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Aspects of Asymmetric Nucleophilic Amine Catalysis:Organocatalyst Design and Implementation

MacMillan Group MeetingIan Storer

February 28, 2005


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Asymmetric Nucleophilic CatalysisOutline

! Introduction to

N-centred nucleophilic catalysts

! Design, development and application of asymmetric nucleophilic catalysts

!concepts and definitions

!origins and requirements

!Natural alkaloid catalysts - Precejus, Wynberg

!Biomimetic histidine containing peptide catalysts - Miller

!

Synthetic alkaloid analogues - Lectka, Hatekeyama, Deng

Useful Reviews:

!

Fance, S.; Guerin, D. J.; Miller, S. J.; Leckta, T., Nucleophilic Chiral Amines as Catalysts inAsymmetric Synthesis. Chem Rev.2003, 103, 2985-3012.

!Fu, G. C. Asymmetric Catalysis with "Planar-Chiral" Derivatives of DMAP. Acc. Chem. Res.2004,37, 542-547.

!Asymmetric DMAP equivalents - Fuji / Fu

!Miller, S. J. In Search of Peptide-Based Catalysts for Asymmetric Organic Synthesis. Acc. Chem.Res. 2004, 37, 601-610.


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Definitions

! Nucleophilic Catalysis

Catalysis by a Lewis base, involving formation of a Lewis adduct as a reaction intermediate. For example,the esterification of anhydrides catalysed by DMAP:

O

OR R

O

O R

O

Lewis base

Lewis base complex

N

Lewis base

! Lewis base

OH

R1 R3

R2N

NMe Me

N

NMe Me

O RO R

O

R3

R1

R2

IUPAC Compendium of ChemicalTerminology

A molecular entity (and the corresponding chemical species) able to provide a pair of electrons and thuscapable of coordination to a Lewis acid, thereby producing a Lewis adduct.

The catalyst has to be a very effective nucleophile and a good leaving group .

! Implication on Choice of catalyst

N

MeMe


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Useful Nucleophilic Catalysts

! Commonly applied 'everyday' nucleophilic catalysts

N

NMe Me

! Common applications

N

N

N N

HN

Nucleophilic Aromatic Amines nucleophilic teriary amines

! Ineffective bases: Nucleophilicity highly sensitive to steric and electronic factors

N

DABCOImidazolePyridineDMAP

good Bronsted bases, poor nucleophilic catalysts

Me N Me N MeMe Me

Me

picoline lutidine collidine

!O-acylation - electrophile activation (pyridine, DMAP)!O-silylation - electrophile activation (imidazole, DMAP)!Baylis-Hilman reaction - nucleophile activation (DABCO, DMAP)

N

N

PPY

N

N

Me

NMI

N

Et

EtEt

TEA


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Cinchona Alkaloids: Earliest Successful Nucleophilic Asymmetric Catalysts

!First used for a resolution of a racemate in 1853 by Pasteur.

N

R1

HOH

H

N

H

Cinchonidine (CD)Quinine (QN)

R1= H

R1= OMe

pseudoenantiomers

N

R1

HHO

N

H

Cinchonine (CN)Quinidine (QD)

R1= H

R1= OMe

H

!Asymmetric Bronsted bases!Asymmetric phase transfer reagents (as salts)!Asymmetric bifunctional catalysts (acid / base)!Asymmetric nucleophilic catalysts

!Several modes of application

Moncure, R. MacMillan Group Meeting, 2003, web. contains a more fully discussion of cinchona alkaloids


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QuinidinePracejus (1964)Wynberg (1983)Simpkins (2001)

site of quaternary saltformation, nucleophilicaddition or basicity

site of modification

site of modification:ether/ ester formation

site of inversion ofconfiguration (epi alkaloids)-pseudoenantiomers

Alkaloids and Derivatives as Nucleophilic Catalysts

! Natural alkaloids

N

OMe

H

N

OH H

O O

O O

N OMe

N

Et

H

N

Et

NMeO

(DHQD)2AQNDeng

N

Me

O

N

OH

Hatakeyama

N

OMe

N

O H

benzoylquinineLectka (2000)

O

! Synthetically modified analogues


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Seminal Findings: Pracejus Methanolysis of Ketenes

!Pracejus proposed a mechanism involving QN activation of methanol.

N

OMe

H

N

OH H

QuinidineMe Ph

O12 mol % quinidine

MeOH, 110 C

up to 76% ee

Precejus, H.; Mtje, H. J. Prakt. Chem. 4. Reihe. 1964, 24, 195.Precejus, H.; Santleben, R. J. Prakt. Chem. 1972, 314, 157.

