Formal Synthesis of Cytostatin by a Convergent Approach

Abstract

A formal synthesis of cytostatin, an antitumor agent, has been achieved according to a convergent approach involving the coupling of a functionalized organolithium (C1-C8 subunit) with an aldehyde (C9-C13 subunit).

Key words

cytostatin - natural products - formal synthesis - dia­stereoselectivity - metathesis

References and Notes

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• This compound was prepared in two steps from butane-1,4-diol by silylation (TBDPSCl, Et₃N, CH₂Cl₂, r.t.) followed by oxidation (PDC, DMF, r.t.), see:
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• 15a

  Acetal 9 was obtained as one major diastereomer (dr > 90:10) having a 1,4-trans-disubstitution pattern based on the coupling constant between H3 and H4 (³ J _H3-H4 = 6.0 Hz), see ref. 15b. However, the diastereomeric ratio varied with the reaction time due to thermodynamic equilibration of 9. Partial equilibration of the compounds bearing an acetalic C1 stereocenter was also noticed during purification on silica gel. This had no consequence since the C1 stereocenter was removed later in the synthesis.

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14

The ¹H NMR data of lactone 8, and in particular the coupling constants J _H3-H4, J _H4-H5 and J _H5-H6 as well as the chemical shifts of the methyl groups (H19 and H20) compare favorably well with those reported for structurally related syn,anti-diastereomeric lactones (Figure [1] ). [5] ^{,7 1}H NMR (400 MHz, CD₃OD): δ = 7.69-7.99 (m, 4 H), 7.43-7.37 (m, 6 H), 7.13 (dd, J = 9.6, 6.5 Hz, 1 H, H3), 5.92 (dd, J = 9.6, 0.7 Hz, 1 H, H2), 4.11 (dd, J = 10.5, 3.1 Hz, 1 H, H5), 3.86-3.74 (m, 2 H, 2 H8), 2.55 (m, 1 H, H4), 2.18 (m, 1 H, H7), 2.05 (m, 1 H, H6), 1.37 (m, 1 H, H7), 1.03 (s, 9 H), 0.98 (d, J = 7.1 Hz, 3 H, 3H19), 0.84 (d, J = 6.8 Hz, 3 H, 3 H20).

20

Compound 20 and its epimer at C9 could be separated by flash chromatography on silica gel. However, the separation of the C9 epimers turned out to be easier for the alkynyl iodide 22.

21

Bis(9H-fluoren-9-ylmethyl)-{(1S,2S,3R)-3-hydroxy-5-iodo-2-methyl-1-[(3S)-3-((2S,3S)-3-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)butyl]pent-4-ynyl} phosphate (22): mp 112 °C; [α]_D +46.5 (c 0.4, CHCl₃). IR: 3353, 2360, 1714, 1449, 1380, 1250, 1106, 1070, 987, 739 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 7.75-7.67 (m, 4 H), 7.54-7.41 (m, 4 H), 7.41-7.20 (m, 8 H), 6.95 (dd, J = 9.5, 6.5 Hz, 1 H), 5.93 (d, J = 9.5 Hz, 1 H), 4.69-4.61 (m, 1 H), 4.36-4.07 (m, 7 H), 3.86 (dd, J = 10.3, 2.4 Hz, 1 H), 2.40 (m, 1 H), 1.83-1.58 (m, 4 H), 1.51-1.41 (m, 1 H), 1.15-1.05 (m, 1 H), 0.98 (d, J = 7.0 Hz, 3 H), 0.89 (d, J = 6.9 Hz, 3 H), 0.78 (d, J = 6.6 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 164.4 (s), 151.6 (d), 143.1 (s, 2 C), 142.9 (s), 142.8 (s), 141.3 (s, 4 C), 127.9 (d), 127.8 (d), 127.7 (d, 2 C), 127.2 (d, 2 C), 127.1 (d, 2 C), 125.0 (d, 4 C), 120.0 (d) and 119.9 (d, 5 C), 94.8 (s), 83.5 (d), 78.4 [d, ² J(¹³C-³¹P) = 5.8 Hz], 69.4 [t, ² J(¹³C-³¹P) = 4.0 Hz], 69.3 [t, ² J(¹³C-³¹P) = 4.3 Hz], 65.1 (d), 47.9 [d, ³ J(¹³C-³¹P) = 8.4 Hz], 47.8 [d, ³ J(¹³C-³¹P) = 8.7 Hz], 43.9 [d, ³ J(¹³C-³¹P) = 3.6 Hz], 33.8 (d), 30.6 [t, ³ J(¹³C-³¹P) = 4.1 Hz], 30.3 (d), 28.4 (t), 14.7 (q), 10.7 (q), 9.1 (q), 1.1 (s).