Parallel and four-step synthesis of natural-product-inspired scaffolds through modular assembly and divergent cyclization

Article abstract of DOI:10.3762/bjoc.8.105

By emulating the universal biosynthetic strategy, which employs modular assembly and divergent cyclizations, we have developed a four-step synthetic process to yield a collection of natural-product-inspired scaffolds. Modular assembly of building blocks onto a piperidine-based manifold 6, having a carboxylic acid group, was achieved through Ugi condensation, N-acetoacetylation and diazotransfer, leading to cyclization precursors. The rhodium-catalyzed tandem cyclization and divergent cycloaddition gave rise to tetracyclic and hexacyclic scaffolds by the appropriate choice of dipolarophiles installed at modules 3 and 4. A different piperidine-based manifold 15 bearing an amino group was successfully applied to demonstrate the flexibility and scope of the unified four-step process for the generation of structural diversity in the fused scaffolds. Evaluation of in vitro antitrypanosomal activities of the collections and preliminary structure - activity relationship (SAR) studies were also undertaken.

Full text of DOI:10.3762/bjoc.8.105

Parallel and four-step synthesis of natural-product-
inspired scaffolds through modular assembly
and divergent cyclization
Hiroki Oguri*1, Haruki Mizoguchi1, Hideaki Oikawa1, Aki Ishiyama2,
Masato Iwatsuki2, Kazuhiko Otoguro2 and Satoshi Ōmura3
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2012, 8, 930–940.
1Division of Chemistry, Graduate School of Science, Hokkaido
University, Sapporo, Kita-ku, Hokkaido 060-0810, Japan, 2Research
Center for Tropical Diseases, Kitasato Institute for Life Sciences,
Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641,
Japan and 3Graduate School of Infection Control Sciences, Kitasato
University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan
doi:10.3762/bjoc.8.105
Received: 06 March 2012
Accepted: 01 June 2012
Published: 22 June 2012
This article is part of the Thematic Series "Recent developments in
chemical diversity".
Email:
Hiroki Oguri* - oguri@sci.hokudai.ac.jp
Guest Editor: J. A. Porco Jr.
* Corresponding author
© 2012 Oguri et al; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
chemical diversity; divergent cyclization; indole alkaloids; modular
assembly; rhodium-catalyzed cyclization–cycloaddition; skeletal and
stereochemical diversity
Abstract
By emulating the universal biosynthetic strategy, which employs modular assembly and divergent cyclizations, we have developed
a four-step synthetic process to yield a collection of natural-product-inspired scaffolds. Modular assembly of building blocks onto a
piperidine-based manifold 6, having a carboxylic acid group, was achieved through Ugi condensation, N-acetoacetylation and
diazotransfer, leading to cyclization precursors. The rhodium-catalyzed tandem cyclization and divergent cycloaddition gave rise to
tetracyclic and hexacyclic scaffolds by the appropriate choice of dipolarophiles installed at modules 3 and 4. A different piperidine-
based manifold 15 bearing an amino group was successfully applied to demonstrate the flexibility and scope of the unified four-step
process for the generation of structural diversity in the fused scaffolds. Evaluation of in vitro antitrypanosomal activities of the
collections and preliminary structure–activity relationship (SAR) studies were also undertaken.
Introduction
Biologically intriguing natural products often possess cyclic specific molecular recognition with biomacromolecules in the
scaffolds bearing dense arrays of functional groups and cellular context [1-3]. To generate diverse collections of the
hydrogen-bond donors or acceptors. The incorporation of elaborated cyclic scaffolds, nature has evolved biosynthetic
multiple sp3-centers on the scaffold creates a unique three- machinery and often employs (1) modular assembly and (2)
dimensional shape of the surface, which is responsible for divergent cyclization [4]. As the simplest example of this struc-
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Beilstein J. Org. Chem. 2012, 8, 930–940.
tural diversification, the biosynthesis of aromatic polyketides is leading to distinct skeletons with complex molecular architec-
outlined in Figure 1a. Employing acetyl CoA as a starter unit, tures.
