Synlett 2008(5): 728-732  
DOI: 10.1055/s-2008-1032101
LETTER
© Georg Thieme Verlag Stuttgart · New York

Synthetic Studies toward the Total Synthesis of Amphidinolide H1

Lisheng Deng, Zhixiong Ma, Gang Zhao*
Laboratory of Modern Synthetic Organic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, P. R. of China
Fax: +86(21)64166128; e-Mail: zhaog@mail.sioc.ac.cn;
Further Information

Publication History

Received 30 November 2007
Publication Date:
26 February 2008 (online)

Abstract

A convergent synthesis of the macrolide core as the immediate precursor to amphidinolide H1 is described, which features a palladium-catalyzed Stille cross-coupling, a methyl ketone diastereoselective aldol reaction, a Mitsunobu esterification, and an intramolecular ring-closing metathesis (RCM) reaction to construct the 26-membered macrocycle as key steps.

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Aldehyde 4: [α]D 24 -4.0 (c 0.60, CHCl3). IR (film): 2958, 2925, 1726, 1459, 1378, 1026 cm-1. 1H NMR (300 MHz, CDCl3): δ = 5.60-5.40 (m, 3 H), 5.27-5.24 (m, 1 H), 4.96 (s, 1 H), 4.81 (s, 1 H), 3.51 (t, J = 7.5 Hz, 2 H), 3.05 (dd, J = 1.8, 6.9 Hz, 1 H), 2.84-2.80 (m, 1 H), 2.32-2.25 (m, 1 H), 2.12 (dd, J = 6.6, 6.9 Hz, 1 H), 1.94 (dd, J = 5.1, 7.8 Hz, 1 H), 1.97-2.04 (m, 1 H), 1.91 (s, 3 H), 1.90-1.40 (m, 4 H), 1.02 (d, J = 6.6 Hz, 3 H), 0.91 (d, J = 6.6 Hz, 3 H), 0.89 (s, 9 H), -0.33 (s, 6 H). 13C NMR (75 MHz, CDCl3): δ = 202.4, 143.9, 140.8, 135.8, 125.9, 119.0, 115.1, 59.3, 59.2, 48.9, 45.8, 38.9, 37.8, 29.6, 19.6, 19.5, 15.0. MS (EI): m/z calcd for C17H26O2 [M]+: 262; found: 262. HRMS (EI): m/z calcd for C17H26O2 + [M]+: 262.1933; found: 262.1925.

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The stereochemistry of at C18 was confirmed on basis of Mosher ester analysis.

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Diol 2: [α]D 24 -2.2 (c 0.51, CHCl3). IR (neat): 3488, 2925, 1708, 1456, 1263, 1151, 1028 cm-1. 1H NMR (500 Hz, CDCl3): δ = 6.76 (t, J = 6.9 Hz, 1 H), 5.87 (dt, J = 6.8, 15.3 Hz, 1 H), 5.56 (s, 1 H), 5.23 (dd, J = 6.9, 14.6 Hz, 1 H), 5.04 (ddd, J = 3.2, 6.0, 12.6 Hz, 1 H), 4.97 (s, 1 H), 4.81 (s, 1 H), 4.74-4.60 (m, 4 H), 4.19 (d, J = 5.2 Hz, 1 H), 4.05-3.96 (m, 1 H), 3.76 (m, 1 H), 3.70 (m, 1 H), 3.65 (m, 1 H), 3.35 (s, 6 H), 3.09 (br s, 1 H), 3.02 (dd, J = 2.1, 7.9 Hz, 1 H), 2.85 (dt, J = 2.1, 8.6 Hz, 1 H), 2.76-2.63 (m, 2 H), 2.33-2.22 (m, 5 H), 2.16 (m, 1 H), 2.10 (dd, J = 5.1, 7.8 Hz, 1 H), 1.97-1.91 (m, 2 H), 1.83 (s, 3 H), 1.82 (m, 1 H), 1.74 (s, 3 H), 1.71-1.65 (m, 1 H), 1.61-1.49 (m, 2 H), 1.43-1.36 (m, 1 H), 1.29-1.21 (m, 2 H), 1.06 (d, J = 6.6 Hz, 3 H), 1.01 (d, J = 6.8 Hz, 3 H), 0.89 (d, J = 6.6 Hz, 3 H). 13C NMR (125 MHz, CDCl3): δ = 210.0, 168.4, 144.3, 142.5, 141.7, 134.2, 129.3, 128.3, 125.4, 114.7, 97.7, 97.3, 84.0, 81.2, 74.0, 66.0, 65.8, 59.1, 58.9, 56.4, 56.2, 46.8, 46.0, 41.5, 40.1, 39.2, 34.7, 31.8, 30.9, 29.8, 27.7, 19.9, 19.8, 14.7, 14.4, 12.6. ESI-MS: m/z calcd for C36H58O10: 650; found C26H58O10Na+: 673 [M + Na]+. ESI-HRMS: m/z calcd for C36H58O10Na+ [M + Na]+: 673.3922; found: 673.3909.

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When we were preparing this manuscript and trying to deprotect the MOM group, Füstner group reported the first example of total synthesis of the amphidinolide H1 (1), see ref. 4b.