chemistry, including a practical synthesis of all four isomers
of natural alkaloid conhydrine.
We started our study with the racemic 2-(phenylamino)cy-
clohexanone (1a) as a standard substrate. The initial hydro-
genation experiment was carried out with catalyst (Sa,R,R)-
3a (Figure 1) in 2-propanol under 50 atm of H2 pressure at
[RuCl2((S)-Xyl-SDP)((R,R)-DPEN)] ((Sa,R,R)-3d, DPEN )
trans-1,2-diphenylethylenediamine), the enantioselectivity of
the hydrogenation of 1a reached 99.6% ee (entry 4), while
the catalyst [RuCl2((S)-Xyl-SDP)((S,S)-DPEN)] ((Sa,S,S)-3d)
has mismatched configurations, which afforded the product
cis-2a in low enantioselectivity (75% ee) with a long reaction
time (24 h) (entry 5). The catalysts (Sa,S,S)-3d and (Sa,R,R)-
3d gave the same configuration of product, indicating that
the configuration of the product was determined by the
configuration of the ligand Xyl-SDP instead of the ligand
DPEN. The activity of the catalyst (Sa,R,R)-3d was remark-
able; it can catalyze the hydrogenation of 1a at a very low
catalyst loading (S/C ) 10000) (entry 6) or under low
hydrogenation pressure (10 atm) (entry 7). Other types of
chiral diphosphine ligands such as BINAP ((Ra,R,R)-4a), Xyl-
BINAP ((Ra,R,R)-4b), and SYNPHOS ((Ra,R,R)-5) can also
catalyze this hydrogenation reaction, although the enanti-
oselectivities were lower (70-89% ee) (entries 8-10).
The scope of substrates for the reaction was studied with
catalyst (Sa,R,R)-3d. Various racemic R-N-alkyl/arylamino
cyclohexanones can be hydrogenated to cis-ꢀ-alkyl/arylamino
cyclohexanols in high yields with excellent enantioselec-
tivities and diastereoselectivities. The substituents on the
N-phenyl ring, whether electron-withdrawing or electron-
donating, had a negligible effect on the enantioselectivity
and diastereoselectivity of the reaction (Table 2, entries
1-12). The hydrogenation reactions of 1e, 1i, and 1j, as well
as 1m, were quite slow, mainly due to the low solubility of
these substrates in 2-propanol (entries 5, 9, 10, and 13). If
the arylamino groups in the substrates were changed to
alkylamino groups, the hydrogenation still went very well,
and the corresponding chiral cis-ꢀ-alkylamino cyclic alcohols
were obtained with high enantioselectivities (98-99.9% ee)
and high diastereoselectivities (>98:2) (entries 14-16). The
R-butylamino cyclohexanone (1p) had the fastest reaction
rate, and its turnover frequency (TOF) in the hydrogenation
was as high as 2000/h (entry 16). When the substrates with
a five-membered ring (1q) and a seven-membered ring (1r)
were subjected to the hydrogenation the desired chiral cis-
ꢀ-alkylamino cyclic alcohols were obtained with high
enantioselectivities (91% and 94% ee, respectively) and high
diastereoselectivities (cis/trans ) 98:2 and 99:1, respectively)
(entries 17 and 18).
Figure 1. Chiral [RuCl2(diphosphine)(diamine)] complexes.
room temperature. The reaction proceeded smoothly, and the
product cis-2-phenylaminocyclohexanol (cis-2a) was isolated
in 97% yield with 98% ee and >99:1 of cis-selectivity within
2 h (Table 1, entry 1). A systematic study of the ligands in
Table 1. Asymmetric Hydrogenation of 1a: Optimization of
Reaction Conditionsa
PH2 time
diphosphine (atm) (h) cis/transb (%)
eec
entry
catalyst
1
2
3
4
5
(Sa,R,R)-3a (S)-SDP
50
50
50
50
50
50
10
10
2
2
2
2
5
24
4
6
6
4
>99:1
>99:1
>99:1
>99:1
93:7
>99:1
>99:1
>99:1
>99:1
>99:1
98
99
92
99.6
75
99.6
99.6
89
70
79
We next focused our attention on the synthesis of 2-(1-
hydroxyalkyl)piperidine, a ubiquitous structural unit existing
in natural products and therapeutics.6 Conhydrine is one of
the alkaloids containing this type of hydroxylated piperidine
structure isolated from the seeds and leaves of hemlock
(Sa,R,R)-3b (S)-Tol-SDP
(Sa,R,R)-3c (S)-An-SDP
(Sa,R,R)-3d (S)-Xyl-SDP
(Sa,S,S)-3d (S)-Xyl-SDP
6d (Sa,R,R)-3d (S)-Xyl-SDP
7
8
9
(Sa,R,R)-3d (S)-Xyl-SDP
(Ra,R,R)-4a (R)-BINAP
(Ra,R,R)-4b (R)-Xyl-BINAP 10
10
(5) For examples of Rh-catalyzed asymmetric hydrogenation of R-N-
monoalkyl/monoarylamino ketones, see: (a) Shang, G.; Liu, D.; Allen, S. E.;
Yang, Q.; Zhang, X. Chem.sEur. J. 2007, 13, 7780. (b) Liu, D.; Gao, W.;
Wang, C.; Zhang, X. Angew. Chem., Int. Ed. 2005, 44, 1687. Noyori and
co-workers reported [RuCl2((S)-Xyl-BINAP)(R)-DaiPEN]-catalyzed asym-
metric hydrogenation of racemic R-amino cyclohexanone, but the amino
group was protected by tert-butoxycarbonyl; see: (c) Ohkuma, T.; Ishii,
D.; Takeno, H.; Noyori, R. J. Am. Chem. Soc. 2000, 122, 6510.
10 (Ra,R,R)-5 (R)-SYNPHOS
a Reaction conditions: S/C )1000, [1a] ) 0.6 mmol/mL, [tBuOK] )
0.06 mmol/mL, iPrOH, room temperature, 100% conversion. b Determined
by HPLC. c ee values for cis-isomer determined by HPLC. The absolute
configuration of the product 2a is (1S,2R). d S/C ) 10000.
(6) For reviews, see: (a) Elbein, A. D.; Molyneux, R. J. In Alkaloids:
Chemical and Biological PerspectiVe; Pelletier, J. W., Ed.; Pergamon: New
York, 1986; Vol. 5, pp 1-54. (b) Casiraghi, C.; Zanardi, F.; Rassu, G.;
Spanu, P. Chem. ReV. 1995, 95, 1677. (c) Michael, J. P. Nat. Prod. Rep.
1997, 14, 619. (d) O’Hagan, D. Nat. Prod. Rep. 2000, 17, 435.
the catalysts RuCl2(SDPs)(diamine) showed that the ligand
Xyl-SDP was the most enantioselective. With the catalyst
Org. Lett., Vol. 11, No. 21, 2009
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