Asymmetric Catalytic Aldol

Special Topic 27/04/2007

Hazel Turner

Contents

• The Aldol Reaction• The Directed Aldol

Chiral AuxiliariesExamples

Mukaiyama AldolAcceptor activation

TitaniumZirconiumCopperBoron

Donor ActivationRhodium, Palladium, Phosporamides

• The Direct AldolBiochemical Catalysis

AldolasesAntibodies

Bifunctional Catalysis OrganocatalysisChiral quaternary Salts

• References

The Aldol Reaction

• Reaction to construct a new carbon-carbon bond.• The reaction between carbonyl nucleophile, i.e. enolizable

aldehyde, ketone or carboxylic acid derivative and a carbonyl electrophile usually an aldehyde but occasionally a ketone.

• Formation of two adjacent new stereocentres.

R1

O

R2

H

R3 H(R4)

O

R1

O

R2

R3

OHH(R4)

The Directed Aldol

• “directed” methodologies rely on prior transformation of the carbonyl nucleophile into its corresponding enolate or enolate equivalent in a separate step.

• These reactions rely on either a stoichiometric chiral source (chiral auxiliary-based aldol) or a catalytic quantity of a chiral promoter principally the Mukaiyama aldol reaction.

• Additional steps required for the attachment/detachment of a chiral inductor and the requirement of stoichiometric quantities can be major disadvantages for this approach.

• However these methods tend to be highly reliable with broad substrate tolerance.

R1

O-M+

R2

R1

N

R2

Li

R1

O

R2

SiR3

R1

N

R2

R2

R1

O

R2

BBu2

aza enolate Sily enol ether enamine boron enolate

Chiral Auxiliary Based Methods

• A chiral auxiliary is attached to an achiral substrate to induce chirality during aldolization and then removed.

• Generation of the Z-enolate via a boron mediated aldol reacts through a 6 membered chair-shaped “Zimmerman-Traxler” model to give the syn aldol product, the E-enolates react to give the anti aldol products.

• Famously exemplified using Evans oxazolidin-2-one developed 20 years ago.

O N

O O

O N

O O

R

OH

a) Bu2BOTf, iPr2EtN, CH2Cl2, 0oC

b) RCHO, -78oC to 0oC

Evans Example

JACS, 1992, 114, 24, 9434-9453

Non Evans syn Aldols

• Evans syn-aldol results from a Zimmerman-traxler type TS with Ti coordinated to both enolate and aldehyde Oxygen.

• Using 2 equivs of TiCl4 it is believed a TS results from a third coordination of Ti with the thiocarbonyl group to give the non-Evans aldol product.

• When either Sparteine or TMEDA are used only the Evans syn product is formed presumably due to coordination with the metal preventing the non Evans pathway.

O N

S O

Ph

O N

S O

Ph

R

OH

O N

S O

Ph

R

OH

RCHO, TiCl4 (1 equiv), TMEDAor (-)-sparteine (2.5 equiv)0oC

RCHO, TiCl4 (2 equiv), iPr2EtN (1 equiv)-78oC

80-90%syn/anti >99:1

80-85%syn/anti >95:5

Evans syn>98:2

non Evans-syn>99:1

Anti-Aldols via auxiliaries

• Most auxiliary mediated methodologies generate the syn Aldol products.

• E-configured enolates needed to give anti products are not favoured• Auxiliaries derived from (-)-norephedrine and camphor have been

employed to generate anti-aldols

Mukaiyama Type Catalytic Aldol Reactions

• The Mukaiyama aldol reaction is the reaction of a silyl enol ether to an aldehyde in the presence of a lewis acid to yield an aldol.

• The reaction involves the stoichiometric generation of a trialkylsily enol ether in a separate and distinct chemical step and so the Mukaiyama reaction is only catalytic in metal promoter.

R1 H

O

R3

OTMS

R1 R3

O O*L

R2 R2R1

R3

O O

R2

R3Si

Mukaiyama-type catalytic Aldol – Acceptor Activation

• The first successful catalytic asymmetric Mukaiyama reactions were achieved with Sn (II) complexes in the presence of chiral diamines.

• The reaction between aldehydes and Ketene silyl acetals are highly enantioselective with ee >98%

• Since then considerable interest has been paid to Titanium (IV) catalysts, along with copper (II) complexes, and Boron complexes.

Titanium Complexes

• The most successful ligands for titanium (IV) have been (R)- or (S) BINOL derived.

Zirconium Catalysis

• Bulky Zr catalysts afford preferentially anti aldols independent of the sily enolate geometry.

• Small amounts of protic additives (alcohols) are critical for catalyst turnover.

JACS, 2002, 124, 3292

Copper Catalysis

• Bis(oxazolinyl)copper (II) complexes have been shown to be effective chiral lewis acids for the Mukaiyama aldol.

