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

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

References and Notes

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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.