Total synthesis and determination of the absolute stereochemistry of the squalene synthase inhibitors CJ-13,981 and CJ-13,982

Total synthesis of alkyl citrate natural products

“…1,7 ent-CJ-13,981 and ent-CJ-13,982: Barrett To date, the only synthesis of CJ-13,981 (4) and CJ-13,982 (3) was reported by Barrett in 2009. 67 This synthesis gave the nonnatural enantiomers along and an additional diastereoisomer of each compound which allowed for the assignment of the absolute configuration of these compounds, however the correct enantiomers are yet to be synthesised. The synthesis followed closely the trachyspic acid 62 and citrafungin A 66 syntheses from the same group.…”

Synthesis of Alkyl Citrates (−)-CJ-13,981, (−)-CJ-13,982, and (−)-L-731,120 via a Cyclobutene Diester

“…Alkyl citrates are challenging synthetic targets owing to their high oxidation state and two contiguous stereocenters, and previous syntheses of both natural (−)- 1 and unnatural (+) - 1 and (+)- 2 are summarized in Figure . The first syntheses of the unnatural enantiomers of CJ-13,982 and CJ-13,981 were reported by Barrett and co-workers, which confirmed the absolute stereochemistry of these compounds. This utilized an aldol/alkylation sequence to construct the contiguous asymmetric centers with good stereocontrol.…”

“…Cross metathesis (CM) with undecene followed by hydrogenation afforded (−)-CJ-13,982 trimethyl ester 18 . This compound compared well with that reported by us and by Barrett (except for the sign of rotation) …”

In vitro studies of maleidride-forming enzymes

“…Indeed simple compounds like CJ-13981 7 should require only a fatty acid synthase and an alkylcitrate synthase, both presumably duplicated from primary metabolism, to produce a compound with useful activity as an inhibitor of squalene synthase. 4,5 Exchange of the FAS for an hr-PKS (and hydrolase) allows more complex chains to be builtfor example squalestatin precursors which are also squalene synthase inhibitors. [46][47][48] Finally, gain of a dehydratase (again almost directly from primary metabolism) and a KI-like protein then allows the pathway to make maleidrides.…”

“…They include relatively simple monomeric compounds such as 1 and 2, piliformic acid 3, 1 oryzines A and B 4–5, 2 sporothriolide 6, 3 CJ-13,981 7 (ref. 4 and 5 ) and hexylitaconic acids 6 known from Aspergillus niger ( Fig. 1 ).…”