Structure influence of chiral 1,1′-biscarboline-N,N′-dioxide on the enantioselective allylation of aldehydes with allyltrichlorosilanes

Article abstract of DOI:10.1016/j.tet.2012.06.042

A series of new axially chiral 1,1′-biscarboline-N,N′-dioxide Lewis base organocatalysts were examined in the asymmetric allylation of aldehydes with allyltrichlorosilane. The chiral catalysts (R)-1a-e bearing ester groups in 3,3′ position provided good y

Full text of DOI:10.1016/j.tet.2012.06.042

Tetrahedron 68 (2012) 6829e6836
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Structure influence of chiral 1,10-biscarboline-N,N0-dioxide on the enantioselective
allylation of aldehydes with allyltrichlorosilanes
,
,
b
,
b,d
Bing Bai b c, Hua-Jie Zhu a , Wei Pan
*
a College of Life Science, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of Ministry of Education, Hebei University, Baoding 071002, PR China
b State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academic of Sciences, Lanhei Road 132#, Kunming 650204,
PR China
c School of Food & Biological Engineering, Zhengzhou University of Light Industry, Zhengzhou 450002, PR China
d Graduate School of CAS, Beijing 100049, PR China
a r t i c l e i n f o
a b s t r a c t
A series of new axially chiral 1,10-biscarboline-N,N0-dioxide Lewis base organocatalysts were examined in
the asymmetric allylation of aldehydes with allyltrichlorosilane. The chiral catalysts (R)-1aee bearing
ester groups in 3,30 position provided good yields of the homoallyl alcohols with excellent enantiose-
lectivities up to 99% for a broad substrate scope that covers aliphatic, aromatic, heteroaromatic, and
Article history:
Received 20 April 2012
Received in revised form 4 June 2012
Accepted 8 June 2012
Available online 15 June 2012
a,b-unsaturated aldehydes. Solvent effects on the conversion and enantioselectivity were elucidated, and
CH2Cl2 proved to be the optimal solvent for the reactions. In addition, the allylation with crotyltri-
chlorosilane was explored and the result showed that anti-isomer was favored from (E)-crotyltri-
chlorosilane with complete diastereoselectivity.
Keywords:
Biscarboline
N,N0-Dioxide
Ó 2012 Elsevier Ltd. All rights reserved.
Allylation
Enantioselective catalysis
1. Introduction
problem of the Lewis base catalyzed allylation: the substrate scope.
A wide range of aliphatic, aromatic, heteroaromatic, and a,b-un-
Asymmetric allylation of aldehydes has been one of the most
efficient methods to form chiral homoallylic alcohols since allyla-
tion of carbonyl compound with allylsilane was first reported by
Sakurai.1 In the pioneer studies, Hoffmann, Roush, Brown, Masa-
mune, and Corey have made important contributions to this field
utilizing chiral allylboranes and allylboronates.2 In recent years,
chiral catalysts such as binaphthyl-derivatives, chiral phosphor-
amides, chiral formamides, and chiral N-oxide have been engaged
in enantioselective allylation of aldehydes and ketones.3,4 Bipyr-
idine N,N0-dioxides are of special interest in cases where the
bipyridine moiety is a part of a rigid skeleton and the N-oxides are
powerful electron-pair donors. Since Nakajima’s report that axially
chiral 2,20-bipyridine N,N0-dioxides are effective as catalysts for the
asymmetric allylation,5 the class of 2,20-bipyridine N,N0-dioxide
derivatives has attracted considerable attention by Hayashi,6 Mal-
kov,7 Denmark,8 Kotora,9 and others.10 In our previous work, we
have developed a new axially chiral Lewis base catalysts (R)-1a with
the biscarboline framework for enantioselective allylation (Fig. 1).11
The use of this type of the catalyst could overcome the common
saturated aldehydes can be catalyzed by (R)-1a and high enantio-
selectivity (up to 91e99% ee) with low catalyst loading (1 mol %)
* Corresponding author. Tel./fax: þ86 312 5994812; e-mail addresses: zhuhuajie@
hotmail.com, hjzhu@mail.kib.ac.cn (H.-J. Zhu).
Fig. 1. Chiral biscarboline N,N0-dioxide derivatives (R)-1aek.
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.06.042

6830
B. Bai et al. / Tetrahedron 68 (2012) 6829e6836
Table 1
were achieved. In this work we will examine the effect of sub-
stituent R in the catalysts on the catalytic activity of asymmetric
allylation of aldehydes. Meanwhile, the crotylation of benzaldehyde
with crotyltrichlorosilane was investigated as well.
Screening of catalystsa
2. Results and discussion
Entry
Cat.
Conv.b (%)
eec (%)
Config.d
General synthetic route to biscarboline N,N0-dioxide derivatives
is illustrated in Scheme 1. In synthesis of 2, the core precursor to
(R)-1, was previously described by us in detail.11 Hydrolysis of the 2
afforded carboxylic acid 3, which was esterified with different al-
cohols to form 4aed. The reduction of 2 using lithium aluminum
hydride afforded 5. Esterification of 5 produced the corresponding
6a, similarly, etherification of 5 produced the corresponding 6bec.
Oxidation of 4aed with m-chloroperoxybenzoic acid (m-CPBA)
afforded dioxide and monoxide (about ratio of 3:2) along with
traces of the unreacted biscarboline (<5%). Unlike 4aed, com-
pounds 6aec could be oxidized completely. The racemates were
resolved into enantiomers by using HPLC with a chiral column.
Absolute configuration of enantiomer was assigned by comparing
the experimental optical rotation (OR) values with the one that was
calculated using density functional theory (DFT), and (þ)-1aek
were assigned as (R) configuration.
1
2
3
4
5
6
7
8
(R)-1a
(R)-1b
(R)-1c
(R)-1d
(R)-1e
(R)-1f
(R)-1g
(R)-1h
(R)-1i
(R)-1j
(R)-1k
100
100
100
100
100
100
100
100
100
100
100
95
95
95
95
95
60
77
79
82
78
81
S
S
S
S
S
S
S
S
S
S
S
9
10
11
a
Reaction condition 7a (0.5 mmol), 8 (0.6 mmol), (R)-1 (1 mol %) as catalyst.
Estimated by recovering unreacted PhCHO.
ee was determined by chiral HPLC.
b
c
d
The configuration was determined by comparing optical rotation data and HPLC
retention times with literature.
Scheme 1. Synthesis of axially chiral catalysts. Conditions: (I) NaOH, CH3OH/H2O, reflux, 6 h; (II) SOCl2, ROH, 60 ꢁC, 12 h; (III) LiAIH4, THF, rt 1 h; (IV) for 6a: acyl halides, Et3N,
CH2Cl2, rt, 12 h; for 6b and 6c: halides, NaH, DMF, rt, 12 h; (V) m-CPBA, CH2Cl2, rt, 6e12 h.
Addition of allyltrichlorosilane 8 to benzaldehyde 7a was
carried out to test the enantioselectivity and reactivity of orga-
nocatalysts (R)-1aek in CH2Cl2 at about ꢀ80 ꢁC. Conversion and
ee value, as determined by HPLC, are summarized in Table 1. The
results indicated that the chiral catalysts (R)-1aek showed sur-
prising differences in chiral induction, although each of them
possesses biscarboline framework with a C2-symmetric axis. The
parent catalyst (R)-1a, bearing methyl ester substituent in 3,30-
position, gave product 9a in 100% conversion and 95% ee (entry
1). This exciting effect suggested that there be a connection be-
tween ester group and selectivity. As expected, catalysts (R)-
1bee, bearing larger substituents like ethyl ester and isopropyl
ester, afforded the product in comparable conversion and ee to
(R)-1a. Subsequently, we turned our attention to catalyst (R)-1f,
which is a reductive product of ester and characterized by its
alcohol group. Surprisingly, the enantioselectivity decreased to
60% even though 100% conversion was recorded using (R)-1f.
Considering the poor selectivity of (R)-1f, its esterifiable and
etherifiable products (R)-1gek were employed as a remedy.
However, 77e82% ee could not be a mark of an excellent catalyst.
Although more substituent has yet to be investigated, the ob-
served results reveals that the ester group in 3,30 position plays
an important role in the catalysis.
