10938
J. Am. Chem. Soc. 1996, 118, 10938-10939
Scheme 1
Direct Catalytic Enantioselective Reduction of
Achiral r,â-Ynones. Strong Remote Steric Effects
Across the C-C Triple Bond
Christopher J. Helal, Plato A. Magriotis, and E. J. Corey*
Department of Chemistry and Chemical Biology
HarVard UniVersity, Cambridge, Massachusetts 02138
ReceiVed August 14, 1996
The example described in Scheme 1 is representative.
Treatment of ketone 1a and oxazaborolidine 3a (0.05 equiv)
with catecholborane (1.2 equiv) as the stoichiometric reductant
at -78 °C in CH2Cl2 produced the (R)-acetylenic alcohol in
98% yield and 97% ee (66:1 enantiomer ratio (er)).7-9 The
acetylenic ketone undergoes enantioselective reduction in the
sense expected for coordination of the catalyst at the carbonyl
lone pair anti to the (triisopropylsilyl)ethynyl unit, which
functions effectively as the larger carbonyl substituent (RL)
versus the n-pentyl group (RS).10 An indication of the scope
of this reduction is provided by the examples shown in Table
1. The products are valuable synthetic building blocks; for
example, 2a for eicosanoid synthesis,1,5b 2c for enediyne
derivatives,3 and 2d for elaboration products of ethynyl oxiranes.
It is noteworthy that for the reduction of ketone 1e isopropyl
corresponds to RS and ethynyl to RL. The previously unknown
(triisopropylsilyl)acetylenic ketones 1a-e were efficiently
prepared via a novel and highly selective Friedel-Crafts
acylation (RCOCl, AlCl3, CH2Cl2, 0 °C) of (triisopropylsilyl)-
(trimethylsilyl)acetylene.11 A greater understanding of the factors
responsible for the high enantioselectivity observed in the
reduction of the R,â-ynones can be gained from the data shown
in Tables 2-4. The results in Table 2 reveal a dramatic
enhancement of the asymmetric induction as the distal group
of the alkyne increases in size from n-pentyl (68% ee, 4:1
enantiomer ratio) to phenyl and trimethylsilyl (87% ee, 14:1
enantiomer ratio) to triisopropylsilyl (96% ee, 49:1 enantiomer
ratio). A consistently greater remote steric effect of the
triisopropylsilyl group relative to the trimethylsilyl group is
documented in Table 3.12 The dependence of the enantiose-
lectivity of reduction of the (triisopropylsilyl)acetylenic ketones
on the alkyl group attached to the boron atom of the catalyst is
clearly shown by the data in Table 4. A systematic increase in
the size of the boron substituent resulted in marked enhancement
of the enantioselectivity of the reduction. Thus, in CH2Cl2, the
percent ee observed increased from 60% (B-Me, catalyst 3c)
to 92% (B-n-Bu, catalyst 3b) to 97% (B-CH2SiMe3, catalyst
3a), whereas in toluene, the percent ee observed increased from
46% ((S)-enantiomer, 3c) to 72% ((R)-enantiomer, 3b) to 95%
(3a).13 It is interesting to note that the selectivity of the
reduction varies with solvent for catalyst 3c (CH2Cl2, 4:1
Chiral propargylic alcohols are extremely useful intermediates
for the enantioselective synthesis of complex molecules, for
example, eicosanoids,1 macrolides,2 and enediyne antibiotics.3
There have been only two principal approaches to the enant-
ioselective synthesis of propargylic alcohols: (1) enantioselec-
tive alkynylation of aldehydes4 and (2) reduction of R,â-ynones5
or their π-Co2(CO)6-protected derivatives.6 Although the last
method6 is catalytic and quite effective, we sought a more direct
catalytic synthesis. This research led to the discovery of a
remarkable steric effect across the acetylenic linkage and a direct
and highly effective catalytic enantioselective reduction of R,â-
ynones.
