Reagent based DOS: A click, Click, Cyclize strategy to probe chemical space

Article abstract of DOI:10.1039/b927161a

The synthesis of small organic molecules as probes for discovering new therapeutic agents has been an important aspect of chemical-biology. Herein we report a reagent-based, diversity-oriented synthetic (DOS) strategy to probe chemical and biological space via a Click, Click, Cyclize protocol. In this DOS approach, three sulfonamide linchpins underwent cyclization protocols with a variety of reagents to yield a collection of structurally diverse S-heterocycles. In silico analysis is utilized to evaluate the diversity of the compound collection against chemical space (PC analysis), shape space (PMI) and polar surface area (PSA) calculations.

Full text of DOI:10.1039/b927161a

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Reagent based DOS: A “Click, Click, Cyclize” strategy to probe
chemical space†
Alan Rolfe,a,b Gerald. H. Lushingtonb,c and Paul. R. Hanson*a,b
Received 5th January 2010, Accepted 15th February 2010
First published as an Advance Article on the web 16th March 2010
DOI: 10.1039/b927161a
The synthesis of small organic molecules as probes for discovering new therapeutic agents has been an
important aspect of chemical-biology. Herein we report a reagent-based, diversity-oriented synthetic
(DOS) strategy to probe chemical and biological space via a “Click, Click, Cyclize” protocol. In this
DOS approach, three sulfonamide linchpins underwent cyclization protocols with a variety of reagents
to yield a collection of structurally diverse S-heterocycles. In silico analysis is utilized to evaluate the
diversity of the compound collection against chemical space (PC analysis), shape space (PMI) and
polar surface area (PSA) calculations.
of approaches. Seminal papers by Evans in 1988 and Schreiber
Introduction
2000 reported the generation of substructural motifs as ligands for
diverse receptors.6 Recently, notable examples of DOS strategies
have been reported by Spring, Park and Shair.3,4 One of the
more notable strategies employing both reagent-based7 and func-
tional group pairing attributes is the build/couple/pair (B/C/P)
paradigm pioneered by Schreiber and coworkers.8
Recently, a number of reports of sultams, the cyclic analogs
of sulfonamides, have emerged demonstrating a broad-spectrum
bioactivity (Fig. 1), yet not “preordained bioactivity” as is
the case with targeted, medicinally active natural products.
In particular, reports include anti-HIV activity,9 antidepressant
activity,10 inhibitors of RSV,11 selective tumour necrosis factor,12
and metalloproteinase.13 In addition to this potent biological
profile, sultams and their sulfonamide precursors possess a
number of advantageous chemical properties. This potency, when
coupled with their unique chemical properties, elevates sultams as
promising candidates for drug discovery.
The synthesis of small organic molecules as probes for discovering
new therapeutic agents has been an important aspect of chemical-
biology.1 Essential to this goal are two fundamental features i)
the production and access to libraries of skeletally diverse small
molecules and ii) biological evaluation and identification of new
probes.2 Such small molecules have had a dramatic effect in
recent years providing invaluable insight into biological targets
and the development of therapeutic agents for curing disease.3
The generation of an open-data, high-throughput screening envi-
ronment of diverse small-molecule libraries has provided both
a number of new molecular probes as well as a novel insight
into unmined chemical space.2 In contrast to natural product-
based targeted libraries premised on improving the biological
activity of the corresponding natural product, diversity-oriented-
synthesis (DOS) derived libraries aim to discover new molecules
that exhibit biological effects beyond those associated with the
natural product. In this regard, DOS has emerged as a powerful
strategy in the generation of structurally complex and skeletally
diverse small molecules.4
Synthetic protocols combined with rational design of small
molecules based on structural diversity, complexity and inherent
physiochemical properties, has emerged as a rich area in chemical
biology.5 The ability to generate a collection of small molecules
that combine not only skeletal and peripheral complexity from
a central building block, while remaining diverse in comparison
to each other has been a challenging goal. Libraries synthesized
utilizing a DOS approach have been generated through a number
aDepartment of Chemistry, University of Kansas, 1251 Wescoe Hall Drive,
Lawrence, KS 66045-7582. E-mail: phanson@ku.edu; Fax: +1 785-864-
3094; Tel: +1 785-864-5396
bThe University of Kansas Center for Chemical Methodologies and Library
Development, 2121 Simons Drive, Structural Biology Center, West Campus,
Lawrence, KS, 66047; Fax: +1 785-864-8179; Tel: +1 785-864-6115
cMolecular Graphics & Modeling Laboratory, University of Kansas,
1251 Wescoe Hall Dr, Lawrence KS 66045; Fax: +1 785-864-5326;
Tel: +1 785-864-1166
Fig. 1 Biologically active sultams and sulfonamides.