We had found that the (R)-1aee were the best catalysts in the
tests using N,N0-dioxides, further optimization of the reaction
conditions were conducted by examining the effect of solvents
(Table 2). At the outset we studied the allylation of benzaldehyde in
commonly used solvent CH2Cl2 (entry 1) and CH3CN (entry 4) with

B. Bai et al. / Tetrahedron 68 (2012) 6829e6836
6831
Table 3
(R)-1c. It proceeded with full conversion to give product (S)-9a with
Asymmetric allylation to aldehydes 7 catalyzed by (R)-1ca
ee of 95% and 90%, respectively. THF, toluene, Et2O, and EtOAc
provided the similarly good enantioselectivities as CH2Cl2 and
CH3CN but in low yields. Thus, CH2Cl2 was used to test the effect of
temperature on the ee. When the reaction temperature was ele-
vated from ꢀ80 ꢁC to ꢀ20 ꢁC, the enantioselectivity declined from
95% to 91% ee. From the results obtained so far, it seems that the
addition of allyltrichlorosilane 8 to benzaldehyde carried out in
CH2Cl2 at about ꢀ80 ꢁC is an optimal condition.
Entry Aldehyde
R
Product Yieldb (%) eec (%) Config.d
1
2
3
4
5
6
7
8
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
7m
7n
7o
7p
7q
Ph
9a
9b
9c
9d
9e
9f
9g
9h
9i
79
83
80
74
77
80
83
76
75
87
80
88
85
82
92
64
50
95
99
97
96
96
93
88
94
95
96
98
93
97
97
93
92
92f
(S)-(ꢀ)
4-MeOePh
3-MeOePh
3-ClePh
4-ClePh
3-NO2ePh
4-NO2ePh
3-FePh
4-CH3ePh
3,4-DiMeOePh 9j
2-Thiophenyl
2-Naphth
1-Naphth
(S)-(ꢀ)
(S)-(ꢀ)
(S)-(ꢀ)
(S)-(ꢀ)
(S)-(ꢀ)
(S)-(ꢀ)
(S)-(ꢀ)
(S)-(ꢀ)
(S)-(ꢀ)
(S)-(ꢀ)
(S)-(ꢀ)
(S)-(ꢀ)
(R)-(þ)
(S)-(ꢀ)e
(R)-(þ)
(S)-(ꢀ)
Table 2
Optimization of solventsa
9
10
11
12
13
14
15
16
17
9k
9l
Entry
Solvent
T (ꢁC)
Conv.b (%)
eec (%)
9m
9n
9o
9p
9q
1
2
3
4
5
6
7
8
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
THF
Toluene
EtOAc
Et2O
ꢀ80
ꢀ40
ꢀ20
ꢀ40
ꢀ80
ꢀ80
ꢀ60
ꢀ60
100
100
100
100
5
10
10
5
95
93
91
90
90
86
85
91
2,6-DiClePh
E-PhCH]CH2
PhCHeCH2
c-C6H11
a
Reaction condition: 7 (0.5 mmol), 8 (0.6 mmol), (R)-1c, (R)-1b (1 mol %) as
catalyst.
b
c
Isolated yield, note that some of the products are fairly volatile.
ee was determined by chiral HPLC.
The configuration was determined by comparing optical rotation data and HPLC
a
Reaction condition: 7a (0.5 mmol), 8 (0.6 mmol), (R)-1c (1 mol %) as catalyst.
Estimated by recovering unreacted PhCHO.
ee was determined by chiral HPLC.
d
b
c
retention times with literatures.
e
Compound 9o is levorotatory in CHCl3 and dextrorotatory in Et2O.
ee was determined by formation of 3,5-dinitrobenzoate ester of 9q.
f
In the next step, catalytic activity and enantioselectivity of the
Table 4
(R)-1c (1 mol %) were tested in the addition of allyltrichlorosilane to
variously substituted aldehydes 7 under the optimal conditions
(Table 3). To our delight, the reaction catalyzed by (R)-1c was found
to be very applicable to a variety of aromatic, heteroaromatic, and
aliphatic aldehydes, which was similar to (R)-1a. Aromatic alde-
hydes include electron-donating and electron-withdrawing sub-
stituents (entries 1e10) gave the expected products 9aek in good
yields and excellent enantioselectivities up to 99%. Further addi-
tions to other aldehydes bearing heteroaromatic (entry 11), steric
Asymmetric allylation of benzaldehyde with allyltrichlorosilanes catalyzed by (R)-
1a, (R)-1c
hindrance (entries 12e14), and
a,b-unsaturated (entry 15) were
Entry
Cat.
Allyltrichlorosilane
Allylic alcohol
Yielda (%)
also found to be efficient with high enantioselectivity of 93e98%. It
was surprised to find that aliphatic aldehydes, especially saturated
aldehydes, which always involves in low enantioselectivities and
reaction rates,6a,7a,8d afforded the corresponding product in good
yield with considerable 92% ee (entries 15e17). It is the highest
reported to date for enantioselective allylation of aliphatic alde-
hydes catalyzed by a chiral N-oxide Lewis base.
Encouraged by the excellent results obtained from addition of
allyltrichlorosilane to various aldehydes, the allylation with cro-
tyltrichlorosilane (prepared as an 86:14 trans/cis mixture by the
CuCl-catalyzed reaction of crotyl chloride with HSiCl3) and various
types of allyltrichlorosilanes was explored to expand the scope of
the reaction and to explain the mechanism (Table 4). It was found
that anti-isomer was produced from (E)-crotyltrichlorosilane with
complete diastereoselectivity and good enantioselectivity (entries
eeb (%)
Config.
1S,2S
1c
2
(R)-1a
(R)-1c
10a R1¼CH3, R2¼R3¼H
10a R1¼CH3, R2¼R3¼H
11ad
64
94 (anti),
95 (syn)
94 (anti),
95 (syn)
96
11a
59
1S,2S
3e
4
5
6
7
(R)-1a
(R)-1c
(R)-1a
(R)-1c
(R)-1a
(R)-1c
10b R1¼Ph, R2¼R3¼H
10b R1¼Ph, R2¼R3¼H
10c R1¼R2¼CH3, R3¼H
10c R1¼R2¼CH3, R3¼H
10d R1¼R2¼H, R3¼CH3
10d R1¼R2¼H, R3¼CH3
11bf
11b
11c
11c
11d
11d
72
88
45
50
19
23
1S,2R
95
1S,2R
94
96
82
80
S
S
S
S
8
a
Isolated yield.
b
c
d
e
f
Determined by HPLC.
E/Z¼86:14.
anti/syn¼86:14.
E/Z>99:1.
anti/syn>99:1.
1 and 2).
similar to (E)-crotyltrichlorosilane (entries 3 and 4). Meanwhile,
-dimethyltrichlorosilane 10c, which has steric hindrance between
R1 and R2 position, gave the enantioselectivities about 96% ee
(entries 5 and 6). However, when -substituted allyltrichlorosilane
10d was employed, the decrease of the enantioselectivities to 82%
ee (entries 7 and 8) was observed.
The observed result above can be rationalized based on the
ZimmermaneTraxler model, according to which the reaction pro-
ceeds through a six-membered chair-like transition state. The
g-(E)-phenyltrichlorosilane gave a good enantioselectivity
controlling factor based on this model is the avoidance of destabi-
lizing 1,3-diaxial interactions in the cyclic transition state (Fig. 2).
Thus, E-allyltrichlorosilanes 10a and 10b give rise to corresponding
anti diastereomer. Obviously, it coincides with the general accep-
tance viewon the reaction mechanism proposed by Nakajima. It was
suggested that N-oxide functional group possess a notable electron-
pair donor property, and exhibits a significant nucleophilicity to-
ward the silicon atom in the transition state structures. This pro-
cedure involved a chair-like six-membered cyclic transition state.
g
b

6832
B. Bai et al. / Tetrahedron 68 (2012) 6829e6836
pressure to give 4a as white solid, 0.65 g, yield 96%. IR (KBr) n 3440,
1703, 1620, 1328, 1260, 1038, 744 cmꢀ1. MS-ESI, m/z 507 [MþH]þ.
