Decarboxylation of allylic β - Harvard...

M.C. White, Chem 253 ππππ-Allyl chemistry -224- Week of November 8, 2004

Decarboxylation of allylic β-ketoestersIndicate the mechanism of the following transformation:

O

O OPd2dba3 2.5 mol%PPh3 10-20 mol%

THF, rt

O

Pd0Ln O

O O

PdIILn

O

O

O

PdIILn

O

O

Pd0Ln

O

Tsuji Acc. Chem. Res. 1987 (20) 140.

CO2


Allylic carbonatesPh O

O

OMe

Pd2dba3 2.5 mol%PPh3 10-20 mol%

THF, rt

note: no external base is needed

Ph

LnPdII

O

OMe

O

CO2

Ph

LnPdII

OMe

+

O

CO2Me

PPh3 Ph

LnPdII

PPh3

OMe

H

Ph

CO2Me

O90%

O

H

CO2MeMe

O

MeO2CMe

Chemoselectivity: allylic carbonates are more reactive towards Pd mediated oxidative addition than allylic acetates.

AcOOCO2Me

+

O

CO2Me

H

Pd2dba3 2.5 mol%PPh3 10-20 mol%

THF, rt

AcO

O

CO2Me

77%

no product corresponding to attack at the allylic acetate was observed.

Olefin geometry: anti/syn isomerization of the π-allyl intermediate occurs at a faster rate than nucleophilic attack.

OCO2Meneryl acetate (Z)

+

O

CO2MePd2dba3 2.5 mol%PPh3 10-20 mol%

THF, rt

O

CO2Me54%, (52:48 E/Z)

Tsuji TL 1982 (23) 4809.review: Tsuji Acc. Chem. Res. 1987 (20) 140.

M.C. White Chem 253 ππππ-Allyl chemistry -226- Week of November 8, 2004

Difunctional allylic alkylating agents

R

OCO2CH3

OCO2CH3

Pd2dba3/dppe 5 mol%

THF, 50oC

CO2Me

CO2MeNa (CH3CN)2W(CO)4 25 mol%

bpy 25 mol%, THF, 50-80oC

R

CO2MeCO2Me

R

CO2MeCO2Me

R

OCO2CH3 CO2Me

CO2Me

R OCO2CH3

MeO2C CO2Me

A

B

R

OCO2CH3 CO2Me

CO2Me

A

R

CO2Me

CO2Me

PdIILn

R

CO2MeCO2Me

R OCO2CH3

MeO2C CO2Me

B

R

MeO2C CO2Me

PdIILn

R

CO2MeCO2Me

Rationalize the formation of different products. In each case indicate the intermediates.

Trost JACS 1987 (109) 2176.


π-Trimethylenemethane cyclizations

CO2CH3

SiMe3

OAc

(Ph3P)4PdDPPE

THF

+

CO2CH3

51 % yield

SiMe3

OAc

PPh2

Pd(0)

Ph2P

SiMe3

PPh2

PdPh2P

OAc

PPh2

PdPh2P

C6H11

O

OCH3

PPh2

PdPh2P

O

OCH3

C6H11

C6H11

CO2CH3

PPh2

PdPh2P

C6H11 CO2CH3

+ PPh2

PdPh2P

palladium π-trimethylenemethanecomplex

The geometry of (E)-olefins is retained in the products, suggesting that the mechanism is concerted ([3+2]) OR that the mechanism is stepwise but collapse of the intermediate enolate is faster than σ-bond rotation. (Z)-olefins give mixtures of syn and anti products; this argues that the mechanism for π-trimethylenemethane cyclizations is in fact stepwise.

Trost ACIEE 1986 (25) 1.

Silicon-carbonbond weakenedby the proximalpositive charge


CyclizationsCarbon and oxygen spirocycles:

OAc

CO2Et

CO2Et

CO2EtCO2Et

OAc

O

CO2Me

O

CO2Me

O

CO2Me

Ln(OAc)PdII

Pd(PPh3)4 7 mol%

NaH, THF , 65oC

66%

note that attack at the least sterically hinderedposition results in abridgehead olefin:

Pd(PPh3)4 7 mol%

NaH, THF , 65oC

>99%Godleski JOC 1982 (47) 383.

O

OTESTESO

TMSO O

Ot-Bu

O

O

OMe

O

OTMS

O

O-tBu

TESOOTES

19-membered ring formation

Pd2dba3 10 mol%

THF, 40oC, 12h

80% O

O O

H

H

CH3

CH3H

H

OH

H3C

HO

CH3

H

H

H

H

(+)-FR182877

Macrocyclizations occur readily. Regioselectivity favors substitution at the least sterically hindered carbon, particularly when bulky nucleophiles are used.

