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Synthetic approaches towards heterocyclic natural products

Xiong, Xin 2005. Synthetic approaches towards heterocyclic natural products. PhD Thesis, Cardiff University.

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Abstract

A variety of tri- and tetrasubstituted pyridines are prepared by new one-pot processes, developed by modification and improvement of the traditional Bohlmann-Rahtz reaction. The use of zinc(II) bromide catalysis, microwave irradiation and conductive heating in a sealed tube is described to facilitate rapid Michael addition-cyclodehydration of an enamine and alkynone in a single synthetic step and with total control of regiochemistry. Expanding the Bohlmann-Rahtz heteroannulation reaction leads to the development of a mild one-pot three-component syntheses of pyridines, a tandem oxidation-heteroannulation process for one-pot synthesis of pyridines from propargylic alcohols, a highly facile combined three-component tandem oxidation-heteroannulation process and a novel tetrasubstituted bromopyridine synthesis mediated by N-bromosuccinimide. The synthesis of dimethyl sulfomycinamate (13), the acidic methanolysis product of the sulfomycin family of thiopeptide antibiotics, from methyl-4-(trimethylsilyl-2-oxobut-3-ynoate (216) is achieved in 13 steps by the Bohlmann-Rahtz heteroannulation of 1-(oxazol-4-yl)enamine 252 or in 12 steps and 9% overall yield by three-component cyclocondensation with N-[3-oxo-3-(oxazol-4-yl)propanoyl]serine 251 and ammonia in methanol, in a 2,3,6-trisubstituted pyridine synthesis that proceeds with total regiocontrol. Bohlmann-Rahtz reaction of a chiral non-racemic enamine 312 and thiazolylpropynone 114 gives a terminal-protected pyridine-containing gamma-amino acid 311 in high optical purity in a sequential one pot multicomponent reaction that proceeds with total control of regiochemistry and with minimal racemisation. Further elaboration has established the first synthesis of the gamma-lactam acidic hydrolysate of the macrocyclic thiopeptide antibiotic cyclothiazomycin, a selective rennin inhibitor, in only four steps and 30% overall yield and has confirmed its structure.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Chemistry
Subjects: Q Science > QD Chemistry
Date of First Compliant Deposit: 30 March 2016
Last Modified: 10 Jan 2018 05:43
URI: http://orca.cardiff.ac.uk/id/eprint/55520

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