Catalytic asymmetric hydrogenation of α-arylcyclohexanones and total synthesis of (-)-α-lycorane

Article abstract of DOI:10.1002/adsc.201300165

An efficient catalytic asymmetric hydrogenation of racemic α-arylcyclohexanones with an ethylene ketal group at the 5-position of the cyclohexane ring via dynamic kinetic resolution has been developed, giving chiral α-arylcyclohexanols with two contiguous

Full text of DOI:10.1002/adsc.201300165

FULL PAPERS
DOI: 10.1002/adsc.201300165
Catalytic Asymmetric Hydrogenation of a-Arylcyclohexanones
and Total Synthesis of (À)-a-Lycorane
Gang Li,a Jian-Hua Xie,a,* Jing Hou,a Shou-Fei Zhu,a and Qi-Lin Zhoua,*
a
State Key Laboratory and Institute of Elemento-organic Chemistry, Nankai University, Tianjin 300071, Peopleꢀs Republic
of China
Fax : (+86)-22-2350-6177; e-mail: jhxie@nankai.edu.cn or qlzhou@nankai.edu.cn
Received: February 19, 2013; Revised: April 18, 2013; Published online: May 15, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300165.
Abstract: An efficient catalytic asymmetric hydroge- (À)-a-lycorane was synthesized in 19.6% overall
nation of racemic a-arylcyclohexanones with an eth- yield over 13 steps from commercially available
ylene ketal group at the 5-position of the cyclohex- starting material.
ane ring via dynamic kinetic resolution has been de-
veloped, giving chiral a-arylcyclohexanols with two
contiguous stereocenters with up to 99% ee and Keywords: Amarylliaceae alkaloids; asymmetric cat-
>99:1 cis/trans-selectivity. Using this highly efficient alysis; chiral spiro catalyst; dynamic kinetic resolu-
asymmetric hydrogenation reaction as a key step, tion; hydrogenation; lycorane
Introduction
a trans-fused octahydroquinoline skeleton which are
difficult to construct by the previous method
The transition metal-catalyzed asymmetric hydroge- (Figure 1).
nation of ketones is a powerful and useful methodolo-
To develop a new strategy for the enantioselective
gy for the preparation of optically active chiral alco- construction of chiral trans-fused octahydroquinoline
hols, which are very important building blocks in the skeleton, we studied the ruthenium-catalyzed asym-
synthesis of natural products and pharmaceuticals.[1] metric hydrogenation of racemic a-arylcyclohexan-
In the last decades, remarkable progress has been
ACHTUNGTRENoNGNU nes 1 containing an ethylene ketal group at the 5-po-
achieved in the asymmetric hydrogenation of ketones sition via dynamic kinetic resolution.[10] Although the
with special focus on the development of efficient a-arylcyclohexanones 1 were base sensitive substrates,
chiral catalysts and the exploration of new types of the chiral spiro ruthenium diphosphine/diACTHNUTRGNEUaGN mine cata-
ketone substrates.[2] However, the studies on the lysts 3 showed high efficiency for the hydrogenation
asymmetric hydrogenations of ketones directed to- of 1 and provided the chiral cyclohexanols 2 in high
wards the synthesis of natural products and pharma-
ceuticals are limited.[3] Recently, we developed several
highly efficient hydrogenations of ketones with chiral
spiro ruthenium and iridium catalysts,[4] which have
been used for the total synthesis of natural products
such as galanthamine,[5] mesembrine,[6] tetrahedrocan-
nabinols,[7] and centrolobine.[8] In particular, the
ruthenium-catalyzed enantioselective hydrogenation
of racemic a,a’-disubstituted cycloalkanones has been
developed for the synthesis of chiral diols with three
contiguous stereocenters in one step, and was applied
to the enantioselective total synthesis of alkaloid
(+)-g-lycorane.[9] However, this synthetic strategy is
unsuitable for the synthesis of other lycorine-type
Amaryllidaceae alkaloids such as (À)-a-lycorane, (À)-
lycorine, and (À)-zephyranthine because they contain Figure 1. Selected lycorine-type Amarylliaceae alkaloids.
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Scheme 1. Asymmetric hydrogenation of racemic a-arylcyclohexanones 1.
yields with excellent enantioselectivities (up to 98% 62% yield (see the Supporting Information) and was
ee) and cis-selectivities (cis/trans >99:1) (Scheme 1). studied for an optimization of the hydrogenation con-
Herein, we report our results on the studies of the ditions. The hydrogenation was firstly performed in i-
asymmetric hydrogenation of racemic a-arylcyclohex- PrOH with (Sa,R,R)-3a as catalyst (S/C=500) and t-
anones 1 with chiral spiro ruthenium catalysts and the BuOK as base (0.033M) under 50 atm of H2. Howev-
application of this new strategy to the enantioselec- er, this base-sensitive substrate gave as by-product 3-
tive total synthesis of (À)-a-lycorane.
isopropoxycyclohex-2-enone 4a, instead of the desired
hydrogenation product 2a (Table 1, entry 1).[11] When
a mixed solvent (i-PrOH/toluene=4:1 v/v) was used,
2a was produced in 75% yield with 93% ee and excel-
lent cis-selectivity (cis/trans >99:1, Table 1, entry 2).
