Enantioselective synthesis of martinelline chiral core and its diastereomer using asymmetric tandem Michael-aldol reaction

Article abstract of DOI:10.1016/j.tet.2008.10.032

The martinelline chiral core 3 and its diastereomer were synthesized by using the asymmetric tandem Michael-aldol reaction as the key step from 4-methoxycarbonylanthranilaldehyde and the α,β-unsaturated aldehyde.

Full text of DOI:10.1016/j.tet.2008.10.032

Tetrahedron 64 (2008) 11568–11579
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Tetrahedron
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Enantioselective synthesis of martinelline chiral core and its diastereomer using
asymmetric tandem Michael–aldol reaction
*
Yayoi Yoshitomi, Hiromi Arai, Kazuishi Makino, Yasumasa Hamada
Graduate School of Pharmaceutical Sciences, Chiba University, Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The martinelline chiral core 3 and its diastereomer were synthesized by using the asymmetric tandem
Received 16 September 2008
Received in revised form 10 October 2008
Accepted 11 October 2008
Michael–aldol reaction as the key step from 4-methoxycarbonylanthranilaldehyde and the
saturated aldehyde.
a,b-un-
Ó 2008 Published by Elsevier Ltd.
Available online 17 October 2008
Keywords:
Martinelline
Martinellic acid
Tandem Michael–aldol reaction
Organocatalyst
Asymmetric synthesis
1. Introduction
dihydroquinoline skeletons. Recently, two enantioselective ver-
sions of this tandem Michael–aldol reaction using a chiral orga-
nocatalyst were reported.11,12 As part of the study on the tandem
Michael–aldol reactions, we now describe the enantioselective
synthesis of the martinelline chiral core 3 and its diastereomer
using the asymmetric tandem Michael–aldol reaction.
Martinelline (1) and martinellic acid (2) constitute a small
family of naturally occurring pyrroloquinoline alkaloids isolated
from the roots of the tropical plant, Martinella iquitosensis, in 1995,
as a nonpeptide bradykinin receptor antagonist (Fig. 1).1 Their
structural features contain a unique pyrroloquinoline with fused
tetrahydroquinoline and pyrrolidine rings and two prenyl guani-
dines. The intriguing biological activity of martinelline coupled
with its unique structure has led several groups, including our own,
to investigate a variety of synthetic methods for the preparation of
the pyrroloquinoline core.2 Since the first total synthesis of marti-
nellic acid was reported by Ma’s group,3a several syntheses of
martinellic acid3,4 and three total syntheses5,6 and many formal
syntheses7 of martinelline have been recorded to date. However,
these syntheses of the optically active martinelline and martinellic
acid have been limited to a diastereoselective synthesis using
a chiral building block. Therefore, the catalytic enantioselective
synthesis of martinelline and martinellic acid remains a challenge
for a more expedient synthesis. We have already demonstrated that
the tandem Michael–aldol reaction2r,8,9 using an anthranilaldehyde
and a Michael acceptor and a palladium-catalyzed intramolecular
allylic alkylation reaction2s,10 as a key step are powerful tools
for the construction of the 1,2,3,4-tetrahydroquinoline and 1,2-
2. Results and discussion
The martinelline chiral core 3 can be constructed from 1,2-
dihydroquinoline 4, which should be obtained for anthranilalde-
hyde 5 and the Michael acceptor 6 using the asymmetric tandem
Michael–aldol reaction (Scheme 1). The required 6 was easily
prepared starting from the commercially available pyrrolidinone 7
in a good overall yield (Scheme 2). The protection of 7 with di-tert-
NH
N
N
H
RO2C
H
N
H
N
N
H
NH
H
H2N
N
Martinelline (1): R =
Martinellic acid (2): R = H
NH
* Corresponding author. Tel.: þ81 43 290 2987.
Figure 1.
E-mail address: hamada@p.chiba-u.ac.jp (Y. Hamada).
0040-4020/$ – see front matter Ó 2008 Published by Elsevier Ltd.
doi:10.1016/j.tet.2008.10.032

Y. Yoshitomi et al. / Tetrahedron 64 (2008) 11568–11579
11569
O
O
HN
O
H
R
MeO2C
R
H
H
+
NHBoc
NH2
NHR"
N
H
N
H
6
4
5
3
NHBoc
Scheme 1.
The asymmetric tandem Michael–aldol reaction using (S)-
R
O
OH
NR
diphenylprolinol triethylsilyl ether as an organocatalyst in the
presence of sodium acetate (NaOAc) and molecular sieves 4 Å
(MS4A) has been previously studied by others.11a We extensively
examined this condition for the reaction of 12 and 6. These results
are shown in Table 1. The reaction was carried out using 12
(1 equiv) and 6 (3 equiv) in the presence of NaOAc (0.5 equiv),
MS4A (500 mg/1 mmol), and (S)-diphenylprolinol triethylsilyl
ether (14) (20 mol %) as the catalyst. The stereochemistry of the
obtained product 13 was tentatively assigned as R from the reaction
mechanism and subsequently confirmed by correlation to the
known compound 3. First, we examined the effects of the pro-
tecting groups at the oxygen and nitrogen functions. Surprisingly,
the protecting group at the phenolic function was an important
factor for enantioselectivity (entry 1). When the tert-butyldime-
thylsilyl group was employed, an almost racemic product was
obtained. In stark contrast, the use of anthranilaldehyde 12 pro-
tected with the benzyl group improved the enantioselectivity to
b
c
NR
NHBoc
9
7: R = H
8: R = Boc
a
10: R = CO2Et
11: R = CH2OH
6: R = CHO
d
e
Scheme 2. Reagents and conditions: (a) Boc2O, DMAP, CH3CN, rt, 99%; (b) DIBAL, THF,
ꢀ78 ꢁC, quant.; (c) Ph3P]CHCO2Et, PhCH3, 100 ꢁC, 99%; (d) DIBALH, CH2Cl2, ꢀ78 ꢁC,
76%; (e) MnO2, CH2Cl2, rt, 92%.
butyl dicarbonate followed by the reduction of 8 with diisobutyl-
aluminum hydride afforded the pyrrolidine 9. The Wittig homolo-
9 proceeded at elevated temperature to give the
-unsaturated ester 10. The reduction of 10 followed by oxidation
of the resulting allyl alcohol 11 furnished the Michael acceptor 6.
gation of
a,b
Table 1
Asymmetric tandem Michael–aldol reaction using organocatalysts
O
O
O
BnO
catalyst (20 mol%)
H
BnO
H
H
NaOAc (0.5 eq)
MS4A (500 mg/1 mmol)
solvent (0.5 M)
rt, time
NHBoc
+
N
NHTs
Ts
12
13
6
NHBoc
Entry
Catalyst
Solvent
Time (h)
Yield (%)
ee (%)
1a
2
14
14
14
14
14
14
14
14
14
14
14
14
15
16
17
18
ClCH2CH2Cl
ClCH2CH2Cl
CHCl3
CHCl3
CPME
20.5
37
39
39
20
20
24
24
24
24
24
2
Quant.
