C O M M U N I C A T I O N S
Scheme 1. Proposed Model for Stereocontrol
In summary, the first catalyst system for effecting asymmetric
[5 + 2] cycloadditions of alkenes and VCPs is described. High
yields and high enantioselectivities are obtained with several
substrates differing in substitution of the reactive functionality and
in the tether. The best results are attained with tethered alkenes as
the 2-π component. Further studies involving the selectivity of the
[5 + 2] reaction are ongoing in our laboratories.
Acknowledgment. This research was supported by a grant
(CHE-0450638) from the National Science Foundation. High-
resolution mass spectra were provided by the Mass Spectrometry
Facility, University of California, San Francisco. Fellowship support
from the Alexander von Humboldt foundation (L.O.H.), KOSEF
(J.L. and Y.J.Y.), and Eli Lilly & Co. (T.J.W. and J.A.L.) is
gratefully acknowledged.
Scheme 2. Stereochemistry-Determining Steps
Supporting Information Available: Full synthetic procedures and
data (including CIF for adduct S7) for all new compounds are described.
This material is available free of charge via the Internet at http://
pubs.acs.org.
References
(1) Alkynes: (a) Wender, P. A.; Takahashi, H.; Witulski, B. J. Am. Chem.
Soc. 1995, 117, 4720. (b) Wender, P. A.; Dyckman, A. J.; Husfeld, C.
O.; Kadereit, D.; Love, J. A.; Rieck, H. J. Am. Chem. Soc. 1999, 121,
10442. (c) Wender, P. A.; Dyckman, A. J. Org. Lett. 1999, 1, 2089. (d)
Wender, P. A.; Barzilay, C. M.; Dyckman, A. J. J. Am. Chem. Soc. 2001,
123, 179. Alkenes: (e) Wender, P. A.; Husfeld, C. O.; Langkopf, E.; Love,
J. A. J. Am. Chem. Soc. 1998, 120, 1940. Allenes: (f) Wender, P. A.;
Glorius, F.; Husfeld, C. O.; Langkopf, E.; Love, J. A. J. Am. Chem. Soc.
1999, 121, 5348. (g) Wender, P. A.; Husfeld, C. O.; Langkopf, E.; Love,
J. A.; Pleuss N. Tetrahedron 1998, 54, 7203. For a review, see: (h)
Wender, P. A.; Gamber, G. G.; Williams, T. J. In Modern Rhodium-
Catalyzed Organic Reactions; Evans, P. A., Ed.; Wiley-VCH: Weinheim,
Germany, 2005; Chapter 13.
(2) For related work, see: (a) Gilbertson, S. R.; Hoge, G. S. Tetrahedron
Lett. 1998, 39, 2075. (b) Wang, B.; Cao, P.; Zhang, X. Tetrahedron Lett.
2000, 41, 8041. Ru(II): (c) Trost, B. M.; Toste, F. D.; Shen, H. J. Am.
Chem. Soc. 2000, 122, 2379. Ni(0): (d) Zuo, G.; Louie, J. J. Am. Chem.
Soc. 2005, 127, 5798. (e) Lee, S. I.; Park, S. Y.; Park, J. H.; Jung, I. G.
Choi, S, Y.; Chung, Y. K.; Lee, B. Y. J. Org. Chem. 2006, 71, 91.
(3) (a) Wender, P. A.; Rieck, H.; Fuji, M. J. Am. Chem. Soc. 1998, 120,
10976. (b) Wender, P. A.; Dyckman, A. J.; Husfeld, C. O.; Scanio, M. J.
C. Org. Lett. 2000, 2, 1609. (c) Wegner, H.; de Meijere, A.; Wender, P.
A. J. Am. Chem. Soc. 2005, 127, 6530.
throughout the reaction. The absolute sense of induction was
established by an independent eight-step synthesis of cycloadduct
(+)-2 from ethyl-(S)-3-(2,2-dimethyl-1,3-dioxolan-4-yl)-(E)-2-pro-
penoate (see Supporting Information).
A mechanistic model for the observed sense of induction is
outlined in Schemes 1 and 2. The reaction begins with coordination
of the VCP to the [((R)-BINAP)Rh]+ cation. The proposed structure
of this intermediate is based on X-ray data for [((R)-BINAP)Rh-
(nbd)]+ (nbd ) norborna-2,5-diene)9c from which the nbd ligand
has been removed and replaced with 1 (Scheme 1, a). The alkene-
VCP fragment aligns itself so that the bulky cyclopropyl and alkenyl
R groups are pointed away from the forward-leaning phenyl groups
of the BINAP ligand (indicated by bold icons in a). Two pathways
lead from a, differing in the sequence of cyclopropane cleavage
and oxidative coupling. DFT studies of an ethyne/VCP [5 + 2]
reaction12 suggest that the step following VCP coordination is
cyclopropane opening to give b (sequence I, also illustrated in
Scheme 2). C-C bond formation follows to give c, from which
the cycloadduct is formed by reductive elimination. A complemen-
tary argument can be made for pathway II proceeding through b′
(see Supporting Information).
