Total synthesis of (-)-20-epiuleine via stereocontrolled one-pot asymmetric azaelectrocyclization followed by novel 1,4-addition reaction

Article abstract of DOI:10.1039/c0ob00627k

The first asymmetric total synthesis of an indole alkaloid, (-)-20-epiuleine, containing the 2,3,4-trisubstituted piperidine core, was achieved using a stereocontrolled one-pot asymmetric 6π-azaelectrocyclization followed by a stereoselective 1,4-addition

Full text of DOI:10.1039/c0ob00627k

View Article Online / Journal Homepage / Table of Contents for this issue
Organic &
Biomolecular
Chemistry
Dynamic Article Links
Cite this: Org. Biomol. Chem., 2011, 9, 257
www.rsc.org/obc
PAPER
Total synthesis of (-)-20-epiuleine via stereocontrolled one-pot asymmetric
azaelectrocyclization followed by novel 1,4-addition reaction†
Taku Sakaguchi, Shohei Kobayashi and Shigeo Katsumura*
Received 26th August 2010, Accepted 6th October 2010
DOI: 10.1039/c0ob00627k
The first asymmetric total synthesis of an indole alkaloid, (-)-20-epiuleine, containing the
2,3,4-trisubstituted piperidine core, was achieved using a stereocontrolled one-pot asymmetric
6p-azaelectrocyclization followed by a stereoselective 1,4-addition reaction of the unsaturated ester
with a Grignard reagent resulting from the novel neighboring participation of the hydroxyl group in
cis-aminoindanol as a chiral nitrogen source.
Introduction
Uleine (1), 20-epiuleine (2), dasycarpidone (3) and 20-
epidasycarpidone (4) are four related members of the Strych-
nos-type indole alkaloids, which were principally isolated from
Aspidosperma sp (Fig. 1.).1 These indole alkaloids lack the two-
carbon chain from tryptophan. Although a number of synthetic
efforts for the racemic 20-epiuleine (2) and epidasycarpidone (4)
along with uleine (1) and dasycarpidone (3) were reported in
the literature,2,3 only a few asymmetric syntheses of these indole
alkaloids have been reported.4,5 The structural feature of these
alkaloids is the 2-aza-bicyclo[3,3,1]nonane skeleton, which has
been constructed from the 3-(2-piperidyl)indole derivative 5 by an
acid-catalyzed cyclization followed by dehydration (Scheme 1).3
The subject, therefore, is how to efficiently synthesize the optically
homogeneous 2-indolyl-3-ethyl-4-carbonyl piperidine compound
such as 5, which is classified as a 2,3,4-trisubstituted piperidine
skeleton and was obtained in the dl-form by the 1,4-addition of
the unsaturated ketone 6 (Scheme 1).3c,3d
Scheme 1 Synthetic strategy of 20-epiuleine.
Previously, we reported the formal synthesis of the optically
active 20-epiuleine (2) utilizing the step-wise asymmetric 6p-
azaelectrocyclization, which was developed as a synthetic strategy
for substituted piperidines.5 This asymmetric azaelectrocyclization
includes highly controlling the stereochemistry at the second
position of the constructed tetrahydropyridine derivative, such
as 7, resulting from a kinetically controlled torquoselective
6p-azaelectrocyclization of a conformationally flexible linear
azatriene, such as 8, prepared from cis-aminoindanol deriva-
tive 9 and dienal 10.5 In that formal synthesis, although we
synthesized the optically homogeneous 2-indolyl-4-acyl-1,2,5,6-
tetrahydropyridine 6, which was identical to the synthetic in-
termediate of (dl)-20-epiuleine reported by Husson’s group, the
transformation to the corresponding chiral 2,3,4-trisubstituted
piperidine derivative 5 was not realized. Thus, the real procedure
for the construction of the chiral 2,3,4-trisubstituted piperidine
framework has not been yet established.
Most recently, in order to establish asymmetric 6p-
azaelectrocyclization as a new strategy for alkaloid synthesis,
we realized a one-pot protocol, which enabled the facile and
highly stereoselective preparation of chiral 2,4-disubstituted- and
2,4,5-trisubstituted-1,2,5,6-tetrahydropyridine derivatives such as
13 under thermodynamic control (Scheme 2).6 Based on
the developed protocol, we achieved the stereoselective total
Fig. 1 Strychnos-type indole alkaloids.
School of Science and Technology, Kwansei Gakuin University, Gakuen
2-1, Sanda, Hyogo, 669-1337, Japan. E-mail: katsumura@kwansei.ac.jp;
Fax: +81 (79) 565-9077; Tel: +81 (79) 565-8314
† Electronic supplementary information (ESI) available: The experimantal
details of 27a–d and 29a–c and 1H and 13C NMR spectra of the products.
See DOI: 10.1039/c0ob00627k
synthesis of (-)-dendroprimine,7 which possesses
a chiral
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 257–264 | 257
©

View Article Online
sequence of DIBAL-H reduction, lead tetraacetate oxidation in
the presence of n-propylamine, reductive N-methylation (HCHO,
NaBH3CN in CH3CN), MnO2 oxidation, methylation with MeLi,
hydrolysis of the N-tosyl group in the indole ring and then DMP
oxidation as previously reported.5 We thus obtained the optically
active methyl ketone derivative 6, which was a key synthetic
intermediate of ( )-20-epiuleine as reported by Husson’s group.
We then attempted the 1,4-addition reaction of (-)-6 under the
reaction conditions described in the literature.3c After a detailed
investigation of the reaction conditions, we obtained the desired
2,3,4-trisubstituted piperidine compound 5 in 48% yield using
excess reagents of ethylmagnesium bromide and copper(I) chloride
in a ratio of 2.5 : 1 in ether. When the one to one ratio of
ethylmagnesium bromide and copper(I) was used, we did not
obtained the desired product and recovered the starting materials.
As the solvent of this 1,4-addition reaction, the yield in ether was
rather better than in THF. Although we obtained the derived 5,
this 1,4-addition reaction was troublesome and sometimes not
reproducible. The yield varied from 48% to 13% under the same
conditions employed. We then examined another method for this
1,4-addition reaction.
Scheme 2 Alkaloid synthesis via 6p-azaelectrocyclization.
2,4,6-trisubstituted piperidine nucleus, and (-)-corynantheidol,8
which has a chiral 2,4,5-trisubstituted piperidine structural unit.
In this paper, we describe in detail the stereoselective total syn-
thesis of (-)-20-epiuleine, which consists of a 2,3,4-trisubstituted
piperidine structural unit having an indole nucleus via the one-
pot asymmetric azaelectrocyclization followed by the unique 1,4-
addition reaction of the unsaturated ester with Grignard reagents
resulting from the novel neighboring participation of the hydroxyl
group in cis-aminoindanol, which was utilized as a chiral nitrogen
source.
