Novel synthesis of para-hydroxy-phenylglycine and related chemistry

Contains fulltext : 19246_novesyofp.pdf (publisher's version ) (Open Access)para-Hydroxy-Phenylglycine (HPG) is an important sidechain in several b-lactam antibiotics. In industry HPG is produced from phenol as the starting material via an electrophilic substitution reaction. A serious problem in this approach is the formation of ortho/para regioisomers, which is caused by activation of both the ortho and para positions of phenol. In this thesis a novel two-step synthesis of HPG from the relatively cheap benzoquinone is described, in which the ortho/para problem is circumvented in an elegant manner. The strategy comprises the selective functionalization of one of the carbonyl groups in benzoquinone, followed by an elimination-addition reaction in the presence of ammonia to give HPG. A quinone methide is proposed as the intermediate species, which is very reactive towards nucleophiles. By conducting the elimination-addition reaction in the presence of several different amines the corresponding N-substituted derivatives of HPG were isolated in high yields. Attempts to isolate the intermediate quinone methide from the solution in the absence of nucleophiles failed, which indicates that it is a very unstable compound. However, by using the Flash Vacuum Thermolysis (FVT) technique this quinone methide could successfully be isolated, which unequivocally confirms the proposed elimination-addition reaction mechanism. Furthermore, a diastereoselective Diels-Alder reaction was observed between several di-substituted cyclohexadienones and cyclopentadiene. Surprisingly, one cycloadduct appeared to be unstable and rearranged into a heterocyclic compound via cleavage of the norbornene structure. Finally, molecular imprinting is considered as a potential solution for the ortho/para problem in the electrophilic substitution to phenol138 p