Asymmetric Synthesis of α-Substituted Allyl Boranes and Their ...

Asymmetric Synthesis of α-Substituted Allyl Boranes and TheirApplication in the Synthesis of Iso-agatharesinol

Yuang Yu Fang and Varinder K. Aggarwal

University of Bristol, UK

Angew. Chem. Int. Ed. 2007, 46, 359-362

Stephan ElznerJanuary 06, 2007

Stephan Elzner @ Wipf Group 1 1/14/2007

Allyl boron reagents

• Important tool in the synthesis of natural products• Allyl addition of organoboron reagents to carbonyl compounds are highly

diastereoselective

• A number of reagents for enatioselective allylation were developed with chiral ligands atthe boron center

• Few protocols were developed in which the chiral center is a structural component of theallylic unit

Introduction

R1

R2

BLn*

R H

O

O

BL2*H

R1

R2

R

R

OH

R1

R2

R2L2B

R1

V. Aggarwal, G. Y. Feng, A. T. Schmidt, J. Am. Chem. Soc. 2005, 127, 1642-1643Y. Yamamoto, N. Asao, Chem. Rev. 1993, 93, 2207-2293

B

2

(lIpc)2B

BO

O CO2iPr

CO2iPr


Allylboration of Imines

T. R. Wu, J. M. Chong, J. Am. Chem. Soc. 2006, 128, 9646-9647

Proposed transition state

O

OB

CF3

CF3

CF3

CF3

NR2

R1

toluene

-78°C to rt

NHR2

R1

- Enantioselective allylation of cyclic imines


Application: Synthesis of Alkaloids

• Crispine A Alkaloid with antitumor activity

• Coniine Neurotoxin found in poison hemlock

• ent-Corynantheidol

T. R. Wu, J. M. Chong, J. Am. Chem. Soc. 2006, 128, 9646-9647


Examples for Enantioselective Allylboration in total synthesis

- (+)-13-Deoxytedanolide

A. B. Smith, C. M. Adams, S. A. Lodise, A. P. Degnan, A. B. Smith, J. Am. Chem. Soc. 2003, 125, 350-351

- (+)-Brasilenyne

S. E. Denmark, S.-M. Yang, J. Am. Chem. Soc. 2004, 126, 12432-12440


1,3-Disubstituted Allylboronate

J. Pietruska, N. Schöne, Chem. Eur. J. 2004, 5011-5019

Aldol addition to chiral α-substituted allyl boronate compounds

R

OH

BO

OR

CO2Et

B*

MeC(OEt)3cat. EtCO2H

135°C

Johnson rearrangement R=Me : 95% Ph : 65%

R=Me : 78% Ph : 82%

PhCHO

CH2Cl2, rt

OMe

OMe

PhPh

PhPh

single diastereomer

R

O

B*

OEtCO2Et

Ph

Ph

OH

> 98% ee

R

OH

BO

OPh

Ph

Ph

Ph MeC(OEt)3cat. EtCO2H

135°C, 48%

RCO2Et

BO O

PhPhPh

Ph

PhCHO

CH2Cl2, rtCO2Et

Ph

Ph

OH

84%, 91%ee


E. M. Flamme, W. R. Roush, J. Am. Chem. Soc. 2002, 124, 13644-13645J. D. Hicks, E. M. Flamme, W. R. Roush, Roush, Org. Lett. 2005, 7, 5509-5512

- One-pot double allylboration with a 1,3-bifunctionalized boron reagent for the diastereo- andenantioselective synthesis of anti-1,5-diols

- Application: Synthesis of C(43)-C(67) fragment of Amphidinol 3

α-substituted allylboronate

α-Substituted Allylboronates

O

O

CHOTBDPSO

B

O

O

Ph

Ph

PhPh

B(lIpc)2

CH2Cl2, -78°C

O

O

TBDPSO

OB(lIpc)2

BO O

PhPhPh

Ph

O

O

TBDPSO

OH

OH

OO

CH2Cl2, rt

70 - 80%, dr 9:1

OO

O

H 43

50

B

O

O

Ph

Ph

PhPh

B(dIpc)2CH2Cl2, -78°C

R1

OB(dIpc)2

BO O

PhPhPh

Ph

R1CHO

(0.82 equiv.) OH R2

OH

R1

R1, R2 = Ph, Ph(CH2)2, (CH3)2CH, C6H11

72 - 95%, 91 - 95%ee

R2CHO

(1.7 eqiv.)

