Creation and manipulation of common functional groups en route to a skeletally diverse chemical library

Article abstract of DOI:10.1073/pnas.1015253108

We have developed an efficient strategy to a skeletally diverse chemical library, which entailed a sequence of enyne cycloisomerization, [4 + 2] cycloaddition, alkene dihydroxylation, and diol carbamylation. Using this approach, only 16 readily available building blocks were needed to produce a representative 191-member library, which displayed broad distribution of molecular shapes and excellent physicochemical properties. This library further enabled identification of a small molecule, which effectively suppressed glycolytic production of ATP and lactate in CHO-K1 cell line, representing a potential lead for the development of a new class of glycolytic inhibitors.

Full text of DOI:10.1073/pnas.1015253108

Creation and manipulation of common functional
groups en route to a skeletally diverse
chemical library
Jiayue Cuia,b, Jason Haoa,b, Olesya A. Ulanovskayaa,b, Joseph Dundasa,c, Jie Lianga,c, and Sergey A. Kozmina,b,1
aChicago Tri-Institutional Center for Chemical Methods and Library Development; bDepartment of Chemistry, University of Chicago, Chicago, IL 60637;
c
and Department of Bioengineering, University of Illinois, Chicago, IL 60607
Edited by Stuart L. Schreiber, Broad Institute, Cambridge, MA 02142, and approved January 26, 2011 (received for review October 28, 2010)
We have developed an efficient strategy to a skeletally diverse
chemical library, which entailed a sequence of enyne cycloisomeri-
zation, [4 þ 2] cycloaddition, alkene dihydroxylation, and diol car-
bamylation. Using this approach, only 16 readily available building
blocks were needed to produce a representative 191-member
library, which displayed broad distribution of molecular shapes
and excellent physicochemical properties. This library further
enabled identification of a small molecule, which effectively sup-
pressed glycolytic production of ATP and lactate in CHO-K1 cell line,
representing a potential lead for the development of a new class of
glycolytic inhibitors.
Sn-catalyzed carbamylation. This synthetic sequence is designed
to efficiently create and rapidly process common functional
groups, which are generated at each stage of the assembly pro-
cess, to enable both skeletal and structural diversification. We
were able to employ only 16 simple building blocks to assemble
a representative library of 191 skeletally diverse, diastereomeri-
cally pure compounds with broad distribution of molecular
shapes as determined by the principal moment-of-inertia (PMI)
computational analysis. Subjection of this library to a cellular
screen monitoring ATP production in CHO-K1 cells with im-
paired mitochondrial activity yielded a unique chemotype that
effectively blocked glycolytic ATP synthesis, inhibited lactate
production, and suppressed cellular proliferation of this cell line.
diversity-oriented synthesis ∣ glycolysis ∣ skeletal diversity
Results and Discussion
tructurally diverse collections of small molecules provide a
validated source of chemical probes for basic and transla-
Our general synthetic strategy is depicted in Fig. 1A. The process
begins with subjection of 1,6-enyne I to different cycloisomeriza-
tion conditions to give diverse products II–IV, containing a com-
mon 1,3-diene subunit and setting the stage for a series of
subsequent [4 þ 2] cycloadditions. Each of the cycloadducts
V–VII contains an alkene unit and provides an opportunity for
a subsequent transformation; i.e., Os-catalyzed dihydroxylation
to furnish a set of vicinal diols VIII–X. Each diol is further
diversified by conversion into carbamates XI–XIII. This process
would enable rapid conversion of a single 1,6-enyne I into a large
number of diverse compounds by using only simple and common
building blocks and reagents.
We first examined a number of protocols for converting
1,6-enyne 1 into a series of structurally diverse 1,3-dienes
(Fig. 1B). Enyne 1 can be efficiently produced by N-sulfonylation
and propargylation of allyl amine (19). Subjection of enyne 1
to 1-trimethylsilyl-hexyne in the presence of TiðOi- PrÞ4 and
i-PrMgCl gave triene 2 (20). Whereas the level of chemoselectiv-
ity of this process was excellent, the main product 2 was produced
as a 5∶1 mixture of inseparable regioisomeric 1,3-dienes. Treat-
ment of enyne 1 with RhðPPh3Þ3Cl and AgOTf resulted in cyclo-
dimerization to give pyrroline-fused cyclohexadiene 3 (21).
