enantioselective protonation: fundamental insights and new concepts

Enantioselective Protonation: Fundamental Insights and New

Concepts

• A presentation by Guillaume Pelletier

• Literature meeting October 12th 2011

Enantioselective Protonnation : An Extremely Simple Transformation!(?)

R1

R2

O

R3

R2

O•

R1

R1 O

R3

R2

R1

R3

OM

-H

R3 M

R2 M

H

X*

H

X*

Si

Re

X* M

X* MH2O

H

R2

O

R3R1

O

R3H

R2R1

(R)

(S)

• Enolates are important as synthetic intermediates Enolates are important as synthetic intermediates : regio and stereoselective generation with the desired counterion, increased knowledge of their structure and reactivity

• Enantioselective protonnation via enol tautomerisation Enantioselective protonnation via enol tautomerisation : require only catalytic amounts of chiral reagent.

• Protonnation of a chiral enolate/ligand complexProtonnation of a chiral enolate/ligand complex

What is the Important Facts to Know Before Exploring «AP» of Enolates

• Enantioselective protonation processes are necessarily kinetically controlled kinetically controlled reactions reactions

• Match the ppKKaa of the proton donnor and the product

• Be concerned about the stereochemistry of the proton acceptor stereochemistry of the proton acceptor : the ability to generate a stereodefined proton acceptor is critical (or not) in order to have good enantioselectivity

• Detailed mechanistic explanations are rare : mixture of many mechanismsmixture of many mechanisms

Presentation Outline

• Lucette Duhamel and J.-C. Plaquevent’s Asymmetric Protonation of Benzylidene Glycinates (1978)

• Charles Fehr’s Synthesis of α- and γ-Damascone (1988)

• Hisashi Yamamoto’s Catalytic Asymmetric Protonation of Silyl Enol Ether with LBA (1994)

• Recent Contributions (Levacher, Genet, Fu, Stoltz…) (2005+)

Fehr, C. Angew. Chem., Int. Ed. 1996, 35, 2566-2587.Eames, J.; Weerasooriya, N. Tetrahedron : Asymmetry 2001, 12, 1-24.Duhamel, L.; Duhamel, P.; Plaquevent, J.-C. Tetrahedron : Asymmetry 2004, 15, 3653-3691.Mohr, J. T.; Hong, A. Y.; Stoltz, B. M. Nature Chem. 2009, 1, 359-369.

First « Synthetically Useful » Example of AP with Substituted Benzylidene Glycinates

Duhamel, L.; Plaquevent, J. C. J. Am. Chem. Soc. 1978, 100, 7415-7416.Duhamel, L.; Plaquevent, J. C. Bull. Soc. Chim. Fr. 1982, II-75-83.Duhamel, L. et al. Tetrahedron 1988, 44, 5495-5506.

R1

N

O

O

R2

(±)

LDA (1.40 equiv)-50 °C, 5 min R1

N

O

O

R2

Li

R1

N

O

O

R2 *

enantioenriched

-70 °C, 15 min

Chiral proton donnor(2.85 equiv)

Influence of the Chiral Acid

CO2H

OH

CO2H

O

O

t-Bu

OH

O

CF3

MeOOH

O

NPhthMe

CO2HHO2C

OCOt-Bu

OCOt-Bu

CO2HMeO2C

OCOt-Bu

OCOt-BuHO2C

CO2H

O

O

HO2C

CO2H

O

O

Ph

85%, 2.4% ee 85%, 5.8% ee 85%, 14.3% ee 80%, 4.0% ee

85%, 50% ee 80%, 19.5% ee 80%, 1.2% ee 80%, 1.6% ee


Ph

N

O

O

R2

(±)

LDA (1.40 equiv)-50 °C, 5 min Ph

N

O

O

R2

Li

Ph

N

O

O

R2 *

enantioenriched

H-A* (2.85 equiv)-70 °C, 15 min

Influence of the Tartaric Acyl Substituents

Entry R3 Yield (%) ee (%) [α]D25

1 Me 85 2.6 ‒2.2 (S)

2 i-Pr 85 12.1 ‒10.5 (S)

3 t-Bu 85 50 ‒41.9 (S)

4 1-adamantyl 79 53.2 -44.7 (S)

5 Ph 80 12.3 -10.3 (S)

6 CH2Ph 81 8.5 -6.95 (S)

7 (CH2)2Ph 83 6.5 +0.4 (R)Duhamel, L.; Plaquevent, J. C. J. Am. Chem. Soc. 1978, 100, 7415-7416.Duhamel, L.; Plaquevent, J. C. Bull. Soc. Chim. Fr. 1982, II-75-83.Duhamel, L. et al. Tetrahedron 1988, 44, 5495-5506.

Ph

N

O

O

R2

(±)


N

O

O

R2

Li

OCOR3

CO2HHO2C

OCOR3

Ph

N

O

O

R2 *

enantioenriched

(2.85 equiv)

-70 °C, 15 min

R1

N

O

O

R2

(±)

LDA (1.40 equiv)-50 °C, 5 min R1

N

O

O

R2

Li

R1

N

O

O

R2 *

enantioenriched

-70 °C, 15 min

OCOt-Bu

CO2HHO2C

OCOt-Bu(2.85 equiv)

Influence of the Amino Acid Side-Chain


Ph

N

O

O

N

O

O

Ph

N

O

O

HN

N

O

O

Ph

N

O

O

85%, 50% ee 85%, 48% ee 65%, 26% ee

95%, 30% ee 82%, 33% ee

N

O

O

Ph

N

O

O

95%, 70% ee

(H+ quench at -105 °C)

MeO

45%, 36% ee (R)(+55% Z-enone)

N

O

O

42%, 34% ee (R)(+58% Z-enone)

(E:Z = 100:0)

(98% ee)

Influence of the Benzylidene Electronic Properties

Entry R2 Yield (%) ee (%)

1 p-CN 75 12.3

2 p-Cl 75 31.3

3 H 85 50

4 p-CH3 82 55

5 o-OMe 70 36.6

6 p-OMe 70 57

7 p-NMe2 75 61Duhamel, L.; Plaquevent, J. C. J. Am. Chem. Soc. 1978, 100, 7415-7416.Duhamel, L.; Plaquevent, J. C. Bull. Soc. Chim. Fr. 1982, II-75-83.Duhamel, L. et al. Tetrahedron 1988, 44, 5495-5506.

