Construction of polyheterocyclic benzopyran library with diverse core skeletons through diversity-oriented synthesis pathway: Part II

Article abstract of DOI:10.1021/co2001907

As a continuation of our previous report (J. Comb. Chem.2010, 12, 548-558), we accomplished the diversity-oriented synthesis of polyheterocyclic small-molecule library with privileged benzopyran substructure. To ensure the synthetic efficiency, we utilized the solid-phase parallel platform and the fluorous-tag-based solution-phase parallel platform to construct a 284-member polyheterocyclic library with six distinct core skeletons with an average purity of 87% on a scale of 5-10 mg. This library was designed to maximize the skeletal diversity with discrete core skeletons in three-dimensional space and the combinatorial diversity with four different benzopyranyl starting materials and various building blocks. Together with our reported benzopyranyl library, we completed the construction of polyheterocyclic benzopyran library with 11 unique scaffolds and their molecular diversity was visualized in chemical space using principle component analysis (PCA).

Full text of DOI:10.1021/co2001907

Research Article
pubs.acs.org/acscombsci
Construction of Polyheterocyclic Benzopyran Library with Diverse
Core Skeletons through Diversity-Oriented Synthesis Pathway: Part II
Mingyan Zhu,† Byung Joon Lim,† Minseob Koh,† and Seung Bum Park*,†,‡
†Department of Chemistry and ‡Department of Biophysics and Chemical Biology, Seoul National University, Seoul 151−747, Korea
S
* Supporting Information
ABSTRACT: As a continuation of our previous report (J. Comb.
Chem. 2010, 12, 548−558), we accomplished the diversity-
oriented synthesis of polyheterocyclic small-molecule library with
privileged benzopyran substructure. To ensure the synthetic effi-
ciency, we utilized the solid-phase parallel platform and the
fluorous-tag-based solution-phase parallel platform to con-
struct a 284-member polyheterocyclic library with six distinct
core skeletons with an average purity of 87% on a scale of 5−
10 mg. This library was designed to maximize the skeletal
diversity with discrete core skeletons in three-dimensional
space and the combinatorial diversity with four different benzo-
pyranyl starting materials and various building blocks. Together
with our reported benzopyranyl library, we completed the construction of polyheterocyclic benzopyran library with 11 unique
scaffolds and their molecular diversity was visualized in chemical space using principle component analysis (PCA).
KEYWORDS: benzopyran, parallel synthesis, fluorous tag, diversity-oriented synthesis, skeletal diversity
for the construction of eleven core skeletons via various chemical
transformations.9a On the basis of our initial report, we also
demonstrated the practical construction of 434-member library
containing five core skeletons using solid-phase parallel
synthesis format.9b Herein, we carried out the construction of
six discrete core skeletons embedded with the benzopyranyl
substructure as a continuation of our previous efforts.
INTRODUCTION
■
The systematic perturbation of gene products with small-
molecule modulators has been one of the major research areas
in the interdisciplinary research field of chemical biology as well
as pharmaceutical industry.1 The development of high
throughput screening technology toward increasing number
of disease targets led to the ever-increasing demand for the
collection of novel drug-like small molecules with maximized
molecular diversity.2 To accomplish this, synthetic communities
adopted a diversity-oriented synthesis (DOS) approach that
aims for the efficient generation of complex and diverse
compound libraries containing a large number of structurally
diversified molecular frameworks.3 We have been particularly
interested in the development of divergent and robust synthetic
pathways for the systematic construction of a library of drug-
like small molecules via the creative reconstruction of polyhe-
terocycles embedded with privileged substructures including
benzopyran, benzodiazepine, pyrazole, pyrazolopyrimidine,
tetrahydroindazolone, and so on; we named this approach a
privileged-substructure-based diversity-oriented synthesis
(pDOS).4 Noteworthy, our novel molecular frameworks with
privileged substructure showed the enhanced selectivity and
relevancy toward multiple biological assay systems as small-
molecule modulators for specific biological targets.5
As shown in Figure 1, our divergent synthetic route was
designed to access six discrete core skeletons from key ben-
zopyranyl intermediates 3{1−4} through a series of chemical
transformations, such as palladium-mediated Suzuki coupling
(Path I), Suzuki coupling-based vinylation followed by aza
Diels−Alder reaction (Path II) and Diels−Alder reaction (Path
III), and subsequent aromatization of Diels−Alder adducts
(Path IV), and Stille coupling-based alkynylation followed by
copper(I)- and ruthenium(II)-catalyzed regioselective alkyne−
azide cycloaddition to produce 1,4-disubstituted triazoles (Path V)
and 1,5-disubstituted triazoles (Path VI), respectively. Paths II,
III, and IV allow the construction of benzopyranyl tetracycles
(8, 9, and 10) with three unique trajectories of core skeletons
in 3-dimensional space. Paths V and VI can generate the regioi-
someric pairs of 1,4- and 1,5-disubstituted heterobiaryl
skeletons (12 and 13) with different orientations of appen-
dence. These synthetic paths were designed to maximize the
molecular diversity of resulting small-molecule library. To
ensure the efficiency in library construction without laborious
To construct novel molecular frameworks using pDOS stra-
tegy, we aimed to develop a practical synthetic route for unique
polyheterocycles containing a benzopyranyl substructure, which
is a well-known privileged structural motif observed in many
biologically active natural products and therapeutic agents.6−8
We previously reported a concise and efficient DOS pathway
Received: November 10, 2011
Revised: December 14, 2011
Published: December 19, 2011
© 2011 American Chemical Society
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Figure 1. (A) Divergent pDOS strategy for the construction of six discrete core skeletons embedded with benzopyran substructure: Suzuki coupling
[Path I]; vinylation, subsequent Diels−Alder reaction with aza dienophile and carbon dienophile, and aromatization reaction [Paths II to IV];
alkynylation and subsequent copper(I) and ruthenium(II)-catalyzed alkyne−azide cycloaddition [Paths V and VI]. (B) Chemical structures of key
benzopyranyl intermediates 3{1−4}.
