Total synthesis of amphidinolactone A

A convergent total synthesis of amphidinolactone A has been achieved, the longest linear sequence being 17 steps with 15.2% overall yield, using a ring-closing metathesis reaction as the macrolactonization step. The RCM precursor was obtained by the union of acid and alcohol fragments derived from (R)-epichlorohydrin and propane-1,3-diol, respectively. The side chain was incorporated following a Wittig reaction to exclusively obtain the cis-isomer.

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(R)-3-(tert-Butyldiphenylsilyloxy)-1-((S)-oxiran-2-yl)propan-1-olC21H28O3Si[α]D25=-6.4 (c 1.2, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (1R,2′S)

(3S,4R)-6-(tert-Butyldiphenylsilyloxy)hex-1-ene-3,4-diolC22H30O3Si[α]D25=-5.0 (c 1.8, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3S,4R)

(3R,4S)-1-(tert-Butyldiphenylsilyloxy)-4-(4-methoxybenzyl-oxy)hex-5-en-3-olC30H38O4Si[α]D25=+6.5 (c 1.3, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3R,4S)

(R,Z)-((3R,4S)-1-(tert-Butyldiphenylsilyloxy)-4-(4-methoxy-benzyloxy)hex-5-en-3-yl)8-(4-methoxybenzyloxy)deca-5,9-dienoateC48H60O7Si[α]D25=+15.2 (c 1.2, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (R,Z)-(3R,4S)

(R,Z)-((3R,4S)-1-(tert-Butyldiphenylsilyloxy)-4-hydroxyhex-5-en-3-yl)-8-hydroxydeca-5,9-dienoateC33H44O5Si[α]D25=+4.2 (c 1.4, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (R,Z)-(3R,4S)

(6Z,9R,10E,12S,13R)-13-(2-(tert-Butyldiphenylsilyloxy)ethyl)-9,12-dihydroxyoxacyclotrideca-6,10-dien-2-oneC30H40O5Si[α]D25=-5.5 (c 1.0, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (6Z,9R,10E,12S,13R)

(6Z,9R,10E,12S,13R)-13-(2-(tert-Butyldiphenylsilyloxy)-ethyl)-9,12-bis(methoxymethoxy)oxacyclotrideca-6,10-dien-2-oneC34H48O7Si[α]D25=+44.1 (c 1.2, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (6Z,9R,10E,12S,13R)

(6Z,9R,10E,12S,13R)-13-(2-Hydroxyethyl)-9,12-bis(methoxy-methoxy)oxacyclotrideca-6,10-dien-2-oneC18H30O7[α]D25=+59.4 (c 0.7, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (6Z,9R,10E,12S,13R)

(6Z,9R,10E,12S,13R)-9,12-Bis-(methoxymethoxy)-((2Z,5Z)-octa-2,5-dienyl)oxacyclotrideca-6,10-dien-2-oneC24H38O6[α]D25=-10.7 (c 1.4, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (6Z,9R,10E,12S,13R)

(6Z,9R,10E,12S,13R)-9,12-Dihydroxy-((2Z,5Z)-octa-2,5-dienyl)oxacyclotrideca-6,10-dien-2-oneC20H30NaO4[α]D25=-57.5 (c 0.55, C6H6)Source of chirality: asymmetric synthesisAbsolute configuration: (6Z,9R,10E,12S,13R)