Highly stereoselective synthesis of natural-product-like hybrids by an organocatalytic/multicomponent reaction sequence

Article abstract of DOI:10.1002/anie.201412074

In an endeavor to provide an efficient route to natural product hybrids, described herein is an efficient, highly stereoselective, one-pot process comprising an organocatalytic conjugate addition of 1,3-dicarbonyls to α,β-unsaturated aldehydes followed by

Full text of DOI:10.1002/anie.201412074

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201412074
German Edition: DOI: 10.1002/ange.201412074
Synthetic Methods
Highly Stereoselective Synthesis of Natural-Product-Like Hybrids by
an Organocatalytic/Multicomponent Reaction Sequence**
Radell Echemendꢀa, Alexander F. de La Torre, Julia L. Monteiro, Michel Pila, Arlene G. CorrÞa,
Bernhard Westermann, Daniel G. Rivera,* and Mꢁrcio W. Paix¼o*
Abstract: In an endeavor to provide an efficient route to
natural product hybrids, described herein is an efficient, highly
stereoselective, one-pot process comprising an organocatalytic
conjugate addition of 1,3-dicarbonyls to a,b-unsaturated
aldehydes followed by an intramolecular isocyanide-based
multicomponent reaction. This approach enables the rapid
assembly of complex natural product hybrids including up to
four different molecular fragments, such as hydroquinolinone,
chromene, piperidine, peptide, lipid, and glycoside moieties.
The strategy combines the stereocontrol of organocatalysis
with the diversity-generating character of multicomponent
reactions, thus leading to structurally unique peptidomimetics
integrating heterocyclic, lipidic, and sugar moieties.
previously validated by nature or derived from chemistsꢀ
synthetic expertise, include biology-,[3] function-,[4] and diver-
sity-oriented[5] syntheses.
Several methodologies relying on cascade or domino
processes[6] and multicomponent reactions (MCRs)[7,8] are
currently being applied to match or even surpass natureꢀs
synthetic ability to generate structurally complex and diverse
scaffolds. Within the class of MCRs, isocyanide-based multi-
component reactions (I-MCRs) stand as powerful
approaches[8] comprising high chemical efficiency, conver-
gency, and atom economy. Not surprisingly, I-MCRs have
been intensively exploited in drug discovery and chemical
biology programs targeting both scaffold decoration and
generation.[9] Moreover, the intrinsic characteristics of
I-MCRs may be further improved when they are combined
with either pre-[10] or post-MCR[11] modifications. However,
most efforts have been devoted to the latter one,[11,12] whereas
examples describing pre-MCR modifications are quite
seldom.[10]
Looking at the repertoire of MCRs, one realizes the
ubiquity of the carbonyl component, that is, ketones or
aldehydes, in these reactions. Only recently, early efforts have
been directed towards the implementation of an amino-
catalytic asymmetric functionalization of such carbonyl
functionalities followed by a subsequent MCR.[11,13] Amino-
catalysis has been applied with great success in the a-, b-, g-
and even e-asymmetric functionalization of carbonyls.[14]
Hence, combination of aminocatalysis with the available
repertoire of MCRs provides endless possibilities for scaffold
generation. In an endeavor to demonstrate the potential of
this concept, we focused on the development of a stereocon-
trolled organocatalytic/multicomponent sequence leading to
compounds with skeletal complexity resembling natural
products.
This article describes a highly stereoselective approach for
the one-pot synthesis of complex natural product hybrids[15]
incorporating fragments such as hydroquinolines, chromenes,
piperidines, peptides, lipids, and glycosides. The approach
involves an asymmetric organocatalytic conjugate addition of
dicarbonyl compounds to a,b-unsaturated aldehydes, fol-
lowed by an intramolecular four-center three-component
reaction including amine and isocyanide components.
