Optically active bicyclic N-heterocycles by organocatalytic asymmetric Michael addition/cyclization sequences

Article abstract of DOI:10.1002/chem.201100233

Highly stereoselective one-pot syntheses of various optically active N-heterocyclic bicycles have been developed. The protocols are based on an organocatalytic, asymmetric Michael addition followed by a condensation/ cycloaddition sequence to furnish aziridine carbonyls, β-lactams, or octahydrobenzo[c]isoxazoles depending on the reaction conditions and applied nucleophiles. Copyright

Full text of DOI:10.1002/chem.201100233

DOI: 10.1002/chem.201100233
Optically Active Bicyclic N-Heterocycles by Organocatalytic Asymmetric
Michael Addition/Cyclization Sequences
Dennis Worgull, Gustav Dickmeiss, Kim L. Jensen, Patrick T. Franke, Nicole Holub, and
Karl Anker Jørgensen*[a]
Organocatalysis has over the last decade been established
as a powerful tool for numerous enantioselective transfor-
mations.[1] Recently, a major effort has been devoted to the
development of domino, cascade, and one-pot reactions.[2]
These approaches allow the construction of structurally di-
verse molecules, while minimizing the number of manual
operations, thereby saving time, effort, and production costs.
Additionally, they are generally considered to be more envi-
ronmentally friendly, ecological, and sustainable, because of
the fewer purification steps than classical stepwise protocols.
Cycloaddition reactions, especially 1,3-dipolar cycloaddi-
tions involving nitrones, have proven their potential as pow-
erful synthetic transformations.[3] Owing to the concerted
nature of cycloadditions, high levels of stereogenic control
are observed, which allow the selective construction of mul-
tiple stereocenters in a single reaction step. Furthermore,
À
based on the intrinsic lability of the N O bond, the hetero-
atoms of the nitrone introduce useful functionalities in the
product, which can be exploited in further syntheses.[4]
We envisioned a one-pot process, in which addition of ma-
lononitrile derivatives 1, with an appropriately tethered
Scheme 1. Synthetic outline for the enantioselective organocatalytic one-
pot formation of aziridine carbonyls 5, b-lactams 6, octahydrobenzo[c]-
isoxazoles 7, and 1,3-amino alcohols 8.
alkyne functionality, to an a,b-unsaturated aldehyde
2
would furnish an intermediate that upon condensation with
an N-aryl hydroxylamine would undergo an intramolecular
1,3-dipolar cycloaddition affording hexahydrobenzo[c]isoxa-
zoles. Owing to the inherent ring strain of the five-mem-
bered dihydroisoxazole ring, they should be able to undergo
a Baldwin rearrangement[5] to the corresponding, densely
functionalized aziridine carbonyls 5 (Scheme 1, path A).
Moreover, the reaction setup would give access to b-lactams
6 by the Kinugasa reaction,[6] if the cycloaddition step for
terminal alkyne functionalized intermediates is carried out
in the presence of a CuI source and a suitable base
(Scheme 1, path B). Ideally, the stereocenter created in the
initial addition step controls the formation of the other ste-
reocenters in a highly selective manner, giving rise to single
diastereoisomers of the optically active products. This highly
divergent synthesis allows fast access to products such as
aziridine carbonyls or b-lactams, which have proven their
synthetic usefulness and biological activity.[7] Finally, the ap-
plication of alkene functionalities in 1 would enable the ste-
reoselective construction of octahydrobenzo[c]isoxazoles 7
by a similar addition/cyclization reaction, and the synthesis
À
of 1,3-amino alcohols 8 from 7 through reductive N O bond
cleavage (Scheme 1, path C).[8] To the best of our knowl-
edge, there have been no reports on these sequences in the
literature to date.
Herein, we report Michael addition/cycloaddition based
one-pot protocols for the highly enantio- and diastereoselec-
tive syntheses of aziridine carbonyls 5, b-lactams 6, and oc-
tahydrobenzo[c]isoxazoles 7 in good yields. Furthermore,
the formation of optically active 1,3-amino alcohols from 7
and the stereoselective hydrolysis of one of the nitrile sub-
stituents in 8 are demonstrated.
To achieve an efficient one-pot protocol, two equivalents
of pent-2-enal and malononitrile 1a (R2 =H) were allowed
to react in dichloromethane with 10 mol% of (S)-2-[bis(3,5-
bis-trifluoromethylphenyl)trimethylsilyloxymethyl]pyrroli-
dine (3) and 10 mol% benzoic acid as catalysts, which pro-
[a] Dr. D. Worgull, G. Dickmeiss, K. L. Jensen, Dr. P. T. Franke,
Dr. N. Holub, Prof. Dr. K. A. Jørgensen
Center for Catalysis, Department of Chemistry
Aarhus University, 8000 Aarhus C (Denmark)
Fax : (+45)8919-6199
E-mail: kaj@chem.au.dk
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201100233.
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Chem. Eur. J. 2011, 17, 4076 – 4080

