Enantioselective Synthesis of 2,3-Dehydro-3-desoxy-10-oxa Epothilone D

Abstract

A short and convergent synthesis of a 10-oxa epothilone analog is based on aldolisation of a β-methallyloxy aldehyde derived from methyl 3-hydroxy-2S-methyl propionate followed by ring-closing metathesis

Key words

epothilone - aldolisation - ring-closing metathesis - macrocycle

References

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24

All new compounds have been characterized by ¹H and ¹³C NMR, and HRMS. Selected data for E- 3b: oil, [α]_D +82 (c 0., CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ (ppm) = 7.00 (s, 1 H), 6.77 (d, J = 15.8 Hz, 1 H), 6.64 (s, 1 H), 6.09 (d, J = 15.8 Hz, 1 H), 5.62 (d, J = 10.5 Hz, 1 H), 5.48 (dd, J = 10.7 and 5.0 Hz, 1 H), 4.18 (d, J = 12.2 Hz, 1 H), 3.70 (ddd, J = 9.5, 2.4 and 1.9 Hz, 1 H), 3.70 (m, 1 H), 3.56 (d, J = 12.2 Hz, 1 H), 3.48 (m, 1 H), 2.97 (qd, J = 6.7 and 9.5 Hz, 1 H), 2.90 (dd, J = 9.8 and 2.4 Hz, 1 H), 2.72 (s, 3 H), 2.70 (dd, J = 10.5 and 11.6 Hz, 1 H), 2.40 (dd, J = 3.4 and 11.6 Hz, 1 H), 2.16 (s, 3 H), 1.70 (s, 3 H), 1.40 (s, 3 H), 1.28 (d, J = 6.7 Hz, 3 H), 1.28 (s, 3 H) and 1.18 (d, J = 7.2 Hz, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ (ppm) 213.7, 164.9, 164.8, 152.3, 151.4, 137.5, 135.1, 125.6, 122.4, 120.0, 116.3, 78.4, 77.4, 76.3, 70.1, 52.5, 46.3, 34.9, 29.6, 23.2, 22.8, 19.2, 17.5, 16.7, 15.5, 13.2. HRMS: [M + Na]⁺ m/z calcd 476.2471. Found: 476.2470. Z- 3b: oil, [α]_D -44 (c 0.2, CHCl₃). ¹H NMR (CDCl₃): δ (ppm) = 7.12 (d, J = 15.8 Hz, 1 H), 6.98 (s, 1 H), 6.58 (s, 1 H), 6.00 (d, J = 15.8 Hz, 1 H), 5.47 (m, 2 H), 3.82 (d, J = 12.1 Hz, 1 H), 3.78 (d, J = 12.1 Hz, 1 H), 3.74 (dd, J = 8.9 and 2.8 Hz, 1 H), 3.72 (dd, J = 7.1 and 2.7 Hz, 1 H), 3.29 (dd, J = 9.1 and 4.1 Hz, 1 H), 3.10 (qd, J = 6.9 and 2.7 Hz, 1 H), 2.95 (broad s, 1 H), 2.71 (s, 3 H), 2.51 (dd, J = 6.9 and 6.8 Hz, 2 H), 2.16 (s, 3 H), 1.74 (m, 1 H), 1.60 (s, 3 H), 1.37 (s, 3 H), 1.27 (s, 3 H), 1.08 (d, J = 6.9 Hz, 3 H) and 0.94 (d, J = 7.2 Hz, 3 H). ¹³C NMR (CDCl₃): δ (ppm) = 214.8, 165.2, 164.7, 152.4, 150.7, 137.8, 134.1, 122.1, 120.1, 119.6 116.1, 78.0, 75.3, 72.1, 72.0, 51.2, 43.2, 36.9, 31.6, 24.0, 22.5, 19.2, 15.4, 14.3 (2 ×), 10.6. HRMS: [M + Na]⁺ m/z calcd 476.2471. Found: 476.2474.