Asymmetric 1,2-reduction of enones with potassium borohydride catalyzed by chiral N,N′-dioxide-scandium(III) complexes

Article abstract of DOI:10.1021/ol302430h

The first catalytic enantioselective 1,2-reduction of enones with 0.45 mol equiv potassium borohydride solution catalyzed by a chiral N,N′-dioxide- Sc(III) complex catalyst was accomplished under mild reaction conditions. A number of optically active allylic alcohols were obtained in good to excellent enantioselectivities (up to 95% ee) with nearly quantitative yields.

Full text of DOI:10.1021/ol302430h

ORGANIC
LETTERS
2012
Vol. 14, No. 19
5134–5137
Asymmetric 1,2-Reduction of Enones
with Potassium Borohydride Catalyzed
by Chiral N,N0‑DioxideꢀScandium(III)
Complexes
Peng He, Xiaohua Liu, Haifeng Zheng, Wei Li, Lili Lin, and Xiaoming Feng*
Key Laboratory of Green Chemistry & Technology, Ministry of Education,
College of Chemistry, Sichuan University, Chengdu 610064, P. R. China
xmfeng@scu.edu.cn
Received September 2, 2012
ABSTRACT
The first catalytic enantioselective 1,2-reduction of enones with 0.45 mol equiv potassium borohydride solution catalyzed by a chiral
N,N0-dioxideꢀSc(III) complex catalyst was accomplished under mild reaction conditions. A number of optically active allylic alcohols were
obtained in good to excellent enantioselectivities (up to 95% ee) with nearly quantitative yields.
The enantioselective reduction of prochiral ketones pro-
vides the most efficient access to optically active secondary
alcohols. It has been successfully achieved with a wide
variety of reducing agents.1 Alkali metal borohydrides are
valuable and commonly used reducing agents in organic
chemistry.2 They take advantage of safety with regards
to use, storage and handling, commercial availability, and
cheapness, as well as efficiency for reducing different func-
tional groups with chemo-, regio-, and diastereoselectivi-
ties.3 Modification of metal borohydrides with chiralamino
alcohols,4 monosaccharide derivatives,3b,5 and carboxy-
lic acids6 was explored to realize asymmetric reduction.
However, stoichiometric amounts of chiral ligands and
reductant were required with varying degrees of enantio-
selectivity.7 The use of a chiral cobalt hydride (CoꢀH)
species for the reduction of chromanone derivatives, which
was generated from optically (β-oxoaldiminato)cobalt(II)
complexes and NaBH4, was reported by Mukaiyama and
co-workers.8,9 Zhao0s group developed a polymer-supported
(1) For reviews, see: (a) Tang, W. J.; Zhang, X. M. Chem. Rev. 2003,
103, 3029. (b) Noyori, R.; Hashiguchi, S. Acc. Chem. Res. 1997, 30, 97.
(c) Ikariya, T.; Blacker, A. J. Acc. Chem. Res. 2007, 40, 1300. For
selected examples, see: (d) Xie, J. H.; Wang, L. X.; Fu, Y.; Zhu, S. F.;
Fan, B. M.; Duan, H. F.; Zhou, Q. L. J. Am. Chem. Soc. 2003, 125, 4404.
(e) Huang, Y.-Y.; He, Y.-M.; Zhou, H.-F.; Wu, L.; Li, B.-L.; Fan, Q.-H.
J. Org. Chem. 2006, 71, 2874. (f) Enthaler, S.; Hagemann, B.; Bhor, S.;
Anilkumar, G.; Tse, M. K.; Bitterlich, B.; Junge, K.; Erre, G.; Beller, M.
Adv. Synth. Catal. 2007, 349, 853. (g) Yun, J.; Buchwald, S. L. J. Am.
