The Kulinkovich Reaction:
Generation of 1,2-dicarbanionic Titanium Species and Their
Use in Organic Synthesis
Literature meeting
Olga Lifchits
September 18, 2007
The next blockbuster
“Low-valence titanium –
Lord of the small rings”
(M. Oestreich, Nachrichten aus
der Chemie, 2004, 52, 805.)
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
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.
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
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)
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.
Proposed reaction mechanism
Kulinkovich, O.G. Russ. Chem. Bull. Int. Ed. 2004, 53, 1065.
“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.
.
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.
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.
Extended scope through ligand exchange
Kulinkovich, O.G.; De Meijere, A. Chem. Rev., 2000, 100, 2789, and references therein.
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.
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.
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.
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.
Asymmetric strategies – Titanium bisTADDOLate
Corey, E.J., et al. JACS 1994, 116, 9345.
Proposed origin of stereoselectivity
Corey, E.J., et al. JACS 1994, 116, 9345.
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.
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
Trans-selective cyclopropanation: answer
Sato, F., Kastakin, A. Tet. Lett. 1995, 34, 6079.
Asymmetric strategies: Oppolzer’s auxiliary
Sato, F. et al. Angew. Chem. Int Ed. 1998, 37, 2666.
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.
Bicyclic cyclopropanol scope
Sato, F. et al. Angew. Chem. Int Ed. 1998, 37, 2666.
Kulinkovich-de Meijere Reaction
De Mejere, A, Chaplinski, V. Angew. Chem. Int. Ed. Engl. 1996, 35, 413.
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.
Kulinkovich-de Meijere Reaction scope
Kulinkovich, O.G.; De Meijere, A. Chem. Rev., 2000, 100, 2789, and references therein.
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.
Surprising behaviour with dienes - rationalization
De Meijere, A. et al. Chem. Eur. J. 2002, 8, 3789.
Application in natural product synthesis
De Meijere, A. et al. Chem. Eur. J. 2002, 8, 3789.
Intramolecular Kulinkovich – de Meijere reaction
Lee, J., Cha, J.K. J. Org. Chem. 1997, 62, 1584.
Beyond cyclopropanes – J.K. Cha
Making the Oxy-Cope precursor
Lee, J., Kim, H., Cha, J.K. JACS, 1995, 117, 9919.
Beyond cyclopropanes – J.K. Cha
Lee, J., Cha, J.K. J. Org. Chem. 1997, 62, 1584.
Beyond cyclopropanes – J.K. Cha
Lee, J., Cha, J.K. J. Org. Chem. 1997, 62, 1584.
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.
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.
Summary
Micalizio’s polypropionate synthesis
Substrate-controlled diastereoselective cyclopropanation
Cha, J,K. et al. Angew. Chem. Int. Ed. 2002, 41, 2160.
Substrate-controlled diastereoselective cyclopropanation
Cha, J,K. et al. Angew. Chem. Int. Ed. 2002, 41, 2160.