Stereoselective Synthesis of the C27–C48 Moiety of Aflastatin A by a Carbohydrate Strategy Using a Tin(II)-Mediated Aldol Reaction

Abstract

The C27–C48 segment of aflastatin A was synthesized by using d-mannoside and l-erythrulose derivatives as chiral building blocks. The aldol reaction of undecan-2-one with mannolactone and a subsequent reduction gave the C37 and C39 stereogenic centers with high selectivity. Another aldol reaction of a tin(II) enolate of a protected erythrulose (C27–C30 segment) with a C31–C48 aldehyde segment gave the C30,C31-syn adduct with the desired stereochemistry. Deprotection of the assembled product proceeded smoothly to give the C27–C48 segment of aflastatin A containing a contiguous polyol moiety.

Key words

stereoselectivity - aflastatin A - aldol reactions - polyols - carbohydrates

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• 18 C27–C48 Fragment 2 20% Pd(OH)₂/C (1.0 mg) was added to a solution of compound 20 (4.2 mg, 3.9 μmol) in THF (1.0 mL), and the mixture was stirred for 13 h under H₂. The mixture was filtered through a pad of Celite and the filtrate was concentrated in vacuo. The residue was purified by column chromatography [silica gel, CHCl₃–MeOH (1:1)] to give a white solid; yield: 1.7 mg (3.5 μmol, 90%); mp 126–127 °C; R_f = 0.30 (CHCl₃–MeOH, 1:1); [α]_D ²⁵ +13.8 (c 1.34, MeOH). IR (thin film, KBr): 3535, 3073, 2959, 2924, 1260, 1124, 796, 668 cm^–1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 6.16–6.12 (br s, 1 H), 5.26 (d, J = 3.9 Hz, 1 H), 4.59 (d, J = 5.2 Hz, 1 H), 4.54 (d, J = 5.2 Hz, 1 H), 4.49 (dd, J = 5.6, 5.6 Hz, 1 H), 4.48 (d, J = 4.1 Hz, 1 H), 4.37 (d, J = 5.2 Hz, 1 H), 4.17 (d, J = 5.0 Hz, 1 H), 4.16 (d, J = 5.0 Hz, 1 H), 4.11 (d, J = 6.1 Hz, 1 H), 3.94–3.81 (m, 2 H), 3.63 (ddd, J = 9.8, 9.8, 3.8 Hz, 1 H), 3.61–3.53 (m, 3 H), 3.48–3.34 (m, 4 H), 3.19 (ddd, J = 9.2, 9.2, 5.6 Hz, 1 H), 2.09–2.01 (m, 1 H), 1.86–1.79 (m, 1 H), 1.53–1.38 (m, 2 H), 1.37–1.15 (m, 16 H), 0.85 (t, J = 6.9 Hz, 3 H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 98.4, 73.1, 71.9, 71.7, 71.3, 70.7, 70.2, 69.3, 67.4, 62.8, 41.6, 38.2, 35.8, 31.3, 29.2, 29.1, 29.0, 28.7, 24.8, 22.1, 14.0. HRMS (ESI): m/z [M + Na]⁺calcd for C₂₂H₄₄NaO₁₁: 507.2776; found: 507.2778.