Multicomponent synthesis of diverse 1,4-benzodiazepine scaffolds

Article abstract of DOI:10.1021/ol302837h

The 1,4-benzodiazepine (BDZ) scaffold is of particular interest in drug design due to a balanced ensemble of beneficial physicochemical properties including a semirigid and compact diazepine ring with spatial placements of several substituents, combined with low number of rotatable bonds, hydrogen bond donors and acceptors, and intermediate lipophilicity. As an alternative to traditional multistep sequential syntheses, we designed routes employing one-pot MCRs to accelerate access diverse BDZ scaffolds in two or three steps.

Full text of DOI:10.1021/ol302837h

ORGANIC
LETTERS
2012
Vol. 14, No. 23
5916–5919
Multicomponent Synthesis of Diverse
1,4-Benzodiazepine Scaffolds
†
,†,§
Yijun Huang,‡,† Kareem Khoury,†,§ Tyler Chanas, and Alexander Domling*
€
Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh,
Pittsburgh, Pennsylvania 15261, United States, and Department of Drug Design,
University of Groningen, A. Deusinglaan 1, 9713 AV Groningen, The Netherlands
a.s.s.domling@rug.nl
Received October 15, 2012
ABSTRACT
The 1,4-benzodiazepine (BDZ) scaffold is of particular interest in drug design due to a balanced ensemble of beneficial physicochemical
properties including a semirigid and compact diazepine ring with spatial placements of several substituents, combined with low number of
rotatable bonds, hydrogen bond donors and acceptors, and intermediate lipophilicity. As an alternative to traditional multistep sequential
syntheses, we designed routes employing one-pot MCRs to accelerate access diverse BDZ scaffolds in two or three steps.
Librarydesignand synthesisisbecoming moreand more
important as the pharmaceutical industry is realizing that
currently available compounds cover not even a glimpse
of the chemical space of drug-like compounds. It is well
documented that current screening libraries are made
for historic targets and rather unsuitable for new target
classes which emerged from the human genome project.
Examples of such a difficult to target class are protein
protein interactions or nuclear hormone receptors. Whereas
many of these targets are cellular and biochemically vali-
dated, missing medicinal chemistry starting points make
them useless for drug discovery. 1,4-Benzodiazepines are
a family of drugs that are used to relieve insomnia and
anxiety, as well as to treat muscles spasm and prevent
seizures.1 Over 40 medications highlight BDZ as a classic
privileged structure with a broad range of therapeutic
treatments, particularly for the central nervous system.2
Since the BDZ scaffold is of particular interest for
drug discovery, many synthetic derivatives with a wide
pharmacological spectrum have been extensively de-
veloped.3 However, the biological activity is highly depen-
dent on the nature of the BDZ scaffold including the
conformation ofthe 1,4-diazepine ring and its substituents,
the propensity of hydrogen bond donor and acceptor, and
the electrostatic profile.4 Consequently, the development
of expedient synthetic approaches to access new BDZ
scaffolds have attracted considerable attention in the dis-
covery of biologically active compounds.5
Multicomponent reaction (MCR) chemistry serves as a
unique and versatile synthetic toolbox to access a range of
highly substituted heterocyclic systems in a convergent
manner.6 Traditionally, substituted BDZs were often accessed
by constitute linear syntheses, which limited the efficiency
and diversity to build combinatorial libraries of varying
sizes and properties.7 In recent years, isocyanide-based
(3) Hadjipavlou-Litina, D.; Hansch, C. Chem. Rev. 1994, 94, 1483.
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2010, 2, 1441.
† University of Pittsburgh.
€
(6) (a) Domling, A.; Wang, W.; Wang, K. Chem. Rev. 2012, 112,
§ University of Groningen.
€
3083. (b) Domling, A.; Huang, Y. Synthesis 2010, 2859. (c) Ruijter, E.;
‡ Department of Pathology & Laboratory Medicine, Perelman School of
Medicine, University of Pennsylvania, Philadelphia, PA 19104.
(1) Sternbach, L. H. J. Med. Chem. 1979, 22, 1.
(2) (a) Duarte, C. D.; Barreiro, E. J.; Fraga, C. A. M. Mini-Rev. Med.
