10.1002/anie.201900059
Angewandte Chemie International Edition
COMMUNICATION
When 1a was subjected to the optimized conditions in the
presence of ethanol-d6, product 2a was achieved in 96% yield
with 97% ee (Scheme 2c). When deuterated sodium formate was
used, the deuterated 2a-d was obtained in 90% yield with >20:1
dr and 98% ee (Scheme 2d). These results indicated that the
sodium formate was the hydride donor of the reaction. Additionally,
careful NOE analysis of 2a-d revealed that the deuterium was syn
to the benzene ring.[10] As is known that the introduction of
deuterium atom into drug molecules can efficiently change the
absorption, distribution, metabolism and excretion properties of
the drugs.[13] To further illustrate the synthetic utility of the reaction,
the D-labeled (D>99%) bicyclo[3.2.1]octanes 2l-d, 2o-d and 2v-d
were successfully produced in good yields with excellent
diastereo- and enantioselectivities (Scheme 2d). What is more, to
figure out the real ratio of the palladium catalyst and the ligand for
the chiral induction, nonlinear effect studies with different
enantiopurity levels of ligands were carried out. A linear
correlation (R2 = 0.99) between ee of the products and the ligands
was found, indicating that the active catalyst species was
consistent with a monomeric nature during the stereodetermining
migratory insertion event.[14]
bicyclo[3.2.1]octanes with complete deuteration, excellent
diastereo- and enatioselectivities.
Acknowledgements
Generous financial support from the National Natural Science
Foundation of China (NSFC21572272), the Innovation Team of
“the Double-First Class” Disciplines (CPU2018GY04 and
CPU2018GY35) and the Foundation of the Open Project of State
Key Laboratory of Natural Medicines (SKLNMZZCX201818). We
are also thankful to Miss Dejing Yin at Jiangnan University for the
single-crystal X-ray diffraction test and analysis.
Conflict of interest
The authors declare no conflict of interest.
Keywords: asymmetric catalysis • reductive Heck •
desymmetrization • bicyclo[3.2.1]octanes • palladium
[1]
[2]
S. Cacchi, A. Arcadi, J. Org. Chem. 1983, 48, 4236.
For selected reviews on reductive Heck reactions, see: a) S. Cacchi,
Pure Appl. Chem. 1990, 62, 713; b) I. P. Beletskaya, A. V. Cheprakov,
Chem. Rev. 2000, 100, 3009; c) J. C. Namyslo, J. Storsberg, J. Klinge,
C. Gärtner, M.-L. Yao, N. Ocal, D. E. Kaufmann, Molecules 2010, 15,
3402; For selected examples on reductive Heck reactions, see: d) B. M.
Trost, F. D. Toste, J. Am. Chem. Soc. 1999, 121, 3543; e) A. B. Dounay,
P. G. Humphreys, L. E. Overman, A. D. Wrobleski, J. Am. Chem. Soc.
2008, 130, 5368; f) J.-Q. Chen, J.-H. Xie, D.-H. Bao, S. Liu, Q.-L. Zhou,
Org. Lett. 2012, 14, 2714; g) S. Diethelm, E. M. Carreira, J. Am. Chem.
Soc. 2013, 135, 8500.
[3]
a) P. Diaz, F. Gendre, L. Stella, B. Charpentier, Tetrahedron 1998, 54,
4579; b) C. Shen, R.-R. Liu, R.-J. Fan, Y.-L. Li, T.-F. Xu, J.-R. Gao, Y.-
X. Jia, J. Am. Chem. Soc. 2015, 137, 4936; c) R.-X. Liang, R.-Z. Yang,
R.-R. Liu, Y.-X. Jia, Org. Chem. Front. 2018, 5, 1840; d) W. Kong, Q.
Wang, J. Zhu, Angew. Chem. Int. Ed. 2017, 56, 3987; Angew. Chem.
2017, 129, 4045; e) X. Qin, M. W. Y. Lee, J. S. Zhou, Angew. Chem. Int.
