h 65%

TBSON

OTBS

OKOH, MeI,Et4NBr, THF,DMSO, rt, 12 h

98%

1-97 1-98

Ultimately, a two-step sequence involving acetylation of the tertiary C(6)

hydroxyl group and subsequent elimination of the acetate with DBU

reintroduced the C(6)–C(7) unsaturation present in lactam 1-99 (Scheme 2.2.10).

Scheme 2.2.10. Reintroduction of the C(6)–C(7) unsaturation

All that remained to complete the total synthesis of isophellibiline was 1,6-

reduction of the diene 1-99, reduction of the lactam, and global deprotection. To

that end, selective 1,6-reduction of diene lactam 1-99 with L-Selectride gave

lactam 1-100 as the only reduction product (Scheme 2.2.11). Reduction of

lactam1-100 with alane–ethyldimethylamine complex gave the corresponding

amine. Finally, hydrolysis of the ortho ester and concomitant cleavage of the silyl

ether under mildly acidic conditions furnished (±)-isophellibiline (1-8) whose

spectroscopic properties were identical to those previously reported and

authentic spectra provided by Dr. Nicole Langlois.28,42 Attempts to convert

isophellibiline (1-8) to phellibiline (1-101) under the conditions (“per passage sur

Scheme 2.2.11. Completion of the total synthesis of (±)-isophellibiline

TBSO

1-99

TBSO

1-97

1. Ac2O, Et3N, DMAP, CH2Cl2, rt, 36 h, 97%

2. DBU, benzene, 80 °C, 24 h 82%

TBSON

1. AlH3•NEt(Me)2, THF, 0 °C, 0.75 h 70%

2. HCl, H2O, THF, rt, 1.75 h 90%

1-99 1-100 1-8isophellibiline

L-Selectride,THF, -78 °C,3 h; 0 °C, 2 h;AcOH, -78 °C

83%

une colonne d’alumine”; basic, neutral and acidic alumina were tested) disclosed

in the isolation paper28 were unsuccessful (Scheme 2.2.12).

Scheme 2.2.12. Attempted conversion of isophellibiline to phellibiline

2.3. Concluding remarks

In conclusion, the first and only total synthesis of a member of the

nonaromatic homoerythrinan class of natural products, (±)-isophellibiline,43 was

completed in 16 linear steps from 2,2-dimethyl-1,3-dioxan-5-one (1-57) in an

overall yield of 2.3%. Not unexpectedly, the seven-membered ring present in the

homoerythrinan class represented an additional challenge. Finally, we have

demonstrated the versatility of the Funk laboratory’s strategy for the preparation

of members of the nonaromatic erythrinan and homoerythrinan subclass of

natural products.

1-8isophellibiline

1-101phellibiline

"alumina"

Chapter 3. Preparation of Dihydro-β-Erythroidine (DHβE) Analogs

3.1. Background and significance

3.1.1. Nicotinic acetylcholine receptors (nAChRs)

Nicotinic acetylcholine receptors (nAChRs) are members of the ligand-

gated ion channels family.44 The nicotinic acetylcholine receptors are the most

extensively studied of the ligand-gated ion channels. Opening of the channel

pore is triggered by the endogenous neurotransmitter acetylcholine (1-102) or

exogenous agonists, such as nicotine (1-103) (Figure 3.1.1).45 nAChRs can be

divided into two groups: muscular and neuronal. Muscular nAChRs are located

at neuromuscular junctions where they mediate neuromuscular transmission.

Neuronal nAChRs are pentameric ion channels composed of α and β subunits

and are critical in signal transmission in the mammalian peripheral and central

nervous system (CNS).46 To date, eight α (α2–α7, α9, and α10) and three β (β2–

β4) subunits have been identified in the mammalian nervous system.47 The

neuronal nAChRs can be further subdivided into two subtypes: (1) the

Figure 3.1.1. Structures of acetylcholine and nicotine

1-103nicotine

NNNO

1-102acetylcholine

homomeric nAChRs composed of an association of α7–α9 subunits that binds α-

bungarotoxin (α-Bgtx), and (2) the heteromeric nAChRs composed of a

combination of α and β subunits that are α-Bgtx insensitive.48 Different

combinations of subunits result in receptors with distinct pharmacological and

physiological properties. The most abundant nAChRs in the CNS, and the most

interesting from a drug discovery perspective, are the α4β2 heteromeric

receptors and the α7 monomeric receptors.45,48a The former constitutes the high-

affinity binding site in the mammalian CNS for nicotine.46,49 α4β2 nAChRs are

therapeutic targets for the treatment of pain, neurodegenerative diseases, such as

Alzheimer’s and Parkinson’s diseases, and psychiatric disorders, such as

schizophrenia, attention deficit hyperactivity disorder (ADHD), anxiety and

depression, drug addiction, and nicotine addiction.50 The development of novel

therapeutic agents that selectively interact with nAChRs has traditionally

focused on full or partial agonists, and more recently, allosteric activators.47,50b

Full agonists are ligands that elicit a maximal response following binding and

anything producing a lower response after binding is a partial agonist. In

contrast, little effort has been directed towards the development of competitive

nAChR antagonists.46 Competitive antagonists are ligands that reversibly bind to

the active site without eliciting a response.

3.1.2. Pharmacophore models for nAChR ligands

A pharmacophore model is a 3D ensemble of the minimal structural

features, such as aromatic rings, hydrophobic centroids, hydrogen bond

acceptors or donors, cations and anions, necessary to permit binding to the active

site and elicit a biological response.46,51 Pharmacophore models can be used in the

identification of novel ligands, through drug design or database searching, that

bind to the same receptor. Given the difficulties associated with the

determination of the structure of membrane bound proteins via X-ray

crystallography or NMR studies, the structurs of nAChRs have only recently

begun to emerge.52 Consequently, ligand-based pharmacophore models for

nACh receptors have been defined, and optimized, based on structure activity

relationships (SAR) and the binding data of a diverse set of ligands.

Beers and Reich53 proposed the first useful pharmacophore model for the

nAChR. They suggested that a ligand required two structural elements: (1) an

onium group (N+) that engages in a coulombic interaction with the receptor, and

(2) a heteroatom (N or O) capable of acting as a hydrogen bond acceptor with the

receptor (Figure 3.1.2). The optimal distance between the van der Waals (vdW)

surface of the hydrogen bond acceptor (X) and the center of the onium group

was found to be 5.9 Å.

Figure 3.1.2. (1) Beers–Reich pharmacophore, (2) as applied to nicotine

Sheridan and coworkers54 utilized an ensemble distance geometry

approach to develop the Beers–Reich pharmacophore further. They proposed a

triangular relationship between three pharmacophore components: (1) an onium

group, (2) a hydrogen bond acceptor, and (3) a “dummy” site (C) representing

the centroid of an aryl ring or the carbon of a carbonyl group (Figure 3.1.3).

Sheridan’s model dictated that the pharmacophoric elements of a ligand meet the

following parameters: (1) a distance of 4.8 Å between the hydrogen bond

acceptor (X) and the onium group (N+), (2) a distance of 1.2 Å between the

hydrogen bond acceptor and the dummy site (C), and (3) a distance of 4.0 Å

between the onium group and the dummy site.

Figure 3.1.3. (1) Sheridan pharmacophore, (2) as applied to nicotine

N+

5.9 Å

onium group

hydrogen bondacceptor X

(1) (2)

vdW surface

3 Å

N+

4.0 Å4.8 Å

1.2 Åaryl centroidor carbonyl C

onium group

hydrogen bondacceptorX

(1) (2)

A key limitation with both the Beers–Reich and Sheridan pharmacophores

is their inherent two-dimensionality. For instance, neither model is capable of

explaining the higher binding affinity of (S)-nicotine compared to (R)-nicotine.

Additional components are required within the pharmacophore model to

provide three-dimensionality.

This deficiency was, in part, addressed by the Abbott “four-point”

model,49,55 which, when compared to previous models, placed less emphasis on

the N-X (onium-hydrogen bond acceptor) distance. Rather the Abbott model

emphasized the directionality of the vectors between the onium group (1), the

hydrogen bond acceptor (2), and their respective protein counterparts (3) and (4)

(Figure 3.1.4).

Researchers at Novo Nordisk56 have proposed a more developed vector

model, which, not unlike the Abbott model, emphasizes the importance of

receptor-related features over the N-X distance. The Novo Nordisk model maps

key interatomic distances and angles (Figure 3.1.5). The three key site points of

the model are: (1) site point a, the receptor feature related to the onium group, (2)

site point b, the receptor feature correlated to the hydrogen bond acceptor, and

(3) site point C which represents the centroid of the aryl ring or the carbon of a

carbonyl group. Site points a and b are located at the end of vectors 2.9 Å in

Figure 3.1.4. Abbott “four-point” pharmacophore as applied to nicotine

Figure 3.1.5. (1) Novo Nordisk pharmacophore, (2) as applied to nicotine

length originating from the onium group and the hydrogen bond acceptor. The

parameters defining the pharmacophore model are the distances from a to C and

a to b, and the angle between these interatomic distance vectors. The model

suggests that the key factor for ligand activity are the vectors to site points a and

b. Thus, the vector model can accommodate ligands with both “short” and

“long” N-‐‑X distances.

It should be noted that acetylcholine (1-102, Figure 3.1.1) only possesses

two pharmacophoric features, an onium group and a hydrogen bond acceptor,

and is extremely flexible. Therefore it cannot be assumed that ligands must

conform to three-point pharmacophore models.57

3.1.3. Dihydro-β-erythroidine (DHβE)

A compound that has been found to interact with the receptor of interest

can be an attractive starting point (lead) for drug discovery and as a biological

N+

XC2.9 Å

7.3 - 8.0 Å

2.9 Å

6.5 - 7.4 Å

30 - 35°

onium group

aryl centroidor carbonyl C

hydrogen bondacceptor

site point b

site point a

N H

(1) (2)

tool for the investigation of receptor function and mechanism. The diverse

biological activities found in Nature have resulted in natural products that

possess a high degree of molecular diversity, thus making them invaluable

sources for drugs as well as lead compounds. A number of natural products that

target nAChRs have served as leads in the development of potential drugs.47,50a

For example, anabaseine (1-104), a toxin isolated from a marine worm, was found

to stimulate all nAChR subtypes (Figure 3.1.6).58 However, a synthetic derivative,

3-(2,4-dimethoxybenzylidene)-anabaseine (DMXBA, 1-105) is a selective α7

nAChR partial agonist.59 DMXBA is in clinical trials for cognition enhancement in

patients with schizophrenia, AD and ADHD.59b Similarly, nicotine (1-103, Figure

3.1.1), epibatidine (1-110), lobeline (1-106), anatoxin A (1-107) and others have

served as leads towards the development of novel therapeutics. To date,

varenicline (Chantix™, 1-109), a partial agonist of α4β2 nAChRs derived from

cytisine (1-108), represents the only nAChR-based therapeutic approved for use

in nicotine replacement therapy that was derived from a rational medicinal

chemistry effort.

The Funk laboratory was intrigued by the notion of examining 2,7-

dihydro-β-erythroidine (DHβE) (1-10, Figure 3.1.6) as a lead compound and to

create structure activity relationships (SAR) that may be useful in designing

subtype-selective nAChR antagonists.

2,7-Dihydro-β-erythroidine (DHβE) (1-10, Figure 3.1.6) is a semi-synthetic

compound that was first prepared by Merck researchers in the 1940’s by partial

hydrogenation of β-erythroidine (β-E) (1-6, Figure 1.1.1).9 While DHβE was

Figure 3.1.6. Structures of lead compounds and synthetic analogues

found to be an extremely potent curarizing agent, undesirable side-effects

limited its use in clinical practice. However, forty years after its discovery,

Williams and Robinson60 determined that DHβE binds with high-affinity (2 nM)

to neuronal receptors in rat brain and that its distribution of binding was similar

to that of [3H]-nicotine and [3H]-acetylcholine. DHβE has since become widely

used in functional assays as a nonselective, competitive antagonist for nAChRs.

DHβE exhibits high-affinity (low nanomolar Ki values) competitive antagonism

for α4β2 nAChRs.61 Decker and coworkers found that DHβE had a 114-fold

greater selectivity for rat α4β2 than rat α7 receptor.61a Furthermore,

electrophysiological measurements on oocytes expressing human α4β2 receptor

1-102,7-dihydro-β-erythroidine

(DHβE)

1-110epibatidine

OOH

HN O

1-107anatoxin A

1-106lobeline

N N

OMe

1-104anabaseine

1-105DMXBA

NH O

1-108cytisine

1-109varenicline(Chantix™)

2 7

indicated that DHβE was approximately fifteen-fold less potent of an inhibitor of

the α3β2 subtype.61c

In order to develop analogues of DHβE that displayed antagonist activity

at the α4β2 receptor, an understanding of the interaction with the receptor was

required. Specifically, it was necessary to determine which structural features of

DHβE confer affinity. In Beers and Reich’s53 examination of β-erythroidine as

compared to acetylcholine, they concluded that the oxygen atoms of the methoxy

group on the A-ring and of the lactone D-ring could both form hydrogen bonds

whose van der Waals surface measured 5.9 Å from the onium site (1-‐‑6, Figure

3.1.7). In their analysis of DHβE (1-10), Sheridan and coworkers54 also noted that

two potential hydrogen bond acceptors, which fit within the pharmacophore

constraints existed. Sheridan and coworkers favored the oxygen of the lactone D-

ring as the hydrogen bond acceptor on the basis of structural analogy to

strychnine (1-111). However, as noted previously, a shortcoming of the Beers–

Reich and Sheridan pharmacophores are their inherent two-dimensionality.

Indeed, application by Funk of the more restrictive Abbott “four-point” model to

Figure 3.1.7. Pharmacophoric elements in β-E as determined by Beers and Reich, and DHβE and strychnine as determined by Sheridan

1-102,7-dihydro-β-erythroidine

(DHβE)

1-6β-erythroidine

(β−E)

HH H

1-111strychnine

the analysis of DHβE led to a different conclusion. Funk concluded that a higher

energy diastereomeric trans-BC bicyclic ammonium salt (1-10b) must be invoked

in order to achieve the correct directionality vectors for the onium site and the

hydrogen bond acceptor if the lactone ring lone pair is to function as the

hydrogen bond acceptor (Figure 3.1.8). Thus, Funk proposed that the methoxy

lone pair served as the hydrogen bond acceptor.

Figure 3.1.8. Conformations of DHβE, protonated-cis and -trans

To test this hypothesis, two 2,7-dihydro-β-erythroidine (DHβE) analogs—

desmethoxy-DHβE (1-112) and deslactone-DHβE (1-113)—were synthesized by

Funk and He, and preliminary [3H]-nicotine binding assays were performed by

Prof. Peter Crooks of the University of Kentucky (Table 3.1.1). The Crooks group

found that the analog lacking the methoxy group (desmethoxy-DHβE) exhibited

an 84-fold decrease in affinity relative to DHβE, whereas the analog lacking the

lactone ring (deslactone-DHβE) exhibited only a 2.6-fold decrease in affinity

relative to DHβE. These results are in keeping with the conjecture that the

methoxy lone pair, as opposed to the lactone lone pair, functions as the hydrogen

bond acceptor.

O O

Hcis

1-10aDHβE

(protonated-cis)

trans

1-10bDHβE

(protonated-trans)

2 1 6 7

1-102,7-dihydro-β-erythroidine

(DHβE)

ΔS.E. =7.8 kcal/mol

Table 3.1.1. Structure and binding results for Funk and He’s DHβE analogs

Compound

Ki (nM)

Human [3H]-nicotine (α4β2)

1-10 25

1-112 2090

1-113 66

Further evidence to support this hypothesis could be found in the

structure activity relationship (SAR) studies performed by Wildeboer.62

Wildeboer prepared two β-erythroidine (1-6) analogs—desmethoxy-βE (1-114) and

βE-diol (1-115)—and performed rat and human [3H]-cytisine binding assays

(Table 3.1.2). In this case, it was found that the analog lacking the methoxy group

(desmethoxy-βE) had no measurable binding to rat α4β2 receptors at

concentrations up to 20 000 nM. However, the reduction in affinity may also be

due to the addition of the third carbon-carbon double bond, not the absence of

the methoxy group; this observation may be an extension of the trend observed

in the affinities of β-E versus DHβE. The analog lacking the lactone ring (βE-diol)

had an affinity that was 3.5-fold greater than that of β-E. The increase in affinity

DHβE

desmethoxy-DHβE

deslactone-DHβE

Table 3.1.2. Structure and binding results for Wildeboer’s β-E analogs

Compound

Ki (nM)

Rat [3H]-cytisine(α4β2)

Human [3H]-cytisine(α4β2)

1-6 1 100±840 Not determined

1-10 140±18 620±170

1-114 >20 000 Not determined

1-115 310±120 240±15

observed for this analog may be due to the absence of the lactone moiety, or

perhaps due to additional hydrogen bonding opportunities afforded by the diol

moiety.

We believed that these results warranted further investigation to

understand the interactions of these compounds with nAChRs. Specifically,

through the preparation of structurally simplified DHβE analogs and subsequent

binding assays, we aimed to determine structure-activity relationships that

β−E

DHβE

desmethoxy-βE

HOHO

βE-diol

would aid in further structural manipulation of these compounds. We initiated

our investigation with the preparation of two groups of novel analogous of

deslactone-DHβE (1-113): Type I analogs that lack the piperidine ring, and Type II

analogs that lack the piperidine and pyrrolidine rings (Figure 3.1.9).

Figure 3.1.9. Type I and Type II analogs of deslactone-DHβE

3.2. Synthesis of DHβE analogs

The synthesis of the deslactone-DHβE analogs lacking the piperidine ring

(Type I) began with the known ester 1-118, prepared from either (R)- or (S)-

tyrosine (1-116) via the protocol developed by Wipf63 (Scheme 3.2.1). The methyl

ester 1-118 was saponified to the corresponding acid, which upon treatment with

ethyl chloroformate provided lactone 1-119. Reductive cleavage of the lactone

with activated zinc and acetic acid gave acid 1-120 with concomitant

deconjugative isomerization of the olefin bond. Barton decarboxylation of acid 1-

120 furnished pyrrolidine 1-121. Reduction of the ketone 1-121 with sodium

borohydride gave alcohol 1-122 as a single diastereomer, which presumably

arose from the expected axial hydride delivery. The stereoselectivity of the

reduction was confirmed through NMR studies (COSY, NOSY) of a downstream

product (1-127). Deprotection of the Boc-carbamate 1-122 with trifluoroacetic

NORH

R NO

Type I analogs

R = H, Me

Type II analogs

R = H, Me

Scheme 3.2.1. Preparation of Type I deslactone-DHβE analogs

acid (TFA) afforded the parent analog 1-123. Reduction of the Boc-

carbamate 1-122 with lithium aluminum hydride provided the N-methyl analog

1-124. The alkoxide derivative of alcohol 1-122 was methylated with methyl

iodide to give methyl ether 1-125. As before, treatment of the Boc-carbamate 1-

125 with TFA gave the O-methyl analog 1-126. Finally, reduction of the Boc-

carbamate 1-125 furnished the bismethyl analog 1-127.