Ph

N

O

O

R2

(±)


N

O

O

R2

Li

OCOt-Bu

CO2HHO2C

OCOt-BuPh

N

O

O

R2 *

enantioenriched

(2.85 equiv)

-70 °C, 15 min

Influence of the Base Additive


NLi N

Li

NLi

N

Li

Ph (R) N

Me

R

LiR = Me, 70%, 60.6% eeR = Et, 84%, 70.2% eeR = i-Pr, 75%, 62.3% ee

Ph (R) N

Me

Li OCOt-Bu

CO2HHO2C

OCOt-Bu

Ph (R) N

Me

Li OCOt-Bu

CO2HHO2C

OCOt-Bu

Ph (R) N

Me

Li OCOt-Bu

CO2HHO2C

OCOt-Bu

85%, 50% ee 80%, 35.6% ee 75%, 22.5% ee70%, 28% ee

75%, 5.6% ee(mismatched)

75%, 38.9% ee 85%, 23.8% ee

Ph

N

O

O(±)

Base (1.40 equiv)-50 °C, 5 min Ph

N

O

OLi

OCOt-Bu

CO2HHO2C

OCOt-BuPh

N

O

O

*

enantioenriched

(2.85 equiv)

-70 °C, 15 min

N

R

R

H

N

O

Ph

MeO

Ph

Li NHR2

N

O

Ph

OMe

Ph

LiR2HN

O

O

R

R

O

O

O

R

R

O

O

O

ROCO

CO2H

H

CO2H

OCOR

H OO

R

O

O

R

(S)-enantiomer

"AP""AP"

(R)-enantiomer

vs


Results Interpretation

OMeO

PhN

Ph

Li N

Enantioselective Protonation of Open-Chain Enolates Without Internal Chelating Atom

• Proton donnor should be only weakly acidic weakly acidic (pKa~15-20)• Proton donnor should contain an electron-rich groupan electron-rich group with chelating ability• The transferred proton should be located in the proximitiy of the stereogenic centerproximitiy of the stereogenic center• Proton donnor should be readily accessible in both enantiomeric form both enantiomeric form and easily easily

recoverablerecoverable

Fehr, C.; Galindo, J. J. Am. Chem. Soc. 1988, 110, 6909-6911.Fehr, C. Angew. Chem., Int. Ed. 1996, 35, 2566-2587.





NNH

O

MePh

HO N

MePh

ephedrine derivative





NNH

O

MePh

HO N

MePh

ephedrine derivative

OMe

O

OMe

OLi

O•

OMgCl

MgCl

ligand

(E:Z ~ 9:1)

MgCl

n-BuLi(1.2 equiv)

(1.3 equiv)

(1.2 equiv) Proton sourceO

*

-Damascone(rose fragrance)

-100 °C

-78 °C

-78 °C

EntryProton source

Enolate composition

Enolate generation

Yield (%)

ee (%)

1 MgCl•MeOLi Grignard 60 58

2 MgCl Ketene 76 51

OMgCl ligand

(E:Z ~ 9:1)

Proton sourceO

*


α-Damascone Synthesis – Ligand effect

NNH

O

MePh

EntryProton source

Enolate composition

Enolate generation

Yield (%)

ee (%)


2 MgCl Ketene 76 51

3 MgCl Ketene N.D. 16

4 MgCl•MeOLi Ketene 75 70

5 MgCl•t-BuOLi Ketene 70 79

OMgCl ligand

(E:Z ~ 9:1)

Proton sourceO

*



NNH

O

MePh

HO N

MePh

EntryProton source

Enolate composition

Enolate generation

Yield (%)

ee (%)


2 MgCl Ketene 76 51

3 MgCl Ketene N.D. 16

4 MgCl•MeOLi Ketene 75 70

5 MgCl•t-BuOLi Ketene 70 79

6Ketene

73 84

7 t-BuOH 70 62

OMgCl ligand

(E:Z ~ 9:1)

Proton sourceO

*



NNH

O

MePh

HO N

MePh

LiO N

MePh

MgCl

α-Damascone Synthesis – Enolate Stereoselectivity Effect

Fehr, C.; Galindo, J. Angew. Chem., Int. Ed. 1994, 33, 1888-1890.Fehr, C. Angew. Chem., Int. Ed. 1996, 35, 2566-2587.

O•

OTMSMgCl

(1.2 equiv)1)

2) TMSCl3) Fractional distillation

(E:Z 98:2)

NHO

MePh

(1.00 equiv)-70 °C

1) MeLi (1.00 equiv)O

80%, 95% ee

O•

OLi1) n-BuLi (1.00 equiv)-100 to -70 °C

(E:Z 97:3)

O

90%, 96% ee



O•

OTMSMgCl

(1.2 equiv)1)


(E:Z 98:2)

NHO

MePh

(1.00 equiv)-70 °C


80%, 95% ee

O•


(E:Z 97:3)

O

90%, 96% ee

O

89%, >98% ee

NHO

MePh(0.95 equiv)

-70 °C

then TMSCl

OTMS

(E:Z 1:1)

+



O•

OTMSMgCl

(1.2 equiv)1)


(E:Z 98:2)

NHO

MePh

(1.00 equiv)-70 °C


80%, 95% ee

O•


(E:Z 97:3)

O

90%, 40% ee

O

89%, >98% ee

NHO

MePh(0.95 equiv)

-70 °C

then TMSCl

OTMS

(E:Z 1:1)

+

(E:Z 1:99<)

OLi

NHO

MePh(1.00 equiv)

-70 °C

γ-Damascone Synthesis – Effect of Alkoxide additives

Fehr, C.; Galindo, J. J. Org. Chem. 1988, 53, 1828-1830.Fehr, C.; Galindo, J. Helv. Chim . Acta 1995, 78, 539-552.