(1) (a) Nicolaou, K. C.; Webber, S. E. J. Am. Chem. Soc. 1984, 106,
5734. (b) Chemin, D.; Linstrumelle, G. Tetrahedron 1992, 48, 1943. (c)
Corey, E. J.; Niimura, K.; Konishi, Y.; Hashimoto, S.; Hamada, Y.
Tetrahedron Lett. 1986, 27, 2199.
(2) Roush, W. R.; Sciotti, R. J. J. Am. Chem. Soc. 1994, 116, 6457.
(3) Vourloumis, D.; Kim, K. D.; Petersen, J. L.; Magriotis, P. A. J. Org.
Chem. 1996, 61, 4848.
(4) (a) Mukaiyama, T.; Suzuki, K.; Soai, K.; Sato, T. Chem. Lett. 1979,
447. (b) Mukaiyama, T.; Suzuki, K. Chem. Lett. 1980, 255. (c) Niwa, S.;
Soai, K. J. Chem. Soc., Perkin Trans. 1 1990, 937. (d) Tombo, G. M. R.;
Didier, E.; Loubinoux, B. Synlett 1990, 547. (e) Corey, E. J.; Cimprich, K.
A. J. Am. Chem. Soc. 1994, 116, 3151
(5) (a) Midland, M. M.; Kazubski, A. J. Am. Chem. Soc. 1982, 47, 2816.
(b) Noyori, R.; Tomino, I.; Yamada, M.; Nishizawa, M. J. Am. Chem. Soc.
1984, 106, 6717. (c) Marshall, J. A.; Robinson, E. D.; Zapata, A. J. Org.
Chem. 1989, 54, 5854. (d) Brown, H. C.; Ramachandran, P. V.; Weissman,
S. A.; Swaminathan, S. J. Org. Chem. 1990, 55, 6328.
(6) Corey, E. J.; Helal, C. J. Tetrahedron Lett. 1995, 36, 9153.
(7) The absolute configuration of the product was determined by
desilylation (1.1 equiv of tetrabutylammonium fluoride, THF, 23 °C) and
comparison of the optical rotation with known (R)-1-octyn-3-o1; [R]D,25
+4.2 (c 0.55, CH2Cl2), [R]D,20 (lit.) +6.5 (c 2.0, CH2Cl2). The absolute
configurations of the other (triisopropylsilyl)acetylenic alcohols (Table 1)
were assigned by analogy.
(8) Catalyst 3a was prepared using (S)-R,R-diphenyl-2-pyrrolidinemetha-
nol and Me3SiCH2B(OH)2. For the catalyst preparation procedure see the
Supporting Information. Physical data for 3a: 1H NMR (400 MHz, CDCl3
(distilled)) δ 7.52 (d, J ) 8.6 Hz, 2H), 7.38 (d, J ) 7.9 Hz, 2H), 7.17-
7.35 (m, 6H), 4.28 (dd, J ) 5.6, 10.0 Hz, 1H), 3.34 (m, 1H), 3.04 (m, 1H),
1.76 (m, 2H), 1.58 (m, 1H), 0.79 (m, 1H), 0.08 (s, 3H), 0.05 (s, 6H) ppm;
13C NMR (100 MHz, CDCl3 (distilled)) δ 148.02, 144.34, 128.04, 127.06,
126.50, 126.39, 126.22, 87.31, 72.61, 43.39, 30.50, 25.95, 0.58, 0.50 ppm;
11B NMR (96 MHz, CDCl3 (distilled)) δ 35.12 (br s) ppm; MS (CI) [M +
H]+ (100%), M+ (35%); HRMS (CI) calcd for [C21H29BNOSi] 350.2111,
found 350.2123. Reduction of 1a: Ketone 1a (1.6 mmol, 449 mg)
(azeotropically dried with toluene under an inert atmosphere) was treated
with catalyst 3a (0.05 equiv, 0.08 mmol, 400 µL of a 0.2 M toluene
solution). The toluene was removed in Vacuo, CH2Cl2 (4 mL) was added,
and the solution was cooled to -78 °C. A solution of catecholborane (1.2
equiv, 1.9 mmol, 200 µL) in CH2Cl2 (800 µL) was then added dropwise
over 10 min. After 5 h of stirring, MeOH (1 mL) was added, the solution
was warmed to 23 °C, diluted with Et2O, washed with 2:1 1 N NaOH-
