Relay catalytic branching cascade: A technique to access diverse molecular scaffolds

Article abstract of DOI:10.1002/anie.201208738

Skeletal diversity: The reactions of alkynoic acids (A, common type of substrates) with various scaffold-building agents (B) under gold catalysis produce a series of multifunctional polyheterocyclic structures (see scheme). The approach enables the preparation of compound libraries with high skeletal diversity. Copyright

Full text of DOI:10.1002/anie.201208738

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DOI: 10.1002/anie.201208738
Diversity-Oriented Synthesis
Relay Catalytic Branching Cascade: A Technique to Access Diverse
Molecular Scaffolds**
Nitin T. Patil,* Valmik S. Shinde, and Balasubramanian Sridhar
The screening of compound libraries to identify useful
modulators of biological systems is fundamental to the drug
discovery process and chemical biology studies.[1] Tradition-
ally, the molecules in these libraries have come from nature,
and there are many examples in which natural products and
their derivatives and analogues are either new drug candi-
dates or tools for chemical biology and medicinal chemistry
research. However, some difficulties are associated with using
natural products in screening experiments; for instance, their
purification, the identification of biologically active compo-
nents, and nature “fails” to provide several analogues, which
are necessary for structure–activity relationship (SAR) stud-
ies. These restrictions make chemical synthesis the only
alternative to obtain unambiguously characterized, diverse,
multifunctional molecules that are similar to natural products.
Diversity-oriented synthesis (DOS), a terminology ini-
tially coined by Schreiber,[2] is a techniques to identify
biologically relevant chemical space.[3] Several DOS strategies
have been reported, such as the build-couple-pair strategy,[4]
the click-click-cyclize strategy,[5] the fragment-based
approach,[6] and others.[7] In recent years, the branching-
cascade technique has gained much interest, because of its
potential to transform a common type of substrate into
diverse and distinct molecular frameworks under the influ-
ence of either different reagents or different reaction
conditions.[8] The branching-cascade approach is appealing
because it enables access to a library of thousands of
compounds in an efficient manner through permutation and
combination. Kumar and co-workers reported a cascade with
twelve branches to access diverse and complex molecular
frameworks from a chromone-based starting material.[9]
Recently, OꢀConnell, Stockman, and co-workers reported
a cascade with twelve branches to access a range of carbo-,
aza-, and oxocycles with fused, bridged, and spiro-polycyclic
structures from a keto diester.[10] Although there are quite
a few reports on branching cascades,[8–10] to the best of our
knowledge, there is no precedence of a catalytic branching
cascade that generates a large scaffold diversity.[11] Scaffold
diversity is very important in DOS, because it is used to
populate chemical space efficiently.[3,12] Therefore, we won-
dered whether it would be possible to develop a catalytic
branching-cascade technique, a process that would allow the
rapid synthesis of several multifunctional polyheterocyclic
scaffolds (Figure 1).[13] More specifically, we expected that the
Figure 1. Concept of relay catalytic branching cascade (RCBC).
SM=easily available starting materials, A=catalysts or reagents, W–
Z=various cascade-initiating molecules, Im=intermediates,
P=diverse scaffolds.
alkynoic acid A (common type of substrate) would react with
several scaffold-building agents (SBAs; variables) in the
presence of suitable metal catalysts, thus leading to the
formation of keto amides B. Compounds B would then
undergo a metal-catalyzed cyclization cascade to produce
various heterocyclic scaffolds C (Scheme 1).[14] Overall, the
process can be termed relay catalytic branching cascade
(RCBC) with regard to the classification of a one-pot catalysis
proposed by us.[15] The main challenge and beauty of the
methodology would be the access to a large scaffold diversity,
as a result of the design of a large number of SBAs (Scheme 2)
in an apparently simple manner.
[*] Dr. N. T. Patil, V. S. Shinde
Division of Crop Protection Chemicals
CSIR—Indian Institute of Chemical Technology
Hyderabad—500007 (India)
E-mail: nitin@iict.res.in
Dr. B. Sridhar
Laboratory of X-Ray Crystallography
CSIR—Indian Institute of Chemical Technology
Hyderabad–500007 (India)
[**] Generous financial support by the Department of Science and
Technology (DST) and the Council of Scientific and Industrial
Research (CSIR), New Delhi, India, is gratefully acknowledged.
V.S.S. thanks the UGC for a senior research fellowship.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201208738.
Scheme 1. Concept of RCBC employing alkynoic acids (common type
of substrates) and SBAs (variables).
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Scheme 2. Structures of various scaffold-building agents (SBAs).
