Critical profiles of chiral diether-mediated asymmetric conjugate aminolithiation of enoate with lithium amide as a key to the total synthesis of (-)-kopsinine

Article abstract of DOI:10.1016/j.tet.2013.02.035

Chiral diether-mediated asymmetric aminolithiation of indolylpropenoate with lithium amide in toluene at -78 °C for 15 min gave, after aqueous ammonium chloride quench, the corresponding conjugate addition product with 97% ee in 89% yield. If hydrogen chloride in methanol was selected as a quencher, however, aminolithiation at -78 °C for 3 h gave the corresponding adduct with 97% ee in 54% yield, along with recovery of the starting enoate in 39% yield. Based on this finding of an incomplete and slow reaction at -78 °C, the aminolithiation conditions were optimized to be at -60 °C for 15 h and subsequent enolate trap with alkyl halide upon an addition of DMPU afforded the desired aminoalkylation product with 98% ee in 89% yield. Further approach toward total synthesis of (-)-kopsinine was carried out by examining asymmetric aminolithiation with N-hydroxyethylamine equivalent, one-pot piperidine formation, and Claisen condensation.

Full text of DOI:10.1016/j.tet.2013.02.035

Tetrahedron 69 (2013) 3264e3273
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Critical profiles of chiral diether-mediated asymmetric conjugate
aminolithiation of enoate with lithium amide as a key to the total
synthesis of (ꢀ)-kopsinine
Shingo Harada a, Takeo Sakai a, Kiyosei Takasu a, Ken-ichi Yamada a,
,
Yasutomo Yamamoto b, Kiyoshi Tomioka b
*
a Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo, Kyoto 606-8501, Japan
b Faculty of Pharmaceutical Sciences, Doshisha Women’s College of Liberal Arts, Kodo, Kyotanabe 610-0395, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Chiral diether-mediated asymmetric aminolithiation of indolylpropenoate with lithium amide in toluene
at ꢀ78 ꢁC for 15 min gave, after aqueous ammonium chloride quench, the corresponding conjugate
addition product with 97% ee in 89% yield. If hydrogen chloride in methanol was selected as a quencher,
however, aminolithiation at ꢀ78 ꢁC for 3 h gave the corresponding adduct with 97% ee in 54% yield,
along with recovery of the starting enoate in 39% yield. Based on this finding of an incomplete and slow
reaction at ꢀ78 ꢁC, the aminolithiation conditions were optimized to be at ꢀ60 ꢁC for 15 h and sub-
sequent enolate trap with alkyl halide upon an addition of DMPU afforded the desired aminoalkylation
product with 98% ee in 89% yield. Further approach toward total synthesis of (ꢀ)-kopsinine was carried
out by examining asymmetric aminolithiation with N-hydroxyethylamine equivalent, one-pot piperidine
formation, and Claisen condensation.
Received 7 January 2013
Accepted 9 February 2013
Available online 19 February 2013
Keywords:
Total synthesis
One-pot
Lithium
Asymmetric reaction
Heterocycles
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
asymmetric conjugate addition is dependent on the structure of
an enoate and is sometimes very slow at low temperature. Another
Chiral diether-mediated asymmetric conjugate addition re-
action of a lithium amide with an enoate has been proven to be
a powerful aminolithiation methodology, mainly because the in-
termediate lithium enolate is applicable as a carbon nucleophile to
a further bond forming reaction with an electrophile, giving nearly
approach toward the total synthesis of (ꢀ)-kopsinine1,2 is also the
subject of the present study.
2. Results and discussion
enantiomerically pure b-amino acid derivatives bearing two vicinal
2.1. Chiral diether-mediated asymmetric conjugate amino-
lithiation with lithium amide and subsequent alkylation
chiral centers in high yield. The conjugate addition step is usually
very rapid and completes within hours, whereas the second al-
kylation step suffers from the low reactivity of an electrophilic alkyl
halide, even in a tolueneeTHF solvent. It is also not so easy to de-
termine whether the first conjugate addition reaction has com-
pleted, because highly reactive anionic species are involved in the
reaction. TLC monitoring is a standard method of tracing the re-
action progress in chemical laboratories; during spotting of the
sample from a capillary, however, the reaction sometimes proceeds
significantly because of an increase in the temperature, leading to
the incorrect information that the reaction has completed. We
describe herein that the speed of the chiral diether-mediated
Chiral diether 3-mediated conjugate addition of lithium N-
benzyl-N-trimethylsilylamide 1 with tert-butyl 3-(N-Boc-indol-3-
yl)propenoate 2a was conducted in toluene at ꢀ78 ꢁC for 15 min
and then quenched with aqueous ammonium chloride to give the
conjugate adduct 5a with 97% ee in 89% isolated yield, indicating
rapid and high yield generation of lithium enolate 4 with 97% ee
(Table 1, entry 1). The sequence of conjugate addition followed by
alkylation of lithium enolate 4 was carried out as previously re-
ported for 1.5 h at ꢀ78 ꢁC and then at ꢀ40 ꢁC for 2 h in order to
confirm the completion of the conjugate aminolithiation,3 and
then, after addition of 222 equiv of THF as a solvent, 6 equiv of
HMPA as an activator by coordination to lithium, and iodide 6a as
an electrophile, at ꢀ40 ꢁC for 3 h. The crude extracts were treated
for protodesilylation with TBAF in THF at rt for 12 h. Silica gel
* Corresponding author. Tel.: þ81 774 65 8676; fax: þ81 774 65 8658; e-mail
address: tomioka@pharm.kyoto-u.ac.jp (K. Tomioka).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.02.035

S. Harada et al. / Tetrahedron 69 (2013) 3264e3273
3265
Table 1
Asymmetric conjugate aminolithiation in toluene-electrophile trap of lithium enolate upon addition of polar additivea
Entry
T1/t1 (ꢁC/h)
Quencher or additive
(equiv)
T2/t2
(ꢁC/h)
5a %
yield
5a % ee
7a %
yield
anti-7a
% ee
anti:syn
2a %
yield
2b %
yield
2c %
yield
1
2
3
4
ꢀ78/0.25
aq NH4Cl
d
89
<1
<1
<5
<8
<8
15
<1
54
79
97
nd
nd
nd
nd
nd
88
nd
97
98
95
98
96
nd
d
70
70
51
60
60
57
73
d
d
d
d
d
89
d
86
82
95
94
95
88
95
d
d
d
d
d
98
d
<2
<2
<5
<1
<2
<1
<1
<1
39
18
5
<2
<1
<1
<1
5
7
0
0
0
3
2
<1
<1
12
3
<1
0
d
11
11
30
16
18
10
13
d
d
d
d
d
2
ꢀ78/1.5 then ꢀ40/2
ꢀ78/1.5 then ꢀ40/2
ꢀ78/1.5 then ꢀ40/2
ꢀ78/1.5 then ꢀ40/2
ꢀ78/1.5 then ꢀ40/2
ꢀ78/1.5 then ꢀ40/2
ꢀ78/1.5 then ꢀ40/2
ꢀ78/3
THF (222)/HMPA (6)
DME (222)/HMPA (6)
DMSO (254)/HMPA (6)
DMF (233)/HMPA (6)
DMF (233)
DMF (30)
DMPU (222)
HCl/MeOH
HCl/MeOH
HCl/MeOH
HCl/MeOH
HCl/MeOH
DMPU (222)
ꢀ40/3
ꢀ40/4
rt/1
ꢀ40/3
ꢀ40/4
ꢀ40/18
ꢀ40/2
d
93:7
93:7
94:6
99:1
99:1
86:14
99:1
d
5
6b
7
8b
9
10
11
12b
13c
14b
ꢀ78/15
d
d
ꢀ78/1.5 then ꢀ40/2
ꢀ65/15
d
75
91
96
<1
d
d
d
ꢀ65/15
d
d
ꢀ65/15
ꢀ40/2
99:1
a
With 3 equiv of 1, 3.6 equiv of 3, and 10 equiv of 6a. Ar¼1-Boc-indol-3-yl.
b
c
Quoted from Ref. 2.
With 1.5 equiv of 1 and 1.8 equiv of 3.
column chromatography gave a 93:7 mixture of anti- and syn-7a
with 86% ee in 70% yield (entry 2). Major byproducts were deBoc
and its N-alkylated products 2b and 2c in 5% and 11% yield, re-
spectively. DeBoc products derived from 5a and 7a were not ob-
served. The chemical yield of 70% and 93:7 diastereomer ratio of 7a
were on the line of acceptance or not; however, 86% ee was rather
poorer than estimation because % ee of lithium enolate 4, produced
at least in 89% yield, should be 97% ee. In addition, it was not clear
why significant amounts of 2b and 2c were produced.
confirmed by the isolation (Table 1, entry 1), it would be nonsense
to doubt the incomplete conjugate addition of 1 to 2a. Yet, this was
shown not to be true by quenching the reaction with hydrogen
chloride (HCl)/methanol, instead of aqueous ammonium chloride
(Table 1, entry 1).
2.2. Quenching of the conjugate addition reaction with hy-
drogen chloride/methanol or aqueous ammonium chloride
Bidentate DME as an additive was similar to THF, giving 7a with
82% ee in 70% yield (entry 3). DMSO was a better additive, giving
anti-7a with 95% ee, albeit in a decreased 51% yield and 2c in 30%
yield at rt for 1 h (entry 4). DMF was also a good additive, giving
anti-7a in 60% yield with high 94% and 95% ee and 99:1 dr in the
absence and presence of HMPA, respectively (entries 5 and 6).2
When the quantity of DMF was decreased to 30 equiv, alkylation
became sluggish and after 18 h gave anti-7a with lower 88% ee and
86:14 dr in 57% yield, 2b in 3% yield, and 2c in 10% yield (entry 7).
DMPU was the best additive among those examined, giving anti-7a
with 95% ee and 99:1 dr in 73% yield, but along with 2b in 2% and 2c
in 13% yield (entry 8).2
The lower yield and poorer % ee production of 7a compared with
5a, and the production of 2b and 2c in significant amounts implied
a couple of possibilities: (1) incomplete conjugate addition reaction
of lithium amide 1 with 2a at the time of addition of the additive,
resulting in 1 and 2a remaining in the reaction mixture, led to the
progression of further conjugate addition reactions without chi-
rality control, and/or (2) addition of the additives to a completed
reaction mixture, resulting in retro-Michael-type reaction of 4 to 1
and 2a, and again conjugate addition but without chirality control.