O

OMePh

Me

NHR3

O

OMePh

Me

NMeO

H

N

HO

Hselective

protonationH

OMe

+MeOH

H-bond activation

!Simpkins proposes alternative nucleophilic mechanism

Me3Si Bn

O

10 mol % quinidine

benzene, 78 C 79-93% ee

O

SPhBn

SiMe3

NMeO

H

N

HO

H

PhSH

O

NR3Bn

SiMe3

selectiveprotonation

Blake, A. J.; Friend, C. L.; Outram, R. J.; Simpkins, N. S.; Whitehead, A. J. Tetrahedron Lett. 2001, 42, 2877.

SPh


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Development of Functionalised Alkaloid Analogues:Catalytic Asymmetric Cycloadditions

!!-lactone synthesis: Romo's expansion of Wynberg's method

N

OMe

HN

O H

Acyl-quinidine

H

O

CCl2R2 O

O

R

2

Cl2C

R1= H, alkyl, arylR2= Cl, alkyl

O

Me

R

1

O

ClR1

O

NR3

R1Base: iPr2NEt

PhMe, 25 C

>90% ee

!The use of pre-acylated catalyst stops unwanted acylation of the catalyst during the reaction.

!Applies a stoichiometric, non-nucleophilic base to turn over the catalyst.

!In situ ketene generation

!Solubility of the Hunigs salt may be crucial to catalyst turnover.

Tennyson, R.; Romo, D. J. Org. Chem. 2000, 65, 7248.

2 mol% cat.

R3Ncat.


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Development of Functionalised Alkaloid Analogues:Catalytic Asymmetric Cycloadditions

N

OMe

H

N

O H

Benzoyl-quinidine

O

!

!-lactam synthesis: Lectka

NO

EtO2C R1

O

ClR1

O

NR3

R

1

N

CO2EtH

Ts

N

CO2EtH

Ts

O

NR3

R

1

EtO2C

NTs

R3Ncat.

10 mol% cat.PhMe, 78 C

Base: proton sponge or K2CO3or NaH

Ts 45-65% yield

95-99% ee25-99:1 dr

Taggi, A. E.; Hafez, A. M.; Wack, H.; Young, B.; Drury, W. J.; Lectka, T. J.. J. Am. Chem. Soc. 2000, 122, 7831.Taggi, A. E.; Hafez, A. M.; Wack, H.; Young, B.; Ferraris, D.; Lectka, T. J.. J. Am. Chem. Soc. 2002, 124, 6626.

cat.

!'Shuttle deprotonation' using excess of a thermodynamic, non-nucleophilic base.!Concomitant Lewis acid activation of the imine later provided better yields

!Proposed transition state


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Development of Functionalised Alkaloid Analogues:Catalytic Asymmetric Halogenation

N

OMe

H

N

O H

Benzoyl-quinidine

O

!Halogenation: Lectka

O

ClR1

10 mol% cat.

THF, 78 C

Base: BEMP orK2CO3or NaH

Wack, H.; Taggi, A. E.; Hafez, A. M.; Drury, W. J.; Lectka, T. J. J. Am. Chem. Soc. 2001, 123, 1531.Hafez, A. M.; Taggi, A. E.; Wack, H.; Esterbrook, J.; Lectka, T. J. Org. Lett. 2001, 3, 2049.

Taggi, A. E.; Wack, H.; Hafez, A. M.; France, S.; Lectka, T. J. Org. Lett. 2002, 4, 627.

OCl

ClCl

Cl

Cl

Cl

O

BrBr

Br Br

MeN NMeP

NEt2NBut

10 mol% cat.

THF, 78 C

Base: BEMP orK2CO3or NaH

O

ClR1

O

OR1

Br

Br

Br

Br

O

OR1

Cl

Cl

Cl

Cl

Cl

Cl

65-85% yield99% ee

55-80% yield>90% ee


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Deng's Application of bis-quinuclidines

N

MeO

O

H

N

H

Et

N N

Ph

Ph

O

N

OMeH

H

N

Et

catalyst

!Mechanism of asymmetric induction not well understood

!Cyanation

O

OEtR3N

CN NC

R1

R2

OO

OEtR3N

Deng, L. et al. J. Am. Chem. Soc. 2001, 123, 7475.

R1

O

R2 NC

O

OEt

10-35 mol% catalyst

CHCl3, 12 to 24 C0.5 - 7 days

NC

R1R2

O

O

OEt

R1

O

R2

R3Ncat.