Results and Discussion
Usual 1,4-additon reaction of unsaturated methyl ketone with
cuprate
Novel 1,4-addition reaction of the unsaturated ester with the
Grignard reagent to produce 2,3,4-trisubstituted piperidine
derivatives; Improved synthesis of (-)-20-epiuleine
As previously reported, the tetracyclic aminoacetal derivative 7
was stereoselectively synthesized by the one-pot asymmetric 6p-
azaelectrocyclization (Scheme 3).6 Thus, the cis-aminoindanol
derivative (-)-9, trisubstituted vinyl iodide 14 and MS4A were
stirred in DMF at room temperature. After checking the con-
sumption of 14 by TLC, indolyl vinyl stannane 15, Pd2(dba)3,
tri(2-furyl)phosphine and LiCl were added, and the resulting
mixture was heated at 80 ◦C for 2 h to produce the desired
aminoacetal 7 in 75% yield resulting from the successive Migita-
Stille coupling, 1-azatriene formation, 6p-azaelectrocyclization
and aminoacetal formation. The stereoselectivity at the second
position and the total yield were better than those obtained by the
previously developed stepwise procedure (75% yield and >16 : 1
stereoselectivity for the one-pot protocol vs. 62% yield and 10 : 1
stereoselectivity for the stepwise method).5,6 The transformation
from 7 to methyl ketone 6 through 16 was accomplished by the
Since it was preferable to construct the 2,3,4-trisubstituted piperi-
dine nucleus of 20-epiuleine at the earlier stage, we attempted the
1,4-addition reaction of the aminoacetal derivative 7, which was
easily obtained by the one-pot asymmetric azaelectrocyclization
of the three components.6 Surprisingly, the treatment of 7 with
an excess amount of the Grignard reagent at 0 ◦C spontaneously
provided the dialkylated ester 17 as a mixture of stereoisomers,
and no 1,4-addition product 18 was detected in the mass spectrum
(Scheme 4). Even though one equivalent of the Grignard reagent
was used, the dialkylated product 17 was admitted as the major
product in the mass spectra along with the starting material 7.
We postulated that the 1,4-addition of an ethyl group to the
unsaturated ester moiety would occur after the alkylation at
the acetal moiety proceeded. We then decided to attempt the
1,4-addition reaction for the aminoindanol derivative 20, which
would be obtained from the aminoacetal 7 by chemoselective
reduction, with ethylmagnesium bromide. The reduction of 7 with
R
LAH or DIBAL-H gave the corresponding diol 19, and Red-Alꢀ
Scheme
3
Synthesis of 20-epiuleine through unsaturated methyl
ketone 6.
Scheme 4 Alkylation and reduction of 7.
258 | Org. Biomol. Chem., 2011, 9, 257–264
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
Table 1 1,4-Addition reaction of unsaturated carbonyl compounds
in toluene chemoselectively reduced the ester group to give the
primary alcohol as a mixture of olefin isomers, while the saturated
derivative gave the corresponding primary alcohol.6 Fortunately,
we found that the treatment of 7 with NaBH4 in the presence of
BF3·OEt2 in THF at 0 ◦C successfully and quantitatively provided
the desired alcohol 20.9 After obtaining 20, we attempted the 1,4-
addition reaction.
The reaction of 20 with an excess amount of ethylmagnesium
bromide in ether at 0 ◦C for 20 min cleanly proceeded to expectedly
afford the 1,4-addition product 21 in 95% yield as a mixture
of stereoisomers, which could not be separately isolated at this
stage (Scheme 5). Removal of the indanol moiety in 21 with
lead tetraacetate under the established condition6 produced the
2,3,4-trisubstituted piperidine 22a and 22b in 24% and 71% yields,
respectively, which were cleanly separated from each other. The
stereochemistry of 22b was determined as 2b, 3a, 4b in the
piperidine ring and that of 22a as 2b, 3a, 4a by a detailed analysis
of the NMR data. Although various attempts of isomerization at
the ester group of 22a (t-BuOK in BuOH, DBU in DMF, etc.) were
not successful, isomerization of the corresponding methyl ketone
5 was successful in literature,3c,d and hence the present synthesis
can be regarded as the stereocontrolled one. On the contrary, the
reaction of compound 23, which was derived from the hydroxyl
compound 20 with TBSCl and imidazole, gave tertiary alcohol
24 with ethylmagnesium bromide resulting from the addition of
an ethyl group to the ester group. Thus, the secondary hydroxyl
group of the aminoindanol moiety is essential for the 1,4-addition
reaction.
Entry 27
29
22
R1
R2
Yield Ratio a : b By-product
1
20
CO2Et 95%
1 : 3.0
2
3
27a 29a
27b 29b
CO2Et 82%
CO2Et 75%
1 : 2.7
1 : 3.8
4
27c 29c
41%
1 : 2.2
of the Grignard reagent with the OMgBr group prepared from the
Grignard reagent and the hydroxyl group in the cis-aminoindanol
moiety was generated during the alkylation process,10 and then
the ethyl group attacked from the opposite direction of the indole
group as shown in structure 26.
In order to investigate the generality of this novel 1,4-addition
reaction assisted by the neighboring hydroxyl group, we applied
the reaction to a phenyl derivative 27a instead of an N-tosyl indole
compound as a representative compound (Table 1). As expected,
the reaction under the same conditions gave the corresponding
1,4-addition product 29a through 28a in 82% yield with the single
stereoisomer at the ethyl group and the similar stereoselectivity at
the ester group. The thiophene derivative 27b6 gave 29b through
28b in 75% yield and a rather better stereoselectivity at the ester
group. On the contrary, attempts of the 1,4-addition reaction of
the corresponding methyl ketone derivative 27c, which was easily
derived from amide 27d, gave the 1,2-addition product 30c along
with 1,4-addition product 29c in 26% and 41% yields, respectively.
In the case of the amide derivative 27d, which was obtained by
the same one-pot azaelectrocyclization using the corresponding
Weinreb amide instead of 14 in Scheme 3 (see experimental), the
reaction gave a complex mixture and 29d was not isolated. Thus,
the unsaturated ester group was appropriate for the desired 1,4-
addition reaction.
Scheme 5 1,4-Addition reaction of unsaturated ester.
A plausible mechanism is shown in Fig. 2. The highly stereose-
lective introduction of an ethyl group at the b-position of the ester
group in 20 could be explained by assuming that the coordination
Total synthesis of (-)-20-epiuleine by the one-pot asymmetric
6p-azaelectrocyclization followed by the novel 1,4-addition
To achieve the total synthesis of 20-epiuleine (Scheme 6), the
obtained 22b was transformed into the methyl ketone 5. Thus,
the reductive N-methylation of a mixture of 22b and 22a was
performed by treatment with a 37% aqueous HCHO solution
and sodium cyanoborohydride in acetonitrile to produce 31b and
31a as a mixture of easily separable epimers. Each of them was
transformed into the aldehyde 32b and 32a by DIBAL-H reduction
followed by Swern oxidation. At this stage, the undesired isomer
32a was epimerized to the desired 32b by a DBU treatment in THF
Fig. 2 Plausible mechanism of 1,4-addition reaction.
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 257–264 | 259
©

View Article Online
1.20 mmol) in ether (5.0 ml) was added. After the mixture
was stirred at this temperature for 30 min, saturated aqueous
NH4Cl and NaHCO3 solutions were successively added and the
resulting mixture was extracted with ethyl acetate. The organic
layers were combined, washed with brine, dried over MgSO4,
filtered and concentrated in vacuo to give the crude products.
