Enantioselective Synthesis of Both Epimers at C-21 in the Proposed Structure of Cytotoxic Macrolide Callyspongiolide

Abstract

Both epimers at C-21 in the proposed structure of (+)-callyspongiolide have been synthesized in a convergent and enantioselective manner. The 14-membered macrolide with a sensitive C2–C3 cis-olefin functionality was installed by a Yamaguchi macrolactonization of hydroxyl alkynoic acid followed by hydrogenation over Lindlar’s catalyst. The C5 methyl stereocenter was constructed by a ring-closing olefin metathesis followed by addition of methyl cuprate to an α,β-unsaturated δ-lactone. Other key reactions are chiral Corey–Bakshi–Shibata (CBS) reduction and Sonogashira coupling to conjoin the macrocyclic core and side chain.

Enantioselective total synthesis and structural assignment of callyspongiolide

“…We have previously established the stereochemical outcome of reduction using both enantiomers of the CBS catalyst by X-ray crystallography. 13 …”

Marine natural products

“…1007. [539][540][541][542] Aurantoside G 543 has been synthesised, 544 while a synthesis of haliclonin A, 545 consistent with the written description of the conguration of the molecule but opposite to that drawn (incorrectly) in the original publication, has been reported. 546 Renieramycin T 547 has been made, 548,549 while the absolute congurations of isowondonins A 1008 and B 1009, 550 isolated from Poecillastra wondoensis, were established following their syntheses.…”

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

“…R f 0.60 (petroleum ether/EtOAc, 9 : 1); a ½ � 23 D + 25.0 (c 0.04, CHCl 3 ), (lit. [22] a ½ � 20 D + 40.6 (c 0.87, CHCl 3 )); 1 Si + 53.3320, found: 553.3322. Analytical data was in agreement with that reported in the literature.…”

“…We focused our initial attention on the synthesis of the macrocyclic core of (+)-callyspongiolide (1 a), with our formal synthesis target identified as di-protected macrocycle 3 based on the total synthesis of this molecule by A. Ghosh et al. [22,23] Our approach to access macrocycle 3 hinged on the key RCM of diene-yne 4 and its subsequent cis-reduction. It was envisaged that Yamaguchi esterification of alcohol 5 and acid 6 could be used to synthesise the required macrocyclisation precursor, 4 (Scheme 1).…”

“…Analytical data was in agreement with that reported in the literature. [22] Characterisation of 40: . Analytical data was in agreement with that reported in the literature for ent-40.…”