Synthesis of molecular frameworks containing two distinct heterocycles connected in a single molecule with enhanced three-dimensional shape diversity

Article abstract of DOI:10.1002/chem.201204293

Herein, we report the synthesis of fused-triazole scaffolds that are connected by pyrimidines, pyrazoles, or pyrazolopyrimidines through carbohydrate-derived stereodivergent linkers. Pyrimidine-, pyrazole-, or pyrazolopyrimidine-based carbohybrids were co

Full text of DOI:10.1002/chem.201204293

FULL PAPER
DOI: 10.1002/chem.201204293
Synthesis of Molecular Frameworks Containing Two Distinct Heterocycles
Connected in a Single Molecule with Enhanced Three-Dimensional
Shape Diversity
Donghyun Lim[a] and Seung Bum Park*[a, b]
Abstract: Herein, we report the synthe-
sis of fused-triazole scaffolds that are
connected by pyrimidines, pyrazoles, or
pyrazolopyrimidines through carbohy-
drate-derived stereodivergent linkers.
Pyrimidine-, pyrazole-, or pyrazolopyri-
midine-based carbohybrids were con-
structed through condensations of the
key intermediates, 2-C-formyl glycals,
with various dinucleophiles. Fused-tri-
intramolecular 1,3-dipolar cycloaddi-
tions after selective functionalization of
the carbohybrid polyol moieties with
azide and alkyne functionalities using
SN2-type alkylations or Mitsunobu re-
actions. Overall, this synthetic method
affords two distinct privileged substruc-
tures in a single molecule, connected
by stereodivergent diol linkers derived
from abundant natural chiral sources,
namely, carbohydrates. The resulting
vicinal diols in the linker were further
modified to achieve unique connectivi-
ties between the two privileged struc-
tures for maximized three-dimensional
shape diversity, which we called the
linker diversification strategy.
Keywords: carbohydrates · cycload-
dition · fused-ring systems · molecu-
lar diversity · privileged structures
ACHTUNGTRENNUNGazole scaffolds were obtained through
Introduction
creased attention in the pharmaceutical industry and aca-
demia to expand the repertoire of “druggable” targets.[6]
Regardless of the type of HTS, the successful discovery of
new small-molecule modulators has been significantly influ-
enced by the molecular diversity of small-molecule screen-
ing libraries.[7] Therefore, it is essential to efficiently con-
struct a collection of druglike small molecules with maxi-
mum molecular diversity. To this end, synthetic chemists
have adopted a diversity-oriented synthesis (DOS) approach
that aims at the efficient generation of complex and druglike
compound libraries that contain large numbers of structural-
ly diverse molecular frameworks.[8] We have been particular-
ly interested in the development of divergent and robust
synthetic pathways for the efficient construction of a drug-
like small-molecule library[9] through the creative assembly
of polyheterocycles embedded with privileged substructures
including benzopyrans,[9a] benzodiazepines,[9b] acetal-fused
pyranopyrones,[9c] and tetrahydroindazolones.[9d] We named
this approach privileged-substructure-based diversity-orient-
ed synthesis (pDOS).[10] It is worth mentioning that our new
polyheterocycles embedded with privileged substructures
showed enhanced selectivities and high relevance in multi-
ple biological assays, which was confirmed by the successful
identification of specific small-molecule modulators for vari-
ous biological targets, including anticancer, antiosteoporosis,
and antidiabetic agents.[11]
One of the greatest challenges in the field of chemical biolo-
gy is the identification of new small-molecule modulators
that can selectively perturb the function of gene products.[1]
Such chemical modulators can serve as specific bioprobes
for the mechanistic studies of mysterious biological systems
at the molecular level, which is the main concept of chemi-
cal genetics.[2] In addition, these small-molecule modulators
can open new doors for the development of new therapeutic
agents with unique modes of action.[3] The discovery of new
bioactive small molecules has been achieved by means of
high-throughput screening (HTS) against various biological
targets, which can be classified into two major approaches:
target-based enzymatic assays and discovery-driven pheno-
typic assays.[4] Recently, the screening paradigm has shifted
toward phenotypic screening as the dominant strategy for
discovering new first-in-class therapeutics.[5] Therefore,
image-based high-content screening (HCS) has received in-
[a] D. Lim, Prof. Dr. S. B. Park
Department of Biophysics and
Chemical Biology/Bio-MAX Institute
Seoul National University
Seoul, 151-747 (Korea)
Fax : (+82)2-884-4025
E-mail: sbpark@snu.ac.kr
Among the synthetic pathways we developed, we have
pursued the further elaboration of a particular molecular
framework, namely, carbohybrids. These are defined as
acyclic polyols fused with various privileged heterocycles,
which are widely dispersed in nature and have interesting
biological activities (Figure 1). For example, bengazoles are
antifungal marine natural products that contain a unique
[b] Prof. Dr. S. B. Park
Department of Chemistry
Seoul National University
Seoul, 151-747 (Korea)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201204293.
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based compound library, and the strategies for their prepa-
ration are still in the early stages of development.[18] As
shown in Figure 2, our carbohybrid-derived new molecular
Figure 2. New molecular frameworks containing two distinct privileged
structures connected with stereodivergent linkers. PMB denotes the
p-methoxybenzyl protecting group.