Column chromatography on silica gel (from 0% to 9% methanol in
chloroform) gave 5 (12 mg, 48%) as a yellow amorphoussolid: [a]D22
-22.1 (c 1.1, CHCl3); IR (KBr disk, cm-1) 2928, 2793, 1714, 1458,
1
1136, 1067, 733; H NMR (400 MHz, CDCl3) d 8.14–8.26 (br s,
1H), 7.76–7.88 (br s, 1H), 7.37 (d, 1H, J = 8.0 Hz), 7.15 (m, 3H),
3.13 (ddd, 1H, J = 11.7, 3.2, 3.2 Hz), 3.03 (d, 1H, J = 8.7 Hz), 2.59
(ddd, 1H, J = 11.5, 11.5, 4.6 Hz), 2.40–2.28 (br s, 1H), 2.16–2.24
(m, 4H), 2.02 (s, 3H), 1.84–1.99 (m, 2H), 1.03–1.20 (m, 2H), 0.62
(t, 3H, J = 7.6 Hz); 13C NMR (100 MHz, CDCl3) d 211.8, 136.3,
122.5, 122.0, 119.4, 116.4, 111.1, 56.5, 54.2, 44.6, 29.2, 28.2, 23.1,
9.2; ESI HRMS m/z calcd for C18H24N2O1 (M+H)+ 285.1967,
found 285.1977.
Scheme 6 Synthesis of (-)-20-epiuleine.
at room temperature. The obtained aldehyde 32b was transformed
into the methyl ketone 5 through 33 by methylation with MeLi,
Swern oxidation and then hydrolysis of the N-tosyl group of the
indole moiety with Cs2CO3 in THF and MeOH (3 : 1). Finally, the
treatment of 5 with p-TsOH in chloroform completed the total
synthesis of (-)-20-epiuleine (2) in 25% yield. The spectral data
(1H NMR, 13C NMR, IR, HRMS) were in good agreement with
those of the natural product. The value of [a]D of the synthesized
compound was -30.1 (CHCl3, c 0.9), which is reported for the first
time.
Ethyl (2S)-1-[(1S,2R)-2-hydroxyl-7-isopropylindan-1-yl]-2-(N-
p-toluenesulfonylindol-3-yl)-1,2,5,6-tetrahydropyridine-4-carboxy-
late (20). To a solution of aminoacetal 7 (6.78 g, 11.4 mmol) in
THF (110 ml) were added sodium borohydride (2.15 g, 56.8 mmol)
and trifluoroborane etherate complex (1.43 ml, 11.4 mmol) at 0 ◦C.
After the mixture was stirred at 0 ◦C for 30 min, saturated aqueous
NaHCO3 solution was added, and the resulting mixture was
extracted with ethyl acetate. The organic layers were combined,
washed with brine, dried over MgSO4, filtered and concentrated
in vacuo to give the crude products. Column chromatography on
silica gel (from 25% to 33% ethyl acetate in hexane) gave the
product 20 (5.85 g, 86%) as a yellow amorphous solid: [a]2D2 -116.4
(c 1.0, CHCl3);IR (KBr disk, cm-1) 2961, 2867, 1711, 1375, 1258,
Summary
In summary, we achieved the first asymmetric total synthesis
of (-)-20-epiuleine (2) using a three-component one-pot 6p-
azaelectrocyclization. The construction of the 2,3,4-trisubstituted
piperidine as the core structure of the indole alkaloid was
established by utilizing the highly stereoselective 1,4-addition
reaction only with the Grignard reagent. This unique 1,4-addition
reaction was due to the novel neighboring participation of the
hydroxyl group of the characteristic aminoindanol moiety, which
was employed as a chiral nitrogen source. The total yield of the first
route via Husson’s enone obtained from the three components in
a one-pot reaction was 1.3% for 10 steps, while that of the second
route was 5.0% for 11 steps.
677; H NMR (400 MHz, CDCl3, 55 ◦C) d 7.99 (d, 1H, J =
1
8.5 Hz), 7.78 (d, 2H, J = 8.5 Hz), 7.38–7.70 (br d, 2H), 7.31
(dd, 1H, J = 7.3, 7.3 Hz), 7.18–7.24 (m, 4 H), 7.00 (d, 1 H, J =
7.8 Hz), 6.88 (d, 1 H, J = 6.6 Hz), 6.81(s, 1 H), 5.15–5.67 (br s,
1 H), 4.45–4.63 (br s, 1 H), 4.32 (d, 1 H, J = 6.6 Hz), 4.12–4.27
(m, 2 H), 2.31–3.10 (br m, 7 H), 2.30 (s, 3 H), 1.27 (t, 3 H, J =
7.9 Hz), 0.91–1.07 (br s, 3 H), 0.25–0.57 (br s, 3H); 13C NMR
(100 MHz, CDCl3, 55 ◦C) d 166.7, 147.7, 145.0, 139.4, 136.7,
135.6, 135.5, 129.9, 129.4, 129.0, 126.9, 124.8, 123.5, 123.1, 121.9,
120.9, 113.7, 60.5, 54.9, 41.3, 26.3, 25.7, 23.8, 22.5, 21.5, 14.2; ESI
HRMS m/z calcd for C35H38N2O5S1 (M+Na)+ 621.2399, found
621.2377.
Experimental
General Procedure
All commercially available reagents were used without further
purification. All solvents were used after distillation. Tetrahy-
drofuran, diethyl ether and toluene were refluxed over and
distilled from sodium. Dichloromethane was refluxed over and
distilled from P2O5. Dimethylformamide (DMF) was distilled
from CaH2. Preparative separation was usually performed by
column chromatography on silica gel. The 1H NMR and 13C
NMR spectra were recorded using a 400 MHz spectrometer,
and chemical shifts were represented as d-values relative to the
internal standard TMS. The IR spectra were recorded by a FT-
IR spectrometer. The high-resolution mass spectra (HRMS) were
measured by a ESI-TOF MS.
Ethyl (2S,3S)-3-ethyl-1-[(1S,2R)-2-hydroxyl-7-isopropylindan-
1-yl]-2-(N-p-toluenesulfonylindol-3-yl)-piperidine-4-carboxylate
(21). To a solution of 20 (3.27 g, 5.46 mmol) in ether (50 ml) was
slowly added ethyl magnesium bromide (109 ml, 109 mmol, 1.0 M
◦
in ether) at 0 C. After the mixture was stirred for 20 min, H2O
and a 1 N HCl solution were carefully added, and the resulting
mixture was extracted with ethyl acetate. The organic layers were
combined, washed with brine, dried over MgSO4, filtered and
concentrated in vacuo to give the crude product 21 (3.26 g, 95%):
[a]2D4 -31.7 (c 1.1, CHCl3); IR (KBr disk, cm-1) 2963, 2869, 1732,
1449, 1374, 1177, 750;1H and 13C NMR was not corrected; ESI
HRMS m/z calcd for C37H44N2O5S1 (M+Na)+ 651.2869, found
651.2850.
