Total Synthesis of Amphidinolide T3 Using Ring-Closing Metathesis and Asymmetric Dihydroxylation Strategy

Abstract

Total synthesis of amphidinolide T3, a 19-membered ring marine macrolide, has been accomplished using a ring-closing metathesis (RCM) and asymmetric dihydroxylation (AD) strategy. A cycloalkene having the C12=C13 double bond was assembled via RCM in 80% yield and in E/Z ratio of 76:24. The (12E)-isomer ­underwent AD using 1 mol% K₂OsO₂(OH)₄ and 4 mol% (DHQD)₂AQN as the chiral catalyst at 0 ˚C for 15 hours, furnishing the desired (12R,13R)-diol and its (12S,13S)-diastereomer in 59% and 25% yields, respectively. Selective monosilylation of (12R,13R)-diol followed by DMP oxidation and desilylation afforded amphidinolide T3 in 3.4% overall yield via a 15-step sequence.

Key words

amphidinolide T3 - dihydroxylation - macrocycles - ­metathesis - total synthesis

References and Notes

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15

Characterization Data for Alcohol 6: colorless oil; [α]_D ^²0 -0.27 (c = 2.25, CHCl₃); R _f 0.27 (5% EtOAc in PE). IR (film): 3358 (br), 3076, 2959, 2928, 1642, 1456, 1020 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 5.69 (ddd, J = 17.2, 10.4, 7.2 Hz, 1 H), 4.95 (d, J = 17.2 Hz, 1 H), 4.92 (d, J = 10.8 Hz, 1 H), 4.88 (s, 1 H), 4.87 (s, 1 H), 3.71 (br s, 1 H), 2.30-2.40 (m, 1 H), 2.21 (dd, J = 14.0, 3.6 Hz, 1 H), 2.00-2.06 (m, 3 H), 1.34-1.52 (m, 4 H), 1.00 (d, J = 6.4 Hz, 3 H), 0.93 (t, J = 7.0 Hz, 3 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 144.8, 143.9, 113.9, 112.8, 68.5, 44.3, 43.3, 39.2, 35.7, 20.1, 18.9, 14.1.

17

Characterization Data for Amphidinolide T3 (3): colorless oil. ^¹H NMR data are identical to those of
natural amphidinolide T3 (see Figure S1 in Supporting Information). HRMS (+ESI): m/z [M + Na⁺] calcd for C₂₅H₄₂O₅Na: 445.2930; found: 445.2916.