HRMS m/z calcd for C30H26N4O4Na [MþNa]þ 529.1857, found
529.1853. 1H NMR (400 MHz, CDCl3)
d
¼1.45 (t, J¼7.0 Hz, 3Hꢂ2), 3.51
(s, 3Hꢂ2, NCH3), 4.50 (m, 2Hꢂ2), 7.40 (t, J¼7.5 Hz, 1Hꢂ2), 7.47 (d,
J¼8.2 Hz, 1Hꢂ2), 7.66 (t, J¼7.6 Hz, 1Hꢂ2), 8.30 (d, J¼7.8 Hz, 1Hꢂ2),
9.01 (s, 1Hꢂ2). 13C NMR (100 MHz, CDCl3)
d 14.5, 32.9, 61.5, 110.0,
117.8, 120.8, 121.3, 121.7, 129.1, 130.6, 136.2, 137.6, 139.9, 142.9, 165.9.
4.2.3. Diisopropyl 9H,90H-1,10-bipyrido[3,4-b]indole-3,30-dicarbox-
Fig. 2. The proposed transition state structure.
ylate (4b). Following the general procedure, 4b was obtained as
a white solid, yield 97%. IR (KBr) n 3428,1722,1699,1257,1104,1039,
3. Conclusion
741 cmꢀ1
C
.
MS-ESI, m/z 535 [MþH]þ. HRMS m/z calcd for
In conclusion, N,N0-dioxides based on the framework of biscar-
boline have been prepared and their potentiality as organocatalyst
has been demonstrated in the addition of allyltrichlorosilanes to al-
dehydes. The desired alcohol products were obtained in high yields
and good to excellent enantioselectivities using a broad range of al-
iphatic, aromatic, heteroaromatic, and unsaturated aldehydes. The
preliminary structureeactivity relationship study reveals that the
ester group in 3,30 position play an important role in catalyzing the
reaction. Moreover, the complete diastereoselectivity verified that
the allylation catalyzed by (R)-1 proceeds via a six-membered chair-
like transition state. In a way, this work furnishes a new dimension
for design of chiral Lewis base catalyst that was not previously at-
tentive. Furtherexperiments todiversifythestructureof the catalysts
and their applications in other reactions are currently in progress.
32H31N4O4 [MþH]þ 535.2345, found 535.2349. 1H NMR (400 MHz,
CDCl3)
d
1.45 (d, J¼6.2 Hz, 6Hꢂ2), 3.57 (s, 3Hꢂ2, NCH3), 5.37 (m,
1Hꢂ2), 7.40 (t, J¼7.5 Hz, 1Hꢂ2), 7.48 (d, J¼8.3 Hz, 1Hꢂ2), 7.66 (t,
J¼7.5 Hz, 1Hꢂ2), 8.30 (d, J¼7.9 Hz, 1Hꢂ2), 9.00 (s, 1Hꢂ2). 13C NMR
(100 MHz, CDCl3)
d 22.0, 33.2, 68.9, 110.1, 117.4, 120.6, 121.3, 121.6,
129.0, 130.5, 136.4, 137.5, 140.1, 143.0, 165.3.
4.2.4. Dibutyl 9,90-dimethyl-9H,90H-1,10-bipyrido[3,4-b]indole-3,30-
dicarboxylate (4c). Following the general procedure, 4b was
obtained as white solid, yield 97%. IR (KBr) n 3436, 2956, 1707, 1260,
736 cmꢀ1
C
(500 MHz, CDCl3)
.
MS-ESI, m/z 585 [MþNa]þ. HRMS m/z calcd for
34H34N4O4Na [MþNa]þ 585.2477, found 585.2474. 1H NMR
d
0.98 (t, J¼7.4 Hz, 3Hꢂ2), 1.45e1.53 (m, 2Hꢂ2),
1.79e1.85 (m, 2Hꢂ2), 3.55 (s, 3Hꢂ2, NCH3), 4.42e4.53 (m, 2Hꢂ2),
7.41 (t, J¼7.5 Hz, 1Hꢂ2), 7.48 (d, J¼8.3 Hz, 1Hꢂ2), 7.67 (t, J¼7.4 Hz,
1Hꢂ2), 8.31 (d, J¼7.8 Hz, 1Hꢂ2), 9.01 (s, 1Hꢂ2). 13C NMR (125 MHz,
4. Experimental section
4.1. General methods
CDCl3)
d 13.8, 19.2, 30.9, 33.0, 65.3, 110.0, 117.6, 120.8, 121.3, 121.7,
129.1, 130.6, 136.2, 137.6, 140.0, 143.0, 165.9.
4.2.5. Diisopentyl 9,90-dimethyl-9H,90H-1,10-bipyrido[3,4-b]indole-
Thin layer chromatography was performed on TLC plates
(GF254). Flash column chromatography was performed with silica
gel (300e400 mesh). Enantiomeric excess was determined using
a Waters HPLC with a 2695 pump and a 2996 diode array detector.
Optical rotations were performed on an Optical Activity AA-55
polarimeter using a 10 cm cell with a Na 589 nm filter. IR spectra
were obtained with an FTIR spectrometer (Bruker Tensor 27). 1H
NMR and 13C NMR were recorded on a Bruker AV-400 or Bruker
DRX-500 spectrometer. The mass spectra were measured on an API
QSTAR Pulsar. All solvents for the reactions were of reagent grade
and were dried and distilled before use. Compounds 2 and 5
were prepared according to our reported method, and allyltri-
chlorosilanes 10aed were prepared according to the literatures.12
3,30-dicarboxylate (4d). Following the general procedure, 4d was
obtained as white solid, yield 98%. IR (KBr) n 3435, 2956, 1707, 1260,
1110, 737 cmꢀ1. MS-ESI, m/z 613 [MþNa]þ. HRMS m/z calcd for
C
36H38N4O4Na [MþNa]þ 613.2790, found 613.2790. 1H NMR
(500 MHz, CDCl3)
d
0.98 (d, J¼6.4 Hz, 6Hꢂ2), 1.73e1.75 (m, 2Hꢂ2),
1.78e1.83 (m, 1Hꢂ2), 3.57 (s, 3Hꢂ2, NCH3), 4.42e4.54 (m, 2Hꢂ2),
7.41 (t, J¼7.5 Hz, 1Hꢂ2), 7.48 (d, J¼8.3 Hz, 1Hꢂ2), 7.67 (t, J¼7.5 Hz,
1Hꢂ2), 8.31 (d, J¼7.8 Hz, 1Hꢂ2), 8.98 (s, 1Hꢂ2). 13C NMR (125 MHz,
CDCl3)
d 22.5, 25.2, 33.0, 37.5, 64.2, 110.0, 117.6, 120.8, 121.3, 121.7,
129.1, 130.6, 136.2, 137.6, 140.0, 143.0, 165.9.
4.2.6. (9,90-Dimethyl-9H,90H-1,10-bipyrido[3,4-b]indole-3,30-diyl)
bis(methylene)bis(3,3-dimethylbutanoate) (6a). To a stirring solu-
tion of 5 (0.5 g, 1.19 mmol) in CH2Cl2 was added Et3N (0.3 g,
2.96 mmol) followed by tert-butylacetyl chloride (0.38 g,
2.84 mmol) and DMAP (5 mol %). The reaction mixture was stirred
at rt for 12 h, washed with water, and dried over anhydrous Na2SO4.
The solvents were then evaporated under reduced pressure. The
residue was purified by chromatography (silica gel) eluting with
petroleum ether/EtOAc/CH2Cl2¼4:0.5:1 to give 6a as a white solid,
4.2. Preparation of biscarbolins
4.2.1. 9,90-Dimethyl-9H,90H-1,10-bipyrido[3,4-b]indole-3,30-dicarboxylic
acid (3). To a solution of 2 (2.7 g, 5.65 mmol) in CH3OH (40 mL) was
added 1 N aqueous sodium hydroxide solution (40 mL), and the
mixture was stirred at 60 ꢁC for 5 h. The brown solution was neu-
tralized with 3 M HCl to pH 3e4. The precipitate was collected by
filtration to give 3 as a pale yellow solid, 2.5 g, yield 98%. IR (KBr)
n
0.65 g, yield 89%. IR (KBr) n 3434, 2954, 1728, 1468, 1245, 1129, 1041,
3434, 2924, 1682, 1329, 1280, 743 cmꢀ1. MS-ESI, m/z 473 [MþNa]þ.
743 cmꢀ1
C
.
