Total synthesis of (+/-)-phomactin B2 via an intramolecular cyclohexadienone annulation of a chromium carbene complex.

Phomactins are novel platelet activating factor (PAF) antagonists isolated from the culture of marine fungus Phoma sp.1 Members of the phomactin family share a unique [9.3.1] pentadecane ring system, and their biosynthetic pathway shares a branchpoint with the taxane family of natural products.1,2 Substantial synthetic efforts have been described in the literature toward the synthesis of several phomactins,3 but of the 11 known members of the phomactin family, total syntheses have only been reported for phomactins A, D, and G.4 The nexus to all of the published retrosynthetic plans, realized or not, is the construction of the six-membered ring prior to the 12-membered ring. We report here a different approach to the phomactins that involves the simultaneous assembly of both the sixand 12-membered rings via an intramolecular cyclohexadienone annulation of a chromium carbene complex and which is rendered to practice in a total synthesis of (()-phomactin B2. The retrosynthetic plan for the synthesis of phomactin B2 presented in Scheme 1 targets the cyclohexadienone 2 as a key intermediate. Access to 2 was envisioned to be possible from the thermolysis of carbene complex 3 which should initiate loss of a carbon monoxide ligand and subsequently an intramolecular reaction of the carbene complex with the alkyne function to generate a cyclohexadienone. The carbene complex 3 was in turn envisioned to be preparable from geraniol. The cyclohexadienone annulation of chiral progaryl ether 6 is known to generate significant 1,4-asymmetric induction in favor of the diastereomer 7 (Scheme 2).5 We have recently reported the first examples of an intramolecular cyclohexadienone annulation with the finding that moderate to good yields of 9 can be obtained when the number of methylenes in the tether of carbene complex 8 is eight or greater.3 Since there are nine carbons in the macrocyclic bridge in the phomactins, the propitious model studies with 8 set the stage for the enactment of the strategy in Scheme 1. The first stage of the synthesis involves the preparation of the carbene complex 3 which begins with geraniol and its conversion to the known bromide 10 in four steps in 49% overall yield.6 Three carbons were then introduced via coupling with 1-trimethylsilyl propargyl lithium, which after deprotection gives 11 in 71% yield (Scheme 3). The E-vinyl iodide in intermediate 12 was then installed by a Negishi carbometalation.7 The control of this stereochemistry is important since the model studies with carbene complex 8 reveal that the E-isomers are much more efficient than their Z-counterparts.3 The terminal alkyne unit is readily installed via oxidation of the allylic alcohol 12 and then reaction with ethynyl Grignard. The resulting alcohol is protected in two forms such that carbene complexes 3a and 3b can both be evaluated. The carbene complexes are prepared by the Fischer method,8 but the generation of a dianion from 14 can be problematic. To prevent metal/halogen exchange prior to deprotonation of the alkyne, phenyllithium is used as base prior to the addition of n-BuLi. Carbene complex 3a could be obtained in reproducible yields of 50% over a range of scales if the chromium carbonyl and alkynyl iodide 14 were mixed prior to the addition of phenyllithium. If the dianion is generated and then reacted with Cr(CO)6, the yields of 3a are unpredictable and range from 0 to 50%. The intramolecular cyclohexadienone annulation of complex 3a gave a mixture of the diastereomers 2a and 15a in a ratio that was Scheme 2