OMgCl

MgCl

(1.05 equiv)Hexanes, 35 to 45 °C

2)

O

OMe

MeOLi1) n-BuLi (1.2 equiv)-78 to 0 °C, THF

HO N

Ph MeO

(s)--Damascone(E selective)



OMgCl

MgCl


2)

O

OMe


HO N

Ph MeO

(s)--Damascone(E selective)H-A* (2.0 equiv)THF/Hexanes

-78 to 0 °C, 60 min(Addition of H-A* to enolate)

H-A* (2.5 equiv)THF/Hexanes0 °C, 60 min

(Addition of enolate to H-A*)

25% ee, 100% Conv.

49% ee, 100% Conv.


OMgCl

MgCl


2)

O

OMe


HO N

Ph MeO

(S)--Damascone


49% ee, 100% Conv.inverse addition

(E selective)



OMgCl

MgCl


2)

O

OMe


HO N

Ph MeO

(S)--Damascone



(E selective)


1) TMSCl (2.0 equiv)-50 to 20 °C, THF

2) MeLi (1.15 equiv)THF/Et2O, 40 °C, 10 min

OLiHO N

Ph Me

O

(S)--Damascone

Conditions



OLiHO N

Ph Me

O

(S)--Damascone

Conditions(Protonation at -50 °C)

Entry

Equiv H-A*

Addition mode

SolventLi-A*

(equiv)

ee (%) at

25% Conv

ee (%) at 50% Conv

ee (%) at

100% Conv

1 1.2 normalTHF/Et2O

none 8 39 62

2 1.2 inverseTHF/Et2O

none 26 35 49


1.0 - 65 68


2.0 - 69 70

5 1.0 inverse THF 2.0 - 75 75

LiO N

Ph Me

Li-A* =

• The elucidation of the reaction mechanism is rendered more complex more complex from the non-non-linear relationship linear relationship between reaction product reaction product and H-A* H-A* enantiomeric purity.


OMgCl

MgCl


2)

O

OMe


HO N

Ph MeO

(S)--Damascone



(E selective)

Fehr, C.; Galindo, J. Helv. Chim . Acta 1995, 78, 539-552.

1) TMSCl (2.0 equiv)-50 to 20 °C, THF

2) MeLi (1.15 equiv)THF/Et2O, 40 °C, 10 min

OLiHO N

Ph Me

O

(S)--Damascone

Conditions

1) LDA (3.0 equiv) or n-BuLi (1.5 equiv)(E:Z > 99:1)2)

HO N

Ph Me

O

OMe

(2.0 to3.3 equiv)

36 to 50% ee(4:1 to 3:1 Product:SM)

-100 to -10 °C

α and γ-Damascone Synthesis – Application to Thioester enolate

Fehr, C.; Galindo, J. Helv. Chim . Acta 1995, 78, 539-552.Fehr, C.; Stempf, I.; Galindo, J. Angew. Chem., Int. Ed. 1993, 32, 1042-1044.

O

X

HO N

Ph Me

(S)

O

XOLi

(E:Z >99:1)

O

X

BA A

DeprotonationAsymmetric Protonation

THF

(+)-

X


Fehr, C.; Galindo, J. Helv. Chim . Acta 1995, 78, 539-552Fehr, C.; Stempf, I.; Galindo, J. Angew. Chem. Int. Ed. 1993, 32, 1042-1044.

O

X

HO N

Ph Me

(S)

O

X

O

X

BA A

DeprotonationAsymmetric Protonation

THF

(+)-

OLi

(E:Z >99:1)

X

Entry X Deprotonnation Protonnation B/Aee (%)

Yield (%)

1 OMen-BuLi (1.5 equiv)

-78 °C, 2.75 h(‒)-H-A* (2.0 equiv) -100 to -10°C,1.75h 22/78 36 (R) -

2 OMeLDA (3.0 equiv)

-78 °C, 3 h(+)-H-A* (3.3 equiv) -100 to -10°C,2.25h 33/67 50 (S) -

3 OMeLDA (3.0 equiv)

-78 °C, 3 haq. HCl (excess),

-78 °C 72/28 - -

4 SPhn-BuLi (2.0 equiv)

-78 °C, 3 h(‒)-H-A* (2.7 equiv) -100 to -10°C,1.75h 43/57 96 (R) 81

5 SPhLDA (3.0 equiv)-78 °C, 2.75 h

(‒)-H-A* (4.0 equiv) -100 to -10°C,1.5h 56/44 97 (R) 84

6 SPhLDA (1.5 equiv)

-78 °C, 3.5 h(+)-H-A* (2.0 equiv) -100 to -10°C,1.5h 45/55 94 (S) 76



SPhO

SPh

HO N

Ph Me O

SPhOLi

(E:Z > 99:1)

O

SPh

B A

LDA (2.0 equiv)

-78 °C, THF, 2.75 h

(+)-

THF, -100 °C, 1.0 hthen -10 °C, 30 min

(4.0 equiv)

97% ee84% yield (B+A)

A



SPhO

SPh

HO N

Ph Me O

SPhOLi

(E:Z > 99:1)

O

SPh

B A

LDA (2.0 equiv)

-78 °C, THF, 2.75 h

(+)-

THF, -100 °C, 1.0 hthen -10 °C, 30 min

(4.0 equiv)


A

OLiO

X

HO N

Ph Me O

XX

(Z:E ~ 19:1) D

n-BuLi (1.5 equiv)

-100 °C, THF2.0 to 4.0 h

( )-

THF, -100 °C, 1.0 hthen -10 °C, 10 min

(2.0 equiv) X = OMe (36% ee)X = OPh (77% ee)

X = SPh (99% ee, 87% yield)X = 2-Naphthyl (99% ee, 82% yield)

C



SPhO

SPh

HO N

Ph Me O

SPhOLi

(E:Z > 99:1)

O

SPh

B A

LDA (2.0 equiv)

