Asymmetric NucleophilicCatalysis

Vedejs, E.; Daugulis, O. J. Am. Chem. Soc. 2003, 125, 4166-4173Shaw, S. A.; Aleman, P.; Vedejs, E. J. Am. Chem. Soc. 2003, 125, 13368-

13369

Me Ph

HOH R O R

OO

Chiral catalyst Me Ph

HOH

Me Ph

HO R

O

NOR2

R1

OX

O

Chiral catalystX = alkyl, OR

NO

O

R2

R1

O

X

Nucleophilic Catalysis: The BasicsReactions Catalyzed by Nucleophiles

Ph OH

OC

Ph

Me CatalystPh O

O

H Ph

Me

Addition of alcohols to ketenes:

Acylation of alcohols to anhydrides:

Ph

OH

Me Me

O

O Me

O Catalyst

Ph

O

Me

Me

O

Rearrangement of O-acylated enolates:

NO

Me

O

Me

Me

O

CatalystN

O

Me

O

Me

O

Me

Nucleophilic Catalysis: The BasicsAcylation of Alcohols

Me

O

O

O

Me Ph

OH

Me

UncatalyzedSlow

Ph

O

Me

Me

O

N

NMe Me

N

N

Me

O

Much strongeracylating agent

O Me

O

Catalyzed Fast

Ph

OH

Me

Fu, G. C. Acc. Chem. Res. 2000, 33, 412-420

DMAP

Nucleophilic Catalysis: The BasicsSteglich Rearrangement

O

NR R

O

O

X5-acyloxyoxazole N

N

N

N

XO

O

NR R

O

O

NR R

O

O X

N

N

DMAP

This can also be done with pyridine asthe catalyst, but it takes 24 hrs at 100 oCversus a few minutes at room temp.

Hofle, G.; Steglich, W.; Vorbruggen, H. Angew Chem., Int. Ed. Engl. 1978, 17, 569

x = Me, OR

Kinetic Resolutions: Theory

ln[(1-c)(1-ee)]ln[(1-c)(1+ee)]

s = =kfast-reacting enantiomerkslow-reacting enantiomer

s = selectivityc = conversion c = 1 – A + B

A0 + B0

ee = %ee of recovered substrate

A = amt. of fast-reacting enantiomer @ time TB = amt. of slow-reacting enantiomer @ time T

A0 = initial amt. of fast-reacting enantiomerB0 = intial amt. of slow-reacting enantiomer

Kinetic resolutions are the best way for getting extremely enantioenriched compounds, usually utilizing an enzyme to preferentially react away one enantiomer of the substrate, leaving behind the other enantiomer of the substrate.

Chen, C.; Fujimoto, Y., Girdaukas, G., Sih, C. J. J. Am. Chem. Soc. 1982, 104, 7294Equation was numerically solved by Clark, C. T. using a TI-85 graphing calculator

%ee of unreacted substrate

0

10

20

30

40

50

60

70

80

90

100

0 20 40 60 80 100

% Conversion

% e

e

s = 3

s = 5

s = 10

s = 25

s = 100

%ee of product

0

10

20

30

40

50

60

70

80

90

100

0 20 40 60 80 100

% Conversion

% e

e

s = 3

s = 5

s = 10

s = 25

s = 100

Kinetic Resolutions: Theory Pt. 2

ln(1-c*(1+ee))ln(1-c*(1-ee))

s = =kfast-reacting enantiomerkslow-reacting enantiomer

s = selectivityc = conversion c = 1 – A + B

A0 + B0

ee = %ee of product

A = amt. of fast-reacting enantiomer @ time TB = amt. of slow-reacting enantiomer @ time T

A0 = initial amt. of fast-reacting enantiomerB0 = intial amt. of slow-reacting enantiomer

What about the other half of what you have? What is the %ee of the product at a given percentconversion with a known value of s?

Chen, C.; Fujimoto, Y., Girdaukas, G., Sih, C. J. J. Am. Chem. Soc. 1982, 104, 7294Equation was numerically solved by Clark, C. T. using a TI-85 graphing calculator

Enantioselective Acylations with Chiral Phosphines:Early Work with Non-Enzymes

(CH2)n

OHOH

OH

PhPh

HO

entry substrate catalyst anhydride %ee 5(conv.)

selectivity (s) 1a n=01b n=1

2

1b1b1b1b1a

22222

PhCH(OH)tBu

346a6b6a

36a46a6b6a

Ac2OAc2OAc2OAc2OAc2O

Ac2OAc2OBz2OBz2OBz2O

3-ClBz2O

9 (40)11 (60)65 (66)42 (80)52 (10)

50 (40)27 (22)22 (31)68 (84)58 (70)81 (25)

1.21.34.52.63.2

2.91.21.65.54.7

12-15

12345

67891011

+

5-10 mol%catalystO

R O R

OOH

RL RS

O

RL RS

OH

RL RS+

R

meso substrates

chiral phosphines:

CH2Cl2

Me Me

Ph2P PPh2PPh PPh

R

R

6a, R = Me6b, R = Et

3 4

Vedejs, E.; Daugulis, O.; Diver, T. S. J. Org. Chem. 1996, 61, 430-431.

perdeuterated Ac2Ogive monoacetate without loss of deuterium: no ketene mechanism operative

5 1

This was the largest s value for a non-enzyme at the time

O

Enantioselective Acylations with Chiral Phosphines:An Improved Catalyst

A selectivity of 12 – 15 is good, but can it be improved?Yes!

