Asymmetric Catalytic Aldol

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Asymmetric Catalytic Aldol

• Special Topic 27/04/2007
• Hazel Turner

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Contents

• The Aldol Reaction
• The Directed Aldol Chiral Auxiliaries Examples
  Mukaiyama Aldol Acceptor activation Titanium
  Zirconium Copper Boron Donor
  Activation Rhodium, Palladium, Phosporamides
• The Direct Aldol Biochemical Catalysis Aldolase
  s Antibodies Bifunctional Catalysis
  Organocatalysis Chiral quaternary Salts
• References

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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.

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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.

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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.

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Evans Example
JACS, 1992, 114, 24, 9434-9453
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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.

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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

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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.

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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 gt98
• Since then considerable interest has been paid to
  Titanium (IV) catalysts, along with copper (II)
  complexes, and Boron complexes.

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Titanium Complexes

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

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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
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Copper Catalysis

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

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Boron Catalysis
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Boron Catalysis-question
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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.

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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.

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Palladium and Phosphoramides as Donor Activators
JACS, 1999, 121, 4982
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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 groupsa) biochemical catalysis
  Aldolases and Antibodiesb) chemical catalysis
  Bifunctional Catalysis and Organocatalysis

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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 additiona) 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.

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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.

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Aldolase mechanism pathways
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Example-Type I
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Example - Type II
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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.

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Example Ab38C2
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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.

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Bifunctional Catalysis
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Bifunctional Catalysis
Chem. Soc. Rev. 2006, 35, 269-279
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Organocatalysis

• L-Proline was shown to promote the aldol addition
  of acetone to an array of aldehydes in upto gt99
  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?

Aldehyde Yield d.r ee
cC6H11CHO 60 gt201 gt99
(CH3)2CHCHO 62 gt201 gt99
Ph(Me)CHCHO 51 gt201 gt95
2-Cl-PhCHO 95 1.51 67
(CH3)3CCH2CHO 38 1.71 gt97
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Transition state
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Organocatalysis
Tetrahedron Asym. 2007, 265-278
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Imidazolidinone Organocatalysis
Angew. Chem. Int, Ed, 2004, 43, 6722-6724
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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
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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