Total synthesis of the CP-molecules and the bissorbicillinoids: How endeavors in total synthesis lead to the invention, discovery and development of new synthetic reactions, technologies, and concepts in organic chemistry.

摘要

CP-263,114 and CP-225,917, isolated from an unidentified fungus by Pfizer scientists in 1997, inhibit squalene synthase and ras farnesyl transferase, and as such, represent important new leads for cholesterol-lowering and anticancer drugs. Nature molded within these structures an exotic display of delicate and rare functionalities which, for a time, beckon to synthetic chemists worldwide. The total synthesis of these compounds was finally accomplished in April of 1999 after a relentless campaign through a daunting synthetic labyrinth plagued with manifold and unexpected obstacles. The first total syntheses of these compounds (racemic) was also accompanied by numerous discoveries, cascade reactions and new synthetic technologies among which the following are, perhaps, most notable: (a) the design and execution of a cascade reaction involving no less than seven steps traversing through previously unknown chemical entities to construct the fused maleic anhydride moiety; (b) the enlistment of another tandem sequence predicated on the ring-chain tautomerization of hydroxy ketones to sculpt the γ-hydroxy lactone moiety onto the bicyclic skeleton; (c) development of a mild and effective method for the construction of extremely hindered diazoketones using acyl mesylates; (d) a new paradigm for the construction of novel heterocycles; (e) a new method for the one-carbon homologation of hindered aldehydes; (f) the daring and counter-intuitive conversion of the structurally robust CP molecule 1 into its hydrated relative CP molecule 2 passing through a multiply-charged intermediate in yet another cascade sequence; (g) new methods for the synthesis of amino sugars and derivatives thereof; (h) a new method for the oxidation adjacent to carbonyl groups and aromatic systems; (i) the rapid construction of complex natural product-like compounds from o-azaquinones, accessible from simple anilides and DMP (Dess-Martin periodinane) and (j) new methods for the synthesis of diverse heterocycles on solid-phase. Special emphasis was made on the mechanistic underpinnings of each new methodology, and often a thorough understanding of the mechanism led to additional designed technologies. The total synthesis of the CP molecules is an excellent example of how total synthesis can act as a driving force for the discovery of new concepts in chemistry. The bissorbicillinoids are natural products displaying an array of interesting biological activities and feature highly unusual and complex molecular architectures. Traditional synthetic approaches and biomimetic approaches to these molecules were undertaken. The first biogenetic hypothesis for the formation of these molecules was put forth and the total synthesis of these molecules from sorbicillin was accomplished. In addition, a number of interesting byproducts and cascade reactions were discovered along the way.