modular and iterative assembly of malonate extender units
produces a linear tetraketide intermediate capable of being Since the naturally occurring indole alkaloids share indole and
folded in at least two ways [5]. Intramolecular Claisen conden- piperidine as common substructures (Figure 1b) [6], we
sation and subsequent enolization produce phloracetophenone conceived the assembly of the substructures and subsequent
(path A), while aldol condensation followed by enolization and intramolecular cyclization between these substructures to form
hydrolysis of the thioester yield orsellinic acid (path B). the fused skeletons (Figure 1c). As a pioneering approach to
Inspired by this simple yet universal biosynthetic strategy, shape the foundation of the “Build-Couple-Pair” (B/C/P)
which generates structural variation among natural products, we strategy [7-15] for diversity-oriented synthesis [16,17], a syn-
envisioned the construction of chemical libraries featuring thetic process to access indole-alkaloid-like scaffolds utilizing a
modular assembly for the rapid connection of simple building piperidine-based manifold 1, was developed in 2005 [18]. By
blocks, as well as divergent cyclization of a common precursor exploiting lactam, carboxylic acid and β-ketocarbonyl func-
Figure 1: (a) Biosynthetic outline of aromatic polyketides; (b) structure of indole alkaloids composed of indole (red) and piperidine (blue) groups; (c)
divergent cyclizations to generate scaffold variations as an illustration of the “Build-Couple-Pair” strategy in diversity-oriented synthesis.
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tional groups on 1, α-diazoketocarbonyl and indole groups were With the intention to produce screening collections, we then
installed to produce a set of tetraketide-like precursors, 2 and 3. devised a second-generation strategy applicable for a parallel
Rhodium(II)-catalyzed tandem cyclization–cycloaddition [19- synthetic protocol. This approach allows unified four-step
21] of the tetraketide-like precursors produced distinct multi- access to a series of indole-alkaloid-like scaffolds. Some of
cyclic scaffolds, 4 and 5, differing in the relative orientations of these results were previously reported as a preliminary commu-
the substructures. This approach illustrates a systematic way of nication in 2009 [22]. As shown in Figure 2a, we conceived the
diversifying skeletal arrays in a controlled manner.
modular assembly of three building blocks onto the piperidine-
Figure 2: (a) Synthetic plans based on modular assembly and divergent cyclizations leading to fused skeletons; (b) structures of naturally occurring
alkaloids bearing aminoacetal moieties and a proposed mode of action of quinocarcin.
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based manifold 6 with a carboxylic acid group. Ugi conden-
sation [23-25] of 6 with indole-3-carbaldehyde 7, isonitrile and
amine building blocks 8 and 9, followed by reaction with an
acetylketene [26] would produce a tetraketide-like precursor 10
composed of five modules. Since two methylene groups in
module 2 in the tetraketide-like moiety 10 are masked as
an imide group and a quaternary center, respectively, the
remaining methylene in module 1 would be regiospecifically
manipulated through diazotransfer to form diazoimide 11 [27].
Rhodium(II)-catalyzed cyclization of 11 between modules 1
and 2 could generate a carbonium ylide intermediate 12. In this
system, there is a dynamic conformational equilibrium of the
tertiary amide, which is expected to allow divergent cycloaddi-
tions with the dipolarophiles installed at modules 3 and 4
leading to either tetracyclic 14 or hexacyclic 13. In this full
account, we also employ a piperidine-based manifold 15
bearing an amino group in order to expand the applicability of
the various building blocks in the four-step parallel synthesis.
The modular assembly of 15 with 16, 17 and 8 based on Ugi
condensation could produce a different dipeptidyl array of the
precursor 18, which is expected to produce the distinct scaffold
19 compared to those produced from manifold 6. According to
this strategy employing rhodium(II)-catalyzed tandem reactions,
four sp2-centers were efficiently converted into the corres-
ponding sp3-centers, including an aminoacetal core. In nature,
there are a variety of alkaloids that possess an aminoacetal
group (Figure 2b). The aminoacetal groups embedded in the
skeleton are prone to undergo C–O bond cleavage to form elec-
trophilic iminium species, which allow covalent bond forma-
tion with biomacromolecules (nucleic acids, proteins) in a
cellular environment, and thereby play pivotal roles in defining
their biological activities [28,29]. As a mechanistic rationale for
the antitumor activities of quinocarcins, DNA alkylation
exploiting the iminium moiety was proposed as shown in
Figure 2b [30].
