Solid-phase Dieckmann condensation

The first cyclative cleavage of a small molecule was Crowley and Rapo-port s study41 of intramolecular Dieckmann condensations on solid phase (Fig. 13), which was complicated by the reversible nature of the cyclization. Despite the unique opportunities afforded by C-C rather than C-X bond formation during cleavage, there are few examples from the combinatorial age. A modern version of the Claisen-type condensation by Kulkarni and Ganesan42 uses a strongly acidic active methylene group to ensure unidirectional cyclization, and furnishes tetramic acids with three points of diversity. 

Application of intramolecular Dieckmann-condensation for the solid-phase synthesis of lactones by Rapoport et al. (7. Macromol. Sci. Chem. 1973,1117)... 

By carrying out the Dieckmann condensation using a polymeric benzyl ester, Crowley and Rapoport (1976) demonstrated the advantage of a purification effect in solid-phase synthesis in addition to hyperentropic efficacy. The Dieckmann cyclization of a nonpolymeric benzylic ester produces a mixture of two soluble keto esters whose separation by some conventional method becomes necessary (a rather difficult separation). 

More recently, Wang and co-workers reported on a solid-phase total synthesis of 1-p-methylcarbapenem 97 because of interest in its potent broad-spectrum antibiotic activity. In this total synthesis (Scheme 3.19), azetidinone 92, bearing a chiral auxiliary, was loaded onto polystyrene-diethyl-silane resin 91 to give 93, which was condensed with allyl bromoacetate to give supported azetidinone 94. Treatment with TMSCl in the presence of NaN(TMS)2 and diphenyl phosphorochloridate (DPPC) promoted a Dieckmann-type cyclization to give supported vinyl phosphate 95 with concomitant release of the chiral auxiliary. Vinyl phosphate resin 95 was treated with thiophenol to give supported 1-P-methylcarbapenem 96, which was released from the solid support upon treatment with tetra-H-butylammonium fluoride (TBAF). 

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