Cyclative Cleavage Strategies for the Solid-Phase Synthesis of Heterocycles and Natural Products

Abstract

Publisher Summary This chapter discusses the cyclative cleavage strategies for the solid-phase synthesis of heterocycles and natural products. Compared to the conventional resin cleavage methods, the cyclative strategy has two principal advantages; first, the resulting cyclic molecule does not have a free vestigial functional group at the point of resin attachment and second, only the final intermediate on solid phase has the necessary functionality for the cyclization reaction. This is of great value when carrying out multiple reaction steps on solid phase, as any by-products or failed intermediates of earlier reactions are unable to undergo the final cyclization. Thus, the overall yield of a cyclative cleavage sequence may be low or high depending on the efficiency of each step. The chapter reviews the cyclative cleavage to five- and six-membered ring heterocycles that is dominated by the synthesis of hydantoins and diketopiperazines, respectively. Among the six-membered ring heterocycles, diketopiperazines are most commonly prepared, and its formation is often observed as an undesirable by-product during peptide synthesis and the facile nature of this cyclization makes it an obvious choice for library generation.