The cyclization of tripeptide derivative (XII) (assembled n three steps from the corresponding amino acids) by means of K2CO3/CaCO3 gives the macrocyclic peptide (XIII), which was reduced at its NO2 group with H2 over Pd/C and treated with tert-butyl nitrite, HBF4 and CuCl2 to obtain the corresponding chloro derivative (XIV). The condensation of (XIV) with the boronic acid derivative (XV) by means of a Pd catalyst affords the biphenyl derivative (XVI), which is desilylated with Bu4NF giving the secondary alcohol (XVII). The hydrolysis of the methyl ester of (XVII) with LiOH yields the corresponding carboxylic acid (XVIII).
Selective deprotection of the benzyloxycarbonylamino group of (XVIII) with H2 over Pd/C gives the corresponding amino derivative (XIX), which is cyclized by means of EDC and HOBT yielding the bicyclic peptide (XX). Elimination of the Boc protecting group of (XX) with formic acid affords the primary amine (XXI), which is acylated with the previously obtained dipeptide intermediate (XI) by means of DEPBT providing the adduct (XXII).
The cyclization of tripeptide derivative (I) (assembled in three steps from the corresponding amino acids) by means of K2CO3/CaCO3 gives the macrocyclic peptide (II), which was reduced at its NO2 group with H2 over Pd/C and treated with tert-butyl nitrite, HBF4 and CuCl2 to obtain the corresponding chloro derivative (III). The condensation of (III) with the boronic acid derivative (IV) by means of a Pd catalyst affords the biphenyl derivative (V), which is desilylated with Bu4NF, giving the secondary alcohol (VI). The hydrolysis of the methyl ester of (VI) with LiOH yields the corresponding carboxylic acid (VII).
Selective deprotection of the benzyloxycarbonylamino group of (VII) with H2 over Pd/C gives the corresponding amino derivative (VIII), which is cyclized by means of EDC and HOBT, yielding the bicyclic peptide (IX). Elimination of the Boc protecting group of (IX) with formic acid affords the primary amine (X) , which is acylated with the tripeptide intermediate (XI) by means of EDC and HOAt, providing the adduct (XII).
The cyclization of (XII) by means of CsF in DMSO gives the tris macrocyclic compound (XIII), which is reduced at the NO2 group with H2 over Pd/C, yielding the amino derivative (XIV). The diazotation of (XIV) with t-Bu-ONO and HBF4, followed by reaction with CuCl2/CuCl, affords the corresponding chloro derivative (XV), which is silylated with Tbdms-N(Me)-COCF3 to provide the bis silyl ether (XVI).
Elimination of the Mem protecting group of (XVI) by treatment with borane (XVII) gives the primary alcohol (XVIII), which is oxidated to the corresponding acid with DMP and NaClO2 and simultaneously methylated with Tms-CHN2 to yield the methyl ester (XIX). The controlled hydrolysis of the cyano group of (XIX) with H2O2 and K2CO3 affords the corresponding amide (XX), which is finally desilylated with TBAF and demethylated with AlBr3 to furnish the target aglycon.
The dipeptide intermediate (XI) has been obtained as follows: The coupling of the two synthons (I) and (II) by means of K2CO3 and 18-C-6 in DMSO gives the diphenyl ether (III), which is reduced at its nitro group with H2 over Pd/C yielding the amine (IV). The treatment of (IV) with tert-butyl nitrite, HBF4 and Cu2O affords the phenol (V), which is methylated with MeI and K2CO3 to provide the corresponding methyl ether (VI). The protection of the primary alcohol of (VI) with benzyl bromide (A) and K2CO3 gives the benzyl ether (VII), which is deprotected at the Mem and trifluoroacetamido groups yielding the aminoethanol derivative (VIII). The condensation of (VIII) with the protected phenylalanine derivative (IX) by means of EDC and HOBT affords the corresponding amide (X), which is finally oxidized with Dess Martin periodinane (DMP) and NaClO2 to afford the desired dipeptide intermediate (XI).
The cyclization of (XXII) by means of CsF in DMSO gives the tris macrocyclic compound (XXIII), which simultaneously eliminates the TEOC protecting group yielding (XXIV) with a free amino group. The silylation of the OH group of (XXIV) with CF3CO-N(Me)-TBDMS (B) affords the silyl ether (XXV), which is protected at its amino group with Troc-Cl (C) providing the fully protected compound (XXVI).
Selective debenzylation of (XXVI) with H2 over Pd/C with simultaneous reduction of its nitro group gives the primary alcohol (XXVII) with an amino group that is treated with t-Bu-ONO, Bu4NF and CuCl2 to obtain the corresponding chloro derivative (XXVIII). The oxidation of the primary alcohol of (XXVIII) with Dess Martin periodinane (DMP) and NaClO2 affords the expected carboxylic acid (XXIX), which is selectively deprotected at the Troc-NH group with Zn/Pb furnishing the free polycyclic polypeptide (XXX).