Sorenson JACS 2002 (124) 4552.

cis-fused decalin systems:

AcO O

CO2R

Pd2dba3/PPh3 cat

NaH, THF, 65oC

CO2RRO2CH

H

EE

O

E

>98% ciscomplements the Robinson annulation approach which generally leads totrans-fused rings.

AcO

O

CO2R

CO2RRO2C

= E

Pd2dba3/PPh3 cat

NaH, THF, 65oCO

E

EEH

H

75%, >98% cis

Backvall TL 1989 (30) 617.review on cyclizations: Trost ACIEE 1989 (28) 1173.


Asymmetric functionalization via deracemization

RR

X

*LnPd0

enantiotopic ends of ameso π-allyl intermediate. a RR

Nu

bRR

Nu

Deracemization

RPd*Ln

R

Nua

b

RPd*Ln

syn/anti

R

Nua

note that syn/anti isomerization results in an errosion in ee's.

Solutions:

N

O

t-Bu

Ph2P

Pd

The stronger π-acceptor properties of phosphines vs.imines results in differential trans-effects between thetwo coordinating functionalities. The strong P-Pd bond translates into a long (weaker) Pd-C bond trans to it.This is thought to increase the ionic nature of the bondresulting in more carbonium character at thecorresponding carbon and preferential attack by thenucleophile at that site.

R R

OAc

R R

MeO2C CO2Me

[ClPd(η3-allyl)]2 1 mol%

2 (2.5 mol%), DMF, 65oC

CO2Me

CO2MeNa

2

alkyl substituted 1,3 allyl's give high ee's:

R = Me, 50% yield, 97% ee i-Pr, 96% yield, 88% ee Ph, 99% yield, 99% ee

Pfaltz's electronic disymmetry. Pfaltz ACIEE 1993 (32) 566.

Challenge: creating an effective asymmetric environment outside the coordination sphere of the metal opposite to the chiral ligand.

Hayashi's nucleophile directing tether: Hayashi TL 1986 (27) 191.

FePPh2

PPh2

Pd

NO

Nu

H

The hydroxyl group on theligand tether is thought tointeract attractively with theincoming nucleophile viaH-bonding and direct ittowards attack at one end of the π-allyl group.

Ar Ar

OAc

O

H

1

[ClPd(η3-allyl)]2 0.5mol%

1 (1 mol%), THF

CO2Me

CO2MeNa

Ar Ar

MeO2C CO2Me

Ar = Ph, 97% yield, 90% ee 1-Np, 40% yield, 92% ee

The 1,3-diphenylallyl systemfavors the syn,syn isomer.Syn-anti isomerizations often lead to erosions in ee's foracyclic substrates.


Asymmetric functionalization via deracemizationChallenge: creating an effective asymmetric enviroment outside the coordination sphere of the metal opposite to the chiral ligand.Solutions:

NH HN

OO

PPh2Ph2P

chiral backbone

linkerlinker

P P

Pd

The primary chirality of the stereogeniccenters of the backbone gets translated via thelinker units into a secondary chirality at thephosphines that are closest to the Pd-allyl unit.The conformational bias for edge-facestacking of the phosphine phenyl groupsenforces chiral "propellers" that reach outtowards the allyl unit and sterically block thetrajectory of nucleophilic attack from one side. The steric bulk of the diphenylphosphine unitsis also thought to retard the rate of syn/antiisomerization.

Cat+ Nu-

open quadrant

3

Trost Acc. Chem. Res. 1996 (29) 355.

Trost JACS 1994 (116) 4089.

Cyclic systems:Because the rxn is performed in nonpolar media, the Nu existsas an ion pair. Trost has found that the molecular recognitionevent depends more on the nature of the cation than of the anion that ultimately attcks the π-allyl unit. The larger the cation, thehigher the ee.

OAc

CO2Me

CO2MeCat[ClPd(η3-allyl)]2 2.5mol%

3 (7.5 mol%), THFCO2Me

CO2Me

+Cat %Yield % ee

Na+

N(CH3)4+

N(n-C6H13)4+

N(n-C6H13)4+

in CH2Cl2

K+

Cs+

Cs+ in CH2Cl2

77%

88%

92%

81%

90%

76%

98%

38%

41%

68%

98%

51%

76%

>99%

All the ammonium cations were added as chloride salts.

CH2Cl2 results in aneven tighter ion pair.