(2S,3S,4R)-(-)-3-Ethyl-4-(acetyl)-N -methyl-2-(indol-3-yl)-
piperidine (5). To a suspension of copper(I) chloride (148 mg,
1.49 mmol) in ether (1.0 ml) was added ethyl magnesium bromide
◦
(1.25 ml, 3.74 mmol, 3.0 M in ether) at 0 C. After the mixture
was stirred for 1 h at this temperature, a solution of 6 (22 mg,
260 | Org. Biomol. Chem., 2011, 9, 257–264
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
Ethyl (2S,3S,4S)-(-)-3-ethyl-2-(N-p-toluenesulfonylindol-3-yl)-
piperidine-4-caboxylate (22a) and Ethyl (2S,3S,4R)-(-)-3-ethyl-
2-(N-p-toluenesulfonylindol-3-yl)-piperidine-4-caboxylate (22b).
To a solution of 21 (924 mg, 1.47 mmol, mixture of diastereomers)
and n-propylamine (1.09 ml, 13.2 mmol) in chloroform (15 ml)
was added lead tetraacetate (2.61 mg, 5.88 mmol) at -50 ◦C. After
the mixture was stirred for 15 min, it was added to an ice-1 N
aqueous NaOH solution. The resulting mixture was filtered and
extracted with chloroform. The organic layers were combined,
washed with H2O, dried over MgSO4, filtered and concentrated
in vacuo to give the crude products of a 3.0 : 1 mixture of C4
stereoisomers. Column chromatography on silica gel (from 0% to
2.8% methanol in chloroform) gave 22a (159 mg, 24%) as a yellow
amorphous solid and 22b (476 mg, 71%) as a yellow amorphous
solid. Data for 22a: [a]D24 -8.1 (c 0.7, CHCl3); IR (KBr disk, cm-1)
(br d, 1H, J = 2.7), 4.63 (ddd, 1H, J = 8.2, 8.0, 8.0), 4.21 (d, 1H,
J = 7.1), 4.09–4.21 (m, 2H), 3.18 (ddd, 1H, J = 11.2, 11.0, 2.7),
3.06 (dd, 1H, J = 15.3, 8.0), 2.96 (dd, 1H, J = 15.6, 9.4), 2.79 (dd,
1H, J = 11.3, 3.6), 2.32–2.49 (m, 2H), 2.18–2.30 (m, 4H), 1.24 (t,
3H, J = 7.1), 1.04 (s, 9H), 0.83 (d, 3H, J = 6.9), 0.31 (s, 3H), 0.22 (s,
3H), 0.05 (d, 3H, J = 6.9); 13C NMR (100 MHz, CDCl3) d 167.0,
147.9, 144.9, 140.5, 140.0, 137.3, 135.8, 135.2, 129.9, 129.8, 128.4,
126.7, 125.9, 124.6, 123.6, 122.8, 122.2, 122.1, 121.2, 113.5, 60.5,
60.4, 55.4, 42.2, 42.1, 27.6, 26.4, 26.1, 25.6, 23.1, 21.4, 18.0, 14.2,
-3.6, -4.0; ESI HRMS m/z calcd for C41H52N2O5S1Si1 (M+Na)+
735.3264, found 735.3232.
3-{(2S)-1-[(1S,2R)-cis-1-(t-butyldimethylsilyloxy)-7-isopropy-
lindan-1-yl]-2-(N-p-toluenesulfonylindol-3-yl)-1,2,5,6-tetrahydro-
pyridin-4-yl}pentan-3-ol (24). To a solution of 23 (53 mg,
0.074 mmol) in ether (2.1 ml) was slowly added ethyl magnesium
bromide (1.2 ml, 1.19 mmol, 1.0 M in ether) at 0 ◦C. After the
mixture was stirred for 3 h, H2O and saturated aqueous NH4Cl
solution were carefully added, and the resulting mixture was
extracted with ethyl acetate. The organic layers were combined,
washed with brine, dried over MgSO4, filtered and concentrated
in vacuo to give the crude products. Column chromatography on
silica gel (from 6.3% to 12% ethyl acetate in hexane) gave the
product 24 (37 mg, 69%) as a yellow amorphous solid: [a]2D5 -80.3
(c 1.0, CHCl3); IR (KBr disk, cm-1) 2960, 2930, 2855, 1375, 1174,
1099,; 1H NMR (400 MHz, CDCl3) d 8.00 (d, 1H, J = 8.5), 7.76
(d, 2H, J = 8.2), 7.69 (d, 1H, J = 7.6), 7.55 (s, 1H), 7.29 (dd, 1H,
J = 7.8, 7.8), 7.12–7.18 (m, 4H), 6.89–6.96 (m, 2H), 5.71–5.75 (br
s, 1H), 5.49–5.52 (m, 1H), 4.65 (dd, 1H, J = 16.0, 8.2), 4.22 (d,
1H, J = 7.1), 3.25 (ddd, 1H, J = 11.0, 11.0, 2.7), 3.06 (dd, 1H, J =
15.6, 8.0), 2.96 (dd, 1H, J = 15.1, 8.0), 2.72 (dd, 1H, J = 15.1, 9.2),
2.48–2.60 (br m, 1H), 2.26 (s, 1H), 1.82–2.10 (m, 1H), 1.80 (d, 1H,
J = 16.0), 1.44–1.63 (m, 4H), 1.03 (s, 9H), 0.81–0.89 (m, 6H), 0.76
(t, 3H, J = 7.6), 0.30 (s, 1H), 0.21 (s, 1H), 0.03–0.13 (br m, 3H);
13C NMR (100 MHz, CDCl3) d 147.9, 144.8, 140.6, 139.4, 137.9,
135.9, 135.3, 130.1, 129.8, 129.7, 128.2, 126.7, 125.4, 124.6, 124.4,
123.8, 123.5, 122.3, 121.1, 113.5, 77.5, 69.7, 55.2, 42.7, 42.2, 32.1,
31.2, 27.6, 27.3, 26.1, 26.0, 25.6, 23.1, 22.8, 21.4, 17.9, 7.8, 7.6
–4.0, -4.7; ESI HRMS m/z calcd for C43H58N2O4S1Si1 (M+Na)+
749.3784, found 749.3752.
