Catalyst-dependent selectivity in the relay catalytic branching cascade

Article abstract of DOI:10.1002/chem.201405736

The synthesis of small organic molecules as probes for discovering new therapeutic agents has been an important aspect of chemical biology. One of the best ways to access collections of small molecules is to use various techniques in diversity-oriented synthesis (DOS). Recently, a new form of DOS, namely relay catalytic branching cascades (RCBCs), has been introduced, wherein a common type of starting material reacts with several scaffold-building agents (SBAs) to obtain structurally diverse molecular scaffolds under the influence of catalysts. Herein, the RCBC reaction of a common type of substrate with SBAs is reported to give two different types of molecular scaffolds and their formation is essentially dependent on the type of catalyst used.

Full text of DOI:10.1002/chem.201405736

DOI: 10.1002/chem.201405736
Communication
&
Relay Catalysis |Hot Paper|
Catalyst-Dependent Selectivity in the Relay Catalytic Branching
Cascade
[
a]
[a]
[a]
[b]
Avinash H. Bansode, Aslam C. Shaikh, Rahul D. Kavthe, Shridhar Thorat,
[
b]
[a]
Rajesh G. Gonnade, and Nitin T. Patil*
Therefore, new strategies must be developed for creating new
collections of drug-like small molecules.
Abstract: The synthesis of small organic molecules as
probes for discovering new therapeutic agents has been
an important aspect of chemical biology. One of the best
ways to access collections of small molecules is to use var-
ious techniques in diversity-oriented synthesis (DOS). Re-
cently, a new form of DOS, namely “relay catalytic branch-
ing cascades” (RCBCs), has been introduced, wherein
a common type of starting material reacts with several
scaffold-building agents (SBAs) to obtain structurally di-
verse molecular scaffolds under the influence of catalysts.
Herein, the RCBC reaction of a common type of substrate
with SBAs is reported to give two different types of mo-
lecular scaffolds and their formation is essentially depen-
dent on the type of catalyst used.
[2]
Diversity-oriented synthesis (DOS) aims to prepare collec-
[3]
tions of skeletally diverse small molecules. As a result of their
non-focused nature, DOS libraries are expected to cover a sig-
[4]
nificant chemical space, impacting our understanding of bio-
logical processes. Therefore, it is not surprising that much at-
tention has to be paid to develop a more general and efficient
[5]
strategy in DOS, to access scaffold diversity. Several strat-
[6]
egies, such as the build/couple/pair strategy, the “click, click,
[7]
[8]
cyclize” strategy, and the fragment-based approach, among
[9]
others have been reported in the literature. Recently, the
branching cascade technique has gained the attention of the
scientific community, as this technique has the potential to
transform a common type of starting material into diverse and
distinct molecular frameworks under the influence of either re-
[10]
agents or conditions.
Kumar and co-workers reported an
The ability of small molecules to interact with macromolecules
and perturb their function has emerged as a powerful tool for
interrogating biological events, and forms the basis of much
eightfold branching cascade targeting diverse and complex
molecular frameworks from a chromone-based starting materi-
[11]
al. Subsequently, O’Connell and Stockman reported a twelve-
fold branching cascade to access a range of carbo-, aza-, and
oxocycles, with fused, spiro, and bridged polycyclic structures
[
1]
modern drug discovery. Traditionally, nature has been the
source of a rich library of small molecules. Natural products,
which are indeed complex and diverse in structure, have been
used for centuries as medicines and have had a profound
impact on human lives. However, some difficulties are associat-
ed with using natural products in screening experiments, such
as: a) their low abundance; b) difficulties associated with purifi-
cation and characterization; c) inability to provide several ana-
logues, which are necessary for structure–activity relationship
[12]
from a ketodiester. Recently, we developed an electrophile-
induced branching cascade as an interesting and a very direct
approach for the efficient generation of a library of drug-like
[
13]
polyheterocycles.
branching cascades;
report on catalytic branching cascades. Very recently, we intro-
Although there are several reports on
[8–11]
until recently, there had been no
[14]
duced the relay catalytic branching cascade (RCBC) as a new
technique to access a series of multifunctional polyheterocyclic
(SAR) studies; and d) the structural complexity of natural prod-
[15]
ucts, which makes chemical derivatization, a process especially
relevant to drug discovery, extremely challenging. These are
among the main reasons for the urgent demand for the high-
throughput screening of natural-product-like/drug-like small
molecules and the subsequent evaluation of their biological
activities to examine if they are potential therapeutic agents.
scaffolds in an efficient manner (Scheme 1).
