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 stereoselective introduction of carbomethoxy group was achieved by treating (-)-29 with dimethyl carbonate in the presence of potassium t-butoxide to give β-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 α-side chain and double bond at C-6 and C-9α delivered (+)-isocarbacyclin methyl-ester. The versatilaty of aldehyde 45 was also proved by the ease introduction of another ω-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 benzylide acetal forming reaction mixture. The tosylated benzylidene acetal (107) was deprotected to hydroxy tosylates by way of acid hydrolysis 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 aldehyde (92) in high yield. Thus, 92, a key intermediate for $LTA_4$ synthesis, was synthesized from 1,2,3-triol (96) through the very short reaction pathway (4 steps) with high yield using a regioselective 1,3-dioxane benzylidene acetal formation as a key step.
류코트리엔 합성에 있어서 중요한 중간체로 인식되는 메틸 5,6,7-트리히드록시 펜타노에이트 (96)를 출발물질로 하여 에폭시 알데히드 (92)를 효과적으로 합성하였다. 메틸 5,6,7-트리히드록시 펜타노에이트의 1,2-히드록시 그룹보다 1,3-히드록시 그룹이 선택적으로 아세탈이 형성된 벤질리딘 아세탈(108)을 얻기 위하여 여러가지 반응조건을 관찰하였다.
벤즈알데히드 용매에서 트리히드록시 화합물 (96)을 녹인 후 촉매량의 루이스산을 가하니 1,3-벤질리딘 아세탈 (108)이 매우 선택적으로 얻어졌다. 순수한 1,3-벤질리딘 아세탈을 토실화하는 반응은 1,3-벤질리딘 아세탈을 합성하는 과정의 반응 혼합물에 피리딘과 토실 클로라이드를 가하여 향상된 수율로 토실화된 벤질리딘 아세탈 (107)을 얻을 수 있었다. 토실화된 벤질리딘 아세탈은 메탄올 용액에서 묽은 염산을 소량 가하고 환류시키거나 오존을 통과시키면 아세탈기가 쉽게 제거 되었다. 이때 얻어지는 히드록시 토실레이트들을 메탄올 용매에서 무수 탄산 칼륨을 가하니 에폭시 알콜 (91)이 좋은 수율로 얻어졌다. 이 에폭시 알콜은 콜린즈 산화제로 산화시켜 에폭시알데히드 (92)를 얻었다. 즉, 메틸 5,6,7-트리히드록시 펜타노에이트로부터 4단계의 아주 짧은 반응공정을 거쳐 에폭시 알데히드를 아주 효과적으로 얻을 수 있었다.