1
2959, 2934, 2876, 1724, 1370, 1177, 749; H NMR (400 MHz,
CDCl3) d 7.97 (d, 1H, J = 8.2 Hz), 7.70–7.75 (m, 3H), 7.54 (s,
1H), 7.29 (dd, 1H, J = 8.2, 7.3 Hz), 7.16–7.23 (m, 3H), 4.39 (d,
1H, J = 9.4 Hz), 4.11–4.25 (m, 2H), 3.13 (ddd, 1H, J = 11.9,
10.1, 3.0 Hz), 2.99 (dd, 1H, J = 8.9, 4.4 Hz), 2.93 (ddd, 1H, J =
11.9, 3.9, 3.9 Hz), 2.32 (s, 1H), 1.78–2.00 (m, 3H), 1.02–1.33 (m,
5H), 0.69 (t, 3H, J = 7.3 Hz); 13C NMR (100 MHz, CDCl3) d
174.3, 144.7, 135.3, 135.2, 130.3, 130.0, 126.7, 124.6, 123.8, 123.0,
120.7, 113.7, 60.4, 60.0, 53.6, 45.2, 42.5, 40.3, 28.6, 22.5, 21.5,
21.0, 14.3, 14.2, 11.6; ESI HRMS m/z calcd for C25H30N2O4S1
(M+H)+ 455.2005, found 455.1996. Data for 22b: [a]2D2 -29.1 (c
1.1, CHCl3); IR (KBr disk, cm-1) 2936, 2812, 1728, 1371, 1175,
749; 1H NMR (400 MHz, CDCl3) d 7.97 (d, 1H, J = 8.2 Hz), 7.79
(d, 1H, J = 7.8 Hz), 7.72 (d, 2H, J = 8.4 Hz), 7.52 (s, 1H), 7.30
(dd, 1H, J = 7.3, 7.1 Hz), 7.22 (dd, 1H, J = 8.2, 7.3 Hz), 7.18 (d,
2H, J = 8.5 Hz), 4.08–4.29 (m, 2H), 3.67 (d, 1H, J = 10.3 Hz),
3.17 (ddd, 1H, J = 11.7, 3.4, 2.7 Hz), 2.76 (ddd, 1H, J = 11.5,
11.2, 3.4 Hz), 2.45 (ddd, 1H, J = 11.2, 11.2, 4.9 Hz), 2.11 (dddd,
1H, J = 10.8, 10.8, 4.1, 4.1 Hz), 1.82–1.96 (m, 2H), 1.26 (t, 3H,
J = 7.3 Hz), 1.11–1.21 (m, 1H), 0.97–1.09 (m, 1H), 0.59 (t, 3H,
J = 7.6 Hz),; 13C NMR (100 MHz, CDCl3) d 175.1, 144.8, 135.4,
135.1, 130.0, 126.7, 124.7, 124.3, 123.9, 123.0, 121.0, 113.7; ESI
HRMS m/z calcd for C25H30N2O4S1 (M+H)+ 455.2005, found
455.1986.
Ethyl (2S)-1-[(1S,2R)-cis-2-(t-butyldimethylsilyloxyl)-7-isopro-
pylindan-1-yl]-2-(N-p-toluenesulfonylindol-3-yl)-1,2,5,6-tetrahy-
dropyridine-4-carboxylate (23). To a solution of 20 (251 mg,
0.419 mmol) in dimethylformamide (4.0 ml) were added tri-
ethylamine (0.6 ml, 8.23 mmol) and t-butyldimethylchlorosilane
(126 mg, 0.84 mmol) and 4,4-dimethylamino-4-pyridine (26 mg,
0.21 mmol) at 0 ◦C. After the mixture was stirred at room
temperatue for 20 h, a saturated aqueous NaHCO3 solution was
added, and the resulting mixture was extracted with ethyl acetate.
The organic layers were combined, washed twice with water for
twice and with brine, dried over MgSO4, filtered and concentrated
in vacuo to give the crude products. Column chromatography on
silica gel (from 6.3% to 33% ethyl acetate in hexane) gave the
product 23 (101 mg, 34%) as a yellow amorphous solid and recover
of the starting material 20 (98 mg): [a]2D4 -76.1 (c 0.7, CHCl3); IR
Ethyl (2S,3S,4S)-(-)-3-ethyl-N-methyl-2-(N-p-toluenesulfonyl-
indol-3-yl)-piperidine-4-carboxylate (31a) and Ethyl (2S,3S,4R)-
(-)-3-ethyl-N-methyl-2-(N-p-toluenesulfonylindol-3-yl)-piperidine-
4-carboxylate (31b). To a solution of 22a, 22b (448 mg,
0.985 mmol, mixture of diastereomers) and 37% aqueous
formaldehyde (400 ml, 4.93 mmol) in acetonitrile (9.8 ml) was
added sodium cyanoborohydride (124 mg,1.97 mmol) at room
temperature. After the mixture was stirred at this temperature
for 30 min, a saturated aqueous NaHCO3 solution was added,
and the resulting mixture was extracted with chloroform. The
organic layers were combined, dried over MgSO4, filtered and
concentrated in vacuo to give the crude products. Column
chromatography on silica gel (from 0% to 1.0% methanol in
chloroform) gave the alcohol product 31a (111 mg, 24%) as a
yellow amorphous solid and 31b (334 mg, 72%) as a yellow
amorphous solid. Data for 31a: [a]2D2 -30.0 (c 1.1, CHCl3); IR
(KBr disk, cm-1) 2939, 2878, 2793, 1727, 1447, 1372, 1177, 749;
1H NMR (400 MHz, CDCl3) d 7.98 (d, 1H, J = 8.3 Hz), 7.87
(d, 1H, J = 7.3 Hz), 7.69 (d, 2H, J = 8.5 Hz), 7.47 (s, 1H), 7.27
1
(KBr disk, cm-1) 2930, 2856, 1713, 1377, 1257, 1097; H NMR
(400 MHz, CDCl3) d 8.00 (d, 1H, J = 8.2), 7.76 (d, 2H, J = 8.2),
7.59 (s, 1H), 7.54 (d, 1H, J = 7.8), 7.31 (dd, 1H, J = 7.3, 7.3), 7.12–
7.22 (m, 4H), 6.90–6.96 (m, 2H), 6.72–6.75 (br m, 1H), 5.80–5.85
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 257–264 | 261
©

View Article Online
(dd, 1H, J = 8.0, 7.3 Hz), 7.12–7.20 (m, 3H), 4.11–4.19 (m, 2H),
3.64 (d, 1H, J = 10.1 Hz), 2.92 (dd, 1H, J = 7.6, 5.0 Hz), 2.81
(ddd, 1H, J = 11.9, 3.4, 3.4 Hz), 2.51 (ddd, 1H, J = 11.9, 11.9,
3.4 Hz), 2.27 (s, 3H), 1.81–2.14 (m, 6H), 1.26 (t, 3H, J = 7.6 Hz),
1.05–1.17 (m, 1H), 0.79–0.92 (m, 1H), 0.58 (t, 3H, J = 7.3 Hz);
13C NMR (100 MHz, CDCl3) d 173.9, 144.6, 135.5, 134.9, 129.6,
129.5, 129.6, 124.6, 124.5, 122.9, 120.9, 62.1, 59.8, 23.2, 22.8, 22.7,
21.4; ESI HRMS m/z calcd for C26H32N2O4S1 (M+H)+ 469.2161,
found 469.2143. Data for 31b: [a]2D2 -75.6 (c 1.2, CHCl3); IR
chromatography on silica gel (from 0% to 9.9% methanol in
chloroform) gave the aldehyde product 32b (926 mg, 95%) as a
yellow amorphous solid: [a]2D4 -72.4 (c 1.1, CHCl3); IR (KBr disk,
1
cm-1) 2944, 2784, 2705, 1447, 1370, 750; H NMR (400 MHz,
CDCl3) d 9.58 (d, 1H, J = 4.1 Hz), 7.99 (d, 1H, J = 8.2 Hz),
7.78–7.86 (br d, 1H, J = 7.3 Hz), 7.70 (d, 2H, J = 8.2 Hz), 7.48
(s, 1H), 7.30 (ddd, 1H, J = 7.3, 7.1, 1.1 Hz), 7.20 (ddd, 1H, J =
7.1, 7.1, 1.0 Hz), 7.16 (d, 2H, J = 8.2 Hz), 3.08 (ddd, 1H, J = 11.5,
3.4, 3.0 Hz), 2.92 (d, 1H, J = 10.3 Hz), 2.26–2.39 (m, 4H), 2.09–
2.22 (m, 2H), 1.76–1.93 (m, 5H), 1.07–1.19 (m, 1H), 0.86–0.98 (m,
1H), 0.56 (t, 3H, J = 7.6 Hz); 13C NMR (100 MHz, CDCl3) d
204.0, 145.1, 136.0, 135.2, 130.0, 126.9, 125.2, 125.0, 123.5, 123.3,
121.6, 114.2, 65.1, 55.5, 52.3, 44.8, 40.3, 26.1, 23.1, 21.7, 9.5; ESI
HRMS m/z calcd for C24H28N2O3S1 (M+H)+ 425.1899, found
425.1902.
