Angewandte
Chemie
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
Angew. Chem. Int. Ed. 2015, 54, 1 – 6
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
These are not the final page numbers!