COMMUNICATION
vided the Michael adduct 4.[2a,f] Gratifyingly, subsequent di-
lution of the reaction mixture and addition of N-phenylhy-
droxylamine furnished the desired, bicyclic aziridine carbal-
dehyde 5a in 68% yield and 92% ee as a single diastereo-
isomer. Encouraged by these findings, we turned our atten-
tion to the scope of the reaction (Scheme 2).
lectivities (90–91% ee). Conducting the reaction with ethyl-
or phenyl-substituted alkynes, provided the analogous aziri-
dine ketones 5j–m in good yields (46–52%), taking into ac-
count the multiple step reaction sequence involved, and in
high enantioselectivities (89–92% ee), thereby significantly
expanding the scope of the reaction.
Next, we turned our attention to the synthesis of b-lac-
tams, which should be accessible through a CuI-catalyzed re-
action[12] from intermediate 4 (Scheme 3). Gratifyingly, in
Scheme 3. Scope for the synthesis of b-lactams 6 and crystal structure of
6a.[9] For details see the Supporting Information.
the presence of 0.25 equivalents CuI, b-lactam 6a was isolat-
ed in 58% yield and 88% ee from the reaction of hexen-2-
al, malononitrile derivative 1a, and N-phenylhydroxylamine.
The relative configuration of 6a was established by X-ray
crystallography.[10,11] As a proof of concept, we investigated
different aliphatic a,b-unsaturated aldehydes, which were
successfully transformed into the corresponding b-lactams
6b and 6c in comparable good yields (46 and 51%) with ex-
cellent enantio- and diastereoselectivities (91 and 90% ee,
d.r.>20:1). Furthermore, unsaturated side chains were well
tolerated, yielding 6d and 6e (52%, 90% ee, and 52%,
88% ee).
Surprisingly, in the formation of 6d,e, no competing side
reaction with the alkene moiety was observed, even though
it is ideally positioned to form a six-membered ring and in
general favored over the alkyne to act as acceptor in 1,3-di-
polar cycloadditions. In the absence of copper, this reactivity
is indeed observed, affording 9 (40%, 88% ee) as the major
product (Scheme 4). This competition experiment clearly
demonstrates the ability of copper to overrule the intrinsic
reactivity of the system, allowing an effective tuning of the
Scheme 2. Scope for the aziridine carbonyls 5 and crystal structure of
5d.[9] For details see the Supporting Information.
In general, the developed reaction protocol proved to be
broad with respect to the employed aldehyde 2, forming the
products as single diastereoisomers. A variety of aliphatic
a,b-unsaturated aldehydes was successfully transformed into
the corresponding aziridine carbaldehydes 5a–c in high
yields (68–76%) and high enantioselectivities (88–92% ee).
Interestingly, branched a,b-unsaturated aldehyde 2d result-
ed in diminished yield (50%) and enantioselectivity
(70% ee) of 5d. Nevertheless, the product gave crystals suit-
able for X-ray diffraction, unambiguously establishing the
relative configuration of the products.[10,11] Aldehydes bear-
ing functionalities in the side chain, such as an alkene or a
dimethylphenylsilyl (DMPS) group, which might serve as a
chemical handle for further transformations, could effective-
ly be utilized, giving the corresponding products 5e and 5 f
in high yields (64 and 57%) and excellent enantioselectivi-
ties (91 and 96% ee). Notably, no undesired cycloaddition
was observed in the case of the aldehyde substituted with an
unsaturated side chain. Furthermore, N-(4-bromophenyl)hy-
droxylamine was successfully applied, affording the aziridine
carbaldehydes 5g–i in high yields (80–89%) and enantiose-
Scheme 4. Competition experiments.
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K. A. Jørgensen et al.
reaction outcome. The relative configuration of 9 was estab-
lished by X-ray analysis.[10,11]
In contrast to the cycloaddition products of alkynes, the
octahydrobenzo[c]isoxazoles 7 obtained by nitrone addition
to alkenes are less strained and not prone to rearrangement.
Importantly, 7 can be transformed into 1,3-amino alcohols
cade. As expected, the exo products were formed yielding
the trans-configured bicycles 7h and 7i in 65% and 67%
yield and enantioselectivities of 92% and 90% ee, respec-
tively.
Unfortunately, neither 7h nor 7i gave crystals suitable for
X-ray structure analysis. Nevertheless, careful analysis of 1D
1
À
after reductive cleavage of the N O bond to give a straight-
and 2D H NMR spectra (see the Supporting Information),
forward access to this class of compounds. Therefore,
alkene-tethered nucleophiles were investigated next
(Scheme 5). Treating the in situ formed Michael adduct with
enabled the assignment of the relative configuration of
7h.[10] As mentioned above, octahydrobenzo[c]isoxazoles 7
constitute direct precursors for 1,3-amino alcohols. Accord-
ingly, to demonstrate the synthetic value of the reaction, re-
À
ductive cleavage of the N O bond was performed on select-
ed substrates (Scheme 6). Compounds 7a,h,i were reduced
