Organic Letters
Letter
produce compound 2p with high yield and excellent
enantioselectivity, which is the key intermediate for the synthesis
of some important biologically active molecules, such as MKC-
242 and WB4101.
AUTHOR INFORMATION
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Corresponding Authors
Our Rh/ZhaoPhos L1 and N-methylation of ZhaoPhos L2
catalytic system are very highly efficient in this asymmetric
hydrogenation. The model substrate methyl benzo[b][1,4]-
dioxine-2-carboxylate 1a was hydrogenated well, catalyzed by
Rh/ZhaoPhos L1 with 0.05 mol % (S/C = 2000) catalyst, 0.02
mol % (S/C = 5000), or even with 0.01 mol % (S/C = 10 000).
Full conversion, high yield, and 98% ee can be obtained (Table
2, entries 1−3). 99% yield and 97% ee can be obtained when S/
C is 24 000 (Table 2, entry 4). The Rh/N-methylation of
ZhaoPhos L2 catalytic system also worked well; almost the same
excellent results can be afforded with S/C = 24 000 (Table 2,
entry 5).
This highly efficient asymmetric hydrogenation methodology
demonstrated powerful synthetic utility. As shown in Scheme 3,
several great and creative synthetic routes were described to
prepare some important biologically active compounds. Hydro-
genation product 2a is the key intermediate for the construction
of antidepressant MKC-242 and potent α1D-adrenergic
antagonist WB4101, which can be easily obtained through our
asymmetric catalytic hydrogenation system in 1.2 g scale with
0.01 mol % catalyst (S/C = 10 000, 99% yield, 98% ee; Scheme
3a). Compound 2a was reduced by diisobutylaluminum hydride
(DIBAL-H) to provide compound 2p, which was treated with p-
TsCl (p-toluene sulfonyl chloride) to afford compound 3 in 96%
yield and without a loss of ee. Finally, compound 3 can react with
amines 4 and 5 to give the corresponding MKC-242 and
WB4101.15b Compound 7 can be easily synthesized through a
similar approach, which could be worked as the important
intermediate for the construction of 5-HT1A receptor agonist
BSF-190555 (Scheme 3b).8 Compound 2o was easily obtained
in 99% yield and 99% ee through this asymmetric hydro-
genation. It then underwent deprotection to give intermediate 9
in 96% yield and 98% ee, which reacted with the amine 10 to
afford (R)-doxazosin·HCl (Scheme 3c).12a,19b
ORCID
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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We are grateful for financial support from the National Natural
Science Foundation of China (Grant Nos. 21432007, 21502145,
21602172), the Natural Science Foundation of Hubei Province
(Grant No. 2016CFB449), the Wuhan Morning Light Plan of
Y ou t h S c i e n c e a n d T e c h n o l o g y ( G r a n t N o .
2017050304010307), and the Fundamental Research Funds
for Central Universities (Grant No. 2042018kf0202). The
Program of Introducing Talents of Discipline to Universities of
China (111 Project) is also appreciated.
REFERENCES
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
General remarks; general procedures for the synthesis of
1a−1j; general procedures for the prpearation of 1k−1s;
characterization of the 1 substrates; screening solvents for
the Rh-catalyzed asymmetric hydrogenation of 1a;
general procedure for the asymmetric hydrogenation of
1; general procedure regarding the high TON experiment
of 1a; NMR and HPLC spectra (PDF)
(14) Kuwabe, S. I.; Torraca, K. E.; Buchwald, S. L. J. Am. Chem. Soc.
2001, 123, 12202−12206.
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