Journal of the American Chemical Society
Article
CONCLUSION
REFERENCES
■
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(1) Penning, T. D.; Zhu, G.-D.; Gandhi, V. B.; Gong, J.; Liu, X.; Shi,
Y.; Klinghofer, V.; Johnson, E. F.; Donawho, C. K.; Frost, D. J.;
Bontcheva-Diaz, V.; Bouska, J. J.; Osterling, D. J.; Olson, A. M.; Marsh,
K. C.; Luo, Y.; Giranda, V. L. J. Med. Chem. 2009, 52, 514.
In conclusion, we have developed a general and enantiose-
lective synthesis of 2,2-disubstituted pyrrolidines or piperidines
containing quaternary stereocenters by simple lithiation−
substitution of N-Boc-2-phenylpyrrolidine or -piperidine. The
combined use of synthetic experiments and in situ IR
spectroscopic monitoring allowed optimum reaction conditions
to be identified. In situ IR spectroscopy allows real-time
monitoring of rotamer interconversion, which is a crucial
requirement for high-yielding lithiation. The Boc rotamer
interconversion was also studied by 1H NMR spectroscopy and
DFT calculations. By studies at different temperatures, an
indication of the propensity for enantiomerization of these
organolithiums was gained. For the pyrrolidine series, the
products were obtained via two separate lithiations. First,
deprotonation of N-Boc-pyrrolidine with s-BuLi/(−)-sparteine
and Negishi coupling gave (R)-N-Boc-2-phenylpyrrolidine
[(R)-5], which was deprotonated with n-BuLi. Electrophilic
quenches provided the 2,2-disubstituted products with
retention of configuration. For the piperidine series, a catalytic
asymmetric reduction led to (S)-N-Boc-2-phenylpiperidine
[(S)-6], which could be lithiated with n-BuLi. Electrophilic
trapping occurred with retention of configuration. During the
course of this study, an interesting difference between the five-
and six-membered rings was discovered: for lithiated N-Boc-2-
phenylpyrrolidine, the rotamers 8 and 9 do not interconvert at
−78 °C, whereas the corresponding piperidine rotamers 10 and
11 readily interconvert at this temperature. This was confirmed
(2) (a) Xiao, D.; Lavey, B. J.; Palani, A.; Wang, C.; Aslanian, R. G.;
Kozlowski, J. A.; Shih, N.-Y.; McPhail, A. T.; Randolph, G. P.;
Lachowicz, J. E.; Duffy, R. A. Tetrahedron Lett. 2005, 46, 7653.
(b) Xiao, D.; Wang, C.; Palani, A.; Tsui, H.-C.; Reichard, G.; Paliwal,
S.; Shih, N.-Y.; Aslanian, R.; Duffy, R.; Lachowicz, J.; Varty, G.;
Morgan, C.; Liu, F.; Nomeir, A. Bioorg. Med. Chem. Lett. 2010, 20,
6313. (c) Mealing, G. A. R.; Lanthorn, T. H.; Small, D. L.; Murray, R.
J.; Mattes, K. C.; Comas, T. M.; Morley, P. J. Pharm. Exp. Ther. 2001,
297, 906. (d) Harrison, T.; Williams, B. J.; Swain, C. J. Bioorg. Med.
Chem. Lett. 1994, 4, 2733.
(3) (a) Stymiest, J. L.; Bagutski, V.; French, R. M.; Aggarwal, V. K.
Nature 2008, 456, 778. (b) Sonawane, R. P.; Jheengut, V.; Rabalakos,
C.; Larouche-Gauthier, R.; Scott, H. K.; Aggarwal, V. K. Angew. Chem.,
Int. Ed. 2011, 50, 3760. (c) Hawner, C.; Alexakis, A. Chem. Commun.
2010, 46, 7295. (d) Bella, M.; Gasperi, T. Synthesis 2009, 1583.
(e) Scott, H. K.; Aggarwal, V. K. Chem.Eur. J. 2011, 17, 13124.
́
(4) Van Betsbrugge, J.; Tourwe, D.; Kaptein, B.; Kierkels, H.;
Broxterman, R. Tetrahedron 1997, 53, 9233.
(5) Tayama, E.; Kimura, H. Angew. Chem., Int. Ed. 2007, 46, 8869.
(6) Kano, T.; Sakamoto, R.; Mii, H.; Wang, Y.-G.; Maruoka, K.
Tetrahedron 2010, 66, 4900.
(7) Foschi, F.; Landini, D.; Lupi, V.; Mihali, V.; Penso, M.; Pilati, T.;
Tagliabue, A. Chem.Eur. J. 2010, 16, 10667.
(8) Zhou, L.; Chen, J.; Tan, C. K.; Yeung, Y.-Y. J. Am. Chem. Soc.
2011, 133, 9164.
(9) Bagutski, V.; Elford, T. G.; Aggarwal, V. K. Angew. Chem., Int. Ed.
2011, 50, 1080.
(10) Hardy, S.; Martin, S. F. Org. Lett. 2011, 13, 3102.
