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Synlett 2011(18): 2709-2712  
DOI: 10.1055/s-0031-1289546
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Short Synthesis of (+)-1-Deoxynojirimycin via a Diastereoselective Reductive Coupling of Alkyne and α-Chiral Aldehyde

Bing Zhou, Huanyu Tang, Huijin Feng, Yuanchao Li*
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhangjiang Hi-Tech Park, 555 Zu Chong Zhi Road, Shanghai 201203, P. R. of China
Fax: +86(21)50807288; e-Mail: ycli@mail.shcnc.ac.cn;
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Publication History

Received 24 July 2011
Publication Date:
19 October 2011 (online)

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Abstract

A short, highly diastereoselective synthesis of (+)-1-deoxynojirimycin from readily available l-isoserine with overall yield of 32.0% in eight steps is described. The key step includes a diastereoselective syn-coupling reaction of Cbz-protected (S)-iso­serinal acetonide 6 and vinylzinc nucleophile, generated conveniently from a protected propargyl alcohol 7 by a hydrozirconation-transmetalation sequence. Significantly, not only does this simple flexible strategy provide a concise approach to (+)-1-deoxynojirimycin, but it also can readily be adopted for the synthesis of other stereoisomers of the 1-deoxynojirimycin family from l- or d-iso­serine through different coupling conditions and stereoselective ­epoxidation of allylic alcohol 4 by the same procedures.

Key words

(+)-1-deoxynojirimycin - diastereoselective coupling - l-isoserine - diastereoselective synthesis - chelation-control transition state

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15

The structure of Garner’s aldehyde is shown in Figure  [²] .

Figure 2

17

Procedure for the Synthesis of 5: To a 250-mL flame-dried flask loaded with zirconocene chloride hydride (4.63 g, 18.0 mmol) under argon was added anhyd CH2Cl2 (35 mL). The resulting suspension was cooled to 0 ˚C after which 7 (3.06 g, 18.0 mmol) was added dropwise. The mixture was then stirred at r.t. until the suspension had fully dissolved forming a yellow solution (1 h). The solution was cooled to -30 ˚C after which diethylzinc (16.5 mL, 18.0 mmol, 1.1 M in toluene) was added dropwise. After 15 min of stirring aldehyde 6 (3.95 g, 15.0 mmol) was added as a CH2Cl2 solution (20 mL) via cannula. After 15 min of further stirring at -30 ˚C, the solution was allowed to warm to 0 ˚C and the orange mixture was stirred overnight. The reaction mixture was diluted with CH2Cl2 (80 mL) followed by addition of sodium potassium tartrate (15 g) and H2O (30 mL, added slowly). The resulting mixture was stirred for 45 min and filtered through a pad of celite. The phases were separated and the aqueous phase was extracted with CH2Cl2 (3 × 40 mL). The organic layer was dried over Na2SO4, and concentrated to give a crude product, which was chromatog-raphed on silica gel (10% EtOAc in cyclohexane) to give compound 5 (4.96 g, 76%) as a colorless oil; [α]D ²5 -12.1 (c = 2.0, CH2Cl2). ¹H NMR (400 MHz, DMSO): δ = 7.31-7.40 (m, 5 H), 5.81 (dt, J = 15.2, 4.0 Hz, 1 H), 5.65 (dd, J = 15.2, 5.2 Hz, 1 H), 5.16 (d, J = 4.8 Hz, 1 H), 5.01-5.10 (m, 2 H), 4.02-4.17 (m, 4 H), 3.46-3.53 (m, 1 H), 3.19 (t, J = 8.8 Hz, 1 H), 1.51 (s, 3 H), 1.44 (s, 3 H), 0.85 (s, 9 H), 0.02 (s, 6 H). ¹³C NMR (100 MHz, DMSO): δ = 152.0, 137.2, 131.4, 128.8, 128.7, 128.3, 128.0, 93.8, 77.2, 71.2, 66.1, 62.9, 46.7, 26.3, 26.2, 24.3, 18.4, -4.8. IR: 3436, 2929, 1710, 1411 cm-¹. LRMS (EI, 70 eV): m/z (%) = 420 (8) [M+ - Me], 91 (100). HRMS (EI): m/z [M+ - Me] calcd for C22H34NO5Si: 420.2206; found: 420.2201.