Treatment of 1,6-enyne 1 with the Grubbs catalyst 4 triggered en-
yne metathesis and afforded the desired 1,3-diene 5 (22). We
found that higher efficiency was achieved when the reaction
was conducted at ambient temperature in the presence of ethy-
lene (23). Another 1,6-enyne cycloisomerization topology could
be realized using of a catalytic amount PdðPPh3Þ2ðOAcÞ to give
bis-methylene pyrrolidine 6 (24). Chemoselective Os-c2atalyzed
dihydroxylation, followed by periodinate-induced oxidative
S
tional biomedical research (1, 2). Variation of the scaffold archi-
tecture of such compound libraries is particularly desirable to
enable identification of new bioactive chemical probes with high-
er probability and greater efficiency. High-throughput synthesis
of skeletally diverse small-molecule libraries represents one of
the most challenging aspects of diversity-oriented synthesis and
requires identification of efficient reaction sequences that can
rapidly convert a small subset of readily available compounds
to a large number of skeletally diverse chemical entities for sub-
sequent biomedical applications (3).
Transition metal-catalyzed cycloisomerization of enynes repre-
sents a powerful method for structural diversification (4–6). Our
group previously demonstrated that various reaction topologies
could be controlled by a proper choice of the transition metal
catalyst, as well as the functionalization of the starting enyne
(7–10). Significant advances in this area can now enable incor-
poration of such transformations into synthetic strategies for
the assembly of skeletally diverse chemical libraries (11–18).
However, several challenges remain to be addressed to facilitate
access to high-diversity chemical libraries. Typically, multiple
cycloisomerization precursors are manually assembled to yield
different skeletal frameworks upon their cycloisomerizations.
A smaller number of building blocks would minimize this labor-
ious process and increase efficiency. Another limitation is the
difficulty of subsequent diversification of cycloisomerization pro-
ducts, which is complicated by the lack of common functional
groups and variable chemical reactivity of such compounds. Ide-
ally, the cycloisomerization should provide access to products
containing the same functional group to enable the next diver-
sity-generating step, which should yield another common func-
tional group. If such common and reactive functional groups
are efficiently produced at every stage of the synthesis, this syn-
thetic pathway can readily provide access to a structurally diverse
library starting with only a small set of building blocks.
Author contributions: J.C., J.H., J.D., J.L., and S.A.K. designed research; J.C., J.H., O.A.U.,
and J.D. performed research; S.A.K. analyzed data; and J.C., J.L., and S.A.K. wrote
the paper.
The authors declare no conflict of interest.
We describe the development of a unique approach, which
harnesses the diversity-generating power of several transforma-
tions, including transition metal-catalyzed 1,6-enyne cycloisome-
rization, [4 þ 2] cycloaddition, Os-catalyzed dihydroxylation and
This article is a PNAS Direct Submission.
1To whom correspondence should be addressed. E-mail: skozmin@uchicago.edu.
This article contains supporting information online at www.pnas.org/lookup/suppl/
doi:10.1073/pnas.1015253108/-/DCSupplemental.
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Fig. 1. (A) Synthetic strategy for assembly of a skeletally diverse chemical library. The approach relies on the initial series of cycloisomerizations of acyclic
enyne, followed by subsequent [4 þ 2] cycloadditions and alkene diversifications via dihydroxylation and carbamylation. (B) Transformations of enyne 1 into a
series of 1,3-dienes. (C) Structures and isolated yields of products of [4 þ 2] cycloadditions of dienes 5, 6, 7, and 8 with dienophiles 9, 10, 11, 12, and 13.
cleavage of the resulting diol and subsequent Wittig olefination
enabled conversion of enyne 1 to dieneyne 7. Moderate diaster-
eoselectivity of the Wittig reaction was improved by treatment of
the olefination product with a catalytic amount of iodine. Treat-
ment of enyne 1 with catalytic amounts of pentamethyl cyclopen-
tadienyl ruthenium dichloride and cyclooctadiene in the presence
of ethylene produced exocyclic 1,3-diene 8 (25). Thus, six struc-
turally diverse 1,3-dienes were readily prepared starting from a
single acyclic enyne precursor 1.