Figure 1. Bioactive small molecules containing carbohybrid (green), py-
rimidine, pyrazole, pyrazolopyrimidine (blue), and triazole (pink) sub-
structures.
frameworks contain two privileged substructures connected
with stereodivergent vicinal diols. Our synthetic scheme was
designed to construct fused triazoles through the intramolec-
ular 1,3-dipolar cycloaddition of azido and alkyne function-
alities, which can be installed at the desired positions of the
polyol moiety. The intramolecular cycloaddition reaction is
quite an efficient transformation and is tolerant of a broad
range of substrates.
Next, we aimed to modify the stereodivergent vicinal diol
functionality in the linker with various chemical reactions,
which would provide new kinds of skeletal diversity through
the creation of additional molecular scaffolds. The various
tetherings of the chirally enriched vicinal diols allowed the
specific display of the two privileged heterocycles in a di-
verse three-dimensional (3D) space owing to the conforma-
tional restriction of the rotatable bonds in the linker region.
In this manuscript, we describe in detail our stereodivergent
synthetic strategy to control the spatial orientation of privi-
leged heterocycles using carbohybrid molecular frameworks.
G
ACHTUNGTRENNUNG
bisACHTUNGTRENNUNGoxazole moiety connected to a carbohydrate-like acyclic
polyol.[12] Many iminoalditols with acyclic polyol chains have
been identified as inhibitors of glycosyltransferases and gly-
cosidases for diverse therapeutic applications.[13] Sialic acid
and its derivatives are polyol-fused heterocyclic molecules
widely distributed in nature.[14] On the basis of these inter-
esting structural motifs, we developed an efficient one-pot
protocol for the synthesis of acyclo-C-nucleosides as carbo-
hybrids starting from 2-C-formyl glycals.[15] Our synthetic
method overcame the limitations of previously reported pro-
tocols that used 2-C-formyl glycals, such as poor yields and
the use of strong base. With this powerful method in hand,
we envisioned the further expansion of our carbohybrid col-
lection through the creation of new molecular frameworks
through the incorporation of various diversity elements, in-
cluding skeletal, stereochemical, and substituent diversity. In
fact, a new type of carbohybrid, elaborated through the
modification of a glycosidic linkage at the polyol moiety, has
been identified in Proteus bacteria (Figure 1, green high-
lights).[16]
Results and Discussion
Preparation of pyrimidine- and pyrazole-based carbohy-
brids: We recently reported the efficient one-pot synthesis
of pyrimidine-, pyrazole-, and pyrazolopyrimidine-based car-
bohybrids from 2-C-formyl glycals.[15] In this study, we
sought to diversify the polyheterocyclic skeletons through
the introduction of fused triazoles in these carbohybrids.
Hence, we prepared the key intermediates 1 and 2 through
the selective protection of hydroxyl groups on d-glucal and
d-galactal, and a subsequent Vilsmeier–Haack formylation.
In brief, the primary hydroxyl group at the C-6 position was
protected with a trityl group, and two of the secondary hy-
droxyl groups were orthogonally protected with p-methoxy-
benzyl (PMB) groups (see the Supporting Information).
Herein, we report a systematic modification of carbohy-
brid collections to create new molecular frameworks that
contain two distinct privileged substructures in a single mol-
ecule. Acyclic polyols fused with pyrimidines, pyrazoles, or
pyrazolopyrimidines served as primary carbohybrid skele-
tons; such heterocycles are privileged substructures fre-
quently observed in bioactive natural products and pharma-
ceutical agents (Figure 1, blue highlights).[17] We also identi-
fied 1,2,3-triazoles fused with diverse heterocycles as modifi-
cation elements for our carbohybrids because they are abun-
dant in many bioactive compounds. In fact, there are only a
half dozen reports on the synthesis of a fused 1,2,3-triazole-
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Molecular Frameworks with Two Heterocycles
FULL PAPER
After formylation in the presence of POCl3 in dimethyl-
ACHTUNGTRENNUNGformACHTUNGTRENNUNGamide (DMF), the intermediates 1 and 2 were trans-
heating at 808C was also required to obtain the desired pyr-
azolopyrimidines 5a,b in moderate to good yields (Table 1,
entries 7 and 8). As observed in the arylhydrazine cases, the
presence of a phenyl substituent at the C-5 position of 3-
aminopyrazole lowered its reactivity and caused a significant
reduction in yield.
formed into acyclic polyol-fused pyrimidines 3, pyrazoles 4,
and pyrazolopyrimidines 5 through the imine formation with
dinucleophiles followed by nucleophilic sugar-ring opening.
As shown in Table 1, this transformation preserved its
broad scope of substrate generality and afforded various
polyheterocycles in moderate to good yields. The dinucleo-
Construction of fused triazoles through intramolecular 1,3-
dipolar cycloadditions: There are many reports on privi-
leged structures as core skeletons for the synthesis of poten-
tially bioactive small molecules and as key binding motifs
for various biopolymers, especially enzymes and proteins.[19]
We previously proposed pDOS[10] as an efficient strategy for
the construction of new polyheterocyclic molecular frame-
works that contain privileged substructures to systematically
perturb various biological processes, including protein–pro-
tein interactions (PPIs). Along this line, we envisioned that
the linking of two privileged substructures in a single hybrid
molecule might be a powerful strategy to modulate potential
PPIs. Each privileged substructure in these hybrid molecules
can serve as a binding motif for different PPI partners,
which could increase the possibility of perturbing a specific
protein–protein interaction in the complex signaling net-
works.
