K-76 is a recently isolated fungal metabolite which acts as a specific inhibitor of the complement enzyme, C5 convertas. As such, K-76 exhibits a remarkable ability to mediate the inflammatory immune response. Good in vitro activity of K-76 has been demonstrated in antipglomuleronephritis, anti-hepatistis, and anti-tumor screens. We sish to devise an efficient means for the laboratory synthesis of K-76 and of certain analogues. Our primary idea makes use of an interesting but little studied variation of the Claisen rearrangement whereby a hindered aryl allyl ether rearranges to an ortho allyl phenol product without inversion of the allyl grtoup. We wish to study this key step, both in the context of a K-76 synthesis and as a general organic synthesis method. In addition to devising synthetic routes to K-76, we have also postulated a potential mode of action, explaining how the molecule might bind to an enzyme. We wish to test our hypothesis by preparing specifically modified K-76 analogues which we expect to have different binding properties. Should our hypothesis prove correct, we have designed a simple molecule which should be readily accessbile synthetically, and which should show the desired biological activity.
