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

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

3. Definition
« usual » reactivity:
C2n= donor, C2n+1= acceptor
Umpolung reactivity:
C2n= acceptor, C2n+1= donor
Umpolung is any process by which donor and acceptor reactivity of an atom are interchanged (reversal in polarity).
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.
Seebach ACIEE 1979, 239

4. Carbonyl Umpolung
Patterns of Carbonyl Reactivity

5. Carbonyl Umpolung
Carbonyl Umpolung intermediates

6. Carbonyl Umpolung Masked Acyl Anion Equivalents
1a. Benzoin Condensation:
Cyanide ion Catalyzed Addition
Must use aromatic or heteroaromatic aldehydes; aliphatic aldehydes tend to undergo an aldol condensation
Cannot selectivity cross couple of two different aldehydes
Lapworth JACS 1903, 995.

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

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

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

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

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

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

13. Carbonyl Umpolung Masked Acyl Anion Equivalents
6. Metallophosphites as Umpolung Catalyst: The Enantioselective Cross Silyl Benzoin Reaction
Johnson JACS 2004, 3070

14. Carbonyl Umpolung Masked Acyl Anion Equivalents
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
1. HgCl2, H2SO4, H2O 2. NaIO4 or m-CPBA 3. MeX (X = I, OTs,…)
(a) Corey, Seebach ACIEE
(b) Corey, Seebach ACIEE

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

16. Zirconium mediated or catalysed Umpolung reactions
Carbonyl Umpolung
Unmasked Acyl Anion Equivalents
Zirconium mediated or catalysed Umpolung reactions
(a) Hanzawa ACIEE 1998, 1696
(a) Hanzawa TL 1998, 6249
(a) Guan Curr. Org. Chem. 2008, 1406

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

18. Carbonyl Umpolung Acyl Anion Equivalents
A Summary (Acyl anions are the most sought umpolung reagents)
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)
Masked Acyl Anion Equivalents
Unmasked Acyl Anion Equivalents
Acylzirconocene chloride

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

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

21. Carbonyl Umpolung Homoenolate Equivalents 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

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

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

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

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

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

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

28. Thank you
for
your attention