With our robust and general transformation of key inter-
mediates 1 and 2 with various dinucleophiles, including sub-
stituted guanidines, benzamidines, hydrazines, and 3-amino-
pyrazoles, we pursued the further modification of our result-
ing carbohybrids. The construction of new core skeletons
through the connection of two distinct privileged substruc-
tures in a single molecule using various linkers has never
been explored in the fields of molecular diversity and diver-
sity-oriented synthesis. Inspired by their abundance in many
bioactive compounds[18b,d] and the early developmental stage
of druglike fused 1,2,3-triazole libraries,[18a,c–f] we designed
the strategic linkage of fused 1,2,3-triazoles at the other
ends of acyclic C-nucleosides 3–5 (Figure 2).
Table 1. Synthesis of pyrimidine-, pyrazole-, and pyrazolopyrimidine-
based carbohybrids.
Entry
R1
R2
R
Conditions
Yield
[%]
Product
1
2
3
OPMB
H
H
H
OPMB
OPMB
NMe2
NMe2
p-chloro-
RT, 16 h
RT, 16 h
RT, 21 h
85
80
52
3a
3b
3c
AHCTUNGTRENNUNG
4
5
6
7
8
H
H
H
H
H
OPMB
OPMB
OPMB
OPMB
OPMB
808C, 21 h
RT, 14 h
808C, 12 h
808C, 11 h
808C, 12 h
68
94
55
70
44
3d
4a
4b
5a
5b
methyl
phenyl
methyl
phenyl
philic condensation of 2-C-formyl d-glucal 1 along with ring
opening gave almost an identical result to that of 2-C-formyl
d-galactal 2 in terms of yield and the reaction time under
the same conditions (Table 1, entries 1 and 2). In our previ-
ous reports, we clearly demonstrated that both 2-C-formyl
d-glucal and 2-C-formyl d-galactal were coupled with vari-
ous dinucleophiles in a similar pattern (see the Supporting
Information).[15] Therefore, in this report we focused on the
formation of fused triazoles and the subsequent diversifica-
tion in spatial orientation of privileged heterocycles using
galactal-based carbohybrids (Table 1, entries 2–8). When
substituted guanidines and benzamidines were used in a salt
form, we generated the free bases of dinucleophiles in the
presence of K2CO3, which afforded the polyol-fused pyrimi-
dines 3a–d in moderate to respectable yields (Table 1, en-
tries 1–4). Synthesis of the pyrazole-based carbohybrid 4a
was successfully achieved in excellent yields by means of the
cyclocondensation with methylhydrazine under the basic co-
solvent conditions at room temperature (Table 1, entry 5).
In the case of phenylhydrazine, the desired product 4b was
not observed under identical conditions, probably owing to
the inherently poor nucleophilicity of arylhydrazines. How-
ever, thermal activation at 808C allowed the formation of
the desired product 4b in modest yield (Table 1, entry 6). In
the case of 5-substituted 3-aminopyrazoles, the conventional
As shown in Scheme 1, the free secondary hydroxyl
groups in 3–5, generated by the cyclocondensations with di-
nucleophiles, were mesylated, and the trityl-protected pri-
Scheme 1. Synthesis of intermediates (6–8) that harbor b-azido hydroxyl
functionality. i) MsCl, TEA, CH2Cl2, 08C–RT; ii) p-TsOH, MeOH, RT;
iii) NaN3, DMF, 1008C. 3a, 6a: R=NMe2, R1 =OPMB, R2 =H, 62%; 3b,
6b: R=NMe2, R1 =H, R2 =OPMB, 88%; 3c, 6c: R=p-chlorophenyl,
R1 =H, R2 =OPMB, 73%; 4a, 7a: R=Me, 67%; 5a, 8a: R=Me, 75%.
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D. Lim and S. B. Park
mary alcohol was unmasked in the presence of p-toluenesul-
fonic acid in methanol. Then, nucleophilic substitution of
the O-mesyl group with NaN3 in DMF afforded intermedi-
ates 6–8 that bore b-azido hydroxyl functionality in excellent
three-step yields. Owing to the mild reaction conditions, no
deterioration of chiral enrichment was observed, which
might have been caused by the epoxide-associated epimeri-
zation through neighboring-group participation (see the
Supporting Information). For the formation of the fused tri-
azoles, alkyne functionality was then introduced by the reac-
tions of the hydroxyl groups in 6–8 with various alkyne
building blocks. As shown in Scheme 2, the nucleophilic sub-
lectively formed single 1,5-regioisomers without copper cat-
alyst, regardless of alkynyl substituents due to the restricted
geometries. However, it is worth mentioning that the cyclo-
addition reaction rate was much slower in the case of the
ester intermediates (Scheme 2, pathway II) than the other
substrates under conventional reflux conditions. Instead, mi-
crowave irradiation in DMF for 3 min at 150 W and 1208C
was sufficient to convert all the ester intermediates to the
desired 1,2,3-triazoles in good yields.
As shown in Tables 2 and 3, we successfully achieved the
efficient synthesis of new chimera compounds (9–11) that
contained various fused triazoles and privileged heterocycles
Table 2. New molecular frameworks containing two distinct privileged
substructures in a single hybrid molecule obtained through pathway I.
