J. Am. Chem. Soc. 1996, 118, 3779-3780
3779
Table 1. Zr-Catalyzed Kinetic Resolution of Five- and
Six-Membered Cyclic Allylic Ethersa
Zirconium-Catalyzed Kinetic Resolution of Cyclic
Allylic Ethers. An Enantioselective Route to
Unsaturated Medium Ring Systems
Michael S. Visser, Joseph P. A. Harrity, and
Amir H. Hoveyda*
Department of Chemistry, Merkert Chemistry Center
Boston College, Chestnut Hill, Massachusetts 02167
ReceiVed January 25, 1996
Allylic alcohols and ethers represent an important and
versatile class of substrates that are often used in the preparation
of a wide range of medicinally noteworthy natural products.
Therefore, methods that allow the preparation of these com-
pounds with high enantioselectivity are valuable to chemical
synthesis. Within this context, the well-known Ti-catalyzed
asymmetric epoxidation procedure of Sharpless1 is often used
to synthesize optically pure acyclic allylic alcohols through the
catalytic kinetic resolution of easily accessible racemic mix-
tures.2 However, when the catalytic epoxidation is applied to
cyclic allylic substrates, reaction rates are retarded and notably
lower levels of enantioselectivity are observed. Ru-catalyzed
asymmetric hydrogenation has been employed by Noyori to
effect resolution of five- and six-membered allylic carbinols;3
in this instance, as with the Ti-catalyzed procedure, the presence
of an unprotected hydroxyl function is required. Herein, we
report the results of our initial studies on the kinetic resolution4
of a variety of cyclic allylic ethers effected by asymmetric Zr-
catalyzed carbomagnesation.5 Importantly, in addition to six-
membered ethers, seven- and eight-membered ring systems can
be readily resolved by this catalytic protocol.
a Reaction conditions: 10 mol % of (R)-(EBTHI)Zr-binol, 5.0 equiv
of EtMgCl, THF, 70 °C. Reaction in entry 8 was carried out with 20
mol % of (R)-(EBTHI)Zr-binol. b Conversions determined by GLC
analysis in comparison with an internal standard, by analysis of the 1H
NMR of the reaction mixture, and through isolation (silica gel
chromatography). c The identity of the recovered starting materials was
determined through comparison with authentic enantiomers (see sup-
porting information for details). Enantiomeric excess was determined
by chiral GLC (BETADEX 120 chiral column by Supelco, entries 1-3,
6, and 7; CHIRALDEX-GTA chiral column by Alltech, entries 8 and
9). Recovered starting materials in entries 1, 3, 6, 7, and 8 were first
converted to their derived epoxides and then analyzed. Enantiomeric
excess was determined by chiral HPLC: CHIRALCEL OB-H for entries
4 and 5 and with CHIRALPAK AD for entry 10. Absolute stereo-
chemistry was directly determined for 3, 4, 5, and 8; the remaining
assignments were made by inference.
As illustrated in Table 1, when the benzyl ether of 2-cyclo-
penten-1-ol (1) is treated with 10 mol % of (R)-(EBTHI)Zr-
binol6 in the presence of 5 equiv of EtMgCl (THF, 70 °C), the
recovered starting material is obtained in 52% ee (65%
conversion;7 chiral GLC). When allylic MEM ether 2, derived
(1) (a) Martin, V. S.; Woodard, S. S.; Katsuki, T.; Yamada, Y.; Ikeda,
M.; Sharpless, K. B. J. Am. Chem. Soc. 1981, 103, 6237-6240. (b) Gao,
Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.; Sharpless,
K. B. J. Am. Chem. Soc. 1987, 109, 5765-5780.
(2) For recent reviews of kinetic resolution, see: (a) Kagan, H. B.; Fiaud,
J. C. Top. Stereochem. 1988, 18, 249-330. (b) Finn, M. G.; Sharpless, K.
B. In Asymmetric Synthesis; Morrison, J. D., Ed.; Academic Press: New
York, 1985; 247-308.