Since the 89% high yield production of 5a with 97% ee was certainly
The conjugate addition reaction of 1 with 2a was quenched with
HCl/methanol instead of aqueous ammonium chloride after 3 h
at ꢀ78 ꢁC to give, to our surprise, a mixture of 5a with 97% ee in 54%
yield and 2a in 39% recovery yield (Table 1, entry 9). A prolonged 15 h
reaction was not sufficient to complete the reaction, giving 5a with
98% ee in 79% yield and recovering 2a in 18% yield (entry 10). The
previouslyestablished reaction conditions, that is, at ꢀ78 ꢁC for 1.5 h
and additional 2 h at ꢀ40 ꢁC, gave 5a with 95% ee in 75% yield, 2a in
5% recovery, and 2b in 12% yield (entry 11). These incomplete con-
jugate addition reactions rationalize the poorer % ee of 7a because
chiral diether 3 is kicked out from chelation and chiral ligand-free
conjugate addition proceeded upon the addition of lithium co-
ordinating additives like THF, DME, DMSO, DMF, HMPA, and DMPU
at the alkylation step.
Fortunately, the reaction at ꢀ65 ꢁC for 15 h gave 5a with 98% ee
in 91% yield along with very small amounts of 2a and 2b (entry 12).
Use of smaller amounts of 1 (1.5 equiv) and 3 (1.8 equiv) led to the
successful production of 5a with 96% ee in 96% yield and trace
amounts of 2a and 2b (entry 13). Under these specified conjugate
addition conditions 7a of 98% ee was satisfactorily obtained in 89%
yield by adding DMPU as the best activator of lithium enolate 4, as
described previously (entry 14).2

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S. Harada et al. / Tetrahedron 69 (2013) 3264e3273
Table 2
Production of deBoc products 2b and 2c from 4 rather than di-
Enantioselectivity and reactivity dependency on N-substituent of 3-
rectly from 2a would be possible at a higher temperature ꢀ40 ꢁC by
nucleophilic attack of lithium amide 1 to an activated vinylogous
type urethane carbonyl group of 4, as shown in Scheme 1. This
could explain the absence of the formation of a deBoc product of 5a.
indolylpropenoate 2a
Bn
NH
CO2t-Bu
3
CO2t-Bu
Bn
TMS
N
Li
+
N
2
1
toluene
5
N
R1
TMS
Li
R1
Bn
N
O
Li
O
Ot-Bu
Entry
1b
2
2
R1
T, t
5
Yield
ee
1
Ot-Bu
N
2a
2e
2f
Boc
Ts
PMB
ꢀ78 ꢁC, 0.25 h
ꢀ78 ꢁC, 3.5 h
ꢀ40 ꢁC, 4 h
5a
5e
5f
89%
83%
85%
97%
90%
45%
2b
NR2
N
O
Ot-Bu
4
3
a
Scheme 1. Production of deBoc product 2b from 4.
With 3 equiv of 1 and 3.6 equiv of 3. Quenched with saturated aq NH4Cl. Less
than 3% recovery of 2.
b
Quoted from Ref. 2.
These reaction profiles above indicate the incomplete conjugate
addition reaction of 2a with 1 at ꢀ78 ꢁC. When DMPU was used as
an activator, a retro-Michael type reaction would not be possible. By
adding HCl/methanol as a quencher, the progress of the conjugate
addition could be determined (Table 1, entry 9).
slower and did not proceed at ꢀ78 ꢁC, but did proceed at ꢀ40 ꢁC for
4 h to give 5f with 45% ee in 85% yield (entry 3).
The remaining problem was to clarify what was happening in
the reaction mixture after the addition of aqueous ammonium
chloride, resulting in the high yield production of 5a. Although
the reason for the increased yield by the aqueous ammonium
chloride quench (Table 1, entry 1 vs entry 9) is not fully clear, it
could be that the reaction mixture becomes a heterogeneous
iceeliquid suspension upon the addition of aqueous ammonium
chloride at ꢀ78 ꢁC, as shown in Fig. 1. Upon removal of the
cooling bath, the green color of the iceeliquid suspension
changed gradually to brown, violet, yellow, and pale yellow (two-
phase solution) during 20 min, suggesting that the quenching
process required that period of time. Because of the slow hy-
drolysis of lithium amide 1 under heterogeneous suspension
conditions, the remaining complex of 1e3 could undergo conju-
gate addition under a gradually elevating temperature to give 5a
with relatively high % ee in high yield. In contrast, a methanolic
hydrogen chloride quench immediately gave a pale yellow solu-
tion, indicating almost spontaneous protonation of the reactive
anionic species to stop the reaction.
The observed order of reactivity of 2aw2e>2f seems to be
consistent with the electron-withdrawing and -donating nature of
the N-substituents. The electron-withdrawing nature of N-Boc and
N-Ts groups, which block the lone pair electrons of the indole
nitrogen from mesomerism with the dienoate system, would be
the origin of the higher reactivity than 2f. On the other hand,
poorer electrophilicity of 2f than that of 2a and 2e could be
explained by the mesomeric effect of the indole nitrogen lone pair
electrons. These results indicated that electron-withdrawing N-
protecting groups, which allow for the reaction to proceed at
a lower temperature, are desirable for obtaining higher % ee of
products.
2.4. Asymmetric conjugate addition of lithium
alkoxyethylamides
Because an N-hydroxyethyl intermediate is required for the total
synthesis of (ꢀ)-kopsinine, we examined the performance of
hydroxyethylamide equivalents 8aec in asymmetric conjugate addi-
tion. The reaction of TMS-amide 8a bearing a p-methoxybenzyl (PMB)
protection group with 2a did not proceed at ꢀ78 ꢁC, but at ꢀ40 ꢁC for
5 h gave product 9a with only 13% ee in 79% yield (Table 3, entry 1).
Bulkier TBS-amide 8b bearing a bulky trityl protection group was
designedtopreventintramolecular five-membered chelateformation
of the oxygen atom to lithium by bulkiness around the oxygen atom,4
because the five-membered chelation kicks out chiral diether 3 from
the lithium amide-3 complex;5 however, the reaction did not proceed
at ꢀ78 ꢁC, but at ꢀ40 ꢁC for 10 h, giving 9b with only 9% ee in 9% yield
(entry 2). When sterically less hindered 8c, having no TBS group, was
utilized, thereactionproceeded at ꢀ78ꢁC to give ent-9bwith only 17%
ee in low yield (entry 3).
2.3. Enantioselectivity and reactivity dependency on N-sub-
stituent of 3-indolylpropenoate
N-Substituted indolylpropenoates 2 other than N-Boc 2a were
examined as a substrate in asymmetric conjugate amination. The
conjugate addition of 1 to N-Ts enoate 2e (R1¼Ts) at ꢀ78 ꢁC for 3.5 h
gave 5e with 90% ee in 83% yield (Table 2, entry 2), lower than that
of N-Boc-enoate 2a giving 5a with 97% ee in 89% yield after 15 min
(Table 1, entry 1). The reaction progress of 2e could be followed by
TLC monitoring, and indicated that the reaction was not so fast
during TLC sampling and spotting. The reaction of electron-
donating N-p-methoxybenzyl (R1¼PMB) enoate 2f was much
Fig. 1. Heterogeneous suspension to two-phase solution (Table 1, entry 1) at 0, 5, 7, 9, and 20 min after aq NH4Cl quench at ꢀ78 ꢁC and cooling bath removal.

S. Harada et al. / Tetrahedron 69 (2013) 3264e3273
3267
Table 3
2.7. Claisen condensation for C2 elongation of 10
Asymmetric conjugate addition of lithium N-(alkoxyethyl)amide 8a
R2O
R2O
R3
The remaining synthetic tasks for the total synthesis of
(ꢀ)-kopsinine were (1) attachment of C2 to the ester moiety of cis-10
by Claisen condensation, (2) replacement of the N-Bn group with
a hydroxyethyl equivalent, and (3) cyclization to the established
intermediate 20. In our previous total synthesis,2 replacement of the
Bn group with a hydroxyethyl equivalent was the first manipulation.
In this work, however, Claisen condensation of cis-10 was examined
to evaluate the effect of the N-substituent of the indole nitrogen.
The transesterification of tert-butyl ester cis-10 under Fischer
methyl esterification conditions proceeded smoothly with con-
comitant removal of the N-Boc group to give methyl ester cis-11a in
94% yield (Scheme 4). The indole nitrogen of cis-11a was separately
protected by Boc, benzoyl (Bz), pivaloyl (Piv), benzyl (Bn), and PMB
groups to give cis-11bef as substrates for the Claisen condensation.7
NH
N
Li
CO2t-Bu
CO2t-Bu
8
+
3
+
2a
toluene
2a R1 = Boc
R1 2b R1 = H
N
Boc
N
9
Entry 8/R2/R3
T/t (ꢁC/h)
9 yield/ee
2a
2b
yield yield
1
2
3
8a/PMB/TMS ꢀ78/12 then ꢀ40/5
9a 79%/13% ee
2%
52%
14%
18%
5%
8b/Ph3C/TBS ꢀ78/17 then ꢀ40/10 9b 9%/9% ee
8c/Ph3C/H
ꢀ78/0.7
ent-9b 18%/17% ee 63%
a
With 3 equiv of 8 and 3.6 equiv of 3. Quenched with saturated aq NH4Cl. The
absolute configuration of 9 was tentatively assigned by analogy.
In these reactions, the deBoc product 2b was again observed
whereas the deBoc product of 9 was not. It is likely that 2b came
from a lithium enolate intermediate like 4, as shown in Scheme 1.
2.5. Cyclization to piperidines
(a) Boc2O, DMAP, CH3CN; (b) BzCl, NaH, DMF; (c) PivCl, DMAP, Et3N,
CH2Cl2; (d) BnBr, NaH, DMF; (e) PMBCl, NaH, DMF.
Cyclization of anti-7a with mesyl chloride and triethylamine in
methylene chloride at rt for 18 h gave piperidine cis-10 in 98% yield
(Scheme 2).2 In the same way, syn-7a was cyclized into piperidine
trans-10 in 83% yield. The coupling constants 5.2 and 10.1 Hz of the
adjacent methine protons, respectively, indicated the relative
configuration of cis- and trans-10.6 The absolute configuration was
confirmed by converting cis-10 into (ꢀ)-kopsinine.2
Scheme 4. N-Substituted methyl esters cis-11aef.
