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Synthesis 2006(20): 3389-3396  
DOI: 10.1055/s-2006-950243
PAPER
© Georg Thieme Verlag Stuttgart · New York

Enantioselective Synthesis of 1,4-Dihydrobenzoxathiins via Sulfoxide-Directed Borane Reduction

Marjorie S. Waters*, Ekama Onofiok, David M. Tellers, Jennifer R. Chilenski, Zhiguo Jake Song
Department of Process Research, Merck Research Laboratories, P.O. Box 2000, Rahway, NJ 07065, USA
Fax: +1(732)5941499; e-Mail: marjorie_waters@merck.com ;
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Publication History

Received 12 May 2006
Publication Date:
10 October 2006 (online)

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Abstract

A novel sulfoxide-directed borane reduction was shown to give a variety of 2-substituted 1,4-dihydrobenzoxathiins. For all substrates evaluated, the reaction is completely stereospecific. Application of this methodology to the chiral synthesis of an artificial sweetener was demonstrated.

Key words

asymmetric synthesis - sulfoxide - dihydrobenzoxathiin - reduction

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15

Ti(Oi-Pr)4 (0.15 mol%), diisopropylethylamine (0.3 mol%), diisopropyl tartrate (0.3 mol%), and H2O (0.15 mol%) as the catalyst and cumene hydroperoxide (CHP, 1.2 equiv) as the oxidant. See ref 5.

16

Compounds 5f and 6f were prepared previously, see reference 5 for experimental details.

17

The catalyst was 2:1:1 molar ratio of Ti(Oi-Pr)4/d-diethyl tartrate/H2O in CH2Cl2. The substrate was added to the catalyst solution followed by cumene hydroperoxide (CHP).

18

Crystal data for compound 7e: C19H22O2S, M = 314.44, orthorhombic, P2121 2 1, a = 9.5087(11) Å, b = 9.5799(11) Å, c = 18.842(2) Å, α = 90, β = 90, γ = 90, V = 1716.4(3) Å3, T = 298(2) K, Z = 4, rcalcd = 1.217 Mg/m3, µ = 0.193 mm-1, F(000) 672, 3456 independent reflections (R int = 0.0421), 18173 reflections collected; refinement method, full-matrix least squares refinement on F2; Goodness-of-fit on F2 = 1.024; Final R indices [I > 2σ(I)] R1 = 0.0412, wR2 = 0.0958.

19

A tentative assignment of the S-configuration for 6a-e and 7a-d can be made based on the mechanism and analogy to 7e. This is consistent with the facial selectivity previously reported by us (see ref. 5).

22

Initially, this sequence was done on commercially available 3-benzyloxy-4-methoxy benzaldehyde; however, the dehydrative cyclization failed to give the desired product.