Preparation of the deslactone-DHβE analogs lacking both the piperidine

and pyrrolidine rings (Type II) began with the known mixture of trans-

dibromides 1-128, prepared in two steps from benzoic acid via Birch reduction,

in situ methylation,64 followed by bromination (Scheme 3.2.2).65 Upon treatment

NH2

CO2HHO

ONHBoc

1-116(R)-tyrosine

(or (S)-tyrosine)

BocH

CO2MeNa2CO3,MeOH

90%

BocH

1-117 1-118

1-119

Zn, TMSCl,BrCH2CH2Br,AcOH

60%NOBocH

CO2HNOBocH

SH , DCC,DMAP;

Bu3SnH, AIBN 60%

NaBH4

90%

1. LiOH 95%

2. Et3N; ClCO2Et 96%

NHOBocH

NOBocH

NaH;MeI 80%

1-120

1. Boc2O, NaOH 77%

2. PhI(OAc)2, 27%

1-121

1-122

1-125

NHHO

HNHO

NHO

1-126

NOH

1-127

1-123 1-124

TFA;K2CO3 40%

TFA;K2CO3

50%

LiAlH4

60%

LiAlH4

65%

of the mixture with sodium bicarbonate, the major dibromocarboxylate

underwent an intramolecular cyclization to give bromolactone 1-129 as the only

neutral product.66 The stereochemistry of the product (1-129) was assigned based

on the work of Ikota and Ganem,66a who prepared the des-methyl derivative of 1-

129. Radical debromination of bromolactone 1-129 gave the reduced lactone 1-

130. After significant experimentation with lactone 1-130 and the corresponding

methyl ester prepared via methanolysis of the lactone, it was found that lactone

1-130 could be converted into amide 1-131 in a slow reaction with ammonia gas

at elevated pressure and temperature. Treatment of amide 1-131 with lead

tetraacetate induces a rearrangement to an intermediate isocyanate, which was

trapped by the transannular hydroxyl group to give the cyclic urethane 1-132.67

Hydrolysis of the urethane gave the primary amine 1-133. Reduction of the

Scheme 3.2.2. Preparation of Type II deslactone-DHβE analogs

OH OO

HO NH2O

NaHCO3

54%

Bu3SnH,AIBN

95%

NH3 (100psi)

89%

Pb(OAc)4

63%

O NH

O N

HO NH2HO HN

HO N

KOH

57%

LiAlH4

71%

LiAlH4

56%

NaH;MeI 78%

1-128 1-129 1-130 1-131

1-132 1-133 1-134

1-135 1-136

BrBr

urethane with lithium aluminum hydride provided the N-methyl analog 1-134.

Methylation of carbamate 1-132 with methyl iodide gave the tertiary amide 1-135

that was subsequently reduced to deliver the N,N-dimethyl analog 1-136.

3.3. Results and discussion

These compounds were evaluated for their affinity in human α4β2,

human α6/α3β2β3, and human CHO α7 receptors under the supervision of

Daniel Yohannes, Senior Director for Drug Discovery at Targacept Inc. (Table

3.3.1). While all of the compounds showed excellent selectivity for the α4β2

receptor, most of the compounds, with the exception of compound (S)-1-123,

failed to bind below a micromolar concentration at the targeted receptors.

Furthermore, analysis of the data failed to reveal any trends that may have aided

in making structural refinements of our compounds in an attempt to increase

their binding affinities. Accordingly, functionality assays (antagonist/agonist)

were not pursued.

Table 3.3.1. Binding results for Type I and II analogs

Compound

Ki (nM)

Human α4β2 Human α6/α3β2β3 Human CHO α7

(R)-1-123 5 400 100 000 79 000

(R)-1-127 5 500 100 000 100 000

(R)-1-124 5 600 100 000 47 000

(R)-1-127 7 900 100 000 68 000

(S)-1-123 990 37 000 100 000

(S)-1-126 1 800 100 000 4 700

(S)-1-124 6 000 45 000 78 000

(S)-1-127 65 000 100 000 28 000

1-133 11 000 100 000 100 000

1-135 18 000 75 000 43 000

1-136 5 600 90 000 100 000

NHHO

NHO

NHOH

NOH

NHHO

NHO

NHOH

NOH

HO NH2

HO HN

HO N

Chapter 4. Experimental

4.1. Materials and Methods

Unless otherwise stated, all reactions were performed in flame-dried

round-bottomed flasks. The flasks were fitted with rubber septa and reactions

were conducted under a positive pressure of nitrogen. Syringes or cannulae were

used to transfer air- and moisture sensitive liquids. Organic solutions were

concentrated on rotary evaporators at ~10 Torr at 30 °C. Anhydrous acetonitrile

(CH3CN), benzene (PhH), tetrahydrofuran (THF), dichloromethane (CH2Cl2),

diethyl ether (Et2O), toluene, triethylamine (Et3N), methanol (MeOH) and

dimethylformamide (DMF) were obtained by passing commercially available

pre-dried, oxygen-free formulations through activated alumina columns. All

other commercial reagents and solvents were used as received without further

purification, unless otherwise noted. Analytical thin–layer chromatography

(TLC) was performed using Al plates (Merck 60F-254) visualized by exposure to

ultraviolet light and an aqueous solution of ceric ammonium molybdate (CAM).

Flash column chromatography was performed as described by Still et al. using

silica gel (SiO2) (60-Å pore size, 32–63 µm, standard grade, Dynamic

Adsorbents).68 Silica gel was deactivated by washing, in order, with Et3N, EtOAc,

and then hexanes. NMR spectra were recorded on Bruker 300, 360 or 400 MHz

spectrometers and referenced from the residual undeuterated solvent in the

NMR solvent (CHCl3: δ 7.26, d6-DMSO: δ 2.50). Data is reported as follows:

chemical shift [multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet),

coupling constant(s) in Hertz, integration]. Carbon-13 NMR spectra were

recorded on Bruker 300, 360 or 400 MHz spectrometers and referenced from the

carbon resonances of the solvent (CDCl3: δ 77.00, d6-DMSO: δ 39.51). Data is

reported as follows: chemical shift. Infrared data (IR) were obtained with a

Perkin-Elmer 1600 IR, and are reported as follows: frequency of absorption (cm–

1). Melting points were obtained on a Thomas Hoover melting point apparatus

and are uncorrected.

4.2. Preparative Procedures

Amidodioxin 1-89: A solution of 4-bromopent-4-ene-1-amine29 (1-86, 10.1 g, 60.8

mmol) in benzene (20 mL) was added via cannula to a suspension of 2,2-

dimethyl-1,3-dioxan-5-one (1-57, 7.26 mL, 60.8 mmol) and Na2SO4 (30 g) in

benzene (200 mL) at 0 °C. The suspension was warmed to rt. After 8 h, the

reaction mixture was passed through a plug of celite and the clear solution was

concentrated to provide 16.8 g (100%) of the crude imine 1-87 as colorless oil,

which was used without further purification.

NCl

H2N

OONa2SO4,benzene,rt, 8 h;

PhNEt2, THF,rt, 12 h 63%

1H NMR (400 MHz, CDCl3): δ 5.57 (s, 1H), 5.41 (s, 1H), 4.33 (s, 2H), 4.20 (s, 2H),

3.19 (t, J = 6.5 Hz, 1H), 2.49 (t, J = 7.2 Hz, 1H), 1.90 (p, J = 7.0, 7.1 Hz, 1H), 1.40 (s,

6H). 13C NMR (75 MHz, CDCl3): δ 169.3, 133.9, 116.9, 100.2, 66.8, 64.7, 60.0, 48.1,

38.9, 28.9, 23.7.

To a solution of the crude imine 1-87 (16.8 g, 60.8 mmol) in THF at -30 °C was

added hexa-3,5-dienoyl chloride30 (1-88, 7.64 mL, 61.5 mmol). After 10 minutes at

-30 °C, PhNEt2 (12.6 mL, 79.1 mmol) was added to the mixture. The mixture was

warmed to rt. After 12 h, the solvent was removed in vacuo. The residue was

taken up in Et2O, filtered and concentrated in vacuo. The orange oil was purified

by flash column chromatography (20% EtOAc/Hex) to give 14.4 g (64%) of

amidodioxin 1-89 as yellow oil.

1H NMR (400 MHz, CDCl3): δ 6.48 (s, 1H), 6.29 (ddd, J = 17.0, 10.2, 10.1 Hz, 1H),

6.07 (dd, J = 15.1, 10.9 Hz, 1H), 5.78 (ddd, J = 15.2, 7.4, 6.8 Hz, 1H), 5.57 (s, 1H),

5.36 (s, 1H), 5.10 (d, J = 16.9 Hz, 1H), 4.99 (d, J = 10.0 Hz, 1H), 4.10 (s, 2H), 3.36

(br. s, 2H), 3.14 (d, J = 6.6 Hz, 2H), 2.39 (t, J = 7.2 Hz, 1H), 1.73 (dt, J = 14.8, 7.4 Hz,

2H), 1.48 (s, 6H). 13C NMR (75 MHz, CDCl3): δ 171.6, 142.0, 136.3, 133.6, 133.2,

127.3, 117.1, 116.5, 114.6, 99.2, 59.4, 45.7, 38.4, 37.1, 26.3, 24.2. IR (thin film): 2994,

2941, 1662 cm-1. HRMS (ES) calc. for C17H25NO3Br [M+H]+: 370.1018. Found:

370.1020

Endo-cycloadduct 1-90 and exo-cycloadduct 1-91: To a solution of amidodioxin

1-89 (14.4 g, 38.9 mmol) in toluene (778 mL) was added butylated

hydroxytoluene (~ 100 mg). The solution was sparged with argon for 10 minutes.

The flask was fitted with a reflux condenser and heated to reflux. After 6.5 h, the

solvent was removed in vacuo. The resulting brown oil was purified by flash

column chromatography (25à66% EtOAc/Hex) to give 1.58 g (13%) of endo-

cycloadduct 1-90 as yellow oil and 7.17 g (59%) of exo-cycloadduct 1-91 as yellow

oil in the order of elution.

Endo-1-90: 1H NMR (400 MHz, CDCl3): δ 9.54 (s, 1H), 5.84 (d, J = 9.8 Hz, 1H), 5.61

(s, 1H), 5.53 (d, J = 9.9 Hz, 1H), 5.41 (s, 1H), 3.28 (ddd, J = 14.6, 9.2, 7.0 Hz, 1H),

3.08 (ddd, J = 14.5, 9.3, 6.4 Hz, 1H), 2.84 (br. s, 1H), 2.66 (dd, J = 16.8, 9.2 Hz, 1H),

2.45 (app. t, J = 6.6 Hz, 2H), 2.21-2.08 (m, 3H), 2.03 (m, 1H), 1.87 (m, 1H), 1.76 (m,

2H). 13C NMR (75 MHz, CDCl3): δ 199.5, 175.2, 133.0, 127.3, 126.2, 117.5, 70.5, 39.6,

38.8, 36.4, 32.6, 27.4, 22.6, 20.0. IR (thin film): 2928, 1731, 1693 cm-1. HRMS (ES)

calc. for C14H19NO2Br [M+H]+: 312.0599. Found: 312.0604.

Exo-1-91: 1H NMR (400 MHz, CDCl3): δ 9.51 (s, 1H), 5.80 (d, J = 9.2 Hz, 1H), 5.58

(s, 1H), 5.49 (d, J = 9.8 Hz, 1H), 5.37 (s, 1H), 3.26 (ddd, J = 14.7, 8.9, 6.2 Hz, 1H),

3.04 (ddd, J = 14.6, 8.0, 5.6 Hz, 1H), 2.81 (br. s, 1H), 2.62 (dd, J = 16.8, 9.1 Hz, 1H),

2.41 (app. t, J = 6.6 Hz, 2H), 2.18-2.03 (m, 3H), 2.02-1.91 (m, 1H), 1.90-1.78 (m, 1H),

Brendo13%

toluene,110 °C,6.5 h

exo59%

1.77-1.63 (m, 2H). 13C NMR (75 MHz, CDCl3): δ 199.4, 175.1, 132.9, 127.1, 126.1,

117.4, 70.4, 39.4, 38.7, 36.3, 32.5, 27.2, 22.4, 19.8. IR (thin film): 2929, 1732, 1694 cm-

1. HRMS (ES) calc. for C14H19NO2Br [M+H]+: 312.0599. Found: 312.0588.

Z-Enoate 1-84: To a solution of 18-crown-6 (3.2 g, 12.0 mmol) in THF (18 mL) at –

78 °C was added (CF3CH2O)2POCH2CO2CH3 (0.764 mL, 3.60 mmol), followed by

dropwise addition of a solution of KHMDS (0.5 Min toluene, 7.2 mL, 3.60 mmol).

After 0.3 h, a solution of the aldehyde 1-91 (750 mg, 2.40 mmol) in THF (9.6 mL)

was added dropwise via cannula. After one hour, excess anion was quenched at

–78 °C by the addition of a half-saturated NH4Cl solution (10 mL). The reaction

mixture was then warmed to room temperature. All volatile organics were

removed in vacuo. The aqueous residue was extracted twice with EtOAc (20 mL).

The combined organic extracts were washed once with water (20 mL), once with

brine (20 mL), dried (MgSO4), filtered and concentrated in vacuo. Purification by

flash column chromatography (50% EtOAc/Hex) provided 703 mg (80%) of Z-

enoate 1-84 as yellow oil.

1H NMR (400 MHz, CDCl3): δ 6.12 (br. d, J = 12.9 Hz, 1H), 5.90 (br. d, J = 12.9 Hz,

1H), 5.77 (m, 1H), 5.59 (d, J = 0.96 Hz, 1H), 5.55, (m, 1H), 5.37 (d, J = 1.59 Hz, 1H),

3.69 (s, 3H), 3.16 (m, 2H), 3.02 (ddd, J = 14.0, 10.5, 5.3 Hz, 1H), 2.63 (dd, J = 16.6,

9.2 Hz, 1H), 2.42 (dd, J = 7.3, 7.3 Hz, 2H), 2.08 (dd, J = 16.6, 5.7 Hz, 2H), 2.02 (m,

2H), 1.87 (m, 1H), 1.76 (m, 1H). 13C NMR (75 MHz, CDCl3): δ 175.1, 165.5, 149.0,

(F3CH2CO)2P O

OMe

18-Crown-6, THF,-78 °C, 1 h 66%

133.2, 127.9, 125.8, 122.4, 117.2, 65.4, 51.9, 39.6, 39.1, 39.0, 37.1, 28.3, 27.1, 20.9. IR

(thin film): 3025, 2927, 1726, 1688 cm-1. HRMS (ES) calc. for C17H23NO3Br [M+H]+:

368.0861. Found: 368.0872.

E-Dienoate S1-1: To vinyl bromide 1-84 (6.70 g, 18.2 mmol) was added sodium

formate (1.48 g, 21.8 mmol) and tetrabutylammonium bromide (11.7 g, 36.4

mmol). The flask was evacuated and backfilled with argon, twice. To this was

added MeCN (182 mL) followed by TEA (5.6 mL, 40.0 mmol, 2.2 equiv.). The

mixture was degassed by three freeze-pump-thaw iterations. The mixture was

heated to 85 °C. A suspension of Hermann’s catalyst (1.71 g, 1.82 mmol) in

MeCN (180 mL, degassed by three freeze-pump-thaw iterations) was added over

8 h via syringe pump to the reaction mixture. After 16 h, the reaction mixture

was cooled to rt. The mixture was diluted with EtOAc (500 mL), filtered through

a plug of silica gel, concentrated in vacuo to give E-dienoate S1-1, which was used

without further purification.

1H NMR (400 MHz, CDCl3): δ 5.82 (s, 1H), 5.78 (m, 1H), 5.46 (br. d, J = 10.0 Hz,

1H), 4.95 (d, J = 0.97 Hz, 1H), 4.79 (d, J = 1.3 Hz, 1H), 4.05 (ddd, J = 14.1, 5.1, 5.1

Hz, 1H), 3.64 (s, 3H), 2.85 (m, 1H), 2.77 (ddd, J = 13.7, 9.4, 3.8 Hz, 1H), 2.60 (dd, J

= 16.4, 8.8 Hz, 1H), 2.54 (m, 1H), 2.25 (ddd, J = 14.1, 9.8, 4.0 Hz, 1H), 2.1-1.75 (m,

7H). 13C NMR (75 MHz, CDCl3): δ 174.4, 166.8, 147.7, 128.3, 126.4, 117.1, 114.2,

PdP

Ar Ar

Ar = o-CH3C6H4

O OPdOO

PAr Ar

NaOCOH, Bu4NBr, Et3N, MeCN, 85 °C, 24 h

67.0, 51.3, 41.1, 39.4, 37.3, 33.9, 29.9, 26.7, 20.9. IR (thin film): 2936, 1727, 1691 cm-1.

HRMS (ES) calc. for C17H22NO3 [M+H]+: 288.1600. Found: 288.1603.

E-Dienoic acid 1-83: To a solution of the crude ester S1-1 (18.2 mmol) in

THF/MeOH/H2O (180 mL, 1:1:1) at 0 °C was added LiOH (3.82 g, 90.9 mmol).

The mixture was warmed to rt. After 3 h at rt, the volatiles were removed in

vacuo. The aqueous residue was extracted three times with CH2Cl2 (50 mL). The

aqueous layer was acidified to pH 2 (2 MHCl) and extracted three times with

EtOAc (100 mL). The combined organic extracts were dried (MgSO4), filtered and

concentrated in vacuo to give 3.23 g (65% over two steps) of acid 1-83.

1H NMR (300 MHz, d6-DMSO): δ 12.2 (s, 1H), 5.88 (s, 1H), 5.75 (br. d, J = 9.6 Hz,

1H), 5.44 (br. d, J = 9.9 Hz, 1H), 4.82 (s, 1H), 4.77 (d, J = 1.7 Hz, 1H), 3.76 (app. t, J

= 18.2, 4.6 Hz, 1H), 2.81 (m, 2H), 2.38 (m, 2H), 2.13 (m, 2H), 1.90 (m, 2H), 1.79 (d, J

= 16.2 Hz, 2H), 1.63 (m, 2H). 13C NMR (75 MHz, d6-DMSO): δ 173.3, 167.6, 163.4,

148.4, 129.0, 126.0, 118.8, 113.6, 66.2, 41.4, 36.7, 33.7, 29.3, 26.9, 20.5. IR (thin film):

2936, 1731, 1681 cm-1. HRMS (ES) calc. for C16H20NO3 [M+H]+: 274.1443. Found:

274.1421.

HOO

LiOH, THF, MeOH, H2O, rt, 3 h 65% (2 Steps)

Tetracyclic lactone 1-82: A solution of acid 1-83 (3.07 g, 11.2 mmol) in toluene

(750 mL) was heated at reflux for 12 h and then concentrated in vacuo.

Purification of the crude oil by flash column chromatography (100% EtOAc)

provided 2.46 g (80%) of lactone 1-82.

1H NMR (400 MHz, CDCl3): δ 5.81 (dd, J = 9.7, 5.8 Hz, 1H), 5.45 (br. d, J = 10.2 Hz,

1H), 4.70 (d, J = 15.5 Hz, 1H), 4.60 (d, J = 15.4 Hz, 1H), 4.29 (ddd, J = 14.2, 10.8, 8.5

Hz, 1H), 3.06 (d, J = 18.0 Hz, 1H), 2.97-2.92 (m, 2H), 2.8 (d, J = 8.3 Hz, 1H), 2.58

(dd, J = 16.6, 8.5 Hz, 1H), 2.31 (t, J = 14.9 Hz, 1H), 2.1-1.7 (m, 7H). 13C NMR (75

MHz, CDCl3): δ 174.7, 170.1, 133.6, 131.7, 127.7, 126.8, 72.1, 67.7, 36.8, 36.3, 35.4,

33.3, 27.3, 26.8, 26.6, 20.2. IR (thin film): 2932, 1744, 1682 cm-1. HRMS (ES) calc. for

C16H20NO3 [M+H]+: 274.1443. Found: 274.1434.

Orthoester 1-93: To a solution of lactone 1-82 (1.00 g, 3.66 mmol) in CH2Cl2 (36

mL) at 0 °C was added ethylene glycol (21 mL, 366 mmol), CH(CH3)3 (4.22 mL,

36.6 mmol) and 10-camphorsulfonic acid (850 mg, 3.66 mmol). The mixture was

warmed to rt. After 12 h, Et3N (1 mL, 7.17 mmol) was added, and the CH2Cl2

removed in vacuo. The residue was taken up in EtOAc (100 mL) and washed

three times with H2O (100 mL), once with brine (100 mL), dried (MgSO4), filtered

HOO

toluene,110 °C,12 h

80%

CH(OMe)3, CSAHOCH2CH2OH,rt, 12 h

78%

and concentrated in vacuo. Purification by trituration (Et2O) gave 902 mg (78%) of

the orthoester 1-93.

1H NMR (400 MHz, CDCl3): δ 5.77 (dd, J = 10.6, 4.1 Hz, 1H), 5.41 (d, J = 10.2 Hz,

1H), 4.25-3.98 (m, 7H), 2.94 (ddd, J = 13.9, 7.6, 2.2 Hz, 1H), 2.87 (d, J = 8.1 Hz, 1H),

2.64 (dd, J = 16.3, 8.3 Hz, 1H), 2.55 (app. dq, J = 16.2, 2.4 Hz, 1H), 2.31 (app. dq, J

= 16.2, 1.5 Hz, 1H), 2.11-1.90 (m, 7H), 1.78 (m, 1H), 1.61 (dd, J = 16.1, 6.2 Hz, 1H).

