The Kulinkovich Reaction:

1. The Kulinkovich Reaction: Generation of 1,2-dicarbanionic Titanium Species and Their Use in Organic Synthesis Literature meeting Olga Lifchits September 18, 2007

2. The next blockbuster “Low-valence titanium – Lord of the small rings” (M. Oestreich, Nachrichten aus der Chemie, 2004, 52, 805.)

3. Titanium • Oxophilic early transition metal • Pure metal is non-toxic even in large quantities • Toxicity associated with Ti complexes comes from ligands (e.g. cyclopentadienyl) • Salts are typically harmless except the chlorides

4. Reactivity of Ti-C sigma bond • Ti-C bond is strong (typically > 60 kcal/mol) but very reactive (thermally unstable) • Low-energy empty d-orbitals favour agostic interactions with neighbouring σ bonds • Agostic interaction with Cα-H promotes decomposition into alkylidenetitanium species by α-hydrogen abstraction in the absence of β-hydrogens Kulinkovich, O.G.; De Meijere, A. Chem. Rev., 2000, 100, 2789; Telnoi, V.I. et al. Dokl. Akad. Nauk SSSR 1967, 174, 1374; Brookhart, M, Green, M.L.H. J. Organomet. Chem. 1983, 250, 395.

5. Reactivity of the Ti-C sigma bond • When β-hydride is present, analogous agostic interaction with Cβ-H assists in β-hydride elimination • Resulting complex exists as two resonance forms favouring titanacyclopropaneB (general trend for oxidized early metals) “1,2- dicarbanion” • Reactivity patterns of both resonance forms are observed Brookhart, M, Green, M.L.H. J. Organomet. Chem. 1983, 250, 395;Steigerwald, M; Goddart, W.A. JACS, 1985, 107, 5027

6. Oleg G. Kulinkovich • Born in Estonia in 1948 • Honors B.Sc., Belorussian State University (BSU), Minsk (1971) • PhD, BSU with Prof. I.G. Tishschenko (1975) • D.Sc., BSU (1987) • Professor and Head of the Department of Organic and Polymer Chemistry at BSU (since 1991)

7. The Kulinkovich Reaction • Original reaction (1989) used a mixture of stoichiometric amount of Ti(OiPr)4 (1 equiv), EtMgBr (3 equiv) and ester at -78oC to -40oC • Catalytic version (1991) uses slow addition of EtMgBr (2 equiv) to a mixture of ester and Ti(OiPr)4 (5-10 mol%) at 18-20oC Kulinkovich, O.G. et al. Zh. Org. Khim. 1989, 25, 2245; Kulinkovich, O.G. et al. Synthesis 1991, 234.

8. Proposed reaction mechanism Kulinkovich, O.G. Russ. Chem. Bull. Int. Ed. 2004, 53, 1065.

9. “Classical” Kulinkovich reaction scope Ester scope: Grignard scope (cis geometry in the absence of chelating groups): Kulinkovich, O.G.; De Meijere, A. Chem. Rev., 2000, 100, 2789, and references therein. .

10. Initial Limitation and Improvements Problem: the reaction requires one “sacrificial” equivalent of the Grignard reagent, which might be expensive and/or difficult to make Solution: methyltitanium triisopropoxide provides a “sacrificial” methyl group (no β-hydrogens on methyl) De Meijere, A. et al. Synlett, 1997, 111.

11. Generating titanacycles through ligand exchange Problem: some olefins failed to exchange (eg. 1-heptene, ethyl vinyl ether) likely due to unfavourable equilibrium Solution: a strained precursor from cyclopentyl or cyclohexyl Grignard Kulinkovich, O.G. et al. Mendeleev Commun., 1993, 230; Cha, K.J. et al. JACS, 1996, 118, 4198.

12. Extended scope through ligand exchange Kulinkovich, O.G.; De Meijere, A. Chem. Rev., 2000, 100, 2789, and references therein.

13. Intramolecular Nucleophilic Acyl Substitution (INAS) Can generate a wide variety of bicyclic cyclopropanols: Cha, J.K. JACS, 1996, 118, 291; Sato, F. et al. 1997, 119, 6984; Sato, F. Tet. Lett. 1996, 37, 1849.

14. Intramolecular Nucleophilic Acyl Substitution (INAS) Proximity of the vinyl group to the ester matters: .. but unsaturated oxacarboxylic acid esters work well for large rings: Cha, J.K. JACS, 1996, 118, 291; Ollivier, J. Org. Biomol. Chem. 2003, 1, 3600.

15. Intramolecular Nucleophilic Acyl Substitution (INAS) • INAS is otherwise not so easy to achieve! • Reactive nucleophile must be generated in presence of carbonyl • The nucleophile must react only intra- and not intermolecularly • Zn, B are not reactive enough; Mg, Li are too reactive Marek, I.,ed. Titanium and Zirconium in Organic Synthesis; Wiley: Weinheim, 2002.

