Desymmetrization of Substituted 1,3-Diketones: A Formal Synthesis of (+)-Stemoamide

Abstract

A reductive desymmetrization of a γ-1,3-diketoester was used as the key step to control the C8, C9 and C9a stereocenters of (+)-stemoamide.

Key words

reduction - desymmetrization - alkaloids - stereoselective synthesis

References and Notes

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11

The structure of the minor isomer was not determined.

12

Synthesis of hydroxy lactone 4: Et₃N (14.2 mL, 100 mmol) was added to a mixture of esters 3 and 3" (6.73 g, obtained from 32.4 mmol of 2) in formic acid (9.4 mL, 250 mmol) at 0 °C. After 5 min, a solution of Noyori’s catalyst (R,R)-I (0.1 M in CH₂Cl₂, 2.5 mL, 0.25 mmol) was added, and the solution was allowed to stir at r.t. for 6 d. The mixture was diluted with EtOAc (10 mL), filtered on a pad of silica gel and the solvent was removed under reduced pressure. After flash column chromatography on silica gel (pet. ether-EtOAc, 9:1 ® 4:1 ® 1:1), a mixture of hydroxy lactones 4 and 4" (4/4" = 4:1) were obtained as a colorless oil (3.50 g, 15.6 mmol, 48% for 2 steps). An analytical sample of the major isomer 4 was isolated by flash column chromatography on silica gel (CH₂Cl₂-Et₂O, 95:5). R _f = 0.31 (CH₂Cl₂-Et₂O, 95:5); IR (film): 3445 (br), 3077, 2924, 1750, 1640, 1196, 993, 910 cm^-1; ¹H NMR (400 MHz, CDCl₃): δ = 5.81 (m, 2 H), 5.10-4.99 (m, 4 H), 4.53 (m, 1 H), 3.62 (m, 1 H), 2.63 (m, 1 H), 2.38-2.07 (m, 6 H), 1.87 (m, 1 H), 1.77-1.63 (m, 2 H), 1.60-1.44 (m, 2 H); ¹³C NMR (100 MHz, CDCl₃): δ = 176.7, 137.8, 137.3, 115.7, 115.5, 82.2, 72.8, 45.8, 35.5, 34.4, 32.2, 29.9, 29.7; Anal. Calcd for C₁₃H₂₀O₃: C, 69.61; H, 8.99. Found: C, 69.66; H, 8.87; [α]_D ²⁰ = -36.3 (c 0.60, CH₂Cl₂).

14

The ¹H NMR analysis of 5 showed a shielding of the H9 proton compared to the one in 6, whereas 6 showed a shielding of the H3 proton compared to the one in 5.

15

The spectral data of compound 10 were in agreement with those previously reported by Khono and Narasaka (see ref. 4a), thus confirming the relative configuration of the three contiguous stereocenters.

16

Compound 10 was obtained in seven steps with an overall yield of 0.88%.