Transcript Asymmetric Catalytic Aldol

Asymmetric Catalytic Aldol
Special Topic 27/04/2007
Hazel Turner
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
Aldolases
Antibodies
Bifunctional Catalysis
Organocatalysis
Chiral 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.
O
O
R2
1
R
H
R3
O
H(R4)
R1

OH
4
 H(R )
R3
R2
The Directed Aldol
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•
•
•
“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.
O-M+
N
2
1
R
R
Li
O
2
1
R
R
aza enolate
1
R
SiR3
R2
Sily enol ether
N
1
R
R2
O
R2
enamine
1
R
BBu2
R2
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
O
N
O
O
O
a) Bu2BOTf, iPr2EtN, CH2Cl2, 0oC
b) RCHO, -78oC to 0oC
O
N
OH
R
Evans Example
JACS, 1992, 114, 24, 9434-9453
Non Evans syn Aldols
O
S
RCHO, TiCl4 (1 equiv), TMEDA
or (-)-sparteine (2.5 equiv)
0oC
O
S
O
80-90%
syn/anti >99:1
O
OH
N
R
Ph
Evans syn
>98:2
N
Ph
O
OH
S
RCHO, TiCl4 (2 equiv),
R
iPr2EtN (1 equiv)
O N
o
-78 C
80-85%
Ph non Evans-syn
syn/anti >95:5
>99:1
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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.
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.
OTMS
O
R1
R3
H
R2
*L
R1
O
R3Si
O

R2
R3
R1
O
O

R2
R3
Mukaiyama-type catalytic Aldol –
Acceptor Activation
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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 Antibodies
b) 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 condensations
and 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
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•
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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.
O
O
R
antibody
R
R2
H
R2
HO H
OH O
N
Ab
R3
R3
R2
R
R3
Transition state
transition state
analogue
R
O
O
S
N
H
O
Ab
reactive immunization
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?
CO2H
N
H
(20-30 mol %)
O
O
OH
RCHO
OH
R
DMSO, rt
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)3CCH2CHO
38%
1.7:1
>97
Transition state
N
R
O
H
H
O
Me
H
O
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
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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