-78 °C, THF, 2.75 h

(+)-

THF, -100 °C, 1.0 hthen -10 °C, 30 min

(4.0 equiv)


A

OLiO

X

HO N

Ph Me O

XX

(Z:E ~ 19:1) D

n-BuLi (1.5 equiv)

-100 °C, THF2.0 to 4.0 h

( )-

THF, -100 °C, 1.0 hthen -10 °C, 10 min

(2.0 equiv) X = OMe (36% ee)X = OPh (77% ee)

X = SPh (99% ee, 87% yield)X = 2-Naphthyl (99% ee, 82% yield)

C

O•

E

THF, >80 °C

-PhSLi

α-Damascone Synthesis – Catalytic Enantioselective Process

O•

E

>-80 °CSlow

Reversible

+ PhSLi

OLi

SPh

• Slow Slow and reversiblereversible generation of the transient enolate


O•

E

>-80 °CSlow

Reversible

+ PhSLi

OLi

SPh

HO N

Ph Me

FastIrreversible

O

SPh

enantioenrichedD

LiO N

Ph Me

• Slow Slow and reversiblereversible generation of the transient enolate• RapidRapid and irreversibleirreversible protonation of the enolate by H-A*


O•

E

>-80 °CSlow

Reversible

+ PhSLi

OLi

SPh

HO N

Ph Me

FastIrreversible

O

SPh

enantioenrichedD

LiO N

Ph MePhSH

FastIrreversible

• Slow Slow and reversiblereversible generation of the transient enolate• Rapid Rapid and irreversibleirreversible protonation of the enolate by H-A*• The rate of regenerationrate of regeneration of the catalyst and enolate can be ajusted with the ajusted with the

external proton source external proton source (PhSH)• Proton exchange between A*- and PhSH must be rapidrapid and completecomplete and

PhSLi must be more nucleophilicmore nucleophilic than Li-A*• Background reaction is suppressed by low [PhSH]low [PhSH]


Fehr, C.; Stempf, I.; Galindo, J. Angew. Chem., Int. Ed. 1993, 32, 1042-1044.Fehr, C.; Stempf, I.; Galindo, J. Angew. Chem., Int. Ed. 1993, 32, 1044-1046.

O•

(1.00 equiv)

O

SArArSH (1.00 equiv), THF

Temperature, Time

LiO

Ph

N

Me(xx equiv)

Entry ArSHLi-A*

(mol %)Temperature

(°C)

ArSH Addition time (h)

ee (%)Yield (%)

1 PhSH 100 -55 3 95 84

2 4-ClPhSh 100 -55 4 97 85

3 PhSH 5 -27 3 89 86

4 PhSH 2 -27 1 77 87

5 4-ClPhSH 5 -27 3 90 81

6 4-ClPhSH 2 -27 3 57 -

Catalytic Enantioselective Protonation – General Scheme

R1

R2

Y

O

R1

R2

Y

O

*

H-A* A*

Z-HZ

Fehr, C. Angew. Chem., Int. Ed. 1996, 35, 2566-2587.

• With preformed enolates, [enolate] > [H-A*][enolate] > [H-A*]• Formally, an external, achiral proton source Z-H selectively protonates A* Z-H selectively protonates A* - -

and not the enolatenot the enolate• Protonation of A*- should be rapid rapid with Z-H (unless there is a catalytic

enantioselective tautomerisation mechanism)

What About Preformed Enolates? (Autocalatylic)


OTMS

MeLi (1.00 equiv)

OLi

HO

MePh

N LiO

MePh

N

O

OLi

H

H

TMSCl

OTMS

O

H

What About Preformed Enolates? (Autocalatylic)


• This autocatalytic process is based on subtile kinetic differences in the proton transfer reactions between H-A*, A*-, the enolate and the non-inducing proton donnor (Z-H).

OTMS

MeLi (1.00 equiv)

OLi

HO

MePh

N LiO

MePh

N

O

OLi

H

H

TMSCl

OTMS

O

H

With E:Z = 98:2and 1.0 equiv H-A* : 80%, 95% ee

With E:Z = 98:2and 0.3 equiv H-A* : 86%, 93% ee


O•

(1.00 equiv)

OLi

n-BuLi (1.05 equiv)

THF, -100 to -70 °C

O

O

OLi

HO

Ph

N

Me

LiO

Ph

N

Me

(E:Z >97:3)



O•

(1.00 equiv)

OLi

n-BuLi (1.05 equiv)

THF, -100 to -70 °C

O

O

OLi

HO

Ph

N

Me

LiO

Ph

N

Me

(E:Z >97:3)55% ee with

0.5 equiv of H-A*



O•

(1.00 equiv)

n-BuLi (1.05 equiv)

HO

Ph

N

Me

LiO

Ph

N

Me

Ph

O

Ph

OLi

OLi

THF, -100 to -70 °C

O

(E:Z >97:3)



O•

(1.00 equiv)

n-BuLi (1.05 equiv)

HO

Ph

N

Me

LiO

Ph

N

Me

Ph

O

Ph

OLi

OLi

THF, -100 to -70 °C

O

(E:Z >97:3)

EntryH-A*

(equiv)PhCH2Ac (equiv)

ee (%)Yield (%)

1 1.1 - 96 90

2 0.2 0.85 94 94

3 0.1 0.95 85 99

4 0.20.8(TMSC

l)98 91

Catalytic Enantioselective Protonation – Protonnation of H-A*/enolate aggregate

n-Bu

OHLi

O

NPh

n-Bu

OHLi

O

Ph

(S)

n-Bu

O

n-Bu

O

(S)-Ketone (RS)-Ketone

Fehr, C.; Galindo, J. Angew. Chem., Int. Ed. 1994, 33, 1888-1890.

