DOI: 10.1002/anie.201106255
Synthetic Methods
Catalytic [3+2] Annulation of Aminocyclopropanes for the
Enantiospecific Synthesis of Cyclopentylamines**
Florian de Nanteuil and Jꢀrꢁme Waser*
Cyclic structures are encountered in the core of most
bioactive synthetic and natural products. Carbo- and hetero-
cyclic rings give rigidity to molecules, thus fixing the spatial
arrangement of the functional groups. As a result, specific
interactions with biomolecules without important entropy
costs become possible. Nitrogen-based functional groups are
especially important in synthetic and medicinal chemistry. In
this respect, cyclopentylamines constitute an important sub-
class of cyclic structures, and are present in both relatively
simple natural products, such as the antibiotic and antiviral
aristeromycin (1),[1] and in dauntingly complex polycyclic
structures, such as palauꢀamine (2), one of the most sought for
targets in modern organic chemistry (Scheme 1).[2] These
alkenes or alkynes,[6] carbonyls,[7] and imines[8] has been
highly successful in the last decades for the synthesis of
cyclopentanes, cyclopentenes, tetrahydrofurans and pyrroli-
dines respectively. Cyclopropanes bearing electron-donating
oxygen-containing or aromatic substituents have been espe-
cially useful in Lewis or Brønsted acid catalyzed reactions. In
contrast, annulation reactions of aminocyclopropanes have
been limited to radical-initiated ring opening involving
electron-rich amines.[9] To the best of our knowledge, no
catalytic [3+2] annulation of aminocyclopropanes has ever
been reported. Donor–acceptor aminocyclopropanes have
been mostly used as 1,4-imino carbonyl precursors,[10] as well
as in a few rare ring-opening reactions.[11] In 2010, we applied
them in an efficient formal homo-Nazarov cyclization for the
synthesis of natural alkaloids.[12] However, a formal cyclo-
addition approach would be inherently more convergent and
efficient to access molecular complexity. Herein, we report
phthalimide-substituted acceptor cyclopropanes as unique
partners in [3+2] annulation reactions with silyl and alkyl enol
ethers (Scheme 2). High yields and diastereoselectivities were
Scheme 1. Cyclopentylamines in natural and synthetic products.
cyclic structures are also found in synthetic drugs. For
example, ramipril (3), an angiotensin converting enzyme
(ACE) inhibitor, was one of the top 100 generic drugs in 2008
for the treatment of high blood pressure and heart failure.[3]
Consequently, the development of new synthetic procedures
to access polysubstituted cyclopentylamines is an important
task for organic chemists.[4]
One of the most efficient ways to access five-membered
rings is by concerted cycloaddition reactions or related
stepwise annulation processes. In particular, the formal
[3+2] cycloaddition, more correctly called the [3+2] annula-
tion, of donor-acceptor activated cyclopropanes[5] with
Scheme 2. Lewis acid (LA) catalyzed reactions of aminocyclopropanes
with enol ethers. Phth=phthaloyl.
obtained using SnCl4 as the catalyst with a broad range of enol
ethers as substrates. The reaction was stereospecific in
relation to the configuration of the enol ether and enantio-
specific, thus giving asymmetric access to chiral cyclopentyl-
amines. Finally, the use of In(OTf)3 as the catalyst gave access
to important acyclic b-amino ketones, and removal of the
phthalimide group, as well as further functionalization, was
possible under mild reaction conditions.
As a model system to study the annulation reaction with
several aminocyclopropanes 4a–f, stable enol silyl 5a was
chosen as an electron-rich alkene, as it was expected to have a
higher reactivity than nonactivated alkenes and should also
allow a good control over the regioselectivity (Table 1). We
started with SnCl4 as the Lewis acid in dichloromethane,
because these reaction conditions have been successful in the
case of oxygen-substituted cyclopropanes.[6f] However, no
reaction was observed with cyclopropanes 4a, 4b, and 4c
bearing a Cbz-protected amine, a lactam, and an oxazolidi-
none substituent, respectively (Table 1, entries 1–3). At this
[*] F. de Nanteuil, Prof. Dr. J. Waser
Laboratory of Catalysis and Organic Synthesis
Ecole Polytechnique Fꢀdꢀrale de Lausanne
EPFL SB ISIC LCSO, BCH 4306, 1015 Lausanne (Switzerland)
E-mail: jerome.waser@epfl.ch
[**] EPFL, F. Hoffmann-La Roche Ltd, and SNF (grant number
200021_129874) are acknowledged for financial support. Dr.
Rosario Scopelliti (EPFL) is acknowledged for the X-ray studies.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2011, 50, 12075 –12079
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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