MS-ESI, m/z 619 [MþH]þ. HRMS m/z calcd for
HRMS m/z calcd for
C
26H18N4O4Na [MþNa]þ 473.1225, found
38H43N4O4 [MþH]þ 619.3284, found 619.3268. 1H NMR (400 MHz,
473.1230. 1H NMR (400 MHz, DMSO-d6):
d
¼3.47 (s, 3Hꢂ2, NCH3), 7.42
CDCl3)
d
1.06 (s, 9Hꢂ2), 2.33 (s, 2Hꢂ2), 3.30 (s, 3Hꢂ2, NCH3), 5.47 (s,
(t, J¼7.4 Hz, 1Hꢂ2), 7.66e7.78 (m, 2Hꢂ2), 8.58 (d, J¼7.9 Hz, 1Hꢂ2), 9.16
2Hꢂ2, ArCH2), 7.34 (t, J¼7.4 Hz, 1Hꢂ2), 7.40 (d, J¼8.0 Hz, 1Hꢂ2),
(s, 1Hꢂ2). 13C NMR (100 MHz, DMSO-d6)
d 32.6, 110.8, 117.4, 120.7,
7.62 (t, J¼7.4 Hz, 1Hꢂ2), 8.23e8.24 (m, 2Hꢂ2). 13C NMR (100 MHz,
120.8, 122.3, 129.2, 129.8, 136.3, 136.7, 139.6, 142.6, 166.8.
CDCl3) d 29.7, 30.8, 31.9, 47.9, 67.3, 109.6, 113.9, 119.9, 120.9, 121.7,
128.8, 130.9, 135.5, 140.0, 142.9, 143.8, 172.1.
4.2.2. Diethyl 9H,90H-1,10-bipyrido[3,4-b]indole-3,30-dicarboxylate
(4a). General procedure for the preparation of 4: To EtOH (25 mL)
cooled to ꢀ15 ꢁC was added dropwise SOCl2 (0.95 g, 8 mmol). After
stirring for 15 min, 3 (0.6 g,1.33 mmol) was added followed by reflux
at 60 ꢁC for 12 h. The reaction mixture was condensed under reduced
4.2.7. 3,30-Bis(methoxymethyl)-9,90-dimethyl-9H,90H-1,10-bipyrido
[3,4-b]indole (6b). General procedure for the preparation of 6b,c: NaH
(80% oil dispersion, 0.13 g, 4.3 mmol) was suspended in anhydrous
DMF (20 mL) under a N2 atmosphere at 0 ꢁC. Compound 5

B. Bai et al. / Tetrahedron 68 (2012) 6829e6836
6833
(0.6 g, 1.4 mmol) was added following by CH3I (0.8 g, 5.68 mmol)
NMR (100 MHz, CDCl3)
d
21.8, 21.8, 29.3, 70.3, 109.8, 118.3, 120.0,
and the mixture was stirred at rt for 12 h, and then poured into ice-
water (60 mL). The mixture extracted with EtOAc, the organic
phase was washed with water and dried over anhydrous Na2SO4.
The solvents were evaporated under reduced pressure. The residue
was purified by column chromatography on silica gel (Petroleum
ether/EtOAc¼2:1) to give 6b as a white solid, 0.54 g, yield 85%. IR
120.8, 121.1, 121.5, 125.9, 128.3, 134.2, 139.1, 143.4, 161.9.
4.3.3. 3,30-Bis(butoxycarbonyl)-9,90-dimethyl-9H,90H-1,10-bipyrido
[3,4-b]indole-2,20-dioxide ((R)-1d). Following the general procedure
above, 1d (yield, 41%) was isolated as pale yellow solid from the re-
action of 4c. Racemic 1d was resolved by HPLC on a Chiralpak-IC
column (250ꢂ10 mm, CH2Cl2/THF/CH3OH¼75:23:2) and both enan-
(KBr)
n 3442, 2927, 2867, 2826, 1621, 1470, 1374, 1242, 1107, 1039,
743 cmꢀ1
C
.
MS-ESI, m/z 451 [MþH]þ. HRMS m/z calcd for
tiomers (R)-(þ)-1d and (S)-(ꢀ)-1d were obtained. [ ]D þ560.4 (c 0.20,
a
28H27N4O2 [MþH]þ 451.2134, found 451.2141. 1H NMR (400 MHz,
CHCl3). Mp >300 ꢁC. IR (KBr) 3434, 2956,1732,1394,1243, 747 cmꢀ1
n .
CDCl3)
d
3.25 (s, 3Hꢂ2, NCH3), 3.57 (s, 3Hꢂ2, OCH3), 4.86 (d,
MS-ESI, m/z 617 [MþNa]þ. HRMS m/z calcd for C34H34N4O6Na
J¼3.5 Hz, 2Hꢂ2, ArCH2), 7.32 (t, J¼7.9 Hz, 1Hꢂ2), 7.37 (d, J¼8.3 Hz,
[MþNa]þ 617.2376, found 617.2370. 1H NMR (400 MHz, CDCl3)
d 0.96
1Hꢂ2), 7.60 (t, J¼7.3 Hz, 1Hꢂ2), 8.24 (d, J¼7.9 Hz, 1Hꢂꢂ2), 8.27 (s,
(t, J¼7.4 Hz, 3Hꢂ2), 1.42e1.51 (m, 2Hꢂ2), 1.75e1.82 (m, 2Hꢂ2), 3.44
(s, 3Hꢂ2, NCH3), 4.40e4.43 (m, 2Hꢂ2), 7.34e7.37 (m, 2Hꢂ2), 7.56 (t,
J¼7.7 Hz, 1Hꢂ2), 8.08 (d, J¼7.9 Hz, 1Hꢂ2), 8.46 (s, 1Hꢂ2). 13C NMR
1Hꢂ2). 13C NMR (100 MHz, CDCl3)
d 31.8, 58.7, 75.9, 109.5, 112.6,
119.8, 120.9, 121.7, 128.6, 130.9, 135.4, 139.8, 142.9, 146.2.
(100 MHz, CDCl3) d 13.7,19.1, 29.3, 30.5, 66.2,109.8,118.7,120.1,120.8,
4.2.8. 3,30-Bis(benzyloxymethyl)-9,90-dimethyl-9H,90H-1,10-bipyrido
[3,4-b]indole (6c). Following the general procedure, further puri-
fied by column chromatography on silica gel (petroleum ether/
EtOAc/CH2Cl2¼4:0.5:1) to give 6c as a white solid, yield 80%. IR
121.1, 121.6, 126.0, 128.3, 133.7, 139.2, 143.5, 162.5.
4.3.4. 3,30-Bis(isopentyloxycarbonyl)-9,90-dimethyl-9H,90H-1,10-bi-
pyrido[3,4-b]indole-2,20-dioxide ((R)-1e). Following the general
procedure above, 1e (yield, 42%) was isolated as pale yellow solid
from the reaction of 4d. Racemic 1e was resolved by HPLC on
a Chiralpak-IC column (250ꢂ10 mm, CH2Cl2/THF/CH3OH¼75:23:2)
and both enantiomers (R)-(þ)-1e and (S)-(ꢀ)-1e were obtained.
(KBr)
n
3442, 3028, 2854, 1621, 1465, 1241, 739 cmꢀ1. MS-ESI, m/z
603 [MþH]þ. HRMS m/z calcd for C40H35N4O2 [MþH]þ 603.2760,
found 603.2749. 1H NMR (400 MHz, CDCl3)
d
3.24 (s, 3Hꢂ2, NCH3),
4.76 (s, 2Hꢂ2, OCH2Ph), 4.97 (s, 2Hꢂ2, ArCH2), 7.30e7.39 (m,
5Hꢂ2), 7.45 (t, J¼7.5 Hz, 2Hꢂ2), 7.60 (t, J¼7.7 Hz, 1Hꢂ2), 8.23 (d,
[
a
]
D þ657.2 (c 0.21, CHCl3). Mp >300 ꢁC. IR (KBr)
n 3436, 2955, 1732,
J¼7.9 Hz, 1Hꢂ2), 8.33 (s, 1Hꢂ2). 13C NMR (100 MHz, CDCl3)
d
31.8,
1394, 1247, 748 cmꢀ1. MS-ESI, m/z 623 [MþH]þ. HRMS m/z calcd for
72.8, 73.6, 109.5, 112.7, 119.7, 121.0, 121.8, 127.7, 127.9, 128.4, 128.6,
131.0, 135.4, 138.2, 139.8, 142.9, 146.4.