13C NMR (75 MHz, CDCl3): δ 174.9, 131.8, 129.3, 128.1, 126.7, 118.3, 68.3, 64.4, 64.2,

37.3, 36.5, 35.1, 32.9, 26.8, 26.7, 25.4, 20.7. IR (thin film): 2927, 1686 cm-1. HRMS

(ES) calc. for C18H24NO4 [M+H]+: 318.1705. Found: 318.1699.

Conjugated diene 1-81: To a solution of lactam 1-93 (300 mg, 0.945 mmol) in THF

(19 mL) at –78 °C was added n-BuLi (2.5 Min hexanes, 1.5 mL, 3.78 mmol)

dropwise. The mixture was stirred for an additional 0.75 h at –78 °C, then a

solution of (PhSe)2 (885 mg, 2.84 mmol) in THF (9.5 mL) was added rapidly.

After one hour at –78 °C, AcOH (0.227 mL, 3.67 mmol) was added to the mixture.

After warming to rt the reaction mixture was diluted with CH2Cl2 (100 mL) and

washed with KHPO4 (100 mL), H2O (100 mL), brine (100 mL), dried (MgSO4),

filtered and concentrated in vacuo. The crude selenide was used without further

purification.

1H NMR (400 MHz, CDCl3): δ 7.73 (dd, J = 5.8, 1.9 Hz, 2H), 7.28 (m, 3H), 5.78 (br.

d, J = 9.9 Hz, 1H), 5.40 (br. d, J = 10.0 Hz, 1H), 7.33-4.02 (m, 7H), 3.50 ( s, 1H), 3.13

1. nBuLi, THF, -78 °C, 0.75 h; PhSeSePh, 1 h2. H2O2, pyridine, CH2Cl2, 0 °C, 1 h

81% (2 steps)

(br. s, 1H), 2.96 (dd, J = 13.9, 7.5 Hz, 1H), 2.77 (dd, J = 16.0, 2.2 Hz, 1H), 2.27 (m,

2H), 2.07-1.80 (m, 6H), 1.63 (dd, J = 15.6, 5.5 Hz, 1H). 13C NMR (75 MHz, CDCl3):

δ 174.6, 133.3, 133.0, 131.5, 131.3, 129.2, 129.1, 127.5, 126.8, 118.3, 68.4, 67.4, 64.5,

64.1, 46.2, 43.8, 37.4, 32.9, 27.3, 27.0, 25.1, 20.6. IR (thin film): 2913, 1685 cm-1.

HRMS (ES) calc. for C24H28NO4Se [M+H]+: 474.1184. Found: 474.1182.

To a solution of the crude selenide (0.945 mmol) in CH2Cl2 (9 mL) at 0 °C was

added sequentially, pyridine (0.322 mL, 3.96 mmol) and H2O2 (50%, 0.316 mL,

5.48 mmol). Stirring was continued for one hour at 0 °C. The mixture was then

poured into saturated NaHCO3 (50 mL) and extracted three times with CH2Cl2

(50 mL). The combined organic layers were dried (Na2SO4), filtered and

concentrated in vacuo. Purification by flash column chromatography (50à100%

EtOAc/Hex) provided 240 mg (81% over two steps) of diene 1-81.

1H NMR (400 MHz, CDCl3): δ 6.57 (dd, J = 10.0, 2.0 Hz, 1H), 6.11 (m, 1H), 5.80 (s,

1H), 4.46 (dt, J = 10.6, 3.5 Hz, 1H), 4.17-3.97 (m, 6H), 3.20 (ddd, J = 14.5, 12.1, 2.5

Hz, 1H), 2.87 (m, 1H), 2.74 (app. dq, J = 17.2, 2.8 Hz, 1H), 2.61 (t, J = 14.5 Hz, 1H),

2.40 (m, 2H), 2.17 (dd, J = 17.2, 2.2 Hz, 1H), 1.85 (dd, J = 15.3, 5.9 Hz, 1H), 1.74 (m,

1H), 1.7-1.5 (m, 2H). 13C NMR (75 MHz, CDCl3): δ 169.4, 158.1, 135.6, 132.2, 127.3,

118.6, 117.8, 68.7, 67.8, 64.2, 40.6, 36.5, 33.0, 28.4, 25.3, 24.2. IR (thin film): 2920,

1674 cm-1. HRMS (ES) calc. for C18H22NO4 [M+H]+: 316.1549. Found: 316.1544.

Deconjugated diene 1-94: To a solution of DIPA (0.126 mL, 0.906 mmol) in THF

(4.5 mL) at –78 °C was added dropwise n-BuLi (2.5 Min hexanes, 0.346 mL, 0.865

mmol). After stirring for 0.5 h at –78 °C, HMPA (0.717 mL, 4.12 mmol) was

added dropwise and stirring was continued for one hour at that temperature. To

this mixture was added dropwise a solution of diene 1-81 (130 mg, 0.412 mmol)

in THF (4.1 mL). After 2.5 h at –78 °C, glacial acetic acid (0.236 mL, 4.12 mmol)

was added followed by a half saturated NH4Cl solution (10 mL). After warming

to rt the reaction mixture was extracted three times with EtOAc (15 mL), dried

(MgSO4), filtered and concentrated in vacuo. Purification by flash column

chromatography (60à80% EtOAc/Hex) provided 125 mg (96%) of the

deconjugated diene 1-94.

1H NMR (400 MHz, CDCl3): δ 5.95 (m, 1H), 5.91 (m, 1H), 5.84 (m, 1H), 4.29 (dt, J =

14.0, 6.9 Hz, 1H), 4.09 (m, 2H), 4.05 (s, 2H), 3.98 (m, 2H), 3.14 (d, J = 19.9 Hz, 1H),

2.93 (m, 2H), 2.83 (dd, J = 16.8, 6.3 Hz, 1H), 2.64 (d, J = 9.3 Hz, 1H), 2.56 (m, 2H),

2.06 (m, 1H), 1.97 (m, 1H), 1.77 (m, 1H). 13C NMR (75 MHz, CDCl3): δ 172.5, 132.8,

130.8, 124.4, 124.3, 118.3, 118.2, 67.8, 65.7, 64.1, 64.0, 38.6, 36.8, 35.8, 33.5, 33.2, 27.4,

26.1. IR (thin film): 2920, 1693, 1672 cm-1. HRMS (ES) calc. for C18H22NO4 [M+H]+:

316.1549. Found: 316.1545.

LDA, HMPA,THF, -78 °C, 2.5 h; AcOH 96%

Diol 1-96: A solution of deconjugated diene 1-94 (161 mg, 0.511 mmol) and rose

bengal (10 mg, 0.01 mmol) in a Pyrex reaction vessel was cooled to 0 °C. An

oxygen sparge was established and the solution irradiated with a GE 275 Watt

sun lamp for 2 h. After warming to rt the reaction mixture was concentrated in

vacuo. The crude endoperoxide 1-95 was used without further purification.

1H NMR (400 MHz, CDCl3): δ 6.79 (m, 2H), 4.81 (dt, J = 5.1, 2.5 Hz, 1H), 4.33

(ddd, J = 13.9, 10.7, 6.5 Hz, 1H), 4.15 (m, 1H), 4.08-3.97 (m, 5H), 3.16 (ddd, J =

13.7, 5.9, 2.1 Hz, 1H), 2.76 (d, J = 16.4 Hz, 1H), 2.62 (dd, J = 14.4, 3.1 Hz, 1H), 2.36

(d, J = 16.4 Hz, 1H), 2.25 (dd, J = 16.9, 2.7 Hz, 1H), 2.17 (d, J = 16.9 Hz, 1H), 2.05

(m, 1H), 1.92-1.77 (m, 3H), 1.65 (m, 1H). 13C NMR (75 MHz, CDCl3): δ 172.5, 134.8,

131.7, 130.7, 129.6, 117.4, 82.1, 69.9, 67.9, 67.4, 64.4, 63.9, 38.8, 31.1, 26.9, 25.6. IR

(thin film): 2933, 1693 cm-1. HRMS (ES) calc. for C18H22NO6 [M+H]+: 348.1447.

Found: 348.1432.

To a solution of the crude endoperoxide 1-95 in MeOH (5 mL) was added

thiourea (58.0 mg, 0.767 mmol). The mixture was stirred at rt for 12 h.

Concentration of the reaction mixture and purification by flash column

chromatography (100% EtOAc) gave 126 mg (70%) of diol 1-96.

1H NMR (400 MHz, CDCl3): δ 6.32 (d, J = 9.7 Hz, 1H), 5.89 (d, J = 9.5 Hz, 1H), 4.29

(m, 2H), 4.16-3.93 (m, 6H), 3.10 (br. s, 1H), 2.67 (d, J = 15.3 Hz, 1H), 2.51 (m, 2H),

2.35 (m, 2H), 2.06 (d, J = 13.6 Hz, 1H), 1.83 (dd, J = 15.0, 4.2, 1H), 1.65 (m, 1H),

HON

OO1O2, hν,rose bengal,

acetone, 0 oC, 2 h;

H2N NH2

MeOH, rt,12h, 70%

1.51 (m, 1H). 13C NMR (75 MHz, CDCl3): δ 173.8, 135.1, 134.3, 130.9, 129.1, 117.4,

74.1, 72.4, 68.6, 66.2, 64.5, 63.9, 41.7, 41.0, 40.0, 34.3, 28.9, 24.8. IR (thin film): 3405,

2917, 1665 cm-1. HRMS (ES) calc. for C18H24NO6 [M+H]+: 350.1604. Found:

350.1615.

Silyl ether 1-97: To a solution of diol 1-96 (40.0 mg, 0.114 mmol) in MeCN (4.6

mL) was added N-t-butyldimethylsilyl-N-methyltrifuoroacetamide (0.531 mL,

2.28 mmol). The mixture was stirred at rt for 12 h. Concentration of the reaction

mixture and purification by flash column chromatography (100% EtOAc) gave 37

mg (70%) of the silyl ether 1-97.

1H NMR (400 MHz, CDCl3): δ 6.32 (d, J = 9.7 Hz, 1H), 5.77 (d, J = 9.7 Hz, 1H),

4.37-4.26 (m, 2H), 4.12-3.90 (m, 6H), 2.97 (dd, J = 11.4, 11.4 Hz, 1H), 2.72 (dd, J =

11.3, 6.3 Hz, 1H), 2.64 (d, J = 15.3 Hz, 1H), 2.58-2.41 (m, 2H), 2.40-2.30 (m, 2H),

2.21 (s, 1H), 2.09 (d, J = 16.5 Hz, 1H), 1.82 (d, J = 15.2 Hz, 1H), 1.62 (m, 1H), 1.51

(m, 1H), 0.88 (s, 9H), 0.08 (s, 6H). 13C NMR (75 MHz, CDCl3): δ 172.8, 135.5, 134.0,

131.2, 129.4, 117.4, 74.0, 71.8, 68.6, 67.0, 64.4, 63.9, 41.4, 40.7, 39.6, 34.8, 28.9, 25.7,

24.6, 18.1, -4.65, -4.69. IR (thin film): 3392, 2929, 1682 cm-1. HRMS (ES) calc. for

C24H38NO6Si [M+H]+: 464.2468. Found: 464.2459.

HON

TBSO

F3C

N TBS

MeCN,rt, 12 h 65%

Acetate S1-2: To a solution of silyl ether 1-97 (8.0 mg, 0.017 mmol) in CH2Cl2

(0.345 mL) at 0 °C was added sequentially Et3N (0.048 mL, 0.35 mmol), DMAP

(11.0 mg, 0.086 mmol) and Ac2O (0.016 mL, 0.17 mmol). The mixture was

warmed to rt. After 36 h, CH2Cl2 (3 mL) was added to the mixture. The combined

organic extracts were washed five times with H2O (3 mL), once with brine (3

mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification by flash

column chromatography (75% EtOAc/Hex) provided 8.5 mg (97%) of the acetate

S1-2.

1H NMR (400 MHz, CDCl3): δ 6.59 (dd, J = 10.8, 1.8 Hz, 1H), 5.73 (dd, J = 9.9, 2.8

Hz, 1H), 4.31 (m, 2H), 4.11 (m, 3H), 3.98 (m, 3H), 3.03 (d, J = 11.7 Hz, 1H), 2.96 (d,

J = 16.6 Hz, 1H), 2.73 (m, 2H), 2.54 (m, 2H), 2.44 (dd, J = 11.2, 9.0 Hz, 1H), 2.05 (d,

J = 16.3 Hz, 1H), 1.95 (s, 3H), 1.85 (dd, J = 15.6, 5.0 Hz, 1H), 1.67 (br. d, J = 10.8

Hz, 1H), 1.6-1.5 (m, 2H), 0.89 (s, 9H), 0.08 (s, 6H). 13C NMR (75 MHz, CDCl3): δ

171.7, 169.4, 135.3, 134.4, 130.6, 127.0, 117.3, 82.7, 72.1, 68.7, 66.8, 64.6, 64.0, 40.7,

40.1, 39.0, 34.4, 29.0, 25.8, 24.6, 22.1, 18.0, -4.4, -4.5. IR (thin film): 2930, 2856, 1737,

1700 cm–1. HRMS (ES) calc. for C26H40NO7Si [M+H]+: 506.2574. Found: 506.2584.

TBSON

OAc

TBSOAc2O, Et3N,DMAP, CH2Cl2,rt, 36 h

97%

Diene lactam 1-99: To a solution of acetate S1-2 (8.0 mg, 0.016 mmol) in PhH

(0.317 mL) was added DBU (0.003 mL, 0.02 mmol), the reaction mixture was

heated to 80 °C. After 24 h, the reaction was cooled to rt and concentrated in

vacuo. Purification by flash column chromatography (100% EtOAcà5%

MeOH/EtOAc) provided 5.8 mg (82%) of diene lactam 1-99.

1H NMR (300 MHz, CDCl3): δ 6.53 (dd, J = 10.0, 2.1 Hz, 1H), 6.00 (d, J = 10.0 Hz,

1H), 5.89 (s, 1H), 4.54 (m, 1H), 4.45 (br. d, J = 14.1 Hz, 1H), 4.1-3.9 (m, 6H), 3.4-

3.15 (m, 2H), 3.11 (dd, J = 11.2, 4.63 Hz, 1H), 2.08 (m, 2H), 1.94-1.7 (m, 2H), 1.1

(ddd, J = 19.1, 7.1, 7.1 Hz, 1H), 0.89 (s, 9H), 0.09 (s, 6H). 13C NMR (75 MHz,

CDCl3): δ 169.1, 157.4, 140.1, 132.9, 127.0, 122.8, 119.6, 117.7, 69.8, 67.8, 67.0, 64.2,

64.1, 43.9, 40.7, 36.0, 28.3, 25.7, 25.2, 18.1, -4.7, -4.8. IR (thin film): 2929, 2856, 1682

cm–1. HRMS (ES) calc. for C24H36NO5Si [M+H]+: 446.2363. Found: 446.2347.

Lactam 1-100: To a solution of diene 1-99 (73.0 mg, 0.164 mmol) in THF (3.3 mL)

at –78 °C was added L-Selectride (1 Min THF, 0.328 µL, 0.328 mmol). After 3

hours at that temperature, the reaction mixture was warmed to 0 °C and stirred

for 2 hours. The mixture was then cooled to –78 °C, AcOH (0.047 mL, 0.82 mmol)

was added, and warmed to rt. The reaction mixture was diluted with EtOAc (10

TBSON

OAc

TBSODBU, benzene,80 °C, 24 h 82%

TBSON

TBSOL-Selectride,THF, -78 oC to 0 oC, 5 h;AcOH, rt

83%

mL) and washed with NaHCO3 (5 mL), H2O (5 mL), dried (MgSO4), filtered and

concentrated in vacuo. Purification by flash column chromatography (80%

EtOAc/Hex) provided 61 mg (83%) of lactam 1-100.

1H NMR (300 MHz, CDCl3): δ 5.59 (br. s, 1H), 4.37 (m, 1H), 4.17-3.93 (m, 7H),

3.09-2.92 (m, 2H), 2.79 (d, J = 18.6 Hz, 1H), 2.66 (dd, J = 10.6, 3.2 Hz, 1H), 2.55-2.38

(m, 2H), 2.33 (br. s, 2H), 2.11-1.98 (m, 1H), 1.87 (dd, J = 15.1, 5.2 Hz, 1H), 1.74 (br.

d, J = 14.0 Hz, 1H), 1.58 (dd, J = 11.5, 11.5 Hz, 2H), 0.88 (s, 9H), 0.05 (s, 6H). 13C

NMR (75 MHz, CDCl3): δ 171.4, 133.2, 132.5,131.2, 121.6, 118.0, 68.3, 68.1, 64.9,

64.4, 63.9, 41.5, 40.5, 36.7, 36.1, 35.5, 28.4, 25.8, 25.7, 18.2, -5.0, -5.1. IR (thin film):

2928, 1707, 1688 cm–1. HRMS (ES) calc. for C24H38NO5Si [M+H]+: 448.2519. Found:

448.2501.

Amine S1-3: To a solution of lactam 1-100 (40.0 mg, 0.089 mmol) in THF (1.8 mL)

at 0 °C was added AlH3•EtNMe2 (0.5 M in toluene, 0.232 mL, 0.116 mmol). After

45 minutes at 0 °C, H2O/THF/Et3N (1:1:0.25, mL) were added to quench the

reaction. The reaction mixture was diluted with EtOAc (10 mL), and the resulting

layers were separated. The organic layer was dried (MgSO4), filtered and

concentrated in vacuo. Purification by flash column chromatography (40%

EtOAc/Hex) provided 27 mg (70%) of the amine S1-3.

1H NMR (300 MHz, CDCl3): δ 5.37 (br. s, 1H), 4.2-3.9 (m, 7H), 3.41 (dd, J = 14.2,

14.1 Hz, 1H), 3.18 (br. d, J = 23.3 Hz, 1H), 3.10 (app. dt, J = 8.4, 7.8 Hz, 1H), 2.79

TBSON

TBSOAlH3•NEt(Me)2,THF,0 °C, 0.75 h 70%

(dd, J = 8.5, 7.9 Hz, 1H), 2.60 (dd, J = 10.8, 2.8 Hz, 1H), 2.55-2.2 (m, 6H), 2.1-1.98

(m, 1H), 1.87-1.68 (m, 3H), 1.51 (dd, J = 11.4, 11.4 Hz, 1H), 1.4-1.25 (m, 2H), 0.88

(s, 9H), 0.05 (s, 6H). 13C NMR (75 MHz, CDCl3): δ 141.0, 131.7, 130.5, 118.4, 117.4,

68.2, 66.0, 64.3, 63.8, 49.7, 47.0, 43.1, 36.9, 35.9, 29.7, 29.3, 28.3, 25.9, 20.7, 18.2, -4.9,

-5.1. IR (thin film): 2925, 2854, 1708, 1688 cm–1. HRMS (ES) calc. for C24H40NO4Si

[M+H]+: 434.2727. Found: 434.2711.

Isophellibiline (1-8): To a solution of amine S1-3 (27.0 mg, 0.062 mmol) in THF

(0.900 mL) was added aqueous HCl (1 Min water, 0.250 mL, 0.249 mmol). After

1.75 h at rt, EtOAc (3 mL) was added to the mixture. The resulting layers were

separated and the aqueous layer was extracted two times with EtOAc (3 mL),

washed once with NaHCO3 (5 mL), dried (MgSO4), filtered and concentrated in

vacuo. Purification by flash column chromatography (0à10% MeOH/CH2Cl2)

provided 15.0 mg (90%) of isophellibiline (1-8).

