Unusual stereoselectivity in the alkylation of pyroglutamate ester urethanes

Previous studies on the alkylation of pyroglutamate ester urethanes have le d to a consensus that alkylation at C-4 occurs to give a mixture of diaster eoisomers, the major isomer of which usually has the alkyl group trans to t he ester group at C-2. We have now discovered that this generalisation is n ot invariably correct and that, although for S(N)1-type electrophiles stere oselectivity is in fact trans, S(N)2-type electrophiles can give the thermo dynamically less stable cis compounds as the predominant products. Use of t he bulky proton source 2,6-di-tert-butylphenol to quench these reactions yi elds the cis isomers as the only products in good yield, thus making direct alkylation of pyroglutamic acid derivatives a useful alternative to our hy drogenation approach to these synthons.