Quant.
NR
NR
91.6
86.6
71.1
63.2
94.2
Quant.
93.0
Quant.
72.5
NR
Quant.
Quant.
0.3
86.0
d
3b
4c
5
d
90.9
90.0
92.6
92.9
91.6
90.9
80.7
89.0
2.8
6
7
8
9
CH2Cl2
CHCl3
Toluene
CH3CN
CH3CN
CH3CN
CH3CN
CPME
CHCl3
CHCl3
CHCl3
10d
11e
12f
13
14
15
16
37.5
24
36
36
d
32
15
HO
HO
Ph
Ph
ORb
CPME:
OH
ORb
O
Ph
Ph
O
N
H
N
H
N
H
OTES
OH
N
H
O
N
O
Me
H
18
14
15
16
17
a
The tert-butyldimethylsilyl ether derivative was used instead of the benzyl ether 12.
The N-tert-butoxylcarbonyl derivative was used instead of 12.
The N-benzyloxycarbonyl derivative was used instead of 12.
Without MS4A.
Without NaOAc.
Without NaOAc and MS4A.
b
c
d
e
f

11570
Y. Yoshitomi et al. / Tetrahedron 64 (2008) 11568–11579
Table 2
Reaction conditions of asymmetric tandem Michael–aldol reaction
O
O
O
H
BnO
BnO
H
catalyst 14 (see, Table)
H
+
NHBoc
CH3CN (0.5 M)
additive (see Table)
temp., time (see Table)
NHTs
N
Ts
12
NHBoc
6
13
Entry
Catalyst (mol %)
6 (equiv)
Additive (mol %)
Conditions
4 ꢁC, 24 h
Yield (%)
ee (%)
1
2
3
4
5
6
7
8
20
10
5
3
3
5
5
5
5
3
3
3
3
3
1
1
2
2
3
3
d
96.6
94.5
Quant.
Quant.
73.8
36.6
63.6
59.3
91.6
96.0
95.6
92.7
90.6
95.4
96.9
96.7
97.2
97.9
97.7
97.8
d
4
4
4
4
ꢁC, 24 h
ꢁC, 24 h
ꢁC, 24 h
ꢁC, 24 h
d
d
AcOH (3)
d
ꢀ20 ꢁC, 24 h
ꢀ20 ꢁC, 24 h
ꢀ20 ꢁC, 24 h
ꢀ20 ꢁC, 24 h
ꢀ20 ꢁC, 24 h
ꢀ20 ꢁC, 24 h
AcOH (5)
d
9
10
11
AcOH (5)
d
5
5
82.9
88.5
AcOH (5)
86.0% ee (entry 2). The sulfonamide proved to be an excellent Mi-
chael donor for this reaction. The use of the urethane-type pro-
tecting groups, tert-butoxycarbonyl (Boc) and benzyloxycarbonyl
(Z), resulted in no reactions (entries 3 and 4).
Michael acceptor 6 in the reaction at ꢀ20 ꢁC. In the presence of
1 equiv of 6, the reaction was extremely slow and, even after 24 h,
incomplete (entry 6). In our efforts to overcome the defect, addition
of acetic acid was found to improve the chemical yield without any
loss of enantioselectivity. However, an excess amount of 6 was
essential for complete reaction. Careful experiments revealed that 6
has a tendency to undergo an intramolecular cyclization that pro-
duces a pyrrolidine derivative. Finally, the reaction using 12
(1 equiv) and 6 (2 equiv) in the presence of the catalyst 14 (5 mol %)
and acetic acid (5 mol %) in CH3CN at ꢀ20 ꢁC for 24 h afforded the
product 13 in 91.6% yield and 97.9% ee (entry 9).
With these encouraging results in hand, we applied this reaction
to the synthesis of the martinelline chiral core 3. The tandem Mi-
chael–aldol reaction using the (R)-catalyst 14 on a preparative scale
gave the (S)-product 13 in quantitative yield and 95.7% ee, which
was reduced with sodium borohydride in the presence of ceric
chloride to afford the allyl alcohol 19 (Scheme 3). We first
attempted several methods for introduction of the nitrogen func-
tion at C4 of the 1,2-dihydroquinoline skeleton, as it was postulated
that the synthesis through a [3,3]-sigmatropic rearrangement, such
as the Overman rearrangement15 or an allyl cyanate-to-isocyanate
rearrangement,16 would offer an attractive route to the convenient
intermediate 20 for the pyrroloquinoline skeleton. However, the
reaction did not take place. Therefore, we employed the previous
As for the effects of the solvent, acetonitrile was the most suit-
able for this reaction regarding the yield and enantioselectivity
(entry 9). In contrast to the reported procedure, the presence of
MS4A indicated a negative effect on the chemical yield (entry 10),
while NaOAc had no effect on the yield and enantioselectivity
(entry 11). Furthermore, the optimized condition without NaOAc
and MS4A afforded a quantitative yield and 89% ee (entry 12). Fi-
nally, we briefly examined the use of other organocatalysts 15–18 in
these asymmetric Michael–aldol reactions (entries 13–16). In-
terestingly, the rubidium salts13 of (S)-proline and (S)-hydroxy-
methylproline14 were excellent catalysts for the reaction and
produced the opposite enantiomer as the major product, but gave
low enantioselectivities (entries 15 and 16).
In order to further enhance the enantioselectivity, we fine tuned
the reaction as shown in Table 2. We were pleased to find that the
enantioselectivity was improved when the reaction was performed
at 4 ꢁC (entry 1). We next examined the catalyst amount. When the
catalyst loading was decreased to 3 mol %, the reactivity remained
constant, but the enantioselectivity was affected (entry 4). We
employed a 5 mol % catalyst and examined the amount of the
O
O
BnO
CHO
BnO
H
H
b
a
+
NHBoc
N
NHTs
Ts
13
NHBoc
12
6
R
O
NHCOR
HN
N
BnO
BnO
OH
NHBoc
NHBoc
N
N
Ts
Ts
Ts
19
20
[3,3]-sigmatropic
rearrangement
Scheme 3. Reagents and conditions: (a) (R)-diphenylprolinol triethylsilyl ether (14) (5 mol %), AcOH (5 mol %), CH3CN (0.5 M), ꢀ20 ꢁC, 24 h, quant., 95.7% ee; (b) NaBH4, CeCl3$7H2O,
MeOH, rt, 18 h, quant.