1H NMR (400 MHz, CDCl3): δ 5.49 (s, 1H), 4.78 (d, J = 15.5 Hz, 1H), 4.62 (d, J =

15.5 Hz, 1H), 3.89 (m, 1H), 3.40 (app. t, J = 12.8 Hz, 1H) 3.20 (d, J = 15.0 Hz, 1H),

3.00 (m, 2H), 2.83 (m, 2H), 2.64-2.43 (br. m, 5H), 2.22 (m, 2H), 2.05 (dd, J = 11.8,

3.8 Hz, 2H), 1.82 (app. dt, J = 13.5, 12.6 Hz, 1H), 1.65 (app. t, J = 11.6 Hz, 1H), 1.43

(d, J = 12.7 Hz, 1H). 13C NMR (75 MHz, CDCl3): δ 170.4, 140.6, 132.1, 132.0, 117.6,

72.6, 67.9, 65.4, 48.9, 46.5, 42.1, 35.7, 35.2, 30.8, 27.7, 20.6. IR (thin film): 3401, 2922,

TBSON

isophellibiline

HCl, H2O,THF, rt,1.75 h

90%

2852, 1738 cm–1. HRMS (ES) calc. for C16H22NO3 [M+H]+: 276.1600. Found:

276.1580.

Acid S1-4: To a solution of ester 1-11863 (353 mg, 1.13 mmol) in

THF/MeOH/H2O (1:1:1, 11.3 mL) was added LiOH-H2O (238 mg, 5.67 mmol).

After 2 hours at rt, a 10% KHSO4 solution (10 mL) and EtOAc (20 mL) were

added sequentially to the mixture. The resulting layers were separated, and the

aqueous layer was extracted twice with EtOAc (10 mL). The combined organic

extracts were dried (MgSO4), filtered and concentrated in vacuo to give 303 mg

(95%) of S1-4 as a brown foamy solid.

1H NMR (360 MHz, CDCl3): δ 6.84 (d, J = 10.3 Hz, 1H), 6.03 (d, J = 10.5 Hz, 1H),

4.60 (dd, J = 5.8, 2.5 Hz, 1H), 4.46 (dd, J = 11.7, 7.1 Hz, 1H), 3.12 (dd, J = 16.7, 6.4

Hz, 1H), 2.55 (m, 2H), 2.22 (m, 1H), 1.49 (s, 9H).

Lactone 1-119: To a solution of acid S1-4 (10.0 g, 34.8 mmol) in THF (140 mL) at 0

°C was added Et3N (5.34 mL, 38.3 mmol). After 0.5 hours at 0 °C, ethyl

chloroformate (3.66 mL, 38.3 mmol) was added to the mixture. The mixture was

warmed slowly to rt. After 12 hours, EtOAc (300 mL) was added to the mixture.

The combined organic extracts were washed once with a saturated NaHCO3

solution (100 mL), once with water (100 mL), once with brine (100 mL), dried

BocH

CO2Me

LiOH, H2O,MeOH, THFrt, 2 h

95% NO

BocH

CO2H

BocH

CO2HNO

BocH

OEt3N, THF, 0 oC, 1 h; ClCO2Et,rt, 12 h

96%

(MgSO4), filtered and concentrated in vacuo. The brown residue was triturated

thrice with Et2O to yield 9.33 g (96%) of 1-119 as a white solid.

1H NMR (360 MHz, CDCl3): δ 6.99 (d, J = 10.4 Hz, 1H), 6.22 (d, J = 10.4 Hz, 1H),

4.69 (br. s, 1H), 4.03 (br. s, 1H), 3.36 (br. d, J = 9.3 Hz, 1H), 2.39 (m, 2H), 2.28 (dd, J

= 11.0, 1.0 Hz, 1H), 1.48 (s, 9H).

Acid 1-120: To a suspension of zinc (3.00 g, 46.1 mmol) in THF (6.6 mL) was

added dibromo ethane (0.060 mL, 0.692 mmol). The mixture was heated to reflux

for one minute. After cooling the mixture to rt, TMSCl (0.070 mL, 0.553 mmol)

was added to the mixture. After 0.25 h at rt, a solution of lactone 1-119 (1.30 g,

4.61 mmol) in THF/AcOH (1:1, 62 mL) was added slowly. After 24 h at rt, the

mixture was filtered (cotton plug), and diluted with EtOAc (300 mL). The

combined organic extracts were washed five times with water (100 mL), once

with brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo. The crude

oil was purified by flash column chromatography (25% EtOAc/Hex) to give 779

mg (60%) of 1-120.

1H NMR (300 MHz, CDCl3): δ 5.77 (br. s, 1H), 4.52–4.45 (m, 2H), 3.56 (dd, J = 15.7,

4.7 Hz, 0.5H), 3.33 (dd, J = 15.7, 4.8 Hz, 0.5H), 3.02 (m, 1H), 2.85–2.73 (m, 2H), 2.24

(m, 1H), 1.48 (s, 5H), 1.42 (s, 4H).

Zn, BrCH2CH2Br,TMSCl, AcOH,THF, rt, 16 h

60%NOBocH

CO2H

BocH

N-Boc amine 1-121: To a solution of acid 1-120 (795 mg, 2.83 mmol) in benzene

(57 mL) was added 2-mercaptopyridine N-oxide (431 mg, 3.39 mmol), N,N’-

dicyclohexylcarbodiimide (875 mg, 4.24 mmol), and DMAP (518 mg, 4.24 mmol).

The mixture was heated to reflux for 2 hours. To the refluxing mixture was

added a mixture of AIBN (93 mg, 0.565 mmol) and freshly distilled tributyltin

hydride (2.28 mL, 8.48 mmol) in benzene (28 mL). After 3 hours at reflux, the

mixture was cooled to rt, and Et2O (100 mL) was added to the mixture. The

mixture was filtered (cotton plug) and concentrated in vacuo. The crude oil was

purified by flash column chromatography (100% Hexà10% EtOAc/Hex) to give

401 mg (60%) of 1-121.

1H NMR (300 MHz, CDCl3): δ 5.74 (m 1H), 4.33 (br. s, 1H), 3.86 (br. s, 1H), 3.27

(dd, J = 17.7, 6.9 Hz, 1H), 3.21 (br. s, 1H), 2.98–2.75 (m, 2H), 2.69–2.55 (m, 1H),

2.55–2.45 (m, 1H), 2.21 (t, J = 9.1 Hz, 1H), 1.47 (s, 9H). IR (thin film): 2974, 2929,

1700, 1697 cm–1.

Alcohol 1-122: To a solution of ketone 1-121 (799 mg, 3.37 mmol) in MeOH (34

mL) at 0 °C was added NaBH4 (128 mg, 3.37 mmol). After 1.5 h at 0 °C, water (50

mL) and EtOAc (100 mL) were added sequentially to the mixture. The resulting

NOBocH

SH , DCC, DMAP, PhH, 80 oC, 2 h;

Bu3SnH, AIBN,80 oC, 3 h 60%

NOBocH

CO2H

NHOBocH

NaBH3, MeOH,rt, 30 min

90%NOBocH

layers were separated, and the aqueous layer was extracted twice with EtOAc (50

mL). The combined organic extracts were washed once with brine (50 mL), dried

(MgSO4), filtered and concentrated in vacuo to give 725 mg (90%) of 1-122.

1H NMR (360 MHz, CDCl3): δ 5.51 (m, 1H), 4.00 (br. s, 2H), 3.71 (br. s, 1H), 3.15

(ddd, J = 17.6, 10.9, 7.1 Hz, 1H), 2.95–2.61 (br. s, 1H), 2.51–2.28 (m, 3H), 1.99 (m,

1H), 1.48 (s, 9H), 1.25 (dd, J = 9.3, 7.2 Hz, 1H). IR (thin film): 3400, 2928, 1670 cm–1.

Amine 1-123: To a solution of carbamate 1-122 (55.0 mg, 0.230 mmol) in CH2Cl2

(2.3 mL) at 0 °C was added TFA (0.460 mL) dropwise. After 1 hour at 0 °C, the

mixture was concentrated in vacuo. The crude TFA salt was dissolved in a K2CO3

solution (2 Min water, 2 mL). The aqueous layer was extracted three times with

EtOAc (5 mL). The combined organic extracts were dried (MgSO4), filtered and

concentrated in vacuo to give 25.0 mg (78%) of 1-123.

1H NMR (400 MHz, CDCl3): δ 5.49 (s, 1H), 3.98 (br. s, 1H), 3.88 (br. s, 2H), 3.47 (br.

s, 1H), 3.22 (m, 1H), 3.04 (m, 1H), 2.52–2.30 (m, 4H), 2.03 (m, 1H), 1.42 (dt, J =

22.0, 11.0 Hz, 1H).

N-Methyl amine 1-124: To a solution of carbamate 1-122 (41.0 mg, 171 mmol) in

Et2O (1.7 mL) at 0 °C was added LiAlH4 (39.0 mg, 1.03 mmol). After warming

slowly to rt, the mixture was heated to reflux. After 15 h at reflux, the mixture

TFA, DCM,0 oC, 1h;K2CO3 (aq)

78%NHOHH

NHOBocH

NHOMeH

LAH, Et2O,35 oC, 15 h

60%NHOBocH

was cooled to 0 °C. To the cooled mixture was added sequentially: (1) water

(0.040 mL), (2) NaOH (4 Min water, 0.080 mL), and (3) water (0.120 mL). The

resulting suspension was filtered and concentrated in vacuo to give 16.0 mg (60%)

of 1-124 as a white solid.

1H NMR (400 MHz, CDCl3): δ 5.36 (s, 1H), 3.97 (m, 1H), 3.13 (t, J = 3.1 Hz, 1H),

2.47 (m, 2H), 2.38 (m, 2H), 2.33 (s, 3H), 2.32–2.14 (m, 2H), 2.05–1.83 (m, 2H), 1.32

(dd, J = 21.3, 11.1 Hz, 1H).

Methyl ether 1-125: To a solution of alcohol 1-122 (440 mg, 1.84 mmol) in DMF

(18 mL) at 0 °C was added NaH (60% in mineral oil, 368 mg, 9.20 mmol). After 15

minutes at 0 °C, MeI (0.286 mL, 4.60 mmol) was added to the mixture. After 1 h,

water (20 mL) and Et2O (80 mL) were added sequentially to the mixture. The

resulting layers were separated, and the combined organic extracts were washed

four times with water (20 mL), once with brine (20 mL), dried (MgSO4), filtered

and concentrated in vacuo. The crude oil was purified by flash column

chromatography (10% EtOAc/Hex) to give 373 mg (80%) of 1-125.

1H NMR (400 MHz, CDCl3): δ 5.51 (s, 1H), 3.96 (br. s, 1H), 3.71 (br. s, 1H), 3.52 (m,

1H), 3.39 (s, 3H), 3.15 (ddd, J = 17.5, 10.8, 6.7 Hz, 1H), 2.60–2.32 (m, 2H), 2.31 (dd,

J = 13.6, 6.5 Hz, 1H), 1.98 (m, 1H), 1.49 (s, 9H), 1.13 (m, 1H).

NaH, DMF,0 oC, 15 min;MeI, 0 oC, 1 h

80%NOBocH

NHOBocH

Amine 1-126: To a solution of carbamate 1-125 (33.0 mg, 0.130 mmol) in CH2Cl2

(2.6 mL) at 0 °C was added trifluoroacetic acid (TFA) (0.261 mL) dropwise. After

1 hour at 0 °C, the mixture was concentrated in vacuo. The crude TFA salt was

dissolved in a K2CO3 solution (2 Min water, 2 mL). The aqueous layer was

extracted three times with EtOAc (5 mL). The combined organic extracts were

dried (MgSO4), filtered and concentrated in vacuo to give 10.0 mg (50%) of 1-126.

1H NMR (400 MHz, CDCl3): δ 5.53 (s, 1H), 3.53 (br. s, 2H), 3.38 (s, 3H), 3.27 (br. s,

1H), 3.12 (br. s, 1H), 2.50 (m, 4h), 2.02 (m, 1H), 1.36 (dd, J = 22.2, 11.1 Hz, 1H).

N-Methyl amine 1-127: To a solution of carbamate 1-125 (20.0 mg, 0.079 mmol) in

Et2O (1.6 mL) at 0 °C was added LiAlH4 (30.0 mg, 0.789 mmol). After warming

slowly to rt, the mixture was heated to reflux. After 15 h at reflux, the mixture

was cooled to 0 °C. To the cooled mixture was added sequentially: (1) water

(0.030 mL), (2) NaOH (4 Min water, 0.060 mL), and (3) water (0.090 mL). The

resulting suspension was filtered and concentrated in vacuo to give 8.6 mg (65%)

of 1-127.

1H NMR (300 MHz, CDCl3): δ 5.37 (s, 1H), 3.51 (m, 1H), 3.39 (s, 1H), 2.36 (m, 1H),

2.52–2.28 (m, 8H), 2.18 (m, 2H), 1.91 (m, 1H), 1.18 (dd, J = 22.0, 10.4 Hz, 1H).

NOHH

TFA, DCM,0 oC, 1h;K2CO3 (aq)

50%NOBocH

NOMeH

NOBocH

LAH, Et2O,35 oC, 15 h

65%

Bromolactone 1-129: To a mixture of trans-dibromides 1-12865 (1.65 g, 5.54 mmol)

in THF (2.2 mL) and water (28 mL) was added NaHCO3 (2.33 g, 27.7 mmol).

After 16 h at rt, Et2O (50 mL) was added to the mixture. The resulting layers were

separated, and the aqueous layer was extracted twice with Et2O (30 mL). The

combined organic extracts were washed once with brine (50 mL), dried (MgSO4),

filtered and concentrated in vacuo. This gave 649 mg (54%) of 1-129 that was

taken on without further purification.

1H NMR (300 MHz, CDCl3): δ 5.78 (br. d, J = 9.1 Hz, 1H), 5.65 (d, J = 9.2 Hz, 1H),

4.84 (br.s, 1H), 4.38 (s, 1H), 2.65 (ddd, J = 19.1, 2.5, 2.5 Hz, 1H), 2.53 (br. s, J = 19.1

Hz, 1H), 1.41 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 175.9, 130.7, 127.2, 80.5, 77.4,

58.0, 47.5, 32.7, 17.5. IR (thin film): 3004, 1785 cm–1.

Lactone 1-130: To a solution of bromide 1-129 (394 mg, 1.82 mmol) in benzene (9

mL) was added Bu3SnH (0.610 mL, 2.27 mmol) and AIBN (15.0 mg, 0.091 mmol).

The mixture was warmed to 85 °C. After 3 h at 85 °C, the mixture was

concentrated in vacuo. The crude oil was purified by flash column

chromatography (100% Hex à 25% Et2O/Hex) to give 239 mg (95%) of 1-130.

1H NMR (360 MHz, CDCl3): δ 5.73 (app. t, J = 10.7 Hz, 2H), 4.82 (s, 1H), 2.45 (s,

2H), 2.25 (dd, J = 10.9, 5.9 Hz, 1H), 1.96 (d, J = 11.0 Hz, 1H), 1.36 (s, 3H). 13C NMR

BrO

OHBr

NaHCO3,H2O, THF,rt, 16 h 54%

BrO

Bu3SnH,AIBN, PhH85 oC, 3 h

95%

(75 MHz, CDCl3): δ 179.0, 132.9, 126.2, 74.1, 41.0, 39.7, 31.3, 18.2. IR (thin film):

2973, 1774 cm–1.

Amide 1-131: A Parr reactor containing solution of lactone 1-130 (408 mg, 2.95

mmol) in iPrOH (29 mL) was charged with NH3 (g) (100 psi). After 5 days at rt,

the mixture was concentrated in vacuo to give 407 mg (89%) of 1-131 that was

taken on without further purification.

1H NMR (400 MHz, CDCl3): δ 6.2-6.0 (br. d, 0.74H), 5.73 (m, 1H), 5.61 (d, J = 10.1

Hz, 1H), 4.00 (s, 1H), 2.96 (s, 2H), 2.25 (d, J = 17.9 Hz, 1H), 2.12 (dd, J = 13.4, 7.2

Hz, 1H), 2.02 (d, J = 17.8 Hz, 1H), 1.65 (d, J = 13.3 Hz, 1H), 1.21 (s, 3H). 13C NMR

(75 MHz, CDCl3): δ 180.9, 129.9, 126.5, 63.9, 42.8, 40.4, 33.0, 26.4. IR (thin film):

3346, 2947, 1643 cm–1.

Carbamate 1-132: To a solution of amide 1-131 (1.00 g, 6.44 mmol) in DMF (130

mL) was added Pb(OAc)4 (4.29 g, 9.67 mmol). The mixture was warmed to 90 °C.

After 2 h at 90 °C, the mixture was diluted with EtOAc (250 mL). The combined

organic extracts were washed five times with water (100 mL), once with brine

(100 mL), dried (MgSO4), filtered and concentrated in vacuo. The crude oil was

purified by flash column chromatography (70% EtOAc/Hexà100% EtOAc) to

give 621 mg (63%) of 1-132.

HO NH2O

NH3 (100psi),iPrOH, rt, 6 d

89%

HO NH2O

Pb(OAc)4,DMF,90 oC, 2 h

63%O NH

1H NMR (400 MHz, CDCl3): δ 7.21 (br. s, 1H), 5.73 (d, J = 9.7 Hz, 1H), 5.60 (d, J =

9.7 Hz, 1H), 4.87 (s, 1H), 2.50 (d, J = 19.1 Hz, 1H), 2.30 (dd, J = 19.1, 2.4 Hz, 1H),

2.00 (dd, J = 12.6, 3.4 Hz, 1H), 1.82 (d, J = 12.8 Hz, 1H), 1.29 (s, 3H). 13C NMR (75

MHz, CDCl3): δ 155.4, 134.5, 123.7, 72.6, 46.8, 34.5, 33.3, 25.8. IR (thin film): 3228,

2968, 1714 cm–1.

Amine 1-133: Carbamate 1-132 (44.0 mg, 0.287 mmol) was taken up in a solution

of potassium hydroxide in water (3M, 4.8 mL, 14.4 mmol). The mixture was

heated to reflux. After 36 h at reflux, the mixture was cooled to rt. The aqueous

layer was extracted three times with 10% iPrOH/CH2Cl2 (10 mL). The combined

organic extracts were dried (Na2SO4), filtered and concentrated in vacuo to give

21.0 mg (57%) of 1-133.

1H NMR (300 MHz, CDCl3): δ 5.64 (ddd, J = 10.0, 3.6, 3.6 Hz, 1H), 5.53 (d, J = 10.8

Hz, 1H), 3.10 (br. s, 1H), 2.20 (s, 2H), 1.84 (dd, J = 13.4, 5.5 Hz, 1H), 1.66 (dd, J =

13.4, 2.0 Hz, 1H), 1.21 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 133.7, 124.7, 65.4, 49.1,

42.0, 34.1, 33.1. IR (thin film): 3340, 3274, 2920 cm–1.

N-Methyl amine 1-134: To a suspension of carbamate 1-132 (35.0 mg, 0.229

mmol) in Et2O (4.6 mL) was added LiAlH4 (87.0 mg, 2.29 mmol). The mixture

O NH

HO NH2

KOH, H2O,100 oC, 36 h

57%

O NH

HO HN

LAH, Et2O,35 oC, 22 h

56%

was heated to reflux. After 22 h at reflux, the mixture was cooled to 0 °C. To the

cooled mixture was added sequentially: (1) water (0.090 mL), (2) 10% NaOH(aq.)

(0.180 mL), and (3) water (0.270 mL). The resulting suspension was filtered

through celite (EtOAc) and concentrated in vacuo. The crude oil was purified by

flash column chromatography (10% MeOH/CH2Cl2, 1% NH4OH) to give 18.0 mg

(56%) of 1-134.

1H NMR (300 MHz, CDCl3): δ 5.71 (m, 1H), 5.56 (dd, J = 10.1, 1.5 Hz, 1H), 4.1 (s,

1H), 3.9-2.7 (br. s, 3H), 3.21 (s, 3H), 2.23 (m, 2H), 1.98 (dd, J = 13.6, 5.0 Hz, 1H),

1.47 (dd, J = 13.6, 2.2 Hz, 1H), 1.15 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 132.0,

126.1, 65.4, 52.2, 38.5, 34.6, 28.2, 26.5. IR (thin film): 3283, 2925 cm–1.

