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Journal of the American Chemical Society
added. After the reaction was maintained at the same temperature
Scheme 2. Synthetic Applications I
1
2
3
for another 24h, it was cooled to room temperature and purified
by silica gel flash chromatography (CAM stain was used to visuꢀ
alize the location of the sample on TLC plate).
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ASSOCIATED CONTENT
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Supporting Information Experimental procedures; specꢀ
tral data. This material is available free of charge via the Internet
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AUTHOR INFORMATION
Corresponding Author
gbdong@cm.utexas.edu; xutao@ouc.edu.cn
Furthermore, a new saturated scaffold can be efficiently
constructed using a mild Rhꢀcatalyzed hydrogenation protocol.16
Two interesting features should be noted: 1) the reaction gives a
perfect diastereoselectivity; 2) the NꢀOMe bond and the amide
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
moiety remained intact after the reaction. In addition,
a
We thank CPRIT, NIGMS (R01GM109054) and the Welch Foundation (F
1781) for research grants. G.D. is a Searle Scholar and Sloan fellow. We
thank Dr. M. C. Young for proofreading the manuscript. We also thank
Dr. V. Lynch and Dr. M. C. Young for Xꢀray structures. Johnson Matthey
is acknowledged for a generous donation of Rh salts. We are grateful to
Ms. V. Garza for her kind assistance on HPLC. Chiral Technologies is
thanked for their generous donation of chiral HPLC columns.
complementary LiAlH4 reduction smoothly provided the
corresponding NꢀOMe piperidine.17
Scheme 3. Synthetic Applications II
O
O
O
Me
N
Me
N
H
H
[Rh(1,5-hexadiene)2Cl]2
H2 (52 bar), pH=7.6, r.t. Hexane
Bu4N(HSO4)
OMe
O
OMe
O
H
62%
2a
8
as a single diastereomer
REFERENCES
O
Me
N
Me
LiAlH4, THF, 0 o
C
OMe
O
OMe
(1) For selected reviews on C−C activation, see: (a) Jones, W. D. Nature
1993, 364, 676. (b) Murakami, M.; Ito, Y. Top. Organomet. Chem.
1999, 3, 97. (c) Rybtchinski, B.; Milstein, D. Angew. Chem., Int. Ed.
1999, 38, 870. (d) Jun, C.ꢀH. Chem. Soc. Rev. 2004, 33, 610. (e) Satoh,
T.; Miura, M. Top. Organomet. Chem. 2005, 14, 1. (f) Necas, D.;
Kotora, M. Curr. Org. Chem. 2007, 11, 1566. (g) Crabtree, R. H.
Chem. Rev. 1985, 85, 245. (h) Ruhland, K. Eur. J. Org. Chem. 2012,
2683. (i) Korotvicka, A.; Necas, D.; Kotora, M. Curr. Org. Chem.
2012, 16, 1170. (j) Seiser, T.; Saget, T.; Tran, D. N.; Cramer, N.
Angew. Chem., Int. Ed. 2011, 50, 7740. (k) Murakami, M.; Matsuda, T.
Chem. Commun. 2011, 47, 1100. (l) Dermenci, A.; Coe, J. W.; Dong,
G. Org. Chem. Front. 2014, 1, 567. (m) C−C bond activation. In
Topics in Current Chemistry; Dong, G., Ed.; SpringerꢀVerlag: Berlin,
2014, Vol. 346. (n) Chen, F.; Wang, T.; Jiao, N. Chem. Rev. 2014, 114,
8613. (o) Souillart, L.; Cramer, N. Chem. Rev. 2015, 115, 9410.
(2) For two seminal works: (a) South, M. S.; Liebeskind, L. S. J. Am.
Chem. Soc. 1984, 106, 4181. (b) Murakami, M.; Itahashi, T.; Ito, Y. J.
Am. Chem. Soc. 2002, 124, 13976.