purification steps, we optimized these synthetic routes in solid-
phase parallel synthesis format using polystyrene resin (Path I)
and the fluorous-tag-based solution-phase parallel synthesis
format (Paths II−VI). In fact, the fluorous technology has
received attention from synthetic community, especially for
high-throughput synthesis, because this technology retains the
advantage of solution-phase reaction without the sacrifice of its
synthetic throughput, due to the simple purification by fluorous-
tag-based solid-phase extraction (F-SPE).10
Scheme 1. Synthetic Scheme for Vinyl Bromide
Intermediates 3 and their Modification on Solid Support 4
and with Fluorous Tag 5
a
RESULTS AND DISCUSSION
■
We initiated the library construction with four different
chromanones (1{1}−1{4}) via pyrrolidine-catalyzed cyclization
of substituted ortho-hydroxyacetophenones with acetone
(See Scheme 1). To enhance the molecular diversity and
biocompatibility of final drug-like polyheterocycles, two of the
chromenones, 1{3} and 1{4}, were prepared with an additional
Suzuki coupling with 3-hydroxyphenylboronic acid to introduce
biphenyl moiety, another privileged substructural motif. Four
resulting chromanones 1{1−4} were subjected to α-bromina-
tion and subsequent silyl protection at phenolic hydroxyl group.
α-Bromoketones 2{1−4} were reduced to α-bromoalcohols by
NaBH4, followed by acid-catalyzed dehydration and subsequent
silyl deprotection, to yield four vinyl bromides containing ben-
zopyranyl substructure, 3{1−4}, as key intermediates.
a
Reagents and conditions: (a) Acetone, pyrrolidine, EtOH, reflux; for
1{3−4}, an additional Suzuki coupling with bromo-substituted
chromanone and 3-hydroxyphenylboronic acid, Na2CO3, Pd(PPh3)4,
EtOH/toluene/H2O, 70 °C; (b) CuBr2, EtOAc/CHCl3/MeOH,
reflux; (c) Triisopropylsilyl chloride, imidazole, DCM, rt; (d)
NaBH4, EtOH, 40 °C; (e) p-TsOH, toluene, 80 °C; (f) TBAF,
THF, rt; (g) TMSCl, DCM; (h) TfOH, DCM; (i) 2,6-Lutidine,
DCM.
As stated earlier, our synthetic routes were adapted to solid-
phase parallel synthesis and the fluorous-tag-based solution-
phase parallel synthesis platform for the efficient library con-
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Scheme 2. Solid-Phase Suzuki Coupling Reaction with Aryl/Heteroaryl-Boronic Acids for the Synthesis of Compounds
6{1−4,1−24} in Path I and the Chemical Structures of Aryl- and Heteroaryl-Boronic Acids
struction. In the case of path I, the desired heterobiaryl com-
pounds 6 were successfully prepared by our reported Suzuki
coupling condition using vinyl bromide intermediates on solid
support, 4{1−4}, without any further optimizations. However,
we observed incomplete reaction, even with prolonged reaction
time and observed side products during the translation into
solid-phase reaction in other synthetic paths (II−VI), which led
us to carry them out in solution-phase with fluorous-tagged
intermediates 5{1−4}. After the activation of (4-methoxyphenyl)-
diisopropylsilylpropyl polystyrene resin with TfOH, vinyl bromide
intermediates 3{1−4} were immobilized on the activated resin
in the presence of 2,6-lutidine to afford polymer-bound inter-
mediates 4{1−4} (see Scheme 1). The average loading level
was about 1.0 mmol/g (see Supporting Information), which
was quantified by the weight gain of loaded resins and con-
firmed with the weight of cleaved products from loaded resins.
For the preparation of vinyl bromide intermediates with
fluorous tag, diisopropyl-(1H,1H,2H,2H-perfluorodecyl)silane
tag was activated with TfOH and subsequently incubated with
vinyl bromide intermediates 3{1−4} in the presence of 2,6-
lutidine to afford perfluorooctanesilyl-labeled hydroxylchrome-
nylbromide intermediates 5{1−4}.