O

O

O

R

R

MeOH5-30 mol% catalyst

Et2OOMe

OH

O

O

R

R

( )n( )n

Deng, L. et al. J. Am. Chem. Soc. 2000, 122, 9542.

!Desymmmetrization of meso anhydrides

52-78% yield87-97% ee

70-99% yield90-98% ee


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Designing Asymmetric Variants of Known Nucleophilic Amine Catalysts

! Considerations

! Synthetic chiral analogues of common nucleophilic heterocycles

!Must be nucleophilc, but maintain good leaving group ability!Must have a valid chiral pocket to transfer asymmetry to product.

FeN

NMeMe

Ph

Ph

Ph

Ph

Ph N

N

H H

OH

Synthetic chiral DMAP equivalents

Fu (1998-current)

N

N

BocHNO

O

NH

NH

Me

Me Me

O

Synthetic chiral imidazole equivalents

Miller

O O

O O

N OMe

N

Et

H

N

Et

NMeO

(DHQD)2AQNDeng

N

OMe

H

N

OH H

QuinineWynberg

N

Me

O

N

OH

Hatakeyama

! Alkaloids and analogues


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Biological Role of Nucleophilic Catalysis

Admiraal, S. J.; Herschlag, D.; J. Am. Chem. Soc., 1999, 121, 5837-5845

!Phosphorylation transfer from ATP is ubiquitous in biological chemistry.!

Histidine often serves as in vivoacceptors of the !-phosphate of ATP.!Proposed mechanism of ATPases and nucleoside diphosphate kinase (NDPK).

O

OH OH

AOPO

O

O

P

O

O

OP

O

O

OO

OH OH

AOPO

O

O

P

O

O

OP

O

O

E

NH

N

O

E

NH

N

ATP

! Mechanism of some kinases - role of histidine

ADP

NDP3 E

NH

N

NTP4fast

!First in vitro example of imidazole participating in phosphoryl transfer from ATP analogues.!N-nucleophiles found to react 30-100 fold faster than O-nucleophiles at physiological temperatures.!Carried out in vitro experiments on ATP.!Supports proposed enzymatic mechanism.

OP

O

O

O P

O

O

NH

N

O

NH

NH2O

NH

N

HOPO32

fast

NO2 O NO2

! In vitro phosphorylation of imidazole


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Miller N-Methyl Imidazole-Containing Tripeptide

! Synthesis of a nucleophilic tripeptide

Miller, S. J.; Copeland, G. T.; Papaioannou, N.; Horstmann, T. E.; Ruel, E. M. J. Am. Chem. Soc. 1998, 120, 1629-1630.

N

N

BocHNO

O

NH

NH

Me

Me Me

O

N

N

H2N

OH

O

N

N

BocHNO

O

NH

NH

Me

Me Me

O

MeO

Ac2O

OAc

acyl imidazolium

!Peptide-substrate interactions are crucial for the fidelity by which an enzyme imparts its selectivity.

!Incorporating an amino acid residue as an analogue of known nucleophilic catalyst N-methyl imidazolium (NMI).

!Work focused on peptides that had propensity to form stable secondary structures (!-turn) in solution.

! Modularity of peptide-based systems allows for the rapid synthesis and screening of many analogues.

!Initial designs drew heavily from the peptide design literature in order to generate a relatively rigid !-turn structure


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Miller Chiral Imidazole Tripeptide:Kinetic Resolution of Alcohols

! Kinetic resolution of amino-alcoholscatalyst

anti, racemic

10 equiv

O

Me O Me

O

5 mol% catalyst0 C

Miller, S. J.; Copeland, G. T.; Papaioannou, N.; Horstmann, T. E.; Ruel, E. M. J. Am. Chem. Soc. 1998, 120, 1629-1630.

NHAc

OH

NHAc

OH

NHAc

O Me

O1.0 equiv CH3CN = 12% eeCH2Cl2 = 40% eePhMe = 84% ee (S = 12.6)

!Amide in amino-alcohols necessary for good levels of stereoinduction

!Non-polar solvents which favour H-bonding work best

!Replacement of the amide with an ester provides only poor selectivity

N

N

BocHNO

O

NH

NH

Me

Me Me

O

! Kinetic resolution of mono-acylated diols

anti, racemic

10 equiv

O

Me O Me

O

5 mol% catalyst0 C

OAc

OH

OAc

OH

OAc

O Me

O1.0 equivPhMe = 14% ee


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Probing Origins of Selectivity

! Diastereomeric catalysts display enantiodivergence

Copeland, G. T.; Miller, S. J. J. Am. Chem. Soc. 1999, 121, 4306.