Y. Yoshitomi et al. / Tetrahedron 64 (2008) 11568–11579
11571
OH
O
BnO
BnO
d
OH
b,c
a
19
NHBoc
NHBoc
MeO2C
N
N
Ts
Ts
22
21
N
O
N
O
BnO
R
i
e
CN
NHBoc
NHBoc
NHBoc
N
Ts
N
Ts
Ts
23
24: R = OBn
25: R = OH
26: R = OTf
28
f
g
h
27: R = CO2Me
R1
N
HN
MeO2C
j
MeO2C
m
3HCl
NHR2
NH2
N
R3
N
H
32
29: R1 = H, R2 = Boc, R3 = Ts
k
30: R1 = Boc, R2 = Boc, R3 = Ts
31: R1 = Boc, R2 = Boc, R3 = H
l
Scheme 4. Reagents and conditions: (a) m-CPBA, CH2Cl2, 0 ꢁC to rt, 45 h, 81.5%, dr 63/37; (b) PPh3, I2, imidazole, benzene, rt, 20 min; (c) Zn, AcOH, MeOH, rt, 30 min, 85.2% (two
steps), dr 51/49; (d) MnO2, CH2Cl2, rt, 15.5 h, 84.1%; (e) KCN, AcOH, H2O, EtOH, 50 ꢁC, 40 min, 98.9%, dr >90/10; (f) H2, Pd/C, EtOAc, rt, 60.5 h, quant., dr 92/8; (g) Tf2O, pyridine,
CH2Cl2, 0 ꢁC to rt, 1 h 40 min, 71.8%, dr >99/1; (h) CO, Pd(OAc)2, dppp, NEt3, MeOH, DMF, 70 ꢁC, 2 h, 45.4%; (i) Raney Ni (W-2), EtOH, H2 (1 atm),50 ꢁC, 24 h; (j) NaBH3CN, MeOH,
AcOH (pH 5), 85% (two steps); (k) (Boc)2O (3.2 equiv), Et3N (2.8 equiv), rt, 1 h, quant.; (l) Mg (51 equiv), MeOH, rt, 18 h, 97%; (m) 2 M HCl/MeOH (0.015 M), ꢀ15 ꢁC, 23 h, 94%.
route (Scheme 4).2r The allyl alcohol 19 was transpositioned to the
Table 3
isomeric allyl alcohol 22 in three steps. Thus, epoxidation of 19 with
Attempts of epimerization
m-chloroperbenzoic acid (m-CPBA) gave the epoxide 21 with the
O
O
diastereomeric ratio of 63/37. Iodination of 21 by iodine and tri-
phenyl phosphine in the presence of the imidazole followed by
reductive cleavage of the resulting iodoepoxide with zinc in the
presence of acetic acid afforded 22 in good yield. The oxidation of
22 with activated manganese dioxide followed by hydrocyanation
MeO2C
base
MeO2C
CN
CN
NHBoc
NHBoc
N
Ts
N
Ts
33
27
of the
a,
b
-unsaturated ketone 23 with potassium cyanide/acetic
cis/trans = 92/8
acid provided tetrahydroquinolone 24 in the diastereomeric ratio of
>90/10. At this point, we were unaware of the misunderstanding in
the stereostructure of 24 as trans because 24 was obtained as
almost a single isomer and the analysis of its 1H NMR spectrum was
difficult. Therefore, we had no reason to suspect the exclusive for-
mation of the trans isomer. Consequently, the synthesis was con-
tinued to the epi-pyrroloquinoline 32. Thus, the conversion of 24 to
27 by the introduction of an ester function at the phenolic function
was carried out by the following three steps. The hydrogenolysis of
24 with palladium/carbon and hydrogen followed by tri-
fluoromethanesulfonylation of the resulting phenol 25 with triflic
anhydride provided the triflate 26, which was subjected to the
Entry
Base (equiv)
Conditions
Ratio of cis/trans
1
2
3
4
5
6
7
8
DBU (1)
DBU (1)
CH2Cl2, rt, 12 h
MeOH, rt, 22 h
MeOH, rt, 22 h
MeOH, rt, 22 h
MeOH, rt, 22 h
THF, -78 ꢁC, 2 h
82/18
82/18
73/27
78/22
72/28
90/10
NR
K2CO3 (1.24)
K2CO3 (14)
CS2CO3 (1.5)
LDA (2.1)
(S)-Pro (1.8)
(R)-Pro (1.8)
Aqueous DMF, rt, 24 h
Aqueous DMF, rt, 24 h
NR
palladium-catalyzed methoxycarbonylation17 using Pd(OAc)2–1,3-
bis(diphenylphosphino)propane (dppp) and triethylamine in the
presence of carbon monoxide in methanol/dimethylformamide to
produce the ester 27.
21.8%
HN
H
MeO2C
H
16.7%
H
NHBoc
O
N
O
29
MeO2C
Ts
11.2%
CN
MeO2C
CN
HN
NHBoc
H
N
Ts
NHBoc
MeO2C
H
H
9.6%
N
Ts
pseudo
33
NH2HCl
1,3-diaxial interaction
N
H
32
27
Figure 2. NOE analysis of 29 and 32.
Figure 3.

11572
Y. Yoshitomi et al. / Tetrahedron 64 (2008) 11568–11579
O
O
MeO2C
MeO2C
b,c,d
a
CN
CN
NHBoc
NHBoc
N
Ts
N
H
34
27
Boc
HN
N
MeO2C
3HCl
NH2
MeO2C
e
NHBoc
N
H
71%
N
H
70%
35
3
Scheme 5. Reagents and conditions: (a) Na (10 equiv), naphthalene (10 equiv), DME, ꢀ78 ꢁC, 1.5 h, 40%, dr 57/43; (b) Raney Ni (W-2), EtOH, H2 (1 atm), 50 ꢁC, 29 h; (c) NaBH3CN
(3.1 equiv), AcOH (pH 4), MeOH, rt, 3 h; (d) (Boc)2O (1.3 equiv), NaHCO3 (5.2 equiv), dioxane/H2O (1/2), 0 ꢁC to rt, 42 h, 70% (three steps); (e) 2 M HCl/MeOH, ꢀ15 ꢁC to rt, 14 h, 71%.
The hydrogenation of 27 with Raney nickel in the presence of
hydrogen in ethanol at 50 ꢁC for 24 h proceeded with cyclization to
produce the pyrroloquinoline imine 28, which without any purifi-
cation was reduced with sodium cyanoborohydride to afford the
pyrroloquinoline 29 as a single isomer in 85% yield in two steps.
After protection of the pyrrolidine nitrogen for purification, se-
quential deprotection of the N-toluenesulfonyl group and two tert-
butoxycarbonyl groups in 30 furnished the 3-epi-core structure 32.
