A Facile and Convenient Synthesis of (±)-Biotin via MgCl₂/Et₃N-Mediated C–C Coupling and Mitsunobu Reaction

Abstract

A synthesis of (±)-biotin is described starting from simple starting materials viz. cyclohexanone and amino malonic acid ester. The key steps involved are MgCl₂/Et₃N coupling of amino malonic acid ester derivative and acid chloride, Mitsunobu reaction, ozonolysis, Staudinger reduction, novel urea formation, and subsequent dibenzylation. This approach is economical and involves high-yielding steps and simple reaction conditions.

Key words

biotin - ozonolysis - Appel reaction - Mitsunobu reaction - Staudinger reduction

• References and Notes

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• 15 Data for Compound 3 R_f = 0.7 (PE–EtOAc = 75:25). ¹H NMR (400MHz, CDCl₃ + CCl₄): δ = 7.43–7.28 (m, 5 H), 5.39–5.23 (m, 3 H), 4.40–4.14 (m, 5 H), 2.48–2.36 (m, 2 H), 1.98 (br s, 2 H), 2.06–1.91 (m, 2 H), 1.79–1.60 (m, 4 H), 1.34 (t, J = 7.2 Hz, 3 H), 1.25 (t, J = 7.2 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃ + CCl₄): δ = 168.5, 150.9, 150.5, 147.3, 134.7, 131.6, 129.4, 128.5, 128.4, 127.9, 68.8, 63.2, 62.4, 57.9, 55.4, 33.9, 24.1, 23.3, 21.7, 14.2, 14.0. IR (CHCl₃): ν_max = 2983, 2938, 1817, 1750, 1728, 1661, 1370, 1024 cm^–1. ESI-HRMS: m/z calcd for C₂₃H₂₇ClN₂O₇Na: 510.1399 [M + Na]⁺; found: 501.1400.
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• 18 Data for Compound 16 R_f = 0.5 (PE–EtOAc = 60:40); mp 87–89 °C. ¹H NMR (400 MHz, CDCl₃ + CCl₄): δ = 7.34–7.21 (m, 10 H), 4.59 (d, J = 6.0 Hz, 1 H), 4.52 (d, J = 14.7 Hz, 1 H), 4.12–3.97 (m, 1 H), 4.10–4.00 (m, 2 H), 3.52–3.45 (m, 1 H), 3.14–3.07 (m, 1 H), 2.22 (t, J = 6.2 Hz, 2 H), 1.77–1.68 (m, 1 H), 1.58–1.49 (m, 3 H), 1.42–1.33 (m, 1 H), 1.20 (dd, J = 6.4, 13.3 Hz, 1 H), 0.84 (s, 9 H), –0.01 (s, 3 H), –0.03 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃ + CCl₄): δ = 160.3, 137.3, 131.1, 130.1, 128.8, 128.4, 128.3, 127.3, 127.2, 62.5, 57.6, 56.5, 46.8, 46.1, 34.2, 25.8, 23.6, 21.6, 18.2., –5.4, –5.5. IR (CHCl₃): ν_max = 3030, 2930, 1698, 1657, 1448, 1357, 1119 cm^–1. ESI-HRMS: m/z calcd for C₃₀H₄₁ClN₂O₂SiNa: 547.2518 [M + Na]⁺; found: 547.2523.
• 19 The urea 16 is the same intermediate which we recently reported in enantiopure form, by following an entirely different strategy for the synthesis of d-(+)-biotin.^6a Based on this, the stereochemistry of other major compounds have been deduced and depicted.
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