A THF solution of N-Boc protected cis-11b was added at ꢀ78 ꢁC
to a THF solution of 4 equiv of sodium enolate 12a (M¼Na), gen-
erated in situ by treating methyl acetate with NaHMDS,8 and the
mixture was stirred at ꢀ40 ꢁC for 2 h. After removal of the cooling
bath, the mixture was further stirred for 1 h at rt (Table 4, entry 1).
Disappointingly, Claisen product cis-13a (R4¼H) was obtained in
only 7% yield, and the major product was a 4:1 mixture of cis- and
trans-11a in 80% yield without the recovery of 11b. At rt, sodium
enolate 12a or methoxide should isomerize cis-11b to trans-11b
through a deprotonationeprotonation sequence, and also attack
the Boc group to give 11a and 13a. The reactions of N-Bz 11c
at ꢀ40 ꢁC for 2 h and at rt for another 2 h, and N-Piv 11d at rt for
15 h also resulted in N-deprotection to give cis-11a in 86% and 95%
yield, respectively (entries 2 and 3). N-Bn cis-11e at rt for 15 h and
N-PMB cis-11f at 0 ꢁC for 4 h and at rt for 2 h were converted to the
desired 13e in 12% and 13f in 26% yield with recovery of a signifi-
cant amount of starting and isomerized methyl esters (entries 4 and
Scheme 2. Cyclization to cis- and trans-piperidines 10.
Table 4
Claisen condensation of 11
2.6. Attempted one-pot [ND2D3] cyclization
OM
Bn
Bn
N
N
OMe
12
As shown in Scheme 2, an enolate trap with 6a and MsCl
treatment of anti-7a gave cis-10 in three steps starting from 2a.
Successful one-pot [Nþ2þ3] cyclization of 2a to piperidine cis-10
used chloroiodopropane 6b as a C3 component (Scheme 3).2 1,3-
Diiodopropane 6c as a much more reactive C3 component, how-
ever, did not yield cis-10 and gave HI elimination product 7b in 90%
yield.
+ cis-11 + trans-11
11 yield (cis:trans)
CO2Me
cis-11
T, t
N
O
N
R4
13
R4 CO2Me
Entry cis-11/R4 12/M
T (ꢁC)/t (h)
13/R4 yield
1
2
3
4
5
6
7
8
11b/Boc 12a/Na ꢀ40/2 then rt/1
11c/Bz
12a/Na ꢀ40/2 then rt/2
11d/Piv 12a/Na rt/15
11e/Bn 12a/Na rt/15
11f/PMB 12a/Na 0/4 then rt/2
13a/H 7%
0%
0%
13e/Bn 12% 11e 68% (0:1)
13f/PMB 26% 11f 74% (3:7)
11a 80% (4:1)
11a 86% (1:0)
11a 95% (1:0)
I
Cl
aq. NH4Cl, 100 C, 0.5 h
6b
then aq. NaHCO3, 100 C, 1 h
cis-10
85%, 98% ee
99:1 dr
11f/PMB 12b/Li ꢀ40/1.5 then 0/14 13f/PMB 90% 0%
11a/H
11g/Li
12b/Li 0/15
12b/Li rt/17
0%
11a 88% (1:0)a
11a 8% (1:0)
or
DMPU
C, 2 h
3
C, 3 h
13a/H 66%
1 + 2a
Bn
a
NH
I
I
toluene
aq. NH4Cl, rt, 5 min
then aq. NaHCO3, rt, 5 min
Other byproducts were 14 and 15 in 24% and 27% yield, respectively.
C, 15 h
6c
Ar
DMPU
7b CO2t-Bu
C, 2 h
90%
Scheme 3. One-pot alkylation with 6.

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S. Harada et al. / Tetrahedron 69 (2013) 3264e3273
5). Fortunately, lithium enolate 12b (M¼Li) afforded the desired
Claisen product 13f in 90% yield starting from cis-11f (entry 6).
Unfortunately, the reaction of N-protection free cis-11a with
16 equiv of 12b at 0 ꢁC for 15 h resulted in the recovery of cis-11a in
88% yield, along with self-Claisen condensation products 14 and 15
in 24% and 27% yield, respectively (entry 7). The production of 14
and 15 was rationalized by the reaction of 12b with methyl acetate,
generated by protonation of 12b with the indole NeH of 11a. Thus,
this self-condensation could be avoidable by using lithiated 11a. To
our delight, the reaction of N-lithiated cis-11g, generated in situ by
the lithiation of cis-11a with LiHMDS, with 16 equiv of 12b at rt for
17 h successfully produced 13a in 66% yield and cis-11a in 8% re-
covery (entry 8).
was measured in CDCl3 unless otherwise mentioned. Chemical
shifts and coupling constants are presented in parts per million
relative to tetramethylsilane and hertz, respectively. Abbreviations
are as follows: s, singlet; d, doublet; t, triplet; m, multiplet; br,
broad. 13C peak multiplicity assignments were made based on DEPT
data. IR spectroscopy of oil and solid samples were measured as
neat liquid films and KBr pellets, respectively. The wave numbers of
maximum absorption peaks of IR spectroscopy are presented in
cmꢀ1. DMSO, DMF, and DMPU were distillated prior to use. TMSCl
was freshly distilled from CaH2 prior to use. Dehydrated solvents
were purchased and used without further desiccation. Other re-
agents were purchased and used as received.
4.2. Starting materials
2.8. Construction of the common intermediate 20 of kopsia
alkaloids
N-Benzyltrimethylsilylamine,10 2-trityloxyethylamine,11 2a,2
3,12 5f,13 and 6a14 were prepared according to reported procedures.
Toward Natsume’s intermediates 18 and 20,1d 13a was N-
methoxycarbonylated to give indole 16 in 95% yield (Scheme 5).
Hydrogenolysis of 16 removed the Bn group from the nitrogen to
give secondary amine 17, which was, without purification,
hydroxyethylated to unstable 18. Mesylation of 18, followed by the
tandem cyclization reported by Natsume1d afforded (ꢀ)-20,9
a pentacyclic common intermediate for kopsia alkaloids in 10%
yield over four steps. The hydrogenolysis step, however, lacked
reproducibility, and the rest of the three-step transformation was
low-yielding, probably due to the concomitant presence of the
secondary amine and ketoester moiety. The problem observed in
this approach was overcome by postponing the Claisen condensa-
tion reaction after the completion of N-hydroxyethylation.2
4.2.1. (E)-tert-Butyl 1-p-toluenesulfonylindole-3-propenoate
(2e). The reported procedure13 using 1-p-toluenesulfonylindole-
3-carbaldehyde15 (13.5 g, 45 mmol), instead of 1-p-methox-
ybenzylindole-3-carbaldehyde, gave the title compound (15.4 g,
86%) as colorless prisms of mp 139.5e140.5 ꢁC: Rf¼0.6 (hexane/
AcOEt 4/1). 1H NMR: 1.54 (9H, s), 2.35 (3H, s), 6.45 (1H, d, J¼16.2),
7.23e7.39 (4H, m), 7.68 (1H, d, J¼16.2), 7.71e7.81 (4H, m), 8.00 (1H,
m). 13C NMR: 21.5 (CH3), 28.2 (CH3), 80.5 (C), 113.8 (CH), 118.4 (C),
120.4 (CH), 120.7 (CH), 124.0 (CH), 125.4 (CH), 127.0 (CH), 128.0
(CH), 128.3 (C), 130.1 (CH), 134.5 (CH), 134.9 (C), 135.7 (C), 145.5 (C)
166.5 (C). IR: 2978, 1705, 1636, 1366, 1150, 980. EIMS m/z: 397 (Mþ),
324 (MꢀOt-Bu). Anal. Calcd for C22H23NO4S: C, 66.48; H, 5.83; N,
3.52. Found: C, 66.34; H, 5.87; N, 3.36.
R
4.2.2. N-Trimethylsilyl(2-p-methoxybenzyloxyethyl)amine. To a so-
lution of 2-p-methoxybenzyloxyethylamine16 (14 g, 77 mmol) in
THF (155 mL) was added a 1.64 M hexane solution of BuLi (49 mL,
80 mmol) at ꢀ78 ꢁC over 10 min, and the mixture was stirred for 1 h
at ꢀ78 ꢁC. Then TMSCl (10 mL, 80 mmol) was added over 5 min, and
the mixture was warmed up to rt and stirred for 3 h. Concentration
and distillation (200e205 ꢁC/0.2 mmHg) gave the title compound
(7.0 g, 36%) as a colorless oil: 1H NMR (C6D6): ꢀ0.06 (9H, s), 0.69
(1H, br s), 2.89 (2H, dt, J¼8.1, 5.7), 3.27 (3H, s), 3.30 (2H, t, J¼5.7),
4.35 (2H, s), 6.80 (2H, d, J¼8.6), 7.23 (2H, d, J¼8.6). 13C NMR (C6D6):
0.14 (CH3), 42.0 (CH2), 54.7 (CH3), 72.9 (CH2), 73.5 (CH2), 114.0 (CH),
129.4 (CH), 131.3 (C), 160.0 (C). IR: 3395, 2955, 1612, 1512, 1250, 841.
EIMS m/z: 253 (Mþ), 222 (MꢀOMe), 121 (PMB). HRMSeFAB m/z:
[MþH]þ calcd for C13H24NO2Si, 254.1576; found, 254.1579.
N
NCCO2Me
LiHMDS
KOt-Bu
13a
THF
C, 20 min
95%
THF/HMPA
C, 1 h; rt, 1 h
N
O
MeO2C
CO2Me
16 R = Bn
Pd/C, HCO2H
ICH2CH2OH, Na2CO3
MsCl, Et3N
17 = H
18 = (CH2)2OH
19 = (CH2)2OMs
N
H
N
H
H
H
O
N
H
N
H
H
20
CO2Me
CO2Me
)-kopsinine
10%, 4 steps
Scheme 5. Construction of the common intermediate 20.
4.2.3. N-tert-Butyldimethylsilyl(2-trityloxyethyl)amine. To
a solu-
tion of 2-trityloxyethylamine (2.5 g, 8.3 mmol), Et3N (1.5 mL,
11 mmol), and DMAP (20 mg, 0.17 mmol) in Et2O (25 mL) was
added TBSCl (1.5 g,10 mmol) at 0 ꢁC, and the mixture was stirred for
19 h at rt. The resulting precipitate was removed by filtration.
