Concise and diversity-oriented synthesis of novel scaffolds embedded with privileged benzopyran motif

Article abstract of DOI:10.1039/b606341a

A branching DOS strategy for an unbiased natural product-like library with embedded privileged benzopyran motif was established to provide complexity and diversity of resulting heterocycles with desired drug-likeness. The importance of skeletal diversity

Full text of DOI:10.1039/b606341a

View Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Concise and diversity-oriented synthesis of novel scaffolds embedded
with privileged benzopyran motif{
Sung Kon Ko, Hwan Jong Jang, Eunha Kim and Seung Bum Park*
Received (in Cambridge, UK) 4th May 2006, Accepted 25th May 2006
First published as an Advance Article on the web 13th June 2006
DOI: 10.1039/b606341a
simplest appendices were energy-minimized and aligned with the
arene region of the benzopyran substructure.4 The resulting rigid
polycycles with skeletal diversity may provide highly selective and
specific interactions with biopolymers by taking advantage of the
prepaid entropic penalty.
A branching DOS strategy for an unbiased natural product-like
library with embedded privileged benzopyran motif was
established to provide complexity and diversity of resulting
heterocycles with desired drug-likeness. The importance of
skeletal diversity conducted on a privileged substructure was
demonstrated through the biological evaluation of a small
molecule library representing 22 unique core skeletons via
in vitro cytotoxicity assay.
Under the goal of accessing the diverse core skeletons through
the recombination of privileged substructures,8 we initiated the
development of a concise and efficient pathway by synthesizing
two key intermediates—dimethylbenzopyran template 3a and
spiro(cyclopentyl)benzopyran template 3b9 (Scheme 1). The
cyclization of 2,4-dihydroxyacetophenone 1a with acetone in the
presence of pyrrolidine afforded 2,2-dimethyl-7-hydroxy-4-
chromanone 2a.10 The intrinsic limitation of less reactive
cyclopentanone with 1a was overcome by using electron-rich
Privileged substructures from bioactive natural products have
played and continue to play an invaluable role in the drug
discovery process.1 The diversification of these heterocyclic
compounds using diversity-oriented synthesis (DOS) has been
proven to be an essential tool to rapidly discover biologically active
small molecules.2 Therefore, the development of a concise and
efficient strategy leading to skeletal and stereochemical diversity
has gained much attention in scientific communities involved in
drug discovery and biomedical research.3 To achieve this goal, it is
crucial to identify a new privileged substructure with the potential
for chemical transformations toward novel key intermediate
skeletons.
2-hydroxy-4-methoxyacetophnone 1b as
a starting material
followed by demethylation with dry pyridine?HCl at 210 uC which
afforded the desired spiro compound 2b. Subsequent series of
reactions (protection & triflation) provided the starting materials
3a and 3b of pathway A with a high overall yield (86%–81%).
Palladium-mediated Stille coupling reaction11 of 3a or 3b,
followed by in situ Diels–Alder reaction, provided diastereochemi-
cally enriched complex steroid-like 4a or 4b (Scheme 1, Table 1).
The endo favored cycloaddition yields polycycles 4a and 4b with
Benzopyran is a privileged structural motif observed in many
biologically active natural products, and it plays an important role
in binding with various biopolymers.5 To date, syntheses of
bioactive benzopyrans have been extensively studied, especially a
combinatorial library based on a privileged benzopyran template
has been reported by Nicolaou and coworkers.6 However,
previous reports focused on limited diversifications of appendices
on the arene region of benzopyrans with a few core structures.
Herein, we report our recent efforts to maximize skeletal diversity
through the branching pathway for constructions of 22 discrete
novel core skeletons (Ia–XIa, Ib–XIb) embedded with a privileged
benzopyran substructure via various chemical transformations
such as Diels–Alder reaction (A1 & B1), click chemistry (A2 &
B2), and palladium mediated cross-coupling (A3 & B3) (Fig. 1A).
