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. “Low-valence titanium – Lord of the small rings”
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 titanacyclopropane B (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 high diastereoselectivity 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.