Natural product synthesis, ring structures 3 + 2 cyclizations

The ring closure of cyclic 2-but-3-enylcycloalkyl radicals (Fig. 7.3) is similar to that of the open-chain system, except that the constraints of the ring impose an almost exclusive 1,2-cis stereochemistry [3, 4]. The critical 1,5-selectivity is still largely cis, and it is this selectivity that has found the most use in the synthesis of polycyclic natural products [5, 6]. In the context of the 2-but-3-enylcyclopentyl radical cyclization, it was argued [7] that the l,5-c stereochemistry is favored because the chair-like transition structure 8a (Fig. 7.4) can achieve effective overlap between the SOMO and the radical center and the olefin n orbitals, with less strain than the other possible chair Sb. 

The synthesis pathway started with the lithiation of ethylbenzene 121 at the benzylic position, followed by acylation of the toluate anirni intermediate at low temperature. It is noteworthy that a potentially competing orf/io-lithiati(Mi of the type championed by Snieckus 85) i.e. between the two stabilizing methoxyl radicals) was not reported under these conditions. Subsequent reduction of benzyUcetone 122 provided smooth access to the t/irco-dimethyl-substituted bicy-clic intermediate 123 via lactonization. DIBAL reduction (—> 124) and reductive debenzylation with palladium on charcoal gave the ring-opened alcohol 125, which was further demethylated to provide a 1,3-diphenol, and then carboxylated under buffered conditions to yield acid 117, also known as phenol B . This compound was formylated with trimethyl orthoformate and acid, then cyclized to give the quinone structure and natural product, 116 (Scheme 3.1). 

Since the determination of the structure of the citrus bitter principle limonin in 1960, the number of structurally defined members of this class of natural products (now called limonoids) has grown to several hundred. Corey s group reported the first enantioselective synthesis of a limonoid, the protolimonoid, by a route which is both short and stereo-controlled (Scheme 9.45) [17j]. Brief exposure of chiral epoxide 35 to 1.2 equiv of MeAlCl at -78°C provided two diastereomeric tricyclic ketones in a 1.5 1.0 ratio with ketone 36 as the minor component. The predominating dia-stereomer in the mixture, in which the appendage a to the carbonyl is axially oriented, could be isomerized to 36 by treatment of the crude mixture with sodium ethoxide in ethanol. Overall, the cationic cyclization and epimerization permit the rapid stereoselective establishment of three rings and five stereocenters in 43% yield. Slow addition of a solution of AIBN and BUjSnH to a heated solution of xanthate... 

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