N-Methyl carbamate 1-135: To a solution of carbamate 1-132 (50.0 mg, 0.326

mmol) in DMF (3.3 mL) at 0 °C was added NaH (60% in oil, 26.0 mg, 0.653

mmol). After 2 h at 0 °C, methyl iodide (0.102 mL, 1.63 mmol) was added to the

mixture. The mixture was warmed slowly to rt. After 16 h at rt, a saturated

NH4Cl solution (5 mL) and EtOAc (10 mL) were added sequentially to the

mixture. The resulting layers were separated, and the aqueous layer was

extracted twice with EtOAc (10 mL). The combined organic extracts were washed

five times with water (5 mL), once with brine (5 mL), dried (MgSO4), filtered and

concentrated in vacuo. The crude oil was purified by flash column

chromatography (2.5% MeOH/CH2Cl2) to give 42.0 mg (78%) of 1-135.

O NH

O N

NaH, DMF,0 oC, 2 h;MeI, 16 h

78%

1H NMR (300 MHz, CDCl3): δ 5.94 (ddd, J = 7.6, 2.2, 1.8 Hz, 1H), 5.72 (dddd, J =

9.8, 3.8, 2.8, 0.9 Hz, 1H), 4.78 (t, J = 3.7 Hz, 1H), 2.93 (s, 3H), 2.55 (m, 1H), 2.34 (m,

1H), 2.21 (m, 1H), 1.84 (dd, J = 13.0, 1.2 Hz, 1H), 1.41 (s, 3H). 13C NMR (75 MHz,

CDCl3): δ 154.8, 132.1, 125.7, 70.5, 50.1, 35.7, 33.7, 29.9, 25.5. IR (thin film): 2955,

1694 cm–1. M.P.: 75-77 °C.

N-Dimethyl amine 1-136: To a solution of methyl carbamate 1-135 (22.0 mg,

0.132 mmol) in Et2O (2.6 mL) was added LiAlH4 (50.0 mg, 1.32 mmol). The

mixture was heated to reflux. After 16 h at reflux, the mixture was cooled to 0 °C.

To the cooled mixture was added sequentially: (1) water (0.050 mL), (2) 10%

NaOH(aq.) (0.100 mL), and (3) water (0.150 mL). The resulting suspension was

filtered through celite (EtOAc) and concentrated in vacuo. The crude oil was

purified by flash column chromatography (3.5% MeOH/CH2Cl2, 1% NH4OH) to

give 15.0 mg (71%) of 1-136.

1H NMR (300 MHz, CDCl3): δ 5.68 (m, 1H), 5.60 (dd, J = 10.3, 1.5 Hz, 1H), 4.08 (s,

1H), 2.24 (m, 8H), 1.28 (d, J = 15.5 Hz, 1H), 1.00 (s, 3H). 13C NMR (75 MHz,

CDCl3): δ 132.8, 125.5, 65.5, 55.5, 38.1, 35.3, 35.1, 18.9. IR (thin film): 3345, 2933 cm–

O N

HO N

LAH, Et2O,35 oC, 16 h

71%

Spectra of Isophellibiline (Authentic and Synthetic)

References

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Part II: Total Synthesis of (±)-Communesin F

Chapter 5. Introduction and Background

5.1. Isolation and structural characterization of the communesins and perophoramidine

Over the last half-century marine organisms have been found to be a rich

source of natural products possessing an enormous range of biological activity

and structural complexity.1 In particular, the somewhat related communesins

and perophoramidine are marine natural products that have proven to be

significant challenges for synthetic chemists. Communesins A (2-1) and B (2-5)

were isolated in 1993 by Numata and coworkers from the mycelium of a strain of

Penecillium sp. stuck on the marine alga Entermorpha intestinalis (Figure 5.1.1).2

The structures of communesins A and B were assigned via extensive NMR

experiments. Numata and coworkers also determined the relative

stereochemistry of all stereocenters, aside from the center at C(21), utilizing nOe

correlations. Subsequent studies by Hemscheidt and coworkers determined the

configuration at C(21) of communesin B (which they mistakenly assigned as the

natural product “nomofungin” (2-10) that bears an N,O acetal instead of the

additional aminal), and its absolute configuration (6R, 7R, 8R, 9S, 11R, 21R).3

These findings have since been confirmed by the total synthesis of communesins

A and B (vide infra). Several other members of the communesin family have also

been identified, including: communesins C (2-6),4 D (2-7),4 E (2-2),5 F (2-8),5 G (2-

3),6 and H (2-4).6 The communesins all possess: (1) a tryptophan derived

heptacyclic skeleton, (2) two bicyclic aminals, and (3) four contiguous

Figure 5.1.1. The communesins and perophoramidine

stereocenters, including two vicinal quaternary centers at C(7) and C(8)

possessing a cis-relationship of the tryptamine derived (vide infra) aminoethyl

moieties. The communesins are differentiated by: (1) their substituents at N(15)

and N(16), and (2) the oxidation state of C(21) and C(22). Communesin F (2-8) is

the only member to not bear an epoxide functionality.

The structurally related natural product perophoramidine (2-9) was

isolated by Ireland and coworkers in 2002 from the colonial ascidian Perophora

nomei (Figure 5.1.1).7 The structure of perophoramidine was elucidated by NMR

experiments. While structurally similar to the communesins, perophoramidine,

in contrast, possesses: (1) a hexacyclic skeleton lacking the azepine ring found in

the communesins, (2) two bicyclic amidines, (3) a trans-relationship of the

aminoethyl moietys at C(7) and C(8), and (4) halogenated aromatic rings. The

absolute configuration has been established via total synthesis.8

N NO H

HNR

N NO H

HN N

N NH

OOO R'

162122

2-1 communesin A, R = R' = CH32-2 communesin E, R = H, R' = CH32-3 communesin G, R = CH3, R' = Et2-4 communesin H, R = CH3, R' = Pr

2-5 communesin B, R = CH32-6 communesin C, R = H2-7 communesin D, R = CHO

2-8 communesin F

N N

2-9 perophoramidine

N O

N NO H

2-10 "nomofungin"

5.2. Pharmacology of the communesins and perophoramidine

Members of the communesin family and perophoramidine have been

shown to possess a variety of biological activities. Communesins A and B inhibit

proliferation of mouse leukemia cells P-388 (ED50 = 3.5 and 0.45 µg/mL,

respectively).2 Communesin B also demonstrated moderate cytotoxicity against

KB and LoVo cells (MIC = 4.5 µg/mL and 2 µg/mL, respectively) by disruption

of the microfilament network in mammalian cells.3 Communesins B, C, and D

exhibited moderate antiproliferation activity when tested on a series of human

leukemia cell lines.4 Communesins A, B, D, E, and F also demonstrate insecticidal

activity against the third instar larvae of silkworms by oral administration.5

Communesins G and H were found inactive in antimicrobial, antiviral, and

anticancer assays.6 Perophoramidine demonstrates cytotoxicity towards HCT116

colon carcinoma cell line (IC50 = 60 µM) and induces apoptosis via

poly(adenosine-5’-diphosphate ribose) polymerase (PARP) cleavage within 24

hours.7

5.3. Biosynthesis of the communesins and perophoramidine

On the basis of biosynthetic labeling studies and the widely accepted

biosynthetic origins of the calycanthaceous alkaloids,9 Mantle and coworkers10

proposed a biosynthetic pathway predicated on an oxidative dimerization of

tryptamine (2-12, Scheme 5.3.1). Thus, oxidation/dimerization of two tryptamine

(2-12) subunits, derived via the decarboxylation of tryptophan (2-11), gives the

C2-symmetric bis-indolenine 2-13. Hydrolysis of the bis-indolenine gives rise to

the tetraaminodialdehyde 2-14, which, following cyclization and methylation,

would give the bis-aminal 2-15. The pathway from the bis-aminal to the

communesins remains unclear.

In response to alternate biosynthetic proposals (vide infra), Mantle and

coworkers11 have since acknowledged that aurantioclavine (2-19, Scheme 5.3.3),

or 4-(dimethylallyl)tryptophan could be key intermediates in the biosynthesis of

the communensins.

Scheme 5.3.1. Mantle’s biosynthetic pathway to communesin B

A related biosynthetic pathway has been proposed for perophoramidine

(Scheme 5.3.2).9 In this case, oxidative dimerization of tryptamine (2-12) gives

rise to the meso isomer 2-16 and subsequently bis-aminal 2-17. Oxidation and

halogenation would yield perophoramidine (2-9).

NH2

CO2H

NNH2

NH2N

2-13C2-symmetric isomer

N NH

2-15

N NH

N NO H

2-5 communesin B

2-11tryptophan

2-12tryptamine

tryptophan decarboxylase dimerase

methylase acylation? prenylation?

mevalonate

[O]?

NH2

H2NH2N

2-14

hydrolysis

Scheme 5.3.2. Biosynthesis of perophoramidine

Stoltz and coworkers have advanced an alternate biosynthetic pathway to

the communesins (Scheme 5.3.3).12 Thus, tryptophan (2-11) or tryptamine (2-12) is

oxidized to the indol-2-one 2-20, which can then react with aurantioclavine (2-19)

in a cycloaddition reaction proceeding through an exo transition state to generate

the strained bridgehead lactam 2-21. An intramolecular ring opening of the

Scheme 5.3.3. Stoltz’s biosynthetic pathway to communesin B

NH2

N N

2-9 perophoramidine

NNH2

NH2N

[O]

2-16meso isomer

2-172-12tryptamine

N NH

N NO H

2-5 communesin B

H2NNH2

CO2H

NH2

H2N

H H

NOH2N2-20

2-182-11tryptophan

2-12tryptamine

NHH

NH2

2-21

NHHN

2-22

2-19aurantioclavine

[O] [O]

lactam by the pendant amine would give spirocyclic lactam 2-22. Further

functionalization would provide communesin B.

Funk and Fuchs proposed a related communesin biosynthesis within a

report of their “biomimetic” synthesis of perophoramidine (Scheme 5.3.4).13

Thus, the cycloaddition reaction of 4-(dimethylallyl)tryptamine (2-23) with indol-

2-one 2-20 proceeding through an exo transition state would give rise to the

strained bridgehead lactam 2-24. A transamidation reaction with one of the

amines would provide spirocyclic lactam 2-25. Reduction of the lactam and

subsequent cyclizations with the remaining amine would give the communesin

ring system 2-25, which could provide communesin B itself upon further

functionalization.

Scheme 5.3.4. Funk’s biosynthetic pathway to communesin B

N NH

N NO H

2-5 communesin B

NH2

H2N

OH2N2-20

H2N

NH2

2-24

H2NHN

2-25

2-234-(dimethylallyl)tryptamine

5.4. Previous synthetic approaches to the communesins

Numerous groups have initiated programs towards the total syntheses of

the communesins due to their unique and fascinating structure, as well as their

potentially useful biological activity. Studies towards the syntheses of the

communesins by the groups of Stoltz and Adlington, as well as the completed

total syntheses of members of the communesins family by the groups of Qin,

Weinreb, and Ma, are summarized in the sections below.

5.4.1. Stoltz’s approach to the communesin ring system

Stoltz prepared the core aminal ring structure of the communesins via an

intermolecular aza-ortho-xylylene cycloaddition reaction. The aza-ortho-xylylene

2-28, generated in situ from chloroaniline 2-27 (Scheme 5.4.1),14 underwent a [4 +

2] cycloaddition reaction with aurantioclavine derivative 2-26 to give the

pentacyclic ring system 2-29 as a 1:1 mixture of diastereomers12a (this product

distribution was reported as a 2:1 mixture in a later publication12b). It was argued

that the poor stereoselectivity was due to the Boc group residing on the face

opposite of the olefin substituent.

Scheme 5.4.1. Stoltz’s approach to the communesin ring system

NBoc

HN N

BocN

Cs2CO3,CH2Cl2,-78 °C, 4 h

89%

2-26 2-27 2-28 2-29

OtBu

NTs

5.4.2. Adlington’s approach to the communesin ring system

Adlington and coworkers reported a synthesis strategy for the

communesin ring system via an intramolecular hetero Diels–Alder reaction that

aimed to construct the vicinal quaternary centers in a single step (Scheme 5.4.2).15

To investigate this idea, aniline 2-31 was prepared in two straightforward steps

from the tryptamine derivative 2-30. Treatment of alcohol 2-31 with

carbonyldiimidazole (CDI) gave 3,1-benzoxazin-2-one 2-32. However, much to

their chagrin, Adlington and coworkers found that heating 3,1-benzoxazin-2-one

2-32 up to 220 °C failed to generate the anticipated aza-ortho-xylylene 2-33

intermediate, and instead returned the starting material unchanged.

Scheme 5.4.2. Adlington’s initial approach to the communesin ring system

Adlington and coworkers did however find that treatment of allylic

alcohol 2-35, prepared in an analogous manner to 2-31, with CDI gave

pentacyclic aminal 2-36, along with allylic imidazole 2-37 and dihydroquinoline

2-38 (Scheme 5.4.3). However, the relative stereochemistry of the vicinal

quaternary centers generated in the cycloaddition reaction is opposite to that

NHBn

BnN O

BocHN

1. N-Boc-isatin, THF, rt, 18 h 81%

2. allyl MgBr, THF, rt, 2 h 73%

2-30 2-31 2-32

BnN O

NBoc

CDI, THF,60 °C, 2 h 83%

2-33

BnN O

NBoc

N NBoc

BnN

2-34

Scheme 5.4.3. Adlington’s modified approach to the communesin ring system

required for the synthesis of the communesins, but would be suitable for the

synthesis of perophoramidine.

5.4.3. Qin’s total synthesis of (±)-communesin F

In 2007, Qin and coworkers reported the first total synthesis of a member

of the communesin family, communesin F (2-8).16 Towards this end, diazoester 2-

40, prepared in six steps from the known 4-bromotryptophol (2-39), underwent a

Cu-catalyzed intramolecular cylcopropanation reaction to yield the stable

cyclopropane 2-41 (Scheme 5.4.4). Staudinger reduction of the azide and

subsequent closure of the resulting amine on the indolenium formed during the

cyclopropane ring opening gave aminal 2-42 as a single diastereomer. After

protection of the aminal, lactone 2-43 was prepared via O-allylation followed by

a stereoselective Claisen rearrangement. The remaining two nitrogen atoms were

then introduced in a 9-step sequence to afford the spirolactam 2-44. A Heck

reaction with 2-methyl-3-buten-1-ol was followed by an acid catalyzed allylic

NHBn

BnN O

BocHN

N NBoc

BnN

2-30 2-35

2-36 (36%)

1. N-Boc-isatin, THF, rt, 18 h 81%

2. vinyl MgBr, THF, rt, 1 h 89%

CDI, THF,40 °C, 48 h

BnN O

2-37 (42%)

BnN O

NBoc

2-38 (10%)

BocN

+ +

substitution reaction to give benzazepine 2-45 along with the diene resulting

from dehydration of the allylic alcohol. Bicyclic amidine 2-46 was prepared from

lactam 2-45 utilizing a strategy pioneered in Fuchs and Funk’s synthesis of

perophoramidine (vide infra). Thus, imidate formation, removal of the Boc

protecting group and a silica gel (SiO2) catalyzed cyclization gave the strained

bridgehead amidine 2-46. To complete the synthesis of (±)-communesin F (2-8),

the methyl carbamate was hydrolyzed and the amidine was reduced in the

presence of excess acetic anhydride to install the acetamide. The total synthesis

was competed in 23 linear steps from 4-bromotryptophol (2-39) in an overall

yield of 1.4%.

Scheme 5.4.4. Qin’s total synthesis of (±)-communesin F

BrOH

BrO O

N3 N

BrO O

NHH

BrO

NCO2MeH

HNOBocHN

N NCO2MeH

HNO

BocNH

N NCO2MeH

NNH

N NHH

NNH

6 steps

CuOTf,CH2Cl2,rt, 1 h

88%

PBu3,aq. THF,0 °C, 0.5 h

83%

9 steps

1. Et3OBF4, iPrNEt2, CH2Cl22. TFA, CH2Cl2

3. SiO2, MeOH CH2Cl2 77% (3 steps)

1. KOH, H2O, MeOH 65% 2. NaBH4, Ac2O AcOH 73%

2-8 communesin F

1. ClCO2Me, DMAP, CHCl3 93%

2. NaH, DMF, 0 °C, 1 h; allyl bromide, 65 °C, 4 h 84%

1. Pd(OAc)2, P(o-Tol)3, 100 °C, µν, 2 h, 68%

2. PPTS, CHCl3 66% (+ 26% diene)

2-40 2-41

2-42 2-43 2-44

2-45 2-46

2-39

5.4.4. Weinreb’s total synthesis of (±)-communesin F

Weinreb and coworkers17 followed Qin and coworkers in 2010 with their

synthesis of communesin F using a spirooxindole-forming Heck reaction

pioneered by Overman.18 Thus, aryl iodide 2-48, prepared in five steps from the

known enol triflate 2-47, underwent an intramolecular Heck reaction to give

spirooxindole 2-49 (Scheme 5.4.5). The nitroarene was converted to the

corresponding Boc-aniline derivative, which cyclized under reductive conditions

to give aminal 2-50. Enamine 2-50 was treated with cyanogen azide to give

lactam 2-51, which was then converted to aldehyde 2-52 over several steps.

Aldehyde 2-52 was subjected to an aldol condensation with acetone and the

lactam was activated for the subsequent transamidation as the imide 2-53.

Scheme 5.4.5. Weinreb’s total synthesis of (±)-communesin F

NBn

OTf

EtO

NCO2EtN

O NO2I

OBOM

N O

BOMOCO2EtN

NO2

N NBoc

BOMOCO2EtN

N NBoc

BOMOBocN

N NBoc

OHN

O N3

N NHH

NNH

5 steps

Pd(OAc)2, PPh3, DMA, K2CO3, nBu4NBr150 °C, 0.5 h 90%

1. Pt/C, H2, toluene, rt2. Boc2O, K2CO3, THF, H2O, 87% (2 steps)

3. AlH3•Me2NEt, THF, 0 °C 74%

1. KOH, EtOH2. NCN3, MeCN 93% (2 steps)

3. KOH, EtOH4. Boc2O, THF LiHMDS 57% (2 steps)

8 steps

1. Me2CO, NaOH, H2O 60 °C, 93%

2. Boc2O, THF LiHMDS 81%

1. PMe3, THF, H2O, 70 °C 88%

2. MeLi, THF 73%

2-8 communesin F

2-47 2-48 2-49

2-50 2-51 2-52

2-53 2-54

5 steps

N NBocH

HNOBocHN

N NBoc

BocN

O N3

Treatment of imide 2-53 with trimethyl phosphine afforded the transamidation

product, and addition of methyl lithium to the enone moiety gave the allylic

alcohol 2-54. The synthesis of communesin F (2-8) was completed, from this point

forward based on the precedent set by Qin and coworkers (vide supra). The total

synthesis was competed in 30 linear steps in an overall yield of 0.9%.

5.4.5. Ma’s total synthesis of (-)-communesin F

In 2010, Ma and coworkers reported the first asymmetric synthesis of

communesin F.19 Thus, indole 2-55, prepared in three steps from 4-

bromotryptophol (2-39), underwent an oxidative cyclization to form

spiroindolenine 2-56 as a mixture of diastereomers (Scheme 5.4.6). Upon

reduction of the nitro group, the indolenine underwent spontaneous cyclization

to a pentacyclic intermediate which was regioselectively methylated to give

aminal 2-57. In addition a diastereomer that was epimeric at all stereogenic

centers except the acyclic one (3.1:1) was isolated. Thus, an acceptable level of

asymmetric induction was imparted by the chiral auxillary. Proceeding with

optically pure material now, protection of aminal 2-57 as the Boc-carbamate was

followed by stereoselective allylation of the corresponding lactam enolate to give

lactam 2-58. Deprotection of the lactam and straightforward transformation of

the vinyl moiety afforded alcohol 2-59. A Heck reaction installed the allyl alcohol

group in 2-60. Treatment of bis-alcohol 2-60 with mesyl chloride presumably

generated a bis-mesylate that spontaneously cyclized to the benzazepine. The

primary mesylate was subsequently converted to azide 2-61. Reduction of the

Scheme 5.4.6. Ma’s total synthesis of (-)-communesin F

azide under anhydrous Staudinger reaction conditions provided the amidine,

which was readily converted to (-)-communesin F (2-8). The total synthesis was

completed in 19 linear steps from 4-bromotryptophol (2-39) in an overall yield of

4.7%.

