Total Synthesis of Rhizoxin D

Abstract

A total synthesis of rhizoxin D (1b), a 16-membered ­antitumoral macrolide, is reported. The strategy relies on the application of a Brown allylation reaction for the C15 and C16 asymmetric centres control. Installation of the C17 hydroxyl function with concomitant building of the (E)-C18-C19 double bond was effected by a diastereoselective addition of vinyllithium derivative 15 to ­aldehyde 10. The terminal enone group was then introduced to achieve the preparation of C11-C20 segment 23. A Heck coupling reaction between C11-C20 fragment 23 and C3-C10 segment 24 (previously prepared in our laboratory) was performed with success to deliver the C3-C20 fragment 25. The total synthesis of rhizoxin D (1b) was achieved after transformation of 25 into the macro­lactone 28, and coupling the C21-C28 side chain using a Wittig-Wadsworth-Emmons reaction.

rhizoxin D - total synthesis - Heck cross-coupling - ­vinyllithium reagents - macrolactonisation

References

Total synthesis:

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10

Addition of MeOH was recommended for an efficient reduction of the intermediate ozonide, and at the same time pyridine must be added to avoid formation of the undesired dimethyl ketal.

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The ‘Evans Revised Model’ could account for the observed selectivity. See:

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17

Some selected data:
Compound 16: ¹H NMR (270 MHz, CDCl₃): δ = -0.06 (s, 3 H), -0.05 (s, 3 H), 0.00 (s, 3 H), 0.01 (s, 3 H), 0.89 (s, 9 H), 0.91 (s, 9 H), 0.91 (d, J = 6.9 Hz, 3 H), 1.57 (s, 3 H), 1.63-1.80 (m, 1 H,), 1.89 (q, J = 6.3 Hz, 2 H), 3.45 (s, 1 H, OH), 3.55 (dt, J = 11.9, 6.3 Hz, 2 H), 3.80 (s, 3 H), 3.90-3.99 (td, J = 6.3, 3.0 Hz, 1 H), 4.09 (d, J = 6.6 Hz, 2 H), 4.37 (br s, 1 H), 4.45 (s, 2 H), 5.79 (t, J = 6.6 Hz, 1 H), 6.88 (m, 2 H), 7.23 (m, 2 H). ¹³C NMR (67.5 MHz, CDCl₃): δ = -4.76 (2 CH₃), -4.45 (2 CH₃), 10.8 (CH₃), 14.0 (CH₃), 17.9 (C), 18.2 (C), 25.9 (6 CH₃), 37.4 (CH), 37.6 (CH₂), 55.2 (CH₃), 59.7 (CH₃), 66.0 (CH₂), 71.4 (CH₂), 74.0 (CH), 74.6 (CH), 113.7 (2 CH), 121.2 (CH), 129.3 (2 CH), 130.7 (C), 139.3 (C), 159.0 (C). IR (film): 3448, 2955, 2857, 1650, 1510, 1380, 1250 cm^-1. MS (CI, NH₃): m/z = 553 [MH⁺]. Anal. Calcd for C₃₀H₅₆O₅Si₂ (552.93): C, 65.17; H, 10.21. Found: C, 65.20; H, 10.23. [α]_D +4.4 (c 1.92, CHCl₃).