Solid-Phase Suzuki Reaction (Path I) to Synthesize
Heterobiaryl Benzopyrans 6 {14, 124}. The vinyl
bromide moiety embedded in benzopyranyl core skeleton 3 is a
good substrate for palladium-mediated C−C cross-coupling
reaction. Therefore, we successfully introduced various aryl and
heteroaryl moieties via Suzuki coupling of aryl/heteroaryl boronic
acids with Pd(PPh3)4 and Na2CO3 in aqueous 1,4-dioxane (10%
H2O). As shown in Scheme 2, vinyl bromide intermediates on
polymer support 4{1−4} were subjected to the parallel syn-
thesis in 96-deep well format for Suzuki-based transformation
with 24 commercially available aryl- and heteroaryl-boronic
acids to yield the desired heterobiaryl benzopyrans 6 in high
yields and purity. These building blocks were selected to ensure
the purity of final products without any loss of molecular
diversity. In the case of 2,6-disubstituted arylboronic acids, we
observed some side products, mainly generated by debromination
of 3, probably due to the steric demands of nearby dimethyl
group to vinyl bromide intermediates. The residual palladium
(or palladium black formed during the reaction) was removed
by washing polymer resins with sodium diethyldithiocarbamate
(0.2 M) in THF. After the standard cleavage protocol of silyl
linkers using HF/pyridine and subsequent quenching with
TMSOEt, the identification and purity of desired heterobiaryl
benzopyrans 6{1−4,1−24} were determined using LC/MS or
1H NMR without any further purifications. As shown in Table 1,
the presence of all desired compounds was unambiguously
confirmed by their molecular mass and the resulting 96-member
small-molecule collection was prepared in a scale of 5−10 mg with
the average purity of 86%.
Synthesis of Benzopyranotetracycles 8{1−4,1−12},
9{3−4,1−12}, and 10{1−2,1−12} through Paths II−IV. In
paths II to IV, the benzopyran-embedded dienes, the key inter-
mediates, were obtained through the palladium-mediated vinyl-
ation to vinyl bromide intermediate 3. In our earlier trial on
solid support, we experienced the incompletion of reaction
even with prolonged reaction time and observed side products,
mainly the debromination of intermediate 3. In addition, we
previously used palladium-mediated Stille reaction employing
tributyl(vinyl) stannane reagent for vinylation, but we tried to
avoid the tin reagent due to its toxic nature and the potential
contamination to final products. Therefore, we optimized the
palladium-mediated Suzuki reaction with vinyl bromide inter-
mediate with fluorous tag 5{1−4} in solution-phase parallel
synthesis to yield dienes 7{1−4} with moderate to good yields
(70−90%, see Supporting Information). For path II, the result-
ing dienes with fluorous tag 7{1−4} were subjected to Diels−
Alder reaction with various dienophiles. Through the building
block screening process, we selected 12 triazolinedione-type
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a
Table 1. Purities of Heterobiaryl Benzopyrans 6{1−4,1−24} in Path I
1
2
3
4
5
6
7
8
9
10
11
12
6{1,R1}
6{2,R1}
6{3,R1}
6{4,R1}
85
97
87
87
13
81
88
80
65
14
88
92
83
81
15
92
95
87
82
16
82
77
73
68
17
90
94
89
81
18
83
85
84
89
19
74
77
82
91
20
87
94
87
95
21
93
91
93
93
22
84
89
94
91
23
93
94
79
87
24
6{1,R1}
6{2,R1}
6{3,R1}
6{4,R1}
95
92
75
81
77
92
81
87
86
97
74
85
83
78
77
80
83
82
71
80
82
79
70
88
95
97
87
99
93
99
75
77
96
96
81
90
97
99
90
91
91
83
73
79
97
82
78
88
a
Purities (%) were obtained by PDA-based LC/MS analysis of final compounds after cleavage from solid-support.
Scheme 3. Fluorous-Tag-Based Parallel Synthesis of 8{1−4,1−12} in Path II [Suzuki-Based Vinylation and Aza Diels−Alder
a
Reaction] and the Chemical Structures of 4-Substituted-1,2,4-triazoline-3,5-diones as Building Blocks
a
Commercially available. Other triazolinediones were in-house synthesized from their precursors, 4-substituted 1,2,4-triazolidine-3,5-diones, by IBD-
based in situ oxidation.11
azadienophiles (Scheme 3) and 12 maleimide-type carbodie-
nophiles (Scheme 4) to ensure high yield and purity of final
library members without the significant loss of their mol-
ecular diversity. In the case of azadienophiles, there is a limited
commercial availability because of their instability, therefore we
in-house prepared the most of 4-substituted-1,2,4-triazoline-
3,5-diones as highly reactive azadienophiles via IBD-based in
situ oxidation of 4-substituted-1,2,4-triazolidine-3,5-diones at
room temperature. The incubation of diene intermediates
7{1−4} with azadienophiles provided the desired hetero-Diels−
Alder tetracyclic adducts with fluorous tag, which can be readily
purified by simple solid-phase extraction with fluorous cartridge
(F-SPE). After removal of fluorous tag, the desired benzopyr-
anotetracycles 8{1−4,1−12} were obtained with over 90% of
average purity in 5−10 mg scale (Table 2).
