Two-directional chain synthesis

Ikemoto, N, Schreiber, S L, Total synthesis of (—)-hikizimycin employing the strategy of two-directional chain synthesis, J. Am. Chem. Soc., 114, 2524-2536, 1992. 

Poss CS, Schreiber SL. Two-directional chain synthesis and terminus differentiation. Acc. Chem. Res. 1994 27 9-17. 

The power of Noyori s Ru -BINAP system in ketone reductions has been amply demonstrated in numerous complex molecule syntheses. Schreiber, for example, has disclosed a route to the macrolide antibiotic mycoticin A (221, Scheme 2.27) [139] that relies on a strategy involving two-directional chain synthesis [140]. Catalytic asymmetric reduction of diketone 216 affords the C2-symmetric diol 217. Conversion of 217 into bis(ketoester) 218 then allows double ketone reduction to furnish 219, which was subsequently elaborated into the skipped polyol chain 220 of mycoticin A (221). 

Numerous notable applications of Brown s chiral borane reagents have been documented [32, 78], with the stereoselective allylation of meso-dialde-hyde 82 serving as an elegant example [79], Treatment of 82 with 16 furnished the bisallylated product 83 in > 98 % ee and >15 1 dr. This example represents an early illustration of the concept of two-directional chain synthesis for the construction of complex molecules [11, 80], In this approach, the symmetry of a given targeted fragment may permit synthetic elaboration to be carried out concurrently at two ends of molecule. Ultimately, such an approach may demand a subsequent step in the sequence to differentiate the two ends of the chain and to break the symmetry. 

Saito examined the dihydroxylation of a collection of bis-allylic ethers, including 294 (Equation 49) and 296 (Equation 50) [202], in the context of a two-directional chain synthesis strategy [203]. Exceptionally high levels... 

SCHEME 13.51 Schreiber s synthesis of (—)-hikizimycin featuring a two-directional chain-elongation strategy involving an aldehyde olefination and face-selective dihydroxylations. 

SCHEME 22.50. Convergent synthesis of complicated polypropionates fragments through one-pot, dissymmetrical, two-directional chain elongation. 

Exner CJ, Turks M, Fonquerne F, Vogel P. Concise synthesis of complicated polypropionates through one-pot disymmetri-cal two-directional chain elongation. Chem. Eur. J. 2011 17 4246 253. 

Perkins, M.V. and Sampson, R.A. (1998) Stereoselective synthesis of an isomer of membrenone-C via an aldol based two directional chain extension. Tetrahedron Lett., 39, 8367—8370. 

Dipyridyldisulfide has been used as the electrophilic reagent by Williams and co-workers in their studies directed toward the synthesis of bicyclomycin (82JA6092). The enolate of (124) was generated by means of lithium diisopropyl amide (LDA) in tetrahydrofuran (THF) at -78°C and added to a solution of 2,2 -dipyridyldisulfide. This gave (125) as a single regio- and stereoisomer in 80-95% yield. Contrary to expectation, the two side chains of the piperazinedione in (125) were disposed cis to each other. 

Scheme 3 illustrates retrosynthetic analysis of the E and F series of PGs. The widely used Corey synthesis (2) takes notice of the presence of the two olefinic bonds in the side chains of PGF2a. The actual synthesis consists of a two-fold Wittig-type chain extension of a chiral dialdehyde equivalent with four defined stereogenic centers derived from cyclopentadiene via a series of bicyclic intermediates. A similar sequential synthesis has been developed at Upjohn Co. (la). These chemical syntheses are much more economical than enzymatic methods and are used for commercial synthesis of certain PGs. An alternative pathway pioneered by Sih is the conjugate addition approach (3). Nucleophilic addition of an E-olefinic co side-chain unit to a cyclopentenone in which the a side chain is already installed leads directly to PGE-type compounds. Untch and Stork used an co chain unit with a Z-olefinic bond (4). The most direct and flexible synthesis is the convergent three-component coupling synthesis via consecutive linking of the two side chains to unsubstituted 4-hydroxy-2-cyclopentenone derivatives (5, 6). 

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