An Expeditious Synthesis of Nocardiolactone

Abstract

Nocardiolactone was synthesized by using a Crimmins asymmetric aldolization followed by a DMAP-mediated removal of the auxiliary with concurrent protection of the carboxylic group as a benzyl ester, activation of the β-hydroxyl group as a mesylate, ­hydrogenolysis of the benzyl ester, and a novel DBU-mediated ­lactonization that converted the syn-configuration to the trans one.

Key words

asymmetric synthesis - chiral auxiliaries - lactones - ring contractions - total synthesis

References

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  For related precedents see: ref. [3] above.

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14

The experimental procedure for the DBU-mediated HGA lactonization. DBU (8.5 µL, 0.056 mmol) was added slowly to a solution of 8 (0.056 mmol) in anhyd THF (1 mL) stirred at 0 °C. After completion of the addition, the mixture was stirred at the ambient temperature (ca. 11 °C) for 23 h before being diluted with Et₂O (100 mL) and washed in turn with 2 N HCl, sat. NaHCO₃, H₂O and brine. The organic phase was dried over anhyd Na₂SO₄. After removal of the solvent the residue was chromatographed on silica gel (1:400 EtOAc-hexanes) to give 1 as a white needle (20 mg, 70%), along with 9 (8 mg, 30%).
Data for 1: a white needle, mp 64-66 °C (lit. [4] mp 66-68 °C). [α]_D ²¹ -12.8 (c 0.30, CHCl₃) {lit. [4] [α]_D ²¹ -12.7 (c 2.5, CHCl₃)}. ¹H NMR (300 MHz, CDCl₃): δ = 4.22 (ddd, J = 7.3, 6.1, 3.9 Hz, 1 H), 3.17 (ddd, J = 9.0, 6.3, 3.8 Hz, 1 H), 1.86-1.68 (m, 3 H), 1.43-1.20 (m, 56 H), 0.88 (t, J = 6.8 Hz, 6 H). IR (KBr): 2955, 2918, 2851, 1806, 1472, 1145, 862, 717 cm^-1. MS (EI): m/z (%) = 506 (10.27) [M⁺], 97 (100), 57 (89.72), 83 (79.90), 111 (63.27), 43 (60.00), 69 (58.15), 55 (54.80), 85 (41.53), 125 (37.18), 139 (18.69). ESI-HRMS: m/z calcd for C₃₄H₆₆O₂Na [M + Na]⁺: 529.4939; found: 529.4955.

15

The FT-IR data for 9: FT-IR (KBr): 2955 (s), 2918 (s), 2849 (s), 2972 (s), 1472 (m), 1462 (m), 1435 (w), 1377 (w), 963 (m), 730 (m), 719 (m) cm^-1 (intensity symbols: s for strong, m for medium, and w for weak).