Volatile materials were removed by evaporation, and the residue
was dried in vacuo (70 ꢁC/0.01 mmHg) to give the title compound
as a colorless oil (2.2 g, 65%): 1H NMR (C6D6): ꢀ0.02 (6H, s), 0.51
(1H, t, J¼8.0), 0.90 (9H, s), 2.94 (2H, dt, J¼8.0, 6.0), 3.11 (1H, t, J¼6.0),
7.02e7.15 (9H, m), 7.55e7.60 (6H, m). 13C NMR: ꢀ4.9 (CH3), 18.5 (C),
26.6 (CH3), 42.9 (CH2), 67.3 (CH2), 86.7 (C), 127.5 (CH), 128.3 (CH),
129.2 (CH), 144.9 (C). IR: 3410, 2931, 1450, 1072. EIMS m/z: 387
(Mꢀ2Me), 243 (Ph3C). The oil was used without further
purification.
3. Conclusion
The reaction speed of chiral diether-mediated asymmetric ami-
nolithiation of indolylpropenoate with lithium amide in toluene at
a low temperature was substrate dependent. Completion of the re-
action could be verified by a hydrogen chlorideemethanol quench,
but not by an aqueous ammonium chloride quench. The Claisen
condensation was successfully conducted under proton source-free
conditions. These findings led to the total synthesis of (ꢀ)-kopsinine.
4. Experimental section
4.1. General
4.3. Table 1
All melting points are uncorrected. Silica gel was used for col-
umn chromatography. NMR (500 MHz for 1H and 125 MHz for 13C)
4.3.1. Typical procedure A (entry 1). (ꢀ)-tert-Butyl (S)-3-benzylamino-
3-(1-tert-butoxycarbonylindol-3-yl)propanoate (5a). To a solution of

S. Harada et al. / Tetrahedron 69 (2013) 3264e3273
3269
N-benzyltrimethylsilylamine (0.29 mL, 1.5 mmol) in toluene (4 mL),
was added a 1.62 M hexane solution of BuLi (0.93 mL, 1.5 mmol)
at ꢀ78 ꢁC over 4 min, and the mixture was stirred for 30 min. Then
a solution of chiral diether 3 (436 mg, 1.8 mmol) in toluene (2 mL)
was added over 5 min, and after 30 min, a solution of enoate 2a
(172 mg, 0.5 mmol) in toluene (2 mL) was added over 6 min. The
mixture was stirred for 15 min, and saturated aq NH4Cl (1.5 mL) was
added. After 5 min, the cooling bath was removed, and the whole
was allowed to warm up to rt. Then, saturated aq NaHCO3 (10 mL)
was added, and the organic layer was separated. The aqueous layer
was extracted with AcOEt, and the combined organic layers were
washed with brine and dried over Na2SO4. Concentration and col-
umn chromatography (hexane/AcOEt 16/1 to 3/2) gave the title
compound2 (200 mg, 89%) with 97% ee as a yellow oil, chiral ligand
3 (436 mg, quant) as colorless plates, 2a (1.6 mg, 1%) as a yellow oil,
and 2b17 (1.5 mg, 1%) as a yellow oil. The enantiomeric excess of 5a
was determined according to the previous report.2
NMR: 1.35 (9H, s), 1.90 (1H, br s), 2.31 (3H, s), 2.66 (1H, dd, J¼5.5,
15.6), 2.78 (1H, dd, J¼8.6, 15.6), 3.56 (1H, d, J¼13.2), 3.65 (1H, d,
J¼13.2), 4.37 (1H, dd, J¼5.5, 8.6), 7.18e7.33 (9H, m), 7.52 (1H, s), 7.69
(1H, d, J¼8.0), 7.74 (2H, d, J¼8.6), 7.99 (1H, d, J¼8.2). 13C NMR: 21.5
(CH3), 27.9 (CH3), 42.2 (CH2), 51.3 (CH2), 51.5 (CH), 80.8 (C), 113.9
(CH), 120.5 (CH), 123.1 (CH), 123.9 (CH), 124.8 (CH), 126.8 (CH), 127.0
(CH), 128.2 (CH), 128.4 (CH), 129.5 (C), 129.78 (C), 129.84 (CH), 135.3
(C) 135.7 (C), 140.2 (C), 144.9 (C), 171.0 (C). IR: 3332, 2978, 1728,
1597, 1450, 1381, 1119. EIMS m/z: 504 (Mþ), 447 (Mꢀt-Bu), 413
(MꢀBn), 389 (MꢀCH2CO2t-Bu). Anal. Calcd for C29H32N2O4S: C,
69.02; H, 6.39; N, 5.55. Found: C, 68.72; H, 6.37; N, 5.39. The en-
antiomeric excess was determined by HPLC (Daicel Chiralcel OD-H,
254 nm, hexane/i-PrOH 50/1, 1.0 mL/min, minor 17.3 min and major
23.4 min).
4.4.2. Entry 3. (ꢀ)-tert-Butyl (S)-3-benzylamino-3-(1-p-methox-
ybenzylindol-3-yl)propanoate (5f). The typical procedure
A of
Table 1 using 2f (363 mg, 1.0 mmol), instead of 2a, gave the title
compound (402 mg, 85%) with 45% ee as a pale yellow oil. 1H and
13C NMR, IR, and MS were identical to those reported.13
4.3.2. Typical procedure B (entry 2). (ꢀ)-tert-Butyl (2S,3S)-3-benzyla-
mino-3-(1-tert-butoxycarbonylindol-3-yl)-2-(3-hydroxypropyl)prop-
anoate (syn-7a). To
a solution of N-benzyltrimethylsilylamine
(0.59 mL, 3.0 mmol) in toluene (8 mL), was added a 1.54 M hexane
solution of BuLi (1.95 mL, 3.0 mmol) at ꢀ78 ꢁC over 3 min, and the
mixture was stirred for 30 min. A solution of chiral diether 3
(872 mg, 3.6 mmol) in toluene (4 mL) was added over 7 min, and
after 30 min, a solution of enoate 2a (344 mg, 1.0 mmol) in toluene
(4 mL) was added over 6 min. The mixture was stirred for 1.5 h at
ꢀ78 ꢁC and further 2 h at ꢀ40 ꢁC, and a solution of 3-(tert-butyl-
dimethylsiloxy)-1-iodopropane (6a) (2.4 mL, 10 mmol) and HMPA
(1.04 mL, 6 mmol) in THF (18 mL) was added over 30 min at ꢀ78 ꢁC.
The mixture was stirred for 2.5 h at ꢀ40 ꢁC, and saturated aq NH4Cl
(2 mL) was added. The cooling bath was removed, and after the
whole was warmed up to rt, saturated aq NaHCO3 (12 mL) was
added. The organic layer was separated, and the aqueous layer was
extracted with AcOEt. The combined organic layers were washed
with brine, dried over Na2SO4, and then concentrated to give a col-
orless oil (4.7 g). The oil was dissolved in THF (15 mL), and
TBAF$3H2O (4.7 g, 15 mmol) was added to the solution at rt. The
mixture was stirred for 12 h, and saturated aq NH4Cl (6 mL) and
saturated aq NaHCO3 (10 mL) were added. The whole was extracted
with benzene (30 mLꢂ3). The combined organic layers were
washed with water (10 mLꢂ3) and brine, and dried over Na2SO4.
Concentration and column chromatography (hexane/AcOEt 9/1 to
1/1) gave chiral ligand 3 (872 mg, quant) as colorless plates, 2b17
(13 mg, 5%) as a pale yellow oil, anti-7a2 (333 mg, 65%) as white
powder of mp 160e162 ꢁC, 2c2 (33 mg, 11%) as a pale yellow oil, and
the title compound (28 mg, 5%) as a pale yellow oil: Rf¼0.2 (hexane/
4.5. Table 3
4.5.1. Entry 1. (ꢀ)-tert-Butyl (S)-3-(2-p-methoxy-benzyloxyethylamino)-
3-(1-tert-butoxycarbonylindol-3-yl)propanoate (9a). The typical pro-
cedure A of Table 1 in 0.54 mmol scale using N-(2-p-methox-
ybenzyloxyethyl)trimethylsilylamine (407 mg, 1.6 mmol), instead
of N-benzyltrimethylsilylamine, gave the title compound (233 mg,
79%) with 13% ee as a colorless oil: Rf¼0.4 (hexane/AcOEt 4/1). [
25
a]
D
ꢀ1.81 (c 1.00, CHCl3). 1H NMR: 1.37 (9H, s), 1.65 (9H, s), 2.08 (1H, br
s), 2.68e2.81 (4H, m), 3.50e3.56 (2H, m), 3.80 (3H, s), 4.38 (1H, dd,
J¼6.3, 7.7), 4.42 (2H, s), 6.86 (2H, dd, J¼1.9, 8.3), 7.19e7.32 (4H, m),
7.52 (1H, s), 7.72 (1H, m), 8.15 (1H, m). 13C NMR: 28.0 (CH3), 28.2
(CH3), 42.6 (CH2), 47.1 (CH2), 52.1 (CH3), 55.2 (CH), 69.3 (CH2), 72.6
(CH2), 80.7 (C), 83.5 (C), 113.7 (CH), 115.2 (CH), 119.8 (CH), 121.9 (C),
122.4 (CH), 123.2 (CH), 124.3 (CH), 129.2 (C), 129.3 (CH), 130.4 (C),
135.8 (C), 149.7 (C), 159.1 (C), 171.1 (C). IR: 3325, 2978, 1736, 1365,
1157. FABMS m/z: 525 [MþH]þ. Anal. Calcd for C30H40N2O6: C,
68.68; H, 7.68; N, 5.34. Found: C, 68.48; H, 7.68; N, 5.32. The en-
antiomeric excess was determined by HPLC (Daicel Chiralcel AD-3,
254 nm, hexane/i-PrOH 25/1, 1.0 mL/min, minor 15.1 min and major
16.6 min).