In path III, the diene intermediate with fluorous tag 7{1−4}
were subjected to Diels−Alder reaction with N-substituted
maleimides in the presence of ZnCl2 as a Lewis acid catalyst
and smoothly formed endo-selective Diels−Alder products
14{1−4,1−12}. However, we observed the spontaneous aroma-
tization during the removal of fluorous tag, especially in the
case of 9{1−2,1−12} due to their inherent instability, but not
in the case of 9{3−4,1−12}. Therefore, we converted 14{1−
2,1−12} to the aromatized Diels−Alder adducts 15{1−2,1−12}
by DDQ-assisted oxidative aromatization, which we classified as
path IV. After the removal of fluorous tag by HF/pyridine and
subsequent quenching with TMSOEt, we obtained Diels−Alder
tetracyclic products 9{3−4,1−12} (Path III) and aromatized
Diels−Alder product 10{1−2,1−12} (Path IV) with two
unique polyheterocyclic core skeletons containing privileged
benzopyran substructure. The final products in Table 2 and 3
were synthesized in a scale of 5−10 mg with over 90% of
average purity, measured by LC/MS analysis of the crude
products after F-SPE without any further purification. It is
worth mentioning that three resulting tetracyclic core skeletons
8, 9, and 10 from paths II−IV contain the privileged ben-
zopyranyl substructure, but they have unique trajectory of their
core skeletons in three-dimensional space, especially the
junction [N(sp3), C(sp3), and C(sp2), respectively] of dieno-
philes in Diels−Alder adducts. Furthermore, the crystal structure
of hetero-Diels−Alder adduct 8 is clearly different from Diels−
Alder adduct 9 because of the ring distortion and steric repul-
sion of lone pair electrons on nitrogen atoms in 8, which can be
clearly visualized in the aligned structures of three core skeletons
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Scheme 4. Solution-Phase Parallel Synthesis of 9{3−4,1−12} and 10{1−2,1−12} Synthesized in Path III [Suzuki-Based
Vinylation and Diels−Alder reaction] and Path IV [Subsequent DDQ-Assisted Oxidative Aromatization], and the Chemical
Structures of N-Substituted Maleimides as Building Blocks
a
Table 2. Purities of Final Products 8{1−4,1−12} in Path II
1
2
3
4
5
6
7
8
9
10
11
12
8{1,R2}
8{2,R2}
8{3,R2}
8{4,R2}
95
97
97
94
96
73
99
83
87
88
96
94
88
90
99
89
91
80
97
99
98
95
99
77
79
85
96
90
95
88
99
92
81
80
98
91
83
96
98
66
97
99
90
98
86
87
89
99
a
Purities (%) were obtained by PDA-based LC/MS analysis of final compounds after F-SPE.
a
Table 3. Purities of Final Products 9{3−4,1−12} and 10{1−2,1−12} in Paths III and IV
1
2
3
4
5
6
7
8
9
10
11
12
9{3,R3}
9{4,R3}
10{1,R3}
10{2,R3}
92
90
80
99
98
86
92
97
96
97
97
96
92
92
93
96
94
93
94
77
95
88
99
94
92
89
80
93
93
81
85
96
87
72
87
93
96
85
99
99
92
89
99
86
76
90
95
94
a
Purities (%) were obtained by PDA-based LC/MS analysis of final compounds after F-SPE.
(see Supporting Information Figure S2). The representative final
products (6, 8, 9, and 10) were fully characterized and analyzed
in Table 4 and the Supporting Information.
yield benzopyranyl 1,4-disubstituted-1,2,3-triazoles 12 after removal
of fluorous tag. Through the building block screening process, nine
alkylazides and six arylazides were selected for the synthesis of a
60-member collection of 1,4-substituted-1,2,3-triazole-containing
benzopyrans 12{1−4,1−15}. The average purity, measured by
LC/MS analysis of crude products, was 87% and the purities of
individual final compounds are shown in Table 5.
To enhance the molecular diversity of final products with
minimum structural perturbation of alkyne intermediates and
azide building blocks, we performed the regioisomeric and
systematic synthesis of 1,5-disubstituted-1,2,3-triazole analogs
with identical substrates and building blocks. In fact, 1,5-
disubstituted-1,2,3-triazole has an important implication in
biological system as a mimic of cis-peptide bond.15 In path VI,
we designed the 1,5-substutited-1,2,3-triazoles as regioisomeric
counterparts of “Click” products from path V. Under this
objective, we selected the ruthenium(II)-catalyzed alkyne−
azide cycloaddition (RuAAC) for the regioselective formation
Synthesis of Benzopyranyl Triazoles 12{1−4,1−15}
and 13{1−4,1−8} through Paths V and VI. For paths V and
VI, we introduced terminal alkyne to the fluorous-tagged vinyl
bromide intermediates 5{1−4} through palladium-mediated
Stille cross-coupling reaction. Along with the ensured regioche-
mical control of resulting triazole analogs, we used the fluorous-
tag-assisted solution-phase parallel synthesis, which allows the
effective removal of toxic tin reagent, ethynyltributylstannane,
compared to solid-phase synthesis. After the alkynylation of
vinyl bromide intermediate with fluorous tag 5{1−4}, the re-
sulting alkynyl benzopyrans 11{1−4} were subjected to copper(I)-
catalyzed 1,3-dipolar cycloaddition, namely Click reaction,12,13
with alkyl- and arylazides14 to afford benzopyranyl triazoles. We
optimized this regioselective transformation using BrCu(PPh3)3,
a soluble Cu-catalyst in organic solvent, and DIPEA at 40 °C to
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Table 4. Purity and Mass Confirmation of Representative Compounds in Paths I−IV
a
b
c
ID
R
R1−3
Yield (%)
Purity (%)
MS (calcd)
MS (found)
6{1,23}
6{2,15}
6{3,11}
6{4,19}
8{1,4}
7-hydroxy
3-methoxyphenyl
4-dimethylaminophenyl
3-acetylphenyl
2-hydroxyphenyl
3-methoxyphenyl
3-nitrophenyl
Benzyl
58
59
53
61
77
51
72
70
69
85
59
75
91
97
283.13
326.17
371.16
377.10
408.42
453.13
468.18
518.14
452.18
516.15
308.10
402.13
283.07
326.21
370.96
377.05
408.17
453.15
468.22
518.23
452.29
516.29
308.10
402.17
8-hydroxy-7-methoxy
6-(3-hydroxyphenyl)
6-chloro-8-(3-hydroxyphenyl)
7-hydroxy
94
>99
88
8{2,10}
8{3,7}
8-hydroxy-7-methoxy
6-(3-hydroxyphenyl)
6-chloro-8-(3-hydroxyphenyl)
6-(3-hydroxyphenyl)
6-chloro-8-(3-hydroxyphenyl)
7-hydroxy
96
96
8{4,3}
4-methoxyphenyl
phenyl
94
9{3,1}
92
9{4,3}
4-methoxyphenyl
methyl
97
10{1,12}
10{2,1}
95
8-hydroxy-7-methoxy
phenyl
>99
a
Yields were calculated by the weight of final compounds obtained after cleavage from solid-support or after removal of fluorous tag and F-SPE.
