asymmetric catalytic aldol special topic 27/04/2007 hazel turner
TRANSCRIPT
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