Angewandte
Research Articles
Chemie
Organocatalysis
Enantioenriched Methylene-Bridged Benzazocanes Synthesis by
Organocatalytic and Superacid Activations
Rodolphe Beaud, Bastien Michelet, Yasmin Reviriot, Agnꢀs Martin-Mingot, Jean Rodriguez,*
Abstract: Achieving in a straightforward way the synthesis of
enantioenriched elaborated three-dimensional molecules re-
lated to bioactive natural products remains a long-standing
quest in organic synthesis. Enantioselective organocatalysis
potentially offers a unique opportunity to solve this problem,
especially when combined with complementary modes of
activation. Here, we report the sequential association of
organocatalytic and superacid activations of simple linear
achiral readily available precursors to promote the formation
of unique highly elaborated chiral methylene-bridged benza-
zocanes exhibiting three to five fully-controlled stereocenters.
This peculiar backbone, difficult to assemble by standard
synthetic approaches, is closely related to bioactive natural and
synthetic morphinans and benzomorphans. The formation of
a highly reactive chiral 7-membered ring N-acyl iminium
superelectrophilic ion, evidenced by low-temperature in situ
NMR experiments, triggers a challenging stereoselective Frie-
del–Crafts-type cyclization.
ical reactivity,[12–14] biocatalysis[15,16] and acid activation.[17,18]
Among acid activations, superacid chemistry[19] has grown
over the last years,[20] especially through the exploitation of
highly reactive in situ protosolvated electrophiles (super-
electrophiles), as first suggested by Olah.[21] Using super-
electrophilic activation, reactions that cannot occur in con-
ventional media can be used to generate innovative organic
compounds,[22] as pioneered by the essential use of HF/SbF5
for the synthesis of the anti-cancer agent Javlor.[23] Here we
show that associating enantioselective organocatalysis with
superacid activation results in an innovative synthetic strategy
to generate otherwise inaccessible enantioenriched molecular
frameworks related to bioactive series.
It has been recently assessed that some areas of research
in synthetic methods would have critical impact in the
pharmaceutical industry. Among them, the concise synthesis
of highly functionalized, constrained chiral bicyclic amines[24]
has been identified as an high potential area[25] to develop new
drugs.[26] Especially, benzomorphans and related bridged
benzazocanes, which mimic morphinan natural products, are
involved in the treatment of neurological disorders,[27] as
exemplified by the development of the promising racemic
sigma 2 receptor agonist UKH-1114 exhibiting antineuro-
pathic pain effect (Figure 1A).[28] However, the direct syn-
thetic access to medium-sized heterocycles from simple
acyclic substrates still constitutes a challenge in modern
synthetic organic chemistry. The eight-membered ring series
is particularly difficult to prepare because of negative
enthalpic and entropic factors.[29] In consequence, the enan-
tioselective synthesis of functionalized methylene-bridged
benzazocane derivatives is limited to one example reported to
date (Figure 1B).[30,31] Recently, we studied the organocata-
lyzed enantioselective synthesis of aza-oxa-bicyclo-
[3.2.1]octanes.[32] Based on this work, we envisioned that
starting from simple achiral a-ketoamides 1 and enals 2,
enantioenriched oxabridged azepanes 3 could be temporarily
generated and subsequently exploited to access stereoselec-
tively the targeted methanobenzazocanes 4. This strategy
relies on the superacid-promoted formation of a highly
reactive N-acyl iminium ion A, which could counterbalance
the unfavorable eight-membered ring formation (Figure 1C).
Overall, this synthetic sequence can be formally seen as a rare
case of enantioselective Pictet–Spengler reaction to achieve
chiral medium-size nitrogen-containing polycyclic deriva-
tives.[33] It exploits the formation of a stable designed chiral
hemiaminal (hemiaminal-masked reactive iminium ion) that
overcomes the existing difficulties associated with the enan-
tioselective acid-promoted version of this reaction.
Introduction
One essential objective in chemical synthesis is to convert
readily available and inexpensive starting materials to com-
plex functional molecules with a perfect stereocontrol.[1]
Excellence and innovation in this field are critical to success
in all phases of drug discovery and development,[2] expanding
the diversity of molecules for modulating biological tar-
gets.[3,4] Conversely, the best chance to break new grounds is
through diversity. Enantioselective organocatalysis offers
powerful solutions to these endeavors.[5] It greatly enhances
the synthetic toolbox by complementing metal-based and
enzymatic approaches.[6] Reaching high level of efficiency,[7]
demonstrated in the total synthesis of biologically active
compounds,[8] organocatalysis has been recently successfully
merged with metal catalysts,[9] chiral anions,[10,11] photochem-
[*] Dr. R. Beaud, Y. Reviriot, Prof. J. Rodriguez, Dr. D. Bonne
Aix Marseille Universitꢀ, CNRS, Centrale Marseille, iSm2
Marseille (France)
E-mail: jean.rodriguez@univ-amu.fr
Dr. B. Michelet, Dr. A. Martin-Mingot, Prof. S. Thibaudeau
Universitꢀ de Poitiers, UMR-CNRS 7285, IC2MP, Equipe Synthꢁse
Organique “Superacid Group”
4 rue Michel Brunet, TSA 51106, 86073 Poitiers Cedex 9 (France)
E-mail: sebastien.thibaudeau@univ-poitiers.fr
Supporting information and the ORCID identification number(s) for
&&&&
ꢀ 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2019, 58, 2 – 9
These are not the final page numbers!