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

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Presentation on theme: "1 Umpolung reactivity Special Topic 27/02/09 Anne Fournier."— Presentation transcript:

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

2 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 3 Definition « usual » reactivity: C 2n = donor, C 2n+1 = acceptor Umpolung reactivity: C 2n = acceptor, C 2n+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 4 Carbonyl Umpolung Patterns of Carbonyl Reactivity

5 5 Carbonyl Umpolung Carbonyl Umpolung intermediates

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

7 7 Carbonyl Umpolung Masked Acyl Anion Equivalents Johnson JACS 2005, b. Cyanide ion Catalyzed Cross Silyl-Benzoin Reaction 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

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

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

10 10 Carbonyl Umpolung Masked Acyl Anion Equivalents 4. Stetter Reaction: Generation of 1,4-dicarbonyls 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 11 Carbonyl Umpolung Masked Acyl Anion Equivalents Rovis JACS, 2002, a. Recent Advancements in Asymmetric Stetter Reactions 5a. Recent Advancements in Asymmetric Stetter Reactions Enantioselective intramolecular Stetter reaction

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

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

14 14 Carbonyl Umpolung Masked Acyl Anion Equivalents (a) Corey, Seebach ACIEE (b) Corey, Seebach ACIEE a. Anions of 1,3-Dithianes (Corey-Seebach reaction) 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. HgCl 2, H 2 SO 4, H 2 O 2. NaIO 4 or m-CPBA 3. MeX (X = I, OTs,…)

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

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

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

18 18 Carbonyl Umpolung Acyl Anion Equivalents A Summary (Acyl anions are the most sought umpolung reagents) 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 19 Carbonyl Umpolung  -Electrophile Equivalents 1.  -Halo Carbonyl Substitution 1.  -Halo Carbonyl Substitution

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

21 21 Carbonyl Umpolung Homoenolate Equivalents 1. The Tautomerism Problem 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

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

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

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

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

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

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

28 28 Thank you for your attention


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