Asymmetric Catalytic Aldol

1. Asymmetric Catalytic Aldol Special Topic 27/04/2007 Hazel Turner

2. Contents • The Aldol Reaction • The Directed AldolChiral Auxiliaries ExamplesMukaiyama AldolAcceptor activation Titanium Zirconium Copper BoronDonor Activation Rhodium, Palladium, Phosporamides • The Direct AldolBiochemical CatalysisAldolases Antibodies Bifunctional CatalysisOrganocatalysis Chiral quaternary Salts • References

3. 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.

4. 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.

5. 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.

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

7. 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.

8. 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

9. 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.

10. 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.

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

12. 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

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

14. Boron Catalysis

15. Boron Catalysis-question

16. 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.

17. 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.

18. Palladium and Phosphoramides as Donor Activators JACS, 1999, 121, 4982

19. 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

20. 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.

21. 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.

22. Aldolase mechanism pathways

23. Example-Type I

24. Example - Type II

25. 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.

26. Example Ab38C2

27. 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.

28. Bifunctional Catalysis

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

30. 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?

31. Transition state

32. Organocatalysis Tetrahedron Asym. 2007, 265-278

33. Imidazolidinone Organocatalysis Angew. Chem. Int, Ed, 2004, 43, 6722-6724

34. 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

35. 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