.
Angewandte
Communications
DOI: 10.1002/anie.201308743
Molecular Diversity Very Important Paper
Synthesis of Complex and Diverse Compounds through Ring
Distortion of Abietic Acid**
Ryan J. Rafferty, Robert W. Hicklin, Katherine A. Maloof, and Paul J. Hergenrother*
Abstract: Many compound screening collections are popu-
lated by members that possess a low degree of structural
complexity. In an effort to generate compounds that are both
complex and diverse, we have developed a strategy that uses
natural products as a starting point for complex molecule
synthesis. Herein we apply this complexity-to-diversity
approach to abietic acid, an abundant natural product used
commercially in paints, varnishes, and lacquers. From abietic
acid we synthesize a collection of complex (as assessed by
fraction of sp3-hybridized carbons and number of stereogenic
centers) and diverse (as assessed by Tanimoto analysis) small
molecules. The 84 compounds constructed herein, and those
created through similar efforts, should find utility in a variety of
biological screens.
transcription factors.[11] In addition, drugs for some indica-
tions (such as bacterial infections) are almost always complex
molecules, possessing physiochemical properties very differ-
ent from those normally found in HTS collections.[12–14]
Natural products are (typically) complex molecules that
have enjoyed notable success in drug discovery.[15] Such
compounds possess considerable three-dimensionality, dis-
play a diversity of chemical functionality, and can modulate
biological systems in ways that simpler compounds often
cannot. For example, FK506 (Tacrolimus) binds simultane-
ously to the proteins FKBP12 and calcineurin,[16] vinblastine
binds tubulin and inhibits its assembly into microtubules,[17]
and ET-743 (Yondelis) selectively and covalently alkylates
specific sequences within the minor groove of DNA.[18]
Unfortunately, the identification of new natural products is
challenging,[19,20] thus the source of complex compounds for
future drug discovery efforts is uncertain. To fill this gap,
several creative strategies for the generation of such com-
pounds have been devised, including diversity-oriented syn-
thesis,[21–27] biology-oriented synthesis,[28] synthesis of natural-
product-inspired scaffolds,[29–32] synthesis of chiral, conforma-
tionally constrained oligomers,[33,34] and synthesis of com-
pounds to probe biological/chemical space.[35]
With the goal of creating structurally diverse compound
screening libraries populated by complex molecules, we
recently reported a general strategy for the synthesis of
complex and diverse compound collections from readily
available natural products.[36] This approach, termed com-
plexity-to-diversity (CtD), was used to prepare over 160
compounds from gibberellic acid, adrenosterone, and qui-
nine.[36]
As changes in the molecular scaffold lead to the most
dramatic changes in overall topology,[37] CtD is focused on
achieving scaffold diversity through the manipulation of core
ring systems. Reaction sequences are designed to rapidly and
dramatically alter ring systems through the use of ring
distortion reactions. These are chemical transformations
that directly alter the composition of rings in a molecule
and include reactions that change ring size (ring expansion
and ring contraction), form or break rings (ring fusion and
ring cleavage), manipulate multiple rings (ring rearrange-
ment), and aromatize rings. The strategic application of ring
distortion reactions to complex natural products provides an
efficient approach for the generation of highly diverse
collections of complex small molecules in few synthetic
steps. Here, we apply CtD to the diterpene abietic acid (AA,
Scheme 1) and construct 84 complex compounds from this
natural product.
H
igh-throughput screening (HTS) is widely used in the
identification of new drug leads. Prior to the advent of HTS,
compound collections were typically enriched in natural
products and/or extracts from natural sources. Advances in
robotics and parallel/combinatorial synthesis in the early
1990s led to a surge in the use of HTS, the results of which
have been significant: for sorafenib, maraviroc, rivaroxaban,
imatinib, lapatinib, ambrisentan, and several other FDA-
approved drugs, the initial leads were identified through
a high-throughput screen.[1–3]
HTS collections are generally populated by highly planar
compounds, molecules with a significant percentage of sp2-
hybridized carbon atoms and few stereogenic centers.[4–8]
These small, flat compounds are useful against some biolog-
ical targets; for example, three of the drugs mentioned above
(sorafenib, imatinib, lapatinib) inhibit kinases, a class of
targets well-suited for modulation by compounds that mimic
the planar base of ATP. There are other cellular targets (e.g.,
PARP-1[9]) that also appear to be effectively bound by planar
compounds with little or no stereochemical complexity.
However, it is likely that such planar compounds will be
unsuitable for the modulation of certain challenging biolog-
ical targets, including protein–protein interactions[10] and
[*] Dr. R. J. Rafferty, R. W. Hicklin, K. A. Maloof, Prof. P. J. Hergenrother
Department of Chemistry
University of Illinois at Urbana-Champaign
261 RAL, Box 36-5, 600 S. Mathews, Urbana, IL 61801 (USA)
E-mail: hergenro@illinois.edu
[**] We are grateful to the Office of Naval Research (N00014-09-1-0249)
and the University of Illinois at Urbana-Champaign for support of
this work. We thank Dr. Danielle Gray for X-ray analysis of
compound AA8. R.J.R. dedicates to Professor Robert M. Williams on
the occasion of his 60th birthday.
AA is the major component of pine tree rosin and has
been used for centuries in varnishes, lacquers, and ship
Supporting information for this article is available on the WWW
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ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 220 –224