5.4.6. Ma’s total synthesis of communesins A and B

In 2011, Ma and coworkers followed up their synthesis of communesin F

with the first total syntheses of communesins A and B.20 Ma and coworkers

found it necessary to redesign their previous route after attempts to prepare

communesins A and B directly from communesin F, or one of its synthetic

intermediates, failed. They speculated that the problem with a direct conversion

BrOH

BrN O

O2N

3 steps

PhTBSO

BrN O

O2N

PhTBSO

BrN O

PhTBSO

BrN O

NBoc

PhHO

BrHN O

NBocH

N NBocH

ONH

N NHH

NNH

2-8(−)-communesin F

LiHMDS, THF-78 °C, 0.5 h; I2, -78 °C, 2 h

1. Fe, NH4Cl, tBuOH, H2O reflux, 18 h

2. KOtBu, THF, 0 °C; MeI50% major isomer (3 steps)

1. KHMDS, THF; Boc2O, 0 °C 89%

2. KOtBu, Et2O; allyl bromide, rt3. TBAF, THF 92% (2 steps)

1. MsCl, Et3N, CH2Cl2

2. NaN3, DMF, nBuN4Br 49% (2 steps)

1. P(nBu)3, toluene2. NaBH4, Ac2O, AcOH

3. TFA, CH2Cl247% (3 steps)

2-55 2-56

2-57 2-58 2-59

2-61

4 steps

Pd(OAc)2, P(o-Tol)3,nBu4NBr, DMF, 140 °C, µν, 0.3 h

67%

HN O

NBocH

2-60

2-39

was the sensitivity of the southern aminal to oxidants. This observation is in

accord with the observations made during previous syntheses of

perophoramidine, wherein the southern amidine functionality was installed by a

facile oxidation of an aminal with MnO2.8,13,21 Therefore, the aurantioclavine

derivative 2-62 was prepared enantioselectively using a Sharpless asymmetric

dihydroxylation in a fourteen step sequence from 4-bromotryptophol (2-39,

Scheme 5.4.7). The indole 2-62 was converted to bridgehead lactam 2-63 utilizing

the oxidative cyclization/reductive cyclization featured in their aforementioned

synthesis of communesin F. Nitrile 2-64 was prepared by methylation of the

Scheme 5.4.7. Ma’s total synthesis of communesins A and B

BrOH

14 steps

O2N

NHH

N NHH

OOH

N NHH

O H

1. LiHMDS, THF, -78 °C to rt; I2, 0.25 h 66%

2. Raney-Ni, H2, THF, MeOH 70%

1. KHMDS, THF; MeI 90%

2. KHMDS, THF, -78°C; ICH2CN 67%

LAH, THFreflux, 0.6 h

NH4OAc,NaBH(OAc)3,MeOH, rt, 45 h

92% (2 steps)

N NHH

O H

2-62 2-63

2-64 2-65 2-66

2-66

2-5communesin B

2-1communesin A

4 steps4 steps

2-39

aminal, and alkylation of the lactam enolate within hexacycle 2-63. Nitrile 2-64

was then reduced to the corresponding lactol 2-65, which was converted to

aminal 2-66 by reductive amination with ammonium acetate. At this stage,

communesin A (2-1) and B (2-5) were each prepared in four steps from aminal 2-

66.

Chapter 6. Studies Towards the Communesins in the Funk Laboratory: An Aza-ortho-xylylene Route

6.1. Introduction

Aza-ortho-xylylenes, also known as ortho-aza-xylylenes or ortho-quinone

methide imines, are extremely versatile and reactive intermediates that undergo

a wide range of reactions.22 Specifically, they undergo: electrocyclization

reactions to give dihydroquinolines,23 cycloadditions with electrophilic23a,23b,24 and

nucleophilic14,25 π-bonds, attack by nucleophiles,23b,26 and dimerization reactions

to produce macrocycles.23a,23b A variety of methods for generating these reactive,

non-isolable intermediates have been reported, including but not limited to

photogeneration,26-27 retrocheletropic extrusion of various species (CO, SO2),22,26,28

[4 + 2] retrocycloaddition of 3,1-benzoxazin-2-ones,29 or by the 1,4-elimination of

various species (H2O, NR3, HF, HCl) from 2-aminobenzyl derivatives.14,30 Some of

the more efficient strategies for generating these intermediates and their

subsequent reactions, with a bias towards examples which undergo a subsequent

cycloaddition, are discussed below.

Ferraccioli29b reported the intramolecular cycloaddition reaction of aza-

ortho-xylylene 2-68, generated from benzoxazin-2-one 2-67 by a

retrocycloaddition with loss of carbon dioxide, to give sultam 2-69 (Scheme

6.1.1). Additionally, they reported the thermolysis reaction of the benzoxazin-2-

one 2-64 bearing an alkyl substituent at C(4) (Scheme 6.1.2). In this case, the

Scheme 6.1.1. Thermal decarboxylation of 3,1-benzoxazin-2-ones

reaction gave ortho-vinylaniline 2-72 as the only product. This result is due to a

competitive [1,5]-sigmatropic hydrogen shift in the Z-isomer of the aza-ortho-

xylylene intermediate 2-71.

Scheme 6.1.2. Competitive [1,5]-sigmatropic hydrogen shift

Tunge and coworkers23a,23b reported the palladium-induced

decarboxylation of vinyl benzoxazinone 2-73 to generate aza-ortho-xylylene

synthon 2-74 which readily undergoes a cycloaddition reaction with benzylidene

malononitrile (2-75) to give dihydroquinoline 2-76 with good diastereoselectivity

(Scheme 6.1.3). The palladium-induced decarboxylation occurs at room

temperature and is significantly milder than the conditions required for the

thermal decarboxylation of benzoxazinones (cf. Scheme 6.1.1).

Scheme 6.1.3. Palladium catalyzed decarboxylation of 4-vinyl-3,1-benzoxazin-2-ones

NOO2S O2S

NO2S

215 °C1,2,4-trichloro-benzene

-CO2

34%

2-67 2-68 2-69

OTs

NTs

HNTs

[1,5]H

75%

2-70 2-71 2-72

215 °C1,2,4-trichloro-benzene

-CO2

NTs

N NTs

OTs

CNPhPh

NC CNPdL2

5 mol%Pd(PPh3)4,CH2Cl2,

rt, 5 h+

99%

8.9 : 1 dr

2-73 2-74 2-75 2-76

Corey and Steinhagen14,25 have developed a simple, efficient method for

generating aza-ortho-xylylenes via base-induced elimination of hydrogen

chloride from the carbamate and sulfonamide derivatives of ortho-

chloromethylaniline 2-77 (Scheme 6.1.4). The generated N-acyl- and N-sulfonyl-

aza-ortho-xylylenes 2-78 undergo inverse-demand Diels–Alder reactions with a

variety of electron rich olefins including enol ethers, ketene acetals, and 2,3-

dihydrofurans.

Scheme 6.1.4. Base-mediated elimination of HCl from o-chloromethylanilines

Wu and coworkers30a have reported the cycloaddition reaction between a

variety of indoles and a variety of aza-ortho-xylylenes 2-81 generated from the

respective 2-aminobenzyl alcohols 2-80 via acid-catalyzed dehydration (Scheme

6.1.5). A noteworthy feature of this methodology is that neither protection of the

aniline nitrogen or conversion of the alcohol to a suitable leaving group is

unnecessary.

Scheme 6.1.5. Acid-catalyzed dehydration of 2-aminobenzyl alcohols

NHR

OEtOEt+

2-77

R = BocR = Ts

2-79

R = Boc, 83%R = Ts, 78%

2-78

Cs2CO3,CH2Cl2,

rt, 4 h

NNH2 NNH2

30 mol% TFA,ClCH2CH2Cl,

40 °C, 16 h

2-82

RRR

2-80

R = H, Cl, Me

2-81

R = H, Cl, Me

2-83

R = H, Cl, Me

100

6.2. Previous synthesis efforts directed towards the communesins in the Funk laboratory

Funk and Crawley initiated a synthesis program towards the

communesins following their realization that the natural products “nomofungin”

(10) and communesin B (5) were in fact the same compound.12a,31 Funk and

Crawley’s initial report described the intramolecular endo-cycloaddition reaction

of aza-ortho-xylylene 2-85 to give the advanced communesin ring system 2-86

that lacked only the pyrrolidine ring and the benzylic substituent on the

benzazepine ring found in the communesins (Scheme 6.2.1).31 The aza-ortho-

xylylene intermediate 2-85 was generated via thermolysis of the phenyl

carbonate 2-84. However, all attempts to functionalize the tertiary benzylic

position (CAN, DDQ, NBS) in order to have a handle to install the vicinal

quaternary centers and the northern aminal proved unsuccessful.32

Scheme 6.2.1. Crawley and Funk’s first-generation synthetic plan

In light of these difficulties, Funk and Crawley investigated an alternate

route wherein functionality for the elaboration of the pyrrolidine ring was

introduced at an earlier stage.33 Thus, aziridine 2-89 was prepared from

tryptamine derivative 2-87 and dibromide 2-88 (Scheme 6.2.2). Treatment of the

Teoc-carbamate 2-89 with TBAF gave endo-cycloadduct 2-91, presumably

N NCO2EtH

2-84 2-85 2-86

CO2Et

NHOCO2Ph

NHCO2Et

160 °Cdichloro-benzene

6 h70%

101

proceeding via the aza-ortho-xylylene 2-90 generated by a decarboxylative ring

opening of the aziridine. Alkyne 2-91 was directly subjected to a gold(I)

catalyzed 7-exo-dig cyclization to give bridgehead enamine 2-92. Unfortunately,

as before, all attempts to functionalize the tertiary benzylic carbon primarily

through intramolecular carbene insertion chemistry failed.32

Scheme 6.2.2. Crawley and Funk’s second-generation synthetic plan

The difficulties associated with the installation of the pyrrolidine ring in

their previous strategies forced Funk and Crawley to develop a third-generation

synthetic plan. This approach entailed the introduction of a lactam moiety as a

handle for the installation of the second quaternary center via enolate alkylation.

The success of this approach rested upon the ability to generate an

unprecedented and presumably more reactive acyl-aza-ortho-xylylene

intermediate such as 2-97 (Scheme 6.2.3). To that end, the 4-acyl-3,1-benzoxazin-

2-one 2-96 (prepared from the tryptamine derivative 2-93 and acid chloride 2-94)

underwent a retrocycloaddition/cycloaddition sequence in the presence of

NH2

OOTMS

N NH

HN N

H AuCl(PPh3),AgOTf, CH2Cl2,40 °C, 12 h

89%

2-87 2-88 2-89

2-90 2-91 2-92

Cs2CO3,CH3CN,rt, 18h

65%

TBAF,THF,rt, 4h

102

ytterbium triflate to give cycloadduct 2-98 as a 2:1 mixture favoring the endo

adduct. The aza-ortho-xylylene intermediate is presumably generated via Lewis

acid mediated decarboxylation of the 4-acyl-3,1-benzoxazin-2-one 2-96 as

significantly elevated temperatures (180 ºC, trichlorobenzene) are required in the

absence of a lanthanide triflate catalyst.32 Gratifyingly, the mixture of epimers

could be stereoselectively alkylated from the convex face to afford the desired

allylated lactam 2-99. With the vicinal quaternary carbons problem solved, it was

hoped, the total syntheses of the communesins were now within reach.

Scheme 6.2.3. Crawley and Funk’s third-generation synthetic plan

N O

NCO2Et

N NCO2Et

N O

N NCO2Et

N O

DMB

DMB DMB

KOtBu,THF, 0 °C;allyl iodide

90%

2-96

2-98 2-99

N O

DMB

2-97

N O

DMB

2-95

NHDMB

CO2Et

Yb(OTf)3,toluene,CH2Cl2,50 °C, 12 h

50%

NaH, DMF,50 °C, 0.5 h;ClC2Et, 0 °C

50%+

DIPEA,CH2Cl2,rt, 12 h

66%

2-942-93

103

Chapter 7. An Approach to the Synthesis of Communesin F: An Aza-ortho-xylylene Route

7.1. Retrosynthetic analysis of communesin F

We were in a position to complete the total synthesis of communesin F on

the basis of Funk and Crawley’s successful model study. Our retrosynthetic

approach to the synthesis of communesin F (2-8) is illustrated in Scheme 7.1.1.

Thus, the natural product could be prepared from azepine 2-100 by taking

advantage of Qin’s pioneering endgame (cf. Scheme 5.4.4) that featured addition

of the benzazepine to the corresponding cyclic imidate obtained by O-

methylation of the spirolactam. The benzazepine ring would be introduced via

the intramolecular hydroamination of allene 2-101, in turn available from azide

2-102 via a reduction/transamidation sequence. The ethyl azide would be

Scheme 7.1.1. Retrosynthetic analysis for communesin F

N NCO2EtH

•DMBN O N3

N NCO2EtH

•DMBN O

N NCO2Et

•DMBN O

N NHH

NNH

2-8 communesin F

N NCO2EtH

HNO

BocNH

N NCO2EtH

HNODMBHN•

2-100 2-101

2-102 2-103 2-104

104

installed by the alkylation of lactam 2-103, in turn available from the benzoxazin-

2-one 2-104 through Lewis acid catalyzed retrocycloaddition/endo-cycloaddition

as previously observed in the Funk laboratory (2-96à2-98, Scheme 6.2.3).

7.2. Synthesis of an advanced intermediate towards the synthesis of communesin F

In the forward sense, access to the key 4-acyl-3,1-benzoxazin-2-one 2-104

(Scheme 7.1.1) began with the preparation of the protected 4-allenyl tryptamine

2-106 from the known aldehyde 2-10534 (Scheme 7.2.1). Thus, addition of

ethynylmagnesium bromide to aldehyde 2-105 gave propargyl alcohol 2-106. The

alcohol was then acetylated to give the corresponding propargyl acetate. The

propargyl acetate could also be prepared in a single step from aldehyde 2-105 by

trapping the alkoxide generated after addition of ethynylmagnesium bromide

with acetic anhydride. However, the two-step procedure was found to deliver

consistently higher yields. The propargyl acetate was then converted into allene

2-107 by the copper mediated addition of methylmagnesium bromide.35

Displacement of the quaternary ammonium salt, generated by treatment of

amine 2-107 with an excess of MeI, with potassium cyanide was accompanied by

desilylation to provide nitrile 2-108. Methylation of indole 2-108 under standard

conditions was followed by reduction of the nitrile functionality to afford

tryptamine 2-109. Finally, amine 2-109 was protected as the 2,4-dimethoxybenzyl

(DMB) amine employing reductive amination conditions to supply the desired

tryptamine derivative 2-110.

105

Scheme 7.2.1. Preparation of allenyl indole 2-110

We next turned our attention towards the preparation of benzoxazin-2-

one 2-114 (Scheme 7.2.2). The known nitromandelic acid (2-111)36 was

hydrogenated to give the corresponding aniline which was directly treated with

phosgene to give benzoxazinone 2-112. The benzyl ester of acid 2-112 was

converted into the corresponding imide derivative 2-113. After reductive

cleavage of the benzyl ester, the resulting acid was cleanly converted to acid

chloride 2-114.

We could prepare the benzoxazinone derivative 2-104 necessary for the

cycloaddition reaction with allenyl indole 2-110 and benzoxazinone 2-114 in

hand (Scheme 7.2.3). To that end, the tryptophol derivative 2-110 was acylated

with acid chloride 2-114 in the presence of Hunig’s base to provide amide 2-104.

Scheme 7.2.2. Preparation of N-acyl-4-acyl-3,1-benzoxazin-2-one 2-114

NTIPS

• NNN

• NC

•

• NHDMBNH2

CH3CCMgBr,THF, -78 °Cto rt, 1 h

95%

1. Et3N, DMAP, Ac2O, CH2Cl2, rt, 14 h, 84%

2. MeMgBr, CuI, LiBr, THF, 0 °C 91%

1. MeI, PhH, rt, 8 h2. KCN, H2O, DMF, 80 °C, 6 h

60% (2 steps)

1. NaH, 0 °C; MeI, 1 h 98%

2. LiAlH4, Et2O 0 °C, 1 h 78%

O OO

MeOH, rt, 16 h;

NaBH4, rt, 1 h 86%

2-105 2-106 2-107

2-108 2-109 2-110

O OH

NO2 NH

O OH

O NCO2Et

O OBn

O NCO2Et

O Cl

1. H2, Pd/C, K2CO3, MeOH rt, 16 h, 95%

2. COCl2, Na2CO3, H2O, toluene, rt, 12 h, 89%

1. BnBr, DMF, Cs2CO3, 50 °C, 5 h 72%

2. BuLi, THF, -78 °C, 1 h; ClCO2Et, rt, 15 h, 87%

1. H2, Pd/C, EtOAc, rt, 24 h, 95%

2. NaH, PhH, rt; (COCl)2, rt, 5 h, 95%

2-111 2-112 2-113 2-114

106

Scheme 7.2.3. Synthesis of aminal 2-103

Gratifyingly, benzoxazinone 2-104 in the presence of yttrium triflate underwent a

smooth retrocycloaddition/cycloaddition sequence to give the endo cycloadduct

2-103, presumably via aza-ortho-xylyene 2-115, in good yield as a single

diastereomer. A number of other lanthanide triflates [Eu(OTf)3, La(OTf)3,

Sc(OTf)3, Yb(OTf)3] also effected the desired retrocycloaddition/cycloaddition

reaction. However, Y(OTf)3 was found to give the highest product yield and the

cleanest reaction profile. The stereoselectivity of the cycloaddition was confirmed

through 1H NMR studies. Key nOe correlations were observed between the C(8)

alpha proton and the C(6) aminal proton, and the alpha proton and the C(19)

proton (2-103a, Scheme 7.2.3). These nOe correlations are consistent with the endo

adduct. On the other hand, the exo adduct would certainly not exhibit the nOe

correlation observed between the C(8) and C(6) protons.

The next task in the synthesis involved introduction of the remaining

quaternary center (Scheme 7.2.4). We hoped to avoid the step intensive

elaboration of the commonly installed allyl functionality to the desired

N NCO2Et

•DMBN O

N NCO2EtH

•DMBN O

iPr2NEt,CH2Cl2,rt, 16 h

78%N

• NHDMB

2-110 2-104

2-103

NCO2Et

OCl

2-114

EtO2C

HHH•

DMBH

nOe

nOeN

CO2Et

DMB•

2-103a

198

2-115

10 mol% Y(OTf)3,ClCH2CH2Cl,90 °C, 8 h

73%

107

Scheme 7.2.4. Alkylation of lactam 2-103

aminoethyl functionality by alkylating directly with 1-azido-2-iodoethane. After

extensive experimentation, we found that treatment of lactam 2-103 with n-BuLi,

followed by HMPA and 1-azido-2-iodoethane provided the desired alkylation

product 2-102 in moderate yield. With azide 2-102 in hand, the stereochemical

relationship of the alkyl side chains was confirmed through NMR studies. Key

nOe correlations were observed between the C(18) proton and the C(6) aminal

proton, and the C(18) proton and the C(19) proton (2-102a, Scheme 7.2.4). These

results suggest a cis relationship between the alkyl substituents. Furthermore, an

nOe correlation between the C(11) allenyl proton and the C(1) aromatic proton,

and the absence of nOe correlations between the C(18) protons and the C(11) and

C(1) protons supports this conclusion. The alkylation, therefore, proceeds

through alkylation of the enolate generated via the less hindered convex face.