However, the spectroscopic data of 32 was not identical to the
reported value of 3. In an effort to determine the stereostructure of
32, we carried out NOE experiments as shown in Figure 2. The
relative stereochemistry of 29 and 32 at the C2, C3, and C4 was
confirmed to be all cis. Accordingly, it proved that the hydro-
cyanation of 23 exclusively produced the cis product 24 and the
subsequent cyclization of 27 with Raney nickel took place without
isomerization of the stereocenters. We expected that the cis-24
might be generated by the kinetic protonation of the enolate in-
termediate in the hydrocyanation reaction and might be thermo-
dynamically unstable. Therefore, we attempted the base-catalyzed
isomerization of cis-27 to trans-33 (Table 3). However, the cis-27
was found to be unexpectedly stable under basic conditions. In
addition, we were unable to obtain the trans-33 as a pure di-
astereomer because both diastereomers are inseparable by column
chromatography. The consideration using a molecular model sug-
gested that the exclusive cis preference arising from the hydro-
cyanation of 23 can be ascribed to the pseudo 1,3-diaxial
interaction between the bulky N-toluenesulfonyl group and 3-
cyanomethyl one (Fig. 3). Therefore, we decided to carry out the
cyclization reaction after removal of the N-protecting group. The
deprotection of 27 with sodium/naphthalene yielded the tetrahy-
droquinolone 34 in 40% yield with the diastereomeric ratio of 57/43
(Scheme 5). Indeed, the ratio was somewhat improved, but still
unsatisfactory. In addition, the reaction had a moderate yield due to
generating an overreduced side product. However, the hydroge-
nation of 34 with Raney nickel and hydrogen followed by N-pro-
tection furnished the desired pyrroloquinoline 35 as almost a single
isomer in 70% yield. This preferential trans formation during the
hydrogenation contrasts the cis preference in the hydrocyanation
reaction of 19, indicating that their stereoselectivities are highly
dependent on the nature of the substituent at N. The fact indicates
that, in the absence of the N-toluenesulfonyl group at N, the re-
action takes place with the isomerization of the 3-cyanomethyl
group for preventing the torsional strain between the 2-(3-tert-
butoxycarbonylaminopropyl) group and the pyrroline ring (Fig. 4).
Exposure of 35 to 2 M hydrochloric acid afforded the martinelline
chiral core 3 in 71% yield, of which the spectroscopic data were
identical with the reported value of 3. This synthesis represents the
first enantioselective synthesis of the martinelline chiral core 3 and
the formal total syntheses of martinellic acid and martinelline.
The above synthesis required the introduction of the C-1 unit on
the aromatic nucleus. Therefore, a more straightforward route was
pursued by employing the 4-methxoycarbonylanthranilaldehyde
derivative 38 as the starting material. The preparation of 38 was
carried out by the slight modification of the known procedure
(Scheme 6).2g The p-aminobenzoic acid methyl ester was protected
with toluenesulfonyl chloride and pyridine and then reacted with
bromine in the presence of sodium acetate in acetic acid, yielding
36 in 95% yield. The Stille coupling of 36 with tributyl(vinyl)tin
followed by ozonization of the resulting styrene derivative 37
afforded the 4-methoxycarbonylanthranilaldehyde 38.
We briefly examined the conditions of the asymmetric tandem
Michael–aldol reaction using 38 (Table 4). The use of the Boc de-
rivative instead of 38 was inadequate for this reaction (entry 1) and
the presence of NaOAc was not necessary (entry 3). The reaction
was sensitive to the catalyst amount. Finally, a 20% catalyst was
essential for a satisfactory yield and enantioselectivity (entry 3).
Thus, the reaction of 38 (1 equiv) with 6 (3 equiv) using the (R)-
catalyst 14 (20 mol %) in acetonitrile at ꢀ20 ꢁC for 24 h furnished
the (S)-1,2-dihydroquinoline 39 in quantitative yield and 99% ee.
The reduction of 39 with sodium borohydride/ceric chloride
followed by epoxidation of the allyl alcohol 40 with m-CPBA pro-
vided the epoxide 41 in quantitative yield with a diastereomeric
ratio of 75/25 to 86/14 (Scheme 7). After the iodination of 41, the
Br
MeO2C
MeO2C
a,b
c
NHTs
NH2
36
O
MeO2C
MeO2C
d
H
N
N
NHTs
NHTs
MeO2C
torsional strain
NHBoc
MeO2C
37
38
NHBoc
N
H
N
H
Scheme 6. Reagents and conditions: (a) TsCl, pyridine, 0 ꢁC to rt, 37 h; (b) Br2, AcONa,
AcOH, rt, 24 h, 95% (two steps); (c) tributyl(vinyl)tin, BHT, (PPh3)4Pd (5 mol %), toluene,
reflux, 5.5 h, 72%; (d) O3, CH2Cl2, ꢀ78 ꢁC, 4.5 h, then (CH3)2S, 92%.
Figure 4.

Y. Yoshitomi et al. / Tetrahedron 64 (2008) 11568–11579
11573
Table 4
Asymmetric tandem Michael–aldol reaction using (R)-diphenylprolinol triethylsilyl ether
O
O
O
H
MeO2C
MeO2C
H
H
(R)-catalyst 14 (see, Table)
+
NHBoc
CH3CN (0.5 M)
additive (see Table)
temp., time (see Table)
NHTs
N
Ts
NHBoc
38
39
6
Entry
Catalyst (mol %)
Additive
Conditions
Yield (%)
ee (%)
1a,b
2b
3
4
5
23
20
20
5
NaOAc (0.56 equiv.)
NaOAc (0.56 equiv.)
d
rt, 43.5 h
NR
d
rt, 43.5 h
Quant.
Quant.
38
87
99
97
96
ꢀ20 ꢁC, 24 h
d
4
4
ꢁC, 24 h
ꢁC, 24 h
5
AcOH (5 mol %)
77
a
The N-tert-butoxycarbonyl derivative was used instead of 38.