Harris, R. F.; Nation, A. J.; Copeland, G. T.; Miller, S. J. J. Am. Chem. Soc. 2000, 122, 11270.

NN

BocHNO

O

NH

NH

Bn

O

OMe

Me Me

O

!Changing a single stereocentre in the catalyst causes a change in secondary structure.

!

Changing a single stereocentre in the catalyst causes a complete switch in enantioselectivity.

! What is the mechanism of binding and role of the peptide backbone structure?

H

Me

N

O

O

NH

NH

Bn

O

OMe

Me Me

OH

HN

N

Me

Boc

S = kSS/ kRR= 3.1 S = kRR/ kSS= 28

L-Pro D-Pro

anti, racemic10 equiv

O

Me O Me

O

5 mol% catalyst0 C

NHAc

OH

NHAc

OH

NHAc

O Me

O1.0 equiv

! Test System: Kinetic resolution


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Miller: Development of a Fluorescence Assay

Copeland, G. T.; Miller, S. J. J. Am. Chem. Soc.. 1999, 121, 4306.Harris, R. F.; Nation, A. J.; Copeland, G. T.; Miller, S. J. J. Am. Chem. Soc.. 2000, 122, 11270.

! Development of a fluorescence probe for rapid reaction conversion analysis

N

O

OMe

H

OAc

N

O

OMe

Non-Fluorescent Fluorescent

!Fluorescence intensity is a function of acetic acid concentration

!Assisted rapid catalyst discovery.

AcOH

! Kinetic resolution of amino-alcohols

O

Me O Me

O

catalyst

NHAc

OH

NHAc

OH

NHAc

O Me

O1.0 equivAcOH

reaction byproduct


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Fuji Chiral DMAP Equivalent:Kinetic Resolution of Alcohols

! Kinetic Resolution of Alcohols catalyst

syn, racemic

O

Bui O iBu

O

5 mol% catalysttoluene, rt, 2-5 h

Kawabata, T.; Nagato, M.; Takasu, K.; Fuji, K. J. Am. Chem. Soc. 1997, 119, 3169-3170.

! Induced-fit Mechanism

N

N

H

H

OH

OCOR

OH

OCOR

OH

OCOR

O iBu

O0.7 equiv81->94% ee

68-72% conv.

N N

H H

HO

H

H

open conformation

NN

H H

reactive, closed conformation

OH

O

H

Me

Me

Nu

!

First non-enzymatic chiral resolution of alcohols

!

Take advantage of charged Lewis adduct!Cation-p interaction holds transition state rigid

O

Bui O iBu

O


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Fu - Planar Chirality: Kinetic Resolution of Alcohols

! Kinetic Resolution of Alcohols

FeN

NMeMe

Ph

Ph

Ph

Ph

Ph

catalyst

OH

R1 R2

racemic

O

Me O Me

O

2 mol% catalystEt3N,t-amyl alcohol

OH

R1 R2

O

R1 R2

O

Me

Me

OH

tBu

OH OHCl

Me

OH

F

Me

OH

Me

OH

Me

OH

Me

99% ee55% conv.

99% ee55% conv.

99% ee55% conv.

99% ee55% conv.

99% ee55% conv.

99% ee55% conv.

99% ee55% conv.

Ruble, J. C.; Latham, H. A.; Fu, G. C. J. Am. Chem. Soc. 1997, 119, 1492-1493.Ruble, J. C.;Tweddell, J.; Fu, G. C. J. Org. Chem. 1998, 63, 2794-2795.

! Very high enantioselectivities for Aryl and Cinnamyl alcohols


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Fu Chiral DMAP: Origins of Enantioselectivity

!Acetyl rotamer consistent with minimization of sterics between the methyl Rgroup and ferrocene.

!Selectivity increases as the size of the alkyl group Rincreases.

!Nucleophile approaches from the top face of the DMAP catalyst.

