Organic Letters
Letter
(5) Kempf, B.; Hampel, N.; Ofial, A. R.; Mayr, H. Chem.Eur. J. 2003,
9, 2209.
(6) Hupe, D. J. Enzyme Reactions Involving Imine Formation. In New
Comprehensive Biochemistry; Page, M. I., Ed.; Elsevier: Amsterdam, 1984;
Vol. 6, pp 271
Scheme 5. Additional α-Functionalization Reactions
Catalyzed by Benzamide 6
(7) (a) Demoulin, N.; Lifchits, O.; List, B. Tetrahedron 2012, 68, 7568.
(b) Lifchits, O.; Demoulin, N.; List, B. Angew. Chem., Int. Ed. 2011, 50,
9680.
(8) Marigo, M.; Fielenbach, D.; Braunton, A.; Kjærsgaard, A.;
Jørgensen, K. A. Angew. Chem., Int. Ed. 2005, 44, 3703.
(9) Steiner, D. D.; Mase, N.; Barbas, C. F., III. Angew. Chem., Int. Ed.
2005, 44, 3706.
(10) Brandes, S.; Niess, B.; Bella, M.; Prieto, A.; Overgaard, J.;
Jørgensen, K. A. Chem.Eur. J. 2006, 12, 6039.
(11) (a) Lalonde, M. P.; Chen, Y.; Jacobsen, E. N. Angew. Chem., Int.
Ed. 2006, 45, 6366. (b) Brown, A. R.; Kuo, W.-H.; Jacobsen, E. N. J. Am.
Chem. Soc. 2010, 132, 9286. (c) Lalonde, M. P.; McGowan, M. A.;
Rajapaksa, N. S.; Jacobsen, E. N. J. Am. Chem. Soc. 2013, 135, 1891.
(d) Huang, H.; Jacobsen, E. N. J. Am. Chem. Soc. 2006, 128, 7170.
(12) For selected examples, see: (a) Yalalov, D. A.; Tsogoeva, S. B.;
Schmatz, S. Adv. Synth. Catal. 2006, 348, 826. (b) Liu, K.; Cui, H.-F.;
Nie, J.; Dong, K.-Y.; Li, X.-J.; Ma, J.-A. Org. Lett. 2007, 9, 923. (c) Ma, H.;
Liu, K.; Zhang, F.-G.; Zhu, C.-L.; Nie, J.; Ma, J.-A. J. Org. Chem. 2010, 75,
1402. (d) Jiang, X.; Zhang, Y.; Chan, A. S. C.; Wang, R. Org. Lett. 2009,
11, 153. (e) Imashiro, R.; Uehara, H.; Barbas, C. F., III. Org. Lett. 2010,
12, 5250. (f) Wang, Y.; Yang, H.; Yu, J.; Miao, Z.; Chen, R. Adv. Synth.
Catal. 2009, 351, 3057.
tuted aldehyde substrates in excellent yields, high enantiose-
lectivities, and short reaction times. Experimental and computa-
tional studies indicate that stereoselectivity may be defined and
limited by the E/Z ratio of the key enamine intermediates. Our
ongoing efforts are directed toward applying this insight toward
the development of more selective catalysts with a broader scope,
with the ultimate goal of devising a broadly general engine for α-
functionalizations of branched aldehydes.
ASSOCIATED CONTENT
* Supporting Information
■
S
(13) See the Supporting Information (SI) for details.
(14) For moderately enantioselective α-hydroxylations of unbranched
aldehydes and ketones using O2 or racemic oxaziridines, see:
Full experimental procedures, syntheses of substrates and
catalyst 6, characterization data for all new compounds, NMR
spectra and HPLC traces for α-functionalization products,
geometries and energies of calculated stationary points, and
crystallographic information (CIF). The Supporting Information
(a) Cor
Am. Chem. Soc. 2004, 126, 8914. (b) Sunden
Ibrahem, I.; Cordova, A. Angew. Chem., Int. Ed. 2004, 43, 6532.
(c) Engqvist, M.; Casas, J.; Sunden, H.; Ibrahem, I.; Cordova, A.