CO2Me

CO2Me

86% yield96% ee

CO2Me

CO2Me

99% yield93% ee

N

O

O

87% yield94% ee

largermetal ion

bulkierammonium

ion

Results under optimal ammonium salt conditions:


Asymmetric functionalization: regio-and stereoselective amination

Me OCO2R

+

Ph NH2

FePPh2

PPh2

N OH

OH6 mol%

Pd2(dba)3 1.5 mol%, THF, 0oC

Me

HN Ph

MeHN Ph

+

87% yield97: 3 (branched: linear)

84% ee

(91:9, E/Z) note: result indicates thatsyn/anti isomerization is slowrelative to nucleophilic attack.

MePd*Ln

MePd*LnH

H

MeH*LnPd

H

Me

Ln*Pd

Me

OCO2Me

+

50%

Me

OCO2Me

50%

conditionsas above

Me

HN Ph

82%

Me

HN Ph

18%

π-σ-π isomerization is fastrelative to nucleophilic attack

Hayashi TL 1990 (31) 1746.

achiral substrate

racemic substrate

R X

or

R

X

*LnPd0

RPd*Ln

π−σ−π (aka η3-η1-η3)isomerization

R

Nu

R

Nu

diastereomeric

Nu

Nu

+ R Nu

Both a regio- and stereoselectivity challenge

R

Ln*Pd

M.C. White/M.W. Kanan Chem 253 ππππ-Allyl chemistry -232- Week of November 8, 2004

Dynamic kinetic asymmetric transformation of 5-Acyloxy-2-(5H)-furanone

Trost JACS 1999 (121) 3543.

OOEtO

O

H3CO OH

IOBocO

OO

OEtO

O

H3CO O

I

OH

O

NH

NH PPh2

PPh2

O

O

+ 1.2 eq.

racemic

2.5 % Pd2dba3, 7.5% 1

30% Bu4NCl, CH2Cl2

1

Pd

OBocOO

Pd0P

P

OO

OOPd

P P

OO

Pd

PP

Cl

PP

OOEtO

O

H3CO O-

I

OOEtO

O

H3CO O

I

OH

O

Pd0P

P

+

+

+ Cl-

- Cl-

+

The addition of Cl- ion is thought to accelerate the equilibration between the two -allyldiastereomers by promoting formation of an η1

intermediate. Since the kinetic discriminationbetween the two reactive diastereomers is high,increasing their rate of equilibration increases theoverall selectivity of the reaction.

racemic

OBocOO

OO

Pd

*

*

*

P P

*

via

OO

Pd

P P

*

via

OOEtO

O

H3CO O

I

OH

O

OOEtO

O

H3CO O

O

H

H

O O

O

H3CO O

O

O

The ee of the product could not be directly determined, however the ee of the product of the subsequent Heck cyclization was > 95%.

reductive Heck

> 95% ee Aflatoxin B

H+

M.C. White/M.W. Kanan Chem 253 ππππ-Allyl chemistry -233- Week of November 8, 2004

Intramolecular asymmetric allylic alkylation in the synthesis of [2.2.2] bicycles

Trost OL 2002 4 3427-3430.

N

HO

CO2Et

OCO2CH3

Pd0P

P

N

CO2EtO

H

N

HO

CO2Et

PdP P

PdP

P

N

OCO2Et

H

Pd0P

P

N

CO2EtH

PdP

P

*+

*

+

OAdecarboxylation

*

*+

*

O

N

CO2Et

Pd

PP

*

O

N

CO2Et

Pd

P

P

*

O

The ligand framework provides moderate diastereocontrol withexcellent enantiocontrol for the major diastereomer in thiscyclization, which can proceed through any of four transition states.

-OMe

CO2

4 possible transition states for cyclization

MeOH

pseudo-enantiomeric

2

N

OCO2Et

H

3

N

HO

CO2Et

OCO2CH3

N

OCO2Et

H

N

OCO2Et

H

+

Pd2dba3 2 mol %

2 3

84 % yield; 2 : 3 = 4.6 : 1; ee 2 = 99%

CH2Cl2, rt

5 mol %Pd0

P

P*

1

Pd0P

P* = HNNH

PPh2 Ph2P

O O


Asymmetric functionalization: regio-and stereoselective alkylation

Ph OAc

CO2Me

CO2MeNa

[Ir(COD)Cl]2 4 mol%, THF

P(C6H4-p-CF3)2

O

N

i-Pr4 mol%

Ph

MeO2C CO2Me

Ph+

CO2Me

CO2Me

99% yield 95:5 (branched:linear)

91% ee

Stereochemical model:

Ph3P

IrIIIPh3P

CO

Cl

NH2 OTf

crystallographically characterized IrIII π-allyl complex

IrI

Ar2P S

ClO

N

i-Pr

Ph OAc

IrIII

Ar2P

ON

i-PrPh

Cl

S

OAc

Ph

MeO2C CO2Me

Nu

The benzylic carbon preferentially orients trans tothe diarylphosphine. Rationale: sterics and/orbetter stablization of the carbonium ion characterresulting from the trans influence of PAr2. The Ph substituent is also oriented trans to the oxazolinei-Pr substituent. Rationale: sterics.

