Isocarbacyclin synthesis

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. 

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],... 

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, 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. 

An intramolecular ketyl/alkyne coupling method has been employed in a synthetic approach to erigerol [91], wherein a reasonably complex tricyclic system was created in high yield (Eq. 80), and in the synthesis of isocarbacyclin (Eq. 81) [92]. Finally, the analogous >-endo cyclization process has also been applied with some success [83], creating functionalized cyclooctenols in modest yield (Eq. 82). 

Alkynic aldehydes likewise undergo intramolecular coupling to generate five- and six-membered ring carbocycles. This protocol has been utilized as a key step in the synthesis of isocarbacyclin (eq TA) Sml2 was found to be superior to several other reagents in this conversion. 

Synthesis of C-labeled isocarbacyclin methyl ester derivative... 

With these results in mind, we were attracted to two key points. The first was that building the complex bicyclic core system (20), with the four stereocenters as desired, could be achieved by diene-ene [2+2+1] cycloaddition of bis-diene (21) followed by reduction. The second attractive point was the diversification that could be achieved by cross metathesis at a late stage to get different analogs from the same bicyclic core (20). As a result, a retro-synthesis was conceived (Scheme 1) of isocarbacyclin methyl ester, or clinprost (3), having only nine steps.The first part of the synthesis, and most difficult part, was to generate bis-diene (21). 

The addihon of (PhMe2Si)2CuLi to aldehydes has been utilized in the elegant synthesis of isocarbacyclin (eq 6). ... 

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