Angewandte
Chemie
both reactivity and enantioselectivity. In the hydrogenation of
a more interesting amino ketone, 9h, with a heteroaromatic
function, (S)-10h and (R)-10h were obtained in 93% yield
with > 99% ee by using 5a and 5b as the catalyst, respectively
(Table 2, entries 8 and 9). An N-benzyl-amino ketone, 9i, was
also hydrogenated to afford amino alcohol 10i in 90% yield
and 96% ee (Table 2, entry 10).
To demonstrate the potential Rh–duanphos-catalyzed
asymmetric hydrogenation of b-secondary-amino ketones as
a practical means for the enantioselective synthesis of g-
secondary-amino alcohols, two particularly interesting sub-
strates, 9b and 9h, which are readily available from the
corresponding ketones in one step, were explored with a low
catalyst loading of the Rh complex 5a (Scheme 3). When 9b
Keywords: amino alcohols · asymmetric catalysis ·
hydrogenation · P ligands · rhodium
.
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Scheme 3. Enantioselective synthesis of pharmaceutical intermediates by a prac-
tical Rh-catalyzed asymmetric hydrogenation. S/C=substrate/catalyst ratio.
9, 193.
following target transformation: .
(1.42 g) was hydrogenated with of 5a (1 mg) as the catalyst
precursor (S/C = 6000) and K2CO3 (0.5 equiv) as the base in
MeOH (10 mL) under H2 (50 bar) at 508C for 12 h, g-amino
alcohol (R)-10b was isolated in 75% yield (TON > 4500) with
98% ee. When 9h (1.52 g) was hydrogenated with 5a (1 mg;
S/C = 6000) under the same reaction conditions, (S)-10h was
also isolated in 75% yield (TON > 4500) and > 99% ee.
Therefore, the described catalytic system is highly efficient for
the reduction of b-secondary-amino ketones in terms of both
enantioselectivity and reactivity. According to literature
procedures,[5a,9] (S)-10b and (S)-10h can be subsequently
converted into (S)-1a and (S)-1d in one step, respectively.
Thus, these results provide one of the shortest (three steps
overall) and most highly enantioselective (> 98% ee without
further recrystallization) syntheses of fluoxetine and dulox-
etine.
In conclusion, a series of b-secondary-amino ketone
hydrochlorides were hydrogenated with remarkably high
enantioselectivity, for the first time, with a Rh complex
containing a highly electron-donating P-chiral bisphospho-
lane ligand, 4. For two substrates of particular interest, 9b and
9h, high turnover numbers were also achieved. These results
established one of the shortest and most potentially practical
means for the synthesis of enantiopure N-monosubstituted g-
amino alcohols, which are important pharmaceutical inter-
mediates.
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[6] a) D. Liu, X. Zhang, Eur. J. Org. Chem. 2005, in press; b) patent
application: X. Zhang, W. Tang (The Penn State Research
Foundation), WO 2003042135, 2003.
[7] The same deamination by-product was previously observed in a
Rh-catalyzed hydrogenation of 6; see: reference [2j].
[8] For syntheses of 9a–i, see Supporting Information.
[9] Y. Gao, K. B. Sharpless, J. Org. Chem. 1988, 53, 4081.
Received: October 1, 2004
Published online: February 3, 2005
Angew. Chem. Int. Ed. 2005, 44, 1687 –1689
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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