Branching cascades: A concise synthetic strategy targeting diverse and complex molecular frameworks

Article abstract of DOI:10.1002/anie.201102440

Touch 'n' transform: A synthetic strategy based on cascade or domino reaction sequences enabled the simultaneous incorporation of skeletal diversity and molecular complexity in focused compound collections. Thus, the treatment of a common multifunctionali

Full text of DOI:10.1002/anie.201102440

Communications
DOI: 10.1002/anie.201102440
Cascade-Reaction Design
Branching Cascades: A Concise Synthetic Strategy Targeting Diverse
and Complex Molecular Frameworks**
Wei Liu, Vivek Khedkar, Baburaj Baskar, Markus Schꢀrmann, and Kamal Kumar*
Dedicated to Professor Lutz F. Tietze
Scaffold diversity and molecular complexity are prerequisites
for a small-molecule collection[1] to deliver either drug
candidates or chemical probes for drug discovery and
chemical-biology investigations, respectively.[2] Therefore,
synthetic strategies that enable the construction of diverse
and complex molecular architectures, in particular those
based on natural product frameworks,[3] present interesting
and demanding challenges to the art of organic synthesis.[4]
Cascade or domino reaction sequences,[5] in which more than
one reaction occurs consecutively in a one-pot process and
molecular complexity is rapidly built up, can immensely
improve the efficiency of such synthetic endeavors.[5a,6]
To address the formidable challenge of incorporating
skeletal diversity in a compound collection, the “branching
Figure 1. a) Branching pathway in DOS. b) Branching cascades.
pathway” strategy has been proposed as a form of diversity-
oriented synthesis (DOS).[7] In this strategy, a common
substrate is transformed into diverse and distinct molecular
scaffolds under the influence of different reagents (Fig-
ure 1a).[8] However, this approach exploits only intermolec-
ular transformations and as a consequence yields only limited
skeletal diversity, often following a multistep synthesis.[8a,b]
For the enrichment of a compound library with molecular
complexity and scaffold diversity,[9] the common precursor
should facilitate a wide range of complexity-generating
transformations in a rapid and concise manner.[10] Herein
we introduce “branching cascades” as an efficient and concise
synthetic strategy that employs cascade reaction sequences in
a branching pathway to generate complex and diverse
molecular frameworks for the desired focused compound
collections. In our approach, different cascade-triggering
molecules X, Y, or Z trigger different cascade reaction
sequences by exploiting the diverse functional sites (F1, F2, F3)
on the common multifunctionalized precursor to yield
structurally diverse, complex, and functionalized molecular
frameworks (Figure 1b).
Substrate 1,[11] which can be prepared readily in high or
even quantitative yield,[12] was chosen as a common precursor
for the branching-cascade strategy. It contains multiple
electrophilic sites, a couple of pronucleophilic moieties, and
a vinylogous ester (a leaving group) to facilitate the interplay
of diverse cascade reaction sequences (Scheme 1).
To exploit the dispersed electrophilicity in 1 for various
cascade reaction sequences to yield different molecular
frameworks, we screened a batch of 21 nucleophiles that
included ten bisnucleophiles (N,N, N,O, N,C, and O,C
bisnucleophiles), six mononucleophiles, four zwitterionic
species, and tert-butylmalonate (Scheme 1) for substrate
conversion, product profiles, and optimal reaction conditions.
We screened the reactions by using a Radleys Carousel
Reaction Station with 12 reaction tubes under an argon
atmosphere at room temperature. Mononucleophiles were
screened as such at different concentrations (for HCl salts of
hydroxylamines, an equimolar amount of triethylamine was
used), and the bisnucleophiles were screened in the presence
and absence of an external base. After a quick aqueous
workup, LC–MS analysis of the crude reaction mixture was
performed. Reactions with high conversion and cleaner
product profiles were then optimized separately (when
required) for better results. It was a pleasant surprise to find
that 10 of the 21 nucleophiles used provided sufficiently clean
reaction profiles and yielded 12 diverse and complex ring
systems (23–30, 40, 43, 44, and 47), including natural product
[*] Dipl.-Chem. W. Liu, Dr. V. Khedkar, Dr. B. Baskar, Dr. K. Kumar
Max-Planck-Institut fꢀr molekulare Physiologie
Otto-Hahn-Strasse 11, 44227 Dortmund (Germany)
Dipl.-Chem. W. Liu, Dr. K. Kumar
Technische Universitꢁt Dortmund
Fakultꢁt Chemie, Chemische Biologie
Otto-Hahn-Strasse 6, 44221 Dortmund (Germany)
Fax: (+49)231-133-2496
E-mail: kamal.kumar@mpi-dortmund.mpg.de
Dr. M. Schꢀrmann
Technische Universitꢁt Dortmund, Anorganische Chemie
Otto-Hahn-Strasse 6, 44221 Dortmund (Germany)
[**] This research was supported by the Max-Planck-Gesellschaft. We
thank Prof. H. Waldmann (MPI, Dortmund) for his constant
support and encouragement.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201102440.