4.5.2. Entry 2. (ꢀ)-tert-Butyl (S)-3-(2-(trityloxy)ethylamino)-3-(1-
(tert-butoxycarbonyl)indol-3-yl)propanoate (9b). The typical pro-
cedure A of Table 1 in 0.45 mmol scale using N-(2-trityloxyethyl)-
tert-butyldimethylsilylamine (559 mg, 1.3 mmol), instead of N-
benzyltrimethylsilylamine, gave the title compound (25 mg, 9%)
AcOEt 3/2). [
a
]
25 ꢀ14.1 (c 1.11, CHCl3). 1H NMR: 1.17 (9H, s),1.48e1.57
D
(4H, m), 1.67 (9H, s), 1.78e1.90 (2H, m), 2.84 (1H, ddd, J¼10.3, 7.7,
2.9), 3.59e3.62 (3H, m), 3.78 (1H, d, J¼13.2), 4.14 (1H, d, J¼7.7),
7.21e7.33 (7H, m), 7.54 (1H, s), 7.67 (1H, m), 8.17 (1H, m). 13C NMR:
24.7 (CH2), 27.6 (CH3), 28.2 (CH3), 30.6 (CH2), 51.5 (CH2), 51.6 (CH),
56.4 (CH), 62.2 (CH2), 80.6 (C), 83.7 (C), 115.3 (CH), 119.8 (CH), 120.2
(C), 122.5 (CH), 124.2 (CH), 124.4 (CH), 127.0 (CH), 128.3 (CH), 128.4
(CH),129.4 (C),135.7 (C) 139.7 (C),149.6 (C),173.6 (C). IR: 3402, 2977,
1728. EIMS m/z: 508 (Mþ), 417 (MꢀBn). HRMSeFAB m/z: [MþH]þ
calcd for C30H41N2O5, 509.3015; found, 509.3029. The enantiomeric
excess was not determined.
with 9% ee as a yellow oil: Rf¼0.5 (hexane/AcOEt 4/1). [
a
]
D
25 ꢀ2.88 (c
1.10, CHCl3). 1H NMR: 1.39 (9H, s), 1.64 (9H, s), 2.07 (1H, br s),
2.69e2.83 (2H, m), 2.74 (2H, t, J¼5.4), 3.17e3.20 (2H, m), 4.38 (1H,
dd, J¼5.6, 7.9), 7.18e7.42 (17H, m), 7.49 (1H, m), 7.72 (1H, m), 8.15
(1H, m). 13C NMR: 28.0 (CH3), 28.2 (CH3), 42.3 (CH2), 47.3 (CH2), 52.1
(CH), 63.1 (CH2), 80.7 (C), 83.5 (C), 86.5 (C), 115.2 (CH), 119.9 (CH),
121.8 (C), 122.4 (CH), 123.3 (CH), 124.4 (CH), 126.8 (CH), 127.7 (CH),
128.7 (CH), 129.0 (C), 135.8 (C), 144.1 (C), 149.6 (C), 171.2 (C).
IR: 3425, 2978, 1738, 1373, 1157. EIMS m/z: 646 (Mþ), 531
(MꢀCH2CO2t-Bu), 403 (MꢀCPh3). HRMSeFAB m/z: [MþH]þ calcd
for C41H47N2O5, 647.3485; found, 647.3499. The enantiomeric ex-
cess was determined after removal of the trityl group (vide infra).
4.4. Table 2
4.4.1. Entry 2. (ꢀ)-tert-Butyl (S)-3-benzylamino-3-(1-p-toluene-
4.5.3. Entry 3. (ꢀ)-tert-Butyl (R)-3-(2-(trityloxy)ethylamino)-3-(1-
(tert-butoxycarbonyl)indol-3-yl)propanoate (ent-9b). The typical
procedure A of Table 1 using 2-trityloxyethylamine (455 mg,
sulfonylindol-3-yl)propanoate (5e). The typical procedure
A of
Table 1 using 2e (397 mg, 1.0 mmol), instead of 2a, gave the title
compound (418 mg, 83%) with 90% ee as a pale yellow oil: Rf¼0.2
1.5 mmol), instead of N-benzyltrimethylsilylamine, gave the title
25
25
(hexane/AcOEt 20/1). [
a
]
ꢀ22.9 (c 1.30, CHCl3) for 96% ee. 1H
compound (57 mg, 18%) with 17% ee as a yellow oil: [
a]
þ5.63
D
D

3270
S. Harada et al. / Tetrahedron 69 (2013) 3264e3273
(c 1.10, CHCl3). 1H and 13C NMR, IR, MS, and Rf were identical to
those of 9b. The enantiomeric excess was determined after removal
of the trityl group (vide infra).
and the title compound (221 mg, 90%) as colorless needles of mp
136e138 ꢁC: Rf¼0.4 (hexane/AcOEt 4/1). [
a]
D
25 ꢀ16.8 (c 1.07, CHCl3).1H
NMR: 1.46 (9H, s), 1.69 (9H, s), 1.74 (1H, br s), 2.05 (1H, m), 2.21 (1H,
m), 2.88 (1H, m), 3.55 (1H, d, J¼12.8), 3.69 (1H, d, J¼12.8), 4.05 (1H, d,
J¼9.8), 4.91e4.95(2H, m), 5.65(1H, m), 7.16e7.35 (7H, m), 7.49 (1H, s),
7.77 (1H, m), 8.16 (1H, m). 13C NMR: 28.06 (CH3), 28.08 (CH3), 34.8
(CH2), 51.3 (CH2), 52.0 (CH), 56.6 (CH), 80.6 (C), 83.6 (C), 115.3 (CH),
116.6 (CH2), 119.9 (CH), 120.2 (C), 122.5 (CH), 124.4 (CH), 124.5 (CH),
126.7 (CH), 128.11 (CH), 128.15 (CH), 129.2 (C), 135.1 (CH), 136.0 (C),
140.4 (C),149.6 (C),173.6 (C). IR: 3120, 2985,1732,1712,1450. EIMS m/
z: 490 (Mþ), 399 (MꢀBn). Anal. Calcd for C30H38N2O4: C, 73.44; H,
7.81; N, 5.71. Found: C, 73.54; H, 7.81; N, 5.59.
4.5.4. Determination of the ee of 9b and ent-9b. (ꢀ)-tert-Butyl (S)-3-
(2-hydroxyethyl)amino-3-(1-tert-butoxycarbonylindol-3-yl)prop-
anoate. To a solution of 9b (10 mg, 0.015 mmol) in CH2Cl2 (1.6 mL)
was added TFA (7
m
L, 0.09 mmol) at ꢀ10 ꢁC. The mixture was stirred
for 12 h at ꢀ10 ꢁC, and saturated aq NaHCO3 (1 mL) was added. The
whole was extracted with AcOEt, and the organic layer was washed
with brine and dried over Na2SO4. Concentration and column
chromatography (hexane/AcOEt 1/4 to 0/1) gave the title com-
pound (5.3 mg, 85%) with 9% ee as a colorless oil: Rf¼0.1 (hexane/
25
AcOEt 3/2). [
a
]
ꢀ1.96 (c 0.53, CHCl3). 1H NMR: 1.42 (9H, s), 1.67
4.8. Scheme 4
D
(9H, s), 1.81e1.97 (2H, br s), 2.73e2.79 (3H, m), 2.85 (1H, dd, J¼8.9,
15.8), 3.57 (1H, td, J¼4.8, 11.1), 3.67 (1H, td, J¼5.4, 11.1), 4.41 (1H, dd,
J¼4.6, 8.9), 7.24 (1H, m), 7.32 (1H, dd, J¼7.0, 7.2), 7.54 (1H, s), 7.69
(1H, m), 8.16 (1H, m). 13C NMR: 28.0 (CH3), 28.2 (CH3), 42.1 (CH2),
48.4 (CH2), 51.4 (CH), 61.2 (CH2), 81.0 (C), 83.7 (C), 115.4 (CH), 119.5
(CH), 121.7 (C), 122.5 (CH), 123.1 (CH), 124.5 (CH), 128.9 (C), 135.8
(C), 149.6 (C), 171.3 (C). IR: 3363, 2978, 1728, 1373, 1157. EIMS m/z:
404 (Mþ), 359 (MꢀCH2OH), 344 (MꢀNHCH2CH2OH), 289
(MꢀCH2CO2t-Bu). HRMSeFAB m/z: [MþH]þ calcd for C22H33N2O5,
405.2389; found, 405.2386. The enantiomeric excess was de-
termined by HPLC (Daicel Chiralcel AD-3, 254 nm, hexane/i-PrOH 9/
1, 1.0 mL/min, minor 8.9 min and major 9.8 min).
4.8.1. Methyl (2RS,3SR)-1-benzyl-2-(indol-3-yl)piperidine-3-carboxylate
(cis-11a). To a solution of (ꢃ)-cis-10 (1.15 g, 2.3 mmol) in MeOH
(20 mL) was added a solution of H2SO4 (0.66 mL,12 mmol) in MeOH
(19 mL) over 15 min at rt, and the whole was stirred under reflux for
14 h. To the mixture, was added saturated aq NaHCO3 (40 mL)
dropwise and then AcOEt (100 mL) at rt. The organic layer was
separated and the aqueous layer was extracted with AcOEt. The
combined organic layers were washed with brine and dried over
Na2SO4. Concentration and column chromatography (hexane/
AcOEt 4/1 to 3/1) gave the title compound (768 mg, 94%) as col-
orless needles of mp 153e155 ꢁC: Rf¼0.3 (hexane/AcOEt 3/2). 1H
NMR: 1.70 (1H, m), 1.85e2.05 (3H, m), 2.52 (1H, ddd, J¼12.2, 4.0,
3.2), 2.62 (1H, J¼ddd, 12.2, 11.3, 3.1), 3.15 (1H, ddd, J¼11.0, 5.0, 4.8),
3.21 (3H, s), 3.30 (1H, d, J¼14.0), 3.55 (1H, d, J¼14.0), 4.84 (1H, d,
J¼4.8), 7.05 (1H, ddd, J¼8.3, 7.0, 1.3), 7.16 (1H, ddd, J¼8.3, 7.0, 1.3),
7.19e7.31 (6H, m), 7.35 (1H, d, J¼8.3), 7.47 (1H, d, J¼8.3), 8.14 (1H, br
s). 13C NMR: 22.1 (CH2), 23.7 (CH2), 45.8 (CH), 46.7 (CH2), 51.1 (CH3),
55.4 (CH), 59.3 (CH2), 110.8 (CH), 119.2 (CH), 119.3 (CH), 121.8 (CH),
122.7 (CH), 126.7 (CH), 128.0 (C), 128.1 (CH), 128.7 (C), 128.8 (CH),
135.1 (C), 140.0 (C), 174.1 (C). IR: 3410, 3122, 2935, 2842, 1737, 1456.
EIMS m/z: 348 (Mþ), 257 (MꢀBn). Anal. Calcd for C22H24N2O2: C,
75.83; H, 6.94; N, 8.04. Found: C, 75.58; H, 7.00; N, 8.03.
