Biomedical Engineering Reference
In-Depth Information
PHOSPHINE ORGANOCATALYSIS AS
A PLATFORM FOR
DIVERSITY-ORIENTED SYNTHESIS
ZHIMING WANG AND OHYUN KWON
4.1
INTRODUCTION
With the supposition that libraries of small organic molecules would expedite the
identification of novel therapeutic lead compounds, combinatorial synthesis has been
forged into one of the pillars of synthetic organic chemistry [1-3]. Whereas the
first libraries generated were based on the combinatorial assembly of readily avail-
able synthetic building blocks (e.g., amino acids) to produce “oligomeric” molecules
[4-8], it did not take long for the allure of synthesizing a large number of “drug-like”
molecules to capture the imagination of synthetic organic chemists. Early combinato-
rial libraries were constructed around a single core scaffold with varying substituents
[9,10]. Structural diversity in those libraries stemmed from the availability and reactiv-
ity of synthetic building blocks, which manifested themselves as variable substituent
groups around the core structure in the final products. Although these “focused”
libraries, in which known synthetic routes have been converted to the solid-phase or
parallel synthesis format, still constitute the majority of chemical libraries, the idea
of constructing combinatorial libraries that possess diversity in their core scaffolds
has been discussed since the early formative years of combinatorial chemistry.
In 1996, Gordon et al. constructed a library of heterocycles (4-thiazolidinones,
-
lactams, pyrrolidines, and dihydropyridines) from imines derived from aldehydes and
resin-bound amino acids [11]. In another early example, Marx et al. prepared a library