from cyclohexenol, is subjected to these conditions, at 63%
conversion the starting material is recovered in 50% ee (chiral
GLC). In contrast, the derived n-butyl ether 3 is resolved more
efficiently (79% ee at 63% conversion). The synthetically more
useful benzyl ether 4 undergoes asymmetric ethylmagnesation
and is recovered with still better enantioselection than was
observed with the above substrates ((S)-4 is recovered in 81%
ee; chiral HPLC);8 the latter substrate reacts faster than 2 or 3
as well (compare entries 2 and 3 with 4). Importantly, as shown
in entry 5, when racemic phenyl ether 5 is treated to the Zr-
catalyzed resolution conditions for 2 h, (S)-5 is obtained in 97%
ee at 60% conversion.9
The resolution data depicted in entries 8-10 in Table 1
indicate the following. (i) Disubstituted allylic ethers can be
resolved through the Zr-catalyzed protocol; phenyl ether 8 is
obtained in 98% ee after 55% conversion. To obtain excellent
levels of enantiomeric purity in the resolution with 8 as the
substrate, 20 mol % of zirconocene (Vs 10 mol %) must be used;
15 mol % of (EBTHI)Zr-binol affords the recovered starting
material in 84% ee at 60% conversion (kfast/kslow ) 8);10 with
10 mol % of precatalyst the reaction does not effectively proceed
(3) Kitamura, M.; Kasahara, I.; Manabe, K.; Noyori, R.; Takaya, H. J.
Org. Chem. 1988, 53, 708-710. For Pd-catalyzed enantioselective synthesis
of cyclic allylic esters, see: Trost, B. M.; Organ, M. G. J. Am. Chem. Soc.
1994, 116, 10320-10321.
(4) For previous reports on kinetic resolution processes through Zr-
catalyzed carbomagnesation, see: (a) Morken, J. P.; Didiuk, M. T.; Visser,
M. S.; Hoveyda, A. H. J. Am. Chem. Soc. 1994, 116, 3123-3124. (b) Visser,
M. S.; Hoveyda, A. H. Tetrahedron 1995, 51, 4383-4394. (c) Visser, M.
S.; Heron, N. M.; Didiuk, M. T.; Sagal, J. F.; Hoveyda, A. H. J. Am. Chem.
Soc. in press.
(5) (a) Morken, J. P.; Didiuk, M. T.; Hoveyda, A. H. J. Am. Chem. Soc.
1993, 115, 6997-6998. (b) Didiuk, M. T.; Johannes, C. W.; Morken, J. P.;
Hoveyda, A. H. J. Am. Chem. Soc. 1995, 117, 7097-7104. For application
of asymmetric Zr-catalyzed carbomagnesation to natural product synthesis,
see: Houri, A. F.; Xu, Z-M.; Cogan, D. A.; Hoveyda, A. H. J. Am. Chem.
Soc. 1995, 117, 2943-2944.
(6) (a) Wild, F. R. W. P.; Waiucionek, M.; Huttner, G.; Brintzinger, H.
H. J. Organomet. Chem. 1985, 288, 63-67. (b) Diamond, G. M.; Rodewald,
S.; Jordan, R. F. Organometallics 1995, 14, 5-7 and references cited therein.
(7) All reactions described herein afford the expected ethylmagnesation
products. In certain cases, due to substrate volatility, the alkylation product
could not be isolated but was detected in the 1H NMR spectrum of the
unpurified mixture. In instances where volatility is not a hindrance, the
product was fully characterized (e.g., with 9 and 10, i and ii were obtained,
respectively). Details (including product stereocontrol) will be provided in
the full account of this study.
(8) All the catalytic resolutions described herein must be carried out with
freshly prepared catalyst batches of high purity. Sluggish reactions and/or
inferior enantioselectivities will be otherwise observed.
(9) The phenyl ether derived from cyclopentenol reacts with the
alkylmagnesium halide in the absence of the catalyst, preempting the
possibility of catalytic kinetic resolution (both at 22 and 70 °C). Nonetheless,
the starting material is recovered in ∼40% ee after 60% conversion.
0002-7863/96/1518-3779$12.00/0 © 1996 American Chemical Society