1
(KBr disk, cm-1) 2940, 2784, 1728, 1369, 1177, 749; H NMR
(400 MHz, CDCl3) d 7.98 (d, 1H, J = 8.2 Hz), 7.77–7.94 (br s,
1H), 7.69 (d, 2H, J = 8.2 Hz), 7.40–7.54 (br s, 1H), 7.29 (dd, 1H,
J = 8.2, 7.1 Hz), 7.20 (dd, 1H, J = 7.6, 7.3 Hz), 7.15 (d, 2H, J =
8.2 Hz), 4.06–4.18 (m, 2H), 3.03 (ddd, 1H, J = 11.0, 3.2, 2.8 Hz),
2.89 (d, 1H, J = 9.8 Hz), 2.38 (ddd, 1H, J = 13.5, 11.4, 3.9 Hz),
2.29 (s, 3H), 1.87–2.24 (m, 7H), 1.23 (t, 3H, J = 7.2 Hz), 1.02–1.14
(m, 1H), 0.76–0.94 (m, 1H), 0.57 (t, 3H, J = 7.6 Hz); 13C NMR
(100 MHz, CDCl3) d 175.1, 144.7, 135.7, 134.9, 129.8, 129.6,
126.5, 124.8, 124.5, 123.4, 123.1, 113.8, 65.5, 60.2, 55.9, 46.1,
44.5, 41.3, 29.3, 23.0, 21.4, 14.2, 9.0; ESI HRMS m/z calcd for
C26H32N2O4S1 (M+H)+ 469.2161, found 469.2145.
(2S,3S,4S)-(-)-3-Ethyl-4-formyl-N-methyl-2-(N-p-toluenesul-
fonylindol-3-yl)-piperidine (32a). To a solution of 31a (73 mg,
0.28 mmol) in toluene (2.8 ml) was added diisobutylaluminium
hydride solution (1.39 ml, 1.39 mmol, 1.0 M in toluene) at -78 ◦C.
After the mixture was stirred at this temperature for 2 h, a saturated
aqueouspotassiumsodiumtartratetetrahydratesolutionwascare-
fully added. The mixture was stirred at room temperature for 1 h,
and extracted with chloroform. The organic layers were combined,
washed with brine, dried over MgSO4, filtered and concentrated
in vacuo to give the crude products. Column chromatography on
silica gel (from 0% to 9.1% methanol in chloroform) gave the
alcohol product (51 mg, 78%) as a white amorphous solid: [a]D26
-33.3 (c 0.9, CHCl3); IR (KBr disk, cm-1) 2955, 2915, 2789, 1597,
(2S,3S,4R)-(-)-3-Ethyl-4-formyl-N-methyl-2-(N-p-toluenesul-
fonylindol-3-yl)-piperidine (32b). To a solution of 31b (300 mg,
0.64 mmol) in toluene (6.4 ml) was added diisobutylaluminium
hydride solution (3.2 mg, 3.2 mmol, 1.0 M in toluene) at
-78 ◦C. After the mixture was stirred at this temperature for
2.5 h, a saturated aqueous potassium sodium tartrate tetrahydrate
solution was carefully added. The resulting mixture was stirred
at room temperature for 1 h, and extracted with chloroform.
The organic layers were combined, washed with brine, dried
over MgSO4, filtered and concentrated in vacuo to give the crude
products. Column chromatography on silica gel (from 0% to 6.3%
methanol in chloroform) gave the alcohol product (237 mg, 87%)
as a yellow amorphous solid: [a]2D2 -86.4 (c 1.0, CHCl3); IR (KBr
disk, cm-1) 2938, 2880, 2786, 1597, 1447, 1370, 1174, 749, 689; 1H
NMR (400 MHz, CDCl3) d 7.98 (d, 1H, J = 8.5 Hz), 7.74–7.82
(br s, 1H), 7.70 (d, 2H, J = 8.2 Hz), 7.49 (s, 1H), 7.27 (dd, 1H, J =
7.8, 7.6 Hz), 7.11–7.20 (m, 3H), 3.50 (dd, 1H, J = 10.5, 3.0 Hz),
3.47 (dd, 1H, J = 10.5, 7.1 Hz), 3.03 (br d, 1H, J = 11.5 Hz), 2.93
(br d, 1H, J = 10.3 Hz), 2.54–2.79 (br s, 1H), 2.26 (s, 3H), 2.11
(dd, 1H, J = 11.4, 10.3 Hz), 1.85–1.97 (m, 3H), 1.50–1.81 (m, 3H),
1.15–1.27 (m, 1H), 0.86–0.91 (br s, 1H), 0.58 (t, 3H, J = 7.6 Hz);
13C NMR (100 MHz, CDCl3) d 144.7, 134.8, 129.5, 126.4, 124.6,
124.4, 124.2, 123.0, 113.7, 64.9, 56.6, 44.6, 40.0, 28.8, 21.3, 20.9,
8.7; ESI HRMS m/z calcd for C24H30N2O3S1 (M+H)+ 427.2055,
found 427.2055.
1
1447, 1370, 1174, 749, 683; H NMR (400 MHz, CDCl3) d 7.98
(d, 1H, J = 8.2 Hz), 7.72–7.79 (br d, 1H, J = 7.1 Hz), 7.70 (d, 2H,
J = 8.2 Hz), 7.44 (s, 1H), 7.27 (dd, 1H, J = 8.2, 7.1 Hz), 7.14–7.22
(m, 3H), 3.82 (dd, 1H, J = 10.3, 10.1 Hz), 3.73 (dd, 1H, J = 10.5,
4.6 Hz), 3.05 (d, 1H, J = 9.8 Hz), 2.83 (ddd, 1H, J = 11.9, 3.9,
3.7 Hz), 2.41 (dd, 1H, J = 12.1, 10.1 Hz), 2.31 (s, 3H), 1.91≥2.18
(m, 7H), -0.89–1.04 (m, 1H), 0.76–0.89 (m, 1H), 0.64 (t, 3H,
J = 7.3 Hz); 13C NMR (100 MHz, CDCl3) d 144.7, 135.6, 135.0,
129.7, 129.6, 126.6, 124.7, 124.3, 123.1, 121.9, 121.0, 113.9, 63.0,
59.1, 51.1, 44.5, 40.0, 26.5, 22.0, 21.5, 11.4; ESI HRMS m/z calcd
for C24H30N2O3S1 (M+H)+ 427.2055, found 427.2059.