The cyclization of (XXX) by means of PyBop gives the complete teicoplanin ring assembly (XXXI), which is deprotected at the Mom-O-CH2 group with Br-catecholborane yielding the primary alcohol (XXXII), which is oxidized with Dess Martin periodinane (DMP) and NaClO2 to afford the corresponding carboxylic acid (XXXIII). Finally, (XXXIII) is fully deprotected with AlBr3/Et-S affording the target teicoplanin aglucon.
Assembly of the target compound: The condensation of the carboxylic acid intermediate (XXI) with the free amino group of the intermediate cyclopeptide (XXII) by means of DEPBT gives the corresponding amide (XXIII), which is cyclized by means of CsF in DMSO yielding the macrocyclic ether (XXIV). The reduction of the nitro group of (XXIV) with H2 over Pd/C affords the corresponding amino derivative (XXV).
The diastereo- and enantioselective condensation of the protected secondary amine (I) with the nitroalkene (II) by means of BuLi in toluene and in the presence of (-)-sparteine gives the (S,S)-carbamate (III) as a single diastereomer. The hydrolysis of the carbamate (III) with HCl in chloroform yields the aldehyde (IV), which is reduced with NaBH4, affording the alcohol (V). The reduction of the nitro group of (V) with Pd/C and ammonium formate gives the amine (VI), which is protected with Boc2O to provide the carbamate (VII). The reaction of (VII) with MsCl and TEA affords the corresponding mesylate (VIII), which is cyclized by means of potassium tert-butoxide in THF, yielding the protected piperidine (IX). Elimination of the Tips group of (IX) with TBAF affords the carbinol (X), which is treated with MsCl and TEA to give the mesylate (XI). The condensation of (XI) with 1,3-benzodioxol-5-ol (XII) by means of NaH in DMF yields the expected adduct (XIII), which is finally deprotected with TFA to furnish the target chiral compound.
The synthesis of intermediate (XI) as been performed as follows: The reaction of 3-benzyloxy-5-methoxystyrene (I) with K2OsO4(OH)4, (DHQ)2PHAL and BocNClNa gives the hydroxyethyl carbamate (II), which is protected with Mem-Cl, yielding (III). The reductive deprotection of (III) with H2 over Pd/C, followed by reaction with trifluoroacetic anhydride (TFAA), affords the amide (IV), which is condensed with the hydroxyethyl carbamate (V) (obtained by reaction of 3-fluoro-4-nitrostyrene (VI) with K2OsO4(OH)4, (DHQD)2PHAL and BocNClNa) by means of K2CO3, providing the diaryl ether (VII). The reduction of the nitro group of (VII) with H2 over Pd/C gives the corresponding amino group, which is converted into the phenol (IX) by reaction with tBu-ONO, BHF4, Cu2O and Cu(NO3)2. The methylation of the phenol (IX) with MeI and K2CO3 yields the corresponding ether (X), which is finally treated with K2CO3 to eliminate the trifluoroacetyl group, yielding the desired intermediate (XI).
The synthesis of intermediate (XXI) has been performed as follows: The condensation of 4-fluoro-3-nitrobenzyl bromide (XII) with the chiral dihydropyrazine (XIII) by means of BuLi and CuCN gives the chiral adduct (XIV), which is treated with TFA to yield the 4-fluoro-3-nitro-D- phenylalanine (XV). The N-protection of (XV) with Teoc-Cl gives the N-protected phenylalanine (XVI), which is condensed with the already described intermediate (XI) by means of PyBop to yield the amide (XVII). The oxidation of the primary OH group of (XVII) with DMP and NaClO2 affords the carboxylic acid (XVIII), which is cyclized to the cyclic amide (XIX). The cleavage of he protecting groups of (XIX) with HCl, followed by selective N-protection with Boc2O, provides primary carbinol (XX), which is finally oxidized with DMP and NaClO2 to give the desired carboxylic acid intermediate (XXI).
The reaction of the amino group of (XXV) with tBu-ONO, BHF4 and CuCl/CuCl2 gives the expected chloro derivative (XXVI), which is silylated at the OH group with CF3CON(Me)-Tbdms, yielding the silyl ether (XXVII). Elimination of the Mem protecting group of (XXVII) with the bromoboronate (XXVIII) affords the carbinol (XXIX), which is oxidized with DMP and NaClO2 to the corresponding carboxylic acid (XXX).
Finally, carboxylic acid derivative (XXX) is deprotected and demethylated by reaction first with TBAF and then with AlBr3 and ethyl mercaptan.