The (S)-catalyst 14 was used.
b
O
MeO2C
R
MeO2C
b
d
a
OH
NHBoc
39
N
NHBoc
Ts
N
Ts
41: R = OH
c
40
42: R = I
O
N
O
OH
MeO2C
e
MeO2C
MeO2C
f
CN
NHBoc
NHBoc
NHBoc
N
N
Ts
Ts
Ts
43
27
44
Scheme 7. Reagents and conditions: (a) NaBH4, CeCl3$7H2O, MeOH, 0 ꢁC to rt, 18 h, quant.; (b) m-CPBA, CH2Cl2, 0 ꢁC to rt, 45 h, quant., dr 75/25 to 86/14; (c) PPh3, I2, imidazole,
benzene, rt, 20 min; (d) Zn, AcOH, MeOH, rt, 30 min, 91% (two steps) dr 80/20; (e) MnO2, CH2Cl2, rt, 15.5 h, quant.; (f) KCN, AcOH, EtOH/H2O (10/1), 0 ꢁC, 40 min, 90%, dr 94/6.
treatment of the iodide 42 with zinc/acetic acid caused ring
cleavage to give the allyl alcohol 43 in 91% yield (two steps). The
oxidation of 43 with activated manganese dioxide followed by
IR-230 spectrometer. NMR spectra were recorded on JEOL JNM-
GSX-400A and JNM-ECP-400 spectrometers with tetramethylsilane
as an internal standard, unless otherwise indicated. Mass spectra
were measured on a JMX-AX-500 spectrometer. Column chroma-
tography was performed with silica gel BW-820MH or BW-200
(Fuji Davison Co.). HPLC analyses were carried out on the chiral
column indicated in each experiment. All commercially available
reagents were used as-received.
hydrocyanation of the resulting
a,b-unsaturated ketone 44 fur-
nished the quinolone 27 in 90% yield with a diastereomeric ratio of
94/6. This route is more efficient for the enantioselectivity and
chemical yield than that described above.
3. Conclusion
4.2. N-tert-Butoxycarbonyl-2-hydroxypyrrolidine (9)
In conclusion, we have achieved the first catalytic enantiose-
lective synthesis of the martinelline chiral core 3 using the asym-
metric tandem Michael–aldol reaction, which represents the
formal total synthesis of martinellic acid and martinelline. In ad-
dition, we have also synthesized the diastereomer 32 of 3. Using the
synthetic routes to these pyrroloquinoline chiral cores, all of the
martinelline diastereomers will be available for studies of these
biological activities.
To a stirred solution of pyrrolidinone 7 (52 mL, 0.686 mol) in
CH3CN (1.3 L) at room temperature were added di-tert-butyl
dicarbonate (Boc2O) (180 g, 0.823 mol) and DMAP (8.4 g,
68.6 mmol) and the reaction mixture was stirred for 2 h. After re-
moval of volatiles in vacuo, the residue was diluted with EtOAc and
the solution was washed with H2O and brine. The organic layer was
dried over Na2SO4, filtered, and concentrated in vacuo. The residue
was purified by silica gel column chromatography (n-hexane/
EtOAc¼2/1) to give N-tert-butoxycarbonylpyrrolidinone 8 (128.1 g,
99.6%) as a yellow oil, which was used for next reaction.
To a stirred solution of 8 (23.6 g, 127 mmol) in THF (635 mL) at
ꢀ78 ꢁC under an argon atmosphere was added dropwise a 1.0 M
solution of DIBALH (183 mL, 190 mmol) and the reaction mixture
was stirred for 1 h. The reaction was quenched with saturated
potassium acetate solution at ꢀ78 ꢁC. The mixture was transferred
to the flask containing saturated aqueous NH4Cl and ether. The
4. Experimental
4.1. General
Melting points were measured with a SIBATA NEL-270 melting
point apparatus and are uncorrected. Optical rotations were mea-
sured on a JASCO P-1020 polarimeter with a sodium lamp (589 nm).
Infrared spectra were recorded on a SIMADZU FT IR-8100 JASCO FT/

11574
Y. Yoshitomi et al. / Tetrahedron 64 (2008) 11568–11579
mixture was allowed to warm to room temperature and stirred
until thick white gel was formed. Then the mixture was filtered
through a Celite pad. The mixture was separated and the aqueous
layer was extracted with ether. The combined organic layers were
washed with saturated aqueous NH4Cl, H2O, and brine, dried over
Na2SO4, and concentrated in vacuo. The residue was purified by
silica gel column chromatography (n-hexane/EtOAc¼2/1) to give
the title compound 9 (24.7 g, quant.) as a colorless oil: 1N NMR
4.6. (2S)-6-Benzyloxy-2-(3-tert-butoxycarbonylaminopropyl)-
3-formyl-1-(toluene-4-sulfonyl)-1,2-dihydroquinoline (13)
To a stirred solution of 6 (8.5 g, 0.04 mol) and (R)-catalyst 14
(370 mg, 1.0 mmol) in CH3CN (40 mL) and AcOH (23 mL, 0.4 mmol)
at ꢀ20 ꢁC was added 12 (7.6 g, 0.02 mol). After stirring the mixture
at ꢀ20 ꢁC for 24 h under an argon atmosphere, the reaction mixture
was diluted with EtOAc, washed with water and brine, dried over
Na2SO4, filtered, and concentrated in vacuo. The residue was puri-
(CDCl3)
d 1.47 (9H, s), 1.78–2.10 (4H, m), 3.46–3.56 (2H, m), 5.47
(1H, br).
fied by silica gel column chromatography (n-hexane/EtOAc¼2/1) to
26
give 13 (11.7 g, quant., 95.7% ee) as yellow amorphous powder: [a]
D
4.3. Ethyl 6-tert-butoxycarbonylaminohex-2-enate (10)
To a stirred solution of 9 (38.1 g, 0.203 mol) in toluene (1.0 L)
þ207.0 (c 0.660, CHCl3, 95.9% ee); IR (neat) 3985, 3943, 3864, 3805,
3773, 3751, 3734, 3677, 3657, 3619, 3569, 3404, 2928, 1671, 1599,
1567, 1488, 1364, 1268, 1223, 1162, 1088, 1017, 861, 813, 739,
was
added
ethoxycarbonylmethylenephosphorane
(81.7 g,
683 cmꢀ1 1H NMR (400 MHz, CDCl3)
; d 1.23–1.41 (11H, m), 1.55–
0.244 mol) and the reaction mixture was stirred at 100 ꢁC for 13 h.