The next stage of our investigation focused on subsequent di-
versification of initially produced 1,3-dienes via a series of [4 þ 2]
cycloadditions. We selected five symmetric dienophiles, including
maleimide 9, azodicarboxylate 10, 1,2,4-triazoline-3,5-dione 11,
maleic anhydride 12 and pyridazine-3,6-dione 13 (Fig. 1C). Diene
2, which was initially produced as a mixture of inseparable regioi-
somers, produced mixtures of the corresponding cycloadducts
and was not used for subsequent reactions. Bicyclic diene 3
proved to be unreactive toward most of the dienophiles. The four
remaining 1,3-dienes 5–8 successfully participated in a majority
of the required [4 þ 2] cycloadditions (Fig. 1C). Cycloaddition
of diene 5 with maleimide 9 readily proceeded at 60 °C to give
cycloadduct 14 as a single diastereomer. Similarly high efficiency
was observed in cycloadditions of diene 5 with azodicarboxylate
10, and 1,2,4-triazoline-3,5-dione 11, to give the adducts 15, 16,
respectively. Cycloaddition of maleic anhydride 12 with diene 5
proceeded with high diastereoselectivity. The initially produced
adduct was subjected to methanolysis to give diester 17 in
94% yield. Reaction of 5 with pyridazine-3,6-dione 13, which
was generated in situ by oxidation of the corresponding maleic
hydrazide with PbðOAcÞ4, efficiently delivered tricyclic cycload-
duct 18. All five cycloadditions of diene 6 produced desired pro-
ducts 19–23 in high yields, under mild conditions. Methanolysis of
the initially produced maleic anhydride adduct was employed to
give diester 22. Tricyclic cycloadduct 23 was produced with higher
efficiency using hypochlorite-induced generation of dienophile 13
(26). All five dienophiles successfully reacted with diene 7 to give
the corresponding adducts 24–28 in 65–90% yield. Single diaster-
eomers 24 and 27 were obtained in the case of maleimide and
maleic anhydride cycloadditions; the latter reaction was again
subjected to methanolysis. The reactivity of exocyclic diene 8
proved low presumably due to the difficulty of achieving the re-
quired s-cis- conformation. Indeed, reactions of diene 8 with 9
and 11 required activation with 4 M lithium bis-trifluorometha-
nesulfonimide in acetone (LTAC) (27) to produce cycloadducts
29 and 31, respectively. Reactions of 8 with maleic anhydride 12
proceeded with low efficiency despite significant optimization ef-
forts. Treatment of diene 8 with azodicarboxylate 10 in the pre-
sence of LTAC resulted in formation of ene-reaction product 30.
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Thus, 19 alkenes were produced successfully with a considerable
level of skeletal diversity ranging from carbocyclic or heterocyclic
rings (i.e., 25, 27, and 30) to bicyclic compounds (i.e., 15, 22, and
28) and fused and spirotricyclic molecules (i.e., 29, 31, and 32).
Our next objective was to identify an efficient and robust pro-
tocol, which would enable subsequent diversification of skeletally
diverse alkenes 14–32 despite their variable level of chemical re-
activity. Among various methods examined, three protocols
proved to be particularly promising, which included dihydroxyla-
tion, aminohydroxylation and epoxidation (Fig. 2A). Treatment
of alkene 14 with N-methylmorpholine N-oxide and catalytic
amount of OsO4 in acetone/water successfully produced diol
35 in 83% yield as a single diastereomer, which was characterized
by X-ray crystallography as an acetal. Subjection of alkene 14 to
Os-catalyzed aminohydroxylation (28, 29) gave N-sulfonyl amino
alcohol 33 in 32% yield as a single regio and diastereomeric
product. Subsequent attempts to increase the efficiency of this
process proved unsuccessful. Treatment of alkene 14 with meta-
chloroperoxybenzoic acid (mCPBA) gave epoxide 34 as a single
diastereomer, which was characterized by X-ray crystallography.