Tetrahedron Lett. 2005, 46, 2053. (d) Ibrahem, I.; Zhao, G.-L.; Sunden
H.; Cordova, A. Tetrahedron Lett. 2006, 47, 4659. (e) Tong, S.-T.;
Brimble, M. A.; Barker, D. Tetrahedron 2009, 65, 4801.
́
dova, A.; Sunden
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, H.; Engqvist, M.; Ibrahem, I.; Casas, J. J.
́
, H.; Engqvist, M.; Casas, J.;
́
́
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,
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AUTHOR INFORMATION
Corresponding Author
■
(15) Benkovics, T.; Du, J.; Guzei, I. A.; Yoon, T. P. J. Org. Chem. 2009,
74, 5545.
(16) Oxaziridine 2 is chiral due to the stereogenicity of the nitrogen
center. However, NMR experiments reveal that it undergoes
racemization within seconds under the conditions of the α-
functionalization reactions.
Notes
The authors declare no competing financial interest.
(17) Beeson, T. D.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127,
8826.
ACKNOWLEDGMENTS
■
This work was supported by the NIH (GM-43214) and an
NDSEG Predoctoral Fellowship to M.R.W. We thank Dr. Shao-
Liang Zheng (Harvard) for crystal structure determination and
Dr. Pamela M. Tadross (Harvard) and Dr. David D. Ford
(Harvard) for helpful discussions.
(18) (a) Burns, N. Z.; Witten, M. R.; Jacobsen, E. N. J. Am. Chem. Soc.
2011, 133, 14578. (b) Witten, M. R.; Jacobsen, E. N. Angew. Chem., Int.
Ed. 2014, 53, 5912.
(19) Acid and base additives are well-precedented promoters of
enamine-catalyzed transformations. See refs 1, 2, 7b, and 11b. See also:
Kwiatkowski, P.; Beeson, T. D.; Conrad, J. C.; MacMillan, D. W. C. J.
Am. Chem. Soc. 2011, 133, 1738.
(20) The effect of various additives on enantioselectivity may be
ascribed to their influence on the equilibrium E/Z ratio of enamine
intermediate 11. Different bases behave quite differently, indicating a
strong dependence on the identity of the countercation. See the SI for
details.
REFERENCES
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(1) (a) Marigo, M.; Jørgensen, K. A. Chem. Commun. 2006, 2001.
(b) Vilaivan, T.; Bhanthumnavin, W. Molecules 2010, 15, 917.
(c) Bertelsen, S.; Jørgensen, K. A. Chem. Soc. Rev. 2009, 38, 2178.
(d) Nielsen, M.; Worgull, D.; Zweifel, T.; Gschwend, B.; Bertelsen, S.;
Jørgensen, K. A. Chem. Commun. 2011, 632.
(21) No improvement in the enantioselectivities of α-fluorination were
observed in reactions carried out at −25 °C.
(22) Reduction in catalyst loading below 20 mol % in the α-
hydroxylation resulted in diminished yields. See the SI for details.
(2) For a comprehensive review, see: Desmarchelier, A.; Coeffard, V.;
Moreau, X.; Greck, C. Tetrahedron 2014, 70, 2491.
(3) San
Org. Lett. 2012, 14, 536.
́ ́
chez, D.; Bastida, D.; Bures, J.; Isart, C.; Pineda, O.; Vilarrasa, J.
(4) (a) Bergmann, E. D.; Zimkin, E.; Pinchas, S. Recl. Trav. Chim. Pays-
Bas 1952, 71, 168. (b) Bergmann, E. D.; Hirschberg, Y.; Zimkin, E.;
Pinchas, S. Recl. Trav. Chim. Pays-Bas 1952, 71, 192. (c) Bergmann, E.
D.; Meeron, E.; Hirschberg, Y.; Pinchas, S. Recl. Trav. Chim. Pays-Bas
1952, 71, 200. (d) Witkop, B. J. Am. Chem. Soc. 1956, 78, 2873.
(e) Knorr, R.; Weiß, A.; Low, P.; Rapple, E. Chem. Ber. 1980, 113, 2462.
̈
̈
(f) Boyd, D. R.; Jennings, W. B.; Waring, L. C. J. Org. Chem. 1986, 51,
992. (g) Capon, B.; Wu, Z.-P. J. Org. Chem. 1990, 55, 2317.
D
Org. Lett. XXXX, XXX, XXX−XXX