2428
J . Org. Chem. 1998, 63, 2428-2429
opening of epoxides with this and other chlorosilanes. In
this paper, we wish to disclose the first catalytic enantio-
selective ring opening of epoxides to afford optically active
chlorohydrins.
En a n tioselective Rin g Op en in g of Ep oxid es
w ith Silicon Tetr a ch lor id e in th e P r esen ce of
a Ch ir a l Lew is Ba se
Our initial experiments with SiCl4 employed HMPA and
cyclohexene oxide. Since HCl (an obvious contaminant in
SiCl4) is known to open epoxides with ease,6 it was essential
to establish that the SiCl4 was HCl free. Further, it was
necessary to establish if SiCl4 alone could open the epoxide
and thus compete with the Lewis base-catalyzed pathway.
To this end, we developed a strict protocol whereby, for each
epoxide, freshly distilled SiCl4 was employed in an uncata-
lyzed reaction, and the background was monitored by 1H
NMR spectroscopy. In all cases studied (vide infra), <5%
conversion was detected even at room temperature. Thus
assured that SiCl4 could not affect ring opening, we then
surveyed a number of Lewis bases for their ability to
promote the opening of cyclohexene oxide as the test
substrate. Low-temperature 1H NMR studies indicated that
as little as 10 mol % of HMPA, DMPU, or pyridine all
promoted the reaction efficiently. Given our success with
chlorosilane activation using phosphoramides we chose the
combination of HMPA and SiCl4 as our standard conditions.
Thus, treatment of cyclohexene oxide with 1.1 equiv of SiCl4
in the presence of 0.1 equiv of HMPA in CH2Cl2 at -78 °C
cleanly afforded trans-2-chlorocyclohexanol in 89% yield.
With a functional protocol in hand, we next surveyed a
variety of epoxide structures, Chart 1, to evaluate the steric
and electronic contributions to rate and regioselectivity. The
details of the ring-opening reactions are compiled in Table
1, and the product chlorohydrins are found in Chart 2.
Scott E. Denmark,* Paul A. Barsanti,
Ken-Tsung Wong, and Robert A. Stavenger
Roger Adams Laboratory, Department of Chemistry,
University of Illinois, Urbana, Illinois 61801
Received J anuary 29, 1998
The facile ring opening of epoxides makes them extremely
versatile intermediates for organic synthesis.1 It is therefore
not surprising that the enantioselective synthesis2 and
transformations3 of epoxides are current topics of significant
activity. Among the myriad of nucleophiles that have been
employed in ring openings, halide ions (which afford the
corresponding vicinal halohydrins) have received consider-
able attention.4,5 The classical reagents for halohydrin
synthesis are strong Lewis4 or hydrohalic acids,6 which
provide powerful electrophilic activation. Methods for the
asymmetric synthesis of chlorohydrins by enantioselective
ring opening of epoxides have relied upon the use of
stoichiometric amounts of chiral Lewis acid halides.7
A
conceptually distinct approach involves nucleophilic activa-
tion of Lewis acids (e.g., TMSCl) by Lewis bases (e.g.,
phosphines).8,9 This method offers unique opportunities for
asymmetric catalysis by disconnecting the roles of activator
and nucleophile. Nevertheless, catalytic, enantioselective
ring opening of epoxides to afford enantiomerically enriched
chlorohydrins has yet to be reported.
In the context of our studies on Lewis base-promoted aldol
additions of trichlorosilyl enolates,10 we assayed the reaction
of epoxides with these enolates. To our surprise, we found
the exclusive formation of the corresponding chlorohydrins.
Since the enolate was not formally involved, we felt that
SiCl4 should be a suitable source of chloride ion and, thus,
initiated a program on the (chiral) Lewis base-promoted
Ch a r t 1
(1) (a) Erden, I. In Comprehensive Heterocyclic Chemistry, 2nd ed.;
Padwa, A., Ed.; Pergamon Press: Oxford, 1996; Vol. 1A, Chapter 1.03. (b)
Barto´k, M.; Lang, K. L. In The Chemistry of Heterocyclic Compounds;
Weissberger, A., Taylor, E. C., Eds.; Wiley: New York, 1985; Vol. 42, Part
3, p 1. (c) Rao, A. S.; Paknikar, S. K.; Kirtane, J . G. Tetrahedron 1983, 39,
2323.
