Total Synthesis and Biological Activity of Neopeltolide and Analogues

Abstract

Combining the core structure of neopeltolide, lactone 16 a, with the oxazole-containing side chain 23 via a Mitsunobu reaction provided the cytotoxic natural product neopeltolide (2). The side chain 23 was prepared from oxazolone 24 via the corresponding triflate. Key steps in the preparation of 23 were a Sonogashira coupling, an enamine alkylation, and a Still-Gennari Horner-Emmons reaction. By changing the Leighton reagent in the allylation step, the 11-epimer of lactone 16 a, compound 50 was prepared. This led to 11-epi-neopeltolide 51. The 5-epimer of neopeltolide, compound 52, could be obtained from the minor isomer of the Prins cyclization. Furthermore, a range of analogues with modifications in the side chain were prepared. All derivatives were checked for toxicity effects on mammalian cell cultures and inhibitory effects on NADH oxidation in submitochondrial particles of bovine heart. Modifications in the lactone part are tolerated to some degree. On the other hand, shortening the distance between the oxazole and the lactone causes a significant drop in activity. Analogue 65 with an additional double bond is equally or even more active than neopeltolide itself.

Total Synthesis and Structure−Activity Investigation of the Marine Natural Product Neopeltolide

“…As with elimination of the oxazole-containing side chain, substitution of this native portion with the octanoyl ( 45 ) or benzoyl ( 44 ) groups also abolished the vast majority of activity, with growth inhibition observed at only the maximum concentration: 10 μ M of the octanoyl ester inhibits 25% of P-388 cell growth and 33% of MCF-7 cell growth, while the benzyl ester is somewhat more effective at the same concentration and inhibits 75% and 78%, respectively. It has been shown that the olefin in the side chain, which is approximated in the benzoyl ester ( 44 ) but not the octanoyl ester ( 45 ), plays a significant role in inhibiting proliferation 53. Both the octanoyl and benzoyl side chains are also significantly shorter in length than the natural side chain.…”

Strategies and Methods for the Synthesis of Anticancer Natural Product Neopeltolide and its Analogs

“…[12] As summarized in Scheme 3, starting from aldehyde 26 , which was synthesized from Noyori asymmetric hydrogenation followed by DIBAL-H reduction, a Leighton asymmetric allylation[13] was used to synthesize compound 28 with the C 11 stereocenter. After 28 was converted to α,β-unsaturated thioester 29 , a Feringa-Minnaard reaction enabled the introduction of the C 9 methyl group in a stereoselective manner.…”

Ether Transfer Methodology: Application to the Synthesis of Polyketide Natural Products

“…100 Neopeltolide, a marine polyketide isolated from a sponge by Wright and coworkers at Harbor Branch, has shown strong antifungal and cytoxic activity and thus became of interest to synthetic chemists. [101][102][103][104][105][106][107][108][109] Reaction of the ether transfer product with methyl propiolate in the presence of phosphine lead to the formation of b-alkoxyacrylate 136. Subsequent radical-mediated cyclization stereoselectively provides the 4-alkoxy-2,6-cis-trisubstituted pyran.…”