Helmchen TL 1997 (38) 8025.

Chen OM 1997 (16) 1159.


Asymmetric functionalization: regio-and stereoselective alkylation/amination

O

OP N

[Ir(COD)Cl]2 2 mol%, THF

4 mol%

MeO2C

MeO2CNa

OAc

Ph1

Ph

OAc

2

Ph

CO2MeMeO2C

from 1: 54% yield 95:5 (branched: linear) 43% eefrom 2: 92% yield 98:2 (branched:linear) 69% ee

Alkylated of (R)-2 (>99 % ee) gives product of 75% ee. Helmchen Chem. Comm. 1999 741.

Hartwig explores amine nucleophiles: Hartwig JACS 2002 (124) ASAP.

Ph OCO2Me

O

OP N

[Ir(COD)Cl]2 1 mol%, THF, 50oC

2 mol%

Ph

Ph NH2

HN Ph


94% ee

(R)

limitations: use of the liganddiastereomer (Ra,RC,RC)-3 gives the opposite enantiomer in diminishedyield (66%) and ee (75%).

Ph

Ph(Ra,RC,RC)-3

Hartwig notes that thebranched allylic carbonate gives aminated productswith low ee's.

Ph

N


96% ee

Ph

N


97% ee

O

* *Ph

HNhex


96% ee

O

HN Ph

58% yield 96:2:2 (branched:linear:bisalkylated)

97% ee

HN Ph

* *

58% yield 96:2:2 (branched:linear:bisalkylated)

97% ee

Precedent for using phosphoramidite ligands to effect asymmetric Ir mediated allylic substitutions:


NH HN

OO

N N

15 mol%

(EtCN)3Mo(CO)3 10 mol%THF, reflux

Ph OCO2CH3

CO2CH3

CO2CH3

Na

Ph

MeO2C CO2Me

+

Ph

CO2Me

CO2Me

from 1:88% yield 32:1 (branched: linear) 99% eefrom 2:70% yield 13:1 (branched: linear) 92% ee

1

Ph

OCO2CH3

2

If the reaction were proceeding via initial preferential formation of one of the two possible diastereomeric π-allylmolybdenumcomplexes, starting with racemic 2 would result in racemicproduct or the products of a kinetic resolution (max. 50% yieldof enantioenriched alkylated product). Since racemic substrategives nearly equivalent levels of ee to those observed for 1, themain pathway is thought to proceed via dynamic π−σ−πisomerization of the initially formed π-allylmolybdenumcomplexes with preferential nucleophilic attack on one of the 2diastereomeric complexes.

Molybdenum-catalyzed asymmetric alkylations

Synthesis of quaternary amino acids

Trost JACS 2002 (124) 7256.

+CH3OH

K2CO3

solvolysis of the crudeazlactone in methanol yields the protected quaternaryamino acids in high yields

Ph OCO2t-Bu

N

O

O

Ph

Me

NH HN

OO

N N

15 mol%

(EtCN)3Mo(CO)3 10 mol%LiHMDS

THF, reflux

N

O

O

Ph

Me

Ph

83% yield of branched product96:4 dr99% ee

Ph

Me

Ph(O)CHN CO2CH3

pro-chiralazlactone

pro-chiralallyl carbonate


Asymmetric functionalization: prochiral nucleophileAsymmetric alkylation

The geometric requirements of the chiralpocket created by the diphenylphosphinepropellers can also effect selectivenucleophilic attack of an allyl unit by one face of a prochiral nucleophile. Whenprochiral allyl units are used, excellentdiastereoselectivities can also beachieved.

NH HN

OO

PPh2Ph2P

chiral backbone

linkerlinker

P P

Pd open quadrant

3

X

Y Z vs. ZX

Y

O O

OR+ OAc


3 (1.2 mol%), tol, rt

TMG (N,N,N',N'-tetramethylguanidine)Upon deprotonation, the base usedresults in the cationic partner to the enolate formed. Na bases gavelower ee's.

