Simple and efficient synthesis of allo- and threo-3,3′-dimethylcystine derivatives in enantiomerically pure form

A simple and efficient method for the synthesis of allo- and threo-3,3′-dimethylcystine derivatives is reported. Various tosyl and bromo derivatives of Cbz-, Boc-, and Fmoc- protected threonine methyl esters have been prepared and subjected to nucleophilic substitution with potassium thiocyanate in acetonitrile to yield the corresponding thiocyanate derivatives in moderate yield. The thiocyanates are readily converted to the corresponding allo- and threo-3,3′-dimethylcystine derivatives via reductive dimerization with benzyltriethylammonium tetrathiomolybdate.

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(2R,3S)-Methyl 2-(benzyloxycarbonyl)-3-thiocyanatobutanoateC14H16N2O4S[α]D = +70 (c 1, CHCl3)Absolute configuration: (2R,3S)

(2R,3S)-Methyl 2-(tert-butoxycarbonyl)-3-thiocyanatobutanoateC11H18N2O4S[α]D = +97 (c 1, CHCl3)Absolute configuration: (2R,3S)

(2R,3S)-Methyl 2-(((9H-fluoren-9-yl)methoxy)carbonyl)-3-thiocyanatobutanoateC21H20N2O4S[α]D = +55.96 (c 1, CHCl3)Absolute configuration: (2R,3S)

(2R,3R)-Methyl 2-(benzyloxycarbonyl)-3-thiocyanatobutanoateC14H16N2O4S[α]D = +25.6 (c 1, CHCl3)Absolute configuration: (2R,3R)

(2R,3R)-Methyl 2-(tert-butoxycarbonyl)-3-thiocyanatobutanoateC11H18N2O4S[α]D = +15.1 (c 1, CHCl3)Absolute configuration: (2R,3R)

(2R,3R)-Methyl 2-(((9H-fluoren-9-yl)methoxy)carbonyl)-3-thiocyanatobutanoateC21H20N2O4S[α]D = +13.7 (c 1, CHCl3)Absolute configuration: (2R,3R)

N,N′-Bis(benzyloxycarbonyl)-allo-3,3′-dimethyl-l-cystine dimethyl esterC26H32N2O8S2[α]D = −98.3 (c 1, CHCl3)

N,N′-Bis(tert-butoxycarbonyl)-allo-3,3′-dimethyl-l-cystine dimethyl esterC20H36N2O8S2[α]D = −54.9 (c 4.38, CHCl3)

N,N′-Bis(9-fluorenylmethoxycarbonyl)-allo-3,3′-dimethyl-l-cystine dimethyl esterC40H40N2O8S2[α]D = −44 (c 1, CHCl3)

N,N′-Bis(benzyloxycarbonyl)-threo-3,3′-dimethyl-l-cystine dimethyl esterC26H32N2O8S2[α]D = +172 (c 0.44, CHCl3)

N,N′-Bis(tert-butoxycarbonyl)-threo-3,3′-dimethyl-l-cystine dimethyl esterC20H36N2O8S2[α]D = +145 (c 1, CHCl3)

N,N′-Bis(9-fluorenylmethoxycarbonyl)-threo-3,3′-dimethyl-l-cystine dimethyl esterC40H40N2O8S2[α]D = +75.6 (c 1, CHCl3)