Chem. 2007, 7, 1108–1119. (b) Welsch, M. E.; Snyder, S. A.; Stockwell,
B. R. Curr. Opin. Chem. Biol. 2010, 14, 347.
Scheffelaar, R.; Orru, R. Angew. Chem. Intl. Ed. 2011, 28, 6234.
(d) Hulme, C.; Dietrich, J. Mol. Div. 2009, 13, 195. (e) Armstrong,
R. W.; Combs, A. P.; Tempest, P. A.; Brown, S. D.; Keating, T. A. Acc.
Chem. Res. 1996, 29, 123.
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(b) Bunin, B. A.; Ellman, J. A. J. Am. Chem. Soc. 1992, 114, 10997.
r
10.1021/ol302837h
Published on Web 11/16/2012
2012 American Chemical Society

MCRs (IMCR) have been proven to be a promising
strategy to access large chemical space of BDZs.8 As part
of our ongoing interest in the efficient discovery of biolog-
ically active compounds,9 we herein report the design of
diverse BDZ scaffolds via Ugi four-component reactions
(Ugi-4CR) and postcondensation modifications (Scheme 1).
(cyclization) (Scheme 2). The UDC strategy allows the
access of 1,4-benzodiazepine-6-ones 6aÀf with different
substitutions derived from the isocyanide and carboxylic
acid inputs (Table 1).
Table 1. Ugi-4CR Route to 1,4-Benzodiazepine-6-ones 6aÀf
Scheme 1. General Strategy for the Design of Novel BDZ
Scaffolds by Employing Bifunctional Orthogonal Starting
Materials in the Ugi-4CR and Subsequent Intramolecular
Cyclization
ID
R1
R2
yieldsa,b
6a
6b
6c
6d
6e
6f
tBu
Me
41%
28%
16%
20%
38%
22%
tBu
cyclohexyl
Me
nPr
mesityl
tBu
tBu
tBu
N-Boc-R-amino-aldehydes have been demonstrated to
be suitable bifunctional starting materials for IMCR.10
Hulme and others utilized the Ugi reaction with N-Boc-R-
amino-aldehydes for a solution phase synthesis of an
array of biologically relevant imidazolines and azepine-
tetrazoles.10,11 Thus, we envisioned novel applications of
Boc-glycinal in the Ugi-4CR for the synthesis of BDZs
utilizing the Ugi-deprotection-cyclization (UDC) strategy.12
Taking advantages of the concise and powerful synthetic
methodologies, this strategy is able to fulfill the drug dis-
covery effort to access uncovered chemical space of BDZs.
Anthranilic acid derivatives have been shown to react in the
Ugi-4CR,13 thus we proposed a synthetic route using methyl
anthranilate 1 as the building block for the synthesis of the
first of four 1,4-benzodiazepine scaffolds (Table 1). In the
first step (Ugi), methyl anthranilate 1 serves as an amine
component for the Ugi-4CR together with an isocyanide 2,
Boc-glycinal 3, and a carboxylic acid 4. The Boc protection
group of 5 is cleaved in the second step (deprotection), and
then the free amine group is condensed with the orthogonal
ester group to form the 1,4-diazepine ring in the third step
cyclopropenyl
pÀF-C6H4
a isolated yields (over three steps). b Method A: (i) MeOH, rt, 2 days;
(ii) DCM (10% TFA), rt, 2 days; (iii) THF, Et3N, triazabicyclodecene
(TBD), 40 °C, overnight.
Aminophenylketones are commonly employed building
blocks for the synthesis of BDZ scaffolds.14 Since amino-
phenylketones have shown good reactivity in MCRs as an
amine component,15 we designed a new UDC strategy for
the rapid access of the second 1,4-benzodiazepine scaffold
starting from aminophenylketones. Initially, aminophe-
nylketones 7 serve as an amine component for the Ugi-4CR
with an isocyanide 2, Boc-glycinal 3, and a carboxylic acid
4. Microwave irradiation was utilized for the Ugi-4CR
to reduce the reaction time.16 In most cases, microwave
was applied when the Ugi product was not able to be
isolated under the convential condition. In the second step,
the deprotected amino group is immediately cyclized
with the ketone functionality to form 1,4-diazepine ring.
A small focused library of 1,4-benzodiazepines 9aÀh with
four points of diversity was obtained using this convenient
method (Table 2).