C
36H39N4O6 [MþH]þ 623.2869, found 623.2865. 1H NMR (400 MHz,
CDCl3)
d
0.95 (d, J¼6.4 Hz, 6Hꢂ2), 1.68e1.82 (m, 3Hꢂ2), 3.45 (s,
3Hꢂ2, NCH3), 4.43e4.46 (m, 2Hꢂ2), 7.34e7.38 (m, 2Hꢂ2), 7.56 (t,
4.3. General procedure for (R)-1
J¼7.7 Hz, 1Hꢂ2), 8.08 (d, J¼7.9 Hz, 1Hꢂ2), 8.45 (s, 1Hꢂ2). 13C NMR
(100 MHz, CDCl3)
d 22.5, 25.1, 29.3, 37.2, 65.1, 109.9, 118.7, 120.0,
m-CPBA (3 mmol) was added portion-wise to a stirred solution
of 1,10-biscarboline (1 mmol) in CH2Cl2 (50 mL) at 0 ꢁC, and stirred
at rt for 24 h. Then the mixture was poured into saturated aqueous
NaHCO3 (50 mL) and extracted with CH2Cl2. The combined organic
layers were dried with Na2SO4 and concentrated in vacuo. The
residue was purified by chromatography (silica gel) eluting with
CH2Cl2/CH3OH¼80:1 to give the corresponding compounds.
120.9, 121.2, 121.6, 126.0, 128.3, 133.7, 139.3, 143.5, 162.6.
4.3.5. 3,30-Bis((3,3-dimethylbutoxy)methyl)-9,90-dimethyl-9H,90H-
1,10-bipyrido[3,4-b]indole-2,20-dioxide ((R)-1i). Following the gen-
eral procedure above, 1i (yield, 89%) was isolated as pale yellow
solid from the reaction of 6a. Racemic 1i was resolved by HPLC on
a Chiralpak-IC column (250ꢂ10 mm, CH2Cl2/CH3OH¼70:30) and
both enantiomers (R)-(þ)-1i and (S)-(ꢀ)-1i were obtained. [
a]
D
4.3.1. 3,30-Bis(ethoxycarbonyl)-9,90-dimethyl-9H,90H-1,10-bipyrido
[3,4-b]indole-2,20-dioxide ((R)-1b). Following the general pro-
cedure above, 1b (yield, 52%) was isolated as pale yellow solid from
the reaction of 4a. Racemic 1b was resolved by HPLC on a Chiralpak-
IC column (250ꢂ10 mm, CH2Cl2/THF/EtOH¼70:10:20) and both
þ329 (c 0.21, CHCl3). Mp >300 ꢁC. IR (KBr)
n 3436, 2954, 1735, 1605,
1396, 1335, 1241, 1127, 1006, 746 cmꢀ1. MS-ESI, m/z 651 [MþH]þ.
HRMS m/z calcd for C38H43N4O6 [MþH]þ 651.3182, found 6351.3181.
1H NMR (500 MHz, CDCl3)
d
1.11 (s, 9Hꢂ2), 2.41 (s, 2Hꢂ2), 3.29 (s,
3Hꢂ2, NCH3), 5.48 (d, J¼14.8 Hz, 1Hꢂ2, ArCH2), 5.68 (d, J¼14.8 Hz,
1Hꢂ2, ArCH2), 7.34 (m, 2Hꢂ2), 7.54 (t, J¼7.7 Hz, 1Hꢂ2), 8.09 (d,
enantiomers (R)-(þ)-1b and (S)-(ꢀ)-1b were obtained. [
a
]
þ637
D
(c 0.16, CHCl3). Mp >300 ꢁC. IR (KBr)
n
3439, 2927, 1735, 1392, 1239,
J¼7.7 Hz, 1Hꢂ2), 8.20 (s, 1Hꢂ2). 13C NMR (100 MHz, CDCl3)
d 29.3,
1008, 747 cmꢀ1. MS-ESI, m/z 539 [MþH]þ. HRMS m/z calcd for
29.7, 30.9, 47.8, 60.6, 109.5, 115.7, 120.8, 121.0, 121.0, 125.4, 128.0,
133.0, 137.7, 138.3, 143.3, 171.8.
C
30H27N4O6 [MþH]þ 539.1930, found 539.1936. 1H NMR (500 MHz,
CDCl3)
d
1.44 (t, J¼7.1 Hz, 3Hꢂ2), 3.44 (s, 3Hꢂ2, NCH3), 4.48
(q, J¼6.7 Hz, 2Hꢂ2), 7.34e7.37 (m, 2Hꢂ2), 7.56 (t, J¼7.4 Hz, 1Hꢂ2),
4.3.6. 3,30-Bis(methoxymethyl)-9,90-dimethyl-9H,90H-1,10-bipyrido
[3,4-b]indole-2,20-dioxide ((R)-1j). Following the general procedure
above, 1j (yield, 86%) was isolated as pale yellow solid from the
reaction of 6b. Racemic 1j was resolved by HPLC on a Chiralpak-IC
column (250ꢂ10 mm, THF/CH3OH¼50:50) and both enantiomers
8.07 (d, J¼7.8 Hz, 1Hꢂ2), 8.48 (s, 1Hꢂ2). 13C NMR (100 MHz, CDCl3)
d
14.2, 29.3, 62.3, 109.8, 118.7, 120.1, 120.8, 121.3, 121.6, 126.1, 128.3,
133.9, 139.4, 143.6, 162.5.
4.3.2. 3,30-Bis(isopropoxycarbonyl)-9,90-dimethyl-9H,90H-1,10-bipyr-
ido[3,4-b]indole-2,20-dioxide ((R)-1c). Following the general pro-
cedure above, 1c (yield, 58%) was isolated as pale yellow solid from
the reaction of 4b. Racemic 1c was resolved by HPLC on a Chiralpak-
IC column (250ꢂ10 mm, CH2Cl2/2-propanol¼78:22) and both en-
(R)-(þ)-1j and (S)-(ꢀ)-1j were obtained. [ D þ235 (c 0.26, CHCl3).
a
]
Mp >300 ꢁC. IR (KBr)
n 3441, 2927, 1604, 1472, 1394, 1194, 1113,
1006, 749 cmꢀ1. MS-ESI, m/z 483 [MþH]þ. HRMS m/z calcd for
C
28H27N4O4 [MþH]þ 483.2032, found 483.2028. 1H NMR (400 MHz,
CDCl3)
d
3.25 (s, 3Hꢂ2, NCH3), 3.67 (s, 3Hꢂ2, OCH3), 4.89 (d,
antiomers (R)-(þ)-1c and (S)-(ꢀ)-1c were obtained. [
a
]
þ705
J¼15.6 Hz, 1Hꢂ2, ArCH2), 4.96 (d, J¼15.5 Hz, 1Hꢂ2, ArCH2), 7.32 (m
D
(c 0.18, CHCl3). Mp >300 ꢁC. IR (KBr)
n 3435, 2929, 1729, 1596, 1390,
2Hꢂ2), 7.53 (t, J¼7.8 Hz, 1Hꢂ2), 8.12 (d, J¼7.8 Hz, 1Hꢂ2), 8.29 (s,
1239, 1096, 1006, 746 cmꢀ1. MS-ESI, m/z 567 [MþH]þ. HRMS m/z
1Hꢂ2). 13C NMR (100 MHz, CDCl3)
d 29.4, 59.5, 69.2, 109.4, 114.2,
calcd for C32H31N4O6 [MþH]þ 567.2243, found 567.2255. 1H NMR
120.8, 120.9, 121.1, 121.4, 125.2, 127.9, 137.2, 140.6, 143.3.
