Asymmetric transfer hydrogenation of cycloalkyl vinyl ketones to allylic alcohols catalyzed by ruthenium amido complexes

Article abstract of DOI:10.1039/c8ob02604a

A chemoselective 1,2-reduction of cycloalkyl vinyl ketones via asymmetric transfer hydrogenation is described. The reduction proceeded smoothly with a chiral diamine ruthenium complex as a catalyst and a HCOOH-NEt₃ azeotrope as both a hydrogen source and solvent under mild conditions. A wide range of 1-cycloalkyl chiral allylic alcohols were obtained in good yields and up to 87% ee. It was found that the alkyl group plays an important role in the enantioselectivity.

Full text of DOI:10.1039/c8ob02604a

Organic &
Biomolecular Chemistry
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Asymmetric transfer hydrogenation of cycloalkyl
vinyl ketones to allylic alcohols catalyzed by
ruthenium amido complexes†
Cite this: Org. Biomol. Chem., 2019,
17, 264
Sensheng Liu,‡a Peng Cui,‡a Juan Wang,a Haifeng Zhou,
*
a,b Qixing Liua and
Jinliang Lv*b
A chemoselective 1,2-reduction of cycloalkyl vinyl ketones via asymmetric transfer hydrogenation is
described. The reduction proceeded smoothly with a chiral diamine ruthenium complex as a catalyst and
a HCOOH–NEt3 azeotrope as both a hydrogen source and solvent under mild conditions. A wide range
of 1-cycloalkyl chiral allylic alcohols were obtained in good yields and up to 87% ee. It was found that the
alkyl group plays an important role in the enantioselectivity.
Received 20th October 2018,
Accepted 4th December 2018
DOI: 10.1039/c8ob02604a
rsc.li/obc
Chiral allylic alcohols are privileged structural subunits of chiral phosphine ligands were necessary for the formation of
various natural products, as well as valuable building blocks metal complex catalysts. Moreover, the substrates were limited
for a wide range of biologically active molecules, such as phar- to simple aryl vinyl ketones and alkyl vinyl ketones. Thus, the
maceuticals and agrochemicals (Fig. 1).1 Thus, much attention synthesis of 1-cycloalkyl chiral allylic alcohols, important inter-
has been paid on developing efficient methods to prepare mediates of pharmaceuticals and natural products, is almost
these compounds.2 Among which, the transition-metal cata- undeveloped.9,10 Therefore, it is highly desirable to develop a
lyzed asymmetric hydrogenation of the carbonyl group of simple and inexpensive catalytic system for the 1,2-reduction
enones is a direct method to produce chiral allylic alcohols.3 of cycloalkyl vinyl ketones under mild conditions to access
In 1995, a breakthrough in this field was realized with chiral 1-cycloalkyl chiral allylic alcohols.
ruthenium/diphosphine/diamine complexes as catalysts,
Asymmetric transfer hydrogenation (ATH) is attractive as an
giving the chiral allylic alcohols in up to 98% ee.4 Since then, alternative to hydrogenation due to convenient operation and
these types of catalysts have been widely used in the asym- avoidance of H2 gas and pressure vessels.11 Ever since the
metric hydrogenation of a variety of cyclic and acyclic enones chiral diamine ruthenium complex, a famous catalyst for ATH,
including simple aryl vinyl ketones and alkyl vinyl ketones to has been discovered by Noyori,12 a large number of chiral
give the corresponding chiral allylic alcohols.5 In addition, diamine-derived Ru, Rh, and Ir complexes have been devel-
borohydride reagents were also applied in the enantioselective oped for the ATH of simple aryl ketones and diaryl ketones.13
1,2-reduction of enones, such as chiral oxazaborolidine cata- However, little attention has been focused on the ATH of
lyzed reduction (Corey–Bakshi–Shibata reduction)6 and the enones.14 Notably, the chiral diamine ruthenium complex is
metal borohydride reduction catalyzed by chiral Lewis acid highly chemoselective for the ATH of the CvO functional
complexes.7 Lately, novel chiral metal hydrides like CuH8 and group and tolerance of the alkene.3a,15 To continue our
NiH9 were also developed for the 1,2-reduction of enones. research interest in the asymmetric synthesis of chiral alco-
Although great progress has been achieved in the enantio- hols,16 we report a chemoselective ATH of cycloalkyl vinyl
selective 1,2-reduction of enones, several drawbacks and chal-
lenges still exist. For example, air-sensitive and expensive
aResearch Center of Green Pharmaceutical Technology and Process, Hubei Key
Laboratory of Natural Products Research and Development, College of Biological and
Pharmaceutical Sciences, China Three Gorges University, Yichang 443002, China.