Results and Discussion
The racemic a-arylcyclohexanone 1a with a 3,4-meth- Better yield (81%) and enantioselectivity (94% ee)
ylenedioxy group was prepared from commercially were obtained by using catalyst (Sa,R,R)-3b (entry 3).
available 1,4-dioxaspiroACTHUNTGRNEUNG[4.5]decan-8-one in 4 steps in Increasing the ratio of toluene in the mixed solvent to
Table 1. Asymmetric hydrogenation of racemic a-arylcyclohexanone 1a.[a]
Entry
3
Solvent
Base
2a/4a[b]
Yield [%][c]
ee [%][d]
1
2
3
4
5
6
7
8
3a
3a
3b
3b
3b
3b
3b
3b
3b
3b
3b
3b
i-PrOH
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuONa
t-BuOLi
t-BuOK
t-BuOK
t-BuOK
t-BuOK
–/100
84/16
87/13
88/12
91/9
–
–
i-PrOH/toluene (4:1)
i-PrOH/toluene (4:1)
i-PrOH/toluene (2:1)
i-PrOH/toluene (1:1)
i-PrOH/toluene (1:2)
i-PrOH/toluene (1:1)
i-PrOH/toluene (1:1)
i-PrOH/toluene (1:1)
i-PrOH/toluene (1:1)
i-PrOH/toluene (1:1)
i-PrOH/toluene (1:1)
75
81
84
87
86
78
29
89
90
90
81
93
94
94
94
92
96
94
96
96
96
95
91/9
82/18
32/68
93/7
94/6
94/6
9[e]
10[f]
11[g]
12[h]
82/18
[a]
Reaction conditions: 1.0 mmol scale, [substrate]=0.17M, 0.2 mol% of catalyst, [base]=0.033M, solvent (6.0 mL), 50 atm
of H2, room temperature (25–308C), 8 h. The cis/trans selectivity of the product 2a for all reactions was >99:1 as deter-
mined by GC.
Determined by H NMR.
Isolated yield.
The ee values of cis-isomers were determined by HPLC, the absolute configuration was (S,S) determined by X-ray analy-
ses of the single crystal of 2a (see the Supporting Information).
100 atm of H2.
[base]=0.017M, 100 atm of H2.
2.0 mmol scale, 0.1 mol% of catalyst, [base]=0.017M, 100 atm of H2.
20.0 mmol scale, 0.01 mol% of catalyst, [substrate]=0.33M, [base]=0.042M, 100 atm of H2, 20 h.
[b]
[c]
[d]
1
[e]
[f]
[g]
[h]
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Catalytic Asymmetric Hydrogenation of a-Arylcyclohexanones and Total Synthesis of (À)-a-Lycorane
Table 2. Asymmetric hydrogenation of racemic a-arylcyclohexanone 1.[a]
Entry
X
2
cis/trans[b]
Yield [%][c]
ee [%][d]
1
2
3
4
5
6
7
8
3,4-O
H
4-Me
4-MeO
4-CF3
3-Me
3-MeO
2-Me
2-MeO
3,4-(MeO)2
G
2a
2b
2c
2d
2e
2f
2g
2h
2i
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
90
90
94
98
91
89
92
68
78
96
87
96
97
99
98
94
94
98
81
57
96
96
9
10
11
2j
2k
3,4-O
[a]
Reaction conditions: 2.0 mmol scale, [substrate]=0.33M, 0.1 mol% of catalyst, [t-BuOK]=0.017M, solvent (3.0 mL i-
PrOH and 3.0 mL toluene), 100 atm of H2, room temperature (25–308C), 8 h.
Determined by GC.
Isolated yield. The major by-products are 4 for all reactions.
The ee value of cis-isomer was determined by HPLC.
[b]
[c]
[d]
1:1 (v/v) slightly improved the yield (87% yield, ents such as 1j and 1k also gave the corresponding al-
entry 5). The base t-BuONa gave a higher enantiose- cohols 2j and 2k, the potential chiral materials for the
lectivity (96% ee) albeit with somewhat lower yield synthesis of Amarylliaceae alkaloids, in high yields
(78%) (entry 7); however, t-BuOLi was not a suitable with excellent enantioselectivities (entries 10 and 11).
base for the reaction because of poor solubility in the
Subsequently, we studied the enantioselective syn-
mixed solvent (entry 8). When the reaction was car- thesis of lycorine-type Amarylliaceae alkaloids by the
ried out at 100 atm of H2, the yield was slightly in- Ru-catalyzed asymmetric hydrogenation of racemic
creased (89%, entry 9). Furthermore, reducing the a-arylcyclohexanones 1. The lycorine-type Amaryllia-
amount of base from 0.033 to 0.017M gave no distinct ceae alkaloids possess a vast array of biological prop-
effect on the yield of reaction (entries 9 and 10). The erties.[13] For example, lycorine, a representative of
hydrogenation can also be performed smoothly at this family, exhibits antineoplastic, antiviral, anti-
0.1 mol% (S/C=1000) of catalyst loading without di- inflammatory activities, as well as an inhibitory effect
minishing the yield and selectivities (entries 10 and on cell apoptosis and DNA binding activity.[14] The
11). However, when the catalyst loading was further major challenge in the synthesis of these alkaloids is
reduced to 0.01 mol% (S/C=10000), the yield de- to construct the intriguing chiral tetracyclic core struc-
creased although the enantioselectivity was main- ture. We selected a-lycorane, one of the degradation
tained (entry 12).[12]
products of lycorine,[15] as a model molecule for syn-
Under the optimal reaction conditions, a series of thesis by using asymmetric hydrogenation as a key
racemic a-arylcyclohexanones 1 was hydrogenated step. Although several methods have been developed
and the results are summarized in Table 2. The elec- for the total synthesis of a-lycorane,[16] examples
tronic property of the substitute on the phenyl ring of using a catalytic enantioselective strategy are scarce.
the substrate has a distinct effect on both yield and ee Xu et al. reported a synthesis of (À)-a-lycorane by
value of the product (Table 2, entries 1–5). Generally, using an asymmetric bifunctional thiourea-catalyzed
an electron-donating substituent at the 3- or 4-posi- cascade reaction.[17]
tion gave a higher yield and ee value, whereby the
Our synthetic route is outlined in Scheme 2. The
substrate 1d with a 4-OMe gave the highest yield hydroxy group of optically active alcohol (S,S)-2a (>
(98%) and the substrate 1c with a 4-Me gave the 99% ee, after recrystallization) was substituted with
highest enantioselectivity (99% ee) (entries 3 and 4). diphenylphosphoryl azide (DPPA) under Mitsunobu
The substrates bearing ortho-substituents afforded reaction conditions (PPh3/DEAD, THF, À408C to
lower yields and ee values (entries 8 and 9). It is grati- room temperature for 3 h), followed by hydrogena-
fying that the substrates with multiple oxo-substitu- tion with H2/Pd-C in MeOH to yield chiral cyclohex-
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Scheme 2. Enantioselective total synthesis of (À)-a-lycorane.
anamine 5 in 75% yield (2 steps). Pictet–Spengler tions of this strategy to the synthesis of other Amaryl-
cyclization of cyclohexanamine 5 with paraformade- lidaceae alkaloids are in progress in our laboratory.
hyde in AcOH at 608C for 20 h furnished the tricyclic
compound 6 with a six-membered aza-ring in 95%
yield. The compound 6 was reacted with bromoacetyl Experimental Section
chloride in the presence of triethylamine, followed by
treatment with hydrochloric acid in THF to offer a- General Remarks
bromoacetamide derivative 7 in 89% yield (2 steps).
