Published on Web 10/01/2009
Toolbox Approach to the Search for Effective Ligands for
Catalytic Asymmetric Cr-Mediated Coupling Reactions
Haibing Guo, Cheng-Guo Dong, Dae-Shik Kim, Daisuke Urabe, Jiashi Wang,
Joseph T. Kim, Xiang Liu, Takeo Sasaki, and Yoshito Kishi*
Department of Chemistry and Chemical Biology, HarVard UniVersity, 12 Oxford Street,
Cambridge, Massachusetts 02138
Received July 20, 2009; E-mail: kishi@chemistry.harvard.edu
Abstract: Chromium catalysts derived from chiral sulfonamides represented by A effect the couplings of
aldehydes with vinyl, allyl, or alkyl halides. With three distinct sites for structural modification, A affords
access to a structurally diverse pool of chiral sulfonamides. The Cr catalysts derived from these sulfonamides
exhibit a broad range of catalyst-substrate matching profiles. A strategy is presented to search for a
satisfactory chiral sulfonamide for a given substrate. In order to demonstrate the generality and effectiveness
of this approach, five diverse C-C bond-forming cases have been selected from the halichondrin synthesis.
For each of the cases, two ligands have been deliberately searched for, to induce the formation of (R)-
and (S)-alcohols, respectively, at the arbitrarily chosen efficiency level of “g80% yield with g20:1
stereoselectivity in the presence of e20 mol % of a Cr catalyst”. For 9 out of the 10 cases studied, a
satisfactory catalyst has been found within this pool of sulfonamides. Even for the remaining case, a Cr
catalyst inducing stereoselectivity up to 8:1 has been identified.
Scheme 1. Cr(III)-Mediated Couplings
1. Introduction
Cr(II)-mediated addition of allyl halides/triflates to aldehydes
was reported by Hiyama, Nozaki, and co-workers in 1977.1 In
this reaction, the active nucleophiles RCrX3 were generated in
situ via oxidative addition of Cr(II) to allyl halides/triflates
(Scheme 1). Since then, new methods have been developed to
form the active nucleophiles RCrX3 from a wide range of halides
and triflates.2 Depending on the activation methods, Cr-mediated
couplings are now divided into three subgroups: (1) Ni/Cr-
mediated alkenylation, alkynylation, and arylation;3 (2) Co- or
Fe/Cr-mediated alkylation, 2-haloallylation, and propargylation;4
and (3) Cr-mediated allylation and propargylation.
Overall, the Cr-mediated C-C bond-forming reaction is
viewed as a Grignard-type carbonyl addition of halides.
However, it is noteworthy that this reaction displays a remark-
able selectivity toward aldehydes over other carbonyl com-
pounds. Activation of halides in the presence of aldehydes
provides us with not only an experimental convenience but also
an opportunity to realize chemical transformations in an
unconventional manner, cf., cyclization.5 Undoubtedly, the most
valuable feature of this reaction is its exceptional compatibility
with a wide range of functional groups. This unique potential
is appreciated most when applied to polyfunctional molecules.
There are numerous examples in which this reaction has been
successfully used at a late stage in a multistep synthesis.6
For its application to a practical synthesis, it is desirable to
develop a catalytic process for the Cr-mediated coupling
reaction. In 1996, Fu¨rstner and Shi reported a catalytic version
of this reaction, in which TMS-Cl and Mn(0) are used as a
dissociating agent of chromium alkoxides and a reducing agent
of chromium, respectively (step 4 and step 1 in Scheme 2).7
Mn(0) is the most effective agent to reduce Cr(III) and
regenerate Cr(II).8 TMS-Cl is an effective dissociating agent,
(1) (a) Okude, Y.; Hirano, S.; Hiyama, T.; Nozaki, H. J. Am. Chem. Soc.
1977, 99, 3179. (b) Takai, K.; Kimura, K.; Kuroda, T.; Hiyama, T.;
Nozaki, H. Tetrahedron Lett. 1983, 24, 5281.
(5) For examples, see: (a) Schreiber, S. S.; Meyers, H. V. J. Am. Chem.
Soc. 1988, 110, 5198. (b) Rowley, M.; Tsukamoto, M.; Kishi, Y. J. Am.
Chem. Soc. 1989, 111, 2735. (c) Namba, K.; Kishi, Y. J. Am. Chem.
Soc. 2005, 127, 15382.
(2) For reviews on Cr-mediated carbon-carbon bond-forming reactions,
see: (a) Saccomano, N. A. In ComprehensiVe Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 1, p 173. (b)
Fu¨rstner, A. Chem. ReV. 1999, 99, 991. (c) Wessjohann, L. A.; Scheid,
G. Synthesis 1999, 1. (d) Takai, K.; Nozaki, H. Proc. Jpn. Acad. Ser.
B 2000, 76, 123. (e) Hargaden, G. C.; Guiry, P. J. AdV. Synth. Catal.
2007, 349, 2407.
(6) For examples, see: (a) Armstrong, R. W.; Beau, J.-M.; Cheon, S. H.;
Christ, W. J.; Fujioka, H.; Ham, W.-H.; Hawkins, L. D.; Jin, H.; Kang,
S. H.; Kishi, Y.; Martinelli, M. J.; McWhorter, W. W., Jr.; Mizuno,
M.; Nakata, M.; Stutz, A. E.; Talamas, F. X.; Taniguchi, M.; Tino,
J. A.; Ueda, K.; Uenishi, J.; White, J. B.; Yonaga, M. J. Am. Chem.
Soc. 1989, 111, 7530. (b) Aicher, T. D. K.; Buszek, R.; Fang, F. G.;
Forsyth, C. J.; Jung, S. H.; Kishi, Y.; Matelich, M. C.; Scola, P. M.;
Spero, D. M.; Yoon, S. K. J. Am. Chem. Soc. 1992, 114, 3162. (c)
Oddon, G.; Uguen, D. Tetrahedron Lett. 1998, 39, 1157.
(3) (a) Jin, H.; Uenishi, J.-I.; Christ, W. J.; Kishi, Y. J. Am. Chem. Soc.
1986, 108, 5644. (b) Takai, K.; Tagashira, M.; Kuroda, T.; Oshima,
K.; Utimoto, K.; Nozaki, H. J. Am. Chem. Soc. 1986, 108, 6048.
(4) (a) Takai, K.; Nitta, K.; Fujimura, O.; Utimoto, K. J. Org. Chem. 1989,
54, 4732. (b) Choi, H.-w.; Nakajima, K.; Demeke, D.; Kang, F.-A.;
Jun, H.-S.; Wan, Z.-K.; Kishi, Y. Org. Lett. 2002, 4, 4435. (c) Kurosu,
M.; Lin, M.-H.; Kishi, Y. J. Am. Chem. Soc. 2004, 126, 12248.
(7) (a) Fu¨rstner, A.; Shi, N. J. Am. Chem. Soc. 1996, 118, 2533. (b)
Fu¨rstner, A.; Shi, N. J. Am. Chem. Soc. 1996, 118, 12349. (c) Fu¨rstner,
A.; Wuchrer, M. Chem.sEur. J. 2006, 12, 76.
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10.1021/ja905843e CCC: $40.75 2009 American Chemical Society
J. AM. CHEM. SOC. 2009, 131, 15387–15393 15387