Angewandte
Chemie
DOI: 10.1002/anie.201207561
Asymmetric Synthesis
Asymmetric Hydrogenation of a,a’-Disubstituted Cycloketones
through Dynamic Kinetic Resolution: An Efficient Construction of
Chiral Diols with Three Contiguous Stereocenters**
Chong Liu, Jian-Hua Xie,* Ya-Li Li, Ji-Qiang Chen, and Qi-Lin Zhou*
Transition-metal-catalyzed asymmetric hydrogenation is one
of the most environmentally benign, atom-efficient, and
powerful methods for the synthesis of chiral organic com-
pounds in optically active form.[1] A particularly useful
method is the transition-metal-catalyzed asymmetric hydro-
genation of configurationally labile substrates through
dynamic kinetic resolution (DKR).[2] For example, the hydro-
genation of racemic a-substituted ketones catalyzed by chiral
ruthenium diphosphine/diamine complexes is a highly effi-
cient method for the one-step preparation of chiral alcohols
containing two vicinal stereocenters.[3] However, despite its
great potential for the synthesis of chiral compounds such as
natural products and biologically active compounds with
multiple stereocenters, the asymmetric hydrogenation of
racemic a,a’-disubstituted ketones to generate chiral alcohols
with three contiguous stereocenters remains a challenge.[4]
Successful hydrogenation of a-substituted ketones
through DKR depends on both the selectivity of the catalyst
for hydrogenation of one of two enantiomers of the racemic
ketones and the ability of the substrates to racemize under the
reaction conditions. As a,a’-disubstituted ketones have four
stereoisomers, enantiocontrol of the hydrogenation is
extremely difficult. To address this challenge, we investigated
the hydrogenation of cycloketones with an a-alkoxycarbonyl-
alkyl group and an a’-aryl group. We expected that the
enantioselective hydrogenation of these racemic a,a’-disub-
stituted ketones through DKR would produce chiral cyclo-
alkanols with three contiguous stereocenters and that these
cycloalkanols could serve as chiral intermediates for the
synthesis of natural alkaloids such as lycorane[5] and hexahy-
droapoerysopine.[6] Herein, we report the highly enantiose-
lective hydrogenation of this type of cycloketones through
DKR to chiral diols with three contiguous stereocenters and
the use of the reaction for the asymmetric total synthesis of
(+)-g-lycorane.
Recently, we reported highly efficient asymmetric hydro-
genations of racemic a-substituted aldehydes and ketones
through DKR, for the syntheses of chiral alcohols with one or
two stereocenters catalyzed by [RuCl2{(S)-SDPs}{(R,R)-dia-
mine}] ((Sa,R,R)-1).[7] Herein, when we used (Sa,R,R)-1 to
catalyze the hydrogenation of racemic a-ethoxycarbonyl-
alkyl-a’-arylcycloketones 2 at room temperature, the corre-
sponding chiral diols 3 were obtained with excellent enantio-
selectivity and cis,cis selectivity (Scheme 1). Interestingly, the
ester groups of 2 were hydrogenated to the corresponding
Scheme 1. [RuCl2{(S)-SDP}{(R,R)-DPEN}]-catalyzed asymmetric hydro-
genation of racemic a-ethoxycarbonylalkyl-a’-arylcycloketones by DKR.
alcohols at room temperature during the reaction, whereas
previously reported examples of the hydrogenation of esters
to primary alcohols required higher temperatures (> 808C).[8]
To evaluate chiral spiro ruthenium catalysts (Sa,R,R)-1, we
selected cis-2-ethoxycarbonylmethyl-6-phenylcyclohexanone
(cis-2a) as a substrate and we found that (Sa,R,R)-1c, which
has 3,5-dimethylphenyl groups on the phosphorus atoms, was
the best catalyst. When cis-2a was hydrogenated with
0.1 mol% of (Sa,R,R)-1c under 50 atm H2 at room temper-
ature (25–308C) in iPrOH containing 10 mol% of KOtBu for
50 h, we were surprised to obtain diol cis,cis-3a in 98% yield
with 98% ee, with none of the expected ketone reduction
product, cis,cis-4 (R = Et or iPr; Scheme 2).[9] When we
intentionally stopped the reaction after 12 h, we obtained
cis,cis-3a in only 5% yield accompanied by lactone cis,cis-5
(32% yield), but cis,cis-4 was still not observed. This result
indicates that diol cis,cis-3a was formed by hydrogenation of
lactone cis,cis-5.
[*] C. Liu, Prof. J.-H. Xie, Y.-L. Li, J.-Q. Chen, Prof. Q.-L. Zhou
State Key Laboratory and Institute of
Elemento-organic Chemistry, Nankai University
Tianjin 300071 (China)
E-mail: jhxie@nankai.edu.cn
[**] We thank the National Natural Science Foundation of China, the
National Basic Research Program of China (2012CB821600), and
the “111” project (B06005) of the Ministry of Education of China for
financial support.
We used (Sa,R,R)-1c to catalyze the hydrogenation of
various 2-ethoxycarbonylmethyl-6-arylcyclohexanones to the
corresponding chiral diols (Table 1, entries 1–9). The sub-
stituent on the phenyl ring of the substrates had little effect on
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2013, 52, 593 –596
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
593