At the outset of this study, our efforts were directed
toward finding appropriate reaction conditions that would
work well for a broad range of SBAs, which were prepared
from easily available starting materials (see the Supporting
Information). Because it is known that the judicious choice of
a p-acid[16] influences the outcome of the reaction, we opted to
study these reactions in greater detail using a variety of
catalysts and solvents, and different temperatures. The
catalyst Ph3PAuOTf in dichloroethane gave the best results
with a large number of SBAs. An equimolar mixture of
scaffold-building agents 1–30 and alkynoic acids aa1–aa8 in
dichloroethane was heated to 1008C for 24–36 h in the
presence of Ph3PAuOTf (5 mol%; Scheme 3). In almost all
cases, the starting materials were completely consumed and
the products were produced in good to high yields.
compounds. To further expand the scope of the RCBC,
indolamines 5 and 9 were reacted with alkynoic acids to give
indolo[1,2-c]pyrido[1,2-a]quinazolinones 5a/5b (branch E)
and 9a/9b (branch I), which were probably formed through
À
an intramolecular attack of the indole N H group to the
incipient iminium ions. The polycyclic benzazepinone indo-
lones 6a and 6b were obtained in 79 and 63% yield from
SBAs 6 and 6’, respectively (branch F). Halo-substituted
compounds, such as 6b, can serve as versatile synthons,
enabling the introduction of various functional groups and
expanding the diversity of the targeted products. When
indole-based amino-substituted aromatic compound 10 was
employed as substrate, products with seven-membered rings
were formed in moderate yields, although relatively longer
reaction times were needed for complete substrate conversion
(branch J).
We first focused our attention on indole-based SBAs, as
this heterocycle occurs widely in nature and its derivatives
have remarkable biological activities. Interestingly, the reac-
tion proved to be very general, and the reaction of more than
ten SBAs gave various indole-fused heterocyclic scaffolds in
good to high yields. For instance, SBA 1 (2-aminophenylin-
dole) afforded dihydroindolo[3,2-c]pyrrolo[1,2-a]quinoli-
nones 1a and 1b in 79 and 69% yield, respectively
(Scheme 3, branch A). Likewise, SBAs 2 and 3 ((indol-4-
yl)methanamines) reacted well with terminal and internal
alkynoic acids to afford the corresponding pyrrolo quinoli-
none 2a (branch B) and pyrrolo isoquinolinones 3a and 3b,
respectively (branch C), with moderate to high yields. Sim-
ilarly, SBA 4 underwent cascade cyclization under the
developed reaction conditions to afford indolo benzazepi-
nones 4a and 4b in 76 and 63% yields, respectively
(branch D). Interestingly, the 2-ethynyl benzoic acid aa7
also reacted well, giving 4c in 59% yield. This experiment
confirms that additional aromatic rings can be introduced in
SBAs to obtain functionalized polycyclic heteroaromatic
Interestingly, when SBA 7 was used, an almost 1:1 mixture
of two regioisomers was obtained (resulting from cyclization
at C4 and C6; branch G). These regioisomers were easily
separable by column chromatography. It should be noted that
each of the regioisomers has a skeletally distinct pyrrolo
phenanthridinone scaffold. Both terminal and internal alky-
noic acids reacted similarly with 7, although the reaction was
somewhat sluggish and took 36 hours until completion. The
SBAs 8 and 8’ also reacted well and afforded C2-cyclized
polyheteroaromatic scaffolds in 78 and 63% yield
(branch H).
To further explore the generality and scope of this
approach, benzimidazole 11 (branch K), 2-(2-aminophenyl)-
imidazole 12, and 2-(2-aminophenyl)tetrazole 13 were used as
substrates, and the expected cascade products were obtained
in very high yields. SBAs 12 and 13 reacted with terminal
(aa1) and internal (aa2) alkynoic acids, leading to the
formation of various scaffolds, such as imidazolo quinazoli-
nones (branch L) and tetrazolo quinazolinones (branch M).
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Scheme 3. Generation of scaffold diversity through RCBC. [a] Reactions conditions: SBAs (0.50 mmol), alkynoic acids (0.50 mmol), Ph3PAuOTf
catalyst (5 mol%) in (CH2Cl)2 (1 m) at 1008C for 24 h. [b] A 1:1 mixture of regioisomers was obtained. [c] Alkynoic acids aa1 and aa2 produced the
same cascade products. For 4c, 7, 10a, 10b, 16b, 8a, 18b, 23a, 23b, 25a, 25b, 26a, 26b, 27a, and 27b, the reaction time was prolonged up to
36 h. For SBAs, see Scheme 2. A–AD represent branches. aa1–aa8=alkynoic acids.
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The reactions of amino benzothiophenes 14 and 15 afforded
C2- and C3-cyclized products, respectively, with good yields
(branch N and branch O). SBA 22 (2-(2-aminophenyl)thio-
phene) also reacted well under the established conditions,
affording dihydropyrrolo[1,2-f]thieno[3,2-c]quinolinone 22a
and 22b with 71 and 79% yield, respectively (branch V).
Interestingly, biaryl 1,4-diamines 16 and 16’ reacted with
alkynoic acid aa1 to give strained seven-membered pyrrolo
diazepinones in good yields (branch P). Moreover, pyrido
phenanthyridinone scaffolds were also obtained from 3’-
methoxybiphenyl-2-amine (SBA 17; branch Q). Gratifyingly,
the pyridine-based SBA 18 also worked well in this trans-
formation and produced fused-ring products with moderate
yields (branch R). It should be noted that the electron-
donating effect of the N,N-dimethylamine group at position 6
of the pyridine moiety plays a key role in this reaction, as the
product is not formed in the absence of this group. With
regard to the prevalence and importance of seven-membered
benzodiazepine scaffolds, we explored the reactivity of SBA
19 and, fortunately, the reaction worked very well (branch S).