Boron Catalysis

Boron Catalysis-question

Mukaiyama-type catalytic Aldol – Donor Activation

• Catalytic activation of the donor rather than the acceptor is an alternative approach.

• Rhodium and Palladium complexes and Phosphamides have been utilised in this way.

Rhodium Complexes

• The Rhodium (I) complex below coordinated with trans-chelating chiral diphosphane TRAP.

• Activation of the ester donor is via the cyano group.• The anti isomers predominate suggesting an open anti-periplanar

transition state.

Palladium and Phosphoramides as Donor Activators

JACS, 1999, 121, 4982

Direct Catalytic Aldol

• “Direct” aldol reactions do not rely on modified carbonyl donors and required sub-stoichiometric quantities of promotor (catalyst)

• Therfore these reactions are atom economical.• Two main groups

a) biochemical catalysis: Aldolases and Antibodiesb) chemical catalysis: Bifunctional Catalysis and

Organocatalysis

Biochemical Catalysis

• Enzymes are generally highly chemo-, regio-, diastereo-, and enantioselective.

• Require mild conditions• Their reactions are often compatible with one another

making one-pot reactions feasible• Environmentally friendly• However narrow substrate tolerance!• Two types of enzymatic catalysts that effect aldol

addition:a) The aldolases: a group of naturally occurring enzymes that catalyse in vivo aldol condensationsand b) Catalytic antibodies that have been developed to mimic aldolases but with improved substrate specificity.

Aldolases

• Aldolases are a specific group of lysases that catalyse the stereoselective addition of a ketone donor to an aldehyde acceptor.

• Over 30 have been identified to date• Type I aldolases are primarily found in animals and

plants and activate the donor by forming a schiff base as an intermediate.

• Type II aldolases are found in bacteria and fungi and contain a Zn2+ cofactor in the active site.

• In both types of aldolases the formation of the enolate is rate determining.

• These enzymes generally tolerate a broad range of acceptor substrates but have stringent requirements for the donor substrates.

Aldolase mechanism pathways

Example-Type I

Example - Type II

Catalytic Antibodies

• Antibodies are designed to resemble the transition states in Aldolases.

• Specific functional groups can be induced into the binding site to perform general acid/base catalysis, nucleophilic/electrophilic catalysis and catalysis by strain or proximity effects.

• Antibodies recently developed have the ability to match the efficiency of natural aldolases while accepting a more diverse range of substrates.

R H

O

R2

O

NAb

R2

R3 R3

R

HO H

R R2

OOH

R3

Transition state

antibody

O

SNH

AbR

OO

reactive immunization

transition stateanalogue

Example Ab38C2

Bifunctional Catalysis

• Catalysts have been developed to mimic Type(II) aldolases with both lewis acid and a lithium binaphthoxide moiety which serves as a Bronsted base.

• These reactions are examples of chemical direct aldols.

• The multifunctional LLB incorporates a central lanthanide atom, which serves as a Lewis Acid and a lithium binaphthoxide moiety serves as a Bronsted Base.

Bifunctional Catalysis

Bifunctional Catalysis

Chem. Soc. Rev. 2006, 35, 269-279

Organocatalysis

• L-Proline was shown to promote the aldol addition of acetone to an array of aldehydes in upto >99% ee.

• The catalytic cycle proceeds via an enamine intermediate.• Enamine mechanisms are prominent in aldol reactions catalysed by

aldolase type I enzymes and antibodies.• Propose the transistion state of acetone RCHO with L-proline?

O

OH

RCHO

NH

CO2H

(20-30 mol %)

DMSO, rt

O

OH

R

OH

Aldehyde Yield d.r ee%

cC6H11CHO 60% >20:1 >99

(CH3)2CHCHO 62% >20:1 >99

Ph(Me)CHCHO 51% >20:1 >95

2-Cl-PhCHO 95% 1.5:1 67

(CH3)3CCH

2CHO 38% 1.7:1 >97

Transition state

OH

NR

H

Me

O

O

H

Organocatalysis

Tetrahedron Asym. 2007, 265-278

Imidazolidinone Organocatalysis

Angew. Chem. Int, Ed, 2004, 43, 6722-6724

Chiral Quaternary Salts

• Binaphthyl derived quaternary ammonium salts in as little as 2 mol% loading have been used to form aldol addition products.

JACS, 2004, 126, 9685-9694

References

• Chem. Soc. Rev. 2004, 33, 65-75• Angew. Chem. Int. Ed. 2000, 39, 1352-1374• Eur. J. Org. Chem. 2002, 1595-1601• Chem. Eur. J. 2002, 8, 37-44• Eur. J. Org. Chem. 2006, 4779-4786