Inspired by these biosynthetic strategies, we report herein the
development of parallel and four-step synthetic processes,
employing manifolds 6 and 15, leading to collections of fused
Scheme 1: Four-step synthesis of hexacyclic skeleton 25.
molecules with installations of diverse functional groups butylisonitrile (21) and p-methoxybenzylamine (22) were
comprising aminoacetal, β-ketoimide and indole groups [31- condensed in methanol under reflux to furnish a dipeptidyl
34]. Evaluation of in vitro antitrypanosomal activities of the product as a 1:1 diastereomeric mixture in 78% yield.
synthetic collections and preliminary SAR studies are also N-Acetoacetylation of this intermediate was achieved by
described [35-41].
reaction with an acetylketene generated by heating of 23.
Subsequent diazotransfer reaction afforded the precursor 24
with a diazoimide group in 73% yield (two steps). Cyclization
Results and Discussion
First, we assembled a linear precursor 24 with installation of a of 24 and subsequent cycloaddition between the resulting carbo-
p-methoxybenzyl group and an indole ring at modules 3 and 4, nium ylide and the indole C2–C3 double bond efficiently
respectively (Scheme 1), according to a procedure previously proceeded by the treatment with 5 mol % Rh2(OAc)4 catalyst in
reported in our preliminary communication [22]. Racemic benzene under reflux to afford hexacyclic scaffold 25 in 78%
manifold 6, indole-3-carbaldehyde derivative (20), tert- yield. The cyclized products were obtained as a 1:1 diastereo-
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Beilstein J. Org. Chem. 2012, 8, 930–940.
meric mixture of 25a and 25b and were easily separable by previously reported protocol [22], Ugi reaction employing allyl-
conventional silica-gel chromatography. X-ray analysis of crys- amine (31) and stepwise installation of a diazoimide group
talline 25b unambiguously determined the relative stereochem- provided 35 in good yield. Upon treatment of 35 with
ical relationships of the multiple sp3 centers embedded in the Rh2(OAc)4 in benzene under reflux, 1,3-dipolar cycloaddition
complex hexacyclic scaffold. In addition, removal of the of the ylide intermediate with the terminal olefin at module 3
N-nosyl protecting group by treatment with benzenethiol led to proceeded to give 39 as a separable 1:1 diastereomeric mixture
26b in quantitative yield [42].
in 94% yield. The relative stereochemistry of 39 was unambigu-
ously determined by X-ray analysis of the crystalline 39b.
To generate skeletal variations by altering the sites of the
cycloadditions, we next synthesized a branched precursor 29 In an effort not only to verify the reaction scope of the olefinic
bearing a pair of identical indole units at modules 3 and 4 group installed at module 3 but also to shift the reaction site
(Scheme 2), as reported previously [22]. Due to the instability (module 3→4), we then prepared a series of cyclization precur-
of the corresponding amine building block bearing the indole sors 36–38 in order of increasing steric hindrance of the olefinic
unit, azide 27 was employed as a precursor. Staudinger/aza- groups as reported previously [22]. Allylamines 32–34 having a
Wittig reaction [43] of 27 and 20 and subsequent condensation di-, tri- or tetra-substituted olefin were employed to synthesize
with 6 and 21 afforded the peptidyl product 28. Installation of a precursors 36–38 based on the unified three-step protocol. The
β-keto imide followed by diazotransfer reaction produced 29. Rh(II)-catalyzed tandem cyclization–cycloaddition of the
Upon the treatment of 29 with Rh2(OAc)4 catalyst (5 mol %), branched precursors 36–38 exclusively occurred at module 3.
the cycloaddition occurred in a highly site-selective manner at The cyclized products 40–42, having the indole group at
module 3 to form 30 in 77% yield. Cycloaddition with the other module 4 intact, were obtained in good yields. It is worth noting
site (module 4) is likely to be hindered by the sterically that the cycloadditions efficiently incorporated consecutive
demanding amide moiety (module 5) in the vicinity of the reac- quaternary centers into the complex fused skeleton, overriding
tion centers.