b
Yields for compounds 6 were two-step yields from 4{1−4}, yields for compounds 8−10 were two- or three-step yields from 7{1−4}. Purities were
obtained by PDA-based LC/MS analysis of final compounds. Mass analysis were performed by electron spray ionization (ESI) method.
c
a
Table 5. Purities of Final Products 12{1−4,1−15} in Path V
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
12{1,R4}
12{2,R4}
12{3,R4}
12{4,R4}
85
77
75
90
84
80
85
97
88
83
84
95
93
95
80
99
92
86
81
96
87
93
75
96
90
86
76
81
76
81
73
96
93
87
87
97
86
94
75
95
81
81
85
96
82
86
92
95
82
81
81
91
82
89
80
95
90
73
90
99
a
Purities (%) were obtained by PDA-based LC/MS analysis of final compounds after F-SPE.
Scheme 5. Stille-Coupling-Based Alkynylation and Cu(I)-Catalyzed Alkyne-Azide Cycloaddition (CuAAC) in Path V and the
Chemical Structures of Alkyl- and Arylazides as Building Blocks
of 1,5-disubstituted-1,2,3-triazoles16 and optimized RuAAC in
solution-phase parallel reaction with fluorous-tagged alkynyl
benzopyran intermediates 11{1−4}. Unlike copper(I)-cata-
lyzed alkyne−azide cycloaddition (CuAAC), we observed the
low conversion of arylazide in RuAAC condition, therefore we
did not use aryl azides as building blocks for path VI. As shown
in Scheme 6, 32-member collection of 1,5-substituted-1,2,3-
triazole-containing benzopyrans 13{1−4,1−8} was successfully
constructed through the modification of reported RuAAC
procedures from 11{1−4} and eight azide building blocks after
the removal of fluorous tag. The identification and purity of
final products 13{1−4,1−8} was confirmed by LC-MS and
their average purity was over 83%. The representative final
products (12 and 13) were fully characterized and analyzed in
Table 6 and Supporting Information.
benzopyran substructure via the DOS-based synthetic exercise
of paths I−VI. We previously reported the construction of 434-
member polyheterocycle library as the first generation of
benzopyran library with five discrete synthetic paths. As shown
in Figure 2, we synthesized over 700 compounds with 11
unique core skeletons embedded with benzopyran substructure.
For the systematic analysis of molecular diversity, we carried
out principal component analysis (PCA) of the whole members
of polyheterocyclic benzopyran library using 14 representative
molecular descriptors (including molecular weight, number of
rotatable bonds, ALogP, topological polar surface area, hydro-
phobic surface area, etc. See Supporting Information for detail).
As shown in Figure 3, individual compounds of 718-member
benzopyran library are widely spread in the chemical space with
large molecular diversity. The 284-member collection contain-
ing six core skeletons of this study is labeled in black square
(part B in Figure 2) and the 434-member collection containing
five core skeletons of previously reported benzopyran library8b
Completion of Benzopyran library with 11 Unique
Core Skeletons. In this study, we constructed a 284-member
pilot library with six unique core skeletons embedded with
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a
Scheme 6. Ru(II)-Catalyzed Alkyne-Azide Cycloaddition and Purities of Final Products 13{1−4,1−8}
a
Purities (%) were obtained by PDA-based LC/MS analysis of final compounds after F-SPE.
Table 6. Purity and Mass Identification of Representative Compounds 12{1−4,1−15} and 13{1−4,1−8} in Paths V and VI
a
b
c
ID
R
R4
yield (%)
purity (%)
MS (calcd)
MS (found)
12{1,1}
12{1,15}
12{2,4}
12{3,2}
12{4,3}
13{1,1}
13{2,4}
13{3,3}
13{4,3}
7-hydroxy
7-hydroxy
n-heptyl
72
82
68
81
73
66
82
77
70
85
90
95
85
95
91
81
73
90
342.21
321.13
410.14
416.23
458.16
342.21
410.15
424.19
458.16
341.97
321.17
410.24
416.33
458.13
342.27
410.16
424.33
458.22
3-pyridyl
8-hydroxy-7-methoxy
6-(3-hydroxyphenyl)
6-chloro-8-(3-hydroxyphenyl)
7-hydroxy
4-methylthiobenzyl
cyclohexylmethyl
2-phenylethyl
n-heptyl
8-hydroxy-7-methoxy
6-(3-hydroxyphenyl)
6-chloro-8-(3-hydroxyphenyl)
4-methylthiobenzyl
2-phenylethyl
2-phenylethyl
a
Yields were calculated by the weight of final compounds obtained after removal of fluorous tag and F-SPE, as two-step yields from 11{1−4}.
b
c
Purities were obtained by PDA-based LC/MS analysis of final compounds. Mass analysis were performed by electron spray ionization (ESI)
method.