Chem. Soc. 1999, 121, 5640. (h) Brown, H. C.; Chandrasekharan, J.;
Ramachandran, P. V. J. Am. Chem. Soc. 1988, 110, 1539. (i) Corey, E. J.;
Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc. 1987, 109, 5551. (j) Zhang,
Z. H.; Jain, P.; Antilla, J. C. Angew. Chem., Int. Ed. 2011, 50, 10961.
(2) For selected examples, see: (a) Brown, H. C.; Mead, E. J.; Subba
Rao, B. C. J. Am. Chem. Soc. 1955, 77, 6209. (b) Brown, H. C.; Subba
Rao, B. C. J. Am. Chem. Soc. 1956, 78, 2582. For reviews, see: (c)
Gribble, G. W. Chem. Soc. Rev. 1998, 395. (d) Periasamy, M.;
Thirumalaikumar, M. J. Organomet. Chem. 2000, 609, 137.
(4) Itsuno, S.; Sakurai, Y.; Shimizu, K.; Ito, K. J. Chem. Soc., Perkin
Trans. 1 1990, 1859.
(5) For selected examples, see: (a) Morrison, J. D.; Grandbois, E. R.;
Howard, S. I. J. Org. Chem. 1980, 45, 4229. (b) Hirao, A.; Nakahama, S.;
Mochizuki, H.; Itsuno, S.; Yamazaki, N. J. Org. Chem. 1980, 45, 4231.
(c) Hirao, A.; Nakahama, S.; Mochizuki, D.; Itsuno, S.; Ohowa, M.;
Yamazaki, N. J. Chem. Soc., Chem. Commun. 1979, 807.
(6) For selected examples, see: (a) Soai, K.; Oyamada, H.; Yamanoi,
T. J. Chem. Soc., Chem. Commun. 1984, 413. (b) Hajipour, A. R.;
Hantehzadeh, M. J. Org. Chem. 1999, 64, 8475. (c) Yamada, S.; Mori,
Y.; Morimatsu, K.; Ishizu, Y.; Ozaki, Y.; Yoshioka, R.; Nakatani, T.;
Seko, H. J. Org. Chem. 1996, 61, 8586.
(3) For selected examples, see: (a) Zeynizadeh, B.; Behyar, T. Bull.
Chem. Soc. Jpn. 2005, 78, 307. (b) Fornasier, R.; Reniero, F.; Scrimin, P.;
Tonellato, U. J. Org. Chem. 1985, 50, 3209. For reviews, see: (c) Ganem,
B.; Osby, J. O. Chem. Rev. 1986, 86, 763. (d) Souza, M. V. N.;
Vasconcelos, T. R. A. Appl. Organomet. Chem. 2006, 20, 798.
(7) (a) Schmitzer, A. R.; Franceschi, S.; Perez, E.; Rico-Lattes, I.;
Lattes, A.; Thion, L.; Erard, M.; Vidal, C. J. Am. Chem. Soc. 2001, 123,
5956. (b) Kim, J.; Bruning, J.; Park, K. E.; Lee, D. J.; Singaram, B. Org.
Lett. 2009, 11, 4358.
r
10.1021/ol302430h
Published on Web 09/26/2012
2012 American Chemical Society

chiral sulfonamide catalyst for the asymmetric reduction
of ketones by treating NaBH4 with Me3SiCl or BF3 OEt2
3
Table 1. Optimization of the Reaction Conditionsa
to generate diborane.10 Nonetheless, the utilization of
simple chiral Lewis acid complexes for asymmetric metal
borohydride reduction has not been reported. The studies
are handicapped probably due to the low solubility of
metal borohydrides in an aprotic solvent and background
reaction.3a Therefore, the development of a highly efficient
and wet-tolerant chiral catalyst is desirable.
