The kinetic resolution of allylic alcohols by a non-enzymatic acylation catalyst; application to natural product synthesis

Article abstract of DOI:10.1039/b002041i

A planar-chiral DMAP derivative is shown to serve as an effective catalyst for the kinetic resolution of allylic alcohols; to illustrate its practical utility, the catalyst is applied to the resolution of two alcohols that have been employed as intermedia

Full text of DOI:10.1039/b002041i

The kinetic resolution of allylic alcohols by a non-enzymatic acylation catalyst;
application to natural product synthesis†
Stéphane Bellemin-Laponnaz, Jennifer Tweddell, J. Craig Ruble, Frank M. Breitling and Gregory C. Fu*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139 USA.
E-mail: gcf@mit.edu
Received (in Corvallis, OR, USA) 7th March 2000, Accepted 24th April 2000
Published on the Web 22nd May 2000
A planar-chiral DMAP derivative is shown to serve as an
effective catalyst for the kinetic resolution of allylic alcohols;
to illustrate its practical utility, the catalyst is applied to the
resolution of two alcohols that have been employed as
intermediates in recent natural product total syntheses.
catalyst 1 (entries 3–8); again, the presence of a phenyl
substituent in the trans position leads to substantially improved
enantioselection (entry 9 vs. entries 3–8). Similarly, kinetic
resolutions of allylic alcohols that possess a substituent cis to
the hydroxy-bearing group generally proceed with good
selectivity (entries 10–12). Furthermore, tetrasubstituted allylic
alcohols are acylated with high stereoselection (entry 13).
During the mid-1990s, Evans et al.1 and Vedejs and Chen2
reported the first stoichiometric chiral acylating agents that are
effective for the kinetic resolution of alcohols [selectivity factor
(s) > 10],3 work that marked an important first step in the
development of non-enzyme-based methods for enantiose-
lective acylation.4 Soon thereafter, the groups of Vedejs,5
Oriyama,6 Fuji,7 Miller8 and ourselves9 described the first chiral
non-enzymatic acylation catalysts that are effective for the
kinetic resolution of alcohols. With regard to substrate scope,
the generality that has been reported to date follows the order:
arylalkylcarbinols10 > cycloalkanols11 > propargylic alco-
hols12 > allylic alcohols.13
Table 1 Kinetic resolutions of allylic alcohols catalyzed by (+)-1 (Ac2O,
NEt3, t-amyl alcohol, 0 °C)
Our work on catalytic enantioselective acylation has focused
on the application of planar-chiral DMAP derivative 1 to the
kinetic resolution of arylalkylcarbinols and of propargylic
alcohols.9 In addition, we observed in a 1997 study that we
could resolve two allylic alcohols with good selectivity.9a,14
Herein, we report a systematic investigation of the kinetic
resolution of allylic alcohols by catalyst 1 [eqn. (1)], establish-
ing fairly broad substrate scope and applying the method to two
alcohols that have served as key building blocks in recent
natural product syntheses.
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We have found that catalyst 1 can effect the kinetic resolution
of most families of allylic alcohols with good selectivity [Table
1; 1.0–2.5% (+)-1, Ac2O, NEt3, t-amyl alcohol, 0 °C]. Allylic
alcohols that do not possess a substituent either geminal or cis
to the hydroxy-bearing group are usually resolved with modest
selectivity (entry 1). A notable exception to this generalization
occurs when there is a phenyl group in the trans position, in
which case the selectivity factor increases dramatically (entry
2).
Allylic alcohols that possess a substituent geminal to the
hydroxy-bearing group are usually resolved effectively by
† Electronic supplementary information (ESI) available: full experimental
details. See http://www.rsc.org/suppdata/cc/b0/b002041i/
DOI: 10.1039/b002041i
Chem. Commun., 2000, 1009–1010
This journal is © The Royal Society of Chemistry 2000
1009