Figure 2. Overall schematic representation of benzopyran library using diversity-oriented synthesis strategy (Paths A and B).
is labeled in gray triangle (part A in Figure 2); this analysis
clearly visualizes that the DOS-based construction of diverse
core skeletons can be effective to maximize the molecular diversity
of drug-like compound library. In addition, a PCA analysis of
284-member library constructed in this study shows that the
different paths (I−VI) allow to access the different chemical
space via the wide distribution of compounds upon changes of
core skeletons and appendices (see Supporting Information
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ACS Combinatorial Science
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Figure 3. Principle component analysis (PCA) of the total in-house synthetized benzopyran library. (A) PCA of the 434-member library labeled in
gray triangle (Path A) and 284-member library labeled in black square (Path B); (B) Color coding of 6 unique core skeletons of path B to visualize
their influence on the molecular diversity of 284-member library. Green, 6{1−4,1−24}; blue, 8{1−4,1−12}; red, 9{3−4,1−12}; orange, 10{1−2,1−12};
pink, 12{1−4,1−15}; brown, 13{1−4,1−8}.
Figure S1). Therefore, we are confident that the development
of novel DOS pathway and subsequent construction of drug-
like compound collections with diverse core skeletons, especially
embedded with privileged substructure (i.e., benzopyran in this
study), can play a pivotal roles for the expansion of molecular
diversity in chemical biology study and drug discovery.
EXPERIMENTAL SECTION
■
General Loading Procedure of Compound 3 on Solid
Support. (4-Methoxyphenyl)-diisopropylsilylpropyl polystyr-
ene resins (1.5 mmol/g, 1.0 equiv) were swelled for 15 min in
CH2Cl2 with TMSCl (4.0 equiv.) to remove residual moisture
trapped in solid supports. After filtration and washing with
CH2Cl2, the resins were treated with 3% (v/v) trifluorometha-
nesulfonic acid (6.0 equiv) in CH2Cl2 for 15 min. Then, the
resins were filtered, washed three times with CH2Cl2, and
suspended in CH2Cl2. The activated resins were incubated with
compound 3 (3.0 equiv) in the presence of 2,6-lutidine (8.0
equiv) at room temperature for 12 h. After filtration, the
resulting resins were washed three times each with CH2Cl2 and
THF and dried in vacuo to afford polymer-bound vinyl bromide
benzopyranyl intermediates 4{1−4}.
General Procedure for the Attachment of Fluorous
Tag to Compound 3. To a solution of diisopropyl-
(1H,1H,2H,2H-perfluorodecyl)silane (1.0 equiv) in anhydrous
CH2Cl2, trifluoromethanesulfonic acid (1.3 equiv) was added at
0 °C, and the mixture was stirred at room temperature for 15 h.
Then, a solution of compound 3 (1.3 equiv) and 2,6-lutidine
(2.6 equiv) in anhydrous CH2Cl2 was added and stirred at
room temperature for additional 2 h. The reaction mixture was
quenched with aqueous NH4Cl and extracted with CH2Cl2 and
ether. The combined organic extracts were dried over anhydrous
MgSO4(s), filtered, and concentrated in vacuo. The resulting
mixture was purified with silica-gel flash column chromatog-
raphy to provide the vinyl bromide benzopyranyl intermediates
with fluorous tag 5{1−4}.
General Purification Procedure of Fluorous-tagged
Compounds by F-SPE. The reaction mixture was dissolved in
minimum amount of DMF and loaded onto a FluorFlash@-
F-SPE cartridge preconditioned with MeOH/H2O (80:20).
The cartridge was eluted with 80:20 MeOH/H2O for the non-
fluorous fraction, followed by about same amount of MeOH for
the fluorous fraction. The positive pressure was given to elute
samples. The fractions were concentrated in GeneVac vacuum
centrifuge. The cartridge was washed thoroughly with acetone
and eluted with MeOH/H2O (80/20, v/v) for reusage.
