Total Synthesis of the CP Molecules CP-263,114 and CP-225,917— Part 1: Synthesis of Key Intermediates and Intelligence Gathering

Abstract

The CP molecules, 114 (1, Scheme 1) and 917 (2), exemplify architectures of unprecedented molecular connectivity and complexity and possess intriguing biological activities. Isolated from an unidentified fungal species by a group at Pfizer (Croton, USA), [1] these substances (absolute configuration unknown) exhibit impressive cholesterol-lowering properties through inhibition of squalene synthase. [1,2] Furthermore, they inhibit farnesyl transferase, an enzyme implicated in cancer, and as such they stand as leads to potential drug candidates for cancer chemotherapy. [1,3] The daunting molecular frameworks coupled with the array of sensitive functionalities present within these structures amount to a formidable synthetic challenge to which synthetic chemists have already begun to respond. [4] In this and the following communication [5] we recount our studies that led to the successful completion of the total synthesis of the CP molecules (1 and 2, racemic), in which a number of novel strategies and cascade reactions were discovered and developed. We begin here with the description of the overall strategy, the construction of a key intermediate (27, see Scheme 2), and of two unsuccessful, and yet highly useful in terms of intelligence gathering, attempts to reach the CP molecules 1 and 2.The key strategic bond disconnections and retrosynthetic blueprint shown in Scheme 1 serve as a conceptual overview of our synthetic rationale. Because of the known conversion of 2 into 1 under anhydrous acid catalysis [1] and the inability of 1 to generate 2 under aqueous acidic conditions [1] it seemed more prudent to target 2. However, the hope of transforming 1 to 2 under basic conditions (for a mechanistic rationale of this expectation see Scheme 2 in the following communication) [5] led us to accept that reaching either of the CP molecules was an opportunity to access the other as well. We soon discovered that seemingly logical routes to 1 or 2 from the intermediate compound 3 (Scheme 1) were plagued with countless unpredictable failures, which presumably arose from the unique peculiarities of the CP skeleton and its sensitive functionalities. Herein we report the lessons learned from two such expeditions. Proper implementation of novel chemistry harvested as a result of these synthetic blockades and explorations finally culminated in a fine-tuned synthetic stratagem capable of effectively addressing these issues.Diverse model studies aimed at deconvoluting this synthetic maze pointed towards the use of key intermediate 27 as a beachhead from which all further synthetic tactics would diverge (Scheme 2). Notable among the envisioned operations of the forward sequence en route to compound 27 were: 1) the intramolecular Diels ± Alder reaction of the prochiral precursor 4 casting the basic elements of the bicyclic core of the CP molecules, [6] 2) stereoselective fastening of the ªupperº side chain by using substrate-directed dithiane chemistry, [7] 3) the installment of the anhydride moiety onto the periphery of the bicyclic CP...

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