the considerable steric hindrance of the dipolarophiles
composed of the tri- and even tetra-substituted olefin groups. To
test the generality of the site-selective cycloaddition at module
3, we then synthesized precursors 45 and 46 with a terminal
alkyne and a furan ring, respectively, by using amine building
blocks 43 and 44 according to the reported procedure [22]. The
Rh(II)-catalyzed tandem reactions of 45 and 46 again proceeded
at module 3 to produce cyclized products 47 and 48 in good
yields. Despite our concern for the potential instability of the
aminoacetal moiety adjacent to the double bond, 47 is stable
under the standard manipulations. Overall, the pair of diastereo-
mers generated by the Ugi condensations were converted
equally through the unified three-step transformations and
easily separated after the cycloadditions.
Whilst the cycloadditions described above demonstrate the pref-
erence for the dipolarophile installed at module 3, we then
attempted to alter the cyclization mode (module 3→4) by
increasing the entropic barrier for medium-sized ring formation
(Scheme 4) as reported previously [22]. For this purpose, we
designed precursors 51 and 52, synthesized through the three-
step protocol employing amines 49 and 50, respectively. Upon
the treatment of 51 with Rh2(OAc)4, cycloaddition predomi-
nantly occurred at module 3 to produce tetracyclic 53 in 65%
yield with formation of a seven-membered ring. Despite the
Scheme 2: Four-step synthesis of hexacyclic skeleton 30.
Taking into account the predominant involvement of the dipo- minor pathway, cycloaddition at module 4 also competed to
larophile installed at module 3, we then designed a branched give 54 in 22% yield. On the other hand, cycloaddition of 52
precursor 35 having a terminal olefin and an indole group at exclusively occurred with the indole group at module 4, giving
modules 3 and 4, respectively (Scheme 3). According to the rise to 56 in 94% yield without eight-membered ring formation
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Beilstein J. Org. Chem. 2012, 8, 930–940.
Scheme 3: Parallel and four-step synthesis of tetracyclic skeletons 39–42 and 47–48.
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Beilstein J. Org. Chem. 2012, 8, 930–940.
In this study, we designed and synthesized a piperidine-based
manifold 15 bearing an amino group in order to produce varia-
tions of branched precursors leading to distinct scaffolds
(Scheme 5). The manifold 15 was readily prepared through
Scheme 4: Synthesis of branched precursors, 51 and 52, using
amines 49 and 50, with different methylene lengths and attempts to
switch reaction sites.
leading to 55. X-ray analysis of the crystalline 56b confirmed
the structure [22]. Accordingly, alteration of the cyclization
mode was achieved by modulating the ring sizes formed via
cycloaddition, which allowed divergent access to hexacyclic
and tetracyclic skeletons.
Scheme 5: Four-step synthesis of hexacyclic scaffold 63 employing
manifold 15. For details of the synthesis of 60 and 61 see Supporting
Information File 1.
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Beilstein J. Org. Chem. 2012, 8, 930–940.
Curtius rearrangement of 6 and subsequent removal of the crystalline 63a allowed its structural determination. The flexi-
resulting carbamate group. Ugi four-component condensation of bility and divergence of the synthetic process with high levels
15, isonitrile 21, indole-3-carboxylic acid derivative 58 and of stereoselectivity are promising for the development of small-
aldehyde 59 produced a 1:1 diastereomeric mixture of the molecule libraries with structural diversity and complexity.
dipeptidyl intermediate. Stepwise installation of the α-diazocar-
bonyl group produced 62 in good yield. The cyclization With collections of the natural-product-inspired molecules in
precursor 62 has a different arrangement of the branched dipep- hand, in vitro anti-trypanosomal activities [35-41] were evalu-
tidyl unit linked to the piperidine-based manifold compared ated by employing a GUTat 3.1 strain of T. brucei brucei
with those derived from 6. Rhodium-catalyzed tandem cycliza- (Table 1) according to the previously reported protocols
tion–cycloaddition proceeded smoothly to produce 63 in 95% (Supporting Information File 1). We found several hit com-
yield. After separation of the diastereomers, X-ray analysis of pounds in the series of the cycloadducts exploiting module 3 as
Table 1: In vitro anti-trypanosomal activities of natural product analogues and approved drugs against T. brucei brucei GUTat 3.1a.
entry
compound
IC50 (μg/mL)
anti-trypanosomal cytotoxicity
activity
Selectivity
Index (SI)
1
>12.5
NDb
(─)
8.7
5.9
39a
39b
41b
2
0.46
4.02
3
5.89
34.64
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Beilstein J. Org. Chem. 2012, 8, 930–940.