In particular, a Diels–Alder adduct from pathway A1 was
successfully transformed into four drastically different core
skeletons using a library-from-library approach; high-yield chemi-
cal transformations of the scaffold with a high degree of
diastereocontrol and atom efficiency.7 The skeletal diversity was
visualized (Fig. 1 B & C) by overlay of 11 unique skeletons (R =
Me, Ia–XIa) for clarity. These representative compounds with the
Fig. 1 A: Synthetic scheme of 22 unique heterocyclic skeletons (Ia–XIa,
Ib–XIb) embedded with benzopyran substructure. B: 3-D structural
difference of 11 distinct skeletons (Ia–XIa) through the alignment of
energy minimized conformers with phenol.4 R: Me, R1 & R2: H, R3: Ph,
R4: Bn. C: individual skeletons were colour-coded to visualize the diverse
3-D orientation of appendices.
School of Chemistry, Seoul National University, Seoul, 151-747, Korea.
E-mail: sbpark@snu.ac.kr; Fax: (+82) 28844035; Tel: (+82) 28809090
{ Electronic supplementary information (ESI) available: experimental
procedures and spectroscopic data for new compounds. See DOI: 10.1039/
b606341a
2962 | Chem. Commun., 2006, 2962–2964
This journal is ß The Royal Society of Chemistry 2006

View Online
Scheme 1 Pathways A1 and B1 (I–IV, VII–IX).
the four newly generated stereocenters (see ESI{), and diastereo-
chemically enriched skeletons were further diversified with various
reaction conditions, such as hydrogenation, aromatization, and
epoxidation. This resulted in the reconstruction of core skeletons 6,
7, and 8, respectively, in completely different 3-D orientations.
Further, the atom efficiency was maximized by quadrupling the
size of the small molecule library without any changes in the
substituent pattern. Both 6a and 6b were yielded as a single
diastereomer by substrate-controlled asymmetric hydrogenation
(see ESI{). The DDQ aromatization successfully converted the
U-shaped core structures 4a–b to flat aromatic skeletons, namely,
7a–b. The initial attempt of the epoxidation with m-CPBA
yielded some aromatization products, and several asymmetric
epoxidation conditions provided desired products in low yield.
However, in the presence of DTBMP as a proton sponge,
m-CPBA epoxidation provided a facile means to access epoxide
products 8a–b as single diastereomers in high yield (see ESI{). To
determine the efficiency profile, several commercially available
building blocks listed in Table 1 were screened to evaluate the
scope of this pathway.
The identical strategy was applied for pathway B by the
synthesis of key intermediates (13a–b) for palladium-mediated
coupling from compounds 2a-b through subsequent series of
reactions (bromination, protection, and dehydration), but the
resulting skeleton from pathway B exhibited distinct differences in
3-D orientations. The substituted vinylation via Stille coupling
followed by the endo-selective Diels–Alder reaction provided the
tetracycles 14 with high diastereochemical enrichment. Although
we tried to pursue the further diversification of 14 with optimized
reaction conditions in pathway A1, hydrogenation and epoxida-
tion did not proceed well and we conjecture the reason to be steric
hindrance of dimethyl and spirocyclopentyl groups.
Further diversification of compounds 3 and 13 was carried out
by alkynylation followed by click chemistry of the resulting 18 and
21 with azide reagents via Huisgen 1,3-dipolar cycloaddition
through the copper–CuSO4 catalyzed process.12 It provided
regiospecific 1,4-disubstituted 1,2,3-triazoles 19 and 22 in high
yield (Scheme 2 Top, Pathway A2 & B2). However, disubstituted
alkyne (Scheme 2 Top, Pathway B2, entry 3) provided regioiso-
meric mixtures of 1,4,5-trisubstituted 1,2,3-triazole in the case of
dimethyl-benzopyran 21a-3, and no desired product in the case of
spirocyclopentyl-benzopyran 21b-3; this did not fulfil the require-
ment for the DOS pathway. In pathway A3 and B3, an array of
benzopyran derivatives was synthesized by the introduction of
aromatic and heterocyclic compounds 24 and 26 via palladium-
mediated Suzuki coupling reaction13 in high yield (Scheme 2
Bottom), which gave a collection of diverse skeletons with a limited
number of freely rotatable bonds.