(400 MHz, CDCl3)
d
1.42 (d, J¼6.3 Hz, 3Hꢂ2), 1.43 (d, J¼6.3 Hz,
3Hꢂ2), 3.45 (s, 3Hꢂ2, NCH3), 5.33 (m, 1Hꢂ2), 7.34e7.38 (m, 2Hꢂ2),
4.3.7. 3,30-Bis(2-hydroxypropan-2-yl)-9,90-dimethyl-9H,90H-1,10-bi-
pyrido[3,4-b]indole-2,20-dioxide ((R)-1k). Following the general
7.56 (t, J¼8.0 Hz,1Hꢂ2), 8.08 (d, J¼7.5 Hz,1Hꢂ2), 8.40 (s, 1Hꢂ2). 13
C

6834
B. Bai et al. / Tetrahedron 68 (2012) 6829e6836
procedure above, 1k (yield, 84%) was isolated as pale yellow solid
from the reaction of 6c. Racemic 1i was resolved by HPLC on
a Chiralpak-IC column (250ꢂ10 mm, THF/CH3OH¼80:20) and both
column (hexane/2-propanol¼95:5, 0.5 mL/min), tR (major)¼
13.8 min (S); tR (minor)¼14.7 min (R), ee¼97%. [ ꢀ68.6 (c 0.87,
a
]
D
CHCl3). The reported value for the S-enantiomer (89% ee) is [a]
D
enantiomers (R)-(þ)-1k and (S)-(ꢀ)-1k were obtained. [
a
]
þ160
ꢀ60.6 (c 1.5, CHCl3)7a and for R-enantiomer (99% ee) is [
D þ63.3 (c
a
]
D
(c 0.25, CHCl3). Mp >300 ꢁC. IR (KBr)
n
3440, 1605, 1471, 1393, 1239,
1.14, CHCl3).13
1196, 1097, 1004, 746 cmꢀ1. MS-ESI, m/z 635 [MþH]þ. HRMS m/z
calcd for C40H35N4O4 [MþH]þ 635.2658, found 635.2668. 1H NMR
4.4.6. (S)-1-(3-Nitrophenyl)but-3-en-1-ol (9f). 1H NMR (400 MHz,
CDCl3)
(400 MHz, CDCl3)
d
3.23 (s, 3Hꢂ2, NCH3), 4.83 (s, 2Hꢂ2, OCH2Ph),
d
2.33 (d, J¼3.1 Hz, 1H), 2.43e2.52 (m, 1H), 2.53e2.62 (m,
5.00 (d, J¼15.8 Hz, 1Hꢂ2, ArCH2), 5.04 (d, J¼15.7 Hz, 1Hꢂ2, ArCH2),
7.29e7.36 (m, 3Hꢂ2), 7.41 (t, J¼7.5 Hz, 2Hꢂ2), 7.51 (m, 3Hꢂ2), 8.11
(d, J¼7.7 Hz, 1Hꢂ2), 8.35 (s, 1Hꢂ2). 13C NMR (100 MHz, CDCl3)
1H), 4.87 (m, 1H), 5.18e5.22 (m, 2H), 5.75e5.85 (m, 1H), 7.53 (t,
J¼7.9 Hz, 1H), 7.71 (d, J¼7.6 Hz, 1H), 8.14 (d, J¼8.0 Hz, 1H), 8.25 (s,
1H).14 Enantiomeric excess was determined by HPLC with a chir-
alpak-IC column (hexane/2-propanol¼90:10, 1.6 mL/min), tR
d¼29.5, 67.0, 73.8, 109.4, 114.4, 120.8, 121.0, 121.1, 121.5, 125.1, 127.9,
128.0, 128.0, 128.6, 137.2, 137.7, 140.8, 143.3.
(major)¼23.9 min (S); tR (minor)¼24.9 min (R), ee¼93%. [
(c 0.83, CHCl3).
a
]D ꢀ51.9
4.4. General procedure for reaction of allyltrichlorosilanes
with aldehydes
4.4.7. (S)-1-(4-Nitrophenyl)but-3-en-1-ol (9g). 1H NMR (400 MHz,
CDCl3)
d
2.30 (d, J¼3.2 Hz,1H), 2.44e2.49 (m,1H), 2.54e2.60 (m,1H),
Allyltrichlorosilane 8 or 10 (0.6 mmol) was added to a solution
of the catalyst (R)-1 (1 mol %), diisopropylethylamine (1.5 mmol),
and aldehyde 7 (0.5 mmol) in anhydrous CH2Cl2 (2 mL) under
nitrogen at ꢀ80 ꢁC. The mixture was stirred at the same tempera-
ture for 16 h and then quenched with aqueous saturated NaHCO3
(1 mL). The aqueous layer was extracted with CH2Cl2. The com-
bined organic layer was washed with saturated NaCl, dried over
Na2SO4, and evaporated under reduced pressure. The residue was
purified by flash chromatography on silica gel (petroleum ether/
EtOAc) to give alcohols 9 or 11.
4.87 (m, 1H), 5.17e5.22 (m, 2H), 5.76e5.80 (m, 1H), 7.53 (d,
J¼10.7 Hz, 2H), 8.22 (d, J¼10.4 Hz, 2H). Enantiomeric excess was
determined by HPLC with a chiralcel OB-H column (hexane/2-
propanol¼90:10, 0.8 mL/min), tR (major)¼15.6 min (S); tR (minor)¼
17.3 min (R), ee¼87%. [
for the S-enantiomer (65% ee) is [
R-enantiomer (98% ee) is [
a
]
D ꢀ51.2 (c 0.70, CHCl3). The reported value
a]
D ꢀ33.2 (c 0.50, CHCl3)9d and for
a]D þ65.8 (c 1.07, CHCl3).
4.4.8. (S)-1-(3-Fluorophenyl)but-3-en-1-ol (9h). 1H NMR (400 MHz,
CDCl3)
d
2.13 (d, J¼3.0 Hz, 1H), 2.45e2.56 (m, 2H), 4.75 (m, 1H),
5.16e5.21 (m, 2H), 5.76e5.82 (m, 1H), 6.95e6.99 (m, 1H), 7.08e7.14
(m, 2H), 7.30e7.34 (m, 1H).15 Enantiomeric excess was determined
by HPLC with a chiralcel OB-H column (hexane/2-propanol¼98:2,
0.8 mL/min), tR (major)¼12.6 min (S); tR (minor)¼18.5 min (R),
4.4.1. (S)-1-Phenylbut-3-en-1-ol (9a). 1H NMR (400 MHz, CDCl3)
d
2.09 (br s, 1H), 2.45e2.56 (m, 2H), 4.74 (dd, J¼7.3, 5.5 Hz, 1H),
5.13e5.19 (m, 2H), 5.76e5.86 (m, 1H), 7.28e7.36 (m, 5H). Enantio-
meric excess was determined by HPLC with a chiralcel OD-H col-
umn (hexane/2-propanol¼95:5, 0.6 mL/min), tR (minor)¼13.2 min
ee¼94%. [ D ꢀ50.2 (c 0.75, CHCl3).