Despite these attributes, general strategies towards the synthesis
of sultam libraries are lacking in the literature.14 To address
this challenge, we report a reagent-based DOS strategy termed
† Electronic supplementary information (ESI) available: General experi-
mental details, experimental data for compounds 2–17 and 19 and 1H and
13C NMR spectra of compounds. See DOI: 10.1039/b927161a
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“Click, Click, Cyclize” en route to structurally diverse sultams
from common sulfonamide linchpins.15,16 In this strategy, skeletal
diversity is incorporated into each small molecule via a chosen
orthogonal reagent used to cyclize each linchpin. As in functional-
group pairing approaches, this DOS strategy provides a pathway
to a collection of diverse sultams.
collection of sultams utilizing the aforementioned “Click, Click,
Cyclize” protocol.15 In this regard, linchpin 2 was synthe-
sized via a “Click” mono-sulfonylation of ethylenediamine with
2-bromobenzene sulfonamide 1, followed by a second “Click”
sulfonylation with tosychloride (TsCl) to generate the desired
linchpin 2 in high yield (Scheme 1).17 Utilizing a variety of reagents,
five sultams and bis-sulfonamides (3–7) were readily synthesised.
Initial cyclization of linchpin 2 was achieved via a microwave-
assisted, Cu-catalyzed, intramolecular N-arylation yielding the
corresponding sultam 3 in 70%.18 Alternatively, cyclization of
linchpin 2 with either 1,2-dibromoethane or 1,3-dibromopropane
provided the desired piperazine 4 and diazepine 6 in good yield.
In contrast, cyclization of linchpin 2 with carbonyl diimidazole
Results and discussion
Linchpin synthesis via “Click, Click, Cyclize” protocol
Taking the aforementioned approach into hand, three unique
sulfonamide linchpins 2, 9 and 15 were designed to yield a
Scheme 1 a) CuI, 1,10-phenanthroline, Cs2CO3, DMF, MW, 70%. b) (CH2Br)2, Cs2CO3, DMF, 60 ◦C, 90%. c) CDI, Et3N, DMF, 60 ◦C, 92%. d)
CH2(CH2Br)2, Cs2CO3, DMF, 60 ◦C, 85%. e) i. Allyl bromide, NaH, THF, RT, ii. Grubbs 2nd Generation, DCM, reflux, 88% (over steps).
Scheme 2 a) Cs2CO3, MeO2CCH(CH2Br)2, DMF, 64%. b) (CH2Br)2, Cs2CO3, DMF, 60 ◦C, 84%. c) CH2(CH2Br)2, Cs2CO3, DMF, 60 ◦C, 76%. d) CuI,
1,10-Phenanthroline, K2CO3, DMF, MW, 56%.
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Fig. 2 Three-dimensional chemical diversity plot of compounds 2–7 (green), 9–13 (red) and 14–19 (blue) relative to 3770 FDA approved compounds as
reported in the ZINC database. The axes reflect normalized projections of three H-sensitive three-dimensional BCUT metrics chosen as having optimal
variance levels within the MLSMR screening set, including the 600 projection of the Burden H-donor (horizontal axis), and the 500 (vertical axis) and
600 (out-out-plane axis) projections of the Burden tab-polar projections, as computed via DiverseSolutions.20
gave the corresponding imidazolidin-2-one 5 in 92% yield. Finally,
allylation followed by RCM yielded 7 in 88% yield, via a “click-
cyclize” 2-step protocol.
15 readily underwent cyclization with 1,2-dibromoethane to yield
bicyclic sultam 19 in good yield.
To evaluate the diversity that is contributed by this collection of
molecules and hence their associated chemical descriptors, in silico
algorithms were utilized to evaluate the S-heterocycles reported.
With each molecule possessing its own set of unique descriptors,
every small molecule has a discrete point in chemical space. There-
fore, the more chemical space probed by a collection of molecules,
the greater the associated diversity. This metric of diversity in
chemical space can be represented by a principle component (PC)
analysis (Fig. 2). In order to gauge the chemical diversity of the
sultams and sulfonamides (3–7, 10–13 and 16–19) reported herein,
we plotted them in a chemical space plot corresponding to a set of
five BCUT descriptors relative to 3770 FDA approved compounds
as reported in ZINC database (Fig. 2).20 This plot demonstrated
that this collection of molecules both covered a significant area of
chemical space but also the compounds did not cluster together
according to the corresponding linchpin they were derived from.