Ed. 2017, 56, 12723; Angew. Chem. 2017, 129, 12897; f) Y. J. Jang, E.
M. Larin, M. Lautens, Angew. Chem. Int. Ed. 2017, 56, 11927; Angew.
Chem. 2017, 129, 12089; g) L. Hou, Y. Yuan, X. Tong, Org. Biomol.
Chem. 2017, 15, 4803; h) Z.-M. Zhang, B. Xu, Y. Qian, L. Wu, Y. Wu, L.
Zhou, Y. Liu, J. Zhang, Angew. Chem. Int. Ed. 2018, 57, 10373; Angew.
Chem. 2018, 130, 10530.
Scheme 3. Proposed mechanism.
On the basis of the above mentioned results and previous
[4]
[5]
a) A. Minatti, X. Zheng, S. L. Buchwald, J. Org. Chem. 2007, 72, 9253;
b) G. Yue, K. Lei, H. Hirao, J. S. Zhou, Angew. Chem. Int. Ed. 2015, 54,
6531; Angew. Chem. 2015, 127, 6631; c) S. Mannathan, S.
Raoufmoghaddam, J. N. H. Reek, J. G. de Vries, A. J. Minnaard,
ChemCatChem 2017, 9, 551.
4a, 6b]
literatures,[3f,
a proposed mechanism of this reaction is
figured in Scheme 3. Firstly, 1a undergoes oxidative addition of
the active palladium catalyst to give the cationic Pd(II)
intermediate I. Next, intramolecular syn-migratory insertion of I
leads to the alkylpalladium intermediate II, which undergoes anion
exchange with HCO2Na to deliver the intermediate III. It should be
noted that the competitive β-H elimination process (Heck
reaction) of the intermediate II is well suppressed by employing
an exquisite catalytic system. The intermediate III converts to the
hydropalladium species IV by releasing a molecular CO2. Finally,
reductive elimination of the intermediate IV delivers product 2a,
and regenerates the palladium catalyst to the next catalytic cycle.
In conclusion, we have described a palladium-catalyzed
asymmetric intramolecular reductive Heck desymmetrization
reaction of cyclopentenes with eliminable β-H to achieve chiral
bicyclo[3.2.1]octanes bearing a quaternary and a tertiary carbon
stereocenters in good yields and excellent enantioselectivities.
Additionally, the reaction could incorporate deuterium in the
For selected examples, see: a) X.-Y. Wu, H.-D. Xu, Q.-L. Zhou, A. S. C.
Chan, Tetrahedron: Asymmetry 2000, 11, 1255; b) X.-Y. Wu, H.-D. Xu,
F.-Y. Tang, Q.-L. Zhou, Tetrahedron: Asymmetry 2001, 12, 2565; c) S.
Liu, J. S. Zhou, Chem. Commun. 2013, 49, 11758.
[6]
[7]
a) C. Wang, G. Xiao, T. Guo, Y. Ding, X. Wu, T.-P. Loh, J. Am. Chem.
Soc. 2018, 140, 9332; b) J. A. Gurak Jr., K. M. Engle, ACS Catal. 2018,
8, 8987.
For selected reviews, see: a) M. H. Filippini, J. Rodriguez, Chem. Rev.
1999, 99, 27; b) M. Presset, Y. Coquerel, J. Rodriguez, Chem. Rev. 2013,
113, 525; c) I. E. Tobal, A. M. Roncero, N. M. Garrido, I. S. Marcos, D.
Díez, Molecules 2018, 23, 1039.
[8]
For selected examples, see: d) C. G. Bashore, M. G. Vetelino, M. C. Wirtz,
P. R. Brooks, H. N. Frost, R. E. McDermott, D. C. Whritenour, J. A. Ragan,
J. L. Rutherford, T. W. Makowski, S. J. Brenek, J. W. Coe, Org. Lett.
2006, 8, 5947; e) M. L. Grachan, M. T. Tudge, E. N. Jacobsen, Angew.
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