An efficient synthesis of a 4'-phosphonodifluoromethyl-3'-formyl-phenylalanine containing SRC SH2 ligand.
A CuBr-mediated, regioselective cross-coupling between methyl 2,5-diiodobenzoate (4) and [(diethoxyphosphinyl)difluoromethyl]zinc bromide is reported. Palladium-catalyzed incorporation of an amino acid side chain, followed by subsequent modifications resulted in the rapid construction of 2. Compound 2 was designed to engage Cys188 of the Src SH2 domain, however, this was not observed spectroscopically.
SH2 domain inhibition: a problem solved?
The past two years have witnessed a number of significant advances in the design of SH2 inhibitors of both Src and Grb2. For Src, several non-peptide templates have been developed with high affinity, and one case, in the context of bone-binding phosphotyrosine bioisostere, has yielded an in vivo active antiresorptive agent. Similarly, high-affinity Grb2 SH2 inhibitors with novel phosphotyrosine replacements have now been reported that demonstrate, for the first time, cellular activities consistent with an anticancer agent.
Synthesis of 2,4-dideoxy-.beta.-D-erythro-hexopyranosyl nucleosides
The synthesis of 1-(2,4-dideoxy-β-D-erythro-hexopyranosyl)thymine (12) 1 was accomplished using two different synthetic routes. It was obtained starting either from 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose or from tri-O-acetyl-D-glucal. The other modified nucleosides, with either a cytosine, guanine, or adenine moiety, were synthesized using the second reaction scheme. Deoxygenation reactions were accomplished with the (2,4-dichlorophenoxy)thiocarbonyl derivatives generated in situ