New catalysts:

P

Me MeH

H

Ph

Me

P

Me MeH

HMe

Me

Me

P

Me MeH

HMe

Me

Me Me

MeMe

Me

1 2

3

Retrosyntheses of catalysts:

P

Me MeH

H

Ar

MeO

SO2

OH

Me

MeMeH

ArPH2

Me

MeOH

HH

OHMe

MeMe

OLi

MeO

O

OTfH

OO

Me

Vedejs, E.; Daugulis, O. J. Am. Chem. Soc. 2003, 125, 4166

Enolate Alkylations Using Lactate Triflates

MeMe

OLi

MeO

O

OTfH

OO

Me

MeO

O

OTfH

OO

Me

MeO

OEt

OTfH

OLiHMe

MeEtO2C

MeH

OTf

OLiHMe

Me

MeCO2EtH

Favored Disfavored due tolone-pair repulsion

–55 oC

OTf

Me

MeOH

HHMe

Me

MeOH

HHMe

10-15 : 1 d.r.

How do you access the minor diastereomer? Use a cryptand-like ester

MeMe

OLiOH

Me

Me

Me H

OTfO

OO

LiOMe Me

MeOH

HHMe

Me

MeOH

HHMe

1 : 6-10 d.r.

LAH52%

OH OH

LAH30-40%

OH OH

–55 oCToluene

Continued Synthesis of Phosphine Catalysts

Me

MeOH

HHMe

OH

SOCl2

OSO

OH

Me

MeMeHCCl4

reflux

RuCl3 3H2ONaIO4

MeCN, CCl4,H2O, 60%

OSO2

OH

Me

MeMeH

PhPHLiTHF SO3Li

OH

Me

MeMeH

HPPh

BuLiSO3Li

OH

Me

MeMeH

LiPPh

P

Me MeH

H

Ph

Me

P

Me MeH

H

Ph

Me

BH3 THF85%

P

Me MeH

H

PhBH3

Me

P

Me MeH

H

Ph

Me

BH3

36:1 d.r.

PyrrolideneP

Me MeH

H

Ph

Me

Acylation of Alcohols Using Phenyl Catalyst

670.1(–40o)t-BuPhPh

10.1Mei-Pri-Pr

16Mec-C3H5i-Pr

724Me2-naphthylPh

130.1i-PrPhi-Pr

160.6t-BuPhMe

250.02t-BuPh1-naphthyl

241t-BuPhPh

sRelative rateR2R1Anhydride R

R1 R2

OH

R O R

O OP

Me MeH

H

Ph

MeR1 R2

O R

O

Toluene, r.t. R1 R2

OH

Syntheses of Other Phosphine Catalysts

OSO2

OH

Me

MeMeH

ArPHLiTHF SO3Li

OH

Me

MeMeH

HPAr

BuLi

P

Me MeH

H

Ar

Me

P

Me MeH

H

Ar

Me

BH3 THF85%

P

Me MeH

H

ArBH3

Me

P

Me MeH

H

Ar

Me

BH3 PyrrolideneP

Me MeH

H

Ar

Me

2 Ar= 3,5-Me2C6H33 Ar= 3,5-t-Bu2C6H3

2 = 43:13 = 91:1

Evaluation of Me2Ph-PBO

sSolventR2R1Anhydride R

12Heptanei-BuPhi-Bu

14Heptanei-PrPhi-Bu

14TolueneMe2-naphthyli-Bu

8.1Toluenet-BuPhPh

R1 R2

OH

R O R

O O

R1 R2

O R

OP

Me MeH

HMe

Me

MeR1 R2

OH

Evaluation of t-Bu2Ph-PBO

390tol/–40 °CMe2,4,6-Me3C6H2i-Pr

220 (328)tol/–40 °CMe2,4,6-Me3C6H2i-Pr

15tol/RTMe2,4,6-Me3C6H2i-Pr

55 (60)hept/–40 °Cn-BuPhi-Pr

18hept/RTn-BuPhi-Pr

17tol/RTMe2-naphthyli-Pr

99 (117)hept/–40 °Ci-PrPhi-Pr

20hept/RTi-PrPhi-Pr

10tol/RTt-BuPhPh

sSolvent/TempR2R1Anhydride R

R1 R2

OH

R O R

O O

R1 R2

O R

OP

Me MeH

HMe

t-Bu

t-BuR1 R2

OH

Summary of Acylations Using PBO Catalysts

• Phosphabicylooctane catalysts can be effectively used for a number ofkinetic resolutions of benzylic alcohols.