4.6. Scheme 2
4.6.1. tert-Butyl (2S,3S)-1-benzyl-2-(1-tert-butoxycarbonylindol-3-
yl)piperidine-3-carboxylate (trans-10). The procedure reported for
cis-102 using syn-7 (67 mg, 0.13 mmol), instead of anti-7, gave the
title compound (54 mg, 83%) as a colorless oil: Rf¼0.8 (hexane/
AcOEt 2/1). 1H NMR: 1.09 (9H, s), 1.61e1.69 (3H, m), 1.64 (9H, s),
1.92e2.02 (2H, m), 2.87 (1H, d, J¼13.2), 2.91e2.98 (2H, m), 3.55 (1H,
d, J¼10.1), 3.89 (1H, d, J¼13.2) 7.15e7.30 (7H, m), 7.50 (1H, s), 8.13
(2H, m). 13C NMR: 24.6 (CH2), 27.5 (CH3), 28.1 (CH3), 28.3 (CH2), 50.2
(CH), 52.6 (CH2), 59.5 (CH2), 63.4 (CH), 79.8 (C), 83.3 (C), 115.0 (CH),
120.6 (C), 121.3 (CH), 122.3 (CH), 124.4 (CH), 124.6 (CH), 126.5 (CH),
128.0 (CH), 128.8 (CH), 129.1 (C), 136.0 (C), 139.3 (C), 149.5 (C), 173.4
(C). IR: 2977, 1728, 1366. EIMS m/z: 490 (Mþ), 399 (MꢀBn).
HRMSeFAB m/z: [MþH]þ calcd for C30H39N2O4, 491.2910; found,
491.2900. The relative configuration was determined on the basis of
the coupling constants between the adjacent methine protons at
2.91e2.98 ppm and 3.55 ppm (J¼10.1 Hz).
4.8.2. Methyl (2RS,3SR)-1-benzyl-2-(1-tert-butoxycarbonylindol-3-
yl)piperidine-3-carboxylate (cis-11b). To a stirred solution of cis-11a
(48 mg, 0.14 mmol) and DMAP (6.4 mg, 0.052 mmol) in CH3CN
(1.4mL), wasaddedBoc2O(0.063mL, 0.28mmol) dropwiseatrt. After
30 min, to the mixture were added saturated aq NH4Cl (2 mL) and
saturated aq NaHCO3 (4 mL). The aqueous layer was extracted with
AcOEt. The combined organic layers were washed with water and
brine, and dried over Na2SO4. Concentration and column chroma-
tography (hexane/AcOEt9/1)gavethetitle compound(56 mg, 90%)as
yellow amorphous solid: Rf¼0.6 (hexane/AcOEt 4/1). 1H NMR: 1.67
(1H, m),1.71 (9H, s),1.85e1.97 (3H, m), 2.56 (1H, ddd, J¼12.2, 4.0, 3.1),
2.69(1H, ddd, J¼12.2,11.6, 2.5), 3.13 (1H, ddd, J¼9.8, 6.0, 4.6), 3.23(3H,
s), 3.38 (1H, d, J¼13.8), 3.46 (1H, d, J¼13.8), 4.75 (1H, d, J¼4.6),
7.14e7.41 (8H, m), 7.70 (1H, m), 8.07 (1H, m).13C NMR:21.8(CH2), 23.5
(CH2), 28.1 (CH3), 45.4 (CH), 46.9 (CH2), 51.0 (CH3), 54.8 (CH), 59.3
(CH2), 83.8 (C),114.8 (CH),116.2 (C),119.7 (CH),122.1 (CH),123.6 (CH),
124.2 (CH),126.8 (CH),128.1 (CH),128.8 (CH),131.6 (C),134.3 (C),139.1
(C), 149.8 (C), 173.3 (C). IR (neat): 2947, 1736, 1450. EIMS m/z: 448
(Mþ), 347 (MꢀCO2t-Bu), 232 (MꢀN-Boc indole). HRMSeFAB m/z:
[MþH]þ calcd for C27H33N2O4, 449.2423; found, 449.2440.
4.7. Scheme 3
4.7.1. Typical procedure. (ꢀ)-tert-Butyl (2R,3S)-2-allyl-3-benzylamino-
3-(1-tert-butoxycarbonylindol-3-yl)propanoate (7b). To a stirred so-
lution of N-benzyltrimethylsilylamine (0.29 mL,1.5 mmol) in toluene
(4 mL), was added a 1.62 M hexane solution of BuLi (0.93 mL,
1.5 mmol) at ꢀ78 ꢁC over 4 min. After 30 min, a solution of chiral
diether 3 (436 mg,1.8 mmol) in toluene (2 mL) was added over 5 min.
After 30 min, a solution of enoate 2a (172 mg, 0.5 mmol) in toluene
(2 mL) was added over 6 min, and the mixture was stirred for 15 h at
ꢀ65 ꢁC. Then, a solution of 1,3-diiodopropane (6b) (0.54 mL, 5 mmol)
in DMPU (8 mL) was added over 22 min at ꢀ78 ꢁC, and the mixture
was stirred at ꢀ40 ꢁC. After 2 h, the reaction was quenched with
saturated aq NH4Cl (2 mL), and the whole was stirred at rt for 5 min.
Then, saturated NaHCO3 (12 mL) was added, and the whole was
stirred for 5 min. The organic layer was separated, and the aqueous
layer was extracted with benzene (10 mLꢂ3). The combined organic
layers were washed with water (10 mLꢂ4) and brine, and dried over
Na2SO4. Concentration and column chromatography (hexane/AcOEt
100/1 to 4/1) gave chiral diether 3 (436 mg, quant) as colorless plates
4.8.3. Methyl (2RS,3SR)-1-benzyl-2-(1-benzoylindol-3-yl)piperidine-
3-carboxylate (cis-11c). To a stirred solution of cis-11a (70 mg,
0.20 mmol) in DMF (2 mL), was added NaH (60% w/w dispersion in
mineral oil; 8 mg, 0.20 mmol) at rt. After 30 min, BzCl (0.023 mL,
0.20 mmol) was added dropwise. After 15 h, another portion of BzCl
(0.012 mL, 0.10 mmol) was added. After 2 h, the reaction was
quenched with water, and the aqueous layer was extracted with

S. Harada et al. / Tetrahedron 69 (2013) 3264e3273
3271
benzene. The combined organic layers were washed with water
and brine, and dried over Na2SO4. Concentration and column
chromatography (hexane/AcOEt 97/3 to 90/10) gave the title
compound (61 mg, 67%) as pale yellow amorphous solid: Rf¼0.6
(hexane/AcOEt 7/3). 1H NMR: 1.66 (1H, m), 1.77e1.92 (3H, m), 2.51
(1H, ddd, J¼12.5, 4.3, 4.0), 2.56 (1H, ddd, J¼12.5, 10.4, 3.0), 3.14 (1H,
ddd, J¼10.2, 4.9, 4.6), 3.27 (3H, s), 3.48 (1H, d, J¼14.0), 3.52 (1H, d,
J¼14.0), 4.71 (1H, d, J¼4.9), 7.22e7.79 (14H, m), 8.36 (1H, m). 13C
NMR: 22.4 (CH2), 23.1 (CH2), 45.0 (CH), 47.2 (CH2), 51.1 (CH3), 55.1
(CH), 59.3 (CH2), 116.0 (CH), 117.8 (C), 119.6 (CH), 123.5 (CH), 125.0
(CH), 125.4 (CH), 126.9 (CH), 128.2 (CH), 128.6 (CH), 128.7 (CH),
129.4 (CH), 131.6 (C), 132.1 (CH), 134.6 (C), 135.4 (C), 139.5 (C), 168.5
(C), 173.3 (C). IR (neat): 2947, 1735, 1690. EIMS m/z: 452 (Mþ), 361
(MꢀBn), 347 (MꢀBz). HRMSeFAB m/z: [MþH]þ calcd for
C29H29N2O3, 453.2178; found, 453.2160.
(60% w/w dispersion in mineral oil; 32 mg, 0.80 mmol) washed
with pentane, in DMF (3 mL) was added cis-11a (200 mg,
0.57 mmol) in DMF (3 mL) over 9 min at 0 ꢁC. After 20 min, PMBCl
(0.087 mL, 0.63 mmol) was added dropwise. After the mixture was
stirred for 80 min at rt, the reaction was quenched with water. The
aqueous layer was extracted with benzene. The combined organic
layers were washed with water and brine, and dried over Na2SO4.
Concentration and column chromatography (hexane/AcOEt 90/10
to 85/15) gave the title compound (233 mg, 86%) as colorless solids
of mp 122.0e123.0 ꢁC: Rf¼0.6 (hexane/AcOEt 3/2). 1H NMR: 1.67
(1H, m), 1.81e2.00 (3H, m), 2.49 (1H, ddd, J¼11.4, 4.0, 3.6), 2.60 (1H,
ddd, J¼12.0, 11.4, 2.5), 3.13 (1H, m), 3.15 (3H, s), 3.31 (1H, d, J¼13.8),
3.51 (1H, d, J¼13.8), 3.68 (3H, s), 4.83 (1H, d, J¼4.1), 5.21 (2H, s), 6.78
(2H, d, J¼8.9), 6.94 (2H, d, J¼8.9), 7.00e7.24 (9H, m), 7.47 (1H, m).
13C NMR: 22.1 (CH2), 23.6 (CH2), 45.8 (CH), 46.8 (CH2), 49.3 (CH2),
50.7 (CH3), 55.0 (CH3), 55.4 (CH), 59.3 (CH2), 109.4 (CH), 110.4 (C),
114.0 (CH), 118.9 (CH), 119.4 (CH), 121.5 (CH), 126.5 (CH), 126.8 (CH),
127.6 (CH), 127.9 (CH), 128.7 (CH), 129.5 (C), 129.6 (C), 135.4 (C),
139.5 (C), 158.9 (C), 173.5 (C). IR (neat): 3024, 2939, 1736. EIMS m/z:
468 (Mþ), 377 (MꢀBn), 347 (MꢀPMB). Anal. Calcd for C30H32N2O3:
C, 76.90; H, 6.88; N, 5.98. Found: C, 76.90; H, 6.94; N, 5.95.
4.8.4. Methyl (2RS,3SR)-1-benzyl-2-(1-pivaloylindol-3-yl)piperidine-
3-carboxylate (cis-11d). To a stirred solution of cis-11a (70 mg,
0.20 mmol) and DMAP (30 mg, 0.24 mmol) in CH2Cl2 (4 mL), were
added Et3N (0.049 mL, 0.34 mmol) and PivCl (0.051 mL, 0.40 mmol)
dropwise at 0 ꢁC. After the mixture was stirred for 15 h at rt, an-
other portion of DMAP (49 mg, 0.40 mmol) and PivCl (0.051,
0.40 mmol) were added, and the whole was stirred for further 3 h.
