Enantioselective total synThesis of the anti-helicobacter pylori agent (+)-spirolaxine methyl ether

Abstract

H. pylori is a bacteria that infects a significant proportion of the human population. It is responsible for most gastric and duodenal ulcers and has been strongly associated with the development of gastric cancer. Eradication of H. pylori can cure these diseases; however the therapies currently used to treat infection are unsatisfactory. (+)-Spirolaxine methyl ether 2b exhibits potent and selective anti-//. pylori activity, and is therefore a promising drug candidate. This thesis reports the convergent enantioselective total synthesis of (+)-spirolaxine methyl ether 2b. The key step in the synthesis of (+)-spirolaxine methyl ether 2b involved a heterocycleactivated Julia olefmation between benzothiazole based spiroacetal sulfone 352b and phthalide aldehyde 226a. Spiroacetal sulfone 352b was prepared from the cyclisation of dihydroxyketone 233b, which in turn was derived from the coupling of acetylene 235b and aldehyde 234. Aldehyde 234 was synthesised from (Al-aspartic acid, which is readily available. Phthalide aldehyde 226a was prepared via intramolecular acylation of bromocarbamate 306a, which was synthesised from 3,5-dimethoxybenzoic acid 314. The (37?)-stereochemistry of phthalide aldehyde 226a was introduced via titanium tetrafluoride-(+)-BINOL mediated allylation of 3,5-dimethoxybenzaldehyde 314. Union of the sulfone 352b and aldehyde 226a fragments successfully completed the first enantioselective total synthesis of (+)-spirolaxine methyl ether 2b, thereby unequivocally establishing the absolute stereochemistry of the natural product to be (3R,2"R,5"R,TR).