General Procedure for Solid-Phase Suzuki Coupling
for the Synthesis of Compound Set 6 (Path I). Vinyl
bromide intermediates on solid supports 4{1−4} were charged
into each well of a 96-deep-well filtration block (∼25 mg/well;
CONCLUSION
■
In conclusion, we accomplished the construction of small-
molecule library with six discrete core skeletons embedded with
privileged benzopyran substructure using DOS strategy. The
practical synthesis was achieved through the versatile appli-
cation of solid-phase parallel synthesis and fluorous-tag-based
solution-phase parallel synthesis. The skeletal diversity of resulting
polyheterocycles was efficiently achieved through the various
chemical transformations of vinyl bromide intermediates 3{1−4},
such as palladium-mediated Suzuki reaction for arylation
(Path I), Suzuki-based vinylation and subsequent aza Diels−
Alder reaction (Path II), Diels−Alder reaction (Path III), and
aromatization (Path IV), Stille-based alkynylation and sub-
sequent copper(I)- and ruthenium(II)-catalyzed alkyne−azide
cycloaddition (Paths V and VI) to yield a 284-member library
with six discrete core skeletons, 6{1−4,1−24}, 8{1−4,1−12},
9{3−4,1−12}, 10{1−2,1−12}, 12{1−4,1−15}, and 13{1−4,1−
8}, respectively. The excellent endo-selectivity of Diels−Alder
reaction yields diastereo-chemically enriched polyheterocycle
9{3−4,1−12}, and aza-Diels−Alder reaction yields conforma-
tionally unique polyheterocycle 8{1−4,1−12}. The metal-
catalyzed regioselective synthesis of triazoles also allows the
construction of two regioisomeric benzopyran-containing core
skeletons with identical building blocks. The second generation
of benzopyran library was constructed with 284 compounds in
a scale of 5−10 mg with over 87% of average purity. In con-
junction of our first generation of benzopyran library, we con-
structed total 718-member polyheterocycle library containing
11 unique core skeletons embedded with privileged benzopyran
substructure. Extensive biological evaluations of this benzopyr-
an library are current underway, which will lead to the identifi-
cation of small-molecule modulators and potential therapeutic
agents.
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ACS Combinatorial Science
Research Article
see Supporting Information) and solutions of 24 different
boronic acids (3.0 equiv) in 1,4-dioxane were dispensed into
the designated wells of the reaction block. Then, the solution of
Pd(PPh3)4 (0.1 equiv), Na2CO3 (5.0 equiv) in H2O/1,4-
dioxane (10% v/v) was added to each well of the reaction
block. The reaction mixture was shaken at 70 °C in a rotating
oven for 24 h, followed by washing with THF, CH2Cl2, DMF,
and MeOH (three times each). The palladium catalyst was
removed by swelling the resin three times, each time for 1 h,
with a metal-chelating solution (sodium diethyldithiocarbamate
0.2 M in THF), and washed with THF and CH2Cl2. After
drying in vacuo, the resins in the reaction blocks were treated
with HF/pyridine/THF (5/5/90) for 4 h at room temperature,
and then ethoxytrimethylsilane was added and allowed to react
for 1 h to quench excess HF (HF/pyridine protocol). After
removing resins by filtration, the filtrate was condensed in
vacuo using a GeneVac vacuum centrifuge to obtain the desired
products 6{1−4,1−24}.
General Procedure of Suzuki-Based Vinylation for the
Synthesis of Diene Intermediate 7. To a solution of
fluorous-tagged vinyl bromide intermediates 5{1−4} (1.0 equiv)
and vinylboronic acid dibutyl ester (1.2 equiv.) in a mixed solvent
of toluene/EtOH/water (1:1:1), Pd(PPh3)4 (0.03 equiv) and
Na2CO3 (2.5 equiv) was added. The reaction vessel was purged
with argon and the reaction mixture was stirred at 70 °C for 12
to 18 h. After the completion of reaction monitored by TLC,
the reaction was stopped and diluted with ethyl acetate. The
organic layer was washed with brine, dried over anhydrous
MgSO4(s), filtered, and condensed under reduced pressure.
The resulting mixture was purified by silica-gel flash column
chromatography to provide the desired diene intermediates 7{1−4}
for the subsequent aza- and carbon-Diels−Alder reaction.
General Procedure of Aza Diels−Alder Reaction (Path II).
Compounds 7{1−4} (∼0.05 mmol each; see Supporting
Information) were dissolved in toluene (0.5 mL) and divided
into individual reaction vials, where 4-substituted-1,2,4-triazo-
line-3,5-dione (0.06 mmol, 1.2 equiv.) was added. The reaction
mixture was stirred at room temperature for 30 min. The
4-substituted-1,2,4-triazoline-3,5-diones used in path II were in-
house prepared through the in situ oxidation of its precursor,
4-substituted-1,2,4-triazolidine-3,5-dione (1.2 equiv.) with iodo-
benzene diacetate (IBD, 1.2 equiv.) for 20 min at ambient
temperature in THF. The reaction completion of 1,2,4-triazoline-
3,5-dione formation was indicated by the color changes of reaction
solution (from clear to red or violet). After the reaction com-
pletion monitored by TLC, the reaction mixture was condensed
in vacuo using a GeneVac vacuum centrifuge. The resulting
residue was redissolved in DMF (0.5 mL) and purified by
F-SPE to provide aza Diels−Alder adducts 8{1−4, 1−12}.
General Procedure of Diels−Alder Reaction and
Aromatization (Paths III and IV). Compounds 7{1−4}
(∼0.05 mmol each; see Supporting Informaion) in toluene (0.5
mL) were divided in individual reaction vials, where N-
substituted maleimide (0.1 mmol, 2.0 equiv) and ZnCl2 (0.01
mmol, 0.2 equiv.) was added. The mixture was heated to 70 °C
for 12 to 24 h. After the completion of reaction monitored by
TLC, the reaction mixture was condensed in vacuo using a
GeneVac vacuum centrifuge. The residue was redissolved in
DMF (0.5 mL) and purified by F-SPE to provide fluorous-
tagged product 14{1−4,1−12}. For aromatization, Diels−Alder
products 14{1−2,1−12} was dissolved in toluene and treated
with 2,3-dichloro-5,6-dicyanao-1,4-benzoquinone (DDQ) (2.0
equiv) for 20 min at ambient temperature. After the completion
of reaction monitored by TLC, the reaction mixture was
condensed in vacuo using a GeneVac vacuum centrifuge.