With azide 2-102 in hand, we investigated the preparation of the

transamidation product 2-101. Reduction of the azide 2-102 functionality to the

corresponding amine 2-116 under Staudinger conditions proceeded uneventfully

(Scheme 7.2.5). However, the proposed transamidation reaction failed to deliver

the desired lactam 2-101 under a variety of conditions. The direct preparation of

lactam 2-101 from azide 2-102 under anhydrous Staudinger reaction conditions

similarly failed. The problematic nature of this conversion presumably arises

N NCO2EtH

•DMBN O

N NCO2EtH

•DMBN O N3nBuLi, THF,

-40 °C, 1 h; ICH2CH2N3,HMPA, 1 h

45%

2-103 2-102

EtO2C

HH•

DMB

HN3

nOe

1918

2-102a

108

Scheme 7.2.5. Attempted transamidation reaction

conditions result

200 °C (µν) HCl, MeOH, 65 ºC, 24 h NaOMe, MeOH, 65 ºC, 24 h

NR NR NR

NaN3, Et3N, DMF, 80 ºC, 20 h37 NR KHMDS, THF, 66 ºC, 16 h38 NR KHMDS, toluene, 110 ºC, 24 h NR LiHMDS, HMDS, 100 ºC, 24 h NR AlH3•Net(Me)2, THF, rt, 1 h32 decomposition

from the low reactivity of the lactam carbonyl. The problem does not appear to

be thermodynamic in origin since molecular modeling (PCMODEL, MMX) of

compounds analogous to 2-116 and 2-101 bearing vinyl and methyl substituents

in place of the dimethylallenyl and DMB groups, respectively, suggests that 2-

101 is favored by 2.9 kcal/mol. In fact, Crawley32 inadvertently was able to effect

a relatedtransamidation reaction while attempting to prepare aminal 2-119 via

the corresponding hemiaminal of lactam 2-117 (Scheme 7.2.6). Surprisingly,

Crawley found that treatment of lactam 2-117 with alane–ethyldimethylamine

complex gave spirolactam 2-118.

Scheme 7.2.6. Crawley’s inadvertent transamidation reaction

N NCO2EtH

•DMBN O N3

2-102

N NCO2EtH

•DMBN O NH2

PPh3;H2O

72%

2-116 2-101

N NCO2EtH

HNODMBHN•

conditions

N NCO2EtH

N O NHBn

N NCO2EtH

BnNOHN

2-117 2-118

AlH3•NEt(Me)2,THF, rt, 1 h

80% N NCO2EtH

NBnN

2-119

109

Scheme 7.2.7. Crawley’s transamidation reaction of tosylimide 2-120

We reasoned that replacing the 2,4-dimethoxybenzyl group with an

electron-withdrawing group, such as an alkoxycarbonyl residue to give the

respective imide, should lead to a more efficient transamidation reaction. Indeed,

Weinreb effected a similar transamidation reaction in his communesin F total

synthesis (2-53à2.54, Scheme 5.4.4) and Crawley32 had also effected the

transamidation of tosylimide 2-120 to spirolactam 2-121 (Scheme 7.2.7). To that

end, we attempted to prepare the corresponding Boc-imide 2-123 (Scheme 7.2.8).

Unfortunately, we were unable to remove the DMB group to furnish lactam 2-

122. The N-benzyl and N-cumyl lactam derivatives of 2-102, prepared in

analogous fashion, proved to be equally recalcitrant to deprotection. The

difficulties experienced can likely be attributed to the dimethylallenyl

functionality, as Crawley successfully deprotected (TFA, anisol, 88%) the

compound analogous to 2-102 lacking the dimethylallenyl functionality.

N NCO2EtH

TsN O N3

N NCO2EtH

HNOTsHN

2-120 2-121

PMe3,THF

80%

110

Scheme 7.2.8. Attempted preparation of a more reactive imide

conditions result

TFA, DCE, 90 ºC decomposition TFA, anisol, 80 ºC decomposition TFA, thioanisol, DCE, 90 ºC decomposition TFA, iPr3SH, 110 ºC39 decomposition TFA, iPr3SH, H2O, 100 ºC40 MsOH, DCE, 60 ºC41

decomposition decomposition

HCO2H, H2O, 100 ºC42 NR CAN, H2O, THF, rt43 decomposition CAN, H2O, MeCN, rt44 decomposition K2HPO4, K2S2O8, H2O, MeCN45 NR tBuLi, THF; O2 –78 ºC46 decomposition DDQ, H2O, CHCl347 decomposition Na, liq. NH3, –78 ºC15 decomposition

7.3. Concluding remarks

In conclusion, we have synthesized an advanced intermediate in the

synthesis of communesin F, which possesses five of the seven rings found in the

target, the vicinal quaternary centers, and all the necessary atoms for

construction of the northern aminal and the two remaining rings. Unfortunately,

all attempts to complete the synthesis of communesin F from this intermediate

were met with failure and thus further efforts were abandoned in view of a more

viable approach.

N NCO2EtH

•DMBN O N3

2-102

N NCO2EtH

•HN O N3

2-122

conditions

N NCO2EtH

•BocN O N3

2-123

111

Chapter 8. Studies Towards the Communesins in the Funk Laboratory: An Indol-2-one Route

8.1. Introduction

The existence of transient indol-2-one intermediates, essentially cyclic aza-

ortho-xylylenes, was first proposed by Stoltz,12a and Funk13 in their respective

biosynthetic routes to the communesins and perophoramidine (cf. section 5.3).

Funk and Fuchs’s communication also described their total synthesis of (±)-

perophoramidine via the base-promoted reaction of a 3-bromoindol-2-one

derivative and a tryptamine derivative, which was believed to proceed through

an indol-2-one intermediate (vide infra). Further studies by Funk and Fuchs48

provided evidence in support of the hypothesis that indol-2-ones are generated

in the base-promoted reactions of 3-bromoindol-2-ones. The most compelling

evidence for the generation of indol-2-one intermediates and their reactivity is

summarized briefly below.

Funk and Fuchs found that treatment of 3-bromoindol-2-one 2-124 with

cesium carbonate provided indolinone 2-126 as the major product (Scheme 8.1.1).

The reaction presumably proceeds via intramolecular attack upon the indol-2-

one intermediate 2-125 and subsequent rearomatization. The calculated LUMO

coefficients for the indol-2-one intermediate are consistent with the observed

112

Scheme 8.1.1. Remote addition of a nucleophile to an indol-2-one intermediate

preference for cyclization at the C(6) position. Possible steric interactions with the

methyl substituent, which also enforce the observed regioselectivity, cannot be

ruled out. An alternative mechanistic pathway wherein the triflamide anion adds

directly to the aromatic ring would seem unlikely.

Additionally, treatment of 3-bromoindol-2-one 2-127 with cesium

carbonate provided quinoline 2-130 (Scheme 8.1.2). It would seem difficult to

arrive at a reasonable mechanism that does not invoke an indol-2-one

intermediate. Thus, the indol-2-one intermediate 2-128 undergoes an

intramolecular cycloaddition with the tethered alkyne to give the bridgehead

lactam 2-129, which extrudes carbon monoxide to give quinoline 2-130, via a

retrocheletropic reaction.

Scheme 8.1.2. Cycloaddition reaction of an indol-2-one intermediate

Methods that have been utilized for generating the reactive indol-2-one

intermediates are similar to those developed by Corey,14,25 and Wu30a for

generating aza-ortho-xylylenes (cf. section 6.1). This reactive intermediate is

N HTf

ONNTf

ONH

(-0.27)

(0.28)

(0.46)

(0.35)

45%

2-124 2-125(LUMO coefficients)

2-126

Cs2CO3,CH2Cl2

rt, 24h

NO N

-CO

59%

2-127 2-128 2-129 2-130

Cs2CO3,CH2Cl2

rt, 24h

113

commonly prepared by acid-catalyzed dehydration of 3-hydroxyindol-2-ones,49

acid-catalyzed elimination of 3-amino- and 3-oxoindol-2-ones,50 and base-

induced elimination of HX from 3-chloroindol-2-ones51 and 3-bromoindol-2-

ones.13,48,52

8.2. Prior work in the Funk laboratory

The synthetic utility of an indol-2-one cycloaddition was demonstrated by

Funk and Fuchs in their total synthesis of the cytotoxin (±)-perophoramidine (2-

9).13 Their synthesis utilized a highly stereoselective indol-2-one cycloaddition

reaction to establish the trans-stereochemistry of the aminoethyl groups on the

vicinal quaternary centers present in the natural product. Thus, treatment of

indole 2-131 with 3-bromoindolin-2-one 2-132 gave indolinine 2-134 in excellent

diastereoselectivity (> 20:1, Scheme 8.2.1). In light of the excellent

diastereoselectivity observed, the reaction is thought to proceed through an

asynchronous endo [4+2] cycloaddition pathway with a high degree of bond

formation between the C(3) positions of both the indole and the indol-2-one 2-

133. Indolenine 2-134 was then converted to the corresponding N-Boc imide,

which, upon reduction of the azide functionality, underwent a cascade reaction

involving transamidation and closure of the Boc-anilide anion upon the

indolenine functionality to give aminal 2-135. Treatment of aminal 2-135 with N-

chlorosuccinimide in acetic acid provided the fully halogenated ring system 2-

136, which was converted to lactam 2-137 over several steps. Lactam 2-137 was

converted with Meerwein’s reagent to the corresponding cyclic imidate 2-138.

114

Scheme 8.2.1. Fuchs and Funk’s total synthesis of (±)-perophoramidine

Deprotection of nosylamide 2-138 was accompanied by formation of the northern

amidine via the cyclization of the liberated secondary amine onto the imidate.

Oxidation of the southern aminal to the corresponding amidine with MnO2

furnished perophoramidine (2-9).

Funk and Crawley proposed using an intramolecular indol-2-one

cycloaddition in the synthesis of the related natural product communesin B

based upon the successful application of the indol-2-one cycloaddition in the

total synthesis of perophoramidine, (2-5, Scheme 8.2.2).32 It was proposed that an

indol-2-one intermediate generated from oxindole 2-142 could undergo an endo-

selective intramolecular cycloaddition to yield cycloadduct 2-143, a species that

would ring open to the indolenine/spirooxindole 2-144. Conversion of lactam 2-

OTIPS

NH Br

N N

N3OTIPS

NNH

N3TIPSOBr

NBocH

HNOTIPSO

Br NH

NBocH

HNOTIPSO

NBocH

NNsO

NHH

NNsO

1. NaH, THF; Boc2O, rt 92%

2. PPh3, THF, H2O, 50 °C 89%

NCS, AcOH,THF, rt

86%

1. Cs2CO3, PhSH, DMF, 45 °C, 24 h 70%

2. MnO2, CH2Cl2 65%

5 steps

2-131 2-132

2-135 2-136

2-137 2-138 2-9perophoramidine

2-134 2-133(endo cycloaddition)

Cs2CO3,CH2Cl2,

rt, 48 h89%

Me3OBF4,DIPEA,CH2Cl2,rt, 48 h

68%

115

144 to the corresponding tosylimide and subsequent methanolysis would give

aminal 2-145.

Initial progress towards the cyclization precursor 2-142 proceeded

smoothly with the Mannich reaction of amine 2-139, 3-hydroxyindole (2-140),

and formaldehyde to give alcohol 2-141. However, at this point, it proved

difficult to convert the alcohol functionality to a suitable leaving group for the

base-induced elimination that was required to generate the desired indol-2-one

intermediate.

Scheme 8.2.2. Crawley and Funk’s intramolecular indol-2-one cycloaddition approach towards the communesins

Funk and Crawley turned their attention towards an intermolecular indol-

2-one cycloaddition approach analogous to that used in the successful synthesis

of perophoramidine, having encountered difficulties in their intramolecular

indol-2-one cycloaddition approach towards the communesins.32 As noted

previously (Section 5.1), a fundamental difference between these related natural

HNNH

HCHO,AcOH,H2O

60%

2-139

2-140

2-141

NNH

ONTs

N OO

2-142

2-1452-144

N NHH

NNH

2-5communesin B

9 9

N N

2-143

116

products is the trans-relationship of the aminoethyl C(7) and C(8) substituents

present in perophoramidine versus the cis-relationship of the aminoethyl C(7)

and C(8) substituents found in the communesins. To establish this relationship,

the key indol-2-one cycloaddition must proceed through an exo transition state

rather than the endo transition state that was shown to be favored in the

perophoramidine synthesis. It was conceivable that the C(4) substituent of indole

2-146 might help to disfavor the endo transition state (Scheme 8.2.3). Thus, an exo

cycloaddition between indole 2-146 and indol-2-one 2-148 would give indolenine

2-149, which possesses the required C(7)–C(8) relationship for the syntheses of

the communesins and therefore merited investigation.

Scheme 8.2.3. Crawley and Funk’s planned intermolecular indol-2-one cycloaddition approach towards the communesins

To this end, azide 2-147 was reacted with indole 2-146 in the presence of

cesium carbonate to provide indolenine 2-150 (Scheme 8.2.4). The lactam was

converted to the corresponding Boc-imide, which, upon reduction of the azide,

underwent a ring opening/cyclization cascade to give aminal 2-151. To aid in the

determination of the stereochemical outcome of the cycloaddition reaction,

lactam 2-151 was converted to the conformationally rigid lactone 2-152. With

lactone 2-152 in hand, the stereochemical relationship of the side chains was

confirmed through 1H NMR studies. Unfortunately, the stereochemistry

OTIPS

NON3

OTIPS

+ Cs2CO3

2-146 2-147

NNH

N3TIPSO

2-149 2-148exo cycloaddition

117

established in the indol-2-one cycloaddition was found to be trans, not the cis

relationship necessary for the syntheses of the communesins. Therefore, it can be

concluded that a C(4) substituent on the indole does not alter the stereoselectivity

of the cycloaddition reaction.

Scheme 8.2.4. Intermolecular indol-2-one cycloaddition and determination of the stereochemical outcome

We believed that this methodology could still be utilized in the

preparation of the communesins despite the fact that the cycloaddition failed to

provide the necessary stereochemical relationship for the syntheses of the

communesins. Specifically, we believed that an indol-2-one cycloaddition

strategy wherein the C(8) quaternary center was introduced late in the synthesis,

as had been done in our aza-ortho-xylylene approach, would provide access to

the communesins.

OTIPS

2-146 2-147

NNH

N3TIPSO

2-150

NBocH

HNOTIPSO1. NaH;

Boc2O 70%

2. PPh3, H2O 78%

2-151

NBocH

O NHONs

NBocH

O NHONs

1. NaHMDS; NsCl 85%

2. TBAF, THF 60%

2-152(endo adduct)

2-153(exo adduct)

7 8 7 8

Cs2CO3,CH2Cl2,rt, 24 h

65%

118

Chapter 9. Total Synthesis of (±)-Communesin F via a Cycloaddition with Indol-2-one

9.1. Retrosynthetic analysis of communesin F

The following retrosynthesis of communesin F was devised bearing in

mind the aforementioned limitations of the indol-2-one cycloaddition reaction

(Scheme 9.1.1). Thus, the natural product could be prepared from bridgehead

lactam 2-154 through stereoselective alkylation of the lactam enolate with 1-

azido-2-iodoethane, reduction of the azide to an amino group, reductive

amination with the reactive bridgehead lactam carbonyl, and acetylation. The

bridgehead lactam 2-154 could arise from an intramolecular lactamization of the

azepine derivative of amine 2-155, in turn prepared via an intramolecular allylic

Scheme 9.1.1. Retrosynthetic analysis for communesin F

N NHH

NNH

2-8communesin F

N NBocH

ONH

N NBocH

O O

H2N

NNH

N3Br

2-157

NBoc

N3 O OH

2-156

2-154 2-155

2-159

2-160

N N

2-158

119

substitution reaction with the primary amine. Allylic alcohol 2-155 could be

derived from bromide 2-156 via a Heck reaction. Aminal 2-156 would be formed

via methanolysis of the Boc-imide derivative of lactam 2-157. Indolenine 2-157

should be available by ring opening of the endo cycloadduct 2-158 derived from

the cycloaddition of indole 2-159 and indol-2-one (2-160). Indole 2-159 could in

turn be prepared in a short sequence from 4-bromotryptophol (2-39). It should be

noted that the stereochemical outcome of the key cycloaddition is in fact

inconsequential; the final stereochemistry at C(8) is set during the alkylation of

lactam 2-154 which should, based on prior experience (2.117à2.102, Scheme

8.2.4), occur on the convex face to set the correct stereochemistry at C(8).

However, the stereochemistry of the cycloadduct does bear on the facility of

generating the enolate of lactam 2-154. Inspection of molecular models suggests

that the proton of the C(8) epimer of 2-154 is more accessible.

9.2. Total synthesis of (±)-communesin F

Our retrosynthesis, therefore, hinged upon our ability to generate the

parent indol-2-one 2-160 that was not possible using the conditions (Cs2CO3,

CH2Cl2) reported in the initial Fuchs and Funk investigation. After examining a

number of base/solvent combinations, we discovered that treatment of 3-

bromoindol-2-one (2-161) with 3-methylindole (2-162) in the presence of silver

carbonate (Ag2CO3) in acetonitrile provided the desired indolenine 2-164 after

ring opening of the intermediate bridgehead lactam 2-163 (Scheme 9.2.1). In

contrast, treatment of 3-bromoindol-2-one with 3-methylindole with alternative

120

Scheme 9.2.1. Reaction of 3-bromoindol-2-one with 3-methylindole

base equiv solvent yield (unoptimized)

Cs2CO3 2.5 CH2Cl2 NR Ag2CO3 2.5 CH2Cl2 < 10% DBU52a 3 THF decomposition Ag2CO3 2.5 acetone ~30% Ag2CO3 2.5 CH3CN 47% Cs2CO3 2.5 acetone NR Cs2CO3 2.5 CH3CN NR

base/solvent combinations resulted in no reaction or complex mixtures of

products and/or decomposition of the 3-bromoindol-2-one (2-161).

We embarked on the synthesis of communesin F having established

conditions for the generation of the requisite indol-2-one intermediate. To this

end, indole 2-159, prepared in two steps form 4-bromotryptophol (2-39), was

treated with freshly recrystallized 3-bromoindol-2-one53 (2-161, 1.6 equiv) and

silver carbonate (0.8 equiv) in acetonitrile to give indolenine 2-157 as a single

diastereomer in good yield (Scheme 9.2.2). The relative stereochemistry was

tentatively assigned as shown based upon an endo transition state and was

confirmed by the X-ray crystallographic derived structure of a downstream

product (2-167, vide infra).

Scheme 9.2.2. Preparation of indolenine 2-157

NHO

2-1642-1602-1622-161

base,solvent N

2-163

BrOH 1. I2, PPh3,

imidazole CH3CN, Et2O, rt, 4 h, 88% 2. NaN3, DMF, 50 °C, 5 h 95%

BrN3

BrAg2CO3(0.8 equiv),MeCN, rt16 h,

70% NNH

2-39 2-159 2-161 2-157

121

Drawing from Funk and Fuchs’s synthesis of perophoramidine, we

attempted to convert indolenine 2-157 to the corresponding Boc-imide. However,

the only product isolated under a variety of conditions was the corresponding O-

acylated oxindole. Thus, indolenine 2-157 was converted to tosylimide 2-165 with

sodium hydride and tosyl chloride (Scheme 9.2.3). Treatment of the reaction

mixture with methanol resulted in direct formation of aminal 2-167, the structure

and stereochemistry of which was confirmed by X-ray crystallography (Figure

9.2.1). Presumably the formation of aminal 2-167 occurs via an initial ring

Scheme 9.2.3. Construction of aminal 2-167

Figure 9.2.1. X-ray crystal structure of aminal 2-167

NNH

NTs

N3 O OH

TsCl (1.02 equiv),NaH (2.1 equiv),THF, 0 oC, 0.5 h

then MeOH, rt, 16 h

NNTs

2-157 2-165

2-167

BrN3 O O

2-166

61%

122

opening of imide 2-165 with methoxide and subsequent cyclization of the tosyl-

anilide anion intermediate 2-166 into the indolenine functionality to give the

aminal.

We next turned our attention towards the methylation of the differentially

protected aminal. After an exhaustive screening of traditional methylating

reagents and procedures (NaH, MeI; KOtBu, MeI; Cs2CO3, MeI; HCHO,

NaBH3CN; (HCHO)n, Ti(OiPr)4, NaBH3CN; MeOTf), we discovered that we could

effect the desired transformation with Meerwein’s reagent and cesium carbonate.

Thus, aminal 2-167 was cleanly converted to its N-methyl derivative (Scheme

9.2.4). The resulting azide 2-168 was then reduced in the presence of excess tert-

butyl pyrocarbonate to provide the Boc-carbamate 2-169.

Scheme 9.2.4. Preparation of amide 2-169

The next task in the synthesis involved elaboration of the aryl bromide to

the allylic alcohol and subsequent closure to the benzazepine ring. Thus,

bromide 2-169 was subjected to conditions employed in Qin, and Ma’s respective

syntheses of communesin F (Scheme 9.2.5). In this case, however, the bromide

proved unreactive and none of the desired allylic alcohol 2-170 was observed.