Encouraged by the previous results, the UDC strategy
was further applied for the synthesis of the third 1,4-
benzodiazepine scaffold. In the first step, aminophenyl-
ketones 7 serve as an amine component for the Ugi-4CR
with an isocyanide 2, Boc-glycinal 3, and trimethyl azide
10. Microwave assisted Ugi-4CRs proceeded in a reaction
time of only 30 min compared to the conventional meth-
odology which required up to 48 h. In the second step, the
deprotected amino group immediately cyclizes with the
ketone functionality to form a 1,4-diazepine ring. A group
€
(8) Huang, Y.; Domling, A. In Isocyanide Chemistry; Nenajdenko, V.,
Ed.; Wiley: New York, 2012; pp 431À450.
(9) Khoury, K.; Sinha, M. K.; Nagashima, T.; Herdtweck, E.;
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Domling, A. Angew. Chem. Intl. Ed. 2012, 51, 10280.
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Tetrahedron Lett. 2002, 43, 3681.
(12) Keating, T. A.; Armstrong, R. W. J. Am. Chem. Soc. 1996, 118,
2574.
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Burdack, C.; Ross, G.; Hiller, W. Tetrahedron Lett. 2004, 45, 6421.
(b) Bonnaterre, F.; Bois-Choussy, M.; Zhu, J. Beil. J. Org. Chem. 2008,
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S. A.; Boursier, E. V.; Flynn, H.; Bouillot, A. M.; Bamborough, P.;
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Nicodeme, E. J. Med. Chem. 2011, 54, 3827. (b) Lecinska, P.; Corres,
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McCluskey, A. Org. Biomol. Chem. 2011, 9, 1419. (b) He, P.; Nie, Y.-B.;
Wu, J.; Ding, M.-W. Org. Biomol. Chem. 2011, 9, 1429. (c) Marcaccini,
S.; Pepino, R.; Pozo, M. C.; Basurto, S.; Garcia-Valverde, M.; Torroba,
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Tetrahedron 2010, 66, 6783.
Org. Lett., Vol. 14, No. 23, 2012
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5917

this concept, we have successfully identified several pepti-
domimetic scaffolds derived from Ugi-4CR as p53-Mdm2
inhibitors.18 Although Boc-glycinal was employed to ac-
cess 1,4-benzodiazepines, the commercial availability of
substituted R-amino-aldehyde derivatives is rather limited.
Therefore, we further developed an alternative approach
for the synthesis of BDZ scaffold with an additional point
of diversity, which would introduce an “anchor” fragment
to the diazepine ring.
Table 2. Ugi-4CR Route to 1,4-Benzodiazepines 9aÀh
N-Boc-amino acid isanideal building block tointroduce
“anchor” fragments, which can be incorporated into drug-
like compounds via MCRs.19 Hence, we employed the
UDC strategy to assemble the orthogonal building block
N-Boc-amino acid for the synthesis of a BDZ scaffold.
First, we developed a synthetic method to allow rapid
access to 1,4-benzodiazepines in just two steps from Boc
glycine. In the first step, aminophenylketones 7 serve as
an amine component for the Ugi-4CR with an isocyanide
2, Boc glycine 13, and an aldehyde 14. The crude Ugi
products 15 were not isolated but immediately treated
with TFA in 1,2-dichloroethane (DCE) to produce 1,4-
benzodiazepines in a one-pot procedure. To our delight,
1,4-benzodiazepines 16aÀf with four points of diversity
were isolated in reasonable to good yields (Table 4).
ID
X
Y
R1
R2
yieldsa
9a
9b
9c
9d
9e
9f
H
Ph
Ph
Me
Ph
Ph
Ph
Ph
tBu
Me
Me
Me
Me
47%b
36%b
43%b
40%c
22%c
24%c
25%c
13%c
H
cyclohexyl
cyclohexyl
Benzyl
tBu
H
H
4-Cl
4-Cl
4-Cl
4-Cl
CH2OH
nPr
tBu
tBu
9g
9h
cyclobutyl
Me
oÀCl-C6H4
benzyl
a isolated yields (over two steps). b Method B: (i) MeOH, rt, 2 days; (ii)
DCE (10% TFA), 40 °C, overnight. c Method C: (i) MeOH, microwave
irradiation (100 °C, 30 min); (ii) DCE (10% TFA), 40 °C, overnight.
