Convergent Synthesis of the C18-C30 Fragment of Amphidinol 3

Abstract

The C18-C30 fragment of amphidinol 3 has been synthesized in a convergent fashion by employing two asymmetric Sharpless dihydroxylations, a Julia-Kocienski olefination and a Wittig reaction as the key steps.

Key words

amphidinol - Julia-Kocienski olefination - Wittig olefination - Sharpless dihydroxylation

References and Notes

• 1 See, for example: Kobayashi J. Shimbo K. Kubota T. Tsuda M. Pure Appl. Chem.  2003,  75:  337 
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• 6 Recently, the C2 stereocenter of AM2 was also proposed to be 2R by chemical correlation on a model structure, see: Kommana P. Chung SW. Donaldson WA. Tetrahedron Lett.  2008,  49:  6209 
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14

Compound 8 was prepared from 3-bromopropan-1-ol in 3 steps (40% yield).

15

The starting aldehyde 11 (20%) was recovered as the corresponding alcohol after the reductive workup and no improvement in conversion was observed when the phosphonium bromide was utilized.

16

On large scale, longer reaction times of up to one week and vigorous stirring were required.

18

NMR study (see ref. 17 for literature data): A syn relationship between the substituents at C23 and C24 was observed for compound 15 (Figure  [¹] ).

Figure 1

19

Other Raney nickel were less selective and both the benzyl and p-methoxybenzyl groups were cleaved.

20

Compound 16 (Mixture of Epimers at C30)
Colourless oil; [α]_D ^²0 -49.3 (c 0.5, CHCl₃). IR (film): 2927, 2855, 1712, 1608, 1513, 1462, 1378, 1248, 1217, 1169, 1094, 1062, 1039, 1006 cm^-¹. ^¹H NMR (400 MHz, C₆D₆):
δ = 7.19-7.13 (m, 2 H), 6.79-6.74 (m, 2 H), 4.40-4.27 (m, 2 H), 3.96-3.86 (m, 2 H), 3.70 (s, 3 H), 3.69-3.60 (m, 3 H), 3.57-3.46 (m, 2 H), 3.40-3.31 (m, 1 H), 1.89-1.79 (m, 1 H), 1.78-1.68 (m, 2 H), 1.66-1.55 (m, 1 H), 1.54-1.31 (m, 4 H), 1.38 (s, 3 H), 1.30-1.01 (m, 7 H), 1.24 (s, 3 H), 0.96-0.89 (m, 3 H), 0.86-0.71 (m, 27 H), 0.02 to -0.07 (m, 18 H). ^¹³C NMR (100 MHz, C₆D₆): δ = 159.1 (s), 130.9 (s), 129.5 and 129.1 (d), 113.7 (d), 107.7 and 107.5 (s), 82.9 (d), 75.1 (d), 75.1 and 74.9 (d), 72.5 and 72.3 (d), 71.6 (d), 69.8 and 69.7 (t), 68.8 and 68.7 (d), 60.6 and 60.4 (t), 55.2 (q), 36.5 and 36.1 (t), 34.2 (t), 33.5 and 33.5 and 33.5 (t), 31.0 (t), 30.7 and 30.6 (t), 29.7 (t), 28.7 and 28.7 (q), 28.5 and 28.4 (d), 26.1 (2C, q), 26.1-25.8 (q), 22.6 and 22.6 (t), 19.8 and 19.8 (q), 18.0-17.9 (s), 16.5 (q), -4.1 to -4.7 (q). ESI-HRMS: m/z calcd for C₄₄H₈₆O₈Si₃ + Na⁺: 849.5523; found: 849.5506.