SBA 23, which features a naphtalene core and an aliphatic
side chain with an NH2 group, also produced a product with
a seven-membered ring through cyclization at the b-position
of the napthalene (branch W). The protocol was equally
successful for 2-(furan-3-yl)aniline 20 and 2-furanyl ethan-
amine 21 as substrates, leading to the formation of
dihydrofuro[2,3-c]pyrrolo[1,2-a]quinolinone and tetrahydro-
furo[2,3-g]indolizinones, respectively (branch T and bran-
ch U). SBAs 24 and 24’ (2-aminophenylbenzofurans) also
reacted well under the optimized conditions and afforded
dihydrobenzofuro[3,2-c]pyrrolo[1,2-a]quinolinones in good
yields (branch X).
have been assigned as privileged structures in drug develop-
ment because of their rigid conformation, which in turn
results in their ability to bind to a multitude of receptors
through a variety of favorable interactions. Therefore the
synthesis of nitrogen-containing polycyclic heteroaromatic
compounds is an important goal in organic synthesis. In this
regards, the approach reported herein is appealing because it
offers the possibility to generate a library of thousands of
nitrogen-containing compounds in an efficient manner.
Because all products that are obtained through the RCBC
technique are chiral, the scaffolds can be accessed in an
optically pure form.
Each scaffold is unique and has several privileged
structures embedded within it.[18] For instance, branch A of
the RCBC (Scheme 3) produced dihydroindolo[3,2-
c]pyrrolo[1,2-a]quinolinone 1a, and embedded into this
single structure are important pharmacophores (Scheme 4),
Scheme 4. RCBC product 1a as a hybrid scaffold.
Next, we turned our attention to reactions of pyrrole-
based SBAs. As anticipated, all reactions with pyrrole-based
SBAs, such as 25, 26, 27, 28, and 29, worked well and afforded
fused heterocyclic products with five-, six-, and seven-
membered rings. SBAs 25, 26, and 27 produced benzo
dipyrrolo diazepinone scaffolds with seven-membered rings
(branches Y, Z, and AA, respectively). The reactions of SBAs
28 and 28’ resulted in C3-cyclized isoindolo[2,1-a]pyrrolo[3,2-
c]quinolinones with six-membered rings (branch AB),
whereas SBAs 29 and 29’ produced C2-cyclized dipyrrolo
quinolinones (branch AC) with high to moderate yields. SBA
30 (dimethoxyphenyl ethanamine) reacted well with alkynoic
acids aa1 and aa3 under the optimized reaction conditions to
produce tetrahydropyrrolo[2,1-a]isoquinolinones 30a and
30b in 90 and 61% yield, respectively (branch AD).
The broad scope and generality of the RCBC technique
and the ease with which skeletally diverse products with fused
five-, six-, and even seven-membered rings can be produced is
obvious. Of note, over one gram of each 11a and 30a
(obtained in 90 and 92% yield, respectively) was prepared by
this method, thus demonstrating the scalability of our
approach. The structures of seven skeletally different final
compounds, that is 6b, 12a, 14b, 16a, 18a, 20a, and 28c, were
unambiguously confirmed by single-crystal X-ray crystallo-
graphic analysis.[17]
such as tetrahydro pyridoindole XXa,[19] tetrahydro indolizi-
noindolone XXb,[20] dihydro pyrroloquinolinone XXc,[21] and
tetrahydro pyrrolopyridine XXd.[22] Because various privi-
leged structures are present in a single scaffold, it can be easily
envisioned that such hybrid structures could find potential
applications in modern drug discovery programs. Because
these scaffolds are expected to cover a significant chemical
space,[3] their great potential to the understanding of biolog-
ical interactions can be anticipated.
In summary, we introduced the relay catalytic branching
cascade (RCBC) as a new technique to access a series of
multifunctional polyheterocyclic scaffolds in an efficient
manner. The key feature of our approach is its extraordinary
scope, because it allows the preparation of a library of
compounds with a high skeletal diversity and a broad scope
for further diversification. Considering the multitude of
reactions that can be catalyzed by metal-based and organo-
catalysts at the same time, and given the vast number of
common types of substrates and variables, we envision
tremendous potential in diversity-oriented synthesis. This
approach should have especially broad applicability, given
that metal catalysis can be combined with organocatalysis,
thus leading to cooperative-catalytic branching cascades
(CCBC).[13b,15] Additional challenges for this chemistry
could include the development of an enantioselective proto-
col that works well for a broad range of SBAs, thus leading to
Nitrogen-containing heterocycles are widespread motifs
in natural products and biologically active molecules. They
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[13] For reports on catalytic approaches to multifunctional polyhe-
enantioselective RCBC. Further studies to exploit this
approach are currently underway in our laboratory.
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Received: October 31, 2012
Published online: January 17, 2013
Keywords: alkynoic acids · branching cascade · gold ·
.
molecular diversity · privileged scaffolds
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