All reactions and manipulations which are sensitive to mois-
According to the modified Umezawaꢀs intramolecular
ture and/or air were performed in an argon-filled glovebox
nucleophilic cyclization method,[16g] the tetracyclic
(VAC DRI-LAB HE 493) or by using standard Schlenk
compound 8 was produced as a single isomer with
67% yield from intermediate 7 by using t-BuOK as
a base in t-BuOH at room temperature for 2 h. Final-
ly, one-pot reduction of both ketone group and amide
group of tetracyclic compound 8 under modified
Wolff–Kishner reduction conditions[18] gave the target
molecule (À)-a-lycorane in 74% yield with 99% ee
(determined by HPLC). The optical rotation of our
synthetic (À)-a-lycorane is consistent with the report-
ed data in the literature {[a]2D2: À29.8 (c 1.0, EtOH);
lit.[16a] [a]2D2: À31.0 (c 0.99, EtOH)}. Thus, using a ruthe-
nium-catalyzed asymmetric hydrogenation as a key
step, the optically active (À)-a-lycorane was synthe-
sized in 19.6% overall yield over 13 steps from the
commercially available 1,4-dioxaspiro-[4.5]decan-8-
one.
techniques. Hydrogen gas (99.999%) was purchased from
Boc Gas Inc., Tianjin. Anhydrous THF and toluene were
distilled from sodium benzophenone ketyl. Anhydrous
CH2Cl2, NEt3, t-BuOH and i-PrOH were freshly distilled
from calcium hydride. t-BuOK was purchased from Acros
Chemical Company. Chiral spiro diphosphine ligands (S)-
SDP and (S)-Xyl-SDP are available from Strem Chemicals
Co. and Zhejiang Jiuzhou Pharmaceutical Co. Melting
points were measured on a RY-I apparatus and uncorrected.
1H and 13C NMR spectra were recorded on Bruker AMX-
300 or Bruker AMX-400 spectrometers. Chemical shifts
were reported in ppm downfield from internal SiACHTNUGTRNEG(UN CH3)4 and
external 85% H3PO4, respectively. Optical rotations were
determined using a Perkin–Elmer 341 polarimeter and an
Autopol-VI automatic polarimeter. GC analyses were per-
formed using a Hewlett–Packard Model HP 6890 Series.
HPLC analyses were performed using an Agilent Technolo-
gies 1260 Infinity. HR-MS were recorded on APEXII and
ZAB-HS spectrometers. IR spectra were recorded on
a Bruker TENSOR 27 spectrometer.
Conclusions
Asymmetric Hydrogenation of Racemic a-Aryl-
cyclohexanones 1; General Procedure
In conclusion, an efficient catalytic asymmetric hydro-
genation of racemic a-arylcyclohexanones with an
ethylene ketal group at the 5-position of the cyclohex-
ane ring via dynamic kinetic resolution has been de-
veloped. With this highly efficient reaction (À)-a-ly-
corane was synthesized conveniently. Further applica-
The catalyst [RuCl2-(Sa)-Xyl-SDP/ACTHNUTRGNEUNG(R,R)-DPEN] [(Sa,R,R)-
3b] (2.2 mg, 0.002 mmol) and anhydrous i-PrOH (2.5 mL)
were placed in a hydrogenation vessel. The vessel was
placed in an autoclave and purged with hydrogen by pres-
surizing to 50 atm and releasing the pressure. The procedure
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Catalytic Asymmetric Hydrogenation of a-Arylcyclohexanones and Total Synthesis of (À)-a-Lycorane
was repeated three times and then the solution was stirred
under 50 atm of H2 for 5 min. After releasing the pressure,
a-arylcyclohexanones 1 (2.0 mmol in 3 mL toluene) and a so-
lution of t-BuOK in i-PrOH (0.2 mmolmLÀ1, 0.5 mL,
0.1 mmol) were added. The autoclave was purged with hy-
drogen and pressurized to 100 atm. The reaction mixture
was stirred at room temperature (25–308C) until no obvious
hydrogen pressure drop was observed (8 h). After the hy-
drogen pressure was released, the solution was concentrated
under vacuum. The residue was purified by column chroma-
tography on silica gel with petroleum ether/ethyl acetate
(2:1) as the eluent to provide the product. The enantioselec-
tivity of the product was determined by HPLC with a chiral
column.
1H NMR (400 MHz, CDCl3): d=7.24 (d, J=8.8 Hz, 2H),
6.86 (d, J=8.8 Hz, 2H), 4.11–3.92 (m, 5H), 3.78 (s, 3H),
3.31 (d, J=8.8 Hz, 1H), 2.66 (dt, J=13.2, 2.4 Hz, 1H), 2.23
(qd, J=13.2, 3.6 Hz, 1H), 2.09 (dt, J=14.0, 3.0 Hz, 1H),
1.98–1.87 (m, 2H), 1.81–1.65 (m, 2H); 13C NMR (100 MHz,
CDCl3): d=158.2, 135.5, 129.0, 113.7, 108.9, 71.5, 64.8, 64.2,
55.3, 46.7, 40.4, 35.3, 23.6; IR (KBr): n=3486, 2905, 1514,
1246, 1086, 989, 814 cmÀ1; HR-MS (ESI): m/z=265.1435,
calcd. for C15H21O4ACHTNUGRTNEUNG
([M+H]+): 265.1434; HPLC (Chiralcel
AD-H; eluent, n-hexane/2-propanol=85:15; pressure,
46 bar; flow rate, 1.0 mLminÀ1; detection, 220 nm light): tR =
13.56 min (7S,8S), tR =15.49 min (7R,8R).
