Enantioselective reduction of esters: Synthesis of optically active α- acetoxy ethers

Article abstract of DOI:10.1016/S0040-4039(00)00470-6

An enantioselective reduction and acetylation of esters to α-acetoxy ethers is described. Reduction with a NaAlH₄-ephedrine reagent followed by in situ acetylation gives 2 with good enantiomeric excess. This reaction is limited in scope, but it demonstrates that enantioselective reductions of esters are possible. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00470-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 3593–3596
Enantioselective reduction of esters: synthesis of optically active
α-acetoxy ethers
Scott D. Rychnovsky ∗ and Brian M. Bax
Department of Chemistry, University of California, Irvine, CA 92697-2025, USA
Received 9 February 2000; revised 15 March 2000; accepted 17 March 2000
Abstract
An enantioselective reduction and acetylation of esters to α-acetoxy ethers is described. Reduction with a
NaAlH4–ephedrine reagent followed by in situ acetylation gives 2 with good enantiomeric excess. This reaction is
limited in scope, but it demonstrates that enantioselective reductions of esters are possible. © 2000 Elsevier Science
Ltd. All rights reserved.
The stereoselective alkylation of acetals to form new C–C bonds is a widely used reaction that usually
proceeds by an SN1 pathway.1 Recently, Kusumoto has reported an SN2-like alkylation of enantiopure
acetals (2) with cuprates that proceeds with inversion of configuration.2 Kusumoto’s chiral acetals
were synthesized by Baeyer–Villager oxidations of the enantiopure α-alkoxy ketones 1. An alternative
approach to Kusumoto’s optically pure α-acetoxy ethers can be envisioned using an enantioselective
reductive-acetylation of simple esters. We have recently reported a DIBAL-H reduction and in situ
acetylation of esters to racemic α-acetoxy ethers.3 The first example of an enantioselective reductive-
acetylation of an ester is reported in Scheme 1.
Scheme 1.
∗
Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00470-6
tetl 16750

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For an enantioselective reduction and acetylation to be effective, the aluminum hemiacetal must
be configurationally stable. We have reported3 that the reduction and acetylation of the macrocyclic
lactone oxacyclohexadecan-2-one gave 2-acetoxyoxacyclohexadecane in 71% yield. If the intermediate
aluminum hemiacetal had been susceptible to loss of configuration by reversible opening and closing,
none of the macrocycle would have been formed: polymerization would predominate over reclosing a
16-membered hemiacetal ring. We concluded that the intermediate aluminum hemiacetals are acetylated
without opening to the aldehyde and without significant loss of configuration.4
The most conservative modification of our reductive-acetylation procedure would be to use a chiral
analogue of DIBAL-H. Chiral analogs of DIBAL-H are known, but are not easily accessible.5 Instead
we focused on modified sodium aluminum hydrides (NaAlH4−nXn), which have been used for the
selective reduction of esters to aldehydes.6 Ethyl O-benzylglycolate (7) is a simple, prochiral ester that
was selected to screen for enantioselective reductive-acetylation by chiral reagents. Several bishydrido
aluminum species were prepared from NaAlH4 and a chiral diol or an amino alcohol. Reduction of 7 and
in situ acetylation gave the α-acetoxy ester 8 (Table 1).7 The optical purity of 8 was assayed by HPLC
on a Chiracel OJ column.
Table 1
Enantioselective reduction and in situ acetylation of ester 7
Reagents analogous to TADDOL8 and BINAL-H9 (entries 1 and 2) did give optically active 8, but
the reaction did not go to completion, and the optical purity of the product was modest. The best results
were found using (1R,2S)-(−)-ephedrine (entry 4), where the product was isolated in 55% yield and 83%
ee.10 Pseudoephedrine gave almost racemic product under the same reaction conditions. The reduction of

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ester 7 with ephedrine shows that good enantioselectivities are possible using ligand-modified NaAlH4
reagents.
The ephedrine system was successful in the enantioselective reduction of closely related substrates,
but it is not general. Table 2 shows the results with three esters analogous to the ester 7. The reaction
works well with the PMB ether 9a, but gave unacceptably low yields with the other two substrates.
The reduction of 9c was very slow, and the majority of the starting material was recovered unchanged.
Product 10c was isolated in 17% ee, demonstrating that an adjacent heteroatom is not necessary for
modest enantioselectivity. While the hydride/ephedrine system reduces aliphatic esters slowly, it does
not reduce aromatic or unsaturated esters at −78°C.
Table 2
Reduction and in situ acetylation with a NaAlH4-ephedrine reagent
The configuration of α-acetoxy ether 8 was determined by correlation with D-glyceraldehyde aceto-
nide (11),11 using the method of Kusumoto.2 Addition of MeMgBr followed by Mitsunobu etherification
and hydrolysis of the acetonide afforded the diol 12 (Scheme 2). Selective alkylation of the 1° alcohol
with Bu2SnO and BnBr, followed by removal of the other isomer by silylation and separation gave the
intermediate secondary alcohol in modest yield.12 Alkylation of the alcohol with ethyl bromide gave 13.
Deprotection of the 4-methoxyphenyl ether with cerric ammonium nitrate, followed by Swern oxidation
gave the ketone 14. Baeyer–Villager oxidation of the ketone gave the α-acetoxy ether 8, which was
shown to have the same absolute configuration as compound 8 from Table 1 by HPLC and by optical
rotation.13
Scheme 2.
The first enantioselective reductive-acetylation of an ester to an α-acetoxy ether with good enantio-
meric excess has been demonstrated.

