CH3O group at the 4′ position achieved excellent enantiose-
lectivity of 98%, while substitution of an electron-attracting
Cl function (2f) slightly reduced the stereoselectivity. The
reaction of 2-naphthyl ketone 2g afforded (R)-3g in 97% ee
with the same sense of enantioselection. Interestingly, the
Ru complex (S,R)-1 also effects asymmetric hydrogenation
of unfunctionalized aryl sec-alkyl ketones. Thus, isobuty-
rophenone (2h) was smoothly converted to (S)-3h in 95%
ee. The degree and sense of enantioselection were the same
as those in the reaction of R-keto acetals 2a-g with the same
S,R catalyst,15 indicating that the TolBINAP/DMAPEN-Ru
catalyst recognizes dialkoxymethyl moiety as a just sec-alkyl
group. This characteristic markedly differs from that of the
former (S)-XylBINAP/(S)-DAIPEN-Ru catalyst, with which
hydrogenation of 2a and 2h gave (S)-3a and (R)-3h in 37%
ee and 99% ee, respectively.7,8 Hydrogenation of 2i in the
presence of (S,R)-1 afforded (S)-3i in >99% ee, which is an
intermediate for the synthesis of a non-narcotic analgesic
and muscle relaxant agent.16
A practical procedure for enantio- and diastereoselective
synthesis of 1-aryl-2-aminoalkanols17 is highly desired
because of their pharmacological18 and synthetic19 utility.
Asymmetric hydrogenation of the corresponding racemic
R-amino ketones via dynamic kinetic resolution with in-situ
mutation of the R stereogenic center is a straightforward
method, yielding a single stereoisomer of products.1,8,11
Despite the synthetic utility of this reaction, no efficient
catalyst has been reported. The TolBINAP/DMAPEN-Ru
catalyst showed excellent performance on both enantio- and
diastereoselectivity in hydrogenation of racemic R-amido
ketones (()-4 (Scheme 2, eq 2). When racemic 2-(benzoyl-
the (1R,2R)-amido alcohol, (1R,2R)-5a, was produced in 98%
ee with a perfect syn-selectivity (Table 1). The excellent
diastereoselectivity clearly shows that the TolBINAP/
DMAPEN-Ru catalyst acts as a bulky metalhydride ac-
cording to the Felkin-Anh model.20 Removal of the amide
protector from (1R,2R)-5a (NaOH, C2H5OH aq, reflux, 12
h) gave (-)-pseudoephedrine, a widely used nasal decon-
gestant18 as well as a useful chiral auxiliary in synthetic
organic chemistry.19 In the same manner, racemic 2-(piv-
aloylamino)propiophenone [(()-4b] was converted to (1R,2R)-
5b in 99% ee (syn/anti ) 96.4:3.6) by hydrogenation with
(S,R)-1. It is noteworthy that hydrogenation of racemic bezoin
methyl ether [(()-6] with (S,R)-1 selectively afforded the
anti (anti:syn ) 96.6:3.4) alcohol (1R,2S)-7 in 98% ee
(Scheme 2, eq 3, and Table 1). This is the first example of
anti-selective asymmetric hydrogenation of R-alkoxy ketones
under dynamic kinetic resolution.21 The exclusive anti-
selectivity suggests that the TolBINAP/DMAPEN-Ru cata-
lyst differentiates between the R-CH3O group and the
R-phenyl ring purely by the size and not by the electrone-
gativity.20,22
In conclusion, the newly devised TolBINAP/DMAPEN-
Ru complex 1 in a base containing 2-propanol efficiently
catalyzes asymmetric hydrogenation of arylglyoxal dialky-
lacetals to chiral R-hydroxy acetals in excellent enantiomeric
excess. Simple aryl sec-alkyl ketones are also hydrogenated
with excellent enantioselectivity. Hydrogenation of racemic
R-amidopropiophenones via dynamic kinetic resolution
selectively gives the syn-R-amido alcohols in excellent ee
by precise control of two contiguous stereocenters. High anti-
and enantioselectivity are also achieved in the hydrogenation
of racemic bezoin methyl ether. Thus, the TolBINAP/
DMAPEN-Ru catalyst provides the most general procedure
for asymmetric hydrogenation of aromatic ketones with
R-branched carbon moieties, that is, CHR2, CH(OR)2, CH-
(R1)NR2COR3, and CH(R1)OR2.
Scheme 2
Acknowledgment. This work was supported by a Grant-
in-Aid from the Japan Society for the Promotion of Science
(JSPS) (No. 18350046).
Supporting Information Available: Preparative methods
and properties of chiral Ru complex 1, synthesis and
procedures for asymmetric hydrogenation of R-branched
ketones, NMR, GC, and HPLC behavior of products, together
with [R]D values and the absolute configuration determina-
tion. This material is available free of charge via the Internet
OL070125+
methylamino)propiophenone [(()-4a] was hydrogenated with
(S,R)-1 in a basic 2-propanol ([4a] ) 0.4 M, [t-C4H9OK] )
33 mM, ketone/Ru/base ) 500:1:45, 30 °C, 8 atm H2, 9 h),
(19) Myers, A. G.; Charest, M. G. In Handbook of Reagents for Organic
Synthesis: Chiral Reagents for Asymmetric Synthesis; Paquette, L. A., Ed.;
Wiley: Chichester, 2003; pp 485-496 and references cited therein.
(20) (a) Che´rest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968,
2199-2204. (b) Anh, N. T. Top. Curr. Chem. 1980, 88, 145-162.
(21) Asymmetric transfer hydrogenation of (()-6 catalyzed by a chiral
arene-Ru complex in a formic acid-(C2H5)3N mixture selectively gave
the syn (not anti) alcohol. See: Murata, K.; Okano, K.; Miyagi, M.; Iwane,
H.; Noyori, R.; Ikariya, T. Org. Lett. 1999, 1, 1119-1121.
(22) Reduction of 6 with potassium tri-sec-butyl borohydride (K-
Selectride), a bulky and non-chelation reducing agent, in ether at -78 °C
predominantly afforded anti-7. See: Davis, F. A.; Haque, M. S.; Przeslawski,
R. M. J. Org. Chem. 1989, 54, 2021-2024.
(15) (R)-3a and (S)-3h are both â alcohols in equation 1.
(16) Nieduzak, T. R.; Margolin, A. L. Tetrahedron: Asymmetry 1991,
2, 113-122.
(17) Asymmetric aminohydroxylation of 1-arylpropenes produced the
1-aryl-2-aminopropanols as only minor regioisomeric products. See: Barta,
N. C.; Sidler, D. R.; Somerville, K. B.; Weissman, S. A.; Larsen, R. D.;
Reider, P. J. Org. Lett. 2000, 2, 2821-2824.
(18) Hughes, D. T. D.; Empey, D. W.; Land, M. J. Clin. Hosp. Pharm.
1983, 8, 315-321.
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