! Geometry of acyl rotamers

FeN

NMeMe

Ph

Ph

Ph

Ph

PhO

Me

FeN

NMeMe

Ph

Ph

Ph

Ph

PhMe

O

HH

Favoured rotamer Disfavoured rotamer

! Crystal Structure of Acyl salt

FeN

NMeMe

Ph

Ph

Ph

Ph

PhO

Me

Nu

Nu


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! The substrate amine is nucleophilic enough to add directly to most acylating agents careful selection of acylating reagent proved necessary to render no background reaction

Kinetic Resolution of Amines

!First non-enzymatic acylation catalyst for kinetic resolution of amines

FeN

Ph

Ph

Ph

Ph

Ph

catalyst

NH2

Ar Me

racemicCHCl3, 50 C

NH2

Ar Me

HN

Ar Me

O

Me

Me

NH2

Me

NH2

s=12 s=27

Arai, S.; Laponnaz-Bellemin, S.; Fu, G. C. Angew. Chem. Int. Ed., 2001, 40, 234-236.

! Very high enantioselectivities for Aryl and Cinnamyl alcohols

NO

OMeO

N

O

!-naph

But

Me

NH2

s=22

MeO

NH2

s=16

Me

10 mol% catalyst

reacts faster with catalystthan substrate amine


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Rearrangement of O-Acylated Azalactones

!First non-enzymatic acylation catalyst for kinetic resolution of amines

FeN

Ph

Ph

Ph

Ph

Ph

catalyst

0 C, t-amyl alcohol2-6 h

Ruble, J. C.; Fu, G. C. J. Am. Chem. Soc., 1998, 120, 11532-11533.

! Direct synthesis of dipeptides

NO

XO

N

O

R2

R1

10 mol% catalyst O

!

N

O

R2

R1

O

X

X = OMe, OBnR1= Me, Et, Bn

R

2

= Me, Ph, PMP

54-90% ee

0 C, t-amyl alcohol2-6 h

O

OBnO

N

OMe 10 mol% catalyst

O

N

OMe

O

BnO

0 C, t-amyl alcohol

2-6 h

10 mol% catalyst

OMe OMe

91% ee91% yield

Me NH

NH

O Me

OMe

O

O

BnO

O

OMe

95% yielddipeptide


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Chiral Planar DMAP Analogues: Rearrangements

!Intramolecular rearrangement of O-acylated oxindoles and benzofurans

FeN

Ph

Ph

Ph

Ph

Ph

catalyst

CH2Cl2, 35 C

Hills, I. D.; Fu, G. C. Angew. Chem. Int. Ed., 2003, 42, 3921-3924.

! A crystal structure was obtained

N

5 mol% catalyst

X = NMe, OR1= alkyl, aryl

72-95% yield88-99% ee

X

R1

O

OR2O

X

O

O

OR2R1

FeN

N

PhPh

Ph

PhPhO

O

R2

OPh

O

endo (cation-!)


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Chiral Planar DMAP Analogues: Rearrangements

!Intermolecular C-acylation of silyl ketene acetals

FeN

Ph

PhPh

Ph

Ph

catalyst

Et2O, CH2Cl2, 23 C

Mermerian, A. H.; Fu, G. C. J. Am. Chem. Soc., 2003, 125, 4050-4051.

N

5 mol% catalyst

R1= aryl

R2= H, Me

73-92% yield80-99% eeO

R2

R2

OTMS

R1O

R2

R2

O

R1Me

O

O

OMe Me

O

!Currently limited to !-aryl substrates

O

NR3Me O Me

O

O

R2

R2

OTMS

R1

O

NR3Me

O

R2

R2

O

R1

cat.cat.

TMSOAc


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Chiral Planar DMAP Analogues: Reactions with Ketenes

!!-lactam Staudinger synthesis

NO

R1

O

NR3

R1

N

R2H

Ts

N

CO2EtH

Ts

O

NR3

R1

EtO2C

NTs

R3Ncat.

10 mol% cat.

PhMe, 78 C

Ts

45-65% yield95-99% ee8:1-15:1 dr

Hodous, B. L.; Fu, G. C. J. Am. Chem. Soc. 2002, 124, 1578-1579.

cat.

!Reaction successful for both symmetrical and unsymmetrical ketenes

FeN

Me

Me

Me

Me

Me

catalyst

N

Ph R1

O

Ph

zwitterion A zwitterion B

R1 = alkyl, R2= alkyl, aryl

PhR2


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Summary and Conclusions

! Miller's combinatorial approach has successfully obtained catalysts that show high selectivity

! Natural and synthetic alkaloids continue to have success across a variety of reaction types, although definitive stereochemical rationale is not always possible

! Fu has developed the first truly general synthetic DMAP analogue catalyst system. Led the way in showing that nucleophilic catalysis is a general and useful concept.

! Chiral amines have become functional nucleophilic catalysts, having been larglyoverlooked until recently.

fu catalyst 1

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