Condensation of N-Boc-L-phenylalaninal (I) with 4-biphenylcarbonyl chloride (II) and KCN in the presence of N-benzylcinchoninium chloride (NBC) afforded alpha-acyloxynitrile (III) as a 4:1 mixture of (2R,3S) and (2S,3S) isomers. Hydrogenation of (III) in the presence of Raney Nickel and tert-butyl carbazate, followed by crystallization of the major isomer from acetonitrile provided hydrazone (IV). Subsequent reduction of (IV) to hydrazine using NaBH3CN and p-toluenesulfonic acid, with concomitant rearrangement of the biphenylcarbonyl group furnished hydrazide (V), which was reduced to the benzyl hydrazine (VI) by means of either BH3 or DIBAL-H. Deprotection of both Boc groups of (VI) with HCl gave diamino compound (VII). Finally, coupling of N-methoxycarbonyl-L-tert-leucine (IX), (prepared by reaction of tert-leucine (VIII) with methyl chloroformate), with diamine (VII) employing O-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N',N'-tetramethyluronium tetra-fluoroborate (TPTU) provided the target bisamide.

Condensation of N-Boc-L-phenylalaninal (I) with 4-biphenylcarbonyl chloride (II) and KCN in the presence of N-benzylcinchoninium chloride (NBC) afforded alpha-acyloxynitrile (III) as a 4:1 mixture of (2R,3S) and (2S,3S) isomers. Hydrogenation of (III) in the presence of Raney Nickel and tert-butyl carbazate, followed by crystallization of the major isomer from acetonitrile provided hydrazone (IV). Subsequent reduction of (IV) to hydrazine using NaBH3CN and p-toluenesulfonic acid, with concomitant rearrangement of the biphenylcarbonyl group furnished hydrazide (V), which was reduced to the benzyl hydrazine (VI) by means of either BH3 or DIBAL-H. Deprotection of both Boc groups of (VI) with HCl gave diamino compound (VII). Finally, coupling of N-methoxycarbonyl-L-tert-leucine (IX), (prepared by reaction of tert-leucine (VIII) with methyl chloroformate), with diamine (VII) employing O-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N',N'-tetramethyluronium tetra-fluoroborate (TPTU) provided the target bisamide.

2) Intermediate (IX) can also be obtained as follows: The cyclization of 4-cyanobenzoic acid methyl ester (XII) with acetylene at 15 Atm by means of cobaltocene in toluene at 180 C gives 4-(2-pyridyl)benzoic acid methyl ester (XIII), which is saponified with NaOH in methanol to the corresponding acid (XIV). The activation of (XIV) with isobutyl chloroformate yields the mixed anhydride (XV), which is condensed with N-(tert-butoxycarbonyl)-L-phenylalaninal (XVI) and KCN in dichloromethane, affording (XVII). The reaction of (XVII) with tert-butyl carbazate (V) by means of acetic acid in methanol gives hydrazone (XVIII), which is reduced to hydrazine (XIX) by means of sodium cyanoborohydride in THF. The isomerization of (XIX) by means of 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTDE) in hot diglyme yields hydrazide (XX), which is finally reduced to intermediate (IX) with diisobutylaluminum hydride in dichloromethane/THF.

In an alternative procedure, condensation of 4-biphenylcarbaldehyde (X) with tert-butyl carbazate afforded hydrazone (XI), which was reduced to the benzylhydrazine (XII) by hydrogenation over Pd/C. Opening of the Boc-protected epoxide (XIII) with hydrazine (XII) gave hydrazinoalcohol (VI). This was deprotected with HCl and then coupled as above with N-methoxycarbonyl-L-tert-leucine (X) by means of TPTU.

1) The reaction of 4-bromobenzaldehyde (I) with trimethylorthoformate (II) and p-toluenesulfonic acid in methanol gives ketal (III), which is condensed with 2-pyridylmagnesium bromide in THF, yielding 4-(2-pyridyl)benzaldehyde (IV). The reaction of (IV) with tert-butyl carbazate (V) in refluxing ethanol affords hydrazone (VI), which is reduced with H2 over Pd/C in methanol to the hydrazine (VII). The condensation of (VII) with the epoxide (VIII) in hot isopropanol gives the expected addition product (IX), which by treatment with HCl or formic acid results in the fully deprotected intermediate (X). Finally, this compound is condensed with N-(methoxycarbonyl)-L-tert-leucine (XI) by means of O-(2-oxo-1,2-dihydro-1-pyridyl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TPTU) in dichloromethane or DMF.

In a variation of this procedure, aryl tetrazole (II) was alkylated with ICH3 to provide methyltetrazole (XV). Condensation of (XV) with tert-butyl carbazate afforded hydrazone (XVI), which was reduced to the benzylhydrazine (XVII) by means of NaBH3CN and p-toluenesulfonic acid. Opening of the Boc-protected epoxide (XVIII) with hydrazine (XVII) gave hydrazinoalcohol (XIX). Acid deprotection of both Boc groups of (XIX) furnished diamino compound (XX), which was finally coupled with N-methoxycarbonyl-L-tert-leucine (X) by means of TPTU.

4-Bromobenzaldehyde dimethyl acetal (I) was converted to the corresponding Grignard reagent and then coupled with 2-bromothiazole (II) in the presence of [1,3-bis(diphenylphosphino)propane]nickel chloride to afford 4-(2-thiazolyl)benzaldehyde dimethylacetal (III). After acid hydrolysis of the acetal group of (II), the resulting aldehyde was condensed with tert-butyl carbazate to give hydrazone (IV), which was further reduced to the benzylhydrazine (V) employing NaBH3CN and p-toluenesulfonic acid. Opening of the Boc-protected epoxide (VI) with hydrazine (V) gave hydrazinoalcohol (VII). Both Boc groups of (VII) were removed by treatment with formic acid to yield diamino compound (VIII). Finally, coupling of (VIII) with N-methoxycarbonyl-L-tert-leucine (IX) by means of O-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N',N'-tetramethyluronium tetra fluoroborate (TPTU) provided the title bisamide.