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4.5.2 Synthesis of a Library of Tricyclic Pyrroles
The methodology involving a cyclocarbonylation/Stetter/Paal-Knorr reaction sequence
that allows the synthesis of tricyclic pyrrole-2-carboxamides 308a-p has been applied to library
synthesis within the University of Pittsburgh Center for Chemical Methodologies and Library
Development (UPCMLD). 213 The library design is based on three points of diversity: (1) amino
acid side chain R 1 ; (2) glyoxylamide used in the Stetter reaction (R 2 ); and (3) amine used in the
pyrrole formation (R 3 ) (Scheme 4.48). While studying the Mo(CO)6-mediated
cyclocarbonylation reaction of allenynes, it was demonstrated that only amino-esters containing
an aromatic group in the side chain afford a stable diastereomer in the reaction that can be taken
the subsequent steps. Therefore the amino-ester building blocks were a limited source of front-
end diversity and were chosen to contain a benzyl, p-fluorobenzyl and p-methoxybenzyl group
(310{1-3}). Similarly, the library was designed using only two glyoxylamide building blocks
(N,N-dimethyl 311{1} and pyrolidinyl 311{2}). Since the pyrrole formation is used as a last step
in the synthesis, the choice of the amine was used as a greatest source of appendage diversity. A
subset of 41 amines 313{1-41} was selected from a larger set of 300 primary amines, based on
calculating properties such as molecular weight, clogP(octanol/water) of the product, cost and
diversity (a range of aliphatic, heteroatom-containing aliphatic, aromatic and heteroaromatic
amines were included).
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