Herein, we report that the product formation in RCBC essen-
tially depends on the type of catalysts used (Scheme 2). This
kind of catalyst-dependent selectivity should be of considera-
ble interest as two sets of libraries can be readily accessed
from the same type of starting materials. To our knowledge,
this study represents the first example of catalyst/reagent-de-
pendent selectivity in branching cascades.
As a part of our ongoing interest in the exploration of p-
acid catalysts and their application in branching cascades, we
envisaged that an alkyne would undergo hydroxy group-assist-
ed hydroamination reactions with various scaffold-building
[
a] A. H. Bansode, A. C. Shaikh, Dr. R. D. Kavthe, Dr. N. T. Patil
Organic Chemistry Division, CSIR-National Chemical Laboratory
Dr. Homi Bhabha Road, Pune - 411 008 (India)
E-mail: n.patil@ncl.res.in
[b] S. Thorat, Dr. R. G. Gonnade
[16]
agents (SBAs) to generate imines (Scheme 3). The incipient
Center for Materials Characterization, CSIR-National Chemical Laboratory
Dr. Homi Bhabha Road, Pune - 411 008 (India)
imine would then undergo the Mannich reaction or a Mannich
reaction/dehydrative cyclization sequence, depending on the
type of catalyst used, to generate two different sets of hetero-
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201405736.
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Scheme 3. Catalyst-dependent selectivity in RCBC: Reaction of alkynols (a
common type of substrates) with variables scaffold-building agents (SBAs).
[
14,15]
Scheme 1. Relay catalytic branching cascade (RCBC): Previous work.
SM=starting material; cat M=catalyst; X=cascade-triggering molecules;
Im=intermediates; P=products
lysts that would work well for
a broad range of alkynols and
SBAs. Careful optimization stud-
ies led us to establish two sets
of
reaction
conditions;
(
1) [Ph PAuOTf], MeOH, 40–808C,
3
and (2) PtCl , MeOH, 80–1008C.
4
Under
the
catalysis
of
a
[
Ph PAuOTf], products P , which
3
resulted from the double addi-
tion of nucleophile to alkynes,
were obtained; whereas, the re-
actions catalyzed by PtCl gave
4
b
the products P . The detailed re-
sults
are
summarized
in
Scheme 2. Catalyst-dependent selectivity in RCBC: This work. SM=starting material; cat M and cat N=catalysts;
X=cascade-triggering molecules; Im=intermediates; P=products.
Scheme 4.
a
b
cyclic scaffolds P or P . It was clear that the judicial choice of
catalysts (p-acid Vs p-acid with Lewis acidity) would be benefi-
a
cial to control the reaction at P or to speed up the reaction to
b
a
P from P .
The alkynols a1–a10 (Figure 1) and SBAs 1–11 (Figure 2) re-
quired for this study are either commercially available or can
[
17]
be readily prepared in high yields.
At the outset of this
study, our efforts were directed to search for appropriate cata-
Figure 1. Structures of alkynols a1–a10.
Figure 2. Structures of scaffold-building agents 1–11.
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Scheme 4. Molecular diversity through catalyst control in RCBC. Reactions conditions: a) Gold catalysis: Alkynol (0.50 mmol), SBAs (0.50 mmol), [Ph
3
PAuOTf]
(5 mol%) in MeOH (0.5 mL) at 40–808C for 12–36 h, as specified in the Supporting Information; b) Platinum catalysis: Alkynol (0.50 mmol), SBAs (0.50 mmol),
4
PtCl (5 mol%) in MeOH (0.5 mL) at 80–1008C for 12–48 h, as specified in the Supporting Information. Note: Alkynols a1 and a2 produced the same cascade
products for branches C and I’. A, B, C…K and A’, B’, C’…K’ represent branches.