• Separation of enantiomers of these catalysts is not exceptionallydifficult, done through use of lactate esters and recrystallizations

• Enantioselectivities are exceptional, with values of s = 380• Selectivites high enough to warrant correction for %ee of catalyst• Synthesis is quite air-sensitive at parts, yields of the alkylations are low,

and the catalyst must be stored as the borane complex, due tointerconversion of diastereomers at phosporus

• The full paper only covered the use of a few catalysts• Will this replace using enzymes for kinetic resolutions? Not yet, I think

Chiral Nucleophilic Pyridine Catalysts:Background

NMe2N

DMAPTwo mirror plane

NMe2NR

H

One mirror plane

NMe2NR

H

MLn

No mirror planesa "planar-chiral" DMAP

NMe2N *R

Substitution with a chiralgroup will also make a chiral

DMAP

Fu's Catalysts:Vedejs' Catalyst

R R

R R

R

N

Me2N

Fe

N

R R

R R

R

FeCH2OTES

N

NMe Me

H

OAcCAr3

Greg Fu was the first person to use these types ofcatalysts for catalytic enantioselective work

Acylations Catalyzed by Planar-Chiral DMAP Analogs

+

racemic

O

Me O Me

OOH

Ph Me

OAc

Ph Me

OH

Ph Me+2 mol% cat

NEt3

1 2Ph Ph

Ph Ph

Ph

N

Me2N

Fe

catalyst

entry % conv.after 1 h

solvent, rt

selectivity

12345

solvent

DMFCH3CNCH2Cl2acetone

THF

6101484

3.43.67.08.79.6

Desymmetrizations:

MeMe

MeMe

OH OH

MeMe

MeMe

OH OH

MeMe

MeMe

OAc OAc

1% cat, Ac2O

NEt3, 0 °Ct-amyl alcohol

98% ee43%

99% ee39%

+

6789

EtOActolueneEt2Ot-amyl alcohol

613838

11111327

entry % conv.after 1 h selectivitysolvent

MeMe

MeMe

OH OH

MeMe

MeMe

OH OAc

99% ee91%

1% cat, Ac2O

NEt3, 0 °Ct-amyl alcohol

racemic

meso

Ruble, J. C.; Tweddell, J.; Fu, G. C. J. Org. Chem. 1998, 63, 2794-2795.

Synthesis of a New Chiral Nucleophilic Catalyst

N

NMe Me

Br2, K2CO3

N

NMe Me

Br

Ph3CCOOH LAH Ph3CCH2OH TPAP, NMO63% Ph3CCHO

t-BuLi

N

NMe Me

LiPh3CCHO

Ac2O58%

N

NMe Me

H

CPh3OAc

N

NMe Me

H

CPh3OAc

Groziak, M. P.; Melcher, L. M. Heterocycles, 1987, 26, 2905.

Me MeCH2SO3H

O1.

in toluene2. NaOH3. Repeat

N

NMe Me

H

CPh3OAc

Ab initio geometry of acyl pyridinium

2096PBOBnPh5895DMAPPhPh9287PBOBniBu9190DMAPPhiBu9091PBOBnallyl9190DMAPPhallyl9090PBOBnBn9599DMAPPhBn8988PBOBnMe9195DMAPPhMe

% ee% yieldcatalystR’R

Comparison of Pyridine Catalyst and t-Bu2Ph-PBO Catalyst

N

OMeO

OCO2R'

RN

OMeO

O

RCO2R'

1 mol % (R)-DMAP catalystor 10 mol % PBO, t-amyl

alcohol, 0 oC, 12h

Substrate Scope for the Chiral Nucleophilic Pyridine Catalyzed Steglich Rearrangement

O

Me

MeOO OPh

O10 mol% (S)-DMAP

THF, 23 oC, 24h OMeO

O O

Me

MeOO

MeCO2Ph

PhO2C

83% yield90% ee

7% yield80% ee

O

Me

O OPh

O1 mol% (S)-DMAP

Et2O, 23 oCO

O

MeO

OPh

92% yield92% ee

O

Ph

O OCH2CCl3

O20 mol% (S)-DMAP

CH2Cl2, –40 oC OO

PhO

OCH2CCl3

92% yield86% ee

NCO2Ph

Ph

O OPh

O

10 mol% (S)-DMAPt-amyl alcohol, 40 oC N

CO2Ph

O

PhOPh

O

93% yield86% ee

Summary of Vedejs’ Nucleophilic Asymmetric Catalysts

• Four new asymmetric nucleophilic catalysts have been synthesized andevaluated by the Vedejs group

• Catalysts are straightforward to make in moderate yields• t-Bu2Ph-PBO and the chiral pyridine catalyst both show high

enantioselectivities when catalyzing a Steglich rearrangement• PBO catalysts have exceptional s values for kinetic resolutions of

benzylic alcohols, and, based on Fu’s research, Vedejs’ chiral pyridinecatalyst could also work well in this reaction