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Scheme 2. Branching cascades leading to diverse scaffolds: a) ketoester 1
(1 mmol), 3 (1.2 mmol), CH2Cl2, room temperature, 4 h; b) ketoester 1
(1 mmol), 4 (1.1 mmol), CH2Cl2, room temperature, 3–6 h; c) ketoester 1
(1 mmol), 11 (1.2 mmol), Ac2O/AcOH (1:3; 4 mL), 1508C, 5 min;
d) ketoester 1 (1 mmol), 5 (1 mmol), CH2Cl2, room temperature, Et3N
(3.0 mmol), 4 h; e) ketoester/aldehyde 1 (1 mmol), 4 (1.2 mmol), CH2Cl2,
room temperature, Et3N (3.0 mmol), 6 h; f) ketoester 1 (1 mmol), 8
(1.2 mmol), CH2Cl2, room temperature, 3 h; g) ketoester 1 (1 mmol), 10
(1.2 mmol), EtOH (10 mL), 608C, 2,6-lutidine (1.5 mmol), AgOTf
(0.1 mmol), 8 h. Tf=trifluoromethanesulfonyl.
Scheme 1. Branching-cascade substrates and nucleophiles. Bn=ben-
zyl, Boc=tert-butoxycarbonyl.
(2-aminophenyl)indole 4, led to the formation of two differ-
ent ring systems under different reaction conditions. When
ketoester substrates 1 were stirred with 4 in dichloromethane
at room temperature, novel chromone-substituted benzo-
[2,3]azocino[4,5-b]indoles 25 were formed. The structural
assignment of compounds 25 was corroborated by complete
spectroscopic analysis and further supported by a palladium-
catalyzed hydrogenation of the iminoester moiety in 25a to
yield the corresponding amine (see the Supporting Informa-
tion for details). This cascade reaction sequence, however,
yielded a minor product with a different molecular architec-
ture, that is, dihydroindolo[3,2-c]pyrido[1,2-a]quinoline 24, in
varying yields (Scheme 3).[13] In the presence of equimolar
triethylamine, the bisnucleophile 4 cleanly transformed 1 into
another ring system, indolo[1,2-c]pyrido[1,2-a]quinazoline 28,
in excellent yields (Schemes 2 and 3). Apparently, different
branching cascades prevailed under basic and nonbasic
reaction conditions and thus led to different molecular
architectures.
related and unprecedented molecular frameworks
(Schemes 2, 3, and 5).
A clear reactivity pattern of the nucleophiles with the
common substrate was observed. Whereas many bisnucleo-
philes reacted nicely with ketoesters 1, the corresponding
reactions with aldehydes 1 often yielded mixtures of products
with varying conversion. Of the tested mononucleophiles and
zwitterions, only a few performed well in the branching
cascades, although they displayed unbiased reactivity towards
ketoester and aldehyde substrates 1. The unsuccessful nucle-
ophiles included diaminoalkane 2 and di-tert-butylmalonate
(12), which yielded a complex mixture of products; amino
alcohols 6 and 7, which reacted sluggishly and gave products
that showed decomposition during column-chromatographic
purification; and o-aminophenol (9), which did not yield any
specific product consistently.
Among the successful N,N bisnucleophiles in the branch-
ing-cascade strategy, 4-aminopiperidine (3) led to the for-
mation of the complex tetrahydro-1,4-ethanopyrido[1,2-
a]pyrimidine ring system 23 in high yields (Scheme 2).
Interestingly, the use of another N,N bisnucleophile, the 2-
Another N,N bisnucleophile, 2-(1H-benzo[d]imidazol-2-
yl)ethanamine (5), transformed ketoester substrates 1 into
novel internal pyridinium salts 27 through yet another
cascade reaction sequence. Complete spectroscopic analysis
supported by palladium-catalyzed hydrogenation of the
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Communications
Scheme 3. Diverse and complex ring systems from branching cascades.
pyridinium ring in 27a to a 1,2-dihydropyridine (see the
Supporting Information) corroborated the structural assign-
ment of compounds 27.
Surprisingly, of the four N,O bisnucleophiles tested in the
branching-cascade strategy, only 2-aminobenzyl alcohol (8)
added to the scaffold diversity by transforming ketoester
substrates 1 into dihydrobenzo[d]pyrido[2,1-b][1,3]oxazine
systems 29 in excellent yields (Schemes 2 and 3).
Two more bisnucleophiles that proved interesting cas-
cade-triggering molecules in the branching-cascade strategy
were the N,C- and O,C-bisnucleophiles 10 and 11, respec-
tively. Both of these nucleophiles displayed very sluggish
reactivities in the initial screening and required further
optimization of the reaction conditions. Interestingly, the
use of di-tert-butyl-2-(2-aminophenyl)malonate (10) led to
the formation of benzoindolizine 30 (Scheme 2): a scaffold
that is part of many biologically active natural products.[14]
The use of silver triflate as a catalyst in ethanol at 608C led to
very good yields for this cascade reaction sequence
(Schemes 2 and 3).[15]
Although 11, an O,C-bisnucleophile, did not show any
promising reactivity in the initial screening, we did not give up
on tapping its potential to provide natural product based
polycyclic quinones, in particular medicinally important
pyranonaphthoquinones.[16] Gratifyingly, the treatment of
ketoester substrates 1 with 11 in the presence of acetic
anhydride/acetic acid (1:3) at 1508C for a few minutes yielded
chromone-substituted pyranonaphthoquinones 26 in good
yields with good diastereoselectivity (see the Supporting
Information).[17] Although aldehyde substrates 1 reacted well
with 11 under these conditions, the corresponding products
were not stable enough and could not be purified.
