合成路线1

Deprotonation of 2,2,6-trimethyl-1,3-dioxin-4-one (I) by means of LDA, generated from BuLi and (i-Pr)2NH, in THF, followed by condensation with 1-cyclopentyl-3-(trimethylsilyl)-2-propyn-1-one (II) affords the protected propargylic alcohol (III), which is then desilylated to compound (IV) by treatment with CsF in MeOH . Sonogashira coupling of propargylic alcohol (IV) with 4-bromo-2,6-diethylpyridine (V) in the presence of PdCl2(PPh3)2, CuI and (i-Pr)2NH in DMF at 90 °C provides the pyridylbutynol adduct (VI), which upon catalytic hydrogenation over Pd(OH)2 in EtOH affords the saturated alcohol (VII). Subsequent lactonization of (VII) in the presence of K2CO3 in MeOH gives rise to the perhydropyran-2,4-dione (VIIIa). Finally, racemic keto lactone (VIIIa) is submitted to reductive aldol condensation with 5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde (IX) in the presence of BH3·Me2NH in MeOH, and resolved by means of chiral HPLC .
In an alternative method, optically pure β-hydroxyacid (X) is activated as the corresponding imidazolide by means of CDI , and optionally, DMAP in MTBE or THF, followed by condensation with magnesium ethyl malonate (XIa) or with potassium ethyl malonate (XIb) in the presence of MgCl2 , to give, after acidic decarboxylation, the keto hydroxy ester (XII). Subsequent lactonization of hydroxy ester (XII) in the presence of K2CO3 in MeOH yields the chiral perhydropyran-2,4-dione derivative (VIIIb). Finally, (R)-keto lactone (VIIIb) , or its dibenzoyl-L-tartrate salt , is submitted to reductive aldol condensation with the triazolopyrimidine aldehyde (IX) in the presence of BH3·pyr in MeOH , THF/MeOH or 2-MeTHF/MTBE .