Table 3. Ugi-4CR Route to 2-Tetrazole Substituted 1,4-Benzo-
diazepines 12aÀf
Table 4. Ugi-4CR Route to 1,4-Benzodiazepines 16aÀf
R1
yieldsa
ID
X
Y
R1
R2
yieldsa,b
ID
X
Y
tBu
29%b
35%b
49%b
32%c
12%c
26%c
16a
16b
16c
16d
16e
16f
H
Ph
Ph
Me
Me
Ph
Ph
tBu
tBu
tBu
tBu
iPr
H
38%
47%
53%
66%
33%
42%
12a
12b
12c
12d
12e
12f
H
Ph
Ph
Me
Ph
H
H
cyclohexyl
cyclohexyl
tBu
H
iPr
H
H
H
4-Cl
4-Cl
H
4-Cl
H
cyclohexyl
cyclohexyl
H
oÀF-C6H4
benzyl
H
Ph
benzyl
a isolated yields (over two steps). b Method F: (i) MeOH, rt, 2 days;
(ii) DCE (10% TFA), 40 °C, overnight.
a isolated yields (over twosteps). b Method D: (i) MeOH, rt, 2 days;(ii)
DCE (10% TFA), 40 °C, overnight. c Method E: (i) MeOH, microwave
irradiation (100 °C, 30 min); (ii) DCE (10% TFA), 40 °C, overnight.
Subsequently, we initiated to test the feasibility for the
synthesis of “anchor” biased compound libraries using
N-Boc-amino acid derivatives. Phenylalanine, leucine, tryp-
tophan and tyrosine, which are abundant in the proteinÀ
protein interaction interface, were selected as examples.
of 2-tetrazole substituted 1,4-benzodiazepines 12aÀf with
three points of diversity were obtained (Table 3).
The above two scaffolds 9 and 12 are unprecedented in
the chemical literature, and scaffold 6 is accessible in an
unprecedented convenient way. Thus they nicely under-
score the ability of the Ugi-4CR to address unexplored
drug-like chemical space. Methyl anthranilate and amino-
phenylketones were for the first time used as the building
block for the synthesis of 1,4-benzodiazepine scaffolds via
UDC strategy. In the course of our efforts to discover
inhibitors of proteinÀprotein interactions (PPI), we aim to
generate small molecules tailored “anchors” (amino acid
motifs deeply buried in PPI interfaces).17 On the basis of
€
(17) (a) Meireles, L. M. C.; Domling, A.; Camacho, C. J. Nucleic
Acids Res. 2010, 38, W407. (b) Czarna, A.; Beck, B.; Srivastava, S.;
Popowicz, G. M.; Wolf, S.; Huang, Y.; Bista, M.; Holak, T. A.;
€
Domling, A. Angew. Chem., Int. Ed. 2010, 49, 5352.
(18) (a) Huang, Y.; Wolf, S.; Bista, M.; Meireles, L.; Camacho, C.;
€
Holak, T. A.; Domling, A. Chem. Biol. Drug Des. 2010, 76, 116.
(b) Huang, Y.; Wolf, S.; Koes, D.; Popowicz, G. M.; Camacho, C. J.;
€
Holak, T. A.; Domling, A. ChemMedChem 2012, 7, 49.
(19) (a) Hulme, C.; Cherrier, M. P. Tetrahedron Lett. 1999, 40, 5295.
(b) Lecinska, P.; Corres, N.; Moreno, D.; Garcia-Valverde, M.;
Marcaccini, S.; Torroba, T. Tetrahedron 2010, 66, 6783.
5918
Org. Lett., Vol. 14, No. 23, 2012

N-Boc-amino acids 17 were subjected to the same protocol
for the synthesis of 1,4-benzodiazepines 16aÀf with vari-
able aminophenylketones and isocyanides. Compounds
20aÀm with four points of diversity were isolated by
chromatography in 22À69% yield over two steps (Table 5).
These examples further demonstrate the ease of synthesis
and the increase in molecular complexity during the
two-step one-pot procedure, which is remarkable for the
efficient synthesis of 1,4-benzodiazepines containing a
variety of “anchor” residues.