Chiral allylic alcohols are key structural subunits of
numerous natural and unnatural products with a wide
range of biological activities.11 The enantioselective 1,2-
reduction of R,β-unsaturated ketones is one of the most
efficient strategies for their construction.12 However, it is
generally complicated by competing 1,2 and 1,4 processes.13
Chemoselective 1,2-reduction of R-enones with NaBH4 in
combination with lanthanoid chlorides was reported early
in 1978.14 Nonetheless, the catalytic asymmetric version
has not been realized yet.15 Herein, we reported the first
catalytic enantioselective reduction of prochiral enones and
ketones by employing potassium borohydride (KBH4)
as the reducing agent. In the presence of a chiral N,N0-
dioxideꢀscandium(III) complex catalyst,16 the reaction
entry
ligand
additiveb
yield (%)c
ee (%)d
1
L1
L2
L3
L4
L5
L3
L3
L3
L3
L3
L6
L6
L6
L6
L6
L6
41
58
75
55
70
99
64
49
67
99
99
80
99
68
99
99
40
48
67
33
48
74
55
52
60
80
90
85
89
82
89
77
2
3
4
5
6
H2O
7
CH3OH
EtOH
iPrOH
8
9
10e
11e
12e,f
13e,g
14e,h
15e,i
16e,j
(8) The author has indicated that the reactive reductant is a cobalt-
hydride species by FAB mass analysis; see: (a) Nagata, T.; Yorozu, K.;
Yamada, T.; Mukaiyama, T. Angew. Chem., Int. Ed. Engl. 1995, 34,
2145. (b) Yamada, T.; Nagata, T.; Sugi, K. D.; Yorozu, K.; Ikeno, T.;
Ohtsuka, Y.; Miyazaki, D.; Mukaiyama, T. Chem.;Eur. J. 2003, 9,
4485.
(9) For 1,4-reduction of R,β-unsaturated carboxylates, see:
Leutenegger, U.; Madin, A.; Pfaltz, A. Angew. Chem., Int. Ed. Engl.
1989, 28, 60.
a Unless otherwise noted, all reactions were performed with ligand
(10 mol %), Sc(OTf)3 (10 mol %), 1a (0.10 mmol), KBH4 solid (0.12
mmol) in THF (1.2 mL) at 0 °C for 2 h. b 20 μL additives were added.
c Isolated yield. d Determined by HPLC analysis (Chiralcel IB). e 22.5 μL
of 2 mol/L KBH4 aqueous solution were used (0.045 mmol of KBH4) at
0 °C for 1.5 h. f 15.0 μL of 2 mol/L aq KBH4 (0.030 mmol of KBH4).
g 30.0 μL of 2 mol/L aq KBH4 (0.060 mmol of KBH4). h The reaction was
performed at 35 °C. i The reaction was performed at ꢀ20 °C. j 22.5 μL of
2 mol/L NaBH4 aqueous solution were used (0.045 mmol of NaBH4).
(10) (a) Hu, J. B.; Zhao, G.; Ding, Z. D. Angew. Chem., Int. Ed. 2001,
40, 1109. (b) Giannis, A.; Sandhoff, K. Angew. Chem., Int. Ed. Engl.
1989, 28, 218.
(11) For reviews, see: (a) Hoveyda, A. H.; Evans, D. A.; Fu, G. C.
Chem. Rev. 1993, 93, 1307. For selected examples, see: (b) Takashima,
Y.; Kobayashi, Y. J. Org. Chem. 2009, 74, 5920. (c) Ma, X.; Li, W. F.; Li,
X. M.; Tao, X. M.; Fan, W. Z.; Xie, X. M.; Ayad, T.; Ratovelomanana-
Vidal, V.; Zhang, Z. G. Chem. Commun. 2012, 48, 5352.
(12) For selected examples, see: (a) Ohkuma, T.; Ooka, H.; Ikariya,
T.; Noyori, R. J. Am. Chem. Soc. 1995, 117, 10417. (b) Moser, R.;
ꢀ
ꢁ
ꢀ
Boskovic, Z. V.; Crowe, C. S.; Lipshutz, B. H. J. Am. Chem. Soc. 2010,
132, 7852.
performed well with 0.45 mol equiv of KBH4 aqueous
solution under mild reaction conditions.
