合成路线1

Protection of ethyl lactate (XXX) with tert-butyldimethylsilyl chloride in DMF in the presence of imidazole provides derivative (XXXI), which is then converted into dipeptide (XXXII) by first hydrolysis with LiOH in THF/H2O followed by coupling with L-proline methyl ester (X) by means of DCC, HOBt and NMM. Next, hydrolysis of the methyl ester of (XXXII) with LiOH in THF/H2O yields carboxylic acid (XXXIII). Esterification of Z-D-N-Me-Leu (XXXIV) with 2-(trimethylsilyl)ethanol (XXXV) by means of EDCI, DMAP and Et3N in DMF furnishes leucine derivative (XXXVI), whose Z protecting group is removed by hydrogenation over Pd/C in MeOH/AcOEt to afford secondary amine (XXXVII). Coupling of carboxylic acid (XXXIII) with amine (XXXVII) is then performed by means of BOPCl, Et3N. Treatment with tetrabutylammonium fluoride in DMF allows protecting group removal to provide carboxylic acid derivative (XXXVIII), which is then attached to macrocycle (XXIX) by means of BOP and NMM in CH2Cl2 to furnish the target didemnin.