Formal total synthesis of isocarbacyclin and an efficient synthesis of $LTA_4$ intermediate

Abstract

A new chiral synthetic route to(+)-isocarbacyclin methyl ester (24) starting from tricyclo [3.3.0.$0^{2,8}$]octan-3-one ((-)-29) was studied. Regio-and stereoslective introduction of carbomethoxy group was achieved by treating (-)-29 with dimethyl carbonate in the presence of potassium t-butoxide to give $\beta$-ketoester (-)-38. Upon treatment of (-)-38 with acetic acid and conc. sulfuric acid, the oxygen functionality was introduced with concommitant opening of the cyclopropane ring to produce (+)-39. Subsequent reduction of (+)-39 with $NaBH_4$ proceeded with excellent stereoselectivity to give (+)-40. Protection of the alcohol (+)-40 as its THP-ether followed by deacetylation afforded the alcohol 42. Alcohol 42 was converted into the aldehyde 45, a key intermediate for isocarbacyclin synthesis, by a three step sequence of reactions: TBDPS protection of the hydroxyl group, reduction of the methoxycarbonyl group, and Collins oxidation. The aldehyde 45 was converted to the another key intermediate 36 by combination of Horner-Emmons reaction and Yamamoto reduction. Finally, construction of $\alpha$-side chain and double bond at C-6 and C-9$\alpha$ delivered (+)-isocarbacyclin methyl-ester. The versatilaty of aldehyde 45 was also proved by the ease introduction of another $\omega$-side chain. 1,3-Dioxane benzylidene acetal (108) was obtained regioselectively from 1,2,3-triol (96) in benzaldehyde in the presence of Lewis acids such as $BF_3Et_2O$, $FeCl_3$ etc. The 1,3-dioxane bebzylidene acetal was tosylated in one-pot reaction by simple addition of pyridine and p-toluenesulfonyl chloride to the benzylidene acetal (107) was deprotected to hydroxy tosylates by way of acid hydrolys is or oxidative cleavage of benzylidene acetal with ozone. The resulting hydroxy tosylates were cleanly transformed to (5S, 6R)-trans-epoxy alcohol (91) by base treatment in methanol. Finally, (5S, 6R)-trans-epoxy alcohol was oxidized by Collins reagent to give (5S, 6R)-trans-epoxy alde...