Entry HetAr
R1
R2
R
Yield [%] Product
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
A
A
A
A
A
A
A
A
A
A
A
A
A
B
OPMB
OPMB
OPMB
OPMB
OPMB
OPMB
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
hydrogen
methyl
ethyl
65
89
90
65
73
67
78
80
89
64
58
84
42
77
60
88
9a
9b
9c
9d
9e
9 f
9g
9h
9i
9j
9k
9l
9m
9n
9o
9p
phenyl
3-methoxyphenyl
1-naphthalene
hydrogen
methyl
H
OPMB
OPMB
OPMB
OPMB
OPMB 4-fluorophenyl
OPMB 4-methoxyphenyl
OPMB
OPMB
OPMB
OPMB
ethyl
phenyl
2-thienyl
methyl
methyl
methyl
C
D
Scheme 2. Synthesis of fused 1,2,3-triazoles. I) Haloalkynes, NaH, DMF
(SN2-type O-alkylation), then heating in toluene at reflux. II) Alkynyl
acids, diisopropyl azodicarboxylate (DIAD), PPh3, THF (Mitsunobu re-
action), then microwave irradiation, 150 W, 1208C, DMF. III) Alkynyl
sulfonamides, DIAD, PPh3, THF (Mitsunobu reaction), then heating in
toluene at reflux.
Table 3. New molecular frameworks containing two distinct privileged
structures in a single hybrid molecule obtained through pathways II and
III.
stitution of various alkynyl halides with the b-azido hydroxyl
moiety in the presence of NaH afforded the corresponding
ether intermediates, which underwent the intramolecular
1,3-dipolar cycloadditions in toluene heated to reflux with-
out further purification to yield the desired morpholine-
fused triazoles 9 in moderate to excellent yields (Scheme 2,
pathway I). The hydroxyl moieties in 6–8 were also convert-
ed to ester linkages through Mitsunobu reactions with al-
kynyl acids, and the subsequent intramolecular 1,3-dipolar
cycloadditions yielded 2-morpholine-fused triazoles 10 in ex-
cellent yields (Scheme 2, pathway II). Alkynyl sulfonamides
were successfully introduced under Mitsunobu conditions,
and the subsequent intramolecular cycloaddition in toluene
heated to reflux afforded piperazine-fused triazoles 11 in
high yields (Scheme 2, pathway III). Unlike Huisgen cyclo-
addition, these intramolecular 1,3-dipolar cycloadditions se-
Entry Path HetAr
R1
R2
R
Yield Product
[%]
1
2
3
4
5
6
7
8
9
II
II
II
II
II
A
A
B
B
C
C
A
A
A
OPMB
H
H
H
H
H
methyl
methyl
methyl
ethyl
methyl
phenyl
hydrogen
phenyl
4-methyl-
phenyl
95
72
92
90
73
77
58
73
70
10a
10b
10c
10d
10e
10 f
11a
11b
11c
OPMB
OPMB
OPMB
OPMB
OPMB
H
II
H
III
III
III
OPMB
OPMB
OPMB
H
H
10
III
A
OPMB
H
4-cyano-
AHCTUNGTRENGNpUN henyl
71
11d
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Molecular Frameworks with Two Heterocycles
FULL PAPER
connected with chirally enriched vicinal diols. This synthetic
route is modular enough to construct any combination of
fused 1,2,3-triazoles with privileged polyheterocycles, which
dramatically enhances the expandability of their molecular
diversity. In addition, we can envision the access to all possi-
ble diastereomers of final compounds by using different
starting d- and l-hexoses.
Modification of the linker to maximize skeletal diversity in
3D space: After the successful construction of new chimera
compounds that contained fused 1,2,3-triazoles and privi-
leged heterocycles connected with chirally enriched vicinal
diols, we pursued the introduction of a new diversity ele-
ment. This was to be achieved through molecular-shape
transformation by using various chemical reactions of the
stereodivergent vicinal diols in the linker. In fact, the actual
arrangement of privileged substructures in 3D space might
be critical to potential interactions with biopolymers.[20] By
interlocking vicinal diols in the linkers of our chimera com-
pounds, the projection of two privileged structures could be
dramatically changed, and the potential interaction of these
unique skeletons to biopolymers can be quite specific due to
their limited conformational freedom with a prepaid entrop-
ic penalty. The generation of molecular-shape diversity
might lead to the diversification of biological activity, with a
similar set of appendages in a complementary 3D fashion.
To this end, the PMB protecting groups were removed in
the presence of 20% trifluoroacetic acid in dichloromethane
to release free vicinal diols in excellent yields (Table 4).
As shown in Scheme 3, the resulting vicinal diols were
modified through various chemical transformations to
uniquely position the two privileged substructures in 3D
space. For example, the acetal exchange reaction of the
glucal-derived (R,R)-vicinal diol 12b with p-anisaldehyde di-
methyl acetal afforded the chimera compound 13b that con-
tained p-methoxyphenyl acetal as a 71:29 diastereomeric
Scheme 3. Modification of the linker to maximize skeletal diversity in 3D
space. i) DDQ, CH2Cl2, 08C–RT; 13b, 59% d.r.=81:19; 13h, 33%, d.r.=
66:34. ii) Anisaldehyde dimethyl acetal, p-TsOH, CH2Cl2, RT; 13b, 55%,
d.r.=71:29. iii) 2,2-Dimethoxypropane, p-TsOH, acetone, RT; 14b, 85%.
iv) Acetic anhydride, TEA, 4-dimethylaminopyridine (DMAP), CH2Cl2,
RT; 15b, 95%; 15h, 89%. v) CDI, CH2Cl2, RT; 16b, 79%. vi) NaN3,
H2O, DMF, 1108C; 17b, 49%.
1
mixture as determined by H NMR spectroscopy. Interest-
Table 4. Deprotection of PMB groups in the linker.
ingly, 13b can also be obtained
by 2,3-dichloro-5,6-dicyanoben-
zoquinone (DDQ) treatment of
PMB-protected 9b in anhy-
drous CH2Cl2 with a similar
Entry
SM
HetAr
R1
R2
R3
R4
R
Yield [%]
Product
81:19
diastereomeric
ratio.
