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T. Jousseaume et al. / Tetrahedron Letters 53 (2012) 1370–1372
key lactone intermediate 19 was finally obtained by treating 29
with DBU. Although the AAA is a shorter route to the common lac-
tone 19, it only allows the formation of 6,6-spiroimines. In con-
trast, the Birch reaction tolerates electrophiles with longer alkyl
chain and could be used for the synthesis of the 6,7-spiroimines
contained in spirolides and pinnatoxins.19
In conclusion, we have demonstrated that the asymmetric Birch
reductive alkylation is a valuable strategy to create the quaternary
carbon of spiroimine analogs of the neurotoxin gymnodimine A 1.
Although the acyclic amides 4a–b could not be converted into an
appropriate substrate for the synthesis of spiroimines, we have
shown that the chiral auxiliary of cyclic amide 5b bearing a pro-
tected alcohol could be easily removed in a three step sequence
to afford the b-ketoester 14 in good enantiomeric ratio. b-Ketoester
14 was a suitable intermediate to access spiroimine analogs 23–24
possessing a biological activity.3 In addition, our study highlights
the difficulties to remove the chiral auxiliary after the asymmetric
Birch reductive alkylation of benzamide derivatives. Thus, when
planning this reaction, particularly with benzamides bearing an
ortho-alkoxy group, the benzoxazepinones (i.e., 3) or related acy-
clic 2-(methoxymethoxymethyl)pyrrolidine benzamides2 should
be considered as a starting material to easily remove the chiral
auxiliary.
Acknowledgments
Scheme 5. Enantioselective synthesis of lactone 19 by AAA.
The authors thank the CNRS and ICSN for financial support, Pro-
fessor J.-Y. Lallemand for his interest in this work. We thank Pro-
fessor Y. Landais, Dr. V. Desvergnes (ISM, University of Bordeaux)
and Dr. J. Molgó (NBCM, Gif-sur-Yvette) for fruitful discussions.
We also thank Elvina Barre for technical assistance with preparing
starting materials.
refluxing methanol and the resulting ammonium 12 transformed
into a methyl carbamate. Methanolysis in presence of cesium car-
bonate afforded the methyl ester 14. Interestingly, this three step
sequence gave b-ketoester 14 in a 65% yield (e.r. = 92/8),12 without
the need for temporary protection of the cyclic ketone.13
With a reliable synthesis of b-ketoester 14 in hand, we then
turned to its transformation into the bioactive spiroimine analogs
23–24 possessing an antagonist effect on nAChRs (Scheme 4).3
Chemoselective hydrogenation of the double bond of 14 with
Crabtree’s catalyst gave the saturated ketone 15 in almost quanti-
tave yield.14 The benzyloxy ether of 15 was oxidized in the pres-
References and notes
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