Coupling of (S)-1-(2-furyl)ethanol (I) with the silylated (S)-3-hydroxybutyric acid (II) afforded ester (III). The silyl protecting group of (III) was then removed by treatment with tetrabutylammonium fluoride to provide the intermediate hydroxy ester (IV). Keto acid (VI) was prepared from the protected furylethanol (V) by oxidative cleavage of the furan ring with N-bromosuccinimide, and further oxidation of the intermediate aldehyde with sodium chlorite. Coupling of keto acid (VI) with hydroxy ester (IV) furnished the corresponding ester (VII). Ketone reduction in (VII) with Zn(BH4)2 yielded alcohol (VIII), which was subsequently protected as the methoxymethyl ether (IX). The PMB group of (IX) was then deprotected by treatment with DDQ to give alcohol (X). Oxidative cleavage of the furan ring of (X) as above gave rise to keto acid (XI). Cyclization to produce the macrolactone (XII) was achieved via activation with trichlorobenzoyl chloride.

Borohydride reduction of the 14-keto group of (XII) produced a mixture of the desired alcohol (XIV) and its epimer (XV). Inversion of the configuration of the undesired alcohol (XV) was carried out by Mitsunobu coupling with formic acid, followed by methanolysis of the resulting formate ester (XV) with MeOH and Et3N. The MOM protecting group of (XIV) was finally cleaved by treatment with trifluoroacetic acid.

Coupling of (S)-1-(2-furyl)ethanol (I) with the silylated (S)-3-hydroxybutyric acid (II) afforded ester (III). The silyl protecting group of (III) was then removed by treatment with tretrabutylammonium fluoride to provide the intermediate hydroxy ester (IV). Keto acid (VI) was prepared from the protected furylethanol (V) by oxidative cleavage of the furan ring with N-bromosuccinimide, and further oxidation of the intermediate aldehyde with sodium chlorite. Coupling of keto acid (VI) with hydroxy ester (IV) furnished the corresponding ester (VII). Ketone reduction in (VII) with Zn(BH4)2 yielded alcohol (VIII), which was subsequently protected as the methoxymethyl ether (IX). The PMB group of (IX) was then deprotected by treatment with DDQ to give alcohol (X). Oxidative cleavage of the furan ring of (X) as above gave rise to keto acid (XI). Cyclization of (XI) to produce the macrolactone (XII) was achieved via activation with trichlorobenzoyl chloride. The MOM protecting group of (XII) was finally cleaved by treatment with trifluoroacetic acid.

The carboxylic acid intermediate (V) has been obtained as follows: The kinetic optical resolution of racemic 1-(2-furyl)ethanol (I) using the Sharpless asymmetric epoxidation reagent gives the (S)-isomer (II), which is protected with Pmb-Cl and NaH, yielding the ether (III). The oxidation of the furan ring of (III) with NBS in acetone affords the aldehyde (IV), which is finally converted to the desired acid intermediate (V) by oxidation with NaClO2. The reaction of methyl 3(S)-hydroxypropionate (VI) with Tbdms-Cl and imidazole gives the silylated hydroxyester (VII), which is hydrolyzed with NaOH in methanol, yielding the corresponding carboxylic acid (VIII). The esterification of acid (VIII) with alcohol (II) by means of DCC, DMAP and CSA affords the ester (IX), which is desilylated by means of TBAF in THF to provide the beta-hydroxyester (X). The esterification of intermediate carboxylic acid (V) with alcohol (X) by means of DCC, DMAP and CSA gives the expected ester (XI), which is reduced at its ketonic group with Zn(BH4)2 to yield the hydroxy compound (XII). The protection of the OH group of (XII) with Mom-Cl and DIEA affords the methoxymethyl ether (XIII), which is selectively deprotected with DDQ to provide the hydroxy compound (XIV). The oxidation of the furan ring of (XIV) with NBS as before gives the aldehyde (XV), which is oxidized with NaClO2 to yield the carboxylic acid (XVI). The macrolactonization of (XVI) by means of trichlorobenzoyl chloride, TEA and DMAP in hot toluene affords the protected macrolactone (XVII), which is finally deprotected with TFA in dichloromethane to provide the target macrocyclic compound.

The optical resolution of the racemic methyl heptenoate (I) by means of lipase Amano P gives a mixture of unreacted (4R,5S)(I) and the deacetylated (4S,5R)(II), which is easily separated. The reaction of (4R,5S) (I) with K2CO3 in methanol yields the chiral alcohol (4R,5S)(II), which is esterified with 3(S)-(tert-butyldimethylsilyloxy)butyric acid (III) by means of DCC, DMAP and CSA to afford the expected ester (IV). The desilylation of (IV) with Ac-OH in THF/water provides the hydroxyester (V). At the same time, the protection of the alcohol (4R,5S)(II) with Tbdms-Cl and imidazole gives the silyl ether (VI), which is hydrolyzed with NaOH in methanol/water to yield the carboxylic acid (VII). The esterification of the alcohol group of (V) with the carboxylic acid (VII) by means of DCC, DMAP and CSA gives the adduct (VIII), which is desilylated by means of Ac-OH in aqueous THF to yield the hydroxyester (IX). The enzymatic hydrolysis of the methyl ester group of (IX) by means of Lipase OF-360 affords the hydroxyacid (X), which is submitted to macrolactonization by means of 2,4,6-trichlorobenzoyl chloride, TEA and DMAP in toluene to provide the protected macrolactone (XI). Finally, this compound is debenzylated by means of AlCl3 in m-xylene to give the target Macrosphelide A.