The reaction mixture was diluted with EtOAc and washed with H2O
and brine. The organic layer was dried over Na2SO4 and concen-
trated in vacuo. The residue was purified by silica gel column
chromatography (n-hexane/EtOAc¼1/1) to give 10 (51.7 g, 99%) as
1.72 (2H, m), 2.31 (3H, s), 3.12 (2H, dt, J¼6.8, 6.8 Hz), 4.56 (1H, br),
5.09 (2H, s), 5.19 (1H, dd, J¼4.4, 9.7 Hz), 6.61 (1H, s), 6.78 (1H, d,
J¼2.8 Hz), 7.02 (2H, d, J¼8.6 Hz), 7.11 (1H, dd, J¼2.9, 9.0 Hz), 7.16
(2H, d, J¼8.2 Hz), 7.34–7.46 (5H, m), 7.72 (1H, d, J¼8.8 Hz), 9.12 (1H,
s); 13C NMR (100 MHz, CDCl3) 21.4, 25.7, 28.3, 28.4, 29.1, 39.7, 51.9,
70.4, 114.2, 118.0, 126.8, 127.5, 127.6, 128.2, 129.1, 135.3, 136.2, 139.0,
139.5, 143.6, 155.9, 157.4, 189.5; HRMS (FAB, NBA) calcd for
C32H36N2O6S 576.2294 (Mþ), found 576.2298. HPLC analysis:
CHIRALCEL AD-H, (n-hexane/i-PrOH¼80/20, 1.0 mL/min), tR¼17.7
min (major) and 23.6 min (minor).
a yellow oil: IR (neat) 3372, 2978, 2934,1714,1519,1268,1169 cmꢀ1
;
1H NMR (CDCl3)
d
1.28 (3H, t, J¼7.1 Hz), 1.44 (9H, s), 1.65 (2H, tt,
J¼7.1, 7.3 Hz), 2.23 (2H, dt, J¼7.1, 8.1 Hz), 3.12–3.15 (2H, m), 4.18 (2H,
q, J¼7.1 Hz), 5.83 (1H, dt, J¼1.7, 15.6 Hz), 6.94 (1H, dt, J¼7.0,
15.7 Hz); 13C NMR (CDCl3)
d 14.1, 28.3, 28.4, 29.3, 39.9, 60.1, 79.1,
121.8, 147.9, 155.8, 166.4; HRMS (FAB, NBA) calcd for C13H24NO4
258.1706 (MþHþ), found 258.1697.
4.7. (2S)-6-Benzyloxy-2-(3-tert-butoxycarbonylaminopropyl)-
3-hydroxymethyl-1-(toluene-4-sulfonyl)-1,2-
dihydroquinoline (19)
4.4. tert-Butyl (6-hydroxyhex-4-enyl)carbamate (11)
To a stirred solution of 10 (839 mg, 3.22 mmol) in CH2Cl2
(13 mL) at ꢀ78 ꢁC under an argon atmosphere was added drop-
wise a 1.0 M solution of DIBALH (6.6 mL, 6.6 mmol) and the re-
action mixture was stirred for 1 h. The reaction was quenched
with saturated aqueous potassium acetate at ꢀ78 ꢁC. The mixture
was transferred to a flask containing saturated aqueous NH4Cl and
ether. The mixture was allowed to warm to room temperature
and stirred until thick white gel was formed. The mixture was
filtered through a Celite pad. The filtrate was separated and the
aqueous layer was extracted twice with ether. The combined or-
ganic layers were washed with saturated aqueous NH4Cl, H2O,
and brine, dried over Na2SO4, and concentrated in vacuo. The
residue was purified by silica gel column chromatography (n-
hexane/EtOAc¼1/1) to give 11 (526 mg, 76%) as a colorless oil: IR
To a stirred solution of 13 (1.05 g, 1.8 mmol) and CeCl3$7H2O
(1.01 g, 2.7 mmol) in MeOH (9.1 mL) was added NaBH4 (137 mg,
3.6 mmol) and the reaction mixture was stirred at room tempera-
ture for 18 h. The reaction mixture was quenched with 1 M KHSO4
and extracted with EtOAc. The organic layer was washed with
water and brine, dried over Na2SO4, and concentrated in vacuo. The
residue was purified by silica gel column chromatography (n-hex-
ane/EtOAc¼2/1 to 1/1) to give dihydroquinoline 19 (1.05 g, quant.)
24
as white amorphous powder: [
a]
þ5.67 (c 1.04, CHCl3, 95.9% ee);
D
IR (neat) 3866, 3750, 3650, 3394, 2976, 2929,1685,1601,1573,1490,
1454, 1365, 1341, 1269, 1222, 1161, 1089, 1020, 895, 812, 750, 684,
655 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d 1.24–1.30 (1H, m), 1.40–1.49
(1H, m), 1.44 (9H, s), 1.80–1.90 (1H, m), 2.33 (3H, s), 2.88 (1H, br),
3.07 (1H, dq, J¼5.2, 14.4 Hz), 3.50–3.61 (1H, br), 3.89 (1H, dd, J¼4.4,
13.9 Hz), 3.98 (1H, dd, J¼4.8, 13.6 Hz), 4.64 (1H, br), 4.97 (1H, d,
J¼10.1 Hz), 5.04 (2H, s), 5.78 (1H, s), 6.54 (1H, d, J¼2.8 Hz), 6.91 (1H,
dd, J¼2.9, 8.8 Hz), 7.07 (2H, d, J¼8.1 Hz), 7.29–7.45 (7H, m), 7.65 (1H,
(neat) 3353, 2975, 2930, 1688, 1526, 1179 cmꢀ1
1.44 (9H, s), 1.57 (2H, tt, J¼7.3, 7.3 Hz), 2.10 (2H, dt, J¼5.7,
7.5 Hz), 3.10–3.14 (2H, m), 4.08 (2H, d, J¼4.2 Hz), 5.62–5.72 (2H,
m); 13C NMR (CDCl3)
28.4, 29.3, 39.6, 39.9, 63.6, 79.2, 129.8,
;
1H NMR (CDCl3)
d
d
d, J¼8.8 Hz); 13C NMR (100 MHz, CDCl3)
d 21.5, 25.7, 27.0, 28.4, 38.5,
132.0, 155.9; HRMS (FAB, NBA) calcd for C11H22NO3 216.1600
54.1, 63.2, 70.2, 79.4, 112.2, 113.8, 119.3, 124.9, 127.2, 127.5, 128.0,
128.6, 128.8, 129.0, 130.2, 135.7, 136.6, 141.9, 143.2, 156.8, 157.3;
HRMS (FAB, NBA) calcd for C32H38N2O6S 578.2451 (Mþ), found
578.2433.
(MþHþ), found 216.1612.
