Presentation on theme: "The Kulinkovich Reaction:"— Presentation transcript:
1The Kulinkovich Reaction: Generation of 1,2-dicarbanionic Titanium Species and Their Use in Organic SynthesisLiterature meetingOlga LifchitsSeptember 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.)
3Titanium Oxophilic early transition metal Pure metal is non-toxic even in large quantitiesToxicity associated with Ti complexes comes from ligands (e.g. cyclopentadienyl)Salts are typically harmless except the chlorides
4Reactivity 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 bondsAgostic interaction with Cα-H promotes decomposition into alkylidenetitanium species by α-hydrogen abstraction in the absence of β-hydrogensKulinkovich, 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.
5Reactivity of the Ti-C sigma bond When β-hydride is present, analogous agostic interaction with Cβ-H assists in β-hydride eliminationResulting 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 observedBrookhart, M, Green, M.L.H. J. Organomet. Chem. 1983, 250, 395; Steigerwald, M; Goddart, W.A. JACS, 1985, 107, 5027
6Oleg 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)
7The 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 -40oCCatalytic version (1991) uses slow addition of EtMgBr (2 equiv) to a mixture of ester and Ti(OiPr)4 (5-10 mol%) at 18-20oCKulinkovich, O.G. et al. Zh. Org. Khim. 1989, 25, 2245; Kulinkovich, O.G. et al. Synthesis 1991, 234.
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..
10Initial Limitation and Improvements Problem: the reaction requires one “sacrificial” equivalent of the Grignard reagent, which might be expensive and/or difficult to makeSolution: methyltitanium triisopropoxide provides a “sacrificial” methyl group (no β-hydrogens on methyl)De Meijere, A. et al. Synlett, 1997, 111.
11Generating titanacycles through ligand exchange Problem: some olefins failed to exchange (eg. 1-heptene, ethyl vinyl ether) likely due to unfavourable equilibriumSolution: a strained precursor from cyclopentyl or cyclohexyl GrignardKulinkovich, O.G. et al. Mendeleev Commun., 1993, 230; Cha, K.J. et al. JACS, 1996, 118, 4198.
12Extended scope through ligand exchange Kulinkovich, O.G.; De Meijere, A. Chem. Rev., 2000, 100, 2789, and references therein.
13Intramolecular 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.
14Intramolecular 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.
15Intramolecular Nucleophilic Acyl Substitution (INAS) INAS is otherwise not so easy to achieve!Reactive nucleophile must be generated in presence of carbonylThe nucleophile must react only intra- and not intermolecularlyZn, B are not reactive enough; Mg, Li are too reactiveMarek, I.,ed. Titanium and Zirconium in Organic Synthesis; Wiley: Weinheim, 2002.
16Further possibilities with ligand exchange Exchange withalkynes:Exchange with a diene:Sato, F. et al. JACS, 1996, 118, 2208; Sato, F. et al. J. Chem. Soc. Chem. Comm. 1996, 197.
18Proposed origin of stereoselectivity Corey, E.J., et al. JACS 1994, 116, 9345.
19But 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 configurationWu, Y-D., Yu, Z.-X. JACS, 2001, 123, 5777.
20Question 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
21Trans-selective cyclopropanation: answer Sato, F., Kastakin, A. Tet. Lett. 1995, 34, 6079.
22Asymmetric strategies: Oppolzer’s auxiliary Sato, F. et al. Angew. Chem. Int Ed. 1998, 37, 2666.
23Proposed 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.
24Bicyclic cyclopropanol scope Sato, F. et al. Angew. Chem. Int Ed. 1998, 37, 2666.
25Kulinkovich-de Meijere Reaction De Mejere, A, Chaplinski, V. Angew. Chem. Int. Ed. Engl. 1996, 35, 413.
26Kulinkovich-de Meijere Reaction Requires stoichiometric Ti(OiPr)4 for useful yieldsDiastereoselectivity is generally lower than with estersCan use ligand exchange to generate active titanacyclesDisubstituted 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.
27Kulinkovich-de Meijere Reaction scope Kulinkovich, O.G.; De Meijere, A. Chem. Rev., 2000, 100, 2789, and references therein.
28Surprising 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.
29Surprising behaviour with dienes - rationalization De Meijere, A. et al. Chem. Eur. J. 2002, 8, 3789.
30Application in natural product synthesis De Meijere, A. et al. Chem. Eur. J. 2002, 8, 3789.
31Intramolecular Kulinkovich – de Meijere reaction Lee, J., Cha, J.K. J. Org. Chem. 1997, 62, 1584.
32Beyond cyclopropanes – J.K. Cha Making the Oxy-Cope precursorLee, J., Kim, H., Cha, J.K. JACS, 1995, 117, 9919.
33Beyond cyclopropanes – J.K. Cha Lee, J., Cha, J.K. J. Org. Chem. 1997, 62, 1584.
34Beyond cyclopropanes – J.K. Cha Lee, J., Cha, J.K. J. Org. Chem. 1997, 62, 1584.
35Beyond cyclopropanes – G. Micalizio Typical convergent approaches must form a central ketone firstTake that, aldol!No protecting group manipulations (free -OH)Stereodefined trisubstituted double bond with no intermediate ketoneDouble bond can be further functionalizedBahadoor, A.B., Flyer, A., Micalizio, G.G. JACS, 2005, 127, 3694.
36Beyond 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 regioselectivityBahadoor, A.B., Flyer, A., Micalizio, G.C. JACS, 2005, 127, 3694; Bahadoor, A.B., Micalizio, G.C. J. Org. Lett. 2006, 8, 1181.