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The branching cascades were used to efficiently transform
the common substrate into diverse molecular frameworks
decorated with functionalities that could be further explored
attacks the ester carbonyl functionality to yield compounds 27
as internal salts (cascade IV), N-addition of the indole amide
derived from 4 (with a base) to the iminium cation in 33
provides 28, and the addition of indole 4 (without a base)
through C3 to the same site in 33 yields 24 through cascade
sequence V (Scheme 4).
for the generation of focused compound collections.[10a]
A
careful analysis of the ring structures formed and their
substitution pattern, for example, the presence of the o-
hydroxyphenone moiety (generated by chromone-ring open-
ing) in some of the products, suggested the involvement of
common intermediates in the different cascade reactions
operating (Scheme 2). Overall, bisnucleophiles appear to
follow five different cascade reaction sequences that generate
eight diverse and complex ring systems (Scheme 4).
In the first cascade reaction sequence (cascade I,
Scheme 4), bisnucleophiles that have at least one amino
group along with another nucleophilic site add to the
ketoester (or aldehyde) to form an intermediate 31, which
undergoes dehydrative cyclization to yield a cyclic aminal 32.
A second nucleophilic addition by bisnucleophiles 3, 8, and 10
to the enamine moiety of 32 with concurrent chromone-ring
opening yields scaffolds 23, 29, and 30, respectively
(Schemes 2 and 4). The formation of azocines 25 follows
the cascade reaction sequence II (Scheme 4). In this reaction
sequence, the generation of a highly conjugated iminoester 34
from 31 is followed by an intramolecular 1,4-addition of the
indole. In the case of the nucleophile o-hydroxynaphthoqui-
none (11), a conjugate addition to ketoester substrates 1 leads
to intermediate 35, which undergoes cyclization to form
anomerically stabilized tricyclic acetals 26 through branching
cascade III (Scheme 4).
Disappointingly, mononucleophiles 13–16 yielded mix-
tures of inseparable products in the initial reaction screening.
However, N-benzyl- and N-phenylhydroxylamines 17 and 18,
respectively, were found to be useful cascade-triggering
substrates. These nucleophiles provided natural product
related highly substituted tricyclic benzopyrones 40 in excel-
lent yields and with appreciable diastereoselectivity
(Scheme 3).[18] In this branching cascade (cascade VI,
Scheme 5), the hydroxylamines act as O nucleophiles[19]
rather than N nucleophiles and add to the keto or aldehyde
group of the common substrate 1 to give an intermediate 36,
which cyclizes to yield an acetal 38. Chromone-ring opening
leads to a dihydropyran 39, which undergoes intramolecular
conjugated addition of the phenol to provide benzopyrones
40. The conjugate addition of the phenol in 39 might occur
preferentially anti to the initially added hydroxylamine for
steric reasons and thus lead to the observed stereoselectivity
in the formation of anomerically stabilized benzopyrone
acetals 40 (Scheme 5). The structure and relative configura-
tion of 40 are corroborated by the results of comprehensive
NMR spectroscopic studies (see the Supporting Information
for details).
Among the zwitterions[20] examined in the initial reaction
screening, 20 did not react at all, and the allene-derived
zwitterion 21 yielded only a trace amount of an unidentified
product. The Huisgen zwitterion 22 (Scheme 1) had been
investigated thoroughly for its reactivity
Intermediate 32 can exist in a zwitterionic form 33, in
which more than two electrophilic sites are available for a
second nucleophilic addition. Whereas the bisnucleophile 5
with various aldehydes and ketones,
including chalcones.[21] On the basis of
its reported chemoselectivity, we were
curious to find out whether the expected
intermediate 42, which is formed by the
addition of 22 to 1, would undergo a
conjugate 1,4-addition to yield 43 or a 1,2-
addition which could provide a novel
chromenodiazepine ring system 44 (cas-
cade VII, Scheme 5).[22] The major prod-
uct in all the cases, however, in particular
in reactions of ketoesters 1, was the
chromone-substituted
pyrrole
ring
system 43. Only in some cases, in reac-
tions of aldehydes 1, could we isolate 44
as a minor product. Nevertheless, com-
pounds containing a pyrazole substituent
on the privileged chromone moiety have
structural features of the flavonoid natu-
ral products and might enrich the collec-
tion with useful related biological activ-
ities.
The zwitterion 19, that is, methyl
isocyanoacetate, displayed unbiased reac-
tivity towards ketoester and aldehyde
substrates 1 and yielded benzopyrones
Scheme 4. Proposed mechanisms of branching cascades with bisnucleophiles.
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Communications
Keywords: diversity-oriented synthe-
.
sis · domino reactions ·
focused libraries ·
molecular complexity ·
molecular diversity
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