Angewandte
Chemie
DOI: 10.1002/anie.201209443
Heterocycles
Diastereoselective Intramolecular Allyl Transfer from Allyl Carbamate
Accompanied by 5-endo-trig Ring Closure**
Oskari K. Karjalainen, Martin Nieger, and Ari M. P. Koskinen*
Pyrrolidin-3-ones, a rare motif in nature, have very few
dedicated syntheses. However, substituted pyrrolidinones can
easily be envisioned to act as foundations for the construction
of organocatalysts, supported organocatalysts, and bioactive
molecules. We therefore set out to design as flexible a route
as possible to this interesting class of molecules.
nucleophiles (such as nitrogen) preferentially attack the
[5]
palladium center instead of the soft allyl cation. Thus, an
intermediate such as 2 (Scheme 1), which could then activate
the enone towards amino palladation, might be plausible.
Another possible activation mode would be the case where
palladium(II) acts as a Lewis acid (or as a p acid) drawing
electron density from the p system by coordination to the
[1]
The most simplifying disconnection would be the cleavage
of one of the CÀN bonds to reveal the enone 3 (Scheme 1).
[6]
carbonyl oxygen atom. This activation mode should gen-
erate an intermediate (2’) with substantial cationic character
[7]
and allow a pseudo-Nazarov reaction to take place.
Regardless of the mechanism, the allyl group would be
trapped by the soft b-ketonitrile nucleophile, thus regenerat-
ing palladium(0) and constructing an all-carbon quaternary
[
8]
center. The atom economy of this approach is also consid-
erable. The allyl carbamate is not merely a protecting group
but in fact an enabling group whose whole potential is being
utilized. During the early stages it acts as a masking group and
when cleaved the released CO pays for whatever entropic
2
costs are necessary, and the allyl portion becomes incorpo-
rated into the final product. To best of our knowledge, this is
an unprecedented reaction, and allows rapid construction of
the complex pyrrolidinone scaffold.
Scheme 1. Retrosynthetic analysis of substituted pyrrolidin-3-ones.
Although the proposed 5-endo-trig cyclization is disallowed
according to the Baldwin rules, we reasoned that suitable
activation of the enone moiety could facilitate this ring
closure mode. We then realized that an allyl carbamate
The unsaturation in 3 (Scheme 1) would suggest the
[
9]
powerful, yet underused, Knoevenagel condensation to
construct it from a wide variety of aldehydes and active
methylene compounds (4), which are readily available from
amino acids using standard methods for ketone synthesis. All
in all, this route would deliver the target compounds in a very
step-economic and modular manner.
[
2]
(
Alloc) group would be ideal for this purpose. The masked
nitrogen nucleophile can be liberated under neutral condi-
tions, a very important factor considering the sensitive nature
of the enone. A related 6-exo heterocyclization has been
demonstrated previously by Martin and co-workers, and a 5-
Initially we used b-ketoesters but despite extensive
experimentation we could not identify mild yet effective
reaction conditions for the Knoevenagel condensation.
Although effective in the cyclization step, we were forced to
abandon the ketoesters. After careful consideration, we
settled for nitrile as the electron-withdrawing group in 4.
The required b-ketonitriles are readily accessible in one step
from the corresponding amino acid esters. They also enable
smooth Knoevenagel condensations in comparison to b-
ketoesters or b-amides. Finally, the nitrile group provides
a versatile handle for further transformations.
[
3,4]
exo cyclization by Tsuji et al.
The allyl palladium(II) species arising from the cleavage
of the allyl carbamate, if sufficiently long lived, might activate
the p system towards a formal 5-endo cyclization through
several conceivable mechanisms. It is known that hard
[
10]
[
*] O. K. Karjalainen, A. M. P. Koskinen
Aalto University, School of Chemical Technology
P. O. Box 16100, 00076 AALTO (Finland)
E-mail: ari.koskinen@aalto.fi
With this plan in mind we set out to prepare the required
b-ketonitriles (Scheme 2). The commercial amino ester salts 5
were benzyl protected by reductive amination using a modi-
[
11]
fied literature procedure, and the crude reaction mixture
was reacted with allyl chloroformate to provide the bis(N-
protected) amino acid esters in good to excellent yields and
Dr. M. Nieger
Department of Chemistry, University of Helsinki, Helsinki (Finland)
[
**] Funding from the National Graduate School of Organic Chemistry
and Chemical Biology is gratefully acknowledged. We also thank
Johanna Mareta for mass spectrometric analyses.
[10]
excellent purity. Condensation with lithiated acetonitrile
provided the necessary b-ketonitriles in good yield. In most
cases the crude reaction mixture was pure enough to carry on
to the next step after silica gel filtration to remove the
Angew. Chem. Int. Ed. 2013, 52, 2551 –2554
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2551