NTs

N3 O OH

NTs

N3 O OH Me3OBF4, Cs2CO3,

CH2Cl2, rt, 24 h 80%

NTs

BocHN O OHBoc2O, PtO2, H2,

EtOAc, rt, 16 h 88%

2-167 2-168 2-169

123

Scheme 9.2.5. Attempted Heck reaction

catalyst ligand base solvent temperature

Pd(OAc)2 P(o-tol)3 Et3N neat 100 ºC (µν) Pd(OAc)2 P(o-tol)3 PMP DMF 140 ºC (µν) Pd(OAc)2 — K2CO3 DMF/H2O 90 ºC

Reasoning that the tosyl amide was in some way attenuating the reactivity

of bromide 2-169 in the Heck reaction, tosyl amide 2-169 was treated with

magnesium in methanol to give aminal 2-171 (Scheme 9.2.6).54 Interestingly, the

addition of ammonium chloride12a accelerated this reaction but also led to a large

amount of the debrominated product.

Scheme 9.2.6. Deprotection of tosylamide 2-169

We again turned our attention towards elaborating the aryl bromide with

aminal 2-171 in hand. To that end, the aminal 2-171 was converted to Boc-aminal

2-172 (Scheme 9.2.7). The resulting bromide 2-172 was then coupled with 2-

methyl-3-buten-1-ol to afford allylic alcohol 2-173 in moderate yield.55

With the allylic alcohol 2-173 in hand, we could investigate the closure to

the benzazepine functionality (Scheme 9.2.8). Attempted cyclization under

conditions utilized in previous syntheses of communesin F by Qin, Weinreb, and

NTs

BocHN O OH

NTs

BocHN O OHOH

2-169 2-170

conditions

BocHN O OH

NTs

BocHN O OH Mg, MeOH,

rt, 18 h

87%

2-169 2-171

124

Scheme 9.2.7. Preparation of bis-Boc allylic alcohol 2-173

Ma afforded none of the desired benzazepine 2-175 and instead led to exclusive

formation of diene 2-174. The diene resulting from dehydration of the starting

allylic alcohol was observed by Qin and Weinreb as substantial byproducts (24-

26%) under acidic conditions in their respective syntheses. Subtle conformational

effects may be at play here. Qin and Weinreb had the spirolactam in place that

favors the planar conformation 2-176 (Figure 9.2.2). The preferred conformation

for our carbamate is cup shaped (2-173), which, in principle, is capable of

cyclization since Ma’s cyclization proceeded through this conformer, albeit,

using a conformationally rigidified lactam (2-60).

Scheme 9.2.8. Attempted benzazepine formation

Concurrent with this work, we discovered that the Heck reaction with the

unprotected aminal 2-171 furnished allylic alcohol 2-177 in a much-improved

yield (93% v. 53%, Scheme 9.2.9). In light of this finding and the difficulties

BocHN O OH

NBoc

BocHN O OH

NBoc

BocHN O OH

2-171 2-172 2-173

Boc2O, KHMDS,THF, rt, 1.25 h

97%

Pd(OAc)2,K2CO3, H2O,DMF, 90 °C, 5h

53%

NBoc

BocHN O OH

NBoc

BocN O O

H+

MsCl, Et3N

2-173

NBoc

BocHN O OH

2-174 2-175not observed

125

Figure 9.2.2. Comparison of cyclization precursor conformations

encountered in forming the benzazepine with the protected aminal, we

proceeded with the unprotected aminal 2-177 with the expectation that

protection of the aminal might be mandated at a later stage.

Subjection of allylic alcohol 2-177 to the aforementioned cyclization

conditions (cf. Scheme 9.2.8) again gave the respective diene as the only product.

However, a thorough review of the literature uncovered a 2010 paper describing

the mercuric triflate catalyzed enantioselective cyclization of anilino sulfonamide

with allylic alcohols.56 In this report, Yamamoto and coworkers disclosed as part

of their optimization studies the asymmetric cyclization of tert-butyl carbamate

2-178 in the presence of mercuric triflate and a chiral auxiliary to give 2-vinyl

indoline 2-179 (Scheme 9.2.10).

Scheme 9.2.9. Preparation of allylic alcohol 2-177

Boc

NHBoc

NBoc

NHBoc

2-1732-602-176R = CO2Me, CO2tBu

BocHN O OH

BocHN O OHPd(OAc)2,

K2CO3, H2O,DMF, 90 °C, 5 h 93%

2-171 2-177

126

Scheme 9.2.10. Allylic amination with mercuric triflate

We were delighted to discover that treatment of allylic alcohol 2-177 with

2.5 mol% mercuric triflate initiated a stereoselective 7-exo-trig cyclization to give

benzazepine 2-180 (Scheme 9.2.11). The structure and stereochemistry of which

was confirmed by X-ray crystallography (Figure 9.2.3). The corresponding diene

resulting from the dehydration of alcohol 2-177 was not observed.

A possible rationale for the excellent stereoselectivity observed in the

mercuric triflate catalyzed cyclization is illustrated in Scheme 9.2.12. The reaction

Scheme 9.2.11. Introduction of the benzazepine ring

Figure 9.2.3. X-ray crystal structure of benzazepine 2-180

NH OHBoc

NBoc

(R)-BINAPHANE (1 mol %),Hg(OTf)2 (1 mol %),mesitylene, rt, 6 h

72% (41% ee)

2-178 2-179

BocHN O OH

BocN O O

HHg(OTf)2,CH2Cl2,rt, 20 h

86%

2-177 2-180

127

is likely initiated by π-complexation,57 or possibly a mercurinium ion, of alkene 2-

177 with mercuric triflate from the face opposite the bulky Boc-carbamate (2-181).

Intramolecular nucleophilic attack by the carbamate nitrogen onto the π-complex

gives the organomercuric intermediate 2-182 and triflic acid. Protonation of the

hydroxyl moiety with the in situ-generated triflic acid and subsequent

demercuration affords the benzazepine 2-180 and regenerates the mercuric

triflate catalyst. The possibility of a triflic acid catalyzed pathway can likely be

discounted in light of the absence of any of the diene resulting from the

dehydration of alcohol 2-177. Finally, it should be noted that the planar

conformations for 2-177 and the corresponding intermediates are more accessible

without the N-Boc-aminal group due to the absence of A1,3 strain.

Scheme 9.2.12. Possible pathway for the mercuric triflate catalyzed cyclization

(TfO)2Hg

OTfOHg

H2O

OTfOHg

TfO

O O

O O OO

HHg(OTf)2

TfOH

Hg(OTf)2

2-177 2-181 2-182

2-183 2-180

TfOH

128

We turned our attention to the construction of the critical bridgehead

lactam with the requisite benzazepine 2-180 in hand. With the anticipated

alkylation of the bridgehead lactam in mind, aminal 2-180 was protected as its

methyl carbamate (Scheme 9.2.13). The Boc-carbamate was then deprotected via

the Ohfune protocol58 to give amine 2-184. Saponification of methyl ester 2-184

with lithium hydroxide provided the corresponding acid. Treatment of the acid

with carbonyldiimidazole (CDI) led directly to the bridgehead lactam 2-185 with

concomitant epimerization of the C(8) proton. The low basicity of imidazole

effectively rules out a pathway wherein the epimer of 2-185 is epimerized. Thus,

the epimerization observed under the reaction conditions might proceed through

a ketene intermediate rather than an acyl imidazole intermediate. Subsequent

protonation of the ketene aminal intermediate from the concave face then yields

the epimerized product. Although epimerization during the course of the

saponification reaction could not be completely ruled out, our inability to effect

C(8) epimerization (NaOMe, MeOH, rt to 65 °C) of methyl ester 2-184 provides

evidence to support our conjecture.

Scheme 9.2.13. Preparation of bridgehead lactam 2-185

BocN O O

NCO2Me

HN O O

N NCO2MeH

ONH

1. (CH3OCO)2O, KHMDS, THF 90%

2. 2,6-lutidine, TMSOTf, CH2Cl2, 97%

2-180 2-184 2-185

1. LiOH, THF, MeOH, H2O, 50 °C, 20 h, 80%

2. CDI, THF, rt, 15 h, 89%

129

Scheme 9.2.14. Attempted alkylation of bridgehead lactam 2-186

base additive solvent electrophile KHMDS — THF ICH2CH2N3 LDA HMPA THF ICH2CH2N3 nBuLi — THF ICH2CH2N3 nBuLi HMPA THF ICH2CH2N3 NaH — DMF ICH2CH2N3 KHMDS — THF ICH2CN LiHMDS — THF ICH2CN LDA — THF ICH2CN

The next task in the synthesis was the installation of the remaining

quaternary center. However, treatment of twisted amide 2-185 with 1-azido-2-

iodoethane under a variety of conditions, including those successfully utilized

during our previous synthesis effort (cf. Scheme 7.2.4), failed to generate

thedesired alkylated product 2-186 (Scheme 9.2.14). Moreover, the conditions

employed (KHMDS; ICH2CN) by Ma and Zuo to alkylate a similar bridgehead

lactam, notably lacking the methoxy carbonyl, in the course of their syntheses of

communesins A and B (cf. 2-63à2-64, Scheme 5.4.7) also failed to provide the

corresponding alkylated lactam.20

We turned to preparing the bridgehead lactam lacking the methoxy

carbonyl moiety drawing upon our previous observation on the influence of

remote substituents on reactivity, and based upon the precedent established by

Ma and Zuo. To this end, Boc-carbamate 2-180 was deprotected to give amine 2-

187. In this case, removal of the Boc protecting group required initial conversion

to the TBS carbamate followed by fluoride treatment. To our dismay, treatment

N NCO2MeH

ONH

N NCO2MeH

ONH

Rconditions

2-185 2-186

130

of ester 2-187 under the previously established conditions (1. LiOH, 2. CDI, 2-

184à2-185, Scheme 9.2.13) failed to yield any of the desired bridgehead lactam 2-

188 (or 2-189) and resulted only in decomposition. However, treatment of ester 2-

187 with trimethylaluminum for 30 minutes at 0 °C cleanly provided the

bridgehead lactam 2-188 (Scheme 9.2.15).59 The stereochemistry of lactam 2-188

was confirmed through 1H NMR studies. While a very small nOe correlation was

observed between the C(8) alpha proton and the C(11) allylic proton, it was the

absence of a strong nOe correlation between the C(8) alpha proton and the C(6)

aminal proton that proved most informative (2-188a, Scheme 9.2.15). This

observation suggests a trans relationship between the C(8) alpha proton and the

C(6) aminal proton as a strong correlation between the C(8) and C(6) protons

would be expected in the cis epimer 2-188. To the best of our knowledge, this

represents the first example of the construction of a twisted, bridged lactam

using this valuable protocol for the preparation of amides. However, the

construction of a pyrimidalized, fused lactam from an amino ester using

Scheme 9.2.15. Preparation of bridgehead lactam 2-188

BocN O O

HN O O

N NHH

ONH

2-180 2-187 2-188

TBSOTf, lutidine, CH2Cl2, rt,3 h;

KF, MeOH,rt, 1 h, 94%

AlMe3, CH2Cl2,0 °C, 1 h

87%

2-188a

nOe

131

triisobutylaluminum as reported by Woodward60 as part of his classic synthesis

of cephalosporin C served as useful precedent.

We again set upon installing the remaining quaternary center with

bridgehead lactam 2-188 in hand. Attempts to alkylate the bridgehead lactam

with 1-azido-2-iodoethane under the conditions previously cited (Scheme 9.2.14)

proved unsuccessful. However, treatment of the bridgehead lactam 2-188 with

potassium hexamethyldisilazide (KHMDS) followed by iodoacetonitrile

provided nitrile 2-189 as a single diastereomer. The stereochemistry of the

alkylation reaction was confirmed through 1H NMR studies. Key nOe

correlations were observed between the C(18) proton and the C(6) aminal proton,

and between the C(18) proton and the C(19) proton (2-189a, Scheme 9.2.16).

These results confirm the desired cis relationship of the eventual aminoethyl

groups.

Scheme 9.2.16. Alkylation of bridgehead lactam 2-188

With nitrile 2-189 in hand, we planned to continue with the endgame

employed by Ma and Zuo20 in their syntheses of communesins A and B for the

preparation of the northern aminal (cf. 2-64à2-66, Scheme 5.4.7). Thus, nitrile 2-

189 was reduced with LiAlH4 to give lactol 2-190 (Scheme 9.2.17). We were

surprised, however, to discover that subjecting lactol 2-190 to the reported

reductive amination/cyclization conditions (NH4OAc, NaBH(OAc)3, MeOH, rt,

N NHH

ONH

N NHH

ONH

2-188 2-189

HHCN

nOe

2-189a

19 18

KHMDS, THF,-78 oC, 0.5 h;ICH2CN, THF,-78 oC, 0.5 h

77%

132

Scheme 9.2.17. Synthesis of 1”-deoxocommunesin F

48 h) cleanly provided 1”-deoxocommunesin F (2-191), not the expected N-H

aminal 2-192.

While surprising, this result is not without precedent. In fact, it was the

observation that reduction of indoles with NaBH4–AcOH gave rise to N-ethyl

indolines (eq. 1, Scheme 9.2.18)61 that led to the discovery of sodium

triacetoxyborohydride (eq. 2, Scheme 9.2.18).62 Abdel-Magid and coworkers have

extended the utility of sodium triacetoxyborohydride as an outstanding reducing

reagent in reductive amination reactions.63 It has been observed that in the case of

many slow reductive amination reactions (>24 h) performed utilizing sodium

triacetoxyborohydride, the formation of up to 5% N-ethyl derivatives as side

products is not uncommon.63 Whereas the pathway leading to N-ethylation is not

well defined, it does not appear to proceed through reduction of an acetamide.

Rather the triacetoxyborohydride in the presence of excess acetic acid is believed

to undergo a self-reduction to generate acetaldehyde, which then participates in

a typical reductive amination sequence with the amine.61,64

N NHH

ONH

2-189

N NHH

NNH

2-1911"-deoxocommunesin F

HH 1"

1. LiAlH4, THF, 60 °C, 1.5 h

N NHH

ONH

2-190

2. NH4OAc, NaBH(OAc)3, MeOH, rt, 48 h

70% (2 steps)

N NHH

HNN

2-192not observed

133

Scheme 9.2.18. N-Ethylation of indolines with acyloxyborohydrides

A possible reaction pathway for the formation of 1”-deoxocommunesin F (2-191)

from lactol 2-190 is outlined in Scheme 9.2.19. Thus, aldehyde 2-193 undergoes

an initial reductive amination reaction with ammonia to afford the primary

amine 2-194 that could undergo a second reductive amination reaction with in

situ generated acetaldehyde to give N-ethylamine 2-195. Collapse of the

hemiaminal 2-195 is followed by condensation of the N-ethylamine side chain

with the newly formed aldehyde 2-196 to give hemiaminal 2-197. Dehydration of

hemiaminal 2-197 generates an iminium ion intermediate 2-198 that is attacked

by the benzazepine nitrogen to give 1”-deoxocommunesin F. Two key alternative

pathways exist which warrant consideration: (1) the dehydration of hemiaminal

2-194 or 2-195 to give a bridgehead iminium ion which then undergoes

cyclization to afford an aminal, and (2) the late-stage reductive amination of

aminal 2-192 (Scheme 9.2.17) to install the ethyl group. The poor orbital overlap

and the highly strained nature of the bridgehead iminium ion formed by a direct

dehydration of hemiaminal 2-194 or 2-195 makes this pathway seem highly

unlikely. Lastly, the relative rates for the reductive amination of the primary

amine with acetaldehyde (fast) versus the ring opening/ring closing reaction

sequence to form the aminal (slow) should favor a pathway featuring an early-

stage reductive amination.

NEt

NaBH4,AcOH

NaBH4 + 3AcOH NaBH(OAc)3 + 3H2

(eq. 1)

(eq. 2)

134

Scheme 9.2.19. A proposed synthetic pathway to 1”-deoxocommunesin F

After extensive screening of mild reducing reagents, amine sources, and a

variety of reaction conditions—pH, temperature, and reaction time—we were

able to establish conditions that permitted the conversion of nitrile 2-189 to

communesin F (2-8, Scheme 9.2.20). Thus, nitrile 2-189 was reduced to give the

lactol derivative, which was treated with ammonium chloride in a saturated

methanolic ammonia solution for five hours at room temperature prior to

treatment with sodium cyanoborohydride for 72 hours. These conditions

preclude the generation of any acetaldehyde. Finally, the resulting crude aminal

was directly acetylated to give (±)-communesin F (2-8) whose spectroscopic

properties were identical to those previously reported.5

N NHH

NNH

2-1911"-deoxocommunesin F

HH 1"

N NHH

ONH

OHNH4OAc,NaBH(OAc)3

2-190

N NHH

NH2NH OH

N NHH

NHNH OH

NaBH(OAc)3

2-194

2-195

N NHH

ONH OH

2-193

N NHH

NHHN

H O

2-196

N NHH

NHN

H HO

N NHH

NNH H

2-1982-197

-H2O

135

Scheme 9.2.20. Completion of the total synthesis of (±)-communesin F

9.3. Concluding remarks

In conclusion, we identified conditions where indol-2-one itself can be

generated and trapped in Diels–Alder cycloadditions. We have successfully

applied this methodology in a concise total synthesis of the marine natural

product (±)-communesin F. The synthesis, which was completed in 15 linear

steps from 4-bromotryptophol (2-39) in an overall yield of 6.7%, is outlined

below (Scheme 9.3.1). To date this represents the shortest, highest yielding total

synthesis of (±)-communesin F (cf. Section 5.4). Highlights of this synthesis

include: (1) the stereoselective cycloaddition with the parent indol-2-one, (2) an

intramolecular mercuric triflate catalyzed cyclization of a carbamate with an

allylic alcohol, (3) the first preparation of a twisted bridgehead lactam from an

amino ester using trimethylaluminum and (4) the nuances (frustrations) of

N NHH

ONH

CN LiAlH4, THF,60 oC, 1.5 h

N NHH

NNH

2-189

2-8communesin F

N NHH

ONH

2-190

N NHH

HNN

2-192

NH3, NH4Cl, MeOH, rt, 1 h;NaBH3CN, 72 h

Ac2O, Et3N, DMAP, CH2Cl2rt, 0.5 h

51% (3 steps)

136

natural product synthesis that are frequently encountered, in this case the

unexpected preparation of 1”-deoxocommunesin F.

Scheme 9.3.1. Total synthesis of (±)-communesin F

BrI

BrOH

I2, PPh3, imid.,CH3CN, Et2O,rt, 4 h

88% NH

BrN3

NaN3, DMF,50 oC, 5 h

95% NH

Ag2CO3,MeCN, rt16 h,

70%

NTs

N3 O OH

TsCl, NaH,THF, 0 oC0.5 h;MeOH, rt16 h, 61% N

TsN

N3 O OHMe3OBF4, Cs2CO3,

CH2Cl2, rt, 24 h, 80%

NTs

BocHN O OHBoc2O, PtO2, H2,

EtOAc, rt, 16 h,

88%NH

BocHN O OHMg, MeOH,

rt, 18 h,

87%

BocHN O OHPd(OAc)2,

K2CO3, H2O,DMF, 90 oC,5 h, 93%

BocN O O

HHg(OTf)2,CH2Cl2, rt, 20 h,

86%NH

HN O O

HTBSOTf, lutidine, CH2Cl2, rt,3 h;

KF, MeOH,rt, 1 h, 94%

AlMe3, CH2Cl2,0 oC, 1 h,

87% N NHH

ONH

KHMDS, THF,-78 oC, 0.5 h;ICH2CN, THF,-78 oC, 0.5 h

77%N N

ONH

CN LiAlH4, THF,60 oC, 1.5 h

N NHH

NNH

2-394-bromotryptophol

2-199 2-159 2-161

2-157 2-167 2-168

2-169 2-171 2-177

2-180 2-187 2-188

2-189

2-8communesin F

N NHH

ONH

2-190

N NHH

HNN

2-192

NH3, NH4Cl, MeOH, rt, 1 h;NaBH3CN, 72 h

Ac2O, Et3N, DMAP, CH2Cl2rt, 0.5 h

51% (3 steps)

137

Chapter 10. Experimental

10.1. Materials and Methods