O O

OR

NH

NN

HO

CO2R

86% yield86% ee

O O

OR +

OCO2Me


3 (1.2 mol%), tol, rt

TMG (N,N,N',N'-tetramethylguanidine)

O

CO2CH2Ph

71% yield97% ee88% de

Trost JACS. 1997 (33) 7879.


Asymmetric functionalization: desymmetrization

NH HN

OO

PPh2Ph2P

chiral backbone

linkerlinker

P P

Pd open quadrant

3

OR OR

ab

Path a depicts ionization of the pro-R leaving group. A "clockwise" twist of the catalyst leading to ionizationpositions the open quadrant of the ligand over the faceof the cyclopentyl allyl, thus minimizing stericallyunfavorable interaction. Inversely, ionization via pathb leads to severe steric interactions between thesubstrate and the phenyl group of thediphenylphosphine.

Desymmetrization of meso-biscarbamates.

Pd0P P

*

O O OO

TsHNNHTs

Pd0P P

*

OO

NHTsPdII

P

P

*TsNHCO2

-

O O

TsHNPd

P

P

*TsNHCO2

-

O O OO

TsHNNHTs

O

TsN

O

R

S

O

TsN OS

R

a

attack via sterically unfavored path b

92% yield85% ee

b

path a

path b

Pd0P P

*

When base is added (NEt3), the ee increases to99%. One rationale given by Trost to account for this dramatic increase in ee is that deprotonationof the carbamate increases the rate ofintramolecular attack relative to intermolecularattack by the displaced carbamate anion.

Trost JACS 1992 (114) 9327.Trost JOC 1998 (63) 1339.


Asymmetric functionalization: desymmetrization

OO

O

Ph

O

Ph

CO2Me

CO2MeNa

NH HN

Ph Ph

OO

PPh2Ph2PO

O

Ph

CO2Me

CO2MeO

O

Ph

MeO2C

MeO2C

NH HN

OO

PPh2Ph2P+

6 mol%

Pd2(dba)3 2 mol%

68% yield92% ee

Pd2(dba)3 2 mol%

6 mol%

80% yield93% ee

Desymmetrization via intermolecular nucleophilic attack:

Trost JACS 1992 (114) 9327.

"From furan to nucleosides" an example of intermolecular nucleophilic attack. Trost JACS 1996 (118) 3037.

OOC(O)PhPh(O)CO

NH HN

Ph Ph

OO

PPh2 Ph2P

N

NN

NH

ClNH HN

Ph Ph

OO

PPh2 Ph2PO

NPh(O)CO

N

N

N

Cl

OOC(O)PhN

N

N

N

Cl

Pd2(dba)3 2 mol%NEt3

6 mol%+6 mol%

Pd2(dba)3 2 mol%NEt3

OOC(O)PhN

N

N

N

H2N

OH OH

L-adenosine

93% ee 93% ee

ONPh(O)CO

N

N

N

H2N

OH OH

D-adenosine

M.C. White/Q. Chen Chem 253 ππππ-Allyl chemistry -240- Week of November 8, 2004

N

Ts

CO2Me

N

H

Me O

CO2Me

O

OMeO

NH

Ts

NH HNO O

NPPh2

racemic

2.5% Pd2dba3•CHCl3, 7.5% L*

CH2Cl2, 0 °C

L* = 88% ee90% yield

(-)-Anatoxin-aaka "very fast death factor"

Total synthesis of (-)-Anatoxin-a via desymmetrization

N

Ts

CO2Me

CO2Me

O

OMeO

NH

Ts

CO2MeN

H

Ts

PdL*

O

MeO

O

CO2

CO2MeNH

Ts

PdL*

H3CO

CO2MeNTs

PdL*

CH3OH

PdL*

trans substituted cyclooctene did not give any cyclization product.

After initially observing slow reaction rates andlow ee's with the standard bis phosphine ligands,the authors reasoned that the "chiral space" created by these standard ligands was too restrictive forthe steric demands of the cyclooctenyl substrate.Alternatively, application of the less stericallydemanding P,N-bidentate chiral ligand shownresulted in dramatic rate enhancements and goodee for the cyclization reaction.

Trost JACS 1999 (121) 3057.

M.C. White Chem 253 ππππ-Allyl chemistry -241- Week of November 8, 2004

QuestionProvide a mechanism for the following transformation.

O O

Ph

O O

H

H

mixture of stereoisomers

Ph

SiMe3AcO

+

(Ph3P)4Pd

toluene, ∆∆∆∆

Decarboxylation of allylic β - Harvard...

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