Organic Letters
Letter
Amblard, F.; Coats, S. J.; Schinazi, R. F. Bioorg. Med. Chem. Lett. 2013,
23, 6325.
expected for a SN2 process, the trans-2h afforded the trans-5h in
an excellent 7.3:1 diastereomeric ratio (dr) with 1.5 equiv of
K2CO3 in only 1.5 h. In contrast, the pure cis-2h furnished the
trans-azetidine as the major isomer (5.1:1), but after 10 h of
reaction. This result revealed that the ring contraction is much
faster for the substrate trans-2h and that the cis isomer evolved
after epimerization to its trans isomer. Surprisingly, with cesium
carbonate at 40 °C for 6 h, the trans-2h afforded the cis-5h with a
1:6 dr. Suspecting product epimerization, we performed a
control experiment that effectively demonstrated that the
azetidine trans-5h (7.3:1 dr) isomerized in such conditions,
giving the more stable cis-5h in a 1:12 ratio. It is worth noting that
in all reactions quantitative conversion in favor of azetidines 5h
was observed by 1H NMR monitoring.
(7) Phillips, D.; Gao, W.; Yang, Y.; Zhang, G.; Lerario, I. K.; Lau, T. L.;
Jiang, J.; Wang, X.; Nguyen, D. G.; Bhat, B. G.; Trotter, C.; Sullivan, H.;
Welzel, G.; Landry, J.; Chen, Y.; Joseph, S. B.; Li, C.; Gordon, W. P.;
Richmond, W.; Johnson, K.; Bretz, A.; Bursulaya, B.; Pan, S.;
McNamara, P.; Seidel, H. M. J. Med. Chem. 2014, 57, 3263.
(8) (a) Zhang, H.-K.; Yu, L.-F.; Eaton, J. B.; Whiteaker, P.; Onajole, O.
K.; Hanania, T.; Brunner, D.; Lukas, R. J.; Kozikowski, A. P. J. Med.
Chem. 2013, 56, 5495. (b) Yu, L.-F.; Eaton, J. B.; Fedolak, A.; Zhang, H.-
K.; Hanania, T.; Brunner, D.; Lukas, R. J.; Kozikowski, A. P. J. Med.
Chem. 2012, 55, 9998.
(9) For a review on Aze synthesis, see: Couty, F.; Evano, G. Org. Prep.
Proc. Int. 2006, 38, 427.
(10) Kern, N.; Hoffmann, M.; Blanc, A.; Weibel, J.-M.; Pale, P. Org.
Lett. 2013, 15, 836.
In conclusion, we have developed a short and very efficient
three-step sequence toward the formation of α-carbonylated N-
sulfonylazetidines from cheap 2-pyrrolidinones. As a key step, the
highly efficient one-pot nucleophilic addition−ring contraction
reaction tolerated various alcohols or anilines as nucleophiles.
Starting from substituted α-bromo N-sulfonylpyrrolidinones,
both diasteroisomers can be obtained in an excellent ratio
depending on the base used in the ring contraction. Further
investigations to apply these azetidine building blocks in total
synthesis are ongoing in our laboratory.
(11) Kern, N.; Hoffmann, M.; Weibel, J.-M.; Pale, P.; Blanc, A.
Tetrahedron 2014, 70, 5519.
(12) For a review, see: Couty, F.; Evano, G. Synlett 2009, 3053.
(13) For the sole known example, although performed on acyclic
compounds, see: Otaka, A.; Mitsuyama, E.; Kinoshita, T.; Tamamura,
H.; Fujii, N. J. Org. Chem. 2000, 65, 4888.
(14) King, A. O.; Anderson, R. K.; Shuman, R. F.; Karady, S.;
Abramson, N. L.; Douglas, A. W. J. Org. Chem. 1993, 58, 3384.
(15) For dehalogenation of α-halogeno ketones, see: Fuji, K.; Node,
M.; Kawabata, T.; Fujimoto, M. J. Chem. Soc., Perkin Trans. 1 1987, 1043.
(16) For deprotection of α-carbonylated N-tosyl azetidines, see:
(a) Burtoloso, A. C. B.; Correia, C. R. D. Tetrahedron 2008, 64, 9928.
(b) Burtoloso, A. C. B.; Correia, C. R. D. Tetrahedron Lett. 2004, 45,
3355. For other related deprotections, see: (c) Ohshita, K.; Ishiyama,
H.; Takahashi, Y.; Ito, J.; Mikami, Y.; Kobayashi, J. I. Bioorg. Med. Chem.
2007, 15, 4910. (d) Takikawa, H.; Maeda, T.; Mori, K. Tetrahedron Lett.
1995, 36, 7689.
ASSOCIATED CONTENT
* Supporting Information
■
S
Complete experimental procedures, characterization data, and
spectral data. This material is available free of charge via the
AUTHOR INFORMATION
Corresponding Authors
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the Agence Nationale de la
Recherche for a grant (ANR-11-JS07-001-01 Synt-Het-Au)
and the CNRS. N.K. thanks the French Ministry of Research for a
Ph.D. fellowship. A.S.F. thanks the Fonds Pierre Fabre pour la
Recherche Pharmaceutique for a postdoctoral fellowship. A.B.
thanks Dr. Pierre de Frem
Coordination, Institut de Chimie, Universite
crystallographic structure refinements of compounds cis-2h and
cis-5h.
́
ont (Laboratoire de Chimie de
de Strasbourg) for
́
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