saturated NaHCO3 until the aqueous layer was colorless, washed with brine,
dried (MgSO4), and concentrated in Vacuo. The addition of Et2O (10 mL)
followed by 0.5 M HCl in MeOH (0.05 equiv, 0.08 mmol, 160 µL) resulted
in precipitation of the amino alcohol hydrochloride salt as a fine powder
which was removed via filtration. The Et2O was removed in Vacuo, and
the residue was passed through a short column of silica gel (30:1 to 15:1
hexanes-EtOAc) to provide 440 mg of 2a as a clear oil (98% yield): [R]D,25
+12.1 (c 1.40, benzene); 1H NMR (500 MHz, CDCl3) δ 4.38 (m, 1H),
1.76 (d, J ) 4.9 Hz, 1H), 1.71 (m, 2H), 1.46 (m, 2H), 1.31 (m, 4H), 1.01-
1.29 (m, 21H), 0.89 (t, J ) 6.9 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3)
δ 108.99, 85.48, 63.12, 37.99, 31.49, 24.86, 22.63, 18.63, 14.01, 11.19 ppm;
FT-IR (neat) 3407, 2957, 2942, 2893, 2865, 1464 cm-1; MS (CI) 300 ([M
+ NH4]+, 100); HRMS (CI) calcd for [C17H38NOSi] ([M + NH4]+)
300.2723, found 300.2736. The enantioselectivity of the reduction was
determined by conversion of the alcohol to the p-nitrobenzoate and HPLC
analysis (Chiralcel OD, 0.05% i-PrOH in hexanes, 0.5 mL/min, λ ) 254
nm) which showed the product to be of 97% ee (tR ) 30.4 min, major;
26.0 min, minor).
(9) The reduction of ketone 1a using 0.1 equiv of catalyst 3a and 1.0
equiv of BH3-Me2S as the stoichiometric reductant in THF at 0 °C gave
the enantiomer of 2a in 40% ee and 88% yield.
(10) While this work was in progress, the stoichiometric and catalytic
(0.5 mol equiv) asymmetric reduction of phenyl-substituted and terminal
acetylenic ketones was reported (2 equiv of B-Me oxazaborolidine 3c, 5
equiv of BH3-Me2S, THF, -30 °C). Under these conditions the acetylenic
group is effectively RS: Parker, K. A.; Ledeboer, M. W. J. Org. Chem.
1996, 61, 3214.
(11) (a) Prepared from (trimethylsilyl)acetylene (n-BuLi, THF, -78 °C)
and triisopropylsilyl chloride (-78 to 23 °C) in 96% yield after distillation
(bp 56-57 °C (0.25 mmHg)). For details see the Supporting Information.
(b) For another selective reaction of (triisopropylsilyl)(trimethylsilyl)-
acetylene, see: Stang, P. J.; Zhdankin, V. V.; Arif, A. M. J. Am. Chem.
Soc. 1991, 113, 8997.
(12) The (trimethylsilyl)acetylenic ketones were prepared according to
established procedures: (a) Birkofer, L.; Ritter, A.; Uhlenbrauck, H. Chem.
Ber. 1963, 96, 3280. (b) Walton, D. R. M.; Waugh, F. J. Organomet. Chem.
1972, 37, 45. (c) Newman, H. J. Org. Chem. 1973, 38, 2254. (d) Earl, R.
A.; Vollhardt, K. P. C. J. Org. Chem. 1984, 49, 4786. (e) Reference 3.
(13) The enantioselectivity of the reduction of the π-Co2(CO)6 complex
of 3-nonyn-2-one also increased with the size of the alkyl group on the
boron atom: 87% ee, 3b; 90% ee, B-i-Bu catalyst; 95% ee, 3a. See ref 6.
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