a]
(R); tR (major)¼15.4 min (S), ee¼95%. [
a]
D ꢀ66.1 (c 0.86, CHCl3). The
4.4.9. (S)-1-p-Tolylbut-3-en-1-ol (9i). 1H NMR (400 MHz, CDCl3)
reported value for the S-enantiomer (92% ee) is [
a
]
D
ꢀ61.2 (c 1.05,
d
2.05 (d, J¼2.6 Hz, 1H), 2.36 (s, 3H), 2.49e2.53 (m, 2H), 4.72 (m,
CHCl3).7a
1H), 5.14e5.19 (m, 2H), 5.77e5.87 (m, 1H), 7.18 (d, J¼7.9 Hz, 2H),
7.26 (d, J¼7.9 Hz, 2H). Enantiomeric excess was determined by
HPLC with a chiralcel OB-H column (hexane/2-propanol¼95:5,
0.7 mL/min), tR (major)¼9.6 min (S); tR (minor)¼10.9 min (R),
4.4.2. (S)-1-(4-Methoxyphenyl)but-3-en-1-ol(9b). 1H NMR (400 MHz,
CDCl3)
d
2.04 (br s, 1H), 2.50 (t, J¼6.8 Hz, 2H), 3.80 (s, 3H), 4.68 (t,
J¼6.4 Hz, 1H), 5.11e5.18 (m, 2H), 5.76e5.83 (m, 1H), 6.88 (d, J¼8.6 Hz,
2H), 7.28 (d, J¼8.6 Hz, 2H). Enantiomeric excess was determined by
HPLC with a chiralcel OD-H column (hexane/2-propanol¼95:5,
0.6 mL/min), tR (minor)¼17.9 min (R); tR (major)¼19.6 min (S),
ee¼95%. [
a
]
ꢀ55.7 (c 0.90, CHCl3). The reported value for the
D
S-enantiomer (89% ee) is [
a
]
D
ꢀ43.4 (c 1.1, CHCl3)6b and for R-en-
antiomer (98% ee) is [
a]
D þ55.7 (c 0.98, CHCl3).13
ee¼99%. [
a
]
ꢀ59.1 (c 0.80, CHCl3). The reported value for the S-en-
4.4.10. (S)-1-(3,4-Dimethoxyphenyl)but-3-en-1-ol (9j). 1H NMR
(400 MHz, CDCl3)
D
antiomer (92% ee) is [
a]
D ꢀ48.0 (c 1.0, CHCl3).7a
d
2.10 (d, J¼2.3 Hz, 1H), 2.49e2.52 (m, 2H), 3.88
(s, 3H), 3.90 (s, 3H), 4.69 (m, 1H), 5.13e5.19 (m, 2H), 5.76e5.86 (m,
1H), 6.83 (d, J¼8.3 Hz, 1H), 6.88 (dd, J¼8.3, 1.6 Hz, 1H), 6.93 (d,
J¼1.6 Hz, 1H). Enantiomeric excess was determined by HPLC with
a chiralcel OB-H column (hexane/2-propanol¼90:10, 0.7 mL/min),
4.4.3. (S)-1-(3-Methoxyphenyl)but-3-en-1-ol (9c). 1H NMR (400 MHz,
CDCl3)
d
2.09 (d, J¼3.0 Hz, 1H), 2.52 (m, 2H), 3.82 (s, 3H), 4.71 (m, 1H),
5.13e5.19 (m, 2H), 5.76e5.86 (m,1H), 6.82 (ddd, J¼8.0, 2.4, 0.8 Hz,1H),
6.93 (m, 2H), 7.26 (dd, J¼9.1, 7.1 Hz, 1H). Enantiomeric excess was
determined by HPLC with a chiralcel OD-H column (hexane/2-
propanol¼95:5, 0.6 mL/min), tR (minor)¼22.7 min (R); tR (major)¼
tR (major)¼18.5 min (S); tR (minor)¼22.0 min (R), ee¼96%. [
a]
D
ꢀ41.3 (c 0.80, CHCl3). The reported value for the S-enantiomer (96%
ee) is [
a]
ꢀ37.8 (c 1.9, benzene).9b
D
24.3 min (S), ee¼97%. [
a
]D ꢀ55.1 (c 0.80, CHCl3). The reported value for
the R-enantiomer (97% ee) is [
a]
D þ53.8 (c 0.9, benzene).13
4.4.11. (S)-1-(Thiophen-2-yl)but-3-en-1-ol (9k). 1H NMR (400 MHz,
CDCl3)
d
2.26 (d, J¼3.9 Hz, 1H), 2.60e2.64 (m, 2H), 5.00 (m, 1H),
4.4.4. (S)-1-(3-Chlorophenyl)but-3-en-1-ol (9d). 1H NMR (400 MHz,
CDCl3) 2.17 (s, 1H), 2.41e2.55 (m, 2H), 4.71 (m, 1H), 5.15e5.20 (m,
5.16e5.23 (m, 2H), 5.79e5.87 (m, 1H), 6.98 (m, 2H), 7.25 (m, 1H).
Enantiomeric excess was determined by HPLC with a chiralcel OB-H
column (hexane/2-propanol¼90:10, 0.8 mL/min), tR (major)¼
d
2H), 5.73e5.84 (m, 1H), 7.21e7.30 (m, 3H), 7.37 (s, 1H). Enantiomeric
excess was determined by HPLC with a chiralcel OB-H column
(hexane/2-propanol¼98:2, 0.7 mL/min), tR (major)¼14.6 min (S); tR
12.7 min (S); tR (minor)¼13.9 min (R), ee¼98%. [
a]
D
ꢀ25.3 (c 0.78,
CHCl3). The reported value for the S-enantiomer (83%ee) is [
a
]D ꢀ19.0
(minor)¼18.7 min (R), ee¼95%. [
a]
D ꢀ54.9 (c 0.95, CHCl3).11
(c 1.0, CHCl3)7a and for S-enantiomer (96% ee) is [
a]
D
ꢀ12.3 (c 1.07,
CHCl3).13
4.4.5. (S)-1-(4-Chlorophenyl)but-3-en-1-ol (9e). 1H NMR (400 MHz,
CDCl3)
d
2.13 (d, J¼2.7 Hz, 1H), 2.41e2.54 (m, 2H), 4.71 (m, 1H),
4.4.12. (S)-1-(Naphthalen-2-yl)but-3-en-1-ol (9l). 1H NMR (400 MHz,
CDCl3) 2.24 (br s, 1H), 2.57e2.66 (m, 2H), 4.92 (m, 1H), 5.15e5.23
(2H, m), 5.79e5.90 (1H, m), 7.48e7.51 (3H, m), 7.82e7.86 (4H, m).
5.14e5.18 (m, 2H), 5.74e5.81 (m, 1H), 7.26e7.33 (m, 4H). Enantio-
d
meric excess was determined by HPLC with a chiralcel OB-H

B. Bai et al. / Tetrahedron 68 (2012) 6829e6836
6835
Enantiomeric excess was determined by HPLC with a chiralcel
Enantiomeric excess was determined by HPLC with a chiralpak-IC
column (hexane/2-propanol¼97:3, 2.0 mL/min), tR (minor)¼
13.7 min ((1R,2S), syn), tR (major)¼14.8 min ((1S,2R), syn); tR
(minor)¼15.6 min ((1R,2R), anti), tR (major)¼16.9 min ((1S,2S),
OB-H column (hexane/2-propanol¼95:5, 0.8 mL/min), tR (major)¼
17.3 min (S); tR (minor)¼19.6 min (R), ee¼93%. [
a
]
ꢀ61.2 (c 0.91,
D
CHCl3). The reported value for the S-enantiomer (90% ee) is [
a
]D ꢀ55.0
(c 1.16, CHCl3).9d
anti), ee¼94%:95% (anti/syn, 86:14). [
a
]
ꢀ82.1 (c 1.42, CHCl3)
D
mixture of anti and syn. The reported value for the (1R,2R)-enan-
4.4.13. (S)-1-(Naphthalen-1-yl)but-3-en-1-ol(9m). 1H NMR (400 MHz,
CDCl3) 2.24 (br s,1H), 2.55e2.63 (m,1H), 2.73e2.78 (m,1H), 5.16e5.24
tiomer (46% ee) is [
a
]
D
þ44.7 (c 0.75, CHCl3) pure anti.12
d
(m, 2H), 5.19 (m, 1H), 5.88e5.94 (m, 1H), 7.46e7.52 (m, 3H), 7.66 (d,
J¼7.2 Hz, 1H), 7.78 (d, J¼8.1 Hz, 1H), 7.87 (d, J¼7.5 Hz, 1H), 8.06 (d,
J¼8.1 Hz, 1H). Enantiomeric excess was determined by HPLC with
a chiralcel OD-H column (hexane/2-propanol¼90:10, 0.8 mL/min), tR
4.4.19. (1S,2R)-1,2-Diphenylbut-3-en-1-ol (11b). 1H NMR (400 MHz,
CDCl3)
d
2.35 (br s, 1H), 3.56 (t, J¼8.4 Hz, 1H), 4.84 (d, J¼7.8 Hz, 1H),
5.20e5.28 (m, 2H), 6.23e6.30 (m, 1H), 7.04e7.23 (m, 10H).17 En-
antiomeric excess was determined by HPLC with a chiralcel OB-H
column (hexane/2-propanol¼95:5, 1.0 mL/min), tR (major)¼
(major)¼10.0 min (S); tR (minor)¼16.2 min (R), ee¼97%. [ ]D ꢀ105.1 (c
a
0.79, CHCl3). The reported value for the S-enantiomer (81% ee) is [
a
]
9.3 min (1S,2R); tR (minor)¼10.3 min (1S,2S), ee¼96%. [
(c 0.93, CHCl3).