1
2
3
4
5
6
7
8
9
9a
9b
9c
9g
9h
9i
9j
9k
9l
A
A
A
A
A
A
A
A
A
A
B
OPMB
OPMB
OPMB
H
H
H
H
H
H
H
H
H
OH
OH
OH
H
H
H
H
H
H
H
H
H
H
hydrogen
methyl
ethyl
hydrogen
methyl
ethyl
99
92
92
99
88
99
96
96
89
76
94
99
12a
12b
12c
12g
12h
12i
12j
12k
12l
When
the galactal-derived
(R,S)-vicinal diol compound 9h
with PMB protecting groups
was treated with DDQ, a differ-
ent p-methoxyphenyl acetal-
containing chimera compound
13h was obtained, with a dia-
stereomeric ratio of 66:34. The
OPMB
OPMB
OPMB
OPMB
OPMB
OPMB
OPMB
OPMB
OPMB
OH
OH
OH
OH
OH
OH
OH
OH
OH
phenyl
4-fluorophenyl
4-methoxyphenyl
2-thienyl
methyl
10
11
12
9m
9n
9o
H
H
H
12m
12n
12o
H
H
glucal-derived
(R,R)-vicinal
C
methyl
diol 12b was tolerant of various
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D. Lim and S. B. Park
diol-based chemical transformations. For example, the acid-
catalyzed acetal exchange reaction of 12b with 2,2-dime-
thoxypropane provided dimethyl acetal 14b in high yield,
and the treatment of 12b with 1,1-carbonyldiimidazole
(CDI) in CH2Cl2 allowed the formation of carbonate 16b in
good yield. However, the galactal-derived (R,S)-vicinal diol
12h did not undergo the ring-forming exchange reaction to
the dimethyl acetal under identical conditions (Scheme 3,
route iii), possibly due to A1,2-strain-like repulsion between
two privileged heterocycles upon acetal-based cyclization of
the vicinal diol. Similarly, the carbonate compound synthe-
sized by the treatment of 12h with CDI was transiently gen-
erated, but readily decomposed back to the starting com-
pound 12h at room temperature, which demonstrated the
instability of the tethered five-membered ring system from
galactal-derived (R,S)-vicinal diols (see Figure 3c).
16b, and 17b) with identical appendages that differed with
respect to stereochemistry and/or tethering moiety of vicinal
diols. The eight compounds were virtually modeled in 3D
space, and their energy-minimized molecular structures
were superimposed and aligned with respect to the pyrimi-
dine group. As shown in Figure 3a, the orientations of mor-
pholine-fused triazoles diverged significantly in 3D space
through the rigidified linker regions, which emphasized the
importance of the shape diversity in our chimera compounds
and the associated spacial display of two privileged substruc-
tures within a single molecule. Moreover, to quantify the
discrete shape differences of eight representative com-
pounds in 3D space, we performed the normalized principal
moments of inertia (PMI) analysis.[22] The PMI analysis has
been used to capture the shape-based distribution of the
small molecule library. The points in the resulting plot
occupy an isosceles triangle defined by the vertices (0,1),
(0.5,0.5), and (1,1), which correspond to the shape of a rod,
disc, and sphere, respectively. As shown in Figure 3b, our
representative compounds were dispersed in the PMI plot,
which indicates that our linker-diversification strategy of
stereodivergent vicinal diols allows access to different chem-
ical spaces by means of the unique display of two privileged
substructures in 3D space.
The differences in the stereochemistry and linker tether-
ing lead to the significant shape and skeletal diversity of
final compounds, thus emphasizing the importance of the
unique design of molecular frameworks and their connectiv-
ity. It is worth mentioning that the overall shape of a small
molecule is the most fundamental element that influences
its specific modulation of biological functions and signaling
pathways. Indeed, a substantial “shape space” coverage (in
other words, molecular-shape diversity) has been correlated
with a broad range of perturbations in biological activi-
ties.[22] In this study, we demonstrated that the shape space
coverage of chimera carbohybrids that contain two unique
privileged substructures could be expanded through the
tethering of the stereodivergent vicinal diols in the linker
region. Therefore, in the field of diversity-oriented synthesis,
our linker-diversification strategy affords a new way to
access molecular-shape diversity in 3D space and a new tool
to expand this molecular diversity without significant
changes in substituents.
Figure 3. a) Overlay of eight representative molecules. Energy-minimized
conformers were aligned with respect to the pyrimidine moiety. Branch-
ing linker atoms are not shown in this figure for clarity. b) PMI plot de-
picting the eight representative compounds. c) The structural differences
in energy-minimized conformers of glucal-derived (R,R)-carbonate 16b
and unstable galactal-derived (R,S)-carbonate.
The further diversification of stereodivergent vicinal diols
was carried out through nucleophilic ring opening of the
cyclic carbonate 16b with NaN3 to yield the monohydroxy-
Conclusion
A
New molecular frameworks were developed through the sys-
tematic incorporation of two distinct privileged substruc-
tures in a single molecule. As substituents of carbohybrids,
pyrimidines, pyrazoles, and pyrazolopyrimidines were syn-
thesized by means of the condensations of common inter-
mediates, 2-C-formyl glycals, with the corresponding dinu-
cleophiles in simple one-pot procedures. To enhance the bio-
logical relevance of these compounds, particularly with re-
spect to the potential perturbations of protein–protein inter-
actions, privileged fused triazoles were introduced at the
diversity of our compound collections, the stereodivergent
vicinal diols were modified with acetylation to provide 15b
and 15h as a linear version of our chimera compounds.
