Synthesis of the AC Ring of Paclitaxel: Formation of the C Ring by [3+2] Cycloaddition with a Preformed A Ring

Abstract

The stereoselective formation of the C ring was accomplished by nitrile oxide [3+2] cycloaddition of an intermediate with the A ring already constructed. We found that stereoelectronic effect to a 1,1-substituted alkene moiety is important in the reaction.

paclitaxel - nitrile oxide - cycloadditions

References

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10

The structure of 7 was determined based on ¹H NMR and DEPT spectra.

11

The β-elimination of the 5-acetoxy group in 13 disabled further transformation.

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13

The aldehyde 15 was prepared as follows: (i) LDA, ethyl 3-methyl-2-butenoate; 2,4-O-benzylidene-2,4-dihydroxy-butanal, 50% d.s., cf. ref.^3b; (ii) LiAlH₄; (iii) TBSCl; (iv) SEMCl; (v) TBAF; (vi) TPAP, NMO.

14

The stereochemistry was determined by the ¹H NMR coupling constants (J _2,3 = J _3,4 = 10 Hz) after acetonide formation for 2,4-diol from 17.

15

Spectral data of 22: IR (neat): 2957, 1798, 1726, 1463, 1362, 1250, 1150, 1070, 837 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 0.02 (s, 9 H), 0.12 (s, 3 H), 0.15 (s, 3 H), 0.89 (s, 9 H), 0.86-0.97 (m, 2 H), 1.03 (s, 3 H), 1.11 (s, 3 H), 1.20 (s, 9 H), 1.33 (s, 3 H), 1.72 (s, 3 H), 2.00-2.17 (m, 2 H), 2.31-2.52 (m, 2 H), 2.43 (dd, 1 H, J = 1.93, 15.00 Hz), 2.69 (dd, 1 H, J = 2.90, 15.00 Hz), 2.87 (d, 1 H, J = 10.60 Hz), 3.55 (dt, 1 H, J = 6.28, 10.10 Hz), 3.60 (d, 1 H, J = 7.25 Hz), 3.74 (dt, 1 H, J = 6.28, 10.10 Hz), 3.77 (d, 1 H, J = 10.60 Hz), 4.15 (d, 1 H, J = 7.25 Hz), 4.32 (s, 1 H), 4.53-4.60 (m, 1 H), 4.56 (d, 1 H, J = 12.60 Hz), 4.60 (d, 1 H, J = 12.60 Hz), 4.70 (d, 1 H, J = 6.77 Hz), 4.81 (d, 1 H, J = 6.77 Hz). ¹³C NMR (99.6 MHz, CDCl₃): δ = -4.5 (CH₃), -4.3 (CH₃), -1.3 (CH₃), 17.7 (CH₃), 18.2 (C), 18.3 (CH₂), 19.5 (CH₃), 24.0 (CH₂), 25.8 (CH₃), 25.9 (CH₃), 27.27 (CH₃), 27.35 (CH₃), 29.4 (CH₂), 29.6 (CH₂), 38.9 (C), 43.0 (C), 43.7 (CH), 56.0 (C), 61.1 (CH₂), 66.7 (CH₂), 68.6 (CH), 78.0 (CH), 80.9 (CH₂), 81.4 (CH), 88.7 (C), 96.5 (CH₂), 126.4 (C), 136.5 (C), 154.8 (C), 160.0 (C), 178.6 (C). ESI-TOF: m/z = 724.4 [M + H]⁺.