Download (3249Kb) - D-Scholarship@Pitt - University of Pittsburgh

1.1.1 Transition Metal-Catalyzed Reactions in Diversity-Oriented Synthesis
Accessing all three forms of diversity requires DOS strategies with branching reaction
pathways available to common synthetic precursors. In this manner, structurally distinct
scaffolds can be obtained from a relatively smaller pool of reactants, thereby increasing the
overall efficiency of the process. Therefore, there is a strong incentive to develop new chemical
transformations and design strategies towards this goal. The development of many useful
transition metal-catalyzed reactions in the last decades has opened the door for their application
to DOS. 22 Transition-metal catalyzed reactions are generally environmentally benign and
economic synthetic processes, proceeding with high levels of selectivity (chemo-, regio-, and/or
stereoselectivity) and minimize the use of raw materials and generation of byproducts. Among
these, Pd-catalyzed coupling reactions (Heck, 23 Stille, 24 Sonogashira, 25 Suzuki, 26 etc.) and allylic
substitution reactions 27 are regarded as some of the most important with highest impact on the
field of modern organic synthesis. Not surprisingly, these reactions have seen the most
application in combinatorial and diversity-oriented synthesis. The majority of classical
combinatorial strategies in the past have been largely limited to utilizing transition metal-
catalyzed coupling reactions only introducing appendage diversity (for examples see Pd-
catalyzed Suzuki, 28 Heck 29 and Stille 30 coupling reactions). In addition, intramolecular versions
of these and related reactions have seen recent use to create skeletal diversity in the synthesis of
small and medium size rings. 31 Related transformations such as the coupling of aryl boronic
acids and amides recently developed by Buchwald 32 are also becoming increasingly popular in
the generation of cyclic-skeletons. 33 Another very important transformation that has found wide
use in combinatorial and diversity-oriented synthesis is the Ru-catalyzed ring-closing
methathesis developed by Grubbs. 34 Some recent examples of diverse cyclic scaffolds generated
9