The epoxide was produced from the more hindered concave face
of 14 possibly due to the directing ability of the imide. However,
opening of epoxide 34 with a range of nucleophiles, including pri-
mary amines under a variety of conditions proved unsuccessful.
This exploratory effort established alkene Os-catalyzed dihydrox-
ylation as the most reliable, efficient and robust method for
further diversification. This method was next applied to all 19
cycloadducts 14–32 (Fig. 1C). We found that 16 reactions
proceeded successfully to give the corresponding diols 35–50
(Fig. 2B). Generally, excellent distereoselectivity was observed
with only 3 reactions proceeding with moderate diastreoselection
(39, 43, and 50). However, in such cases, major products were
obtained in diastereomerically pure form following simple chro-
matographic purification.
We next examined three alternative strategies for diol functio-
nalization (Fig. 3A). Subjection of a representative substrate 35 to
hexyl isocyanate in the presence of a catalytic amount of dibutyl-
tin dilaurate afforded a 6∶1 mixture of regioisomeric carbamate
products, with the major isomer 51 isolated in 75% yield. Treat-
ment of diol 35 with 5-hexenoic acid in the presence of diisopro-
pylcarbodiimide (DIC) and scandium triflate gave diester 52.
Subjection of diol 35 to 2,2-dimethoxypropane in the presence
of camphor sulfonic acid (CSA) afforded the corresponding acet-
al 53. Whereas all reactions showed promise, we felt that both the
acetal and the ester functionalities in 52 and 53 may not be com-
patible with cell-based screening conditions. To avoid such
complications, we selected the transformation of diols to the cor-
responding carbamates as the final diversification strategy. The
carbamates would be expected to elicit greater chemical stability
and higher resistance to the action of hydrolytic enzymes. This
approach proved to be general for converting a series of repre-
sentative diols 42, 49, and 50 into the corresponding carbamates
54, 55, and 56 (Fig. 3B). Such reactions could be readily per-
formed on the desired scale to produce an average of 15 mg
of final products following parallel liquid chromatography mass
spectrometry (LCMS) purification.
The final stage of the synthesis entailed parallel carbamylation
of 16 diols with a set of reactive and structurally diverse isocya-
nates. We identified a representative set of commercially avail-
able 10 isocyanates (Fig. 4A) that would efficiently participate
in this process and afford compounds with structurally diverse
and favorable physicochemical properties (vide infra). We then
employed dibutyltin dilaurate-based catalytic protocol for paral-
lel diversification of 16 diols 35–50 to produce a collection of the
corresponding carbamates (Fig. 4A). We determined that 159 of
the 160 reactions proceeded successfully. Depending on the
structure of each diol, either mono- or bis-carbamates were pro-
duced in high purity (typically greater than 90%) and 66% aver-
Fig. 2. (A) Selected chemical transformations of alkene 14. Such reactions were designed to enable subsequent structural diversification of this representative
cycloadduct. (B) Results of Os-catalyzed dihydroxylations of alkenes 14–32. Structures of major diastereomers of each product are shown, as well as isolated
yields following by silica gel chromatographic purification. Diastereoselectivity of each transformation was determined by analysis of crude reaction mixtures
by 1H NMR. Structures of 35, 36, 37, 38, 39, 42, 43, 49, and 50 were determined by X-ray crystallography of either the parent diol or the corresponding acetal (SI
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Fig. 3. (A) Representative transformations of diol 35. Such reactions were investigated to enable subsequent diversification of all the initially produced diols.
(B) Carbamylation of a selected subset of diols using n-hexyl isocynate. Depending on the structure of the diol, either mono- or bis-carbamates were selectively
produced.
age yield following parallel preparative LCMS purification.