4.5. tert-Butyl (6-oxohex-4-enyl)carbamate (6)
To a stirred solution of 11 (514 mg, 2.38 mmol) in CH2Cl2
(12 mL) at room temperature was added activated MnO2 (2.57 g)
and the reaction mixture was stirred for 12 h. The reaction mix-
ture was filtered through a Celite pad and the filtrate was con-
centrated in vacuo. The residue was purified by silica gel column
chromatography (n-hexane/EtOAc¼1/1) to give 6 (466 mg, 92%) as
a colorless oil: IR (neat) 3355, 2976, 2933, 1694, 1519, 1250,
4.8. {3-[6-Benzyloxy-1a-hydroxymethyl-3-(toluene-4-
sulfonyl)-1a,2,3,7b-tetrahydro-1-oxa-3-aza-
cyclopropa[a]naphthalen-2-yl]-propyl}-carbamic acid tert-
butyl ester (21)
To a stirred solution of 19 (7.09 g, 12 mmol) in CH2Cl2 (49 mL) at
0 ꢁC was added m-CPBA (4.53 g, 18 mmol) and the reaction mixture
was stirred at room temperature for 45 h. The reaction mixture was
quenched with saturated aqueous Na2SO3 and extracted with
EtOAc. The organic layer was washed three times with water and
brine, dried over Na2SO4, and concentrated in vacuo. The residue
was purified by silica gel column chromatography (n-hexane/
EtOAc¼1/1) to give 21 (5.94 g, 81.5%, dr 63/37) as yellow
1171 cmꢀ1
;
1H NMR (CDCl3)
d
1.44 (9H, s), 1.71 (2H, tt, J¼7.1,
7.1 Hz), 2.38 (2H, dt, J¼6.8, 8.4 Hz), 3.15–3.20 (2H, m), 6.14 (1H,
ddt, J¼1.5, 7.9, 15.6 Hz), 6.85 (1H, dt, J¼6.8, 15.5 Hz), 9.52 (1H, d,
J¼7.8 Hz); 13C NMR (CDCl3)
d 28.2, 29.8, 39.8, 52.2, 79.2, 133.1,
155.9, 157.4, 193.8; HRMS (FAB, NBA) calcd for C11H20NO3 214.1443
(MþHþ), found 214.1436.

Y. Yoshitomi et al. / Tetrahedron 64 (2008) 11568–11579
11575
24
amorphous powder: [
46); IR (neat) 3403, 2929, 1685, 1608, 1496, 1454, 1365, 1340, 1247,
1159, 1089, 1019, 892, 851, 812, 749, 678, 655 cmꢀ1 1H NMR
(400 MHz, CDCl3) 1.01–1.08 (1H, m), 1.43 (9H, s), 1.57–1.65 (2H,
a
]
ꢀ58.4 (c 0.525, CHCl3, 95.9% ee, dr: 54/
129.4, 129.9, 132.7, 134.1, 136.0, 141.0, 144.0, 155.8, 157.5, 181.3;
HRMS (FAB, NBA) calcd for C32H36N2O6S 576.2294 (Mþ), found
576.2329.
D
;
d
m), 1.77–1.80 (1H, m), 2.34 (3H, s), 3.09 (1H, dd, J¼5.4, 15.4 Hz), 3.43
(1H, d, J¼12.9 Hz), 3.47 (1H, s), 4.07 (1H, d, J¼12.9 Hz), 4.72 (1H, br),
4.89 (1H, d, J¼11.2 Hz), 5.03 (2H, s), 6.84 (1H, d, J¼2.9 Hz), 6.97 (1H,
dd, J¼2.9, 8.8 Hz), 7.15 (2H, d, J¼8.3 Hz), 7.33–7.45 (7H, m), 7.74 (1H,
4.11. (2S,3R)-6-Benzyloxy-2-(3-tert-butoxylcarbonyl
aminopropyl)-3-cyanomethyl-1-(toluene-4-sulfonyl)-
1,2,3,4-tetrahydroquinolin-4-one (24)
d, J¼8.8 Hz); 13C NMR (100 MHz, CDCl3)
d
21.6, 25.2, 26.7, 28.4, 38.7,
To a stirred solution of 23 (2.02 g, 3.5 mmol) in EtOH (17.5 mL)
at room temperature were added KCN (0.48 g) in H2O (1.75 mL)
and AcOH (0.3 mL, 5.2 mmol) and the reaction mixture was stirred
at 50 ꢁC for 40 min. The reaction mixture was concentrated in
vacuo. The residue was diluted with EtOAc, washed with water and
brine, dried over Na2SO4, and concentrated in vacuo. The residue
was purified by silica gel column chromatography (n-hexane/
52.4, 53.8, 59.4, 62.0, 70.2, 79.4, 115.3, 115.5, 116.1, 126.1, 127.4, 127.5,
127.5, 127.8, 128.1, 128.2, 128.6, 128.8, 129.5, 135.4, 135.5, 136.3,
136.4, 143.0, 156.6, 156.7, 157.6; HRMS (FAB, NBA) calcd for
C32H38N2O7S 594.2400 (Mþ), found 594.2396.
4.9. (2S)-6-Benzyloxy-2-(3-tert-butoxycarbonylaminopropyl)-
4-hydroxy-3-methylene-1-(toluene-4-sulfonyl)-1,2,3,4-
tetrahydroquinoline (22)
EtOAc¼2/1) to give 24 (2.09 g, 98.9%, dr >90/10) as yellow amor-
25
phous powder: [
a
]
D
þ48.0 (c 0.550, CHCl3, 95.9% ee, dr >90/10); IR
(neat) 3404, 2976, 1691, 1605, 1487, 1432, 1355, 1245, 1161, 1087,
To a stirred solution of 21 (472 mg, 0.79 mmol, dr 54/46) in
benzene (3.2 mL) at room temperature were added imidazole
(135.2 mg, 1.98 mmol), triphenyl phosphine (520 mg, 1.98 mmol),
and iodine (402 mg, 1.59 mmol), and the reaction mixture was
stirred at room temperature for 20 min. The reaction mixture was
quenched with saturated aqueous Na2SO3 and extracted with
EtOAc. The organic layer was washed with water and brine, dried
over Na2SO4, and concentrated in vacuo.
Activated Zn (415 mg, 6.35 mmol) was added to a stirred solu-
tion of the above residue in MeOH (4.0 mL) and AcOH (0.4 mL) at
room temperature, and the reaction mixture was stirred at room
temperature for 30 min. The reaction mixture was diluted with
EtOAc and washed with 0.5 M Na2S2O3, saturated aqueous NaHCO3,
water, and brine, dried over Na2SO4, and concentrated in vacuo. The
residue was purified by silica gel column chromatography (n-hex-
1020, 815, 750 cmꢀ1 1H NMR (400 MHz, CDCl3)
;
d
1.26–1.32 (1H,
m), 1.38–1.48 (1H, m), 1.41 (9H, s), 1.66 (2H, dt, J¼8.1, 13.4 Hz), 2.26
(1H, dd, J¼9.2, 17.6 Hz), 2.41 (3H, s), 2.53 (1H, dt, J¼4.9, 9.7 Hz), 2.86
(1H, dd, J¼4.8, 17.8 Hz), 3.04–3.12 (1H, m), 3.15–3.20 (1H, m), 4.51
(1H, br), 4.80 (1H, dt, J¼3.8, 12.8 Hz), 5.08 (2H, s), 7.24–7.30 (3H, m),
7.33–7.45 (6H, m), 7.60 (2H, d, J¼8.2 Hz), 7.91 (1H, d, J¼9.2 Hz); 13C
NMR (100 MHz, CDCl3) d 14.3, 21.5, 23.0, 26.5, 28.2, 39.1, 44.8, 58.5,
70.3, 79.0, 110.5, 117.2, 123.7, 125.1, 126.7, 127.1, 127.5, 128.1, 128.2,
128.6, 130.0, 130.3, 132.4, 135.9, 136.3, 144.8, 156.0, 156.6, 190.8;
HRMS (FAB, NBA) calcd for C33H37N3O6S 603.2403 (Mþ), found
603.2431.