Scheme 2 illustrates the favored and disfavored stereochemistry-
determining steps for sequence I, the DFT-preferred path. Stereo-
chemistry would be set irreversibly in the conversion of b to c, so
the relative energies for the transformations of b to c and dia-b to
dia-c would dictate the sense and degree of enantioselectivity.
Examination of models of intermediates b and c in the favored
pathway indicates little destabilizing interaction between the
substrate and ligand. In contrast, in the disfavored pathway,
destabilizing interactions occur in dia-b and persist in the product
dia-c. One of these interactions is between alkene substituent (R)
and a phenyl group of the BINAP ligand. This is consistent with
the observation that increased steric bulk at this position gives higher
enantiomeric excesses. This model is also consistent with the high
selectivity observed for methyl-substituted VCP 15 in which a
methyl group would be placed in a space unencumbered by the
ligand in the favored starting complex (and transition structure)
but would be placed in a sterically occupied space in the disfavored
path.
(4) (a) Wender, P. A.; Sperandio, D. J. Org. Chem. 1998, 63, 4164. (b)
Wender, P. A.; Williams, T. J. Angew. Chem., Int. Ed. 2002, 41, 4550.
Further examples can be found in refs 1-3.
(5) Wender, P. A.; Love, J. A.; Williams, T. J. Synlett 2003, 1295.
(6) For example, phorbol: (a) Wender, P. A.; Rice, K. D.; Schnute, M. E. J.
Am. Chem. Soc. 1997, 119, 7897. For a review, see: (b) Evans, F. J.
Naturally Occurring Phorbol Esters; CRC Press: Boca Raton, FL, 1986.
(7) Dictamnol: (a) Wender, P. A.; Fuji, M.; Husfeld, C. O.; Love, J. A. Org.
Lett. 1999, 1, 137. Aphanamol: (b) Wender, P. A.; Zhang, L. Org. Lett.
2000, 2, 2323. Tremulane sesquiterpenes: (c) Ashfeld, B. L.; Martin, S.
F. Org. Lett. 2005, 7, 4535.
(8) For a review on another asymmetric cycloaddition ([4 + 3]) for seven-
membered ring synthesis, see: Hartung, I. V.; Hoffmann, H. M. R. Angew.
Chem., Int. Ed. 2004, 43, 1934.
(9) Achiral catalysts: (a) Wender, P. A.; Jenkins, T. E. J. Am. Chem. Soc.
1989, 111, 6432. (b) Jolly, R. S.; Luedtke, G.; Sheehan, D.; Livinghouse,
T. J. Am. Chem. Soc. 1990, 112, 4965. (c) Wender, P. A.; Jenkins, T. E.;
Suzuki, S. J. Am. Chem. Soc. 1995, 117, 1843. Also see ref 2a,b,e. Chiral
catalysts: (d) McKinstry, L.; Livinghouse, T. Tetrahedron 1994, 50, 6145.
(e) Gilbertson, S. R.; Hoge, G. S.; Genov, D. G. J. Org. Chem. 1998, 63,
10077. (f) O’Mahony, D. J. R.; Belanger, D. B.; Livinghouse, T. Synlett
1998, 443. (g) Heath, H.; Wolfe, B.; Livinghouse, T.; Bae, S. K. Synthesis
2001, 2341. We find that 5a gives both 6a and 6b with different
enantiomeric excesses (see Supporting Information).
(10) Analogous results for the conversion of 3 to 4 were observed, 54% ee at
80% conversion and 70 °C.
(11) Prepared from [(nbd)RhCl]2. See: (a) Miyashita, A.; Yasuda, A.; Takaya,
H.; Toriumi, K.; Ito, T.; Souchi, T.; Noyori, R. J. Am. Chem. Soc. 1980,
102, 7932. (b) Toriumi, K.; Ito, T.; Takaya, H.; Souchi, T.; Noyori, R.
Acta Crystallogr., Sect. B: Struct. Sci. 1982, 38, 807. (c) Fairlie, D. P.;
Bosnich, B. Organometallics 1988, 7, 936.
(12) Yu, Z.-X.; Wender, P. A.; Houk, K. N. J. Am. Chem. Soc. 2004, 126,
9154.
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