Rational Design of Templates for Intramolecular O,N-Acyl Transfer via Medium-Sized Cyclic Intermediates Derived from L-Cysteine. Definition of an Experimental Maximum in Effective Molarity through the Study of "Tunable" Templates

Article abstract of DOI:10.1021/jo00268a020

Rate constants and effective molarities for intramolecular O,N-acyl transfer have been measured for a series of unsymmetrical disulfides derived from cysteine and having the general structure H-Cys(S-XY-OAc)-OMe, for which XY is a rigid molecular spacing element that maintains a fixed OS distance lying in the range of 4.5-6.5 Angstroem.A synthetic route is described to 4-hydroxy-6-mercaptodibenzothiophene, involving lithiation of 4-methoxydibenzothiophene followed by reaction with elemental sulfur and positional isomer separation.A maximum effective molarity (EM) value of 5 M is seen for 4,6-disubstituted dibenzofuran function (OS = 5.45 Angstroem) while EM values of less than 0.1 M are seen for 4,6-disubstituted phenoxathiin and 4,6-disubstituted dibenzothiophene functions (OS = 3.90 and 6.30 Angstroem, respectively).Distance calculations and estimates of strain energy based on torsional and van der Waals terms are used to show that this result is consistent with a cyclic transition state containing one conformation of the cysteine framework.Energy minimization calculations were carried out by using a novel null-vector procedure for finding allowed torsional motions.They imply that the transition state for O,N-acyl transfer is strained by ca. 6 kcal/mol in the dibenzofuran case.