(11) The importance of three-dimensional shape in potential
pharmaceuticals has recently been discussed. See: Lovering, F.;
Bikker, J.; Humblet, C. J. Med. Chem. 2009, 52, 6752.
(12) (a) Gallagher, D. J.; Beak, P. J. Org. Chem. 1995, 60, 7092.
(b) Bertini Gross, K. M.; Beak, P. J. Am. Chem. Soc. 2001, 123, 315.
(13) (a) Coldham, I.; Copley, R. C. B.; Haxell, T. F. N.; Howard, S.
Org. Lett. 2001, 3, 3799. (b) Krow, G. R.; Herzon, S. B.; Lin, G.; Qui,
F.; Sonnet, P. E. Org. Lett. 2002, 4, 3151. (c) Ashweek, N. J.; Coldham,
I.; Haxell, T. F. N.; Howard, S. Org. Biomol. Chem. 2003, 1, 1532.
(d) Santiago, M.; Low, E.; Chambournier, G.; Gawley, R. E. J. Org.
Chem. 2003, 68, 8480.
1
by the H NMR spectroscopy study. For N-Boc-2-phenyl-
pyrrolidine 5, the half-life (t1/2) for rotation of the Boc group
was ∼10 h at −78 °C, ∼3.5 min at −50 °C, and ∼0.3 s at 0 °C,
while for N-Boc-2-phenylpiperidine 6, t1/2 was determined to
be ∼4 s at −78 °C. Therefore, higher temperatures are required
for yields above 40% for the pyrrolidine series. As a result of
this work, it should now prove possible to construct small
libraries of 2-substituted 2-arylpyrrolidines and -piperidines for
evaluation of their pharmaceutical properties.
ASSOCIATED CONTENT
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(14) (a) Basu, A.; Thayumanavan, S. Angew. Chem., Int. Ed. 2002, 41,
716. (b) Gawley, R. E. Top. Stereochem. 2010, 26, 93.
(15) Barker, G.; O’Brien, P.; Campos, K. R. Org. Lett. 2010, 12, 4176.
(16) Campos, K. R.; Klapars, A.; Waldman, J. H.; Dormer, P. G.;
Chen, C.-y. J. Am. Chem. Soc. 2006, 128, 3538.
S
* Supporting Information
Full experimental procedures and spectroscopic data, together
with copies of NMR spectra, and computational details. This
material is available free of charge via the Internet at http://
(17) For our previous studies on in situ IR spectroscopic monitoring
of lithiations of N-Boc heterocycles, see: (a) Stead, D.; Carbone, G.;
O’Brien, P.; Campos, K. R.; Coldham, I.; Sanderson, A. J. Am. Chem.
Soc. 2010, 132, 7260. (b) Barker, G.; McGrath, J. L.; Klapars, A.; Stead,
D.; Zhou, G.; Campos, K. R.; O’Brien, P. J. Org. Chem. 2011, 76, 5936.
(18) Grainger, D. M.; Campbell Smith, A.; Vincent, M. A.; Hillier, I.
H.; Wheatley, A. E. H.; Clayden, J. Eur. J. Org. Chem. 2012, 731.
(19) (a) Fleming, I.; Mack, S. R.; Clark, B. P. Chem. Commun. 1998,
713. (b) Clayden, J.; Yasin, S. A. New J. Chem. 2002, 26, 191.
(20) The regiochemistry of lithiation of N-Boc-2-phenylpyrrolidine
can be controlled using s-BuLi and a chiral diamine (see: Stead, D.;
O’Brien, P.; Sanderson, A. Org. Lett. 2008, 10, 1409 ). We previously
reported the successful lithiation−trapping of N-Boc-pyrrolidine 3
using s-BuLi in THF at −78 °C (see ref 15).
AUTHOR INFORMATION
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Corresponding Author
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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We thank the EPSRC (Grants EP/E012272/1 and EP/
F000340/1), Merck, AstraZeneca (Leigh Ferris), and the
Universities of Sheffield and York for support of this work.
We are grateful to H. Adams (University of Sheffield) for X-ray
crystal structure analyses, B. F. Taylor (University of Sheffield)
for help with the NMR spectroscopic studies, and E. Cochrane
and S. Lovell (University of Sheffield) for assistance.
(21) (a) Fry, D. F.; Fowler, C. B.; Dieter, R. K. Synlett 1994, 836.
(b) Zalan, Z.; Martinek, T. A.; Lazar, L.; Fulop, F. Tetrahedron 2003,
́
́
́
̈
̈
59, 9117. For an alternative route to N-Boc-2-phenylpiperidine 6, see:
(c) Coldham, I.; Leonori, D. Org. Lett. 2008, 10, 3923. (d) Coldham,
I.; Raimbault, S.; Whittaker, D. T. E.; Chovatia, P. T.; Leonori, D.;
Patel, J. J.; Sheikh, N. S. Chem.Eur. J. 2010, 16, 4082.
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dx.doi.org/10.1021/ja211398b | J. Am. Chem. Soc. 2012, 134, 5300−5308