The synthesis of the C-28 through C-38 segment of the marine natural product okadaic acid was accomplished employing a highly enantio-and diasteroselective aldol condensation reaction of a chii vinylogous urethane enolate. The stereocenter at C-29 was addressed utilizing a diastereoselective hydroboration reaction, 0 1998 Elsevier Science Ltd. All rights reserved.
Okadaic acid 1 is a marine natural product isolated from the Halichondria okadaia and Halichondia melanodocia.~ Currently, there are two total syntheses of okadaic acid which, in contrast to our approach, begin with carbohydrate starting materials.2 Our route to okadaic acid relies on the generation of chirality via auxiliary driven enantioselection. The previous three papers described the efficient synthesis of the three segments representing C-l through C-26 of okadaic acid 1. The key carbon-carbon bond forming reactions illustrated in these papers employ either a stereoselective aldol, acylation-reduction or alkylation protocol utilizing chiral nonracemic vinylogous urethane (VU) enolates. okadaic acid, 1 Scheme 1 This paper will provide an account of our recent effort towards the preparation of the spiroketal 19 which embodies C-28 through C-38 of okadaic acid 1 .3 The syn-anti stereochemical triad (C-3 1 to C-29) will be addressed by incorporating two stereochemical determining reactions. An enantioselective syn aldol condensation using a chiral pyrrolidine auxiliary will establish the C-30/C-31 stereocenters while a diastereoselective hydroboration will configure the third chiral center at C-29.
Recent studies from the Schlessinger group have described the application of VU enolatcs in syn selective aldol condensation reactions .4 Application of this technology will provide a facile entry into the spiroketal fragment 19 (C-28 to C-38) of okadaic acid. Condensation of the VU enolate, prepared from 2 and LDA, with methacrolein provided the syn vinylogous urethane lactone (VUL) 3 with high levels of enantio-and diastereoselectivity.