Isocarbacyclins

Table I shows the composition of lipo-PGEj. Oleic acid was used to improve the stability of PGEj. Glycerol was added to make the water phase isotonic. Isocarbacyclin, a prostacyclin derivative (TEI9090), was incorporated into the lipid microspheres (lipo-PGI2) in a similar composition except for the use of oleic acid.

Inoue, K., Aoki, Y., Hayashi, M., Kitahara, S., Tanabe, H., Kiyoki, M., and Araki, H., Ex vivo anti-platelet effects of isocarbacyclin methyl ester incorporated in lipid microspheres in rabbits, Arzneim-Forsch/Drug Research, 1995, 45, 980-984. 

Two di-tritiated isocarbacyclin methyl esters 116 and 117 in the title have been synthesized95 from (Z)-olefinic precursors 118 and 119 at the >-side chain by catalytic hydrogenation with tritium gas (equations 44 and 45). The therapeutic candidates for cardiovascular deseases96, 116 and 117, were required for preclinical studies and for use in RIA analysis. 

By analogy with the intramolecular insertion of phenylthiocarbenes, the reaction of (oo-oxido)diazoalkanes 93 resulted in the formation of cycloalkenes 94.38 However, the reaction was proven to proceed not via a carbene route b but a nitrene route a as shown in Scheme 26. The nitrene route is supported by the formation of heterocyclic products 98 and 99.39 This insertion reaction was used in the cydization step to the cyclopentene ring formation of isocarbacycline 97.40... 

More recently, the total synthesis of isocarbacyclin, a therapeutically useful agent against numerous vascular diseases, was reported by Saito et al. [56]. Again, the crucial cycloaddition step was carried out using a stoichiometric amount of Co2(CO)8. The reaction was completed within 3h and gave 78% yield of the desired cyclopentenone (Eq. 8). 

A model which rationalizes the sense of asymmetric induction has been proposed73. The alkenyl-sulfoximines 4 and 6 are useful intermediates in the synthesis of biologically active carbacyclins and isocarbacyclins 75- 77,78. 

We have developed asymmetric syntheses of isocarbacyclin [3] (Scheme 1.3.2) and cicaprost [4] (Scheme 1.3.3) featuring a Cu-mediated allylic alkylation of an allyl sulfoximine [5-7] and a Ni-catalyzed cross-coupling reaction of a vinyl sulf-oximine [8-10], respectively, transformations that were both developed in our laboratories. The facile synthesis of an allyl sulfoximine by the addition-elimination-isomerization route aroused interest in the synthesis of sulfonimidoyl-sub-stituted aiiyititanium complexes of types 1 and 2 (Fig. 1.3.2) and their application as chiral heteroatom-substituted allyl transfer reagents [11]. 

Scheme 1.3.2 Asymmetric synthesis of isocarbacyclin by the vinyl-allyl sulfoximine route.

BINOL-Ti catalysis is also applicable to carbonyl-ene reaction with formaldehyde or vinylogous and alkynylogous analogs of glyoxylates in the catalytic desymmetrization (vide infra) approach to the asymmetric synthesis of isocarbacycline analogs (Scheme 8C.7) [24],... 

Minagawa, T., Kohno, Y., Suwa, T., and Tsuji, A. (1994) Entrapping ef ciency of an oil-in-water emulsion containing isocarbacyclin methyl ester (TEI-9090) in dog and human BbBarm. Res., 11 1677-1679. 

Isocarbacyclin (148) also exhibited fairly powerful inhibition of platelet aggregation (83TL3493). Therefore, chiral synthesis of a useful intermediate 147 (84TL1067) for (+)-isocarbacyclin (148) was tried with success (87CC269). 

Cyclization of l,b)-dihalo [or bis(tosyloxy)] alkanes with methyl methylthiomethyl sulfoxide in the presence of a base such as Bu"Li or KH gave three-, four-, five- and six-membered 1-methylsulfinyl-l-methylthiocycloalkanes that are easily converted to the corresponding ketone by acid hydrolysis. This is applicable to the formation of the key intermediate for the synthesis of isocarbacyclin, a potent prostacyclin analog. ... 

Mandai, T., Matsumoto, S., Kohama, M., Kawada, M., Tsuji, J., Saito, S., Moriwake, T. A new, highly efficient method for isocarbacyclin synthesis based on tandem Claisen rearrangement and ene reactions. J. Org. Chem. 1990, 55, 5671-5673. 

Mandai, Saito and cowoikers recently described a new synthesis of isocarbacyclin, which features a crucial one-pot, three-step transformation tandem tertiary allyl vinyl ether formation, Claisen rearrangement, and ene cyclization led from alcohol (57) directly to bicyclo[3.3.0]octane (59 Scheme 10). Clearly, due to improvements in the preparation of the allyl vinyl ether moiety, there is a trend even in the classical CHaisen rearrangement to taclde more complex structural challenges successfully. 

An elegant application of the reaction of vinyllead triacetates with p-ketoesters was described in a convergent synthesis of (+)isocarbacyclin, an analogue of prostacyclin (PGI2). This synthesis involved the vinylation of a benzyl p-ketoester. i l The benzyl ester was later removed under conditions compatible with the other functionalities of the molecule. 

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