Total Syntheses of 1,2,4-Thiadiazole Natural Products

Abstract

Only five distinct natural products have been assigned as containing a 1,2,4-thiadiazole motif, of which, dendrodoine (5) and penicilliumthiamine B (19) have been previously synthesised.This thesis describes the total syntheses of all remaining 1,2,4-thiadiazole-containing natural products; polycarpathiamines A and B (12 and 13) derived from the ascidian Polycarpa aurata, along with the Isatis indigotica derived insatindigothiadiazoles A-D (33a-d) and the unnamed alkaloids 24a and 24b.Thioacylguanidine 126 underwent a novel one-pot, copper(II)-catalysted benzylic oxidationoxidative heterocyclisation sequence to form the 3-amino-5-acyl-1,2,4-thiadiazole core of the polycarpathiamines 132. Simple deprotection steps then completed the synthesis of polycarpathiamines A and B (12 and 13). Initial synthetic efforts towards the Istais indigotica derived alkaloids 24a and 24b focused on a late-stage intermolecular Heck coupling of 5-chloro-1,2,4-thiadiazole 217 with spiro-5',6'-dihydrothiopyran (±)-280 to forge the heterocyclic framework of the natural products (±)-289. Ultimately, this strategy was unsuccessful since the desired 5',6'-dihydrothiopyran (±)-280 was formed as a minor product alongside the 3',6'-dihydrothiopyran (±)-281, and attempts to suppress isomerisation in the intramolecular Heck cyclisation were ineffective. A successful approach to 24a and 24b was inspired by the proposed biosynthesis of the natural product. Insatindigothiadiazoles A-D (33a-d) were first prepared through the oxidative dimerisation of thioamide (±)-388. A selective dehydration of insatindigothiadiazoles A-D (33a-d) furnished diene (±)-31 which underwent regioselective thio-Diels-Alder reaction with 3-thioisatin 32 to form natural products 24a and 24b, along with diastereomer 144a/b. The result of the biomimetic thio-Diels-Alder reaction was supported by DFT analysis and corroborated the postulate made in the original report that the C-2' alcohol of (±)-31 is too distant from the forming spirocentre to exert any diastereocontrol in the cycloaddition. As such, diastereomer 144 was also thought to be present in Isatis indigotica. Recent communication with the isolation author, Professor Jiangong Shi, verified this postulate by confirming the recent isolation of both 144a and 144b from I. indigotica.