Overall, the vicinal diol modifications introduced new
skeletal diversity in our compound collection: two heterocy-
clic substructures could be uniquely oriented in 3D space
through the tethering process of vicinal diols. To visualize
the shape diversity we achieved, we selected eight represen-
tative chimera compounds (9h, 12b, 13b, 13h, 14b, 15b,
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FULL PAPER
cleophile (2 equiv) and K2CO3 (5 equiv) in ethanol (3 mL). The reaction
mixture was stirred at room temperature or 808C until the full conver-
sion of starting materials monitored by TLC. The solvent was removed
under reduced pressure and the residue was partitioned between ethyl
acetate and water. The aqueous layer was extracted with ethyl acetate
twice, and the combined organic layer was dried over anhydrous Na2SO4.
The filtrate was condensed under reduced pressure and subjected to flash
column chromatography. Carbohybrid 3b: Prepared from 2 and 1,1-dime-
other end of the resulting carbohybrids. The b-azido hydrox-
yl moieties in the key intermediates were prepared by selec-
tive polyol modifications, and the primary hydroxyl groups
were modified with various alkyne building blocks. The re-
sulting intermediates, which contain both azido and alkyne
functionalities, were then subjected to intramolecular
copper-free 1,3-dipolar cycloaddition by conventional heat-
ing or microwave irradiation to efficiently yield the fused
1,2,3-triazoles as a single 1,5-regioisomer. The key feature of
these carbohybrids was the connection of two privileged het-
erocycles with a stereochemically enriched vicinal diol
linker, which was further utilized for the expansion of mo-
lecular-shape diversity through tethering of the stereodiver-
gent vicinal diols using various chemical reactions. This al-
lowed the unique orientation of privileged substructures in
3D space. This linker-diversification strategy offers a new di-
versity element through molecular-shape transformation
without substituent changes. PMI analysis and the structure
alignment of energy-minimized representative compounds
clearly demonstrated the importance of stereochemistry and
linker-modification chemistry of vicinal diols. The molecular
recognition of bioactive small molecules by biopolymers is
significantly influenced by their 3D conformations.[23] There-
fore, the linker-diversification strategy and our new molecu-
lar frameworks can provide a valuable platform on which to
build molecular diversity in 3D space, ultimately leading to
the identification of specific bioactive small molecules, par-
ticularly protein–protein interaction modulators.
thylguanidine sulfate salt, amorphous white solid. Yield: 80%; [a]D25
=
À9.69 (c=0.91, CHCl3); Rf =0.17 (EtOAc/hexane 1:2); 1H NMR
(500 MHz, CDCl3): d=8.24 (s, 2H), 7.42 (d, J=8.1 Hz, 6H), 7.30–7.22
(m, 9H), 7.15 (d, J=8.6 Hz, 2H), 6.82–6.78 (m, 4H), 6.69 (d, J=8.3 Hz,
2H), 4.40 (d, J=11.2 Hz, 1H), 4.24 (d, J=7.6 Hz, 1H), 4.18 (d, J=
11.2 Hz, 1H), 4.11–4.05 (m, 3H), 3.78 (s, 3H), 3.76 (s, 3H), 3.73 (dd, J=
7.6, 2.4 Hz, 1H), 3.27 (dd, J=9.3, 6.1 Hz, 1H), 3.21 (s, 6H), 3.08 (dd, J=
9.3, 6.4 Hz, 1H), 2.39 ppm (d, J=7.6 Hz, 1H); 13C NMR (125 MHz,
CDCl3): d=162.4, 159.5, 159.4, 157.9, 144.1, 130.2, 129.8, 129.7, 128.9,
128.0, 127.2, 119.1, 114.0, 113.8, 86.9, 81.0, 76.5, 74.3, 70.3, 70.0, 64.7, 60.6,
55.5, 37.4, 14.4 ppm; HRMS (FAB+): m/z calcd for C45H47N3O6 [M+H]+
: 726.3543; found: 726.3536.
General procedure for the preparation of key intermediates 6–8 that
harbor b-azido hydroxyl functionality: Triethylamine (TEA; 3 equiv) and
MsCl (Ms=mesylate; 2 equiv) were added to a stirred solution of pri-
mary carbohybrid 3–5 (1 equiv) in anhydrous CH2Cl2 at 08C. The mixture
was stirred at 08C for 2 h, diluted with CH2Cl2 and washed with brine.
The aqueous layer was extracted with CH2Cl2, and the combined organic
layer was dried over anhydrous Na2SO4. After removal of the organic sol-
vent under reduced pressure, the crude mesylated product was dissolved
in methanol, followed by the addition of p-TsOH (1.5 equiv). After stir-
ring for 8 h at room temperature, the solvent was removed under the re-
duced pressure, and the residue was partitioned between ethyl acetate
and saturated NaHCO3 solution. The aqueous layer was extracted with
ethyl acetate twice, and the combined organic layer was dried over anhy-
drous Na2SO4. The filtrate was condensed under reduced pressure and
subjected to flash column chromatography. The detritylated product
(1 equiv) was dissolved in DMF and NaN3 (5 equiv) was added, after
which the mixture was stirred at 1008C for 12 h. The solvent was re-
moved and the residue was partitioned between ethyl acetate and water.