The reaction was quenched by addition of saturated aq NH4Cl
(2 mL) and saturated aq NaHCO3 (4 mL). The aqueous layer was
extracted with AcOEt. The combined organic layers were washed
with 10% Na2CO3 and brine, and dried over Na2SO4. Concentration
and column chromatography (hexane/AcOEt 97/3 to 95/5) gave the
title compound (74 mg, 81%) as colorless oil: Rf¼0.6 (hexane/AcOEt
4/1). 1H NMR: 1.51 (9H, s), 1.70 (1H, m), 1.86 (1H, m), 1.95e1.99 (2H,
m), 2.51 (1H, ddd, J¼12.5, 4.3, 4.0), 2.68 (1H, ddd, J¼12.5, 10.1, 3.1),
3.16 (1H, ddd, J¼7.3, 7.3, 4.9), 3.28 (3H, s), 3.55 (2H, s), 4.63 (1H, d,
J¼4.9), 7.18e7.43 (8H, m), 7.83 (1H, s), 8.48 (1H, m). 13C NMR: 22.5
(CH2), 23.1 (CH2), 28.6 (CH3), 41.2 (C), 44.2 (CH), 47.4 (CH2), 51.2
(CH3), 55.4 (CH), 59.0 (CH2), 117.0 (CH), 117.6 (C), 119.2 (CH), 123.2
(CH),123.9 (CH),125.2 (CH),126.9 (CH),128.2 (CH),128.7 (CH),130.1
(C), 136.2 (C), 138.9 (C), 175.0 (C), 177.0 (C). IR: 2947, 1736, 1690.
EIMS m/z: 432 (Mþ), 375 (Mꢀt-Bu), 341 (MꢀBn). HRMSeFAB m/z:
[MþH]þ calcd for C27H33N2O3, 433.2491; found, 433.2501.
4.9. Table 4
4.9.1. Typical procedure(entry 4). Methyl 3-((2RS,3SR)-1-benzyl-2-(1-
benzylindol-3-yl)piperidin-3-yl)-3-oxopropanoate (13e). To a stirred
0.5 M THF solution of NaHMDS (12.4 mL, 6.2 mmol), was added
AcOMe (0.49 mL, 6.2 mmol) in THF (6 mL) over 10 min at ꢀ78 ꢁC.
After 1 h, cis-11e (170 mg, 0.39 mmol) in THF (6 mL) was added over
10 min, and the mixture was stirred for 15 h at rt. The reaction was
quenched with saturated aq NaHCO3 (10 mL), and the aqueous layer
was extracted with Et2O. The combined organic layers were washed
with brine and dried over Na2SO4. Concentration and column
chromatography (DIOL silica gel MB100-40/75, hexane/AcOEt 15/1)
gave 13e (23 mg, 12%) as yellow solids of mp 138.5e140.0 ꢁC: Rf¼0.4
(hexane/AcOEt 3/2). 1H NMR: 1.67 (1H, m), 1.81e1.97 (3H, m), 2.45
(1H, ddd, J¼11.9, 4.3, 4.0), 2.56 (1H, ddd, J¼11.9, 11.3, 2.5), 2.99 (1H,
d, J¼15.5), 3.35 (1H, d, J¼15.5), 3.36 (1H, d, J¼13.5), 3.37 (1H, m),
3.52 (3H, s), 3.58 (1H, d, J¼13.5), 4.85 (1H, d, J¼4.4), 5.32 (2H, s),
7.03 (1H, m), 7.06e7.30 (13H, m), 7.46 (1H, m). 13C NMR: 22.1 (CH2),
23.2 (CH2), 46.8 (CH2), 47.6 (CH2), 50.1 (CH2), 52.0 (CH3), 52.6 (CH),
55.1 (CH), 59.2 (CH2), 109.8 (CH), 119.1 (CH), 119.6 (CH), 122.0 (CH),
126.5 (CH), 126.8 (CH), 127.6 (CH), 127.6 (CH), 128.2 (CH), 128.6 (C),
128.7 (CH), 128.8 (CH), 129.2 (C), 135.7 (C), 137.4 (C), 139.4 (C), 167.7
(C), 203.3 (C). IR (neat): 3031, 2947, 1744, 1705, 1620, 1450. EIMS m/
z: 480 (Mþ), 389 (MꢀBn). HRMSeFAB m/z: [MþH]þ calcd for
C31H33N2O3, 481.2491; found, 481.2498: and trans-11e (115 mg,
68%) as yellow solids of mp 108.0e109.5 ꢁC: Rf¼0.6 (hexane/AcOEt
3/2). 1H NMR: 1.61e1.72 (3H, m), 1.97e2.04 (2H, m), 2.87 (1H, d,
J¼13.4), 2.98e3.09 (2H, m), 3.27 (3H, s), 3.68 (1H, d, J¼10.4), 3.92
(1H, d, J¼13.4), 5.23 (1H, d, J¼16.2), 5.29 (1H, d, J¼16.2), 7.01e7.25
(14H, m), 8.06 (1H, br s). 13C NMR: 24.7 (CH2), 28.8 (CH2), 49.7
(CH2), 50.6 (CH), 51.0 (CH3), 52.6 (CH2), 59.2 (CH2), 62.6 (CH), 109.6
(CH), 115.6 (C), 119.1 (CH), 120.9 (CH), 121.8 (CH), 126.4 (CH), 126.5
(CH), 127.0 (C), 127.2 (CH), 127.4 (CH), 127.9 (CH), 128.6 (CH), 128.9
(CH), 136.9 (C), 137.7 (C), 139.7 (C), 175.0 (C). IR (neat): 3420, 3028,
2945, 2790, 1732, 1454. EIMS m/z: 438 (Mþ), 347 (MꢀBn). Anal.
Calcd for C29H30N2O2: C, 79.42; H, 6.89; N, 6.39. Found: C, 79.51; H,
6.90; N, 6.42.
4.8.5. Methyl (2RS,3SR)-1-benzyl-2-(1-benzylindol-3-yl)piperidine-
3-carboxylate (cis-11e). To a suspension of NaH (60% w/w disper-
sion in mineral oil; 38 mg, 0.95 mmol), washed with pentane, in
DMF (4 mL) was added cis-11a (250 mg, 0.72 mmol) in DMF (3 mL)
over 5 min at 0 ꢁC. After the mixture was stirred for 25 min at rt,
BnBr (0.10 mL, 0.86 mmol) was added dropwise. After 1.2 h, to the
mixture was added water. The aqueous layer was extracted with
benzene. The combined organic layers were washed with water
and brine, and dried over Na2SO4. Concentration and column
chromatography (hexane/AcOEt 9/1 to 4/1) gave the title com-
pound (273 mg, 87%) as colorless solids of mp 128.0e128.5 ꢁC:
Rf¼0.6 (hexane/AcOEt 3/2). 1H NMR: 1.69 (1H, m), 1.85e2.00 (3H,
m), 2.50 (1H, ddd, J¼12.0, 4.0, 3.3), 2.60 (1H, J¼ddd, 12.0, 10.0, 3.1),
3.16 (1H, ddd, J¼11.0, 4.8, 4.6), 3.19 (3H, s), 3.32 (1H, d, J¼14.0), 3.53
(1H, d, J¼14.0), 4.84 (1H, d, J¼4.8), 5.33 (2H, s), 7.02e7.06 (3H, m),
7.12 (1H, m), 7.20e7.30 (10H, m), 7.49 (1H, m). 13C NMR: 22.2 (CH2),
23.6 (CH2), 45.9 (CH), 46.9 (CH2), 49.9 (CH2), 50.9 (CH3), 55.5 (CH),
59.5 (CH2), 109.4 (CH), 110.7 (C), 119.1 (CH), 119.5 (CH), 121.7 (CH),
126.4 (CH), 126.7 (CH), 127.0 (CH), 127.5 (CH), 128.1 (CH), 128.7 (CH),
128.8 (CH), 130.0 (C), 135.6 (C), 137.8 (C), 140.0 (C), 173.8 (C). IR
(neat): 3028, 2947, 2804, 1734, 1454. EIMS m/z: 438 (Mþ), 347
(MꢀBn). Anal. Calcd for C29H30N2O2: C, 79.42; H, 6.89; N, 6.39.
Found: C, 79.38; H, 6.83; N, 6.27.
4.9.2. Entry 1. Methyl 3-((2RS,3SR)-1-benzyl-2-(indol-3-yl)piperidin-
3-yl)-3-oxopropanoate (13a). To a stirred 0.5 M THF solution of
NaHMDS (2.0 mL, 1.0 mmol), was added AcOMe (0.079 mL,
1.0 mmol) in THF (1 mL) over 3 min at ꢀ78 ꢁC. After 1 h, cis-11b
(112 mg, 0.25 mmol) in THF (1 mL) was added over 4 min, and the
mixture was stirred for 2 h at ꢀ40 ꢁC. Then the cooling bath was
4.8.6. Methyl (2RS,3SR)-1-benzyl-2-(1-p-methoxybenzylindol-3-yl)
piperidine-3-carboxylate (cis-11f). To a stirred suspension of NaH

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S. Harada et al. / Tetrahedron 69 (2013) 3264e3273
removed, and the mixture was stirred for further 1 h. The reaction
was quenched with saturated aq NaHCO3 (3 mL), and the aqueous
layer was extracted with AcOEt. The combined organic layers were
washed with brine and dried over Na2SO4. Concentration and
column chromatography (hexane/AcOEt 4/1 to 3/2) gave 11a
(70 mg, 80% cis/trans 4/1) as yellow oil and the title compound
(8 mg, 7%) as yellow gum: Rf¼0.3 (hexane/AcOEt 3/2). 1H NMR:
1.69 (1H, m), 1.81e1.99 (3H, m), 2.46 (1H, ddd, J¼12.2, 4.0, 3.2),
2.56 (1H, ddd, J¼12.2, 11.0, 2.5), 2.99 (1H, d, J¼15.6), 3.34 (1H, d,
J¼13.7), 3.36 (1H, d, J¼15.6), 3.37 (1H, m), 3.52 (3H, s), 3.57 (1H, d,
J¼13.7), 4.85 (1H, d, J¼4.5), 7.05e7.46 (10H, m), 8.34 (1H, m). 13C
NMR: 22.1 (CH2), 23.1 (CH2), 46.6 (CH2), 47.9 (CH2), 52.0 (CH3),
52.6 (CH), 54.9 (CH), 59.0 (CH2), 111.2 (CH), 118.7 (CH), 119.7 (CH),
122.1 (CH), 123.3 (CH), 126.8 (CH), 128.2 (CH), 128.3 (C), 128.6 (C),
128.7 (CH), 135.2 (C), 139.4 (C), 167.8 (C), 203.7 (C). IR: 3039, 2947,
1743, 1704. EIMS m/z: 390 (Mþ), 358 (MꢀMeOH), 299 (MꢀBn).
