Chemistry

Long-Distance Stereochemistry

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Science  21 Dec 2001:
Vol. 294, Issue 5551, pp. 2433
DOI: 10.1126/science.294.5551.2433b

Cytosolic phospholipase A2 plays an important role in cell proliferation and inflammation, so there was much interest when in 1995 an inhibitor, pinnaic acid, was isolated from the bivalve Pinna muricata. The amount of inhibitor obtained was too small, however, to establish the stereochemistry of the compound. The stereochemistry of one carbon center (C-14) remained uncertain, and another (C-17) could not be assigned at all.

To resolve this issue, Carson et al. embarked on a total synthesis of pinnaic acid. At the outset, the authors assumed that the initial tentative assignment of stereochemistry of pinnaic acid (14R) was unlikely to be correct because it differed from that of the structurally related alkaloid halichlorine, another phospholipase inhibitor isolated from the sponge Halichondria okadai. Through a combination of synthesis and degradation steps, the authors synthesized pinnaic acid and determined its stereochemistry (14S, 17R) to be the same as that of halichlorine. They also found a remarkable instance of asymmetric induction during reduction of the C-17 ketone; long-range interactions between other parts of the molecule and the chiral center at C-14 led almost exclusively to the R configuration of the alcohol. The biological activity of pinnaic acid can now be pursued, and new therapeutic lead compounds can be developed and tested.—JU

Angew. Chem.Int. Ed.40, 4450; 4453 (2001).

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