AHCTUNGTREG(NNUN 7S,8S)-8-[4-(Trifluoromethyl)phenyl]-1,4-dioxaspiro-
[4.5]decan-7-ol (2e): White solid; mp 90–928C; yield: 91%;
94% ee; [a]2D0: +56.5 (c 1.0, CHCl3); Rf =0.5 (PE:EA=1:1).
1H NMR (400 MHz, CDCl3): d=7.55 (d, J=8.0 Hz, 2H),
7.43 (d, J=8.0 Hz, 2H), 4.16–3.94 (m, 5H), 3.54 (d, J=
9.6 Hz, 1H), 2.75 (dt, J=13.2, 2.0 Hz, 1H), 2.36–2.21 (m,
1H), 2.10 (dt, J=14.0, 2.8 Hz, 1H), 2.00–1.88 (m, 2H), 1.84–
1.68 (m, 2H); 13C NMR (100 MHz, CDCl3): d=147.6, 128.6
(q, J=32 Hz), 128.5, 125.1 (q, J=3.7 Hz), 124.5 (q, J=
273 Hz), 108.7, 71.1, 64.8, 64.3, 47.5, 40.4, 35.1, 23.4; IR
(KBr): n=3501, 2957, 2929, 1421, 1328, 1161, 1123,
ACHTUNGTRENNUNG(7S,8S)-8-(Benzo[d]ACHUTNRTGEG[NNUN 1,3]dioxol-5-yl)-1,4-dioxaspiroACHTNUGERTN[NUGN 4.5]-
decan-7-ol (2a): White solid; mp 147–1498C; yield: 90%;
96% ee; [a]2D0: +54.0 (c 1.0, CHCl3); Rf =0.5 (PE:EA=1:1).
1H NMR (400 MHz, CDCl3): d=6.85 (s, 1H), 6.81–6.62 (m,
2H), 6.03–5.77 (m, 2H), 4.12–3.86 (m, 5H), 3.35 (d, J=
9.2 Hz, 1H), 2.62 (dt, J=13.2, 2.8 Hz, 1H), 2.25–2.01 (m,
2H), 1.98–1.84 (m, 2H), 1.80–1.63 (m, 2H); 13C NMR
(100 MHz, CDCl3): d=147.4, 145.9, 137.4, 120.9, 108.7,
108.6, 107.9, 100.8, 71.5, 64.7, 64.1, 47.2, 40.3, 35.1, 23.7; IR
(KBr): n=3480, 2889, 2942, 1490, 1438, 1255, 1125, 1087,
1033, 930, 849, 808 cmÀ1; HR-MS (ESI): m/z=301.1040,
calcd. for C15H18O5Na ([M+Na]+): 301.1046; HPLC (Chiral-
cel AD-H; eluent, n-hexane/2-propanol=75:25; pressure,
51 bar; flow rate, 1.0 mLminÀ1; detection, 205 nm light): tR =
10.50 min (7S,8S), tR =12.04 min (7R,8R).
849 cmÀ1
;
HR-MS (ESI): m/z=303.1205, calcd. for
C15H18F3O3 ([M+H]+): 303.1203; HPLC (Chiralcel AD-H;
eluent, n-hexane/2-propanol=85:15; pressure, 46 bar; flow
rate, 1.0 mLminÀ1; detection, 220 nm light): tR =8.47 min
(7S,8S), tR =9.71 min (7R,8R).
ACHUTNGREN(NUG 7S,8S)-8-(3-Methylphenyl)-1,4-dioxaspiroACHTUNGTERN[NUGN 4.5]decan-7-ol
A
E
(2b):
(2f): Colorless oil; yield: 89%; 94% ee; [a]2D0: +65.4 (c 1.0,
White solid; mp 78–808C; yield: 90%; 97% ee; [a]2D0: +70.2
CHCl3). H NMR (400 MHz, CDCl3): d=7.23–7.15 (m, 1H),
1
(c 0.9, CHCl3); Rf =0.5 (PE:EA=1:1). H NMR (400 MHz,
7.14–7.06 (m, 2H), 7.02 (d, J=7.6 Hz, 1H), 4.13–3.89 (m,
5H), 3.29 (d, J=9.2 Hz, 1H), 2.66 (dt, J=12.8, 2.8 Hz, 1H),
2.33ACTHNUTRGENU(GN s, 3H), 2.35–2.19 (m, 1H), 2.08 (dt, J=14.0, 2.8 Hz,
CDCl3): d=7.31 (d, J=4.0 Hz, 4H), 7.25–7.16 (m, 1H),
4.17–3.92 (m, 5H), 3.35 (d, J=9.2 Hz, 1H), 2.71 (dt, J=12.8,
2.8 Hz, 1H), 2.28 (qd, J=13.2, 3.4 Hz, 1H), 2.11 (dt, J=
14.0, 2.8 Hz, 1H), 2.02–1.88 (m, 2H), 1.85–1.67 (m, 2H);
13C NMR (100 MHz, CDCl3): d=143.4, 128.3, 128.2, 126.5,
108.9, 71.4, 64.8, 64.2, 47.6, 40.5, 35.3, 23.4; IR (KBr): n=
1H), 1.97–1.85 (m, 2H), 1.82–1.64 (m, 2H); 13C NMR
(100 MHz, CDCl3): d=143.2, 137.6, 128.8, 128.1, 127.1,
125.1, 108.8, 71.3, 64.7, 64.1, 47.4, 40.4, 35.2, 23.2, 21.6; IR
(KBr): n=3522, 2930, 2882, 1122, 1091, 703 cmÀ1; HR-MS
(ESI): m/z=249.1490, calcd. for C15H21O3 ([M+H]+):
249.1485; HPLC (Chiralcel AD-H; eluent, n-hexane/2-prop-
anol=85:15; pressure, 44 bar; flow rate, 1.0 mLminÀ1; detec-
tion, 220 nm light): tR =6.46 min (7S,8S), tR =8.84 min
(7R,8R).