We formulated two main selection criteria for the organo-
catalytic and multicomponent approaches. First, the organo-
catalytic process should provide enantiomerically enriched
natural-product-like scaffolds having a pair of reactive
functionalities suitable for a subsequent I-MCR. Second, we
aimed at utilizing intramolecular I-MCRs, as these typically
provide better stereocontrol as compared to their intermo-
T
he generation and decoration of privileged natural product
scaffolds is a successful strategy for obtaining libraries of
bioactive compounds.[1] Scaffold decoration entails the uti-
lization of both combinatorial and rationally designed
approaches to functionalize biologically validated molecular
targets. Scaffold generation, in contrast, focuses on the
application of methodologies capable of generating structures
which cover a larger part of the chemical and biological
space.[2] Since scaffold generation is pivotal during the early
stage of drug discovery, issues like chemical efficiency,
stereocontrol, and easy diversification are crucial in process
development. Relevant strategies for exploring the broader
chemical space by targeting dissimilar chemotypes, either
[*] M. Sc. A. F. de La Torre, M. Sc. J. L. Monteiro, Prof. Dr. A. G. CorrÞa,
Prof. Dr. M. W. Paix¼o
Departamento de Quꢀmica, Universidade Federal de S¼o Carlos
S¼o Carlos, 97105-900, SP (Brasil)
E-mail: mwpaixao@ufscar.br
M. Sc. R. Echemendꢀa, M. Sc. M. Pila, Prof. Dr. D. G. Rivera
Center for Natural Products Research
Faculty of Chemistry, University of Havana
Zapata y G, 10400, La Habana (Cuba)
E-mail: dgr@fq.uh.cu
Prof. Dr. B. Westermann
Department of Bioorganic Chemistry
Leibniz Institute of Plant Biochemistry
Weinberg 3, 06120 Halle (Saale) (Germany)
and
Martin-Luther-University, Halle Wittenberg, Institute of Chemistry
Kurt-Mothes-Str. 2, 06120 Halle (Germany)
[**] D.G.R. is grateful to FAPESP for a visiting professor grant (2013/
21599-8). The authors also kindly acknowledge financial support
from CNPq (INCT-Catꢁlise), CAPES/MES-Cuba, and FAPESP. Dr.
S. S. van Berkel is also acknowledge for his fruitful suggestions.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201412074.
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Table 1: Screening of the one-pot organocatalytic conjugate addition/four-center three-component
reaction sequence to 2-amido-hydroquinolin-6-ones and concise reaction mechanism.
Initial experiments using meth-
anol, toluene, or dichloromethane
in the second reaction step were
unsatisfactory, as the first solvent
gave a mixture of products and the
two latter ones did not lead to any
product
formation
(Table 1,
entries 1–4). The products 5 and 6
were formed in a ratio of about
1.5:1 when methanol was used, as
a result of the competition between
the rearrangement of the a-adduct
(i.e., migration of the amine com-
ponent) and the addition of meth-
anol to the conjugated position. As
shown in Table 1, the intermediate
a-adduct is a rigid, fused bicyclic
system, in which the low conforma-
tional flexibility may disfavor the
amine migration, thus enabling the
attack of a nucleophilic solvent like
methanol. To circumvent this prob-
lem, TFE was used and led to the 2-
amido-hydroquinolin-6-one 5 as the
sole product in good yield (Table 1,
entry 5). Importantly, the use of
microwave irradiation enabled the
reaction to proceed in similar chem-
ical efficiency and significantly
shorter reaction times, that is,
15 minutes at 708C (entry 6). Since
the second step did not proceed in
CH2Cl2, we evaluated the possibility
Entry[a]
R
Conditions[b]
5/6 Yield [%][c]
5 d.r. (cis/anti)[d]
5 ee [%][e]
1
2
3
4
5
6
7
8
H
Me
H
Me
H
Me
Me
Me
MeOH, RT[f]
39/25
42/28
n.r.
54:46
>99:1
–
92
>99
–
–
93
>99
>99
>99
MeOH, MW[g]
toluene, MW[g]
CH2Cl2, RT[f]
n.r.