The aqueous layer was extracted with ethyl acetate, and the combined or-
ganic layer was dried over anhydrous Na2SO4. The filtrate was condensed
under reduced pressure and subjected to flash column chromatography
to obtain key intermediates 6–8. Intermediate 6a: Prepared from carbo-
hybrid 3a, white syrup. Yield: 62%; [a]2D5 =À55.11 (c=0.74, CHCl3); Rf =
0.19 (EtOAc/hexane 1:1); 1H NMR (500 MHz, CDCl3): d=8.31 (s, 2H),
7.22–7.18 (m, 4H), 6.86–6.84 (m, 4H), 4.63 (s, 2H), 4.47–4.43 (m, 2H),
4.23 (d, J=11.2 Hz, 1H), 3.80 (s, 6H), 3.65 (t, J=5.4 Hz, 1H), 3.60 (d,
J=4.9 Hz, 2H), 3.26 (q, J=5.1 Hz, 1H), 3.22 (s, 6H), 1.94 ppm (brs,
1H); 13C NMR (125 MHz, CDCl3): d=162.4, 159.51, 159.49, 157.6, 130.3,
129.9, 129.8, 129.6, 117.9, 114.0, 113.9, 81.1, 78.4, 74.9, 70.6, 63.5, 62.3,
55.39, 55.36, 37.3 ppm; HRMS (FAB+): m/z calcd for C26H32N6O5
[M+H]+: 509.2512; found: 509.2515.
Experimental Section
General: All commercially available reagents and solvents were used
without further purification unless noted otherwise. All the solvents were
purchased form commercial venders. 1H and 13C NMR spectra were ob-
tained using Bruker DRX-300 (Bruker Biospin, Germany), Agilent 400-
MR DD2 (Agilent, USA), or Varian Inova-500 (Varian Assoc., Palo
Alto, USA) instruments. Chemical shifts were reported in ppm from tet-
ramethylsilane (TMS) as internal standard or the residual solvent peak
1
(CDCl3; H: d=7.26 ppm; 13C: d=77.23 ppm). Multiplicity was indicated
as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet),
dd (doublet of doublet), dt (doublet of triplet), td (triplet of doublet),
brs (broad singlet), and so on. Coupling constants are reported in hertz.
Mass spectrometric analysis was performed using a Finnigan Surveyor
MSQ Plus LC/MS (Thermo) with electrospray ionization (ESI). Micro-
wave reaction was performed using a CEM Discover Benchmate micro-
wave synthesizer. The conversion of starting materials was monitored by
thin-layer chromatography (TLC) using precoated glass-backed plates
(silica gel 60; F254 =0.25 mm), and the reaction components were visual-
ized by observation under UV light (254 and 365 nm) or by treatment of
TLC plates with visualizing agents such as KMnO4, phosphomolybdic
acid, ceric sulfate, and ninhydrin followed by heating. Products were pu-
rified by flash column chromatography on silica gel (230–400 mesh) using
a mixture of EtOAc/hexane or MeOH/CH2Cl2 as eluents. The energy-
minimized structures of molecules were obtained by Vconf Interface v2.0
using default parameters and visualized by Discovery Studio 3.0. The
principal moment of inertia (PMI) of the energy-minimized structures
was calculated using PreADMET v2.0 and visualized by a PMI plot as
described previously.[22a]
General procedure for the preparation of morpholine-fused triazoles 9:
NaH (2 equiv) was added to a stirred solution of key intermediates 6–8
in anhydrous DMF at 08C. After stirring the mixture for 15 min at 08C,
alkynyl halide (1.5 equiv) was added, and the mixture was stirred at
room temperature for 5 h. The solvent was removed under reduced pres-
sure, and the residue was partitioned between ethyl acetate and brine.
The aqueous layer was extracted with ethyl acetate, and the combined or-
ganic layer was dried over anhydrous Na2SO4. The filtrate was condensed
under reduced pressure and dissolved in toluene. The mixture was heated
to reflux for 4 h. After removal of the solvent, the residue was subjected
to flash column chromatography. In some cases, the crude mixture in
DMF was heated to 1108C to give morpholine-fused triazoles 9 in a one-
pot manner. After completion of the reaction, the purification step was
the same as described above. Triazole 9b: prepared from intermediate 6a
and 1-bromo-2-butyne; white solid. Yield: 89%; [a]2D5 =À60.08 (c=0.58,
CHCl3); Rf =0.09 (EtOAc/hexane 1:1); 1H NMR (500 MHz, CDCl3): d=
8.25 (s, 2H), 7.15–7.10 (m, 4H), 6.80–6.78 (m, 4H), 4.62–4.50 (m, 4H),
4.45–4.40 (m, 2H), 4.34 (d, J=11.2 Hz, 1H), 4.15–4.10 (m, 3H), 3.76–3.74
General procedure for the preparation of pyrimidine-, pyrazole-, and pyr-
azolopyrimidine-based carbohybrids 3–5: A solution of 2-C-formyl glycal
1 or 2 (100 mg) in THF (3 mL) was added to a stirred solution of dinu-
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D. Lim and S. B. Park
(m, 7H), 3.18 (s, 6H), 2.08 ppm (s, 3H); 13C NMR (125 MHz, CDCl3):
d=162.1, 159.4, 159.3, 157.7, 136.6, 130.2, 129.84, 129.79, 129.7, 127.5,
117.7, 113.8, 80.4, 77.4, 74.8, 70.0, 64.7, 62.0, 56.0, 55.33, 55.31, 37.2,
9.8 ppm; HRMS (FAB+): m/z calcd for C30H36N6O5 [M+H]+: 561.2825;
found: 561.2821.