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I
II
In the presence of gold catalyst, 2-(1H-benzo[d]imidazol-2-
yl)aniline (SBA 1) reacted with 4-pentyn-1-ol (a1), hex-5-yn-1-ol
10c were obtained from 2-aminobenzamide (SBA 10 , 10 and
IV
10 ) and alkynols a1 and a4 in yields ranging from 65% to
(
a3), and hex-3-yn-1-ol (a4) to afford products dihydrobenzimi-
74% under [PPh AuOTf] catalysis (Scheme4, branch J). Similar-
3
III
dazoquinazolines 1a, 1b, and 1c in 63, 65, and 69% yields, re-
spectively (Scheme 4, branch A). In contrast, on reaction with
alkynols a1 and a4 under platinum catalysis, SBA 1 afforded
tetrahydrobenzimidazopyrroloquinazoline products 12a and
ly, when SBA 10 was treated with a1 and a4 under PtCl cat-
4
alysis, the tetrahydropyrroloquinazolinones 21a and 21b were
obtained in 59 and 63% yields, respectively (Scheme4,
branch J’).
1
2b in 63 and 61% yields, respectively (Scheme4, branch A’).
The structures of four skeletally different products, 1b, 11 d,
21a, and 22a, were unambiguously confirmed by single-crystal
X-ray crystallographic analysis (Scheme 4).
Under Au catalysis, 5-methoxy-2-(thiophen-3-yl)aniline (SBA 2)
reacted with alkynols a1 and a3 to give products dihydrothie-
noquinolines 2a and 2b (Scheme4, branch B), whereas the use
of PtCl gave tetrahydropyrrolothienoquinoline products 13a
and 13b from alkynols a1 and a7 in moderate yields
[18]
The broad scope and generality of the developed technique
and the ease with which it produces skeletal diversity with
fused five, six, and even seven membered ring products is
promising. Each and every compound accessed through this
4
(Scheme4, branch B’).
I
II
[19]
Next, we focused our attention to indole-based SBAs 3 , 3 ,
technique follows the Lipinski “rule of five”. Moreover, the
[17]
and 4. Under gold catalysis, the dihydroindoloquinolines 3a–
c and dihydroindoloquinazolines 4a and b were obtained in
moderate to good yields (Scheme 4, branches C and D). Simi-
products are a hybrid of privileged scaffolds and have at
3
least one sp carbon to attribute three-dimensional character.
Since the scaffolds of known bioactive small molecules play
a key role in guiding chemists’ navigation of biologically rele-
vant chemical space, the present library would be useful for
systematic exploration of molecular diversity and thus for the
discovery of novel chemical entities in chemical biology and
I
larly, when alkynols were treated with SBAs 3 and 4 under
PtCl4 catalysis, the tetrahydroindolopyrroloquinolines 14a–
c and tetrahydroindolopyrroloquinazolines 15a and b were ob-
tained in good yields (Scheme 4, branches C’ and D’). Next, the
substrate scope with 6-(2-aminophenyl)-N,N-dimethylpyridin-2-
amine (SBA 5) was studied under gold catalysis, which gave
products dihydrobenzonaphthyridinamines 5a, 5b, and 5c
from alkynols a1, a3, and a4 in 65, 61, and 60% yields, respec-
[20]
drug discovery. Very importantly, all of the products exhibits
chirality and hence there exists a possibility to access these
scaffolds in optically pure forms with the use of chiral cata-
[21]
lysts.
tively (Scheme4, branch E). In the presence of PtCl , the alky-
In summary, we have achieved catalyst-dependent selectivity
in the catalytic branching cascade. The reaction of alkynols (a
common type of starting materials) with various SBAs under
metal catalysis afforded two different types of molecular scaf-
fold and their formation was dependent on the type of catalyst
used. Knowledge in the field of catalysis and DOS should com-
bine the benefits offered from each technique and in doing so
provide enhanced opportunities to deliver small molecules; es-
4
nols a1 and a4, on reaction with SBA 5, afforded tetrahydro-
benzopyrrolonaphthyridinamines 16a and 16b in moderate
yields (Scheme4, branch E’). The alkynols a1 and a3, on reac-
II
tion with 2-(benzo[b]thiophen-2-yl)-5-methoxyaniline (SBA 6 )
under [Ph PAuOTf] catalysis gave the expected dihydrobenzo-
3
thienoquinoline products 6a and 6b in 61 and 63% yields, re-
spectively (Scheme4, branch F). In contrast, the reaction of al-
I
II
[20]
kynols a4 and a9 with SBAs 6 and 6 in the presence of PtCl
pecially in optically active form.