Catalytic Enantioselective Protonation of Cylic Lithium Enolates

Yanagisawa, A.; Kuribayashi, T.; Kikuchi, T.; Yamamoto, H. Angew. Chem., Int. Ed. 1994, 33, 107-109.Yanagisawa, A.; Kikuchi, T.; Wanatabe, T.; Kuribayashi, T.; Yamamoto, H. Synlett 1995, 372-273.Yanagisawa, A.; Ishihara, K.; Yamamoto, H. Synlett 1997, 411-420.

n-BuLi (1.1 equiv)

THF, 0 °C, 2 h

OTMS

(1.0 equiv)

OLi O

HN ON

Ph Ph

Z-HZ

O

O

LiN ON

Ph Ph

O

O


Kemp, D. S.; Petrakis, K. S. J. Org. Chem. 1981, 46, 5140-5149.Rebek, J., Jr.; Askew, B.; Killoran, M.; Nemeth, D.; Lin, F.-T. J. Am. Chem. Soc. 1987, 109, 2426-2433.

CO2HCO2H

CO2H

(Kemp's triacid)

1) aq. NH4OHDMAP (20 mol%)

110 °C, 12 h

2) SOCl2 (5.0 equiv)reflux, 3 h

HN ClOO

O

79% over 2 steps

H2N OH

Ph Ph

Et3N, DCM2) SOCl2

HN ON

Ph Ph

O

O

1)

92% over 2 steps

n-BuLi (1.1 equiv)

THF, 0 °C, 2 h

OTMS

(1.0 equiv)

OLi O

HN ON

Ph Ph

Z-HZ

O

O

HN ON

Ph Ph

O

O


OLi

HN ON

Ph Ph

O

O

(xx equiv)i)

THF, -78 °C, 20 minii) Achiral proton source

(1.0 equiv)Addition over 2 h, -78 °C

O

72-85% yield

EntryAchiral proton

H-A* (equiv)

ee (%)

1 1.0 87

2 0.10 83

3 0.05 72

4 0.10 90

5 0.01 81

6 0.10 88

7 0.01 80

Yanagisawa, A.; Kikuchi, T.; Wanatabe, T.; Kuribayashi, T.; Yamamoto, H. Synlett 1995, 372-273.Yanagisawa, A.; Ishihara, K.; Yamamoto, H. Synlett 1997, 411-420.

NH

O

O

OH

t-Bu

t-BuMe

t-Bu

O

t-Bu

O

*With a TMSCl quench at -78 °C!*With a TMSCl quench at -78 °C!


Yanagisawa, A.; Kikuchi, T.; Wanatabe, T.; Kuribayashi, T.; Yamamoto, H. Synlett 1995, 372-273.Yanagisawa, A.; Ishihara, K.; Yamamoto, H. Synlett 1997, 411-420.

ON

PhH Ph H

ONO

LiH

R

R O Me

re

si

ON

HPhHPh

O NO

LiH

R

ROMere

si

R

R

OLi

Me

(R)

O

R

R

Me (S)

O

R

R

Me

(R)-Ketone (S)-Ketone

Enantioselective Protonation of Prochiral Silyl Enol Ethers and Ketene Silyl Acetals

Ishihara, K.; Kaneeda, M.; Yamamoto, H. J. Am. Chem. Soc. 1994, 116, 11179-11180.Ishihara, K.; Nakamura, S.; Kaneeda, M.; Yamamoto, H. J. Am. Chem. Soc. 1996, 118, 12854-12855.

OTMS

Ph Chiral Brnsted Acid

OTMS

TMSOPh

Me

or

O

Ph

O

TMSOPh

Me

or* *

O

Ph

HL SiMe3

O-Protonnation

C-Protonnation



OTMS

Ph Chiral Brnsted Acid

OTMS

TMSOPh

Me

or

O

Ph

O

TMSOPh

Me

or* *

O

Ph

HL SiMe3

O-Protonnation

C-Protonnation

• Silyl enol ether is a « stable metal enolate equivalentstable metal enolate equivalent » which can be isolated

• In general, it is difficult the control the enantioselectivity difficult the control the enantioselectivity with protonation of silyl enol ether with chiral Brønsted acids

• Two main reason for poor induction is bonding flexibility bonding flexibility between H and A* and chiral pool chiral pool of H-A* is limited of H-A* is limited to sulfonic and carboxylic acids

Enantioselective Protonation of Prochiral Silyl Enol Ethers


OTMS

Ar

OTMS

TMSOAr

R

or

O

Ar

O

MeOAr

R

or

O

O

H

H

Lewis acid assisted chiral Brnsted Acid (LBA)

SnCl4

(1.0 equiv)

-78 °C, Toluene, 1 h

>95% yield

Enantioselective Protonation of Prochiral Silyl Enol Ethers


OTMS

Ar

OTMS

TMSOAr

R

or

O

Ar

O

MeOAr

R

or

O

O

H

H

Lewis acid assisted chiral Brnsted Acid (LBA)

SnCl4

(1.0 equiv)

-78 °C, Toluene, 1 h

>95% yield

O

91% ee

O

93% ee

O

42% ee

CO2Me CO2Me

CO2Me

Cl

CO2Me

Cl

Br

92% ee

91% ee 84% ee

60% ee



O

Sn

Cl

Cl

Cl

O

ClH

R2

R1

OSiR3

O

Sn

Cl

Cl

Cl

O

ClSiR3

PhR2

R1 H

O

+

Asymmetricprotonation

Catalytic Enantioselective Protonation of Prochiral Silyl Enol Ethers

Ishihara, K.; Nakamura, S.; Kaneeda, M.; Yamamoto, H. J. Am. Chem. Soc. 1996, 118, 12854-12855.