E-mail: zhouhf@ctgu.edu.cn; Fax: +86(717)639-5580
bYichang Humanwell Pharmaceutical Co., Ltd., Yichang 443005, China.
E-mail: lvjinliang@renfu.com.cn
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c8ob02604a
Fig. 1 Representative pharmaceuticals and natural products containing
‡These authors contributed equally.
chiral allylic alcohols.
264 | Org. Biomol. Chem., 2019, 17, 264–267
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ketones with a chiral diamine ruthenium complex as a catalyst ratio F/T = 1.1/1) as a hydrogen source and solvent; however, a
and a HCOOH–NEt3 azeotrope as a hydrogen source under lower yield and ee value were observed (Table 1, entry 12).
mild conditions, giving a variety of 1-cycloalkyl chiral allylic Next, the reaction was conducted with HCOONa as a hydrogen
alcohols in good yields and high enantioselectivities.
source in an aqueous medium, such as H2O/MeOH (v/v = 1 : 1),
Our investigation was started with the ATH of (E)-1-cyclo- H2O/DMF (v/v = 1 : 1), H2O/TFE (v/v = 1 : 1), and H2O/i-PrOH
propyl-3-phenylprop-2-en-1-one (2a) as a model reaction. To (v/v = 1 : 1), but inferior results were obtained in comparison
our delight, when the bifunctional oxo-tethered ruthenium with the F/T system (Table 1, entries 13–16). Finally, the opti-
complex (S,S)-1a was used as a catalyst with HCOOH–TEA mized reaction conditions were set as: 5 mol% of (S,S)-1d, F/T
(molar ratio F/T = 5/2) as a hydrogen source and solvent, the (5 : 2) as a hydrogen source and solvent, 40 °C, and 24 h
reaction performed exclusively to give the target product 3a in (Table 1, entry 4).
71% yield and 60% ee (Table 1, entry 1). Notably, the olefin
As shown in Scheme 1, a variety of styryl cyclopropyl
moiety of 2a remained intact. A survey of different chiral ketones 2a–2w were efficiently hydrogenated to give the corres-
monosulfonyl diamine ruthenium complexes 1b–1i indicated ponding chiral allylic alcohols with good yields and high
that (S,S)-1d was the best choice with respect to the yields and enantioselectivities under the optimized reaction conditions.
enantioselectivities (Table 1, entries 2–9, entry 4; 90% yield, In general, it was found that the substrates bearing a substitu-
81% ee). It was reported that the counteranion effect of these
kinds of catalysts plays an important role in the reactivity and
enantioselectivity.17 Therefore, the anion effect of ruthenium
complexes was also evaluated with catalysts (S,S)-1j and (S,S)-
1k, but no positive effect was observed (Table 1, entries 10 and
11). Kelkar and coworkers reported that both reactivity and
enantioselectivity of the ATH of imines were improved by
varying the molar ratio of F/T from 5/2 to 1.1/1.18 Then, the
reaction was attempted with an acidic mixture of F/T (molar
Table 1 Optimization of the reaction conditionsa
Entry Cat.
