L. Yin et al. / Tetrahedron: Asymmetry 21 (2010) 2390–2393
2393
structure, also gave 97% enantioselectivity (Table 1, entry 6). On
the other hand, (R,R)-Ts-CDA L6, a cyclohexanediamine ligand,
4.3. Typical procedure for the asymmetric transfer
hydrogenation of T-10 in water (HCOONa–H O system)
2
showed comparable catalytic activity (82.0% ee) to Ts-DPEN
(Table 1, entry 8).
A mixture of [Ir Cp*Cl
2 2
] (0.4 mg, 0.001 mmol) and (S,S)-Cs-
In order to obtain a green approach towards enantiopure tol-
DPEN (0.5 mg, 0.0012 mmol) in water (0.5 mL) was heated at
40 °C for 1 h and then cooled to room temperature. Next, T-10
(0.446 g, 1.0 mmol), 2.5 M HCOONa (2 mL, 5.0 mmol) and 2 mL of
dichloromethane were introduced and the reaction mixture was
stirred at the same temperature for some time before being
extracted with dichloromethane. The organic phase was dried over
anhydrous sodium sulfate, filtered and concentrated in vacuo to
vaptan, we started to investigate the asymmetric preparation of
T-1 by asymmetric transfer hydrogenation with HCOONa–H O as
2
the hydrogen donor. In this context, Ir-Cs-DPEN, an effective cata-
lyst for asymmetric transfer hydrogenation of simple aromatic
1
0
ketones in water, was tested for the asymmetric transfer hydro-
genation of the useful pharmaceutical intermediate T-10 in our
study. The results showed that Ir-Cs-DPEN was a very good catalyst
for the asymmetric transfer hydrogenation of T-10. At an S/C ratio
of 200:1, complete conversion with more than 99% ee was ob-
tained. Even with an S/C ratio of 1000:1 in open air and water,
give
a crude product, which was purified by silica gel
chromatography.
4.4. Preparation of (S,S)-Cs-OH-DPEN L7
To a mixture of 0.43 g (1 mmol) of (S,S)-Cs-DPEN L5 in methane
9
6% conversion with >99% ee was obtained (Table 1, entries (10
and 11). On the other hand, (S,S)-CsOH-DPEN L7, the analogue of
L5, also showed excellent catalytic activity (97.0% ee, Table 1,
entry 12).
It is also worth noting that all of the above asymmetric trans-
fer hydrogenation reactions were conducted in an open air
atmosphere without inert gas protection especially for the irid-
ium complexes, that is, these catalysts were insensitive to air
and water, which is a promising prospect for industrial appli-
cation.
4
were added 45.4 mg (1.2 mmol) of NaBH in portions under ice-
bath. After stirring for 1 h at the same temperature, the reaction
mixture was evaporated in vacuo and the residue was washed with
water and extracted with dichloromethane. The organic phase was
dried over anhydrous sodium sulfate, filtered and concentrated to
give 0.40 g of (S,S)-Cs-OH-DPEN L7 as a white powder with quan-
1
titative conversion. H NMR (400 MHz, CDCl
3
): d 7.40–7.27 (m,
10H), 4.59 (d, J = 4.8 Hz, 1H), 4.36 (d, J = 4.8 Hz, 1H), 3.95–3.92
m, 1H), 2.58–2.55 (d, J = 14.0 Hz, 1H), 2.05–2.02 (m, 2H), 1.72–
.56 (m, 5H), 1.52–1.44 (m, 1H), 1.37–1.24 (m, 3H), 1.04–0.97
m, 1H), 0.76 (s, 3H), 0.55 (s, 3H).
(
1
(
3
. Conclusion
In conclusion, enantiopure tolvaptan, the first and only oral
Acknowledgements
vasopressin antagonist for hyponatremia was achieved with up
to 99% ee in a single step via Ru or Ir catalyzed asymmetric transfer
hydrogenation reactions in open air and water for the first time.
This efficient and practical approach to enantiomerically pure tol-
vaptan is a very promising prospect for industrial application.
We appreciate the Ministry of Science and Technology of China
(
No. 2009ZX09501-017) and the 2009 national visiting doctoral
student project of Ministry of Education for the financial support.
Reference
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1
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8
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1
[
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1
1
7
.53–6.88 (m, 10H), 5.30 (s, 1H), 4.88–4.86 (m, 1H), 2.77–2.08
(
m, 4H), 2.38 (s, 3H), 2.34 (m, 3H), 1.76–1.73 (m, 2H); HPLC condi-
i
tions: Chiral OD-H column, hexane– PrOH = 70:30, 1.0 mL/min,
54 nm.
2