Building on this analysis, sultams and sulfonamides (3–7, 10–13
and 16–19), were plotted according to the normalized principal
moment of inertia (PMI) formalism of Sauer and Schwartz, in or-
der to gauge the shape-based distribution (Fig. 3).21 The PMI plot
is a rapid and visual way to demonstrate diversity corresponding to
the area of shape space covered by a collection of molecules. This
Building on these results, sulfonamide linchpin
9 was
synthesized via sulfonylation of 2-bromobenzylamine 8 with
2-chloroethanesulfonyl chloride followed by an aza-Michael
reaction with n-butylamine (Scheme 2).19 It was envisioned that
cyclization with four commercially available reagents would yield
four skeletally diverse sultams (10–13).
Sultam 10 was synthesised via cyclization of linchpin 9 utilizing
methyl 3-bromo-2-(bromomethyl)propionate. Utilizing the same
cyclization protocol as for the synthesis of 4 and 5, sultams
11 and 12 were synthesized via cyclization of linchpin 9 with
1,2-dibromoethane or 1,3-dibromopropane, respectfully. Finally,
sultam 13 was synthesized utilizing a microwave-assisted, copper-
catalyzed N-arylation protocol.
Utilizing a previously developed Cu-catalyzed, N-arylation
protocol, sulfonamide linchpin 15 was readily synthesized on
scale from sulfonylchloride 14 (Scheme 3).18 The first cyclization
route, utilized a CDI cyclization protocol yielding sultam 16 in
good yield. In an attempt to synthesize sultam 18, linchpin 15
was treated with 3-bromo-2-(bromomethyl)propionate in DMF
◦
at 60 C. However, the desired product 18 was not isolated and
instead sulfonamide 17 was isolated in 78% yield. Finally, linchpin
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Scheme 3 a) CDI, Et3N, DMF, 60 ◦C, 96%. b) Cs2CO3, MeO2CCH(CH2Br)2, DMF, 78%. c) (CH2Br)2, Cs2CO3, DMF, 60 ◦C, 87%.
Fig. 3 Principal moment of inertia (PMI) plot of compounds 3–7 (green), 10–13 (red) and 16–19 (blue) as computed for energetically minimized
conformers of the compounds using Gasteiger-Marsili electrostatics.
is a significant property for a collection of molecules to possess,
as broad biological activity has been correlated to shape space.21
Hence, screening collections possessing a high degree of molecular
shape diversity increases the chances of a broad range of biological
activity. Each molecule was aligned to principal inertial moment
axes in SYBYL,22 and the normalized PMI values were computed
via a program developed in-house (available upon request to the
authors). With this plot in hand, Fig. 3 demonstrates a large
coverage of shape space for sultams and sulfonamides (3–7, 10–13
and 16–19). Of note is the coverage by compounds 10–13 (red
data points) derived from linchpin 8 further demonstrating the
diversity achieved utilizing a “Click, Click, Cyclize” approach.
In addition to diversity in both chemical and shape space, polar
surface area of a small molecule is a key feature in terms of
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Fig. 4 Surface electrostratic profiles of sultams and sulfonamides 3 (78.33), 4 (100.61), 5 (125.49) and 7 (92.95). The compounds have been mutually
aligned so that the conserved phenylsulfonyl moiety is located in the upper left corner for each molecule. The surface corresponds to the H2O-accessible
Connolly surface, and the colouring reflects the Gasteiger-Marsili charge distribution, such that electronegative areas are colored red, electro positive
areas are blue.
diverse bioactive molecules involved in ligand-receptor binding.
Rigid scaffolds bearing diverse polar surface areas interact dif-
ferently with various key interactions such as hydrogen bonding,
electrostatic and other non-covalent interactions. This is further
exemplified by reports that demonstrate the diverse biological
activity associated with small molecules with diverse polar surface
areas resulting from different orientations of heteroatoms.4a In
this regard, polar surface area distribution of sultams 3, 4, 5
and 7 were plotted (Fig. 4). Comparison among the four further
demonstrates the degree of diversity achieved from linchpin 2
utilizing a “Click, Click, Cyclize” protocol. Surface electrostatic
profiles were calculated by projecting the Gasteiger-Marsili charge
distribution onto a Connolly surface generated via the MOLCAD
tool in SYBYL.22
authors and do not necessarily represent the official view of the
NCRR or NIH.
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This publication was made possible by the Pilot-Scale Libraries
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