Barium Carbonate → p-Cyanobenzyl alcohol

Participants

Reaction Steps

The chemical synthesis of PTP probes I and II involved synthesizing a common intermediate 10 in a 7-step procedure (Scheme 1) and its subsequent coupling with the biotin-NHS ester analogues, followed by the deprotection of the phosphonate diethyl ester (Scheme 2). Thus, 4-cyanobenzyl bromide 3 was hydrolyzed in the presence of barium carbonate to produce 4-cyanobenzyl alcohol 4, which was subsequently reduced with lithium aluminum hydride under strict argon atmosphere to yield 4-hydroxymethyl-benzyl-ammonium chloride 5, upon acidic aqueous extraction (17). The amine functionality of 5 was then first masked by t-butyl carbamate to render (4-hydroxymethyl-benzyl)carbamic acid tert-butyl ester 6 (Far et al., 2002). Corey oxidation (Corey & Suggs, 1975) with pyridinium chlorochromate/sodium acetate gave the reactive aldehyde 7. The condensation of 7 with diethyl phosphite in the presence of triethylamine produced {[4-(tert-butoxycarbonylamino-methyl)-phenyl]-hydroxy-methyl}-phosphonic acid diethyl ester 8 as a racemic mixture. This racemic mixture of 8 was used as such in the following step of the synthesis. Bromination of the secondary alcohol, 8, to yield 9 was achieved using dibromotriphenyl phosphorane in pyridine (Gaida, 1990). Finally, deprotection of t-butyloxycarbonyl with neat trifluoroacetic acid gave [(4-aminomethyl-phenyl)-bromo-methyl]-phosphonic acid diethyl ester (10). The coupling of 10 with (+) biotin N-hydroxysuccinimide ester (for I) and (+) biotinamidohexanoic acid N-hydroxysuccinimide ester (for II) in DMF gave 11 and 12 respectively. The phosphonate diesters (11 & 12) were deprotected with bromotrimethylsilane in DMF to yield I and II (McKenna et al., 1977).

Provenance & Evidence