Synthesis of (–)-Muricatacin and (–)-(R,R)-L-Factor Involving an Organocatalytic Direct Vinylogous Aldol Reaction

Dedicated to Professor Victor Snieckus on the occasion of his 80^th birthday

Abstract

Concise syntheses of the polyketide natural product (–)-muricatacin and (–)-(R,R)-L-factor (natural product enantiomer) were achieved in four steps by employing an organocatalytic asymmetric direct vinylogous aldol reaction of γ-crotonolactone and suitable aliphatic aldehydes as the key step.

Key words

muricatacin - L-factor - direct vinylogous aldol - organocatalysis

• References and Notes

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Organocatalytic vinylogous aldol reactions of substituted γ-crotonolactones:
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• 21 General Procedure for the Reduction of 20 and 21 To a solution of the ketone (1 equiv) in dry THF was added K-Selectride (1.5 equiv, 1 M in THF) at –78 °C, and the mixture was stirred at –78 °C for 1 h. Saturated NH₄Cl (5 mL) was added at –78 °C, and the mixture was warmed to r.t. The mixture was then extracted with EtOAc (3 × 5 mL), and the combined extracts were dried (Na₂SO₄) and concentrated. The crude product was purified by flash chromatography on silica gel. (R)-5-[(R)-1-Hydroxytridecyl]dihydrofuran-2(3H)-one – (–)-Muricatacin (1) The reaction of ketone 20 (50 mg, 0.18 mmol) and K-Selectride (0.27 mL, 0.27 mmol, 1.0 M in THF) in dry THF (1 mL) for 30 min according to the general procedure provided, after purification by flash chromatography on silica gel (CH₂Cl₂/EtOAc, 9:1), 37 mg (74%) of 1 as a white solid. R_f = 0.30 (CH₂Cl₂/EtOAc, 9:1); [α]_D ²³–18.6 (c 1.77, CH₂Cl₂), mp 65.5–69.1 °C; lit.^8a [α]_D ²³–17.5 (c 1.0, CH₂Cl₂), mp 66–68 °C; lit.^8o [α]_D ²³–19 (c 1.8, CH₂Cl₂), mp 68–70 °C. IR (neat): 3415(br), 2957, 2916, 2847, 1761, 1471, 1462, 1267, 1189, 1331, 1104, 1082, 1011 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 4.42 (td, 1 H, J = 7.3, 4.6 Hz, OCH), 3.58 (quint, 1 H, J = 5.3 Hz, CHOH), 2.69–2.46 (m, 2 H, CH₂), 2.33–2.04 (m, 2 H, CH₂), 1.95–1.85 [br m, 1 H, OH (D₂O exchange)], 1.64–1.20 (m, 22 H, CH₂), 0.88 (t, 3 H, J = 6.6 Hz, CH₃). ¹³C NMR (75 MHz, CDCl₃): δ = 177.2 (C(O)O), 83.0 (OCH), 73.7 (CHOH), 33.0 (CH₂), 31.9 (CH₂), 29.7 (CH₂), 29.64 (2 × CH₂), 29.58 (CH₂), 29.51 (CH₂), 29.50 (CH₂), 29.4 (CH₂), 28.7 (CH₂), 25.5 (CH₂), 24.1 (CH₂), 22.7 (CH₂), 14.1 (CH₃). HRMS (ESI, pos): m/z calcd for C₁₇H₃₂O₃ [M]⁺: 284.2351; found: 284.2340; m/z calcd for C₁₇H₃₃O₃ [M + Na]⁺: 307.2249; found: 307.2232. (R)-5-[(R)-1-Hydroxyhexyl]dihydrofuran-2(3H)-one – (–)-L-Factor (3) The reaction of ketone 21 (60 mg, 0.33 mmol) and K-Selectride (0.48 mL, 0.49 mmol) in dry THF (2 mL) for 1 h according to the general procedure provided, after purification by flash chromatography on silica gel (CH₂Cl₂/EtOAc, 9:1), 48 mg (78%) of 3 as a white solid. R_f = 0.22 (CH₂Cl₂/EtOAc, 4:1); [α]_D ²³ –29.3 (c 1.27, CHCl₃), mp 41–43 °C; lit.^8a [α]_D ²⁵–27.1 (c 0.6, CHCl₃), mp 42–44 °C; lit.^8b [α]_D ²³ –32.8 (c 1.54, CHCl₃), mp 45–48 °C. IR: 3450 (br), 2954, 2928, 2858, 1765, 1185, 1133, 1075, 1057, 1023, 992, 929, 907 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 4.42 (td, 1 H, J = 7.3, 4.4 Hz, OCH), 3.62–3.52 (br m, 1 H, CHOH), 2.69–2.46 (m, 2 H, CH₂), 2.32–2.01 [m, 3 H, CH₂, OH (D₂O exchange)], 1.62–1.21 (m, 8 H, CH₂), 0.89 (t, 3 H, J = 6.7 Hz, CH₃). ¹³C NMR (75 MHz, CDCl₃): δ = 177.3 (C(O)O), 83.0 (OCH), 73.6 (CHOH), 32.9 (CH₂), 31.7 (CH₂), 28.7 (CH₂), 25.1 (CH₂), 24.1 (CH₂), 22.5 (CH₂), 14.0 (CH₃). HRMS (APPI, pos): m/z calcd for C₁₀H₁₈O₃ [M]⁺: 186.1256; found: 186.1252; m/z calcd for C₁₀H₁₉O₃ [M + H]⁺: 187.1334; found: 187.1325.