Table 1: In vitro anti-trypanosomal activities of natural product analogues and approved drugs against T. brucei brucei GUTat 3.1a. (continued)
4
>12.5
NDb
(─)
39c
25a
25b
5
5.9
24.47
4.1
6
>12.5
NDb
(─)
7
>12.5
NDb
(─)
30b
8
9
pentamidinec
suraminc
0.00158
1.58
5.71
>100
>100
3600
>63
10
eflornithinec
2.27
>44
aCulture of trypanosome (2.0–2.5 × 104 trypanosomes/mL for GUTat 3.1 strain) was used. The cytotoxicities were evaluated with MRC-5 cells, and
the selectivity index (SI) for trypanosomiasis was calculated as (IC50 for MRC-5)/(IC50 for T. brucei brucei). bND means “not determined”. cExisting
antitrypanosomal drugs.
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Beilstein J. Org. Chem. 2012, 8, 930–940.
dipolarophiles. While compound 39a shows negligible activi- study provided insights into the potential pharmacophore, based
ties, the diastereomer 39b exhibits the most potent activity on the key features of scaffold, substructure and stereochem-
(IC50 = 0.46 μg/mL), indicating the critical importance of the istry, which could be the proof of concept of our synthetic ap-
stereochemistry on the peptidyl unit (Table 1, entries 1 and 2). proach toward lead generation exploiting natural-product-
The IC50 value of the antitrypanosomal activity is comparable inspired collections.
to or greater than those of the approved drugs, suramine and
eflornithine. Unfortunately, 39b exhibits relatively potent cyto-
Supporting Information
toxicity (IC50 = 4.02 μg/mL) against a human cell line (MRC-5
cells), and its selectivity index (SI) is calculated to be 8.7 as a
Supporting Information File 1
means to assess the combined potencies of both anti-
trypanosomal and cytotoxic activities. Incorporation of
dimethyl substituents on the scaffold resulted in diminished
activity (41b: IC50 = 5.89 μg/mL) (Table 1, entry 3). Removal
of the nosyl group (39b→39c) also caused substantial loss of
the activities, suggesting the critical role of the aromatic sulfone
amide moiety (Table 1, entry 4). Aside from 25a, which shows
moderate activity (IC50 = 5.9 μg/mL) (Table 1, entry 5), the
antitrypanosomal activities of hexacyclic compounds, 25b and
30b, (Table 1, entries 6 and 7) are negligible. In addition, the
hexacycles (63a and 63b) generated from manifold 15 also
showed insignificant activities (data not shown). Thus, this
preliminary assessment supports the idea that the collections of
natural-product-inspired scaffolds could have high hit rates
against biological screenings, even without having structural
information about the biological targets and small-molecule
modulators related to the targeted cellular functions. Further
screening investigations of the synthetic collections prepared in
the four-step process are currently underway in our laboratories.
Experimental procedures and NMR spectra of compounds.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-8-105-S1.pdf]
Acknowledgements
We thank Prof. Kiyoshi Tsuge (University of Toyama) and
Yuko Fujimura (Shionogi & Co., Ltd.) for performing the X-ray
analysis of crystalline compounds. This work was supported by
Grants-in-Aid for Challenging Exploratory Research
[20651054] and Scientific Research (B) [23310156] to H. Oguri
and also supported in part by FINDS: pharma-innovation
discovery competition Shionogi, the Naito Foundation, the
Drugs for Neglected Diseases initiative (DNDi), and the
Science and Technology Research Partnership for Sustainable
Development (SATREPS) program of the Japan Science and
Technology Agency (JST). A fellowship to H. M. from the
JSPS is gratefully acknowledged. We also thank Ms. Miyuki
Namatame (Kitasato University) for her technical assistance.
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