16. Further possibilities with ligand exchange Exchange with alkynes: Exchange with a diene: Sato, F. et al.JACS, 1996, 118, 2208; Sato, F. et al. J. Chem. Soc. Chem. Comm. 1996, 197.

17. Asymmetric strategies – Titanium bisTADDOLate Corey, E.J., et al. JACS 1994, 116, 9345.

18. Proposed origin of stereoselectivity Corey, E.J., et al. JACS 1994, 116, 9345.

19. But why the cis geometry? Quantum-chemical calculations of a model reaction suggest.. When applied to the Ti-TADDOLate reaction, this mechanism gives the same absolute configuration Wu, Y-D., Yu, Z.-X. JACS, 2001, 123, 5777.

20. Question for the audience Draw the mechanism of this intramolecular Kulinkovich reaction and explain the observed highdiastereoselectivity for the trans product: Note: diastereoselectivity is under thermodynamic control

21. Trans-selective cyclopropanation: answer Sato, F., Kastakin, A. Tet. Lett. 1995, 34, 6079.

22. Asymmetric strategies: Oppolzer’s auxiliary Sato, F. et al. Angew. Chem. Int Ed. 1998, 37, 2666.

23. Proposed origin of stereoselectivity • Cooperative effect of the auxiliary and the chiral α-alkyl group • “Mismatched” sultam 3 gave a lower dr (92:8) • Absence of auxiliary (ester 4) gave a lower dr (66:34) • Evans auxiliary (N-acyloxazolidinone 5) gave a lower dr (74:26) Sato, F. et al. Angew. Chem. Int Ed. 1998, 37, 2666.

24. Bicyclic cyclopropanol scope Sato, F. et al. Angew. Chem. Int Ed. 1998, 37, 2666.

25. Kulinkovich-de Meijere Reaction De Mejere, A, Chaplinski, V. Angew. Chem. Int. Ed. Engl. 1996, 35, 413.

26. Kulinkovich-de Meijere Reaction • Requires stoichiometric Ti(OiPr)4 for useful yields • Diastereoselectivity is generally lower than with esters • Can use ligand exchange to generate active titanacycles • Disubstituted alkenes and cycloalkenes react! • Can easily access primary amines by catalytic debenzylation: De Mejere, A, Chaplinski, V. Angew. Chem. Int. Ed. Engl. 1996, 35, 413.

27. Kulinkovich-de Meijere Reaction scope Kulinkovich, O.G.; De Meijere, A. Chem. Rev., 2000, 100, 2789, and references therein.

28. Surprising behaviour with dienes Given a choice, a more substituted double bond is cyclopropanated.. … but in the absence of a less substituted bond, there’s no conversion: De Meijere, A. et al. Chem. Eur. J. 2002, 8, 3789.

29. Surprising behaviour with dienes - rationalization De Meijere, A. et al. Chem. Eur. J. 2002, 8, 3789.

30. Application in natural product synthesis De Meijere, A. et al. Chem. Eur. J. 2002, 8, 3789.

31. Intramolecular Kulinkovich – de Meijere reaction Lee, J., Cha, J.K. J. Org. Chem. 1997, 62, 1584.

32. Beyond cyclopropanes – J.K. Cha Making the Oxy-Cope precursor Lee, J., Kim, H., Cha, J.K. JACS, 1995, 117, 9919.

33. Beyond cyclopropanes – J.K. Cha Lee, J., Cha, J.K. J. Org. Chem. 1997, 62, 1584.

34. Beyond cyclopropanes – J.K. Cha Lee, J., Cha, J.K. J. Org. Chem. 1997, 62, 1584.

35. Beyond cyclopropanes – G. Micalizio Typical convergent approaches must form a central ketone first • Take that, aldol! • No protecting group manipulations (free -OH) • Stereodefined trisubstituted double bond with no intermediate ketone • Double bond can be further functionalized Bahadoor, A.B., Flyer, A., Micalizio, G.G. JACS, 2005, 127, 3694.

36. Beyond cyclopropanes – G. Micalizio • Various diastereomers of the homopropargylic alcohol and aldehyde were coupled – Felkin selectivity in all cases (generally ≥ 2:1) • Regioselectivity was found to be a function of the stereochemistry of both coupling partners! • The role of a neighbouring alkoxide implicated in regioselectivity Bahadoor, A.B., Flyer, A., Micalizio, G.C. JACS, 2005, 127, 3694; Bahadoor, A.B., Micalizio, G.C. J. Org. Lett. 2006, 8, 1181.

37. Summary

39. Micalizio’s polypropionate synthesis

40. Substrate-controlled diastereoselective cyclopropanation Cha, J,K. et al. Angew. Chem. Int. Ed. 2002, 41, 2160.

41. Substrate-controlled diastereoselective cyclopropanation Cha, J,K. et al. Angew. Chem. Int. Ed. 2002, 41, 2160.