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the situation observed using 1 – the fused bicyclic product 38
was not observed. This represents the first example of a catalytic
a-substitution reaction involving anhydride enolisation under
mild neutral conditions.
These findings opened a route to the organocatalytic
generation of enantioenriched chiral anhydride electrophilic
synthetic building blocks of considerable potential utility. An
extensive catalyst screen identified the highly modified alkaloid
derivative 39 as a promoter that could mediate the addition of
the prototype anhydride 36 to 26 to form 37, which was then
derivatised for analysis as the bicycle 40 in near perfect enantio-
and diastereocontrol (Scheme 5). The para-cyano variant 41 was
also amenable to the transformation – yielding product 43 via
adduct 42 in 71% ee and ca. 9 : 1 dr.
Scheme 3 Cycloaddition catalysed by N-methylpyrrolidine.
calculated pathway experimentally. Calculations indicated that
This publication has emanated from research supported by
DIPEA failed to promote the cyclisation reaction primarily for the Science Foundation Ireland (SFI – 12-IA-1645).
steric reasons, so use of an amine base of similar size to NMe
3
should have led to the calculated cyclised keto-acid product.
Conflicts of interest
Notes and references
2
mers. Derivatisation by esterification with TMSCHN allowed
Gratifyingly, exchange of DIPEA for N-methylpyrrolidine
(Scheme 3) in the reaction between 1 and 21 led to quantitative There are no conflicts to declare.
cyclisation after 1 h. Liberation of the amine-bound carboxylic
acids followed by extraction afforded a mixture of diastereo-
1
Y. Tamura, A. Wada, M. Sasho and Y. Kita, Tetrahedron Lett., 1981,
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Review: M. Gonzalez-Lopez and J. T. Shaw, Chem. Rev., 2009, 109, 164.
the separation of the diastereomers 35a and 35b (with retention
of dr) in a combined isolated yield of 93%.
2
2
We were also interested in evaluating the reactivity of other
enolisable anhydrides – in particular those in which the
formation of a dienol species such as 1a is not possible.
p-Nitrophenylsuccinic anhydride (36) was reacted with 26 in the
presence of catalytic DIPEA – smoothly leading to 37 as a single
diastereomer (Scheme 4). An attempt to derivatise by hydrolysis
caused 37 to precipitate as a white solid. Interestingly – mirroring
3 (a) Y. Tamura, A. Wada, M. Sasho, K. Fukunaga, H. Maeda and
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(
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4
5
6
7
Y. Tamura, A. Wada, M. Sasho and Y. Kita, Chem. Pharm. Bull., 1983,
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8
9
R. J. Spangler and J. H. Kim, Tetrahedron Lett., 1972, 13, 1249.
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1
1
0 F. T. Smith and R. V. Atigadda, J. Heterocycl. Chem., 1991, 28, 1813.
1 For an example see: N. G. Ramesh, K. Lio, A. Okajima, S. Akai and
Y. Kita, Chem. Commun., 1998, 2741.
Scheme 4 Amine-catalysed a-substitution of 36.
1
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1
5
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4 DFT study of the cycloaddition between 1 and aldehydes: C. Trujillo,
1
I. Rozas, A. Botte and S. J. Connon, Chem. Commun., 2017, 53, 8874.
Scheme 5 Catalytic asymmetric a-substitution of arylsuccinic anhydrides. 15 Amine bases deprotonate 1, ref. 13e and 14.
Chem. Commun.
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