4
gave the corresponding tetrahydrobenzothienopyrroloquino-
line products 17a and 17b in 64 and 63% yields, respectively
I
Experimental Section
(
Scheme4, branch F’). The 2-aminophenyl indoles (SBAs 8 and
II
8
) also reacted well under the [PPh AuOTf] catalysis to afford
3
Representative procedure
dihydroindoloquinoxalines 8a–e in good yields (Scheme4,
I
To an oven-dried screw-capped vial equipped with a magnetic stir
bar was added scaffold-building agent (SBAs 1–11; 0.50 mmol), al-
branch H). However, in the presence of PtCl catalyst, SBAs 8
4
III
and
8
gave tetrahydroindolopyrroloquinoxaline products
kynol (a1–a10; 0.50 mmol), and metal catalyst ([Ph PAuOTf] or
3
19a–c in moderate yields (Scheme4, branch H’).
PtCl ; 5 mol%) in MeOH (0.5 mL). The reaction vial was fitted with
4
To further probe the scope of this catalyst-dependent selec-
a cap, evacuated, and charged with nitrogen. The reaction mixture
was heated as specified in the Supporting Information. The reac-
tion mixture was then allowed to cool to ambient temperature, di-
luted with ethyl acetate (5 mL), and filtered through a plug of
silica gel. The filtrate was concentrated and the residue thus ob-
tained was purified by column chromatography on silica gel using
EtOAc/petroleum ether or MeOH/DCM as eluent to afford analyti-
cally pure compounds.
tivity, pyrrole-based SBAs were examined. As expected, SBAs
I
II
I
II
I
II
III
7
, 7 , 9 , 9 , 11 , 11 , and 11 , with substitution at C2, C3 and N
positions, reacted with various alkynols to afford dihydropyrro-
loquinolines 7a–c, 9a–c and dihydropyrroloquinazolines 11 a–f
in satisfactory to good yields (Scheme4, branches G, I, and K).
This reaction also tolerated halo-substituted pyrrole-based
SBAs to give product 7b in 73% yield, after reaction with alky-
nol a1 under gold catalysis (Scheme4, branch G). The same
Acknowledgements
SBAs reacted smoothly with various alkynols under PtCl catal-
4
ysis to afford the desired tetrahydrodipyrroloquinoline prod-
Generous financial support by the DST-New Delhi (No. SB/S1/
OC-17/2013) and CSIR-New Delhi (CSC0108 and CSC0130) is
gratefully acknowledged. We thank the Director of CSIR-NCL
ucts 18a, b, and 20a, and tetrahydrodipyrroloquinazolines
22a–d in moderate to good yields (Scheme 4, branches G’, I’,
and K’). The products dihydroquinazolinones 10a, 10b and
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for providing a generous start-up grant (MLP029626). A.H.B.,
A.C.S., and R.D.K. thank CSIR-New Delhi for the award of re-
search fellowship. N.T.P. is thankful to Dr. P. R. Rajamohanan for
recording NMR spectra.
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Keywords: alkynols · cascade synthesis · chemoselectivity ·
diversity-oriented synthesis · homogeneous catalysis
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Received: October 20, 2014
Published online on && &&, 0000
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COMMUNICATION
DOS prompt: Catalyst-dependent selec-
tivity in the relay catalytic branching
cascade has been reported. The reaction
of a common type of substrate (alky-
nols, A) with variable scaffold-building
agents (bis-nucleophiles, B) gave two
different types of molecular scaffolds
&
Relay Catalysis
A. H. Bansode, A. C. Shaikh, R. D. Kavthe,
S. Thorat, R. G. Gonnade, N. T. Patil*
&
& – &&
Catalyst-Dependent Selectivity in the
Relay Catalytic Branching Cascade
a
b
(AB and AB ) and their formation is es-
sentially dependent on the type of cata-
lyst used.
Catalyst (Au versus Pt)-dependent selectivity……in
diversity-oriented synthesis is illustrated by the diver-
gent road in the picture. When the lorry bearing the
substrates passes through the golden gate or the plat-
inum gate, two different types of molecular scaffolds
are formed. Two buildings for storing these molecules
represent the library of molecular scaffolds generated
by this approach. For more details, see the Communi-
cation by N. T. Patil et al. on page && ff.
&
&
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