3494, 2917, 2887, 1496, 1168, 1123, 1091, 852, 747, 698 cmÀ1
;
HR-MS (ESI): m/z=257.1150, calcd. for C14H18O3Na ([M+
Na]+): 257.1148; HPLC (Chiralcel AD-H; eluent, n-hexane/
2-propanol=85:15; pressure, 47 bar; flow rate, 1.0 mLminÀ1
;
detection, 210 nm light): tR =7.18 min (7S,8S), tR =8.81 min
(7R,8R).
ACHUTNGREN(NUG 7S,8S)-8-(3-Methoxyphenyl)-1,4-dioxaspiroACHTUNTGREN[NUGN 4.5]decan-7-
A
E
ol (2g): White solid; mp 114–1168C; yield: 92%; 98% ee;
(2c): White solid; mp 114–1168C; yield: 94%; 99% ee; [a]2D0:
+66.0 (c 1.0, CHCl3); Rf =0.5 (PE:EA=1:1). 1H NMR
(400 MHz, CDCl3): d=7.22 (d, J=7.2 Hz, 2H), 7.14 (d, J=
7.6 Hz, 2H), 4.25–3.84 (m, 5H), 3.31 (s, 1H), 2.69 (d, J=
12.8 Hz, 1H), 2.33 (s, 3H), 2.41–2.18 (m, 1H), 2.11 (d, J=
13.6 Hz, 1H), 2.02–1.87 (m, 2H), 1.84–1.67 (m, 2H);
13C NMR (100 MHz, CDCl3): d=140.3, 135.8, 129.0, 127.9,
108.9, 71.4, 64.8, 64.2, 47.1, 40.4, 35.2, 23.4, 21.1. IR (KBr):
[a]2D0: +64.4 (c 1.0, CHCl3). H NMR (400 MHz, CDCl3): d=
1
7.23 (t, J=7.8 Hz, 1H), 6.93–6.84 (m, 2H), 6.76 (dd, J=8.0,
2.4 Hz, 1H), 4.17–3.93 (m, 5H), 3.79 (s, 3H), 3.32 (d, J=
8.8 Hz, 1H), 2.68 (dt, J=13.2, 2.4 Hz, 1H), 2.25 (qd, J=
13.2, 3.6 Hz, 1H), 2.10 (dt, J=14.0, 3.0 Hz, 1H), 2.00–1.88
(m, 2H), 1.83–1.69 (m, 2H); 13C NMR (100 MHz, CDCl3):
d=159.5, 145.0, 129.1, 120.5, 114.0, 111.6, 108.8, 71.3, 64.8,
64.2, 55.2, 47.5, 40.4, 35.2, 23.3; IR (KBr): n=3309, 2938,
3481, 2959, 1515, 1449, 1416, 1167, 1123, 1107, 850, 820 cmÀ1
;
2882, 1600, 1540, 1489, 1263, 1122, 1091, 1040, 699 cmÀ1
;
HR-MS (ESI): m/z=249.1484, calcd. for C15H21O3 ([M+
HR-MS (ESI): m/z=265.1437, calcd for C15H21O4 ([M+
H]+): 249.1485; HPLC (Chiralcel AD-H; eluent, n-hexane/
H]+): 265.1434; HPLC (Chiralcel AD-H; eluent, n-hexane/
2-propanol=85:15; pressure, 46 bar; flow rate, 1.0 mLminÀ1
;
2-propanol=80:20; pressure, 50 bar; flow rate, 1.0 mLminÀ1
;
detection, 220 nm light): tR =7.56 min (7S,8S), tR =9.60 min
(7R,8R).
detection, 220 nm light): tR =7.66 min (7S,8S), tR =10.42 min
(7R,8R).
A
E
ACHUTGTNREN(NUG 7S,8S)-8-(2-Methylphenyl)-1,4-dioxaspiroACHTUNGTERN[NUGN 4.5]decan-7-ol
decan-7-ol (2d): White solid; mp 120–1228C; yield: 98%;
(2h): White solid; mp 99–1018C; yield: 68%; 81% ee; [a]2D0:
+67.0 (c 1.0, CHCl3); Rf =0.5 (PE:EA=1:1). 1H NMR
98% ee; [a]2D0: +67.2 (c 1.0, CHCl3); Rf =0.5 (PE:EA=1:1).
Adv. Synth. Catal. 2013, 355, 1597 – 1604
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Gang Li et al.
FULL PAPERS
(400 MHz, CDCl3): d=7.39 (d, J=7.6 Hz, 1H), 7.24–7.08
(m, 3H), 4.12–3.93 (m, 5H), 3.30 (d, J=8.8 Hz, 1H), 2.95
(dt, J=12.8, 2.8 Hz, 1H), 2.44–2.28 (m, 1H), 2.33ACTHNUGRTNEUNG(s, 3H),
Enantioselective Synthesis of (À)-a-Lycorane
Compound 5: Diethyl azodicarboxylate (3.1 mL, 20 mmol)
was added dropwise via syringe to a solution of 2a (2.78 g,
10 mmol) and triphenylphosphine (5.24 g, 20 mmol) in THF
(100 mL) under nitrogen atmosphere at À408C. After stir-
ring for 5 min, diphenyl phosphorazidate (2.2 mL, 10 mmol)
was slowly added. The mixture was allowed to warm to
room temperature and stirred for additional 3 h to complete
the reaction (TLC detected, EtOAc/petroleum ether=1:4).
The reaction mixture was concentrated under vacuum. The
residue was purified by column chromatography on silica
gel with petroleum ether/ethyl acetate (10:1) as the eluent
to provide a mixture of products including the desired azide
product and the hydroxy group eliminated product; yield:
2.8 g (white solid; the azide and eliminated products were
difficult to separate by column chromatography).
The mixture was dissolved in methanol (50 mL).To the so-
lution was added 10% Pd/C (0.28 g, 10 wt%), and the mix-
ture was stirred under 5 atm of hydrogen at room tempera-
ture for 10 h to complete the hydrogenation. The Pd catalyst
was removed by filtration, washed with methanol (2ꢂ
20 mL), and the filtrate was concentrated under vacuum.