(2) (a) J ohnson, R. A.; Sharpless, K. B. In Comprehensive Organic
Synthesis, Vol. 7, Oxidation; Ley, S. V., Ed.; Pergamon Press: Oxford, 1991;
Chapter 3.2. (b) J ohnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric
Synthesis; Ojima, I., Ed.; VCH: Weinheim, 1993; Chapter 4.1. (c) J acobsen,
E. N. In Catalytic Asymmetric Synthesis; Ojima, I., Ed.; VCH: Weinheim,
1993; Chapter 4.2.
(3) For leading references of enantioselective ring opening of epoxides,
see: (a) Nugent, W. A. J . Am. Chem. Soc. 1992, 114, 2768. (b) Mart´ınez, L.
E.; Leighton, J . L.; Carsten, D. H.; J acobsen, E. N. J . Am. Chem. Soc. 1995,
117, 5897. (c) Tokunaga, M.; Larrow, J . F.; Kakiuchi, F.; J acobsen, E. N.
Science 1997, 277, 936. (d) Cole, B. M.; Shimizu, K. D.; Krueger, C. A.;
Harrity, J . P. A.; Snapper, M. L.; Hoveyda, A. H. Angew. Chem., Int. Ed.
Engl. 1996, 35, 1668. For a recent review see: (e) Hodgson, D. M.; Gibbs,
A. R.; Lee, G. P. Tetrahedron 1996, 52, 14361.
Both cyclic and acyclic epoxides with various substitution
patterns cleanly afford the corresponding chlorohydrins in
excellent yields. Among the cyclic substrates, it was noticed
that cyclooctene oxide (3) reacted at a considerably lower
rate most likely due to hindered approach in the lowest
energy boat-twist chair conformation.11 Substrates 4 and
512 also reacted slowly, presumably for electronic reasons.
The opening of all epoxides was accompanied by inversion
of configuration as verified by comparison with the known
chlorohydrins.13 The regioselectivity in reactions of unsym-
metrical epoxides is governed by both steric and electronic
effects.14 This is illustrated in the high level but opposite
sense of regioselectivity in the opening of terminal epoxides
6 and 7. Surprisingly, both di- and trisubstituted epoxides
(4) Bonini, C.; Righi, G. Synthesis 1994, 225.
(5) Halohydrins also serve as important synthetic intermediates in their
own right and are critical subunits for the synthesis of halogenated marine
natural products. For reviews see: Fenical, W. Marine Natural Products;
Scheuer, P. J ., Ed.; Academic: New York, 1980; Vol. 2, p 174.
(6) Cross, A. D. Quart. Rev. Chem Soc. 1960, 14, 317.
(7) (a) J oshi, N. N.; Srebnik, M.; Brown, H. C. J . Am. Chem. Soc. 1988,
110, 6246. (b) Naruse, Y.; Esaki, T.; Yamamoto, H. Tetrahedron 1988, 44,
4747.
(8) (a) Andrews, G. C.; Crawford, T. C.; Contillo, L. G., J r. Tetrahedron
Lett. 1981, 22, 3803. (b) Garrett, C. E.; Fu, G. C. J . Org. Chem. 1997, 62,
4534.
(9) Silicon tetrafluoride has been used together with Hu¨nig base to open
epoxides. Shimizu, M.; Yoshioka, H. Tetrahedron Lett. 1988, 29, 4101.
(10) (a) Denmark, S. E.; Winter, S. B. D.; Su, X.; Wong, K.-T. J . Am.
Chem. Soc. 1996, 118, 7404. (b) Denmark, S. E.; Winter, S. B. D. Synlett
1997, 1087. (c) Denmark, S. E.; Wong, K.-T.; Stavenger, R. A. J . Am. Chem.
Soc. 1997, 119, 2333. (d) Denmark, S. E.; Stavenger, R. A.; Wong, K.-T. J .
Org. Chem. 1998, 63, 918.
(11) Calculated at the MM2* level (Macromodel 5.5), Monte Carlo search
with 104 steps. The boat-twist chair was found to be the global minimum
with six similar conformations within 1.6 kJ /mol.
(12) Garner, P.; Park, J . M. Synth. Commun. 1987, 17, 189.
(13) (a) For compounds 10, 11, 13, 15, and 16, see ref 8b. (b) Compound
12: Allinger, N. L.; Tushaus, L. A. Tetrahedron 1967, 23, 2051. (c)
Compound 17: Caputo, R.; Ferrer, C.; Noviello, S.; Palumbo, G. Synthesis
1986, 499. (d) Compound 18: Besse, P.; Renard, M. F.; Veschambre, H.
Tetrahedron: Asymmetry 1994, 5, 1249.
(14) The regiochemical assignment was confirmed by preparation of the
trifluoroacetate of 17 and the acetate of 18.
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