The synthesis of the carboxylic acid intermediate (VIII) has been performed as follows: The reaction of D-valine (I) with benzyl chloroformate and NaHCO3 gives the protected valine (II), which is esterified with pentafluorophenol and EDAC to yield the activated ester (III). The condensation of (III) with the lithium enolate of methyl acetate (IV) affords the beta ketoester (V), which is stereoselectively reduced with KBH4 and crystallized to afford the desired enantiomeric beta hydroxyester (VI). The silylation of (VI) with Tips-OTf and lutidine provides the silyl ether (VII), which is hydrolyzed with NaOH to give the desired carboxylic acid intermediate (VIII). The synthesis of the activated ester intermediate (XV) has been performed as follows: The reaction of L-valine (IX) with NaNO2 and H2SO4 gives the hydroxyacid (X), which is esterified with allyl bromide (XI) and K2CO3 to yield the allyl ester (XII). The condensation of (XII) with the intermediate (VIII) by means of EDAC and DMAP affords the adduct (XIII), which is treated with Pd(PPh3)4 to provide the carboxylic acid (XIV). Finally, this compound is esterified with C6F5-OTf to give the activated ester intermediate (XV).

The hydrogenolysis of the benzyloxycarbonyl protecting group of tetrapeptide (XVI) with H2 over Pd/C gives peptide (XVII) with a free amino group, which is condensed with the activated ester intermediate (XV) by means of DIEA and DMAP to yield the fully protected linear precursor (XVIII). The mild cleavage of the SEM ester by means of MgBr2 affords the carboxylic acid (XIX), which is hydrogenolyzed with H2 over Pd/C to provide linear peptide (XX) with a terminal amino group. The cyclization of (XX) promoted by HATU gives the protected macrocyclic peptide (XXI).

The two remaining protecting groups of (XXI) are simultaneously removed by treatment with HCl in ethyl acetate to give the free cyclopeptide (XXII). Finally, this compound is condensed with (S)-lactoyl-S-prolyl-S-(N-methyl)leucine (XXIII) by means of DEPBT and DIEA to yield the target cyclopeptide (-)-tamandarin B.

The synthesis of the carboxylic acid intermediate (VIII) has been performed as follows: The reaction of D-valine (I) with benzyl chloroformate and NaHCO3 gives the protected valine (II), which is esterified with pentafluorophenol and EDAC to yield the activated ester (III). The condensation of (III) with the lithium enolate of methyl acetate (IV) affords the beta ketoester (V), which is stereoselectively reduced with KBH4 and crystallized to afford the desired enantiomeric beta hydroxyester (VI). The silylation of (VI) with Tips-OTf and lutidine provides the silyl ether (VII), which is hydrolyzed with NaOH to give the desired carboxylic acid intermediate (VIII). The synthesis of the activated ester intermediate (XV) has been performed as follows: The reaction of L-valine (IX) with NaNO2 and H2SO4 gives the hydroxyacid (X), which is esterified with allyl bromide (XI) and K2CO3 to yield the allyl ester (XII). The condensation of (XII) with the intermediate (VIII) by means of EDAC and DMAP affords the adduct (XIII), which is treated with Pd(PPh3)4 to provide the carboxylic acid (XIV). Finally, this compound is esterified with C6F5-OTf to give the activated ester intermediate (XV).

The hydrogenolysis of the benzyloxycarbonyl protecting group of tetrapeptide (XVI) with H2 over Pd/C gives peptide (XVII) with a free amino group, which is condensed with the activated ester intermediate (XV) by means of DIEA and DMAP to yield the fully protected linear precursor (XVIII). The mild cleavage of the SEM ester by means of MgBr2 affords the carboxylic acid (XIX), which is hydrogenolyzed with H2 over Pd/C to provide linear peptide (XX) with a terminal amino group. The cyclization of (XX) promoted by HATU gives the protected macrocyclic peptide (XXI).

The two remaining protecting groups of (XXI) are simultaneously removed by treatment with HCl in ethyl acetate to give the free cyclopeptide (XXII). Finally, this compound is condensed with (S)-lactoyl-S-prolyl-S-(N-methyl)leucine (XXIII) by means of DEPBT and DIEA to yield the target cyclopeptide (-)-tamandarin B.