(13) For selected examples of 1,2- and 1,4-reduction, see: (a)
Nutaitis, C. F.; Bernardo, J. E. J. Org. Chem. 1989, 54, 5629. (b) Langer,
R.; Leitus, G.; Ben-David, Y.; Milstein, D. Angew. Chem., Int. Ed. 2011,
50, 2120. (c) Voigtritter, K. R.; Isley, N. A.; Moser, R.; Aue, D. H.;
Lipshutz, B. H. Tetrahedron 2012, 68, 3410. (d) Wang, X. M.; Han, Z. B.;
Wang, Z.; Ding, K. L. Angew. Chem., Int. Ed. 2012, 51, 936. (e) Li, X. F.;
Li, L. C.; Tang, Y. F.; Zhong, L.; Cun, L. F.; Zhu, J.; Liao, J.; Deng, J. G.
J. Org. Chem. 2010, 75, 2981. (f) Peach, P.; Cross, D. J.; Kenny, J. A.;
Mann, I.; Houson, I.; Campbell, L.; Walsgrove, T.; Wills, M. Tetra-
hedron 2006, 62, 1864. (g) Tondreau, A. M.; Lobkovsky, E.; Chirik, P. J.
Org. Lett. 2008, 10, 2789.
(14) (a) Luche, J. L. J. Am. Chem. Soc. 1978, 100, 2226. (b) Gemal,
A. L.; Luche, J. L. J. Am. Chem. Soc. 1981, 103, 5454.
(15) For asymmetric induction in selective 1,2-reduction, see:
Motohashi, S.; Nagase, K.; Nakakita, T.; Matsuo, T.; Yoshida, Y.;
Kawakubo, T.; Miura, M.; Toriyama, M.; Barybin, M. V. J. Org. Chem.
2011, 76, 3922.
(16) For reviews, see: (a) Liu, X. H.; Lin, L. L.; Feng, X. M. Acc.
Chem. Res. 2011, 44, 574. For highlights, see: (b) Huang, S. X.; Ding,
K. L. Angew. Chem., Int. Ed. 2011, 50, 7734. For recent examples, see: (c)
Liu, Y. L.; Shang, D. J.; Zhou, X.; Liu, X. H.; Feng, X. M. Chem.;Eur.
J. 2009, 15, 2055. (d) Cai, Y. F.; Liu, X. H.; Jiang, J.; Chen, W. L.; Lin,
L. L.; Feng, X. M. J. Am. Chem. Soc. 2011, 133, 5636. (e) Shen, K.; Liu,
X. H.; Wang, G.; Lin, L. L.; Feng, X. M. Angew. Chem., Int. Ed. 2011,
50, 4684. (f) Li, W.; Liu, X. H.; Hao, X. Y.; Hu, X. L.; Chu, Y. Y.; Cao,
W. D.; Qin, S.; Hu, C. W.; Lin, L. L.; Feng, X. M. J. Am. Chem. Soc.
2011, 133, 15268.
In the initial study, (E)-4-phenylbut-3-en-2-one 1a
and KBH4 were chosen as the substrate and reductant,
respectively. The reaction was performed in THF at 0 °C
with 10 mol % of chiral N,N0-dioxideꢀscandium(III)
complexes, generating allylic alcohol 2a as the sole product
(Table 1). The structure of the ligand was optimized
first. As for the amino acid backbone, L-ramipril derived
N,N0-dioxide L3 was superior to both L1 (derived from
L-proline) and L2 (derived from L-pipecolic acid) (Table 1,
entry 3 vs entries 1 and 2). Meanwhile, steric hindrance
of the amide moiety of the ligand played a key role in
promoting the enantioselectivity of the reaction (Table 1,
entry 3 vs entries 4 and 5). An array of protic additives
(Table 1, entries 6ꢀ9) were surveyed to distinguish which
one(s) may exert steric and electronic influences upon
the reactivity of the substituted complex ion from metal
borohydride.14b,17 Interestingly, when a small amount of
water was added, the reduction rate was dramatically
Org. Lett., Vol. 14, No. 19, 2012
5135

accelerated with a complete conversion. And the ee value
was increased to 74% (Table 1, entry 6). Other protic
additives, such as CH3OH, EtOH, and iPrOH, which were
commonly used as solvents in the reduction with NaBH4,
delivered the products with poor results (Table 1, entries
7ꢀ9). These results prompted us to investigate the optimal
reaction conditions in the presence of water. To our de-
light, when the aqueous solution of KBH4 was used instead
of the use of a solid reductant and water additive separa-
tively, the reaction performed in a homogeneous catalyst
system. The loading of KBH4 could be decreased to
0.45 mol equiv, and the chiral allylic alcohol was obtained
in excellent yield with 80% ee (Table 1, entry 10). Remark-
ably, when the highly sterically demanding ligand L6 was
employed, 90% ee and 99% yield were achieved (Table 1,
entry 11 vs 10). Further screening of the amount of
reductant and reaction temperature resulted in no better
outcomes (Table 1, entries 12ꢀ15). When the NaBH4
aqueous solution was used, the enantioselectivity slightly
decreased (Table 1, entry 16).