Table 1 Synthesis of pathway A1 with some building blocks
Yieldb (%)
4a
4b
6a
6b
7a
7b
8a
8b
Entry
1c
R1
R2
Ph
Ph
Bn
Ph
T/uCa
40
H
84
82
81
80
83
82
85
84
b
98
97
96
94
95
95
96
95
88
86
87
85
87
85
—
—
76
74
75
73
77
75
—
—
2c
MeOCH2
60
The main objective of our work was to merge two different
concepts, being privileged structural motifs merging with unbiased
structural diversity, into a single entity and to elucidate how
structural diversity conducted on a privileged scaffold affects
biological activity. After realization of the branching DOS
pathway, the collection of small molecules which represents the
22 unique core skeletons with limited variations of appendices was
3c
Ph
H
40
4d
40
a
Temperature (Diels–Alder reaction)
deprotection). X = CH X = N
Isolated yield (before
c
d
This journal is ß The Royal Society of Chemistry 2006
Chem. Commun., 2006, 2962–2964 | 2963

View Online
facilitate the discovery of novel chemical entities through extensive
biological evaluations.
In conclusion, we have developed a branching DOS pathway
leading to the synthesis of a natural product-like small molecule
library embedded with a privileged benzopyran motif. The endo-
selectivity in a Diels–Alder reaction yielded compounds with
complex and diverse core skeletons. The resulting heterocycles
were further diversified by simple transformation in order to
quadruple the number of compounds using a single set of building
blocks, which maximizes the atom efficiency in library construc-
tion and the drastic differentiation in the 3-D orientations of
appendices on diverse polyheterocycles as biopolymer-binding
elements. At the same time, these pathways furnished substrate-
controlled diastereochemical enrichment. The preliminary biologi-
cal evaluation of these core skeletons with a benzopyran
substructure provided fruitful results, and the construction of the
full-scale small molecule library through these pathways on solid
support is currently underway. We envision that these molecules
will provide valuable tools for the drug discovery process as well as
for the exploration of biological space.
This work is supported by (1) MarineBio21, Ministry of
Maritime Affairs and Fisheries, Korea (MOMAF), (2) Center for
Biological Modulators (CBM) of the 21st Century Frontier R&D
Program, the Ministry of Science and Technology, Korea
(MOST), and (3) Korean Science and Engineering Foundation
(KOSEF). K.S.K., H.J.J. and K.E. are grateful for the award of a
BK21 fellowship.
Scheme 2 Pathways A2 & 3 and B2 & 3.
subjected to in vitro cytotoxicity assay against human cancer cell
line (A549 lung carcinoma cell)14 to emphasize the structure–
activity relationship based on skeletal diversity (see ESI{). Cell
viability assay demonstrated interesting results (Table 2); the
compounds exhibited a wide range of IC50 values. For instance,
9b-3 demonstrated excellent in vitro cytotoxicity (IC50 = 1.0 mM)
which is 30–60 fold more potent than 10a-3, 10b-3, and 11b-3, a set
of molecules with same appendices and different core skeletons.
These examples show the importance of core skeletons, not
appendices for their biological activities. The ultimate aim of this
study was to emphasize the importance of well-designed diverse
core skeletons in small molecule collections, and dramatic
differences in in vitro cytotoxicity assay results demonstrated the
high correlation of core skeletons with their biological activities.
Thus, DOS with unbiased skeletal diversity embedded with
privileged structural motif might provide a systematic strategy to
Notes and references
1 Review: (a) R. Balamurugan, F. J. Dekker and H. Waldmann, Mol.
BioSyst., 2005, 1, 36; (b) D. A. Horton, G. T. Bourne and M. L. Smythe,
Chem. Rev., 2003, 103, 893 (and references therein); (c) R. E. Ziegert,
J. Tora¨ng, K. Knepper and S. Bra¨se, J. Comb. Chem., 2005, 7, 147.
2 (a) S. L. Schreiber, Science, 2000, 287, 1964; (b) M. D. Burke and
S. L. Schreiber, Angew. Chem., Int. Ed., 2004, 43, 46; (c) T. U. Mayer,
Science, 1999, 286, 971.