O

O

H

H

SnCl4

OTMS

Ph

O

Ph

O

O

TMS

H

SnCl4

OHOTMS

Chiral LBA

Catalytic Enantioselective Protonation of Prochiral Silyl Enol Ethers


O

O

H

H

SnCl4

OTMS

Ph

O

Ph

O

OH

SnCl3

OHOTMS

Chiral LBA

TMSCl+

SnCl4

Achiral LBA

Catalytic Enantioselective Protonation of Prochiral Silyl Ketene Acetals

O

O

H

H

SnCl4OTMS

Ph

O

Ph

O

O

Me

H

SnCl4

(R)-BINOL LBA (R)-BINOL-OMe LBA

OH

Me Me

(1.1 equiv)

(slow addition)

SnCl4 (xx mol%)Chiral LBA (xx mol%)

toluene, -80 °C100% conversion



O

O

H

H

SnCl4OTMS

Ph

O

Ph

O

O

Me

H

SnCl4


OH

Me Me

(1.1 equiv)

(slow addition)



Entry Chiral LBA (mol %)SnCl4

(mol %)Time (h)

ee (%)

1 (R)-BINOL-OMe (2)(2) 110 1 90

2 (R)-BINOL-OMe (5)(5) 110 0.5 91

3 (R)-BINOL (5)(5) 110 0.5 80

4 (R)-BINOL-OMe (2)(2) 50 2 90

5 (R)-BINOL-OMe (20)(20) 16 1 0

6 (R)-BINOL-OMe (100)(100) 100 0.2 98Ishihara, K.; Nakamura, S.; Kaneeda, M.; Yamamoto, H. J. Am. Chem. Soc. 1996, 118, 12854-12855.


O

O

H

H

SnCl4OTMS

Ph

O

Ph

O

O

Me

H

SnCl4


OH

Me Me

(1.1 equiv)

(slow addition)



Entry Chiral LBA (mol %)SnCl4

(mol %)Time (h)

ee (%)

1 (R)-BINOL-OMe (2)(2) 110 1 90

2 (R)-BINOL-OMe (5)(5) 110 0.5 91

3 (R)-BINOL (5)(5) 110 0.5 80

44 ((RR)-BINOL-OMe (2))-BINOL-OMe (2) 5050 22 9090

5 (R)-BINOL-OMe (20)(20) 16 1 0

6 (R)-BINOL-OMe (100)(100) 100 0.2 98Ishihara, K.; Nakamura, S.; Kaneeda, M.; Yamamoto, H. J. Am. Chem. Soc. 1996, 118, 12854-12855.


O

O

H

H

SnCl4

OTMS

Ph

O

O

Me

H

SnCl4

(R)-BINOL LBA

(R)-BINOL-OMe LBA

(1.1 equiv)

toluene-d8, -80 °C5 min

O

O

H

SnCl3

OTMS

Ph

(1.1 equiv)

toluene-d8, -80 °C5 min

TMSCl+

O

O

Me

SnCl3

O

OTMS

H

SnCl4+

15% 85%

>95%

0.26 ppm

+0.16 ppm

TMSCl+

+0.16 ppm

• 97% Conversion with (R)-BINOL-OMe LBA vs 17% Conversion with phenol-LBA and 0% with SnCl4 (no acid present)!Ishihara, K.; Nakamura, S.; Kaneeda, M.; Yamamoto, H. J. Am. Chem. Soc. 1996, 118, 12854-12855.

Recent Improvements with Chiral Brønsted Acids (Chiral N-Triflylthiophosphoramide)

Cheon, C. H.; Yamamoto, H. J. Am. Chem. Soc. 2008, 130, 9246-9247.

n

OTMS

R O

O

i-Pr

i-Pr

t-Bu

PO

NHTfi-Pr

i-Pr t-Bu

n

O

R

Chiral Phosphoramide (5 mol %)

OH

(1.1 equiv)

toluene, rt, 6 to 40 h

Chiral Phosphoramide



n

OTMS

R O

O

i-Pr

i-Pr

t-Bu

PO

NHTfi-Pr

i-Pr t-Bu

n

O

R


OH

(1.1 equiv)



O O O O

O OO

OMe Cl

O

97%, 82% ee 98%, 84% ee 95%, 84% ee 99%, 87% ee

99%, 90% ee (with 5.0 mol%)99%, 88% ee (with 0.1 mol%)80%, 86% ee (with 0.01 mol%)

97%, 90% ee 97%, 58% ee 96%, 68% ee



n

OTMS

R O

O

i-Pr

i-Pr

t-Bu

PO

NHTfi-Pr

i-Pr t-Bu

n

O

R


OH

(1.1 equiv)



O

O

Ar

Ar

PO

NHTf+

OH OH2

O

O

Ar

Ar

PO

TfN

Oxonium ion pair

O

PhOxonium ion pair

or H-A*

TMSO

Ph

TMS

HTfNPO(OR*)2

O

PhH

HO TMSO

+ H-A*

Intermediary chiralion pair

Recent Improvements with Chiral Chincona as Latent HF Source

Poisson , T.; Dalla, V.; Marsais, F.; Dupas, G.; Oudeyer, S.; Levacher, V. Angew. Chem., Int. Ed. 2007, 46, 7090-7093.

Ph

O

F+ EtOH

Ph

O

OEt

Generation ofHF

R*N

R*

R*

R*N

R*

R*H

F

Proton Shuttle

OTMS

R

O

RH

In situ Desilylation/Asymmetric Protonation

Recent Improvements with Chiral Chincona as Latent HF Source

Poisson , T.; Dalla, V.; Marsais, F.; Dupas, G.; Oudeyer, S.; Levacher, V. Angew. Chem., Int. Ed. 2007, 46, 7090-7093.

Ph

O

F+ EtOH

Ph

O

OEt

Generation ofHF

R*N

R*

R*

R*N

R*

R*H

F

Proton Shuttle

OTMS

R

O

RH

In situ Desilylation/Asymmetric Protonation

O

R

SiMe3

HN

R*

FO O

OO

N

OMe

N

N

MeO

N

R*3N cat: (DHQ)2AQN

R

OTMSR*

3N cat (10 mol%)

PhCOF (1.05 equiv)

EtOH (1.05 equiv)

DMF, rt, 12 h

R

O

84%, 85% ee (R = Bn) 88%, 81% ee (R = Me)70%, 78% ee (R = Et)

Chiral Guanidine Catalyzed Conjugate Addition/Enantioselective Protonation

Leow, D.; Lin, S.; Chittimalla, S. K.; Fu, X.; Tan, C.-H. Angew. Chem., Int. Ed. 2008, 47, 5641-5647.