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General procedure for the preparation of 2-morpholione-fused triazoles
10: Diisopropyl azodicarboxylate (1.2 equiv) was added slowly to a stir-
red solution of key intermediates 6–8 (1 equiv), triphenylphosphane
(1.2 equiv), and akynic acids (1.2 equiv) in anhydrous THF at 08C. The
mixture was stirred at 08C for 1.5 h. After removal of the solvent, the
residue was subjected to flash column chromatography to give ester inter-
mediates. They were dissolved in DMF and heated in a capped micro-
wave vessel under microwave irradiation (150 W, 1208C) for 3 min. After
removal of the solvent, the residue was subjected to flash column chro-
matography. Triazole 10a: Prepared from intermediate 6a and 2-butynoic
acid, yellow solid. Yield: 95%; [a]2D5 =À16.09 (c=0.61, CHCl3); Rf =0.19
(EtOAc/hexane 1:1); 1H NMR (300 MHz, CDCl3): d=8.42 (s, 2H), 7.14
(d, J=8.7 Hz, 2H), 7.03 (d, J=8.7 Hz, 2H), 6.85–6.76 (m, 4H), 4.68–4.64
(m, 1H), 4.54 (d, J=5.8 Hz, 1H), 4.46–4.40 (m, 3H), 4.33 (d, J=10.5 Hz,
1H), 4.23 (d, J=10.5 Hz, 1H), 4.16 (d, J=11.1 Hz, 1H), 3.92–3.89 (m,
1H), 3.79 (s, 3H), 3.78 (s, 3H), 3.22 (s, 6H), 2.54 ppm (s, 3H); 13C NMR
(75 MHz, CDCl3): d=162.6, 159.8, 159.7, 158.1, 156.7, 148.9, 131.0, 130.1,
129.2, 128.4, 121.8, 117.0, 114.1, 114.0, 79.3, 77.4, 74.9, 70.6, 68.5, 55.7,
55.5, 55.4, 37.3, 11.4 ppm; HRMS (FAB+): m/z calcd for C30H34N6O6
[M+H]+: 575.2618; found: 575.2622.
General procedure for the preparation of piperazine-fused triazoles 11:
Diisopropyl azodicarboxylate (1.5 equiv) was added slowly to a stirred
solution of key intermediates 6–8 (1 equiv), triphenylphosphane
(1.5 equiv), and akynic sulfonamides (1.5 equiv) in anhydrous THF at
08C. The mixture was stirred at room temperature for 12 h. After remov-
al of the solvent, the residue was subjected to flash column chromatogra-
phy, and the resulting intermediate was stirred in toluene heated at
reflux for 3 h. After removal of the solvent, the residue was subjected to
flash column chromatography. Triazole 11b: prepared from intermediate
6a and 4-methyl-N-(3-phenylprop-2-yn-1-yl)benzenesulfonamide, yellow
solid. Yield: 73%; [a]2D5 =À50.39 (c=0.46, CHCl3); Rf =0.20 (EtOAc/
hexane 2:3); 1H NMR (400 MHz, CDCl3): d=8.39 (s, 2H), 7.60–7.55 (m,
4H), 7.46–7.43 (m, 2H), 7.37–7.32 (m, 3H), 7.08–7.03 (m, 4H), 6.77–6.71
(m, 4H), 4.72–4.67 (m, 2H), 4.46 (d, J=11.7 Hz, 1H), 4.34–4.19 (m, 3H),
4.15–4.09 (m, 2H), 4.02 (d, J=11.7 Hz, 1H), 3.71 (s, 3H), 3.69 (s, 3H),
3.52 (dd, J=13.1, 5.7 Hz, 1H), 3.17–3.13 (m, 7H), 2.46 ppm (s, 3H);
13C NMR (100 MHz, CDCl3): d=162.4, 159.59, 159.57, 157.9, 144.9, 141.9,
132.8, 130.8, 130.6, 130.4, 129.5, 129.1, 129.0, 128.2. 127.8, 126.3, 125.4,
117.5, 113.99, 113.98, 80.2, 75.1, 74.8, 69.8, 57.2, 55.4, 55.3, 44.4, 42.8, 37.3,
21.8 ppm; HRMS (FAB+): m/z calcd for C42H45N7O6S [M+H]+:
776.3230; found: 776.3234.
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Acknowledgements
This work was supported by the Bio & Medical Technology Development
Program (2012M3A9C4048780), the Global Frontier Project Grant
(2011-0032150), the WCU program (R31-10032), and the Basic Research
Laboratory (2010-0019766) funded by the National Research Foundation
of Korea (NRF). D.L. is grateful for fellowships awarded by the Seoul
Science Fellowship.
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Molecular Frameworks with Two Heterocycles
FULL PAPER
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Received: December 3, 2012
Revised: February 13, 2013
Published online: && &&, 0000
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D. Lim and S. B. Park
A privileged few: Molecular frame-
works were synthesized from carbohy-
drates through the incorporation of
two unique privileged substructures
connected by stereodivergent diol link-
ers (see scheme). The vicinal diols
were modified by tethering chemistry
to maximize molecular-shape diversity
through the distinct display of two
privileged substructures in 3D space,
namely, the linker diversification
Fused-Ring Systems
D. Lim, S. B. Park* .......... &&&& — &&&&
Synthesis of Molecular Frameworks
Containing Two Distinct Heterocycles
Connected in a Single Molecule with
Enhanced Three-Dimensional Shape
Diversity
AHCTUNGTRENNsGUN trategy.
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