The residue was purified by a column chromatography on
silica gel with ethyl acetate/triethylamine (10:1) as the
eluent to provide the product 5 as a white solid; yield: 2.1 g
(75% for two steps); mp 102–1048C; [a]2D0: À17.0 (c 1.0,
CHCl3); Rf =0.2 (EA:Et3N=50:1). 1H NMR (400 MHz,
D2O): d=7.03–6.72 (m, 3H), 5.98 (s, 2H), 4.22–3.95 (m,
4H), 3.43 (td, J=12.0, 4.0 Hz, 1H), 2.67 (td, J=11.2, 3.6 Hz,
1H), 2.28 (dt, J=12.4, 3.2 Hz, 1H), 2.01–1.70 (m, 5H);
13C NMR (100 MHz, D2O): d=147.8, 146.6, 133.9, 121.3,
109.0, 108.1, 107.7, 101.2, 64.3, 64.2, 52.8, 46.9, 38.5, 33.4,
29.5; IR (KBr): n=2942, 2883, 1504, 1487, 1439, 1247, 1122,
1038, 934, 808 cmÀ1; HR-MS (ESI): m/z=278.1393, calcd.
for C15H20NO4 ([M+H]+): 278.1387.
2.12 (dt, J=14.0, 3.0 Hz, 1H), 2.01–1.90 (m, 2H), 1.82–1.62
(m, 2H); 13C NMR (100 MHz, CDCl3): d=141.0, 135.3,
130.3, 127.8, 126.3, 125.9, 108.9, 69.3, 64.8, 64.2, 43.2, 40.7,
35.6, 23.3, 19.7; IR (KBr): n=3519, 2930, 2886, 1445, 1125,
1081, 748 cmÀ1; HR-MS (ESI): m/z=249.1487, calcd. for
C15H21O3 ([M+H]+): 249.1485; HPLC (Chiralcel AD-H;
eluent, n-hexane/2-propanol=90:10; pressure, 42 bar; flow
rate, 1.0 mLminÀ1; detection, 220 nm light): tR =7.56 min
(7S,8S), tR =10.15 min (7R,8R).
ACHTUNGTRENNUNG(7S,8S)-8-(2-Methoxyphenyl)-1,4-dioxaspiroACHTUTGNREN[NUGN 4.5]decan-7-
ol (2i): White solid; mp 90–928C; yield: 78%; 57% ee; [a]2D0:
+52.0 (c 0.9, CHCl3); Rf =0.5 (PE:EA=1:1). 1H NMR
(400 MHz, CDCl3): d=7.33 (d, J=7.6 Hz, 1H), 7.20 (t, J=
7.4 Hz, 1H), 6.94 (t, J=7.6 Hz, 1H), 6.85 (d, J=8.0 Hz,
1H), 4.17 (d, J=9.2 Hz, 1H), 4.09–3.94 (m, 4H), 3.82 (s,
3H), 3.28–3.12 (m, 2H), 2.28 (qd, J=13.2, 3.6 Hz, 1H), 2.08
(dt, J=14.0, 2.8 Hz, 1H), 2.03–1.88 (m, 2H), 1.81–1.65 (m,
2H); 13C NMR (100 MHz, CDCl3): d=156.7, 131.3, 128.4,
127.3, 120.4, 110.0, 109.1, 69.3, 64.8, 64.2, 55.3, 40.4, 39.8,
35.5, 22.6; IR (KBr): n=3525, 2945, 2886, 1600, 1492, 1238,
1126, 1082, 1029, 753 cmÀ1; HR-MS (ESI): m/z=265.1434,
calcd. for C15H21O4 ([M+H]+): 265.1434; HPLC (Chiralcel
AD-H; eluent, n-hexane/2-propanol=90:10; pressure,
46 bar; flow rate, 1.0 mLminÀ1; detection, 220 nm light): tR =
8.82 min (7S,8S), tR =12.49 min (7R,8R).
ACHTUNGTRENNUNG(7S,8S)-8-(3,4-Dimethoxyphenyl)-1,4-dioxaspiroCAHTUNGTRENN[UGN 4.5]-
decan-7-ol (2j): White solid; mp 134–1368C; yield: 95%;
96% ee; [a]2D0: +55.6 (c 0.9, CHCl3); Rf =0.5 (PE:EA=1:1).
1H NMR (400 MHz, CDCl3): d=6.91–6.77 (m, 3H), 4.15–
3.93 (m, 5H), 3.87 (s, 3H), 3.85 (s, 3H), 3.29 (d, J=8.8 Hz,
1H), 2.65 (dt, J=13.2, 2.8 Hz, 1H), 2.22 (qd, J=13.2,
4.0 Hz, 1H), 2.10 (dt, J=14.0, 3.0 Hz, 1H), 2.00–1.86 (m,
2H), 1.83–1.63 (m, 2H); 13C NMR (100 MHz, CDCl3): d=
148.7, 147.6, 136.1, 119.9, 111.5, 111.1, 108.9, 71.5, 64.8, 64.2,
56.0, 55.9, 47.1, 40.4, 35.3, 23.8; IR (KBr): n=3523, 2933,
Compound 6: A mixture of 5 (1.9 g, 7.0 mmol) and para-
AHCTUNGTREGfNNNU ormaldehyde (210 mg, 7.0 mmol) dissolved in acetic acid
(70 mL) was heating at 608C for 20 h. Then the reaction
mixture was poured into ice water, basified with K2CO3
(powder). The mixture was extracted with CH2Cl2 (5ꢂ
40 mL). The combined organic phase was dried with anhy-
drous Na2SO4 and concentrated under vacuum. The residue
was purified by a column chromatography on silica gel with
ethyl acetate/triethylamine (20:1) as the eluent to provide
the product 6 as a white solid; yield: 1.9 g (95%); mp 148–
1508C; [a]2D0: À135 (c 1.0, CHCl3); Rf =0.3 (EA:NEt3 =
2834, 1517, 1456, 1263, 1141, 1119, 1087, 1028, 845 cmÀ1
;
HR-MS (ESI): m/z=317.1363, calcd. for C16H22O5Na ([M+
Na]+): 317.1359; HPLC (Chiralcel AD-H; eluent, n-hexane/
2-propanol=75:25; pressure, 54 bar; flow rate, 1.0 mLminÀ1
;
detection, 210 nm light): tR =11.54 min (7S,8S), tR =
13.95 min (7R,8R).