a
]
ꢀ11.1
D
D
ꢀ84.1 (c 1.0, CHCl3)6b and for R-enantiomer (98% ee) is [
a
]
þ98.6 (c
D
1.06, benzene).13
4.4.20. (S)-2,2-Dimethyl-1-phenylbut-3-en-1-ol (11c). 1H NMR
(400 MHz, CDCl3) 0.96 (s, 3H),1.01 (s, 3H), 2.05 (s,1H), 4.43 (s, 1H),
4.4.14. (R)-1-(2,6-Dichlorophenyl)but-3-en-1-ol (9n). 1H NMR
(400 MHz, CDCl3) 2.65e2.71 (m, 1H), 2.82e2.87 (m, 1H), 2.89
d
d
5.09 (d, J¼17.5 Hz, 1H), 5.14 (d, J¼10.8 Hz, 1H), 5.92 (dd, J¼17.5,
10.8 Hz, 1H), 7.26e7.31 (m, 5H). Enantiomeric excess was de-
termined by HPLC with a chiralcel OD-H column (hexane/2-
propanol¼95:5, 0.6 mL/min), tR (major)¼11.0 min (S); tR (minor)¼
(d, J¼9.8 Hz, 1H), 5.08e5.15 (m, 2H), 5.50 (m, 1H), 5.81e5.86 (m,
1H), 7.13 (t, J¼7.9 Hz, 1H), 7.29 (d, J¼7.9 Hz, 2H). Enantiomeric
excess was determined by HPLC with a chiralcel OD-H column
(hexane/2-propanol¼98:2, 0.7 mL/min), tR (major)¼11.4 min (R);
14.8 min (R), ee¼96%. [
a
]
D ꢀ42.6 (c 0.47, CHCl3). The reported value
tR (minor)¼12.6 min (S), ee¼97%. [
a
]
D þ9.1 (c 0.88, benzene). The
for the R-enantiomer (66% ee) is [
a
]
D þ22 (c 0.8, benzene).12
reported value for the S-enantiomer (84% ee) is [
a
]
D ꢀ59.4 (c 0.5,
CH2Cl2).16
4.4.21. (S)-3-Methyl-1-phenylbut-3-en-1-ol(11d). 1H NMR (400 MHz,
CDCl3)
d
1.81 (s, 3H), 2.15 (d, J¼1.7 Hz, 1H), 2.43 (d, J¼7.0 Hz, 2H), 4.82
4.4.15. (S)-(E)-1-Phenylhexa-1,5-dien-3-ol (9o). 1H NMR (400 MHz,
CDCl3) 1.96 (s, 1H), 2.37e2.47 (m, 2H), 4.36 (m, 1H), 5.16e5.22 (m,
(t, J¼6.8 Hz, 1H), 4.87 (d, J¼1.2 Hz, 1H), 4.93 (d, J¼1.4 Hz, 1H),
7.28e7.40 (m, 5H). Enantiomeric excesswas determined byHPLC with
a chiralcel OD-H column (hexane/2-propanol¼97:3, 0.6 mL/min), tR
d
2H), 5.83e5.90 (m, 1H), 6.25 (dd, J¼15.9, 6.3 Hz, 1H), 6.61 (d,
J¼15.9 Hz, 1H), 7.24 (d, J¼7.4 Hz, 1H), 7.32 (t, J¼7.6 Hz, 2H), 7.26 (d,
J¼7.4 Hz, 2H). Enantiomeric excess was determined by HPLC with
a chiralcel OD-H column (hexane/2-propanol¼90:10, 0.7 mL/min),
(major)¼15.6 min (S); tR (minor)¼17.3 min (R), ee¼82%. [
a
]
ꢀ44.4
D
(c0.18, CHCl3). ThereportedvaluefortheR-enantiomer(66%ee)is[
a]
D
þ51.8 (c 0.58, benzene).12
tR (minor)¼9.3 min (R); tR (major)¼13.5 min (S), ee¼93%. [
a]
D
ꢀ30.6 (c 0.95, CHCl3) and [
a]
þ11.2 (c 0.86, Et2O). The reported
D
Acknowledgements
value for the S-enantiomer (83% ee) is [
a
]
D ꢀ36.9 (c 1.06, CHCl3) and
[
a]
D þ10.3 (c 1.31, Et2O),6b for R-enantiomer (96% ee) is [
D ꢀ9.8 (c
a
]
We thank the funds support from the NSFC (30873141), 973
program (2009CB522300), Hebei University, and the Key State of
Laboratory of Phytochemistry and Plant Resources in West Chian.
1.12, Et2O).13
4.4.16. (R)-1-Phenylhex-5-en-3-ol (9p). 1H NMR (400 MHz, CDCl3)
d
1.66 (d, J¼5.2 Hz, 1H), 1.78e1.82 (m, 2H), 2.15e2.22 (m, 1H),
References and notes
2.28e2.34 (m, 1H), 2.66e2.73 (m, 1H), 2.78e2.86 (m, 1H), 3.68 (m,
1H), 5.13e5.17 (m, 2H), 5.77e5.86 (m, 1H), 7.18e7.22 (m, 3H),
7.27e7.31 (m, 2H). Enantiomeric excess was determined by HPLC
1. (a) Hosomi, A.; Endo, M.; Sakurai, H. Chem. Lett. 1976, 5, 941e942; (b) Hosomi,
A.; Sakurai, H. Tetrahedron Lett. 1976, 17, 1295e1298.
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with
a
chiralcel OD-H column (hexane/2-propanol¼95:5,
0.8 mL/min), tR (minor)¼10.2 min (S); tR (major)¼14.9 min (R),
ee¼92%. [
a
]
D
þ12.1 (c 0.98, CHCl3). The reported value for the R-
enantiomer (49% ee) is [
a
]
þ1.8 (c 0.9, CHCl3)6b and for S-enan-
D
3. For review see: (a) Denmark, S. E.; Fu, J. P. Chem. Rev. 2003, 103, 2763e2793; (b)
tiomer (87% ee) is [
a
]
D ꢀ25.4 (c 1.0, benzene).13
ꢀ
ꢁ
Malkov, A. V.; Kocovsky, P. Eur. J. Org. Chem. 2007, 29e36; (c) Chelucci, G.;
Murineddub, G.; Pinnab, G. A. Tetrahedron: Asymmetry 2004, 15, 1373e1389.
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CDCl3)
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2H), 5.78e5.89 (m, 1H). Enantiomeric excess was determined by
formation of 3,5-dinitrobenzoate ester of the title compound
d
1.02e1.32 (m, 5H),1.58 (d, J¼3.9 Hz,1H),1.67e1.89 (m, 6H),
5. (a) Nakajima, M.; Saito, M.; Shiro, M.; Hashimoto, S. J. Am. Chem. Soc. 1998,
120, 6419e6420; (b) Nakajima, M.; Saito, M.; Uemura, M.; Hashimoto, S.
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shimoto, S. Tetrahedron: Asymmetry 2002, 13, 2449e2452; (d) Nakajima, M.;
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9589e9594.
followed by HPLC with
a chiralcel OD-H column (hexane/
ethanol¼95:5, 0.8 mL/min), tR (minor)¼12.5 min (R); tR (major)¼
13.5 min (S), ee¼97%. [
a]
ꢀ11.8 (c 1.18, EtOH). The reported value
D
for the R-enantiomer (73% ee) is [
a
]
D
þ5.3 (c 1.0, EtOH).13
6. (a) Shimada, T.; Kina, A.; Ikeda, S.; Hayashi, T. Org. Lett. 2002, 4, 2799e2801; (b)
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(400 MHz, CDCl3) anti-isomer
0.86 (d, J¼6.8 Hz, 3H), 2.23 (br s,
1H), 2.43e2.52 (m, 1H), 4.34 (d, J¼7.9 Hz, 1H), 5.17e5.22 (m, 2H),
5.76e5.85 (m, 1H), 7.25e7.38 (m, 5H). syn-Isomer 1.00 (d,
d
7. (a) Malkov, A. V.; Bell, M.; Orsini, M.; Pernazza, D.; Massa, A.; Herrmann, P.;
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J¼6.8 Hz, 3H), 2.06 (br s, 1H), 2.55e2.60 (m, 1H), 4.60 (d, J¼7.9 Hz,
ꢀ
ꢁ
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B. Bai et al. / Tetrahedron 68 (2012) 6829e6836
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ꢁ
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ꢀ
ꢁ
ꢁ
ꢀ
ꢁ