Year
2003
Degree Name
Doctor of Philosophy
Department
Department of Chemistry
Recommended Citation
Pham, Tien Quoc, The synthesis of carbocyclic hydantocidin and 6,7-di-epi-carbocyclic hydantocidin via a phosphine-catalysed (3+2) cycloaddition, Doctor of Philosophy thesis, Department of Chemistry, University of Wollongong, 2003. https://ro.uow.edu.au/theses/1207
Abstract
this thesis describes the total synthesis of the carbocyclic analogue of hydantocidin and its 6,1-di-epi diastereoisomer. The essential feature of the carbocyclic analogue of hydantocidin was the spirocyclic structure, which consisted of a functionalised cyclopentane ring attached via a spiro carbon to a hydantoin ring. This structure was produced via a phosphine-catalysed cycloaddition reaction of an appropriate alkyne or allene with an electron deficient alkene. Two regioisomers are possible from this cycloaddition, regioisomers A and B.
Our retro-synthetic analysis revealed two possible pathways for the synthesis of the spirocyclic ring system. In pathway A, the functionalised cyclopentane can be produced first with functional groups set up for subsequent hydantoin ring formation, while in pathway B, the hydantoin forms part of the electron deficient alkene, as a 5- methylene hydantoin, in the cycloaddition reaction.
Chapter 2 describes our attempts at pathway A using the alkyne, ethyl 2- butynoate, as the 3 carbon synthon and methyl 2-[(diphenylmethylene)amino]acrylate as the electron deficient alkene. Only regioisomer A, 3-ethyl, 1-methyl 1- [(diphenylmethylene)amino]-3-cylcopentene-l,3-dicarboxylate, was produced. The hydantoin component was produced by conversion of this cycloadduct to a urea derivative upon treatment with KCNO in HCI followed by base catalysed hydantoin cyclisation. The study showed that protection of the nitrogens of the hydantoin was necessary for further synthetic transformations.
chapter 3 showed, in preparation for pathway B, that N, N'-diprotected 5- methylene hydantoins could be prepared from amino acids cystine, 5-methyl cysteine and serine. The latter was shown to be the most versatile in synthetic manipulation. The phosphine-catalysed cycloaddition reaction of these 5-methylene hydantoins with the achiral alkyne, ethyl 2-butynoayte, and achiral allene, ethyl 2,3-butadienoate, discussed in Chapter 4, also showed preference for formation of regioisomer A. Using Oppolzers chiral camphorsultam as the chiral auxiliary on an A^-2-alkynoate derivative, optically active cycloadducts of regioisomer A could be produced and readily separated by column chromatography. In contrast the use of an Af-2-aikynoate derivative of an oxazolidin-2-one resulted in reversal of regioselectivity, that is, preference for formation of regioisomer B. Furthermore, the use of (4S)-benzyl-2-oxazolidinone as the chiral N- 2-alkynoate oxazolidinone derivative gave diastereoselective products of regioisomer B.
To complete the total synthesis of carbocyclic hydantocidin and its 6,7-dipimer, the cycloadduct ethyl l,3-dibenzyl-2,4-dioxo-l,3-diazaspiro[4.4]non-7-ene-7- carboxylate, regioisomer A of the phosphine-catalysed cycloaddition reaction, underwent a series of synthetic transformations, as discussed in Chapter 5, including; deconjugation of the double bond, ds-dihydroxylation of the double bond, protection of the alcohols, reduction of the ester group to an alkyl alcohol and deprotection of the N-benzyl and O-acetates.
Unless otherwise indicated, the views expressed in this thesis are those of the author and do not necessarily represent the views of the University of Wollongong.