B*

B*-H Nu

Nu

R1

R2

O B*-H

R1

O

R2

Transient enolate

Nu-H

R1

O

R2

Nu

*

Protonation step

Michael addition

Chiral Guanidine Catalyzed Conjugate Addition/Enantioselective Protonation

Leow, D.; Lin, S.; Chittimalla, S. K.; Fu, X.; Tan, C.-H. Angew. Chem., Int. Ed. 2008, 47, 5641-5647.

B*

B*-H Nu

Nu

R1

R2

O B*-H

R1

O

R2

Transient enolate

Nu-H

R1

O

R2

Nu

*

Protonation step

Michael addition

CO2t-Bu(phth)N

NH

N

Nt-Bu t-Bu

(10 mol%)

ArSH (1.10 equiv)-50 °C, Et2O, 0.5 to 4 h

CO2t-Bu(phth)N

SAr

NH

N

Nt-Bu t-Bu

(10 mol%)

(R)2POH (1.10 equiv)0 °C, toluene, 1.5 to 8 h

N

O

O

MesN

O

O

Mes

PO

RR

ArSH = PhSH (90% ee) = 2-CF3SH (93% ee) = Thiophen-2-ylSH (91% ee)

92-99% yield

H

H

79-95% yield

(R)2POH = (2-EtC6H4)2POH (92% ee) = (3-ClC6H4)2POH (92% ee) = (naphth-1-yl)2POH (98% ee)

Rhodium Catalyzed Conjugate Addition/Enantioselective Protonation

Navarre, L.; Darses, S.; Genet, J.-P. Angew. Chem., Int. Ed. 2004, 43, 719-723.Navarre, L.; Martinez, R.; Genet, J.-P.; Darses, S. J. Am. Chem. Soc. 2008, 130, 6159-6169.

NHAc

CO2Me

+ ArBF3K

[Rh(cod)2]+PF6- (3 mol%)

(R,R)-BINAP (6.6 mol%)

Guaiacol (1.0 equiv)

toluene, 110 °C, 20 h

NHAc

CO2Me

Ar

OMe

OH

Guaiacol

NHAc

CO2Me

NHAc

CO2Me

NHAc

CO2Me

NHAc

CO2Me

NHAc

CO2Me

NHAc

CO2Me

MeO

F

S

Me

89%, 90% ee 89%, 90% ee 88%, 87% ee

66%, 89% ee68%, 81% ee82%, 83% ee



RhL

PP

OR

* Ar BF3K

RO BF3K

RhL

PP

Ar

*

RhPP

Ar

* NHAc

CO2Me

LNHAcMeO2C

RhPP

*

O

MeO2CNHAc

Ar

RO HL +

O

MeO2CNHAc

Ar

*

RO H

Ar H

Transmetallation

Coordination to Amidoacrylate

Carbo-rhodation(Insertion of Ar)

Oxa- -allylrhodiumIntermediate

Protonation f rom the Re Face



NHPG

CO2R

+ PhBF3K



guaiacol (1.0 equiv)toluene, 110 °C, 20 h

NHPG

CO2R

Ph

Entry PG RpKa

of SMYield (%)

ee (%)pKa of Prod

1 Ac Me 13.1 91 90 14.7

2 CBz Me 9.4 92 43 11.0

3 Boc Me 9.6 82 90 11.2

4 Phth Me - 91 10 -

5COCF

3Me 8.05 100 15 9.67

6 Ac i-Pr - 87 91 -

7 Boc i-Pr - 76 93 -

8 Boc t-Bu - 70 95 -



NAc

CO2Me

+ PhBF3K





NAc

CO2Me

Ph

OMe

OH

Guaiacol

Me

12%, 20% ee

Me

NHAc

CO2Me

+ PhBF3K



(R)- or (S)- or

rac-BINOL (1.0 equiv)


NHAc

CO2Me

Ph

27% ee

NHAc

CO2Me

+ PhBF3K



Guaiacol-d (1.0 equiv)


NHAc

CO2Me

Ph

81%, 90% ee28% D incorporation

D

NHAc

CO2Me

+ PhBF3K


(R)-Difluorphos (6.6 mol%)



NHAc

CO2Me

Ph

86%, 92% ee

O

O

O

O

F

F

F

F

PPh2

PPh2

(R)-Difluorphos

Protonation by Chiral Brønsted Base – G. C. Fu

Hodous, B. L.; Ruble, J. C.; Fu, G. C. J. Am. Chem. Soc. 1999, 121, 2637-2638.Wiskur, S. L.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 6176-6177.

Catalyst

RLO

•

RS

cat.

O

RS

RL

RO H

cat.

O

RS

RL

H*

OR

RO

O

RS

RL

H*



• ee% of product varies linearly with with ee% of starting catalyst

NOR

Me

Me

Me Me

Me

FeR = OMe, 27% eeR = OTES, 28% eeR = OTBS, 77% ee (87%)R = OTBDPS, 68% ee

R

R

R R

R

FeN

Me2N

R = Ph, >5% eeR = Me, >5% ee

MeO

•

Ph

+ MeOHcat. (10 mol%)

2,6-di-t-butylpyridinium triflate (12 mol%)toluene, -78 °C, 24 h

O

MeO

Me

Ph

cat. =

NOR

Me

Me

Me Me

Me

FeNH

OR

Me

Me

Me Me

Me

Fe

MeOH + OMe

MeO

•

Ph

+ MeOHcat. (10 mol%)

toluene, -78 °C, 24 h

O

MeO

Me

Ph

56% ee

Fe

N

Me

Me

Me

Me

Me

OTBS

O

Ph

Me

H

Fe

N

Me

Me

Me

Me

Me

OTBS

O

Ph Me

H

MeO MeO

O

MeOMe

H Ph

O

MeOPh

H Me

S- Unfavored

Fe

N

Me

Me

Me

Me

Me

OTBS

O

Me

Ph

H

Fe

N

Me

Me

Me

Me

Me

OTBS

O

Me Ph

H

R- Favored


Hodous, B. L.; Ruble, J. C.; Fu, G. C. J. Am. Chem. Soc. 1999, 121, 2637-2638.M. Poirier Literature Meeting (Oct 2th 2007)

