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

2. 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

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 TiCl 4 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 groups a) biochemical catalysis: Aldolases and Antibodies b) 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 condensations and 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 Zn 2+ 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. 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? AldehydeYieldd.ree% cC 6 H 11 CHO 60%>20:1>99 (CH 3 ) 2 CHCHO 62%>20:1>99 Ph(Me)CHCHO51%>20:1>95 2-Cl-PhCHO95%1.5:167 (CH 3 ) 3 CCH 2 CHO 38%1.7:1>97

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