HRMSeFAB m/z: [MþH]þ calcd for C24H27N2O3, 391.2022; found,
391.2014.
title compound (727 mg, 66%) as a yellow gum and 11a (82 mg, 8%)
as a pale yellow oil.
4.10. Scheme 5
4.10.1. Methyl 3-((2RS,3SR)-1-benzyl-2-(1-methoxycarbonylindol-3-
yl)piperidin-3-yl)-3-oxopropanoate (16). To a stirred solution of
13a (640 mg, 1.6 mmol) in THF (32 mL) was added a 1.0 M THF
solution of LiHMDS (4.9 mL, 4.9 mmol) over 3 min at ꢀ78 ꢁC. After
40 min, NCCO2Me (0.50 mL, 6.2 mmol) was added over 2 min. After
20 min, the reaction was quenched with saturated aq NH4Cl (4 mL),
and the whole was warmed up to rt. After addition of saturated aq
NaHCO3 (10 mL), the organic layer was separated, and the aqueous
layer was extracted with AcOEt. The combined organic layers were
washed with brine and dried over Na2SO4. Concentration and col-
umn chromatography (DIOL silica gel MB100-40/75, hexane/AcOEt
9/1) gave the title compound (701 mg, 95%) as yellow oil: Rf¼0.4
(hexane/AcOEt 3/2). 1H NMR: 1.70 (1H, m), 1.81e2.03 (3H, m), 2.50
(1H, ddd, J¼12.5, 4.0, 4.0), 2.62 (1H, ddd, J¼12.5, 11.0, 3.1), 3.05 (1H,
d, J¼15.5), 3.31 (1H, d, J¼15.5), 3.36 (1H, ddd, J¼10.2, 5.2, 4.6), 3.41
(1H, d, J¼13.7), 3.54 (3H, s), 4.04 (3H, s), 4.05 (1H, d, J¼13.7), 4.76
(1H, d, J¼4.6), 7.11e7.41 (8H, m), 7.63 (1H, s), 8.17 (1H, m). 13C NMR:
21.9 (CH2), 22.9 (CH2), 46.6 (CH2), 47.6 (CH2), 52.0 (CH), 52.1 (CH3),
53.8 (CH3), 54.2 (CH), 59.0 (CH2), 115.1 (CH), 116.2 (C), 119.3 (CH),
123.0 (CH), 124.9 (CH),127.0 (CH),128.3 (CH),128.4 (CH), 128.7 (CH),
131.1 (C), 134.7 (C), 138.9 (C), 151.3 (C), 167.5 (C), 202.8 (C). IR: 3024,
2954, 1743, 1628. EIMS m/z: 448 (Mþ), 357 (MꢀBn). HRMSeFAB m/
z: [MþH]þ calcd for C26H29N2O5, 449.2076; found, 449.2062.
4.9.3. Entry 5. Methyl 3-((2RS,3SR)-1-benzyl-2-(1-p-methoxybenzy-
lindol-3-yl)piperidin-3-yl)-3-oxopropanoate (13f). The typical pro-
cedure using cis-11f (50 mg, 0.11 mmol), instead of cis-11e, gave the
title compound (14 mg, 26%) as a yellow oil: Rf¼0.4 (hexane/AcOEt
3/2). 1H NMR: 1.67 (1H, m), 1.81e1.98 (3H, m), 2.45 (1H, ddd, J¼11.9,
4.0, 3.1), 2.56 (1H, ddd, J¼11.9, 11.0, 2.4), 2.97 (1H, d, J¼15.6), 3.34
(1H, d, J¼15.6), 3.35 (1H, m), 3.37 (1H, d, J¼13.4), 3.52 (3H, s), 3.56
(1H, d, J¼13.4), 3.76 (3H, s), 4.85 (1H, d, J¼4.4), 5.23 (1H, d, J¼15.9),
5.27 (1H, d, J¼15.9), 6.82 (2H, d, J¼8.9), 6.99 (2H, d, J¼8.9),
7.05e7.31 (9H, m), 7.45 (1H, m). 13C NMR: 22.2 (CH2), 23.2 (CH2),
46.8 (CH2), 47.6 (CH2), 49.6 (CH2), 52.0 (CH3), 52.6 (CH), 55.1 (CH3),
55.2 (CH), 59.2 (CH2), 109.6 (C), 109.8 (CH), 114.2 (CH), 119.1 (CH),
119.5 (CH), 121.9 (CH), 126.8 (CH), 127.5 (CH), 127.8 (CH), 128.2 (CH),
128.7 (CH), 129.2 (C), 129.4 (C), 135.6 (C), 139.5 (C), 159.1 (C), 167.8
(C), 203.3 (C). IR: 3024, 2931, 1744, 1712, 1612. FABMS m/z: 511
(MþH). HRMSeFAB m/z: [MþH]þ calcd for C32H35N2O4, 511.2597;
found, 511.2604.
4.10.2. (ꢃ)-20-Deethyl-2
b,16b-dihydro-17-oxovincadifformine
(20). A suspension of 16 (43 mg, 0.096 mmol) and Pd/C (10 wt %,
34 mg, 0.032 mmol) in HCO2H (1.8 mL) was stirred for 5 h at rt and
filtrated through a Celite pad, which was successively washed with
MeOH. The combined filtrate and washings were concentrated. To
the residue, was added saturated aq Na2CO3 (3 mL), and the whole
was extracted with AcOEt. The combined organic layers were
washed with brine, dried over Na2SO4, and concentrated to give
yellow oil (29 mg).
4.9.4. Entry 7. Methyl 5-hydroxy-2-methoxycarbonyl-5-methyl-3-
oxocyclohexen-1-acetate (15). The typical procedure using a solu-
tion of LiHMDS (2.8 mL, 1.9 mmol), AcOMe (0.14 mL, 1.7 mmol) in
THF (1.5 mL), and cis-11a (37 mg, 0.11 mmol) in THF (1.6 mL), in-
stead of a solution of NaHMDS (6.2 mmol), AcOMe (6.2 mmol) in
THF, and cis-11e (0.39 mmol) in THF, respectively, followed by
column chromatography (hexane/AcOEt 17/3) gave cis-11a (33 mg,
88%) as a colorless solid, 1418 (23 mg, 24%) as a colorless oil, and the
title compound (24 mg, 27%) as a colorless oil: Rf¼0.1 (hexane/
AcOEt 7/3). 1H NMR: 1.33 (3H, s), 2.64 (1H, d, J¼15.6), 2.65 (1H, d,
J¼15.6), 2.82 (1H, d, J¼16.2), 2.94 (1H, d, J¼16.2), 3.54 (2H, s), 3.70
(3H, s), 3.74 (3H, s), 3.99 (1H, br s). 13C NMR: 27.3 (CH3), 44.5 (CH2),
50.4 (CH2), 51.7 (CH3), 52.1 (CH2), 52.3 (CH3), 70.1 (C), 136.1 (C),
163.2 (C), 167.3 (C), 172.5 (C), 203.2 (C). IR: 3510, 2954, 1736. FABMS
m/z: 257 (MþH). HRMSeFAB m/z: [MþH]þ calcd for C12H17O6,
257.1025; found, 257.1026.
The residual yellow oil was dissolved in CH3CN (1.8 mL), and
Na2CO3 (61 mg, 0.58 mmol) and 2-iodoethanol (45 mL, 0.58 mmol)
were added. The mixture was stirred for 21 h at 60 ꢁC, and water
(3 mL) and benzene were added. The organic layer was separated,
and the aqueous layer was extracted with benzene. The combined
organic layers were washed with water and brine, dried over
Na2SO4, and concentrated to give yellow oil (29 mg).
The residual yellow oil was dissolved in CH2Cl2 (2 mL), and Et3N
(0.13 mL, 0.96 mmol) and MsCl (8.9 mL, 0.12 mmol) were added.
After 20 h, the reaction was quenched with water (3 mL), and the
organic layer was separated. The aqueous layer was extracted with
AcOEt, and the combined organic layers were washed with brine,
dried over Na2SO4, and concentrated to give yellow oil (16 mg).
The residual yellow oil was dissolved in THF (1.0 mL) and HMPA
(0.20 mL), and a 1.0 M solution of KOt-Bu in THF (0.24 mL,
0.24 mmol) was added over 1 min at ꢀ78 C. The mixture was stirred
for 1 h at ꢀ78 ꢁC and then 1 h at rt, and the reaction was quenched
with saturated aq NH4Cl (0.5 mL) and saturated aq NaHCO3 (2 mL).
The organic layer was separated, and the aqueous layer was
extracted with AcOEt. The combined organic layers were washed
with brine and dried over Na2SO4. Concentration and column
chromatography (hexane/AcOEt 4/1) gave the title compound
(3.0 mg, 10%) as colorless oil. 1H and 13C NMR, IR, and MS were
identical to those reported.9
4.9.5. Entry 8. Methyl 3-((2RS,3SR)-1-benzyl-2-(indol-3-yl)piperidin-
3-yl)-3-oxopropanoate (13a). To a stirred solution of 11a (1.0 g,
2.9 mmol) in THF (11 mL), was added a 1.0 M THF solution of
LiHMDS (5.7 mL, 5.7 mmol) over 3 min at ꢀ78 ꢁC. After 1 h, the
solution was added over 5 min to a preformed solution of enolate,
prepared from AcOMe (3.7 mL, 47 mmol) and LiHMDS (1.1 g,
66 mmol) in THF (180 mL) at ꢀ78 ꢁC. The mixture was stirred for
17 h at rt, and saturated aq NaHCO3 (100 mL) was added. The or-
ganic layer was separated, and the aqueous layer was extracted
with Et2O. The combined organic layers were washed with brine
and dried over Na2SO4. Concentration and column chromatography
(DIOL silica gel MB100-40/75, hexane/AcOEt 6/1 to 3/1) gave the
Acknowledgements
We are grateful to JSPS and JST for financial support.

S. Harada et al. / Tetrahedron 69 (2013) 3264e3273
7. Davis, F. A.; Chao, B.; Fang, T.; Szewczyk, J. M. Org. Lett. 2000, 2, 1041.
3273
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