In order to demonstrate the utility of this method, we have
applied catalyst 1 to the kinetic resolution of two allylic alcohols
that have served as key intermediates in recent natural product
total syntheses. For example, Brenna et al. employed (2)-2 in a
1997 synthesis of (2)-baclofen,15 which is used as a muscle
relaxant. We have determined that catalyst 1 effects the kinetic
resolution of racemic 2 with a selectivity factor of 37 [eqn. (2)].
This reaction was run on a 2 g scale, exposed to air, thereby
illustrating the practicality of the process. At the conclusion of
the kinetic resolution, 96% of the catalyst was recovered.
Notes and references
1 D. A. Evans, J. C. Anderson and M. K. Taylor, Tetrahedron Lett., 1993,
34, 5563.
2 E. Vedejs and X. Chen, J. Am. Chem. Soc., 1996, 118, 1809.
3 Selectivity factor = [(rate of fast-reacting enantiomer)/(rate of slow-
reacting enantiomer)]. For a review of kinetic resolution, see: H. B.
Kagan and J. C. Fiaud, Top. Stereochem., 1988, 18, 249.
4 For a review of enantioselective acylations of alcohols by enzymes, see:
K. Drauz and H. Waldmann, Enzyme Catalysis in Organic Synthesis: A
Comprehensive Handbook, VCH, New York, 1995.
5 (a) E. Vedejs, O. Daugulis and S. T. Diver, J. Org. Chem., 1996, 61,
430; (b) E. Vedejs and O. Daugulis, J. Am. Chem. Soc., 1999, 121,
5813.
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6 T. Oriyama, Y. Hori, K. Imai and R. Sasaki, Tetrahedron Lett., 1996, 37,
8543; T. Sano, K. Imai, K. Ohashi and T. Oriyama, Chem. Lett., 1999,
265.
7 T. Kawabata, M. Nagato, K. Takasu and K. Fuji, J. Am. Chem. Soc.,
1997, 119, 3169.
8 S. J. Miller, G. T. Copeland, N. Papaioannou, T. E. Horstmann and
E. M. Ruel, J. Am. Chem. Soc., 1998, 120, 1629; G. T. Copeland, E. R.
Jarvo and S. J. Miller, J. Org. Chem., 1998, 63, 6784; E. R. Jarvo, G. T.
Copeland, N. Papaioannou, P. J. Bonitatebus, Jr. and S. J. Miller, J. Am.
Chem. Soc., 1999, 121, 11 638.
9 (a) J. C. Ruble, H. A. Latham and G. C. Fu, J. Am. Chem. Soc., 1997,
119, 1492; (b) J. C. Ruble, J. Tweddell and G. C. Fu, J. Org. Chem.,
1998, 63, 2794; (c) C. E. Garrett, M. M.-C. Lo and G. C. Fu, J. Am.
Chem. Soc., 1998, 120, 7479; (d) B. Tao, J. C. Ruble, D. A. Hoic and
G. C. Fu, J. Am. Chem. Soc., 1999, 121, 5091.
Aldol adduct (+)-3 is a key intermediate in the recent Sinha–
Lerner synthesis of epothilone A,16 an exciting new potential
anti-cancer drug.17 Adduct (+)-3 has itself been the focus of
much attention, owing to the fact that it can be generated by an
aldolase antibody through kinetic resolution of racemic 3 (96%
ee at 60% conversion » s ~ 17).16,18 We have determined that
catalyst 1 can also effect the kinetic resolution of this
compound, with a selectivity factor of 107 [eqn. (3); reaction
run exposed to air on a 1.2 g scale; acetylated 3: 52% yield,
91.8% ee].19
10 Fourteen examples with s > 10: refs. 5, 6 and 9(a)–(c).
11 Thirteen examples with s > 10: refs. 6–8.
12 Eight examples with s > 10: ref. 9(d).
13 Three examples with s > 10: refs. 5(b) and 9(a).
14 The most prominent non-enzymatic method for the kinetic resolution of
allylic alcohols is the Sharpless asymmetric epoxidation: R. A. Johnson
and K. B. Sharpless, in Comprehensive Organic Synthesis, ed. B. M.
Trost, Pergamon, New York, 1991; vol. 7, ch. 3.2.
15 E. Brenna, N. Caraccia, C. Fuganti, D. Fuganti and P. Grasselli,
Tetrahedron: Asymmetry, 1997, 8, 3801.
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16 S. C. Sinha, C. F. Barbas, III and R. A. Lerner, Proc. Natl. Acad. Sci.
USA, 1998, 95, 14603.
17 For example, see: S. Borman, Chem. Eng. News, Jan. 31, 2000, p. 7.
18 For commentaries, see: P. G. Schultz, Proc. Natl. Acad. Sci. USA, 1998,
95, 14 590; S. Borman, Chem. Eng. News, Dec. 14, 1998, p. 15.
19 In the air, t-amyl alcohol (8.75 mL; distilled from CaH2) and NEt3 (0.36
mL, 2.6 mmol; EM Science, 98%) were added to a vial containing the
alcohol (1.16 g, 4.42 mmol) and (+)-1 (29.0 mg, 0.0439 mmol). The vial
was closed with a Teflon-lined cap and sonicated to help dissolve the
catalyst. The reaction mixture was cooled in an ice bath, and Ac2O (0.25
mL, 2.6 mmol; Mallinckrodt, 99.8%) was added. After 42.5 h, the
reaction was quenched with MeOH (0.25 mL). The mixture was passed
through a silica gel column (20 ? 100% EtOAc–hexanes, then 50%
NEt3–EtOAc) to separate the alcohol and the acetate from the catalyst
[27.6 mg (95%) of pure catalyst was recovered]. The alcohol and the
acetate were then separated by flash chromatography (10 ? 25%
EtOAc–hexanes), which afforded 0.70 g (52%) of acetate (HPLC
analysis » 91.8% ee) and 0.55 g (47%) of alcohol (HPLC analysis »
98.0% ee). These ee values correspond to a selectivity factor (s) of 107
at 51.6% conversion.
In conclusion, we have established that planar-chiral DMAP
derivative 1 is the most versatile non-enzymatic acylation
catalyst for the kinetic resolution of allylic alcohols that has
been reported to date, furnishing good selectivity for most
substrates. Furthermore, we have illustrated the usefulness of
this method by applying it to the kinetic resolution of two
alcohols that have served as intermediates in recent natural
product total syntheses.
Support has been provided by Bristol-Myers Squibb, Merck,
the Natural Sciences and Engineering Research Council of
Canada (predoctoral fellowship to J. T.), the National Institutes
of Health (National Institute of General Medical Sciences, R01-
GM57034), Novartis, Pfizer, and Pharmacia & Upjohn.
This paper is dedicated to the memory of John A. Osborn.
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Chem. Commun., 2000, 1009–1010