[H] sourceb Solvent (v/v)
Yield (%) ee (%)
1
2
3
4
5
6
7
8
(S,S)-1a F : T (5 : 2)
(S,S)-1b F : T (5 : 2)
—
71
57
49
90
65
68
70
69
75
62
65
76
60
61
53
81
77
79
77
73
79
77
79
80
25
47
18
39
—
—
—
—
—
—
—
—
—
—
(S,S)-1c F : T (5 : 2)
(S,S)-1d F : T (5 : 2)
(S,S)-1e F : T (5 : 2)
(S,S)-1f F : T (5 : 2)
(S,S)-1g F : T (5 : 2)
(S,S)-1h F : T (5 : 2)
(S,S)-1i F : T (5 : 2)
(S,S)-1j F : T (5 : 2)
(S,S)-1k F : T (5 : 2)
(S,S)-1d F : T (1.1 : 1)
(S,S)-1d HCOONa
(S,S)-1d HCOONa
(S,S)-1d HCOONa
(S,S)-1d HCOONa
9
10
11
12
13
14
15c
16
H2O/MeOH (1 : 1) 45
H2O/DMF (1 : 1)
H2O/TFE (1 : 1)
53
62
H2O/i-PrOH (1 : 1) 52
a Reaction conditions: 2a (0.2 mmol), 5 mol% catalyst, 40 °C, 24 h,
1.0 mL of solvent, isolated yield, the ee values were determined by
HPLC analysis. b The data in the brackets are the molar ratio.
c TFE : CF3CH2OH.
Scheme 1 Substrate scope. Reaction conditions: Cyclopropyl vinyl
ketone 2 (0.2 mmol), (S,S)-1d (5 mol%), F/T (1.0 mL, molar ratio = 5 : 2),
40 °C, 24 h; isolated yield; the ee values were determined by HPLC
analysis.
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ent at the ortho- or meta-position on the phenyl ring gave rela- ketones to prepare 1-cycloalkyl chiral allylic alcohols. The
tively higher ee than the para-substituted ones due to the reduction was conducted with a chiral diamine ruthenium
steric effect. For example, both products 3c and 3i have 85% complex as a catalyst and a HCOOH–NEt3 azeotrope as both a
ee, but product 3n has only 79% ee. In addition, substrates hydrogen source and solvent under mild conditions. The
bearing an electron-deficient phenyl ring (2b–2e; 2h–2k; studies revealed that the alkyl group plays an important role in
2n–2q) gave slightly higher ee than the electron-rich ones the enantioselectivity.
(2f, 2g; 2l, 2m; 2r–2t). Notably, substrate 2u with two CH3O
groups on the phenyl ring gave only 74% ee. In contrast, up to
87% ee was obtained for substrate 2w bearing two electron- Conflicts of interest
withdrawing groups, NO2 and Cl, on the phenyl ring.
There are no conflicts to declare.
Furthermore, when the R group of substrate 2 was switched to
naphthyl and furyl, the corresponding chiral allylic alcohols 3x
and 3y were obtained in 82% and 85% ee, respectively. Most
importantly, in addition to the arylvinyl cyclopropyl ketones,
Acknowledgements
the alkylvinyl cyclopropyl ketone 2z was also applicable to this
We are grateful for financial support from the Hubei Key
Laboratory of Natural Products Research and Development,
China Three Gorges University (NPRD 2018007), a research
ATH, giving the chiral allylic alcohol 3z in 83% ee (Fig. 2).19
To further demonstrate the important role of cyclopropyl in
the enantioselectivity, substrates with a larger cycloalkyl like
fund for excellent dissertation of China Three Gorges
2aa and 2ab were also investigated. As shown in Scheme 2,
University (2018SSPY138), and a joint research fund from
Yichang Humanwell Pharmaceutical Co., Ltd. (SDHZ2017032).
product 3aa bearing a cyclobutyl was obtained with 67% ee. In
sharp contrast, a racemate of cyclohexylated product 3ab was
observed. Interestingly, when the cyclopropyl was replaced by
isopropyl, the ee value was decreased from 81% to 39%.
Moreover, the substrate containing a tert-butyl gave product
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