–
TFE, RT[f]
77/0
75/0
64/0
71/0
58:42
>99:1
>99:1
>99:1
TFE, MW[g]
CH2Cl2/TFE, RT[f,h]
CH2Cl2/TFE, MW[g,h]
[a] First step performed with 1 (1 equiv) and 2 (1.3 equiv). [b] Second step performed either with benzyl
or (S)-a-methylbenzyl amine (1.3 equiv) and cyclohexylisocyanide (1.3 equiv). [c] Yield of isolated
product after two steps. [d] Determined by 1H NMR analysis of the crude reaction mixture and
confirmed by HPLC. [e] Determined by chiral-phase HPLC analysis. [f] Conducted at room temperature
(RT) for 36 h. [g] Conducted under microwave irradiation (MW) for 15 minutes at 708C. [h] Addition of
TFE to the reaction mixture containing CH2Cl2 to make a 1:1 (v/v) mixture. Ar=3,5-(CF3)-C6H3,
MW=microwave, TFE=trifluoroethanol, TMS=trimethylsilyl.
of
implementing
a
one-pot
lecular versions.[10,17] As shown in Table 1, the first procedure
is an organocatalytic cascade developed independently by the
groups of Rueping[18] and Jørgensen.[19] The cascade process
comprises the asymmetric conjugate addition of 1,3-cyclo-
alkanediones to a,b-unsaturated aldehydes followed by
acetalization, thus enabling the installation of two reactive
functionalities onto a single skeleton. Dimedone (1) and 2-
pentenal (2) were initially selected for the organocatalytic
conjugate addition as the first step in the multicomponent
sequence. Reaction conditions originally described by Ruep-
ing et al.,[18b] employing 10 mol% of the catalyst diarylproli-
nol silyl ether 3, successfully produced the chromenone 4.
This intermediate fulfills the requisite of being a biologically
relevant core for scaffold diversification as well as having two
functionalities suitable or I-MCRs, that is, an aldehyde and
a conjugated enol.
Both racemic and enantiomerically enriched 4 were
prepared and subsequently subjected to the I-MCR by
treatment with a primary amine and an isocyanide. Such
a multicomponent process resembles the Ugi–Smiles reac-
tion,[20] which has been previously implemented with hetero-
cyclic and conjugated enols[21] as surrogates of the classic
phenol component. However, neither intramolecular variant
of this type of I-MCR nor combinations with a pre-MCR
organocatalytic process have been reported so far.
sequence by addition of TFE after formation of organo-
catalytic product 4, thus carrying out the second step in the
solvent mixture CH2Cl2/TFE (1:1, v/v). To our delight, both
the yield and stereoselectivity remained high in this one-pot
process comprising the organocatalytic step and the I-MCR
(entries 7 and 8). Importantly, the presence of secondary
amine catalyst 3 did not interfere in the I-MCR, as no product
including this fragment was detected.
A key feature of this approach is the different stereo-
chemical outcome derived from variation of the primary
amine. As illustrated in Table 1, the use of benzylamine led to
almost no diastereoselectivity in the I-MCR, thus producing
5a as a mixture of diastereoisomers (entries 1 and 5).
Conversely, the utilization of the chiral (S)-a-methylbenzyl
amine provided the enantiomerically pure product 5b with an
excellent diastereoselectivity (> 99:1). The relative configu-
rations of 5a,b were determined by NMR analysis on the basis
of the absolute configuration at C4 of 4, as previously assessed
by X-ray analysis.[18] The solid-state structures showed the
axial orientation (directing toward the a face) of the sub-
stituent at position 4 in 4. In the first instance, the two
diastereoisomers of 5a, derived from benzyl amine, were
isolated and analyzed by NMR spectroscopy. In the major
stereoisomer of 5a (and also in the only one of 5b), various
NOE couplings between hydrogen atoms of the ethyl chain at
2
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position 4 and the substituent at
position 2 were found. Similarly,
strong NOE couplings were
observed between the amide sub-
stituent at position 2 and one of the
geminal methyl groups of the fused
bicyclic skeleton. These results
unambiguously prove the cis con-
figuration in which both substitu-
ents at positions 2 and 4 have
a pseudo-axial orientation directed
toward the a-face of the hydro-
quinolin-6-one skeleton. As high-
lighted in Scheme 1, these NOE
couplings are only possible
because of the 1,3 and 1,5-diaxial
interactions of the amide substitu-
ent at C2, the substituent at posi-
tion 4, and the geminal axial
methyl group. In contrast, the
minor stereoisomer of 5a showed
a strong NOE coupling between
the hydrogen at C2 and the ethyl
group at C4, thus indicating the
trans configuration of substituents
at positions 2 and 4.