Table 2. Substrate Scope of the Asymmetric Reduction of
Enonea
The utility of this reducing system was further explored
with the reduction of structurally different R,β-unsatu-
rated ketones by using 0.45 mol equiv of KBH4 aqueous
solution (Table 1, entry 11). Such asymmetric 1,2-reduc-
tions were alsoefficienttoprovidethe corresponding chiral
allylic alcohols 2 in excellent yields and good to excellent
enantioselectivities within 1.5 h (Table 2). The electron-
withdrawing groups on the aromatic ring of enones 1hꢀ1k
led to some loss of enantioselectivity due to the competi-
tion of the background reaction (Table 2, entries 1ꢀ7 vs
8ꢀ11). The disubstituted R,β-unsaturated ketones with
electron-donating groups were also good substrates and
afford the chiral allylic alcohols in 90ꢀ94% ee (Table 2,
entries 12ꢀ14). The substrate with a β-cinnamyl group still
gave an excellent yield with 90% ee (Table 2, entry 15).
It was noteworthy that the reaction could also be extended
to fused-ring and heteroaromatic enones, affording the
products in excellent yields with 85%ꢀ90% ee (Table 2,
entries 16ꢀ18). Moreover, when β-ionone was used,
the allylic alcohol 2s, which could be used for spices in
food and cosmetics,18 was formed exclusively in 90% ee
(Table 2, entry 19).
a Unless otherwise noted, all reactions were performed with the ligand
L6 (10 mol %), Sc(OTf)3 (10 mol %), enones 1 (0.1 mmol), 22.5 μL of
2 mol/L KBH4 aqueous solution in THF (1.2 mL) at 0 °C for 1.5 h.
b Isolated yield. c Determined by HPLC analysis. The absolute configura-
tion was determined by comparison with the reported optical rotation or
CD spectra with 3a (see the Supporting Information). d Reaction time was 5 h.
Scheme 1. Scope of Saturated Ketones in the Catalytic Asym-
metric Reduction Reaction
Next, the catalytic system was expanded to the reduc-
tion of saturated ketones under the defined conditions
(Scheme 1). By prolonging the reaction time to 8 h, the
chiral secondary alcohol products were isolated in moder-
ate to good enantioselectivities with quantitative yields.
Indan-1-one 1v incorporating a five-membered ring was a
suitable substrate for the reaction, delivering the product
2v with 86% ee.
To show the synthetic utility of the catalyst system, the
reduction of (E)-4-phenylbut-3-en-2-one 1a was expanded
to a gram scale. As shown in Scheme 2, the product could
be isolated in 99% yield with 89% ee. After a simple re-
crystallization, the enantioselectivity increased to 99% ee
with a 75% yield. Notably, the allylic alcohol 2a could be
easily transformed into the epoxy alcohol 3a, which is a
valuable and versatile intermediate in organic synthesis.19
Furthermore, hydrogenation of 2a smoothly generated
(17) Rickborn, B.; Wuesthoff, M. T. J. Am. Chem. Soc. 1970, 92,
6894.
