Total Synthesis of the Macrocyclic N-Methyl Enamides Palmyrolide A and 2S-Sanctolide A

Abstract

Full details of the total syntheses of the initially reported and revised structures of the neuroprotective agent palmyrolide A are reported. The key macrocyclization step was achieved using a sequential ring-closing metathesis/olefin isomerization reaction. Furthermore, the total synthesis of the related macrolide (2S)-sanctolide A is reported. The synthesis used key elements from the synthesis of palmyrolide A, including the RCM/olefin isomerization sequence. The synthetic work described herein serves to facilitate the assignment of stereochemistry of the natural product sanctolide A and demonstrates the utility of this approach for the synthesis of macrocyclic tertiary enamide natural products.

Stereoselective Total Synthesis of the Marine Macrolide Sanctolide A

“…13 C NMR (75 MHz, CDCl 3 ): δ C = 134.9, 118.0, 70.7, 41.9, 36.7, 31.8, 25.3, 22.6, 14.0 ppm. The spectroscopic data are consistent with those reported in the literature 8,17. HRMS (EI): calcd.…”

“…1 H NMR (500 MHz, CDCl 3 ): δ H = 5.82 (dt, J = 17.2, 10.2, 7.1 Hz, 1 H), 5.13–4.99 (m, 2 H), 3.34 (s, 3 H), 3.24–3.16 (m, 1 H), 2.28–2.24 (m, 2 H), 1.51–1.18 (m, 8 H), 0.92–0.85 (m, 3 H) ppm. The spectroscopic data are consistent with those reported in the literature 8,17 . 13 C NMR (125 MHz, CDCl 3 ): δ C = 135.0, 116.6, 80.5, 56.5, 37.7, 33.3, 32.0, 24.9, 22.6, 14.0 ppm.…”

“…HPLC [Chiral Pak‐IC (250 × 4.6 mm, 5 μm); 5 % isopropyl alcohol (IPA) in hexane]: t R = 14.571 (major isomer with area of 99.368 %) and 13.196 min (minor isomer with area of 0.632 %). [ α ] D 20 = –8.6 ( c = 1.8, CHCl 3 ); ref 8. [ α ] D 19 = –8.28 ( c = 1.15, CHCl 3 ); ref 17.…”

“…Purification by flash column chromatography on silica gel (0.5 % EtOAc/hexanes) afforded compound 13 (5.4 g, 98 % yield) as a colorless oil; R f = 0.72 (5 % EtOAc/hexanes). [ α ] D 20 = –11.4 ( c = 1.192, CHCl 3 ); ref 8. [ α ] D 19 = –11.7 ( c = 1.5, CHCl 3 ); ref 17.…”

“…In continuation of our efforts on the total syntheses of macrolides,7 we herein report the first total synthesis of sanctolide A. To the best of our knowledge, there has only been one report of the synthesis of (2 S )‐sanctolide A, a diastereomer of the natural product, which was accomplished by using a ring‐closing methathesis (RCM)/olefin isomerization sequence to form the macrocyclic ring and construct the N ‐methyl enamide moiety 8…”