A Ring Closing Metathesis Approach to the Formal Synthesis of (+)‐Callyspongiolide

Abstract

An enantioselective synthesis of macrocyclic core of (+)-callyspongiolide is described, constituting a formal synthesis of this natural product. The synthetic strategy constructs the 14-membered macrocyclic domain via Yamaguchi esterification followed by a challenging ring-closing metathesis (RCM) to effect the final formation of the macrolactone.

The Synthesis and Bioactivity of the Marine Macrolide Callyspongiolide

“…For the synthesis of the ester linkage, Yamaguchi esterification has been used successfully as the macrocyclization step (Xu and Ye, [26] A. Ghosh [32, 33] ), and earlier in the macrocycle synthesis (S. Ghosh), however, when it was utilized in the presence of the C2,3 Z ‐olefin it was seen that isomerization of this bond occurred (Bosch and Amat, [53] Brimble [58] ). Esterification using the Mitsunobu reaction avoided this issue for Bosch and Amat, [53] whereas the Brimble group determined that later re‐isomerization of this bond was possible [58] . Fürstner et al.…”

“…It was envisaged that acid ent ‐ 134 could be accessed by using homocrotylation of aldehyde 149 (Scheme 28). [58] …”

“… Brimble group′s synthetic approach to the synthesis of the macrocyclic core of (+)‐callyspongiolide ( 1 b ), established through the synthesis of model macrocycle 146 [58] …”

“… Brimble group′s synthesis of acid coupling partner ent ‐ 134 [58] . Reagents and conditions: i) PPh 3 , CCl 4 , THF, reflux, 81 %; ii) Li, THF, reflux, 86 %; iii) TBSCl, imidazole, CH 2 Cl 2 , rt, 96 %; iv) n BuLi, ethyl chloroformate, THF, −78 °C, 83 %; v) Lindlar′s catalyst, quinoline, H 2 , EtOAc/1‐octene, rt, quant.…”

“…[32,33] It was envisaged that acid ent-134 could be accessed by using homocrotylation of aldehyde 149 (Scheme 28). [58] Our initial approach to the synthesis of aldehyde 149 was based around the use of ac hiral auxiliary,h owever,asynthesis based on opening of the knownc hiral lactone 150 provedt o be higher yielding. According to literature precedent, 150 was synthesized from 3-methylglutaric anhydride [59] and this was converted to dichloro-olefin 151 before reductivee limination and protection to give alkyne 152.A ddition of ethyl chloroformate to the deprotonated alkyne, followed by reduction using Lindlar's catalyst afforded Z-alkene 153.R emoval of the TBS ether followed by DMP oxidation to aldehyde 149 allowed Krauss homocrotylation [56,57,60] to install the C7 and C9 stereocenters,b efore protection of the formed hydroxyl group as a TBS ether and hydrolysis of the ester gave acid ent-134 (Scheme 29).…”