(18) Humpf, H. U.; Schreier, P. J. Agric. Food Chem. 1992, 40, 1898.
(19) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune,
H.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765.
5136
Org. Lett., Vol. 14, No. 19, 2012

Scheme 2. Synthetic Utility of the Catalyst System
Scheme 3. Proposed Mechanism of the Catalytic Asymmetric
1,2-Reduction of (E)-4-Phenylbut-3-en-2-one 1a
of enone was crucial for the initiation of the reaction.
On the basis of the experimental results and the structure
of the ScIIIꢀN,N0-dioxide complex,16a a possible catalytic
process was proposed in Scheme 3. The enone coordinated
with the L6ꢀSc(OTf)3 catalyst form the intermediate. The
Re face of activated enone 1awas shielded by the rear bulky
amide moiety of the ligand. Subsequently, the Hꢀ ion of the
reducing species attacked from the Si face of carbonyl
group, followed by a quick protonation of the oxygen ion
with water to generate the desired product (R)-2a.
In summary, we have developed the first catalytic en-
antioselective 1,2-reduction of enones and ketones em-
ploying 0.45 mol equiv KBH4 as the reductant catalyzed
by a N,N0-dioxideꢀscandium(III) complex under mild
reaction conditions. A number of optically active allylic
alcohols were obtained in good to excellent enantioselec-
tivities (up to 95% ee) and quantitative yields within a
short reaction time. The catalytic system features a con-
venient operation, a low amount of the reductant, and
air and moisture tolerance. Further studies of the applica-
tion of the catalyst to other reduction reactions are
underway.
4-phenyl-butan-2-ol 4a in excellent yield (99%) without
any loss of enantioselectivity, which is an important inter-
mediate for the synthesis of antitumor compounds.20
We next try to shed light on the function of H2O in this
catalytic asymmetric reduction. First, direct proof of the
critical reductant species in the reaction mixture was
confirmed by HRMS spectra experiments.21 The spectrum
of the sample by treating KBH4 with H2O revealed ions
at m/z 92.9890 (MS ESþ) and 68.9915 (MS ESꢀ), which
corresponded to [KBH3OH þ Naþ] and KBH3Oꢀ. It
suggested that the initial reducing species was KBH3OH,
generated from the reaction of KBH4 and H2O (Scheme 3).
The comparative experiments verified the hydrogen source
of the reduction. The use of 0.45 and 0.30 mol equiv of
KBH4 gave 99% and 80% isolated yields, respectively
(Table 1, entries 11 and 12). Deuterium labeling experi-
ments were performed to elucidate the source of the
hydrogen atom of the products.21 These results indicated
that the reductant could provide no less than 2 equiv of
hydrogen ions for the reaction in this case. The monosub-
stituted species BH3ORꢀ (R = alkoxy or H) was found to
be more reactive than BH4ꢀ (Table 1, entry 10 vs 3).14b,17,22
The presence of water could also benefit proton transfer
to accelerate the catalytic cycle. Additionally, the existence
of water enhanced the solubility of the reductant and the
reaction could be carried out in a homogeneous system.
In light of the sluggish reaction rate of enone 1a at 0 °C
without the scandium complex catalyst, the activation
Acknowledgment. Wethank theNational Natural Science
Foundation of China (Nos. 21021001 and 21172151), the
Ministry of Education (No. 20110181130014), and National
Basic Research Program of China (973 Program: No.
2010CB833300) for financial support. We also thank the
State Key Laboratory of Biotherapy for HRMS analysis.
(20) Huang, L. J.; Hou, S. J.; Li, J. B.; Yu, D. Q. J. Asian Nat. Prod.
Res. 2007, 9, 223.
(21) For details, see the Supporting Information.
(22) The use of alcohols is unfavorable for both the yield and the
enantioselectivity. The species generated from alcohol and KBH4 is
varied which is less reactive for the reduction. Additionally, the inter-
action between the substrate and metal center might be intervened by
preferential binding of alcohols.
Supporting Information Available. Experimental pro-
cedures, spectral and analytical data for the products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
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