N
65%
9
2a
3. CONCLUSIONS
In summary, we have developed a highly enantioselective Rhꢀ
catalyzed carboacylation of oxime C=N bonds via C−C
activation. Using this method, unique polycyclic lactam scaffolds
can be efficiently accessed from benzocyclobutenoneꢀcoupled
oximes. The reaction conditions do not use a strong acid or base,
and are overall redox neutral. High enantioselectivity can be
achieved despite using a mixture of the E/Z isomers of the
oximes. Considering the novelty of these structures, the potential
pharmaceutical applications of the fused heterocyclic products are
being investigated. Moreover, given the importance of amideꢀ
bond formation, this catalytic asymmetric C−C activation method
should also have broad implications beyond this work. Detailed
mechanistic studies and expansion of the reaction scope to other
2πꢀinsertion reactions are ongoing in our laboratory.
(3) Souillart, L.; Cramer, N. Angew. Chem. Int. Ed. 2014, 53, 9640.
(4) Souillart, L.; Cramer, N. Chem. Eur. J. 2015, 21, 1863.
(5) Li, B.ꢀS.; Wang, Y.; Jin, Z.; Zheng, P.; Ganguly, R.; Chi, Y. R. Nature
Comm. 2015, 6, 6207.
(6) For examples of drugs containing a chiral lactam moiety, see: (a) St
Georgiev, V.; Van Inwegen, R. G.; Carlson, P. Eur. J. Med. Chem.
1990, 25, 375. (b) Mekonnen, B.; Weiss, E.; Katz, E.; Ma, J.; Ziffer, H.;
Kyle, D. E. Biorg. Med. Chem. 2000, 8, 1111. (c) Ding, Y.ꢀS.; Lin, K.ꢀ
S.; Logan, J.; Benveniste, H.; Carter, P. J. Neurochem. 2005, 94, 337.
(d) Lin, K.ꢀS.; Ding, Y.ꢀS. Biorg. Med. Chem. 2005, 13, 4658. (e) Alꢀ
tomare, C.; Carotti, A.; Casini, G.; Cellamare, S.; Ferappi, M.; Gavuzzo,
E.; Mazza, F.; Pantaleoni, G.; Giorgi, R. J. Med. Chem. 1988, 31, 2153.
(f) Altomare, C.; Cellamare, S.; Carotti, A.; Casini, G.; Ferappi, M.;
Gavuzzo, E.; Mazza, F.; Carrupt, P.ꢀA.; Gaillard, P.; Testa, B. J. Med.
Chem. 1995, 38, 170.
(7) For a seminal mechanistic study on metalꢀmediated cleavage of
benzocyclobutenone C–C bonds, see: (a) Huffman, M. A. ; Liebeskind,
L. S.; Pennington, W. T. Organometallics, 1990, 9, 2194. (b) Huffman,
M. A.; Liebeskind, L. S.; Pennington, W. T. Organometallics, 1992,
11, 255. For a detailed computational mechanistic study of Rhꢀ
catalyzed C–C activation of benzocyclobutenones, see: (c) Lu, G.; Fang,
C.; Xu, T.; Dong, G.; Liu, P. J. Am. Chem. Soc. 2015, 137, 8274.
4. EXPERIMENTAL SECTION
General Conditions for the Rhꢀcatalyzed Carboacylation of
C═N Bonds:
In a nitrogen filled glove box, an 8 mL vial was charged with the
benzocyclobutenone substrate (1a to 1n, 0.1 mmol),
[Rh(cod)2]BF4 (2.1 mg, 0.005 mmol, 5 mol%), (R)ꢀxylꢀSDP (2.1
mg, 0.003 mmol, 3 mol%) and (S)ꢀxylꢀBINAP (2.2 mg, 0.003
mmol, 3 mol%) {or [Rh(cod)2]BF4 (2.1 mg, 0.005 mmol, 5
mol%), (R)ꢀxylꢀSDP (4.2 mg, 0.006 mmol, 6 mol%) for 1e;
[Rh(CH3CN)2(cod)]BF4 (3.7 mg, 0.01 mmol, 10 mol %) and (R)ꢀ
xylꢀBINAP (9.2 mg, 0.0125 mmol, 12.5 mol%) for 1n}. After
adding 2 mL 1,4ꢀdioxane, the vial was capped and stirred at room
temperature for 5 minutes. The solution was then maintained at
110 °C (1a, 1e, 1f, 1h, 1i, 1j, 1m) or 130 °C (1b, 1c, 1d, 1g, 1k,
1l, 1n) for 24h before another portion of the same catalyst were
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