Structures, yields, and selected physicochemical properties of
four randomly selected carbamates are shown in Fig. 4B. This
data illustrate the high efficiency of each final reaction, excellent
purity, and favorable physicochemical properties of these com-
pounds. This effort completed the assembly of a 191-compound
library, which included 16 alkenes (Fig. 1C), 16 diols (Fig. 2B),
and 159 carbamates (Fig. 4A).
Recent cheminformatics studies strongly suggest that the
higher molecular weight of bioactive compounds can be tolerated
provided that the lipophilicity and aqueous solubility are prop-
erly addressed (30). Such parameters can be estimated by calcu-
lating logarithmic value of n-octanol/water partition coefficient
Fig. 4. (A) Carbamylation of diols 35–50. Reactions were performed on 18–20 mg scale to deliver final compounds, which were purified by preparative LCMS.
(B) Structures, yields, purities, and selected physicochemical properties of four selected library members. (C) Molecular shape analysis using PMI computational
method. The graph shows broad shape distribution of the 191-member library using a standard triangular plot.
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(LogP), which should ideally fall within a range of 0–5. We
employed the XLogP3 program (31) to calculate lipophilicity
distribution of our 191-member compound library. This effort
revealed that LogPs of 90% of the library fell into the range
of 0–6 with an average value of 2.64 (SI Appendix and Fig. S1A).
The average molecular weight was determined to be 599
(SI Appendix and Fig. S1B). No decomposition of any compounds
was observed in either neat form or when dissolved in methanol
or dimethyl sulfoxide, which demonstrated their high chemical
stability. We also assessed the overall diversity level of the library
using a computational method based on the normalized PMI
ratios (32) (Fig. 4C), which was recently employed by Schreiber,
Clemons, and coworkers (15). We first derived three-dimensional
structures for each compound using the OMEGA software (33).
The three principal moments of inertia (I1, I2, and I3) were then
calculated for each structure and sorted in ascending order
(I1 < I2 < I3). The two characteristic normalized PMI ratios
(I1∕I3 and I2∕I3) were then calculated for each compound and
plotted against each other. Due to the intrinsic characteristics
of the inertia tensor, all plotted values will fall within an isosceles
triangle defined by the points (0,1), (0.5,0.5) and (1,1). The three
points (0,1), (0.5,0.5) and (1,1) of the triangle also define the
three extreme principal shapes of rod, disk, and sphere, respec-
tively and intermediary shapes will fall at various locations within
the triangle. Plotting the normalized PMI ratios using this scheme
provides a descriptive visualization of the shape diversity of a
compound library. Using this method, we analyzed the normal-
ized PMI ratios for all individual compounds of our 191-member
library using lowest energy conformers of each compound
(Fig. 4C). This analysis revealed that the molecular shapes are
evenly distributed within the intermediate region of the triangular
plot, indicating that the library members elicit substantial shape
diversity. We also randomly selected 300 diverse compounds from
a commercial library subset from ZINC (ChemDiv, 60% Tanimo-
to cut-off) (34) and subjected them to the same analysis. The
commercial library PMI ratio plot revealed a high concentration
of points located toward the upper left of the triangular plot re-
presenting rod and rod-disk shape compounds (SI Appendix and
Fig. S2). This analysis demonstrated unique structural features of
our library, which was overall more spherically distributed in
shape compared to a representative commercially available com-
pound collection and consistent with presence of stereochemi-
cally rich, polycyclic structures.