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References
1. Alexakis, A.; Mangeney, P. Tetrahedron: Asymmetry 1990, 1, 477–511.
2. Kusumoto, T.; Matsutani, H.; Ichikawa, S.; Yaruva, J.; Hiyama, T. J. Am. Chem. Soc. 1997, 119, 4541–4542.
3. Rychnovsky, S. D.; Dahanukar, V. H. J. Org. Chem. 1996, 61, 8317–8320.
4. This conclusion was further supported by a negative cross-over experiment: unpublished work, Sinz, C.; Rychnovsky, S.
D.
5. (a) Yur’ev, V. P.; Kuchin, A. V.; Yakovleva, T. O.; Tolstikov, G. A. Zh. Obshch. Khim. 1974, 44, 2084–2087; (b) Giacomelli,
G.; Menicagli, R.; Caprousso, A. M.; Lardicci, L. J. Org. Chem. 1978, 43, 1790–1793; (c) Giacomelli, G.; Lardicci, L.;
Palla, F. J. Org. Chem. 1984, 49, 310–313.
6. (a) Kanazawa, R.; Tokoroyama, T. Synthesis 1976, 526–528; (b) Cha, J. S.; Kim, J. M.; Jeoung, M. K.; Kwon, O. O.; Kim,
E. J. Org. Prep. Proced. Int. 1995, 27, 94–97.
7. A 50 mL flask was charged with THF (2 mL) and NaAlH4 (0.772 mL, 2.0 M in ether). To this mixture was added a solution
of (1R,2S)-(−)-ephedrine (0.255 g, 1.54 mmol) in THF (2 mL) over 4 min. The solution was stirred for 15 min then cooled
to −78°C. The ester 7 (100 mg, 0.514 mmol) was added to this solution neat and the mixture was stirred for 2 h at −78°C.
Acetic anhydride (0.291 mL, 3.08 mmol) and DMAP (0.252 g, 2.06 mmol) were added to the reaction and the flask was
warmed up to room temperature over 16 h. The yellow solution was diluted with ether and 1N HCl. The aqueous layer
was extracted with ether (twice). The combined organic layers were washed successively with sat. K2CO3, brine, dried
with MgSO4 and concentrated. The residue was purified by flash chromatography (5% ethyl acetate/hexanes) to give 64
mg of 8 as a clear oil (55%): [α]2D3 +4.0 (c 0.40, CHCl3); IR (neat) 3031, 2979, 1743, 1239, 1115 cm−1; H NMR (500
1
MHz, CDCl3) δ 7.36–7.30 (m, 5H), 6.01 (t, J=5.1 Hz, 1H), 4.64 (d, J=12.1 Hz, 1H), 4.59 (d, J=12.1 Hz, 1H), 3.80 (dq
J=9.7, 7.1 Hz, 1H), 3.65 (dq J=9.7, 7.1 Hz, 1H), 3.61 (dd J=10.7, 5.1 Hz, 1H), 3.56 (dd J=10.7, 5.1 Hz, 1H), 2.11 (s, 3H),
1.25 (t, J=7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 170.7, 137.8, 128.4, 127.7, 127.7, 95.7, 73.4, 70.3, 65.5, 21.2,
15.0; HRMS (CI-Isobutane) calcd for C13H17O4 (M−H)+: 237.1127, found: 237.1134. Anal. calcd for C13H18O4: C, 65.53;
H, 7.61. Found: C, 65.77; H, 7.41. The product was determined to be 83% ee by analysis on a CHIRACEL OJ column
(hexane:2-propanol=97:3 at a flow rate of 0.8 ml/min). The retention times were 12.5 min for the minor R-enantiomer and
13.5 min for the major S-enantiomer.
8. Seebach, D.; Dahinden, R.; Marti, R. E.; Beck, A. K.; Plattner, D. A.; Kuhnle, F. N. M. J. Org. Chem. 1995, 60, 1788–1799.
9. Noyori, R.; Tomino, I.; Yamada, M.; Nishizawa, M. J. Am. Chem. Soc. 1984, 106, 6709–6716.
10. An old bottle of ephedrine gave cloudy solutions with NaAlH4 and lower yields and % ee, perhaps due to adventitious
water.
11. Schmid, C. R.; Bryant, J. D. Org. Synth. 1993, 72, 6–13.
12. Ohno, M.; Nagashima, N. Chem. Pharm. Bull. 1991, 39, 1972–1982.
13. Both the sign and the magnitude of the optical rotations for the two samples of compound 8, prepared in Table 1 and in
Scheme 2, are consistent with them having the same absolute configuration. Both samples also showed the same retention
time on a Chiracel OJ column.