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Title: Synthetic approaches towards heterocyclic natural producers
Author: Xiong, Xin
ISNI:       0000 0004 2747 1590
Awarding Body: Cardiff University
Current Institution: Cardiff University
Date of Award: 2005
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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.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available