合成路线1

The condensation of the acetylenic tetrahydropyranyl ether (I) with propionaldehyde (II) by means of BuLi in THF gives 6-(tetrahydropyranyloxy)-4-hexyn-3-ol (III), which by reduction with H2 over Lindlar catalyst in hexane yields compound (IV). The Swern oxidation of (IV) with oxalyl chloride in dichloromethane affords enone (V), which is condensed with the lithium enolate (VI) in THF to afford the addition keto ester (VII). Cyclization of (VII) by means of potassium tert-butoxide, followed by acylation with pivaloyl chloride gives the cyclohexenone (VIII). Elimination of the tetrahydropyranyl protecting group of (VIII) with TsOH in methanol yields the carbinol (IX), which is oxidized with oxalyl chloride and TEA in dichloromethane to afford the carbaldehyde (X). The enolization of the aldehyde group of (X) with TIPSOTf, DBU and DMAP in dichloromethane provides exclusively the (E)-enol ether (XI), which is submitted to a Sharpless' asymetric dihydroxylation using DHQ-PHN as a chiral ligand to give the chiral alpha-hydroxy aldehyde (XII). Elimination of the pivaloyl group of (XII) with N,N'-dimethylethylenediamine and potassium methoxide in refluxing benzene, followed by reprotection with TIPSCl in THF provides aldehyde (XIII). The reaction of the ketonic group of (XIII) with PhSCH(Li)TMS in THF affords the dienol silyl ether (XIV), which by condensation with 2-bromo-4,5-dihydrobenzaldehyde dibenzyl acetal (XV) by means of t-BuLi in the presence of t-BuMgCl furnishes the expected addition compound (XVI) as a single isomer. Protection of the vicinal diol of (XVI) with trimethyl borate and pyridine in benzene gives the boronic ester (XVII), which is cyclized by means of (i-PrO)2TiCl2 in dichloromethane to yield the polycyclic compound (XVIII). The hydrolysis of the boronic ester of (XVIII) with pinacol and DMAP in benzene, followed by silylation with t-Bu2SiHCl and BuLi in THF affords the cyclic silyl ether (XIX). Reduction of the ketonic group of (XIX) with DIBAL in dichloromethane, followed by silylation with TBDMS-OTf affords the silyl ether (XX), which is dihydroxylated by oxidation with O2 and light using TPP as catalyst, and desulfurized by treatment with Bu3SnH and AIBN in refluxing benzene to provide diol (XXI).

合成路线2

In a further method, the lithium acetylide of 2-(propargyloxy)tetrahydropyran (XXXIV) was alkylated with 1-bromo-3-chloropropane (XXXV) to afford chloride (XXXVI). Displacement of the Cl atom of (XXXVI) with NaCN yielded nitrile (XXXVII), which was further hydrolyzed to carboxylic acid (XXXVIII) under basic conditions. Esterification of (XXXVIII) with concomitant tetrahydropyranyl group cleavage in ethanolic H2SO4 gave hydroxy ester (XXXIX). Conversion of (XXXIX) to the corresponding mesylate, followed by treatment with KI, provided ethyl 7-iodo-5-heptynoate (XL). (R)-(+)-nopinone (XXVI) was then alkylated with the propargyl iodide (XL) in the presence of LDA to afford (XLI). Conversion of (XLI) to oxime (XLII), followed by reduction with TiCl3 and BH3•t-BuNH2, provided amino ester (XLIII). Then, partial hydrogenation of the triple bond of (XLIII) over Lindlar catalyst furnished the precursor aminoalkene ester (XLIV).

合成路线3