Optically active 13,y-disubstituted-ct-methylene-y-butyrolactones were synthesized by palladium(II)-catalyzed cyclization reactions of homochiral allylic 2-alkynoates. The reaction was applied to the total synthesis of methylenolactocin in both enantiomeric forms. G. ZHU and X. Lu our work we developed an efficient way for the enantiospecific synthesis of the 13,~,-disubstituted-c~-methyleney-butyrolactones s and report here a successful enantiospecific synthesis of both enantiomers of methylenolactocin as shown in the retrosythetic route in Scheme I. COOH %--4 i O:~O)'""C5H11 (-)-methylenolactocin > CH2X Scheme I Ill // O~L'~O J'"'IC5HI 1 ,// >. oS' ""cSHl l optically active
RESULTS AND DISCUSSION
In our synthetic strategy (Scheme II), the starting material, optically active allylic alcohol is easily available from Sharpless asymmetric epoxidation of 2-octen-l-ol and subsequent reduction. 9 The ester (S)-3 was obtained by esterification in the presence of DCC and a catalytic amount of DMAP (70%). The palladiumcatalyzed cyclization of allylic propynoate (S)-3 was carried out as follows. To a solution of CuBr2, LiBr and Pd(OAc)2 (5 retool%) in HOAc, the ester (S)-3 was added, then the mixture was stirred at rt. After the reaction was complete, the cyclic products 4 were purified by column chromatography on silica gel in 90% yield with 71:29 (trans:cis) diastereoselectivity. While difficulties were encountered in the direct separation of (3R,4S)-4 from its diastereomer, the two diastereomers could be separated by column chromatography on silica gel after further transformation of 4 to 5.
Since the basic skeleton for methylenolactocin was constructed, we focused our attention on the further elaboration of the C-Br bond into the natural product. Due to the base sensitive lactone ring, the hydrolysis condition for the alkyl bromide unit is critical, e g, the lactone ring was perfectly opened in many ways using NaOH, LiOH or NaI-ICO3 as bases. Finally according to Dibble's method ~° (but dioxane was replaced by DMSO), the hydrolysis of 4 in refluxing DMSO/H20 solution with CaCO3 provided the c~-bromomethylene 13hydroxymethyl-y-butyrolactone (3S, 4S)-5 together with its diastereomer (3R, 4R)-5 in 55% yield, which were easily separated by column chromatography on silica gel. Reduction of the vinyl bromide of (3S, 4S)-5 with Zn-Ag couple under Heathcock's condition ~ afforded the (3S, 4S)-6 in 90% yield. The direct oxidation of the hydroxyl group in 5 or 6 to a carboxyl group failed under many oxidation conditions. The exocyclic carboncarbon double bond was believed to make the oxidation reaction complex. Protection of the exocyclic double bond using PhSH (91%), ~2 followed by oxidation of the hydroxyl group with PDC in DMF solution 13 did afford the 13-carboxyl lactone (3R, 4S)-8.
Finally, after deprotection, TM (-)-methylenolactocin was