As shown in Table 1, the dia-
stereoselection of this process
derives from the preferential addi-
tion of the isocyanide to the con-
formationally fixed imine (or imi-
nium ion) by the same face of ethyl
group (cis addition). Further addi-
Scheme 1. One-pot synthesis of hydroquinolin-6-one and piperidinocoumarine hybrids by an organo-
catalytic conjugate addition/I-MCR sequence. Yields are those of the isolated products. The d.r. values
1
were determined by H NMR analysis of the crude reaction mixture and confirmed by HPLC. The
ee values were determined by HPLC analysis on a chiral stationary phase.
tion of the enolate oxygen atom leads to the a-adduct
featuring the trans disposition between the ethyl group and
the exocyclic amine moiety. Finally, migration of the amine
(rearrangement) generates the piperidine ring with the cis
configuration of the amide substituent at C2 with respect to
the ethyl group at C4. Additional evidence that the stereo-
control lies at the isocyanide addition step is that the acyclic
side-product 6b, derived from methanol addition, was
obtained with the same diastereoselectivity of 5b, whilst
formation of side-product 6a proceeded with poor stereo-
selection, as for 5a. To gain deeper insight into stereoselec-
tivity, we implemented the reaction sequence with variation
of the four different components.
For this, we focused on the one-pot synthesis of more
complex molecular hybrids having a piperidine core structure.
Piperidine-containing alkaloids, including the tetrahydroqui-
nolines and tetrahydroisoquinolines, represent an important
class of natural products displaying a wide variety of
pharmacological activities.[22] As shown in Scheme 1, the
hybrid scaffolds 7 and 10 were produced by variation of four
structural elements, that is, the 1,3-dicarbonyl and aldehyde
incorporated in the organocatalytic step, as well as the amine
and isocyanide in the I-MCR. As before, the one-pot
processes were performed without isolation of intermediates
4 and 9, but simply carrying out the subsequent I-MCR
through addition of TFE, the amine, and isocyanide compo-
nents immediately after completion of the organocatalytic
step. This diversity-oriented approach gives rise to a unique
class of hydroquinolin-6-one and piperidinocoumarine
hybrids substituted at positions 1, 2, and 4.
The stereoselectivity of the multicomponent sequence
leading to the hexahydroquinolinones 7 and piperidinocou-
marines 10 proved to be excellent when the amine is chiral (a-
MeBn and amino acids), whereas unbranched n-butyl- and
benzylamines provided poor stereocontrol. Again, NMR
evidence proved the cis configuration for major isomers.
The use of either S- or R-a-methylbenzyl amine as well as
either d- or l-amino acid methyl esters provided the same
stereodifferentiation to the cis isomers of the hybrids 7a–e.
An interesting result was obtained when the bulky character
of the achiral amine was increased from cyclohexyl to tert-
butylamine. Thus, cyclohexylamine gave the compound 7 f
with moderate diastereoselectivity, while the highly crowed
tert-butylamine rendered 7g with excellent diastereoselectiv-
ity. This outcome confirms that not only chiral amines, but
also achiral ones with great steric congestion at the a-position
reinforce the stereoselection in this I-MCR. An additional
experiment proceeding through the enantiomer of intermedi-
ate 4 (prepared using the enantiomer of catalyst 3) resulted in
the highly stereoselective formation of 7h, which is the
enantiomer of 7g as revealed by chiral-phase HPLC and
optical rotation analysis. This result is consistent with a sub-
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hybrids. From a synthetic point of
view, the present approach can
be regarded as an asymmetric
multicomponent ligation pro-
cess[25] which integrates up to
four different molecular frag-
ments into a single skeleton.