ACHTUNGTRENNUNG(7S,8S)-8-(7-Methoxybenzo[d]ACHTUNGTRNE[NUGN 1,3]dioxol-5-yl)-1,4-dioxa-
1
50:1). H NMR (400 MHz, CDCl3): d=6.77 (s, 1H), 6.47 (s,
spiroACHTUNGTRENNUNG[4.5]decan-7-ol (2k): White solid; mp 145–1478C; yield:
1H), 5.97–5.81 (m, 2H), 4.11 (d, J=16.0 Hz, 1H), 4.06–3.83
(m, 5H), 2.71 (td, J=11.0, 3.2 Hz, 1H), 2.36–2.19 (m, 2H),
2.00 (dt, J=12.4, 2.8 Hz, 1H), 1.95–1.84 (m, 1H), 1.71 (td,
J=13.6, 4.4 Hz, 1H), 1.59 (t, J=12.4 Hz, 1H), 1.51–1.33 (m,
2H); 13C NMR (101 MHz, CDCl3): d=146.2, 145.8, 130.8,
128.9, 108.9, 106.1, 106.0, 100.7, 64.5, 64.4, 56.6, 49.3, 43.0,
42.4, 35.2, 26.6; IR (KBr): n=3468, 2924, 1711, 1503, 1227,
1038, 741 cmÀ1; HR-MS (ESI): m/z=290.1391, calcd. for
C16H20NO4 ([M+H]+): 290.1387.
Compound 7: To the stirred solution of 6 (1.9 g, 6.7 mmol)
in CH2Cl2 (50 mL), triethylamine (1.4 mL, 10.0 mmol) and
2-bromoacetyl chloride (0.7 mL, 8.0 mmol) were added and
the mixture was stirred at room temperature for 1 h. Satu-
rated aqueous NaHCO3 (20 mL) was added to quench the
reaction and the aqueous phase was extracted with CH2Cl2
87%; 96% ee; [a]D20: +54.5 (c 1.0, CHCl3); Rf =0.5
1
(PE:EA=1:1). H NMR (400 MHz, CDCl3): d=6.53 (d, J=
0.9 Hz, 1H), 6.47 (d, J=0.9 Hz, 1H), 5.99–5.87 (m, 2H),
4.11–3.93 (m, 5H), 3.89 (s, 3H), 3.32 (d, J=9.2 Hz, 1H),
2.61 (dt, J=13.2, 2.4 Hz, 1H), 2.24–2.04 (m, 2H), 1.97–1.86
(m, 2H), 1.80–1.65 (m, 2H); 13C NMR (100 MHz, CDCl3):
d=148.7, 143.3, 138.2, 133.8, 108.8, 107.5, 102.4, 101.3, 71.5,
64.8, 64.2, 56.7, 47.6, 40.5, 35.3, 23.8; IR (KBr): n=3502,
2942, 2888, 1633, 1509, 1428, 1125, 1089, 1044, 825 cmÀ1
;
HR-MS (ESI): m/z=331.1151, calcd. for C16H20O6Na ([M+
Na]+): 331.1152; HPLC (Chiralcel AD-H; eluent, n-hexane/
2-propanol=75:25; pressure, 51 bar; flow rate, 1.0 mLminÀ1
;
detection, 220 nm light): tR =12.26 min (7S,8S), tR =
14.39 min (7R,8R)
1602
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ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2013, 355, 1597 – 1604

Catalytic Asymmetric Hydrogenation of a-Arylcyclohexanones and Total Synthesis of (À)-a-Lycorane
3.76 (d, J=15.2 Hz, 1H), 3.10 (q, J=8.4 Hz, 1H), 2.81 (dt,
(3ꢂ20 mL). The combined organic phase was dried with an-
hydrous Na2SO4 and concentrated under vacuum. The resi-
due was dissolved in THF (50 mL) and cooled to 08C by
ice-water bath, and 2N HCl (60 mL) was added over
a period of 10 min. The reaction mixture was allowed to
warm to room temperature and stirred for 10 h. Then the
mixture was extracted with ethyl acetate (3ꢂ40 mL). The
combined organic phase was dried with anhydrous Na2SO4
and concentrated under vacuum. The residue was purified
by column chromatography on silica gel with petroleum
ether/ethyl acetate (2:1 to 1:2) as the eluent to provide
product 7 as a white solid; yield: 2.2 g (89% for two steps);
mp 218–2208C (decomposed); [a]2D0: À39.8 (c 1.0, CHCl3);
Rf =0.4 (PE:EA=1:1). 1H NMR (400 MHz, CDCl3): d=
6.88–6.71 (m, 2H), 5.97 (d, J=4.8 Hz, 2H), 4.53 (d, J=
14.8 Hz, 1H), 4.33 (d, J=14.4 Hz, 1H), 4.17–3.80 (m, 2H),
3.69 (t, J=10.6 Hz, 1H), 3.31 (d, J=13.6 Hz, 1H), 2.90 (t,
J=10.8 Hz, 1H), 2.75–2.57 (m, 2H), 2.57–2.31 (m, 2H), 1.87
(qd, J=12.8, 4.8 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=
207.4, 165.6, 147.8, 146.4, 131.2, 128.6, 107.0, 104.9, 101.3,
56.6, 47.4, 45.0, 40.3, 40.0, 26.8, 24.9; IR (KBr): n=3291,
J=9.2, 2.8 Hz, 1H), 2.53–2.30 (m, 3H), 2.28–2.15 (m, 1H),
1.94–1.51 (m, 6H), 1.24–1.07 (m, 1H); 13C NMR (100 Hz,
CDCl3): d=146.2, 145.5, 135.1, 128.9, 107.0, 104.6, 100.8,
64.6, 54.7, 54.3, 37.0, 34.0, 28.0, 26.2, 25.0, 21.0; IR (KBr):
n=2921, 2872, 1504, 1481, 1239, 1039, 935, 847 cmÀ1; HR-
MS (ESI): m/z=258.1489, calcd. for C16H20NO2 ([M+H]+):
258.1489; HPLC (Chiralcel OJ-H; eluent, n-hexane/2-propa-
nol=70:30; pressure, 60 bar; flow rate, 1.0 mLminÀ1; detec-
tion, 220 nm light): tR =6.35 min (minor), tR =7.33 min
(major).