Protonation by Chiral Brønsted Acid – G. C. Fu


Me

Me

Me Me

Me

FeN

Me2N

EtO

•

Ph

+

Chiral DMAP (3 mol%)

toluene, rt, 2 h

O

O

Et

Ph

PhOH +

Me

Me

Me Me

Me

FeN

Me2N

HPhO

OH

R

t-Bu

R = (H), 47% eeR = (4-CF3), 35% eeR = (4-MeO), 72% eeR = (2-MeO), 80% ee

R = 2-(Me), 81% eeR = 2-(i-Pr), 80% eeR = 2-(Ph), 81% eeR = 2-(t-Bu), 91% ee (89%)

R OH R

(1.04 equiv)

O

OPh

t-Bu

O

O

Me

PMP

t-Bu

O

O

t-Bu

S

87%, 88% ee 78%, 94% ee 94%, 79% ee

Protonation by Chiral Brønsted Acid – G. C. Fu


Catalyst

RLO

•

RS

RO H

RO

O

RS

RL

RO

O

RS

RL

H*

cat. H OR

cat. H

Protonation by Palladium Mediated Decarboxylative Protonation – B. M. Stoltz

Mohr, J. T.; Nishimata, T.; Behenna, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2006, 128, 11348-11349.Marinescu, S. C.; Nishimata, T.; Mohr, J. T.; Stoltz, B. M. Org. Lett. 2008, 10, 1039-1042.Behenna, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2004, 126, 15044-15045.

OMe

O

O

PPh2 N

O

t-BuPd2(dba)3

Et2O, rt, 10 h

O

Me

PdN P

*

OMe

97%, 92% ee


Mohr, J. T.; Nishimata, T.; Behenna, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2006, 128, 11348-11349.Marinescu, S. C.; Nishimata, T.; Mohr, J. T.; Stoltz, B. M. Org. Lett. 2008, 10, 1039-1042.Behenna, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2004, 126, 15044-15045.

OMe

O

O

PPh2 N

O

t-BuPd2(dba)3

Et2O, rt, 10 h

O

Me

PdN P

*

OMe

97%, 92% ee

H

OMe

H

?


Mohr, J. T.; Nishimata, T.; Behenna, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2006, 128, 11348-11349.Marinescu, S. C.; Nishimata, T.; Mohr, J. T.; Stoltz, B. M. Org. Lett. 2008, 10, 1039-1042.

OMe

O

O

PPh2 N

O

t-Bu

Pd(OAc)2 (10 mol%)

HCO2H (2.5 equiv), 4Å MSDioxane [0.033M], 3 to 22 h

(12.5 mol%)

OMe

H

88%, 94% ee



OMe

O

O

PPh2 N

O

t-Bu

Pd(OAc)2 (10 mol%)


(12.5 mol%)

OMe

H

88%, 94% ee

OF

H

79%, 88% ee

MeO

MeO

OMe

H

62%, 94% ee

Bn

O

91%, 92% ee

H

NBn

O

81%, 84% ee

H



OMe

O

O

PPh2 N

O

t-Bu

Pd(OAc)2 (10 mol%)


(12.5 mol%)

OMe

H

88%, 94% ee

OF

H

79%, 88% ee

MeO

MeO

OMe

H

62%, 94% ee

Bn

O

91%, 92% ee

H

NBn

O

81%, 84% ee

H

• Excess of HCO2H led to decreased enantioselectivitydecreased enantioselectivity, while smaller amounts of HCO2H increased allylation.increased allylation.

• Small amount of 4Å MS decreased enantioselectivity, decreased enantioselectivity, while large quantity increased allylation.increased allylation.

• 5-8 equiv of HCO5-8 equiv of HCO22H H and 1.80g 4Å MS/mmol 1.80g 4Å MS/mmol substrate was optimal…



OMe

O

O

PPh2 N

O

t-Bu

Pd2(dba)2 (5 mol%)

Meldrum's acid (2.5 equiv)Dioxane [0.033M], 0.5 to 5 h

(12.5 mol%)

OMe

H

86%, 90% ee (on 0.1 mmol)86%, 77% ee (on 0.3 mmol)

O O

O O

Meldrum's acid

HO


HO


H

OTBDPS

O

97%, 85% ee (on 0.1 mmol)97%, 80% ee (on 0.3 mmol) 79%, 61% ee (on 0.3 mmol)

O

Me

H



PdL

P N

L

*

- CO2

O

OO

O

OO

Pd

L

P

N

*O

Pd

OOP N

*

PdO

P N

*

O O

O O

HO

R

O O

O O

PdP N

*

O O

OO

Concluding Remarks – Take Home Message

S

CO2H

Me

CO2H

AMDase (cat.)Tris/HCl buffer

H2O

Me

Ar

O

O

O

OH

HS

Cys188

Gly78

-CO2 S

CO2H

Me

H

Wild-type enzyme, 99% eeG74C mutant, 0% ee

G74C/C1885 mutant, -94% ee

Matoishi, K.; Ueda, M.; Miyamoto, M.; Ohta, H. J. Mol. Catal. B 2004, 27, 161-168.Blanchet, J.; Baudoux, J.; Amere, M.; Lasne, M.-C.; Rouden, J. Eur. J. Org. Chem. 2008, 5493-5506.

• A great deal of energy has been put to introduce a simple proton to form chiral enantioenriched tertiary carbon center

• Although we have ennumerated numerous parameters that are critical to achieve high enantioselectivities, few mechanistic understanding of their behaviour are proposed yet.

• ‘‘AP’’ can be used for making α- and β-amino acids and few natural products• Enantioselective protonnation should continue to rise as an important tool for understanding

general organic chemistry

enantioselective protonation: fundamental insights and new concepts

Documents

chiral acid duhamel

proton donnor

stereodefined proton

enol tautomerisation

important facts

amino acid

useful example of ap

new concepts