To a solution of oxalyl chloride (0.02 mL, 0.77 mmol) in
dichloromethane (2.0 ml) was added DMSO (0.04 ml, 0.93 mmol)
at -78 ◦C. After the mixture was stirred for 10 min at this temper-
ature, a solution of the produced alcohol (132 mg, 0.31 mmol) in
dichloromethane (2.0 ml) was added. After the mixture was stirred
for 40 min, triethylamine (0.18 ml, 1.55 mmol) was added. After
the mixture was stirred for 5 min at this temperature, it was stirred
for an additional 20 min at room temperature, then H2O was
added, and the resulting mixture was extracted with chloroform.
The organic layers were combined, washed with a saturated
aqueous NaHCO3 solution and brine, dried over MgSO4, filtered
and concentrated in vacuo to give the crude products. Column
chromatography on silica gel (from 0% to 9.9% methanol in
chloroform) gave 32a (83 mg, 63%) as a white amorphous solid:
[a]2D6 -37.1 (c 1.3, CHCl3); IR (KBr disk, cm-1) 2960, 2788, 1717,
1447, 1370, 750; 1H NMR (400 MHz, CDCl3) d 9.94 (s, 1H), 7.99
(d, 1H, J = 8.5 Hz), 7.78 (d, 1H, J = 7.9 Hz), 7.71 (d, 2H, J =
8.5 Hz), 7.46 (s, 1H), 7.31 (dd, 1H, J = 7.1, 7.1 Hz), 7.15–7.23
(m, 3H) 3.28 (d, 1H, J = 10.3 Hz), 2.15–2.36 (m, 5H), 1.91–2.11
To a solution of oxalyl chloride (0.162 mL, 5.74 mmol) in
dichloromethane (8.0 ml) was added DMSO (0.307 ml, 6.89 mmol)
◦
at -78 C. After the mixture was stirred for 10 min at this tem-
perature, a solution of the produced alcohol (980 mg, 2.30 mmol)
in dichloromethane (10.0 ml) was added. After the mixture was
stirred for 40 min, triethylamine (1.32 ml, 11.5 mmol) was added.
After the mixture was stirred for 5 min at this temperature, then
stirred for an additional 20 min at room temperature, H2O was
added, and the resulting mixture was extracted with chloroform.
The organic layers were combined, washed with a saturated
aqueous NaHCO3 solution and brine, dried over MgSO4, filtered
and concentrated in vacuo to give the crude products. Column
262 | Org. Biomol. Chem., 2011, 9, 257–264
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
(m, 5H), 1.24–1.39 (m, 1H), 0.87–1.00 (m, 1H), 0.64 (t, 3H, J =
7.3 Hz); 13C NMR (100 MHz, CDCl3) d 204.5, 144.8, 135.7, 135.0,
129.7, 126.7, 124.9, 124.5, 123.8, 123.1, 121.1, 114.0, 64.3, 52.7,
46.0, 44.3, 43.9, 25.6, 22.3, 21.5, 11.7; ESI HRMS m/z calcd for
C24H28N2O3S1 (M+H)+ 425.1899, found 425.1898.
8.0 Hz), 3.06 (ddd, 1H, J = 11.7, 3.4, 3.2 Hz), 2.89 (d, 1H, J =
10.4 Hz), 2.52 (ddd, 1H, J = 11.2, 11.2, 4.8 Hz), 2.30 (s, 1H), 2.07–
2.27 (m, 5H), 1.82–1.92 (m, 5H), 0.98–1.06 (m, 1H), 0.74–0.88 (br
s, 1H), 0.53 (t, 3H, J = 7.6 Hz); 13C NMR (100 MHz, CDCl3) d
211.5, 145.0, 135.9, 135.2, 129.8, 126.8, 125.1, 124.8, 123.5, 123.4,
121.8, 114.1, 56.3, 53.7, 44.7, 29.3, 28.8, 23.1, 21.7, 9.4; ESI HRMS
m/z calcd for C25H30N2O3S1 (M+H)+439.2055, found 439.2038.
(2S,3S,4R)-(-)-3-Ethyl-4-formyl-N-methyl-2-(N-p-toluenesul-
fonylindol-3-yl)-piperidine (32b). To a solution of 32a (83 mg,
0.20 mmol) in THF (4 ml) was added DBU (0.05 ml, 0.29 mmol)at
room temperature. After the mixture was stirred for 24 h, a
saturated aqueous NH4Cl solution was added, and the resulting
mixture was extracted with ethyl acetate. The organic layers
were combined, washed with brine, dried over MgSO4, filtered
and concentrated in vacuo to give the crude products. Column
chromatography on silica gel (from 0% to 9.9% methanol in
chloroform) gave the epimerized product 32b (62 mg, 75%) as
a yellow amorphous solid, and the recovered starting material 32a
(11 mg, 13%) as a yellow amorphous solid.
(2S,3S,4R)-(-)-3-Ethyl-4-acetyl-N-methyl-2-(indol-3-yl)-pipe-
ridine (5). To a solution of 33 (499 mg, 1.02 mmol) in methanol
(7.0 ml) and THF (14.0 ml) was added caesium carbonate (1.33 g,
4.09 mmol) at room temperature. After the mixture was stirred at
65 ◦C for 6 h, a saturated aqueous NH4Cl solution was added and
the resulting mixture was extracted with ethyl acetate. The organic
layers were combined, washed with brine, dried over MgSO4,
filtered and concentrated in vacuo to give the crude products.
Column chromatography on silica gel (from 1.5% to 9% methanol
in chloroform) gave 5 (255 mg, 88%) as a yellow amorphous solid.
(2S,3S,4R) -(-)-3-Ethyl-4-acetyl-N-methyl-2-(N-p-toluenesul-
fonylindol-3-yl)-piperidine (33). To a solution of 32b (471 mg,
1.11 mmol) in THF (10 ml) and ether (10 ml) was added a methyl
(-)-20-Epiuleine (2). To a solution of 5 (17 mg, 0.060 mmol)
in chloroform (6.0 ml) was added p-toluenesulfonic acid mono-
hydrate (51 mg, 0.299 mmol) at room temperature. After the
mixture was stirred at 60 ◦C for 24 h. an aqueous 10% NH3
solution was added, and the resulting mixture was extracted with
dichloromethane. The organic layers were combined, washed with
water, dried over MgSO4, filtered and concentrated in vacuo to give
the crude products. Column chromatography on silica gel (from
50% to 75% ethyl acetate in hexane) gave (-)-20-epiuleine (4 mg,
25%) as a yellow amorphous solid: [a]2D3 -30.1 (c 0.9, CHCl3);
IR (KBr disk, cm-1) 3422, 2961, 2930, 1447, 1319, 739; 1H NMR
(400 MHz, CDCl3) d 8.20–8.28 (br s, 1H), 7.56 (d, 1H, J = 8.0 Hz),
7.34 (d, 1H, J = 8.0 Hz), 7.19 (ddd, 1H, J = 8.0, 6.9, 1.2 Hz), 7.10
(ddd, 1H, J = 8.0, 6.9, 1.2 Hz), 5.18 (s, 1H), 4.95 (s, 1H), 4.03
(d, 1H, J = 2.0 Hz), 2.62–2.66 (br s, 1H), 2.43 (dd, 1H, J = 11.2,
4.6 Hz), 2.19–2.30 (m, 4H), 1.94–2.10 (m, 2H), 1.84–1.90 (m, 1H),
1.64–1.76 (m, 1H), 1.37–1.44 (br d, 1H, J = 12.4 Hz), 1.02 (t, 3H,
J = 7.6 Hz); 13C NMR (100 MHz, CDCl3) d 142.2, 136.5, 135.9,
128.9, 122.7, 119.9, 119.7, 112.2, 110.7, 104.5, 54.8, 46.4, 44.9,
44.7, 38.6, 28.5, 23.6, 12.1; ESI HRMS m/z calcd for C18H22N2
(M+H)+ 267.1861, found 267.1850.
