Enantioselective total synthesis and structural assignment of callyspongiolide

Abstract

We have elucidated the complete absolute configuration of callyspongiolide and unambiguously assigned its stereochemistry at the C-21 center through synthesis. Four stereoisomers of callyspongiolide were synthesized in a convergent and enantioselective manner. A late-stage Sonogashira coupling forges the diene-ynic side chain. Other notable reactions are Yonemitsu’s variation of the Yamaguchi macrolactonization to cyclize an alkynic seco acid, highly trans-selective Julia-Kocienski olefination, CBS reduction to set the C-21 stereocenter, and methyl cuprate addition to an unsaturated pyranone to install the C-5 methyl center.

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

“…This structural revision was also confirmed by the successful synthesis of both C21 epimers of 2 by Xu and Ye et al [21] . and subsequently A. Ghosh et al [23] . (Figure 2).…”

“…In summary, we have reported the synthesis of macrocycle 3 in 15 steps from commercially available cyclic anhydride 31 , constituting an enantioselective formal synthesis [22,23] of (+)‐callyspongiolide ( 1 a ), the unnatural isomer of the natural product. Anhydride desymmetrisation and a Kraus homocrotylation successfully established the C5, C7 and C9 stereocentres.…”

“…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).…”

“…At the onset of our work no syntheses of callyspongiolide had been reported, however in the intervening time the synthesis of callyspongiolide has attracted significant interest. Total syntheses of both C21 epimers (1 a and 1 b) of the originally proposed callyspongiolide structure by the groups of Xu and Ye [21] and A. Ghosh [22,23] in 2016 enabled optical rotation and NMR comparisons with the published data to establish that structure 1 a in fact represented the unnatural (+)-callyspongiolide, allowing the natural product (À )-callyspongiolide to be assigned the structure 2 with the (R) configuration at C21. This structural revision was also confirmed by the successful synthesis of both C21 epimers of 2 by Xu and Ye et al [21] and subsequently A. Ghosh et al [23] (Figure 2).…”

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.…”