Synthesis of (2-mercaptoacetyl)-L-[2-14C]tryptophan as a selective metallo-β-lactamase inhibitor via [2-14C]indole based on chiral pool strategy
Metallo-beta-lactamase enzymes make bacteria resistant to a broad range of commonly used beta-lactam antibiotics. Several thiol derivatives of L-amino acids have been shown their inhibitory effects against the metallo-β-lactamase IMP-1. In this study, (2-mercaptoacetyl)-L-tryptophan as a new inhibitor of metallo-β-lactamases labeled with carbon-14 in the 2-position of the indole ring was prepared from [2-14C]indole as a key synthetic intermediate based on chiral pool strategy. The overall synthesis was performed in 10 steps with the overall radiochemical yield 3.6% on the basis of the barium [14C]carbonate as a starting material.
Use of dibutyl[14C]formamide as a formylating reagent in the Vilsmeier-Haack reaction and synthesis of a 14C-labeled novel phosphodiesterase-4 (PDE-4) inhibitor
A simple, high-yielding synthesis of dibutyl[14C]formamide ([14C]DBF; 1) from 14CO2 was developed (Scheme 1): reaction of LiBEt3H and 14CO2 followed by aqueous workup gave H14CO2H in high yield. Conversion of the [14C]formic acid to 1 was effected by a standard carbodiimide coupling procedure. The utility of 1 as an alternative to dimethyl[ 14C]formamide ([14C]DMF) in alkylation reactions and in the [14C]Vilsmeier-Haack reaction was demonstrated for several substrates (Table 2). A 14C-labeled phosphodiesterase-4 (PDE-4) inhibitor, [14C]-2, was synthesized by application of this technology (Scheme 2).
Ho, Jonathan Z.,Elmore, Charles S.,Wallace, Michael A.,Yao, Dan,Braun, Matthew P.,Dean, Dennis C.,Melillo, David G.,Chen, Cheng-Yi
p. 1040 - 1047
(2007/10/03)
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