Umpolung reactivity

1. Umpolung reactivity Special Topic 27/02/09 Anne Fournier

2. Heteroatoms impose an alternating acceptor and donor reactivity pattern X = halogen, O, N d = donor (-) a = acceptor (+) An odd number of carbons between functional groups An even number of carbons between functional groups The synthetic problem

3. Umpolung is any process by which donor and acceptor reactivity of an atom are interchanged (reversal in polarity). « usual » reactivity: C2n= donor, C2n+1= acceptor Umpolung reactivity: C2n= acceptor, C2n+1= donor Reactivity enables us to construct new bonds which are difficult to construct or cannot be achieved by « usual » reactivity, particulary the construction of 1,2 or 1,4-difunctionality. Definition Seebach ACIEE1979, 239

4. Carbonyl Umpolung Patterns of Carbonyl Reactivity

5. Carbonyl Umpolung Carbonyl Umpolung intermediates

6. Carbonyl Umpolung Masked Acyl Anion Equivalents Cyanide ion Catalyzed Addition • 1a. Benzoin Condensation: • Must use aromatic or heteroaromatic aldehydes; aliphatic aldehydes tend to undergo an aldol condensation • Cannot selectivity cross couple of two different aldehydes LapworthJACS1903, 995.

7. 1b. Cyanide ion Catalyzed Cross Silyl-Benzoin Reaction [1,2]-Brook Rearrangement Kinetic control, regiosepecific, (but need to make acyl silane), lower yields often result from aliphatic aldehydes (improvement with La(CN)3 catalyst) Carbonyl Umpolung Masked Acyl Anion Equivalents Johnson JACS 2005, 1833

8. 2. N-Heterocyclic Carbenes Catalyzed Acyloin Formation Effective for aliphatic and (hetero)aromatic aldehydes Applicable to acylsilanes Carbonyl Umpolung Masked Acyl Anion Equivalents (a) Breslow JACS 1958,3719. (b) Enders Acc. Chem. Res. 2004, 534.

9. 3. Recent Progress in Asymmetric Benzoin Reactions Carbonyl Umpolung Masked Acyl Anion Equivalents Enders ACIEE, 2002, 1743

10. 4. Stetter Reaction: Generation of 1,4-dicarbonyls Scope includes unsaturated esters, nitriles, ketones and aldehydes Carbonyl Umpolung Masked Acyl Anion Equivalents (a) Stetter ACIEE 1976, 639. (b) Scheidt JACS 2004, 126, 2314

11. 5a. Recent Advancements in Asymmetric Stetter Reactions Enantioselective intramolecular Stetter reaction Carbonyl Umpolung Masked Acyl Anion Equivalents Rovis JACS, 2002, 10298

12. 5b. Quaternary Stereocenters via Asymmetric Stetter Carbonyl Umpolung Masked Acyl Anion Equivalents Rovis JACS, 2004, 8876

13. 6. Metallophosphites as Umpolung Catalyst: The Enantioselective Cross Silyl Benzoin Reaction Carbonyl Umpolung Masked Acyl Anion Equivalents JohnsonJACS2004, 3070

14. 7a. Anions of 1,3-Dithianes (Corey-Seebach reaction) • Usually formed from corresponding aldehydes by thioacetalization • R = primary, secondary and tertiary alkyl, allyl, benzyl, aryl, and O-containing groups • Biggest drawback: removal of dithiane Carbonyl Umpolung Masked Acyl Anion Equivalents 1. HgCl2, H2SO4, H2O 2. NaIO4 or m-CPBA 3. MeX (X = I, OTs,…) (a) Corey, Seebach ACIEE 1965 1075 (b) Corey, Seebach ACIEE 1965 1077

15. 7b. Anions of 1,3-Dithianes (Corey-Seebach reaction) Carbonyl Umpolung Masked Acyl Anion Equivalents

16. Zirconium mediated or catalysed Umpolung reactions Carbonyl Umpolung Unmasked Acyl Anion Equivalents (a) HanzawaACIEE1998, 1696 (a) Hanzawa TL1998, 6249 (a) GuanCurr. Org. Chem. 2008, 1406

17. Zirconium mediated or catalysed Umpolung reactions Carbonyl Umpolung Unmasked Acyl Anion Equivalents (a) HanzawaTL 1998, 8141 (b) Hanzawa ACIEE, 1999, 2395 (c) Hanzawa T 2002, 8141

18. A Summary (Acyl anions are the most sought umpolung reagents) Masked Acyl Anion Equivalents • 1,3-Dithianes (stoichiometric synthesis, pre-functionalization) • Cyanohydrin derivatives (stoichiometric synthesis, pre-functionalization) • Isonitriles, Nitronates anions, t-Butyl hydrazones, Vinyl thioether anions,… • Metal cyanides (catalytic formation, direct) • Nucleophilic carbenes (catalytic formation, direct) • Metallophosphites (catalytic formation, direct) Unmasked Acyl Anion Equivalents • Acylzirconocene chloride Carbonyl Umpolung Acyl Anion Equivalents

19. 1. -Halo Carbonyl Substitution Carbonyl Umpolung -Electrophile Equivalents

20. 2. Anodic Oxidation of Silyl Enol Ethers Carbonyl Umpolung -Electrophile Equivalents MollerJACS 2003, 36

21. 1. The Tautomerism Problem • Enolates • tautomerism is generally not a problem because oxyanionic tautomer still acts as carbon nucleophile • Homoenolates • tautomerism is a much larger problem because it is often irreversible and oxyanioic tautomer rarely acts as a carbon nucleophile Carbonyl Umpolung Homoenolate Equivalents

22. 2. The Acetal Approach Carbonyl Umpolung Homoenolate Equivalents BoschJOC 2003, 1919

23. 3. Silyl Enol Ethers of Ketones Synthesis of ()-δ-Araneosene Carbonyl Umpolung Homoenolate Equivalents KuwajimaChem. Comm. 1979, 708 CoreyOrg. Lett. 2002, 2441

24. 4a. Cyclopropane Ring Opening : Titanium Homoenolates Homoaldols Reactions of Titanium Homoenolates Carbonyl Umpolung Homoenolate Equivalents -hydroxyesters lactones • (a) Nakamura, KuwajimaJACS 1977, 7360 • (b) Nakamura, KuwajimaJACS 1986, 3745

25. 4b. Zinc Homoenolates: Preparation • Cyclopropane Ring Opening Nakamura, Organometallics, 1985, 641 • Direct Oxidative Addition Yoshida, TL, 1985, 5559 Carbonyl Umpolung Homoenolate Equivalents

26. Carbonyl Umpolung Homoenolate Equivalents • 4b. Zinc Homoenolates: Reactivity • Copper-Catalyzed Conjugate Additions KuwajimaJACS 1984, 3368 • Catalytic Homo-Reformatsky Reactions Nakamura, KuwajimaJACS 1987, 8056

27. 4b. Zinc Homoenolates: Reactivity • Palladium Coupling Reactions Nakamura JOC, 1987, 8056 Carbonyl Umpolung Homoenolate Equivalents

28. Thank you for your attention