Compound 23: ¹H NMR (270 MHz, CDCl₃): δ = 0.00 (s, 3 H), 0.13 (s, 3 H), 0.78 (s, 9 H), 0.98 (d, J = 6.9 Hz, 3 H), 1.58 (s, 3 H), 1.81 (s, 3 H), 1.83-1.93 (m, 1 H), 2.34 (dd, J = 15.2, 2.3 Hz, 1 H), 2.97 (dd, J = 15.2, 9.2 Hz, 1 H), 3.14 (s, 3 H), 3.16 (d, J = 7.3 Hz, 1 H), 3.78 (s, 3 H), 4.04-4.16 (m, 3 H), 4.42 (s, 2 H), 5.50 (t, J = 6.1 Hz, 1 H), 5.73 (s, 1 H), 5.93 (s, 1 H), 6.85 (m, 2 H), 7.25 (m, 2 H). ¹³C NMR (67.5 MHz, CDCl₃): δ = -4.9 (CH₃), -4.8 (CH₃), 9.5 (CH₃), 11.9 (CH₃), 17.6 (CH₃), 17.9 (C), 25.7 (3 CH₃), 39.4 (CH₂), 42.1 (CH), 55.3 (CH₃), 56.1 (CH₃), 65.9 (CH₃), 70.1 (CH), 71.7 (CH ₂ ), 88.7 (CH), 113.7 (2 CH), 125.3 (CH₂), 126.5 (CH), 129.4 (2 CH), 130.4 (C), 136.1 (C), 145.2 (C), 159.1, (C), 200.7 (C). IR (film): 2955, 2856, 2380, 1678, 1530, 1385, 1250 cm^-1. MS(CI, NH₃): m/z = 491 [MH⁺]. Anal. Calcd for C₂₈H₄₆O₅Si (490.75): C, 68.53; H, 9.45. Found: C, 68.69; H, 9.38. [α]_D -23.0 (c 1.23, CHCl₃).
Compound 25: ¹H NMR (400 MHz, CDCl₃): δ = 0.00 and 0.12 (2 s, 6 H), 0.79 (s, 9 H), 1.03-1.12 (m, 13 H), 1.15 (d, J = 6.8 Hz, 3 H), 1.55 (m, 1 H), 1.57 (m, 2 H), 1.60 (s, 3 H), 1.82 (s, 3 H), 1.86 (m, 1 H), 1.91-2.12 (m, 2 H), 2.27 (dd, J = 15.3, 2.1 Hz, 1 H), 2.59-2.69 (m, 2 H), 3.18 (s, 3 H), 3.20 (d, J = 8.2 Hz, 1 H), 3.60 (dd, J = 15.3, 9.7, 1 H), 3.70 (t, J = 5.7 Hz, 2 H), 3.80 (s, 3 H), 4.05-4.19 (m, 4 H), 4.50 (2 d, J = 11.5 Hz, 2 H), 5.53 (t, J = 5.8 Hz, 1 H), 6.04 (dd, J = 14.6, 7.8 Hz, 1 H), 6.47 (dd, J = 14.6, 10.9 Hz, 1 H), 6.87 (m, 2 H), 7.00 (d, J = 10.9 Hz, 1 H), 7.10 (m, 2 H), 7.40 and 7.60 (2 m, 5 H). MS (CI, NH₃): m/z = 925 [MH⁺].
Compound 28: ¹H NMR (400 MHz, CDCl₃): δ = 0.71 (dt, J = 12.5, 13.0 Hz, 1 H), 0.99 (d, J = 6.8 Hz, 3 H, H3), 1.07 (m, 21 H), 1.24 (d, J = 7.0 Hz, 3 H), 1.60 (s, 3 H), 1.68 (m, 1 H), 1.72 (m, 1 H), 1.80 (m, 1 H), 1.80 (s, 3 H), 1.95 (ddd, J = 12.5, 11.5, 9.5 Hz, 1 H), 2.12 (dd, J = 17.5, 10.5 Hz, 1 H), 2.18 (m, 1 H), 2.30 (m, 1 H), 2.33 (dquint, J = 9.5, 7.0 Hz, 1 H), 2.52 (m, 1 H), 2.80 (dd, J = 17.5, 5.5 Hz, 1 H), 3.20 (s, 3 H), 3.31 (d, J = 9.0 Hz, 1 H), 3.68 (ddd, J = 11.5, 7.0, 3.0 Hz, 1 H), 3.80 (s, 3 H), 3.86 (dd, J = 11.5, 4.0 Hz, 1 H), 4.05 (d, J = 6.0 Hz, 2 H), 4.48 (d, J = 11.5 Hz, 1 H), 4.50 (d, J = 11.5 Hz, 1 H), 4.60 (dd, J = 10.5, 3.0 Hz, 1 H), 5.16 (dd, J = 15.0, 9.5 Hz, 1 H), 5.53 (t, J = 6.0 Hz, 1 H), 5.62 (dt, J = 14.5, 1.5 Hz, 1 H), 5.75 (d, J = 11.5 Hz, 1 H), 6.25 (dd, J = 15.0, 11.5 Hz, 1 H), 6.77 (ddd, J = 14.5, 10.5, 5.5 Hz, 1 H), 6.83 (m, 2 H), 7.08 (m, 2 H). IR (film): 2950, 2850, 1730, 1650, 1510, 1380, 1250, 1185 cm^-1. [α]_D -2 (c 0.12, CHCl₃).

18

Spectral data are in excellent agreement with those previously reported. See ref. 7.