This report confirms that the
asymmetric aminocatalytic func-
tionalization of carbonyl com-
pounds is an effective pre-MCR
process capable of providing
enantiomerically enriched build-
ing blocks for subsequent multi-
component diversification. The
versatility of this diversity-ori-
ented strategy relies on the vast
number of 1,3-dicarbonyls and
a,b-unsaturated
aldehydes
which could be combined with
amines and isocyanides of bio-
molecular nature. Such a facile
variation of reaction components
combines the great levels of
molecular complexity available
with low synthetic cost. Finally,
we envision that other iminium,
enamine, and N-heterocyclic car-
bene organocatalytic processes
may be combined with varied
MCRs, hence expanding the rep-
ertoire of stereoselective multi-
component cascade reactions.
Scheme 2. One-pot stereoselective synthesis of natural product hybrids including hydroquinolinone,
chromene, lipidic, peptidic, and saccharidic moieties. Yields are those of the isolated products. The
d.r. values were determined by 1H NMR analysis of the crude reaction mixture and confirmed by HPLC.
The ee values were determined by HPLC analysis on a chiral stationary phase.
strate-controlled reaction and confirms the great stereofacial
selectivity of the isocyanide addition. Although the origin of
the stereocontrol[23] remains to be determined, it is clear that
the magnitude of the diastereoselectivity for the cis product is
dependent on the steric bulk of the amine. Computational
modeling may aid in elucidating the mechanistic insights that
explain such a stereocontrol.[24]
Having demonstrated the efficacy of the organocatalytic/
I-MCR sequence for the stereoselective preparation of
molecular hybrids, we focused on the generation of further
skeletal diversity and complexity through variation of the
amine and isocyanide components. To this end, we inves-
tigated the possibility of incorporating natural product frag-
ments of peptidic, lipidic, and saccharidic nature into
piperidine-based hybrid architectures. Scheme 2 illustrates
the one-pot approach leading to the hydroquinolin-6-one and
piperidinocoumarine hybrids 11–16 utilizing the enantiomer-
ically enriched chromenone 4 and piranocoumarine 9. As
before, enantiomerically pure hybrids were produced in an
excellent diastereomeric ratio, with the cis isomers as major
products. The use of epimeric dipeptides having either l- or
d-Leu at the N-terminus generates the hybrids 12a and 12b,
respectively, and both feature the cis configuration.
Keywords: carbohydrates · diversity-oriented synthesis ·
multicomponent reactions · organocatalysis · synthetic methods
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Received: December 16, 2014
Revised: March 19, 2015
Published online: && &&, &&&&
Angew. Chem. Int. Ed. 2015, 54, 1 – 6
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Communications
Synthetic Methods
R. Echemendꢁa, A. F. de La Torre,
J. L. Monteiro, M. Pila, A. G. CorrÞa,
B. Westermann, D. G. Rivera,*
M. W. Paix¼o*
&&&& — &&&&
Highly Stereoselective Synthesis of
Natural-Product-Like Hybrids by an
Organocatalytic/Multicomponent
Reaction Sequence
One shot complexity: The combination of
an organocatalytic conjugate addition
with a stereoselective multicomponent
reaction (MCR) enables the one-pot syn-
thesis of enantiomerically pure natural
product hybrids. Such interplay between
organocatalysis and MCRs allows the
tunable diversification of up to four
structural elements, thus facilitating the
rapid exploration of a large chemical
space.
6
www.angewandte.org
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 1 – 6
These are not the final page numbers!