Purification by F-SPE provided the aromatization product
15{1−2,1−12} with fluorous tag.
General Procedure of Stille-Based Alkynylation for
the Synthesis of Intermediate 11. To a solution of com-
pounds 5{1−4} in anhydrous THF, Pd(PPh3)4 (0.05 equiv.)
and ethynyltributylstannane (2.0 equiv.) was added. The reaction
mixture was purged with argon and heated to 60 °C for 5 to 8 h.
After the completion of reaction monitored by TLC, the reaction
mixture was quenched with brine and extracted with ethyl acetate.
The combined organic extracts were dried over anhydrous
MgSO4(s), filtered, and condensed under reduced pressure.
The residue was purified by silica-gel flash column chromatog-
raphy to provide alkynyl benzopyran intermediates 11{1−4}
for the subsequent cycloaddition with azide building blocks.
General Procedure of Copper(I)-Catalyzed Alkyne−
Azide Cycloaddition (Path V). To compounds 11{1−4}
(∼0.05 mmol each; see Supporting Information) divided in
individual reaction vials, a solution of azide (0.1 mmol, 2.0
equiv), BrCu(PPh3)3 (0.005 mmol, 0.1 equiv), and diisopro-
pylethylamine (0.06 mmol, 1.2 equiv) in toluene (0.5 mL) was
added. The reaction mixture was heated to 40 °C for 5 h. After
reaction completion monitored by TLC, the reaction mixture
was condensed in vacuo using a GeneVac vacuum centrifuge,
resuspended in DMF (0.5 mL), and purified by F-SPE to
provide benzopyranyl 1,4-disubstituted-1,2,3-triazoles 12{1−
4,1−15} with fluorous tag.
General Procedure of Ruthenium(II)-Catalyzed Al-
kyne−Azide Cycloaddition (Path VI). To compounds
11{1−4} (∼0.05 mmol each; see Supporting Information) divided
in individual reaction vials, a solution of azide (0.125 mmol, 2.5
equiv.) and Cp*RuCl(PPh3)2 (0.005 mmol, 0.1 equiv.) in 1,2-
dichloroethane (0.5 mL) was added. The reaction mixture was
purged with argon and heated to 80 °C for 4 h. After reaction
completion monitored by TLC, the reaction mixture was con-
densed in vacuo using a GeneVac vacuum centrifuge, resuspended
in DMF (0.5 mL), and purified by F-SPE to provide benzopyranyl
1,5-disubstituted-1,2,3-triazoles 13{1−4,1−8} with fluorous tag.
General Procedure for the Removal of Fluorous Tag
and Purification of Final Product with F-SPE. Fluorous tag
was removed by treating fluorous-tagged final products with
HF/pyridine/THF (5/5/90) solution (1.0 mL) for 2 h at
ambient temperature, followed by the addition of TMSOEt
(1.0 mL) to quench excess HF (HF/pyridine protocol). The
resulting mixture was condensed in vacuo using a GeneVac
vacuum centrifuge. The residue was redissolved in DMF (0.3 mL)
and purified by F-SPE. The desired untagged product was
collected in the MeOH/H2O fraction, which was condensed in
vacuo using a Genevac vacuum centrifuge. After the lyophili-
zation of cleaved product in acetonitrile/water (1/1, v/v), the
final products was obtained in powder and analyzed by LC/MS
1
and H NMR.
ASSOCIATED CONTENT
■
S
* Supporting Information
Detailed synthetic procedures, full characterization and 1H/13C,
2D NMR spectra of representative compounds, LC/MS analysis
and principal component analysis of all library members, X-ray
crystal structure and 3-D structure alignment of representative
compounds 8, 9, and 10. This material is available free of charge
via the Internet at http://pubs.acs.org.
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ACS Combinatorial Science
Research Article
(7) Borges, F.; Roleira, F.; Mihazes, N.; Santana, L.; Uriarte, E.
Simple coumarins and analogues in medicinal chemistry: occurrence,
synthesis and biological activity. Curr. Med.Chem. 2005, 12, 887−916.
(8) For previous synthesis of compound libraries based on
benzopyran “privileged structure” especially remarkable work by
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Construction of a 10 000-membered benzopyran library by directed
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A.; Barluenga, S.; Mitchell, H. J.; Roecker, A. J.; Cao, G.-Q. Natural
product-like combinatorial libraries based on privileged structures. 3.
The “libraries from libraries” principle for diversity enhancement of
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diversity-oriented synthesis of novel scaffolds embedded with
privileged benzopyran motif. Chem. Commun. 2006, 2962−2964.
(b) Oh, S.; Jang, H. J.; Ko, S. K.; Ko, Y.; Park, S. B. Construction of a
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12, 548−558.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: sbpark@snu.ac.kr.
Funding
This study was supported by (1) National Research Foundation
of Korea (NRF) grants (NRF-2009−0078236); (2) MarineBio
Program funded by Ministry of Land, Transport, and Maritime
Affairs (MLTM), Korea; and (3) the World Class University
program (R31-−2010-−000-10032-0). M.Z. and M.K. are
grateful for the fellowships awarded by the BK21 Program
and the Seoul Science Fellowship.
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