3 (a) H. E. Pelish and M. D. Shair, J. Am. Chem. Soc., 2001, 123, 6740; (b)
S. L. Schreiber, Chem. Eng., 2003, 3, 51.
4 Energy minimized conformer of each molecules were calculated and
aligned with Accelrys Cerius 2 software.
5 (a) E. J. Martin and R. E. Critchlow, J. Comb. Chem., 1999, 1, 32; (b)
S. J. Teague and A. M. Davis, Angew. Chem., Int. Ed., 1999, 38, 3743.
6 (a) K. C. Nicolaou and H. J. Mitchell, J. Am. Chem. Soc., 2000, 122,
9939; (b) Y. D. Gong and S. E. Yoo, J. Comb. Chem., 2003, 5, 577; (c)
J. Y. Hwang and Y. D. Gong, J. Org. Chem., 2005, 70, 10151; (d)
K. C. Nicolaou and J. A. Prefferkorn, Org. Biomol. Chem., 2003, 1, 908;
(e) K. Sivakumar and Q. Wang, Org. Lett., 2004, 6, 4603; (f)
V. A. Ashwood and K. Willcocks, J. Med. Chem., 1986, 29, 2194; (g)
R. Bergmann and R. Gericke, J. Med. Chem., 1990, 33, 2759.
7 J. M. Ostresh, B. Do¨rner, S. E. Blondelle and R. A. Houghten,
Combinatorial Chemistry – Synthesis and Application, ed. S. R. Wilson
and A. W. Czarnik, John Wiley and Sons, Inc., New York, 1997, 225.
8 (a) J. A. Tallarico and M. D. Shair, J. Comb. Chem., 2001, 3, 312; (b)
O. Kwon, S. B. Park and S. L. Schreiber, J. Am. Chem. Soc., 2002, 124,
13402.
Table 2 Cell viability test of representative compounds
Compound
ID
IC50/mM
(A549)
Core Type R1
R2 R3 R4
9b-3
IIb
Ph
Ph
Ph
Ph
H
Bn
Bn
Bn
Bn
Ph
Ph
—
—
—
—
—
—
—
—
—
Bn
Bn
—
—
—
—
—
—
—
—
—
—
—
—
NO2-Ph
1.0
33.5
63.9
28.6
7.0
11.1
30.0
6.5
39.2
157.2
25.9
53.4
10a-3
10b-3
11b-3
15a-2
15b-2
15a-3
15b-3
15b-4
20b-1
23b-1
25b-2
IIIa
IIIb
IVb
VIIa
VIIb
VIIa
VIIb
VIIIb
Vb
9 US Pat., 1993, Dec. 7, patent number 5,268.
10 (a) S. E. Yoo and N. C. Jeong, Bio. Med. Chem. Lett., 1992, 2, 381; (b)
R. Bergmann and R. Gericke, J. Med. Chem., 1992, 33, 492.
11 Review: P. Espinet and A. M. Echavarren, Angew. Chem., Int. Ed.,
2004, 43, 4704.
12 (a) L. V. Lee and C. H. Wong, J. Am. Chem. Soc., 2003, 125, 9588; (b)
Z. P. Demko and K. B. Sharless, Angew. Chem., Int. Ed., 2002, 41, 2110.
13 (a) S. R. Chemler and S. J. Danishefsky, Angew. Chem., Int. Ed., 2001,
40, 4544; (b) O. Takayuki and A. Suzuki, J. Org. Chem., 1993, 58, 2201.
14 T. Mosmann, J. Immunol. Methods, 1983, 65, 55.
H
MeOCH2 Ph
MeOCH2 Ph
H
—
—
—
Ph
—
—
—
Xb
VIb
2964 | Chem. Commun., 2006, 2962–2964
This journal is ß The Royal Society of Chemistry 2006