Thioxanthene Dioxide Based Amino-Protecting Groups Sensitive to Pyridine Bases and Dipolar Aprotic Solvents

Article abstract of DOI:10.1021/jo00286a019

In pursuit of an analogy between fluorine and thioxanthene dioxide, the suitability of the D-TMOC and related functions as base-sensitive amino-protecting groups was examined.Such compounds were found to be cleaved by mild pyridine bases against which the analogous FMOC derivatives are stable.Deblocking gives as a byproduct the methylene sulfone 5 or its adducts with an appropriate secondary deblocking amine.Certain solvents such as DMSO, DMF, etc., were also found to deblock the D-TMOC group, especially on warming, whereas the compounds were stable in ordinary nonpolar solvents (e.g., CH2Cl2, benzene, THF).For practical use the D-TMOC function suffers from excessive solvent sensitivity and the low solubility of some derivatives.To overcome this problem tert-butyl groups were introduced into the 2,7-positions of the xanthene nucleus.The resulting DBD-TMOC function proved easier to handle in terms of both solubility and reactivity.The key alcohol 12 was synthesized from diphenyl sulfide 13 by tert-butylation followed by Friedel-Crafts cyclization using methyl dichloromethyl ether to give a 50-50 mixture of thioxanthene 15 and corresponding thioxanthone 16.Without separation of the mixture, oxidation gave a mixture of the dioxides 17 and 18, and again without separation the mixture was reduced by P/HI to give the desired compound 17 in an overall yield of 60-65percent.Formylation of 17 followed by reduction gave 12, from which urethanes 11 were obtained in the normal manner via the chloroformate.The DBD-TMOC group was stable to strong acids (TFA, HBr-HOAc) but deblocked by catalytic hydrogenolysis as well as via mild bases and warming in dipolar aprotic solvents.Upon deblocking of 11 in DMSO the byproduct 27 separated completely, especially if 3-5percent water is present or added subsequently.This process provides a clean solution of the deblocked amine, thus simplifying the use of the DBD-TMOC function in peptide synthesis.An example given is that of leucine enkephalin, in which all coupling steps were effected by acid chlorides and all deblocking steps by warming in DMSO.It was shown with model compounds that coupling could be effected under appropriate conditions without racemization.