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D. Xiao et al. / Tetrahedron: Asymmetry 17 (2006) 2596–2598
in the reaction media. This problem was reduced by the
inverse addition of an iminium ion solution 11 to a diluted
solution of PhMgBr in THF pre-cooled to À78 °C, which
afforded 12 with >20:1 stereoselectivity in 34% yield along
with 20% of side product 13. The ratio of 12:13 did not
change when activated with TESOTf and TIPSOTf. The
stereochemistry of 12 was assigned by extensive NMR
study.13 To further improve the reaction, additional
NMR studies of the formation of the iminium ion were
conducted. When 10 was treated with 4 equiv of TBSOTf
(to ensure complete conversion) in CD2Cl2, the CN peak
at 118.1 ppm in carbon NMR disappeared and the forma-
tion of an iminium ion peak at 190.1 ppm was observed,
which was in agreement with the work of Husson et al.14
We accidentally found that the activation in CDCl3 affor-
ded a complex mixture and no iminium ion formed. This
finding prompted us to examine the reaction in other chlo-
rinated solvent, such as ClCH2CH2Cl. When aminonitrile
10 was treated with 4 equiv of TBSOTf in ClCH2CH2Cl,
followed by inverse addition to PhMgBr solution, forma-
tion of 13 was not observed and the yield of 12 increased
to 52% as an 8:1 mixture at C6. To our surprise, the proton
NMR spectra of TBSOTf activations in CD2Cl2 and
ClCD2CD2Cl were almost identical, suggesting that the
different product profiles were a result of the addition of
Grignard reagent to iminium ion 11 in different solvent
mixtures. Although the nature of this solvent effect and
the origin of 13 warranted further investigation, the useful
yield of 12 allowed completion of the synthesis by hydroge-
nation of 12 at 65 psi for 48 h to deliver 1. The salient fea-
ture of the CNRS approach is the introduction of both
nucleophiles and electrophiles to the quaternary center,
which would expand the availability of reagents and hence
the diversity of products.
Acknowledgements
We would like to thank Dr. Jianshe Kong and Mr. Tao
Meng for providing intermediate 9, and Dr. John J. Piwin-
ski for supporting this research program.
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3. Conclusion
In conclusion, we have developed two general asymmetric
syntheses of the 2,2-disubstituted piperidine NK1 antago-
nist 1. During this process, we discovered an interesting
solvent effect on the Grignard addition to aminonitrile
10. These conditions may be useful in expanding the gen-
eral utility of the CNRS method. More importantly, the
two syntheses described herein delivered two complemen-
tary approaches that were suitable for further SAR investi-
gations of several different sites of medicinal chemistry
interest of the NK1 structural motif. The first approach
delivered key intermediates such as 5 and 7, which were
best suited for C4 and C5 functionalizations. The CNRS
method was well suited for modification at C6 and two
exocyclic groups. Application of these syntheses towards
the discovery of orally active NK1 antagonists will be re-
ported in the future.
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