rt, 24h


Aggarwal: Preliminary work

- Enantioselective synthesis of secondary alcohols and amines using chiral organoboranes generated from sulfonium ylides

V. Aggarwal, G. Y. Feng, A. T. Schmidt, J. Am. Chem. Soc. 2005, 127, 1642-1643

Mechanism

S+

O

BF4-

R1

BR31.2 eq. LiHMDS

dioxane, THF, 5°CR

R1

BR2R

R1

OH

H2O2, NaOH

R

R1

NH2

70 -87%, 95- 96%ee

NH2OSO3H

68-72%, 96-97%ee

R1 = Et, nBu, Ph

R = H, Me, Cl

S+

OR1

-


Main article: Synthesis and application of α-substituted allyl boranes

V. Aggarwal et al, Angew. Chem. Int. Ed. 2001, 40, 1430-1433

V. Aggarwal, G. Y. Feng, A. T. Schmidt, Angew. Chem. Int. Ed. 2007, 46, 359-362

- Aldol addition to α-substituted allyl boranes

OH

Ph

HO

• Excellent enantio- and diastereoselectivity• High Z selectivity• Chiral sulfide recovered (>90%)• Side reaction (< 20%):

- Synthesis of the sulfonium salt

SO2ClO

SO

1) PPh3 dioxane/H2O reflux, 92%

2) PhCOCH2Cl K2CO3, 82%

SO

h!

Ph

O

S

O76%

S

O

endo/exo 20:1

1) PdS/C, H2

2) recryst. 84%

S+

O

Ph1) LiHMDS, -78°C THF/CH2Cl2 30 min

2)

B

R-100°C

BF4-

B

Ph R

PhCHO

-100°CPh R

Ph

OH

9

BnBrNaBF4 (aq.)

CH2Cl2

S+

O

Ph

BF4-

48% overall


Mechanism

Aggarwal, Angew. Chem. Int. Ed. 2007, 119, 363-366


Expansion of Methodology

V. Aggarwal, G. Y. Feng, A. T. Schmidt, Angew. Chem. Int. Ed. 2007, 46, 359-362

1,3 borotropic rearrangement:

- Other enatiomer acessible via borane-isomerisation/aldol sequence

S+

O

Ph1) LiHMDS, -78°C THF/CH2Cl2 30 min

2)

B

R-100°C

BF4-

B

RPhCHO

-78°CPhR

Ph

OH

15

Ph

B

RPh

-100°C to 0°C


Application: Total synthesis and structural confirmation of(+)-iso-agatharesinol

V. Aggarwal, G. Y. Feng, A. T. Schmidt, Angew. Chem. Int. Ed. 2007, 46, 359-362 C.-X. Yang, S.-S.-Huang, X.-P. Jang, Z.-J. jia, Planta Med. 2004, 70, 446-451

Confirmation of relative stereochemistry (racemic)

1) LiHMDS, -78°C THF/CH2Cl2 30 min

2)

B

-100°C

OTBS

3) TBSOCH2CHO

OTBS

OH

OTBSOPiv

72%, > 99%ee

1) LiBH4

2) TBAF

OH

OH

OHOH

S+

O

BF4-

OPiv

81%

→ matched NMR data

S+

OPiv

BF4- 1) LiHMDS, -78°C

THF/CH2Cl2 30 min

2)

B

-100°C

OTBS

3) TBSOCH2CHO

OTBS

OH

OTBSOPiv

78%

1) LiBH4

2) TBAF

OH

OH

OHOH

OH

OH

OHOH

1) DEAD, PPh3 p-NO2C6H4CO2H

2) LiBH43) TBAF

Asymmetric total synthesis

(+)-Iso-agatharesinol: Nor-lignane, isolated from asparagus gobicus (2004)


Conclusion

• A stereocontrolled synthesis of α-substituted allyl boranes wasdeveloped

• Subsequent aldol reaction yielded Z-configured homoallylicalcohols in excellent enantio- and stereoselectivity

• The methodology was expanded via 1,3-borotropicrearrangement and subsequent aldol reaction

• Applied to the first total synthesis of (+)-iso-agatharesinol


Asymmetric Synthesis of α-Substituted Allyl Boranes and Their ...

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