◦
lithium solution (6.93 ml, 11.1 mmol, 1.6 M in ether) at -40 C.
After the mixture was stirred at this temperature for 30 min, H2O
was carefully added, and the resulting mixture was extracted with
chloroform. The organic layers ware combined, washed with brine,
dried over MgSO4, filtered and concentrated in vacuo to give the
crude products. Column chromatography on silica gel (from 2% to
4% methanol in chloroform) gave the sec-alcohol product (320 mg,
65%) in a 1 : 1 mixture of diastereomers as a yellow amorphous
solid: [a]2D4 -90.6 (c 1.1, CHCl3); IR (KBr disk, cm-1) 2963, 2785,
1447, 1370, 1175, 749; 1H NMR (400 MHz, CDCl3) d 7.97 (d, 1H,
J = 8.4 Hz), 7.76–7.87 (br s, 1H), 7.70 (d, 2H, J = 8.4 Hz), 7.43–7.50
(br s, 1H), 7.25–7.32 (m, 1H), 7.13–7.23 (m, 3H), 4.00–4.10 (m,
1H), 3.04–3.11 (m, 1H), 2.88–2.96 (m, 1H), 3.32 (s, 3H), 1.53–2.20
(m, 8H), 1.08–1.40 (m, 4H), 0.77–0.94 (br m, 1H), 0.57–0.68 (m,
3H);13C NMR (100 MHz, CDCl3) d 144.7, 144.7, 135.7, 135.0,
129.6, 126.6, 124.7, 124.5, 123.1, 113.9, 113.8, 67.3, 66.4, 56.7,
44.7, 44.6, 43.4, 43.2, 23.4, 23.0, 21.5, 21.0, 20.7, 20.5, 17.2, 8.8,
8.4; ESI HRMS m/z calcd for C25H32N2O3S1 (M+H)+ 441.2212,
found 441.2201.
To a solution of oxalyl chloride (0.085 mL, 3.00 mmol) in
dichloromethane (3.0 ml) was added DMSO (0.160 ml, 3.60 mmol)
at -78 ◦C. After the mixture was stirred for 20 min at this
temperature, a solution of the produced sec-alcohol afforded above
(529 mg, 1.20 mmol) in dichloromethane (6.0 ml) was added.
After the mixture was stirred for 40 min, triethylamine (0.693
ml, 6.00 mmol) was added. After the mixture was stirred for
5 min at this temperature, it was stirred for an additional 20 min
at room temperature, then H2O was added, and the resulting
mixture was extracted with chloroform. The organic layers were
combined, washed with a saturated aqueous NaHCO3 solution,
dried over MgSO4, filtered and concentrated in vacuo to give the
crude products. Column chromatography on silica gel (from 0% to
0.5% methanol in chloroform) gave 33 (449 mg, 85%) as a yellow
amorphous solid: [a]D22 -71.6 (c 1.0, CHCl3); IR (KBr disk, cm-1)
Acknowledgements
This work was supported by a Grant-in-Aid for Science Research
on Innovative Areas and a Matching Fund Subsidy for a Private
University.
Notes and references
1 J. Bosch and J. Bonjoch, Pentacyclic Strychnos Indole Alkaloids. In
Studies in Natural Products Chemistry; Atta-ur-Rahman, ed.; Elsevier:
Amsterdam, 1988; Vol. 1, pp 31–88.
2 Synthesis of uleine: (a) A. Jackson, N. D. V. Wilson, A. J. Gaskell and
J. A. Joule, J. Chem. Soc. C, 1969, 2738; (b) G. Buchi, S. J. Gould and F.
Naf, J. Am. Chem. Soc., 1971, 93, 2492; (c) T. Kametani and T. Suzuki,
J. Org. Chem., 1971, 36, 129.
3 Synthesis of 20-epiuleine: (a) L. J. Dolby and H. Biere, J. Org. Chem.,
1970, 35, 3843; (b) M. Natsume and Y. Kitagawa, Tetrahedron Lett.,
1980, 21, 839; (c) M. Harris, R. Besselievre, D. S. Grierson and H.-P.
Husson, Tetrahedron Lett., 1981, 22, 331; (d) D. S. Grierson, M. Harris
and H.-P. Husson, Tetrahedron, 1983, 39, 3683; (e) E. S. Tasber and R.
M. Garbaccio, Tetrahedron Lett., 2003, 44, 9185.
1
2938, 2784, 1707, 1447, 1340, 1175, 1121; H NMR (400 MHz,
CDCl3) d 7.98 (d, 1H, J = 8.2 Hz), 7.78–7.90 (br s, 1H), 7.69 (d,
2H, J = 8.2 Hz), 7.42–7.50 (br s, 1H), 7.30 (ddd, 1H, J = 8.5, 6.1,
1.1 Hz), 7.21 (ddd, 1H, J = 8.0, 7.1, 0.9 Hz), 7.16 (d, 2H, J =
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 257–264 | 263
©

View Article Online
4 M. Saito, M. Kawamura, K. Hiroya and K. Ogasawara, Chem.
Commun., 1997, 765. Enantioselective synthesis of Strychnos indole
alkaloids and related compounds: J. Bonjoch and D. Sole, Chem. Rev.,
2000, 100, 3455.
5 (a) K. Tanaka and S. Katsumura, J. Am. Chem. Soc., 2002, 124, 9660;
(b) K. Tanaka, T. Kobayashi, H. Mori and S. Katsumura, J. Org. Chem.,
2004, 69, 5906.
7 T. Kobayashi, F. Hasegawa, K. Tanaka and S Katsumura, Org. Lett.,
2006, 8, 3813.
8 (a) T. Kobayashi, K. Takeuchi, J. Miwa, H. Tsuchikawa and
S. Katsumura, Chem. Commun., 2009, 3363; (b) Y. Li, T.
Kobayashi and S. Katsumura, Tetrahedron Lett., 2009, 50,
4482.
9 H.-P. Husson and J. Royer, Chem. Soc. Rev., 1999, 28, 383.
10 K. Higashiyama, H. Inoue and H. Takahashi, Tetrahedron, 1994, 50,
1083.
6 T. Kobayashi, M. Nakashima, T. Hakogi, K. Tanaka and S. Katsumura,
Org. Lett., 2006, 8, 3809.
264 | Org. Biomol. Chem., 2011, 9, 257–264
This journal is
The Royal Society of Chemistry 2011
©