Synthesis of (–)-Hennoxazole A: Integrating Batch and Flow Chemistry Methods

Abstract

A new total synthesis of (–)-hennoxazole A is reported. The synthetic approach is based on the preparation of three similarly sized fragments resulting in a fast and convergent assembly of the natural product. The three key reactions of the synthesis include a highly stereoselective 1,5-anti aldol coupling, a gold-catalyzed alkoxycyclization reaction, and a stereocontrolled diene cross-meta­thesis. The synthesis involves integrated batch and flow chemistry methods leading to the natural product in 16 steps longest linear ­sequence and 2.8% overall yield.

Key words

flow chemistry - polymer-supported reagents - meta­thesis - total synthesis - natural products

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• 14 Data for Compound 2 Mp 74–79 °C. R_f = 0.34 (EtOAc–PE, 1:1); [α]_D ^29.4 –23 (c 0.13, CHCl₃). IR (neat): 3464, 2984, 2932, 2837, 2365, 2337, 1639, 1615, 1578, 1512, 1449, 1380, 1362, 1302, 1247, 1171 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 8.09 (1 H, s), 7.61 (1 H, s), 7.24 (2 H, d, J = 8.7 Hz), 6.86 (2 H, d, J = 8.7 Hz), 5.84 (1 H, ddt, J = 17.0, 10.3, 6.6 Hz), 5.08 (1 H, dq, J = 17.1, 1.6 Hz), 5.01 (1 H, dq, J = 10.2, 1.4 Hz), 4.97 (1 H, d, J = 9.7 Hz), 4.46 (2 H, d, J = 2.7 Hz), 4.18 (1 H, s), 3.94–3.83 (2 H, m), 3.79 (3 H, s), 3.21 (3 H, s), 2.93 (2 H, t, J = 7.6 Hz), 2.56 (2 H, q, J = 7.1 Hz), 2.26–2.19 (2 H, m), 2.03–2.00 (1 H, m), 1.90 (1 H, dt, J = 14.6, 10.2 Hz), 1.42–1.39 (1 H, m), 1.36 (3 H, s), 1.26 (1 H, q, J = 11.8 Hz). ¹³C NMR (125 MHz, CDCl₃): δ = 165.5, 159.1, 155.3, 144.8, 137.8, 136.1, 134.1, 130.6, 129.7, 116.1, 113.8, 100.1, 70.8, 70.4, 69.7, 68.5, 55.2, 47.8, 42.1, 41.8, 37.7, 30.7, 27.5, 23.6. ESI-HRMS: m/z calcd for C₂₇H₃₄N₂NaO₇ ⁺ [M + Na]⁺: 521.2258; found: 521.2250.
• 15 An authentic sample of (–)-hennoxazole A was kindly provided by Prof. Thomas E. Smith (Williams College).