À
Scheme 6. Formation of 1,3-amino alcohols 8 by reductive N O bond
cleavage and selective hydrolysis to 10. For details see the Supporting In-
formation.
Scheme 5. Scope for the octahydrobenzo[c]isoxazoles 7 and crystal struc-
ture of 7g. For details see the Supporting Information.
with zinc dust and acetic acid in diethyl ether to cleanly
afford the corresponding 1,3-amino alcohols 8a–c in excel-
lent yields of 90–95%. To our delight, under basic, aqueous
conditions selective hydrolysis of one of the geminal nitriles
was achieved in good yield,[2a] thereby providing 1,3-amino
alcohol 10 bearing a quaternary fifth stereocenter.
Scheme 7 summarizes the developed sequences leading to
aziridine carbonyl compounds 5 and b-lactams 6. Michael
adduct 4 condenses with N-phenylhydroxylamine to form ni-
trone I. The latter undergoes intramolecular 1,3-dipolar cy-
cloaddition with the alkyne moiety. Subsequently, spontane-
N-phenylhydroxylamine resulted in 7a (52%, 92% ee) as a
single cis-diastereoisomer formed via an exo-transition state.
Fortunately, variation of the aldehyde was uncritical, as
hexen-2-al and non-2-enal could successfully be employed,
affording the corresponding products 7b and 7c in compara-
ble yields (49 and 50%, respectively) and high enantioselec-
tivities (92 and 91% ee, respectively). Moreover, alkenyl-
substituted a,b-unsaturated aldehydes were well tolerated as
demonstrated for 7d (54%, 92% ee). Employment of either
N-(4-bromophenyl)hydroxylamine or 4-bromo- and 4-meth-
ylphenyl-substituted nucleophiles was possible, yielding 7e–
À
ous N O bond cleavage of II and concomitant formation of
5, known as the Baldwin rearrangement, occur (top,
Scheme 7). In case of the Kinugasa reaction, copper acety-
lide nitrone III undergoes intramolecular 1,3-dipolar cyclo-
addition, forming vinyl cuprate IV. This collapses to ketene
V, which, after aniline addition/tautomerization, affords b-
lactams 6 (bottom, Scheme 7).
g
in 45–56% yield and high enantioselectivities (91–
92% ee). X-ray diffraction unequivocally established the ab-
solute configuration of 7g.[11] Carrying out the reaction with
a Z-alkene-substituted malononitrile should, due to the con-
certed nature of the cycloaddition, give access to diastereo-
meric octahydrobenzo[c]isoxazoles, thereby further enhanc-
ing the synthetic usefulness of the developed reaction cas-
In conclusion, we have developed a highly divergent
access to a variety of optically active three-, four-, and five-
membered bicyclic N-heterocycles in good to high yields
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Bicyclic N-Heterocycles
COMMUNICATION
Scheme 7. Mechanistic outline for the formation of aziridine carbonyls 5 and b-lactams 6.
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relies on an organocatalytic conjugate addition/cycloaddition
sequence. Baldwin rearrangement of transient hexahydro-
benzo[c]isoxazoles affords aziridine carbonyls in high yields
and stereoselectivities. In the presence of copper(I) salts, the
sequence can be altered to yield b-lactams by the Kinugasa
reaction from a common intermediate. Finally, an efficient
asymmetric synthesis of octahydrobenzo[c]isoxazoles, their
straightforward conversion into 1,3-amino alcohols, and the
stereoselective hydrolysis of one of the nitrile functionalities
were demonstrated.
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Acknowledgements
This work was made possible by grants from OChemSchool, the Carls-
berg Foundation, FNU, and the Deutsche Forschungsgemeinschaft (D.W.
and N. H.). We thank Dr. Jacob Overgaard, Dr. Helle Svendsen, and Dr.
Nina Lock for performing X-ray analysis.
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Keywords: 1,3-dipolar cycloaddition · N-heterocycles · one-
pot reactions · organocatalysis
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[9] For reasons of a clearer presentation, the X-ray structure depicted is
a mirror image of those deposited in the CCDC files (see Ref. [11]).
Only the relative configuration was determined.
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K. A. Jørgensen et al.
[10] We assume that the reaction products all possess the depicted abso-
lute stereochemistry, as catalyst 3 has shown to generate (R)-config-
ured stereocenters in conjugate additions of malononitriles to a,b-
unsaturated aldehydes. See references [2a] and [2f] and X-ray struc-
ture of 7g.
The Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif.
[12] Modified conditions to those previously reported were applied: M.
Miura, M. Enna, K. Okuro, M. Nomura, J. Org. Chem. 1995, 60,
4999.
[11] See the Supporting Information for crystal structures. CCDC-806423
(5d) 809909 (6a) 806422 (7g) 807038 (9) contain the supplementary
data for this paper. These data can be obtained free of charge from
Received: January 21, 2011
Published online: March 4, 2011
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