Acknowledgements
We thank the National Natural Science Foundation of China,
the National Basic Research Program of China (973 Pro-
gram, No.2012CB821600), “111” Project of the Ministry of
Education of China (Grant No. B06005), and Program for
New Century Excellent Talents in University (NCET-08-
0292) for financial support.
2890, 1715, 1646, 1505, 1485, 1419, 1276, 1036, 931, 733 cmÀ1
;
HR-MS (ESI): m/z=388.0153, calcd. for C16H16BrNNaO4
([M+Na]+): 388.0155.
Compound 8: A mixture of 7 (730 mg, 2.0 mmol) and t-
BuOK (448 mg, 4.0 mmol) in t-BuOH (20 mL) was stirred at
room temperature under a nitrogen atmosphere for 2 h. The
reaction was quenched with 1N HCl (40 mL) and extracted
with CH2Cl2 (4 ꢂ 20 mL). The combined organic phase was
dried with anhydrous Na2SO4 and concentrated under
vacuum. The residue was purified by a column chromatogra-
phy on silica gel with petroleum ether/ethyl acetate (3:1 to
1:1) as the eluent to provide the product 8 as a white solid;
yield: 380 mg (67%); mp 195–1978C (decomposed); [a]2D0:
À47.8 (c 1.0, CHCl3); Rf =0.3 (PE:EA=1:1). 1H NMR
(400 MHz, CDCl3): d=6.73 (s, 1H), 6.62 (s, 1H), 6.02–5.88
(m, 2H), 4.97 (d, J=17.2 Hz, 1H), 4.25 (d, J=17.2 Hz, 1H),
3.85 (dd, J=10.4, 9.2 Hz, 1H), 3.33 (q, J=9.6 Hz, 1H),
2.82–2.42 (m, 6H), 1.94–1.79 (m, 1H); 13C NMR (100 MHz,
CDCl3): d=209.3, 171.9, 147.1, 147.0, 129.4, 125.4, 106.7,
105.3, 101.4, 59.9, 43.6, 43.3, 38.9, 37.5, 31.8, 22.8; IR (KBr):
n=3290, 3212, 1710, 1682, 1557, 1540, 1506, 1120, 1036,
References
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C16H15NO4Na ([M+Na]+): 308.0893.
(À)-a-Lycorane: stirred mixture of
;
HR-MS (ESI): m/z=308.0895, calcd. for
A
8
(142 mg,
0.5 mmol) and tosylhydrazone (130 mg, 0.7 mmol) in THF
(5 mL) was refluxed for 4 h under nitrogen atmosphere. The
reaction mixture was cooled to 08C and LiAlH4 (38 mg,
1.0 mmol) was added. The mixture was stirred for 1 h at
room temperature and then refluxed for 3 h. The reaction
mixture was cooled to 08C and quenched with water
(0.5 mL) carefully. The mixture was diluted with saturated
aqueous NaHCO3 (10 mL) and extracted with ethyl acetate
(3ꢂ20 mL). The combined extracts were washed with brine,
dried over anhydrous Na2SO4 and concentrated under
vacuum. The residue was purified by chromatography on
silica gel with ethyl acetate/triethylamine (50:1) as the
eluent to provide the (À)-a-lycorane as a white solid; yield:
97 mg (74%); mp 89–918C; 99% ee; [a]2D0: À29.8 (c 1.0,
EtOH) {lit.[16a] [a]D22: À31.0 (c 0.99, EtOH)}; Rf =0.2
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1
(EA:Et3N=50:1). H NMR (400 MHz, CDCl3): d=6.69 (s,
1H), 6.58 (s, 1H), 5.88 (s, 2H), 4.09 (d, J=15.2 Hz, 1H),
Adv. Synth. Catal. 2013, 355, 1597 – 1604
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1603

Gang Li et al.
FULL PAPERS
[10] For reviews on the asymmetric hydrogenation of race-
mic a-substituted ketones via DKR, see: a) H. Pellissi-
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dron 2008, 64, 1563. For selected recent papers on
asymmetric hydrogenation of racemic a-substituted ke-
tones via DKR, see: c) M. Akashi, N. Arai, T. Inoue, T.
Ohkuma, Adv. Synth. Catal. 2011, 353, 1955; d) W.-J.
Bai, J.-H. Xie, Y.-L. Li, S. Liu, Q.-L. Zhou, Adv. Synth.
Catal. 2010, 352, 81; e) T. Hibino, K. Makino, T. Sugiya-
ma, H. Takaya, ChemCatChem 2009, 1, 237; f) S. Liu,
J.-H. Xie, W. Li, W.-L. Kong, L.-X. Wang, Q.-L. Zhou,
Org. Lett. 2009, 11, 4994; g) J.-H. Xie, S. Liu, W.-L.
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[11] The cyclohexanone with an ethylene ketal group at its
3 position is sensitive under base conditions, forming 3-
alkoxycyclohex-2-enone. See T. K. M. Shing, C. M. Lee,
H. Y. Ho, Tetrahedron 2004, 60, 9179. The poor solubil-
ity of 1a in i-PrOH is also a major reason for the for-
mation of by-product 4a. The poor solubility of com-
pound 1a in i-PrOH slows down the reaction rate of
the hydrogenation. At the same time, the base-sensitive
compound 1a is converted to by-product 4a. When tol-
uene is added as a co-solvent, the solubility of com-
pound 1a increases remarkably and the hydrogenation
reaction speeds up. As a result, the formation of by-
product 4a is suppressed.
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periment suggested that the hydrogenation of sub-
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