We next examined the ability of this skeletally diverse small-
molecule library to enable identification of unique inhibitors
of aerobic glycolysis. Such compounds would be useful not
only as chemical probes of cellular energy metabolism but also as
potential leads for development of drugs targeting upregulation
of aerobic glycolysis in cancer (35). We employed our recently
developed chemical genetic screen (36), which monitors glycoly-
tic ATP production in cells with suppressed mitochondrial activ-
ity. This screen was performed by subjecting antimycin A-treated
CHO-K1 cells to a newly synthesized 191-member library and
measuring effects of each library member on ATP synthesis
following 30 min of incubation. This effort identified compound
57 as the most potent inhibitor (Fig. 5A), which depleted ATP
production with an IC50 of 2.2 μM in the presence of antimycin
A while not substantially altering ATP levels in cells with normal
mitochondrial activity (Fig. 5B). To validate suppression of glyco-
lysis in CHO-K1 cells by 57, we examined the effects of this com-
pound on lactate production, cell cycle progression, and cellular
proliferation. Subjecting CHO-K1 cells to 57 resulted in dose-
dependent suppression of lactate production (Fig. 5C) and
growth inhibition (Fig. 5D). Both effects were fully consistent
with impairment of glycolysis by 57 with similar potency to that
observed in the primary ATP screen. Furthermore, exposure of
CHO-K1 cells to 57 (16.7 μM) for 18 h resulted in a marked
increase in the G0/G1 population to 54% from 44% in the con-
Fig. 5. Effects of compound 57 on ATP synthesis, lactate production and cell
proliferation. (A) Chemical structure of 57. (B) Inhibition of intracellular ATP
level in CHO-K1 cells upon treatment with 57 in the presence or absence of
antimycin A. (C) Inhibition of lactate production in CHO-K1 cells upon treat-
ment of 57. (D) Effect of 57 on the growth of CHO-K1 cells. All values are
presented as percentage of vehicle treated samples. Each value is the mean ꢀ
SEM of duplicate or triplicate values from a representative experiment.
trol, and a decrease in the S cell population to 19% from 29%
(SI Appendix and Fig. S3), which was again fully consistent with
inhibition of glycolysis.
In closing, we presented an efficient synthetic strategy for par-
allel assembly of a skeletally diverse chemical library starting
from a small number of simple and readily available building
blocks. This general approach required the availability of reactive
fragments at every stage of the parallel assembly process and
robust reactions for efficient functionalization of compounds with
common functional groups but diverse reactivity profiles. This
concept was validated by a production of a unique 191-member
library with broad distribution of molecular shapes starting from
only 16 simple building blocks. Subsequent cellular screen of this
compound collection identified a unique small-molecule probe
57, which effectively suppressed glycolytic production of ATP
and lactate in CHO-K1 cell line. Determination of the cellular
mechanism of action of 57 and further optimization of its activity
profile are in progress and will be reported in due course.
Materials and Methods
Cycloisomerizations of Enyne 1. Six detailed experimental procedures for
conversion of 1.6-enyne 1 to 1,3-dienes 2, 3, 5, 6, 7, and 8 are provided in
the SI Appendix, as well as characterization of all unique compounds by
1H NMR, 13C NMR, and MS.
[4 þ 2] Cycloadditions. Detailed procedures for cycloadditions of dienes
5–8 with dienophiles 9–13 are provided in the SI Appendix. All unique
compounds were fully characterized by 1H NMR, 13C NMR, and MS.
Alkene Dihydroxylation. Experimental protocols for Os-catalyzed dihydroxyla-
tion of 16 alkenes 14–32 to give the corresponding diols 35–50 are provided
in the SI Appendix. All unique compounds were fully characterized by 1H
NMR, 13C NMR and MS. Relative stereochemistry was established at this stage
for all products 35–50 either by X-ray crystallography or a combination of
NMR spectroscopic techniques (SI Appendix and Tables S1–S10).
Diol Carbamylation. A general protocol of conversion of 16 diols 35–50 to the
corresponding 159 carbamates is described in the SI Appendix. Several repre-
sentative carbamates were fully characterized by 1H NMR, 13C NMR, and MS.
In addition, detailed analytical purity characterization of 32 randomly
selected carbamates following their LCMS preparative purification is also
provided in the SI Appendix.
Cui et al.
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Institutes of Health (Grant P50 GM086145) and the Chicago Biomedical
Consortium with support from the Searle Funds at the Chicago
Community Trust.
ACKNOWLEDGMENTS. We thank Kevin Marin for LCMS purifications, Dr. Ian
Steele for X-ray analysis, Marco Maggioni, and Dr. Weifan Zheng for help
in generating 3D structures. This work was funded by the National
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