The condensation of decanal (I) with silyl enol ether (II) by means of a chiral catalyst and Sn(OTf)2 in dichloromethane gives the chiral thiocarboxylic ester (III), which is treated with chlorothioformate (IV) and pyridine in refluxing dichloroethane to yield the thiocarbonic ester (V). The reduction of (V) with Bu3SnH and AIBN in refluxing toluene affords the chiral thioester (VI), which is reduced with LiAlH4 in THF to provide the alcohol (VII). The oxidation of (VII) with oxalyl chloride in DMSO/dichloromethane gives the corresponding aldehyde (VIII), which is condensed with phosphorane (IX) to yield the unsaturated ester (X). The reduction of the ester group of (X) with DIBAL in dichloromethane affords the allyl alcohol (XI), which is submitted to a Sharpless epoxidation with tert-butyl hydroperoxide (TBHP) and Ti(O-iPr)4 in the presence of diethyl D-tartrate, providing the chiral epoxide (XII). Methylation of the epoxide ring of (XII) with MeLi and CuI in ethyl ether gives the diol (XIII), which is treated with the dimethyl acetal (XIV) and Ts-OH in dichloromethane to yield the 1,3-dioxane (XV). The reductive cleavage of (XV) with DIBAL in the same solvent affords the Pmb ether (XVI), whose primary alcohol is oxidized with oxalyl chloride in DMSO/dichloromethane to provide the aldehyde (XVII). The condensation of (XVII) with phosphorane (XVIII) in refluxing THF gives the unsaturated ester (XIX).

The reduction of the ester group of (XIX) with DIBAL in dichloromethane gives the alcohol (XX), which is oxidized with TPAP and NMO in the same solvent, yielding the corresponding aldehyde (XXI). The condensation of (XXI) with phosphorane (XVIII) in refluxing THF affords the diunsaturated ester (XXII), which is reduced with DIBAL as before to provide the alcohol (XXIII). The oxidation of (XXIII) with TPAP and NMO as before gives the aldehyde (XXIV), which is condensed with the silyl enol ether (II) by means of Sn(OTf)2, Bu2Sn(OAc)2 and a chiral catalyst to yield the unsaturated thioester (XXV). The reaction of the OH group of (XXV) with Tes-OTf and lutidine in dichloromethane affords the silyl ether (XXVI), which is reduced with DIBAL in the same solvent to provide the corresponding aldehyde (XXVII).

The condensation of aldehyde (XXVII) with phosphorane (XVIII) in refluxing THF gives the triunsaturated ester (XXVIII), which is reduced with DIBAL in dichloromethane to yield the primary alcohol (XXIX), which is oxidized with TPAP and NMO, affording the aldehyde (XXX). Further oxidation of (XXX) with NaClO2 in tert-butanol/water provides the carboxylic acid (XXXI), which is esterified with the chiral alcohol (XXXII) by means of DCC and DMAP in refluxing dichloromethane to give the ester (XXXIII). Elimination of the silyl protecting groups of (XXXIII) with HCl in THF yields the dihydroxy compound (XXXIV). Oxidation of the secondary and primary OH groups of (XXXIV) with DMP and NaClO2 affords the corresponding oxo acid (XXXV), which is finally treated with BCl3 in dichloromethane to eliminate the Pmb protecting groups and afford the target compound.

Synthesis of intermediates: Iodinated pivalate (X): The condensation of 3-iodo-2-methyl-2-propenal (I) with the silylated enol ether (II) by means of Zr(O-tBu)4 and 3,3'-I2-BINOL in toluene gives the iodopentenoic acid (III), which is treated with Tips-Cl and imidazole to yield the silyl ether (IV). The reduction of (IV) by means of DIBAL in dichloromethane affords the 5-iodopenten-1-ol (V), which is oxidized by means of (COCl)2 in DMSO/dichloromethane to provide the aldehyde (VI). The Wittig condensation of (VI) with phosphorane (VII) in refluxing THF leads to the heptadienoic ester (VIII), which is reduced with DIBAL in dichloromethane giving the primary alcohol (IX). Finally this alcohol is esterified pivaloyl chloride and pyridine to affords the target iodinated pivalate (X).

Alkenylboronic acid (XV): The intermediate tetradecyl aldehyde derivative (XII) has been obtained by an already reported sequence (see scheme no. 23979101a, intermediates (I) to (XVII)) starting from decanal (XI). The reaction of aldehyde (XII) with CBr4 and PPh3 in dichloromethane gives the dibromovinyl derivative (XIII), which is treated with BuLi and Me-I in THF to yield the alkyne (XIV). Finally, this compound is condensed with catecholborane to provide the target alkenylboronic acid (XV).

Synthesis of the target compound: The condensation of the iodinated pivalate (X) with the alkenylboronic acid (XV) by means of TlOEt and Pd(PPh3)4 in hot THF gives the adduct (XVI), which is treated with DIBAL in dichloromethane to eliminate the pivaloyl group and yield the primary alcohol (XVII). The oxidation of (XVII) with MnO2 affords the aldehyde (XVIII), which is oxidized to the carboxylic acid (XIX) by means of NaClO2 in tert-butanol/water. The esterification of acid (XIX) with alcohol (XX) by means of DCC and DMAP in refluxing dichloromethane affords the ester (XXI), which is desilylated by means of HCl in THF to provide the dihydroxy compound (XXII). The oxidation of diol (XXII) first with DMP and then with NaClO2 leads to the ketoacid (XXIII), which is finally debenzylated by a treatment with BCl3 in dichloromethane to give the target Khafrefungin.