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Synthesis 2005(20): 3517-3530  
DOI: 10.1055/s-2005-918425
PAPER
© Georg Thieme Verlag Stuttgart · New York

Asymmetric Synthesis of 2-Keto-1,3-diols and Protected 1,2,3-Triols Bearing Two Quaternary Stereocenters

Dieter Enders*, Irene Breuer, Gerhard Raabe
Institut für Organische Chemie, Rheinisch-Westfälische Technische Hochschule, Landoltweg 1, 52074 Aachen, Germany
Fax: +49(241)8092127; e-Mail: Enders@RWTH-Aachen.de;
Further Information

Publication History

Received 3 June 2005
Publication Date:
12 October 2005 (online)

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Abstract

The asymmetric synthesis of 1,3-dihydroxy-2-ketones bearing two quaternary stereocenters in α- and α′-position starting from 2,2-dimethyl-1,3-dioxan-5-one-SAMP-hydrazone is described. The protocol involves four consecutive α/α′-alkylations, the last one being carried out in the presence of DMPU as additive. After acidic cleavage of both the chiral auxiliary and the acetal function in a two-phase system, the title compounds are obtained with high stereoselectivity (de ≥ 91-97%, ee ≥ 96%) and in moderate to very good overall yields (14-61%). In addition, 1,2-quaternary 1,3-protected 1,2,3-triols were obtained by nucleophilic 1,2-addition to the carbonyl group as single stereoisomeres (de, ee ≥ 96%) in excellent yields.

Key words

asymmetric synthesis - quaternary stereocenters - α-alkylation - SAMP/RAMP-hydrazones - 1,2-addition

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X-ray Crystallographic Study of 4c: The compound crystallizes in orthorhombic space group P212121 (Nr. 19) (C14H20O3, Mr = 236.31). The cell dimensions are a = 9.165 (7), b = 9.700(2), and c = 15.365 (4) Å. A cell volume of V = 1366.0(11) Å3 and Z = 4 result in a calculated density of ρcalcd = 1.149 gcm-3. 3164 reflections were collected in the ω/2θ mode at T = 150K on an Enraf-Nonius CAD4 diffractometer employing graphite-monochromated CuKα-radiation (λ = 1.54179 Å). Data collection covered the range -11 ≤ h ≤ 11, -11 ≤ k ≤ 11, and -18 ≤ l ≤ 18 (Friedel pairs) up to Θ max = 72.11°. µ = 0.639 mm-1, with no absorption correction. The structure was solved by direct methods as implemented in the Xtal3.7 suite of crystallographic routines [31] where GENSIN was used to generate the structure-invariant relationships and GENTAN for the general tangent phasing procedure. 2589 observed reflections [I > 2σ (I)] were included in the final full-matrix least-squares refinement on F involving 162 parameters and converging at R(w) = 0.072 (0.74, w = 1/[20.0 σ2 ( F)], S = 1.927, and a residual electron density of -0.41/0.31e Å-3. Due to a large standard deviation the result of an attempted determination of the absolute configuration using Flack’s method [32] turned out to be insignificant. However, based on chemical evidence the chirality of the molecule could be assigned as shown in Figure [1] . The hydroxyl hydrogen atoms could be located and have been refined isotropically. Most of the other hydrogen positions have been calculated in idealized positions, and their Us have been fixed at 1.5 times U of the relevant heavy atom without refinement of any parameters. The crystal structure of 4c has been deposited as supplementary publication no. CCDC 268224 at the Cambridge Crystallographic Data Centre. Copies of the data can be obtained free of charge on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: +44 (1223)336033; e-mail: deposit@ccdc.cam.ac.uk, or http//www.ccdc.cam.ac.uk).