It has to be noted that the same scaffold 16 synthesized
here in 2 steps is also accessible by the Ellman’s method via
a versatile solid phase synthesis of 1,4-benzodiazepines
over seven steps.20 Thus we have significantly improved
the efficiency and diversity for the synthesis of new BDZs
using a convergent Ugi-4CR followed by deprotection and
intramolecular cyclization. These scaffolds can serve as
novel chemotypes for the drug design efforts especially on
less tractable targets, since the pseudopeptidic backbone of
the 1,4-benzodiazepine and its derivatives have shown the
potential to develop PPI inhibitors.18a,21
Finally we have created virtual libraries based on the
herein described BDZ scaffolds. These virtual libraries are
now part of the ∼25 million MCR compound comprising
database of recently initiated pharmacophore-based vir-
tual screening platform AnchorQuery (http://anchorqu-
ery.ccbb.pitt.edu) for the discovery of PPI inhibitors.22
In addition, 1000 randomly selected compounds of each
scaffold were analyzed for drug likeness (Supporting
Information, Figures S1ÀS8). Around 75% of these com-
pounds pass at least 3 criteria of Lipinski’s rule of five.
Although a majority of these compounds have a molecular
weight above 500 Da (mean MW: 6 = 553 ( 85 Da, 9 =
578 ( 62 Da, 12 = 463 ( 56 Da, 16 = 601 ( 71 Da), it has
Table 5. Synthesis of Anchor-directed 1,4-Benzodiazepines 20aÀm
ID
X
Y
R1
anchor
yieldsa,b
20a
20b
20c
20d
20e
20f
H
Ph
Ph
Ph
Ph
Me
Me
Ph
Ph
Ph
Ph
Ph
Ph
Me
tBu
tBu
Phe
Leu
Phe
Leu
Phe
Leu
Phe
Leu
Trp
Tyr
Trp
Tyr
Trp
41%
41%
50%
69%
44%
46%
32%
43%
26%
29%
65%
60%
22%
H
H
cyclohexyl
cyclohexyl
tBu
H
H
H
tBu
20g
20h
20i
4-Cl
4-Cl
H
tBu
tBu
tBu
20j
H
tBu
20k
20l
H
cyclohexyl
cyclohexyl
benzyl
H
20m
H
a isolated yields (over two steps). b Method F: (i) MeOH, rt, 2 days;
(ii) DCE (10% TFA), 40 °C, overnight.
to be mentioned that our AnchorQuery libraries are
targeted specifically for PPIs. The molecular weight of
potential inhibitors will most likely need to be larger than
compounds targeting classical protein pockets.23 Work is
ongoing to profile the herein described scaffolds and its
chemical space for small molecule inhibitors of proteinÀ
protein interactions.
Acknowledgment. This work was supported partially by
grants from NIH (1R21GM087617-01A1, 1P41GM094055-
01, and 1R01GM09708201). The assistance of Valerie Nolt
and Neal McCall are acknowledged.
(20) Bunin, B. A.; Ellman, J. A. J. Am. Chem. Soc. 1992, 114, 10997.
(21) (a) Grasberger, B. L.; Lu, T.; Schubert, C.; Parks, D. J.; Carver,
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K. L.; Calvo, R. R.; Maguire, D.; Lattanze, J.; Franks, C. F.; Zhao, S.;
Ramachandren, K.; Bylebyl, G. R.; Zhang, M.; Manthey, C. L.;
Petrella, E. C.; Pantoliano, M. W.; Deckman, I. C.; Spurlino, J. C.;
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Chem. 2005, 48, 909. (b) Nicodeme, E.; Jeffrey, K. L.; Schaefer, U.;
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Supporting Information Available. Experimental pro-
cedures including the synthesis and characterizations of
small molecules, as well as the analysis of virtual libraries
are provided. This material is available free of charge via
the Internet at http://pubs.acs.org.
€
Popowicz, G. M.; Wolf, S.; Holak, T.; Domling, A.; Camacho, C. J.
PLoS One 2012, 7, e32839.
The authors declare no competing financial interest.
(23) Wells, J. A.; McClendon, C. L. Nature 2007, 450, 1001.
Org. Lett., Vol. 14, No. 23, 2012
5919