4.12. (2S,3R)-2-(3-tert-Butoxylcarbonylaminopropyl)-3-
cyanomethyl-6-hydroxy-1-(toluene-4-sulfonyl)-1,2,3,4-
tetrahydroquinolin-4-one (25)
ane/EtOAc¼2/1) to give 22 (391 mg, 85.2%, dr 51/49) as yellow
25
amorphous powder: [
a
]
ꢀ48.9 (CHCl3, c 0.555, 95.9% ee, dr 51/
To a stirred solution of 24 (292 mg, 0.48 mmol, dr >90/10) in
EtOAc (2.4 mL) at room temperature was added Pd/C (29.2 mg) and
the reaction mixture was stirred for 60.5 h under an atmosphere of
hydrogen. The reaction mixture was filtered through a Celite pad
and the filtrate was concentrated in vacuo. The residue was purified
by silica gel column chromatography (n-hexane/EtOAc¼1.5/1 to 1/
D
49); IR (neat) 3403, 2929, 1685, 1606, 1491, 1454, 1342, 1249, 1157,
1089, 1019, 813, 749, 675 cmꢀ1 1H NMR (400 MHz, CDCl3)
;
d
1.41
(9H, s), 1.44–1.63 (4H, m), 2.35 (3H, s), 3.08–3.14 (2H, m), 4.47 (1H,
br), 4.76–4.86 (1H, m), 4.99 (1H, d, J¼2.6 Hz), 5.04 (1H, s), 5.07 (2H,
s), 6.97–7.01 (2H, m), 7.14 (2H, d, J¼7.9 Hz), 7.27 (2H, d, J¼8.2 Hz),
7.34–7.48 (5H, m), 7.62 (1H, d, J¼8.6 Hz); 13C NMR (100 MHz, CDCl3)
1) to give 25 (255 mg, quant., dr >98/2) as yellow amorphous
26
d
21.5, 26.5, 28.4, 30.4, 32.8, 39.7, 58.7, 62.6, 66.3, 67.0, 70.2, 79.1,
powder: [
a]
þ79.0 (c 0.515, CHCl3, 95.7% ee, dr >92/8); IR (neat)
D
113.9, 114.6, 115.9, 125.8, 127.0, 127.3, 127.6, 128.1, 128.1, 128.3, 128.6,
128.8, 129.0, 129.3, 129.6, 134.8, 135.0, 135.8, 136.5, 136.6, 143.1,
143.5, 143.7, 157.6, 157.9; HRMS (FAB, NBA) calcd for C32H38N2O6S
578.2451 (Mþ), found 578.2446.
3865, 3750, 3710, 3374, 2977, 1684, 1609, 1493, 1452, 1352, 1303,
1248, 1160, 1087, 846, 825, 752, 707, 678 cmꢀ1; 1H NMR (400 MHz,
CDCl3) d 1.24–1.28 (1H, m), 1.40–1.45 (1H, m), 1.44 (9H, s), 1.55–1.69
(2H, m), 2.30 (1H, dd, J¼10.1, 17.6 Hz), 2.41 (3H, s), 2.51 (1H, dt,
J¼4.4, 9.5 Hz), 2.85 (1H, dd, J¼5.3, 17.6 Hz), 3.07–3.18 (2H, m), 4.65
(1H, br), 4.78 (1H, dt, J¼3.8, 12.5 Hz), 6.60 (1H, br), 7.14 (1H, dd,
J¼3.1, 9.0 Hz), 7.26–7.29 (3H, m), 7.59 (2H, d, J¼8.4 Hz), 7.84 (1H, d,
4.10. (2S)-6-Benzyloxy-2-(3-tert-butoxylcarbonyl
aminopropyl)-3-methylene-1-(toluene-4-sulfonyl)-
1,2,3,4-tetrahydroquinolin-3-one (23)
J¼9.0 Hz); 13C NMR (100 MHz, CDCl3)
d 14.3, 21.6, 23.1, 26.6, 28.3,
39.6, 44.8, 58.6, 80.0, 112.3, 117.5, 123.6, 125.3, 126.8, 128.2, 130.4,
131.3, 136.3, 144.9, 155.0, 156.7, 191.0; HRMS (FAB, NBA) calcd for
C26H32N3O6S 514.2012 (MþHþ), found 514.1994.
To a stirred solution of 22 (2.60 g, 4.49 mmol) in CH2Cl2
(22.5 mL) at room temperature was added activated MnO2 (18.2 g)
and the reaction mixture was stirred for 15.5 h. The reaction mix-
ture was filtered through Celite and the filtrate was concentrated in
vacuo. The residue was purified by silica gel column chromatog-
4.13. (2S,3R)-2-(3-tert-Butoxylcarbonylaminopropyl)-3-
cyanomethyl-1-(toluene-4-sulfonyl)-6-(trifluoro-
methanesulfonyl)-1,2,3,4-tetrahydroquinolin-4-one (26)
raphy (n-hexane/EtOAc¼2/1) to give 23 (2.18 g, 84.1%) as yellow
26
amorphous powder: [
a
]
D
þ113.2 (c 0.650, CHCl3, 95.9% ee); IR
(neat) 3650, 3420, 2976, 1682, 1602, 1485, 1432, 1352, 1247, 1162,
To a stirred solution of 25 (184 mg, 0.36 mmol, dr >92/8) in
CH2Cl2 (1.8 mL) and pyridine (0.18 mL) at 0 ꢁC was added dropwise
1089, 1004, 811, 751, 680 cmꢀ1 1H NMR (400 MHz, CDCl3)
;
d
1.42
(9H, s), 1.37–1.46 (1H, m), 1.59–1.69 (3H, m), 2.33 (3H, s), 3.07–3.22
(2H, m), 4.51 (1H, br), 5.03–5.06 (1H, m), 5.11 (2H, ABq, J¼11.4,
15.2 Hz), 5.27 (1H, s), 5.96 (1H, s), 7.08 (2H, d, J¼8.2 Hz), 7.24 (2H, d,
J¼8.2 Hz), 7.29 (1H, dd, J¼3.3, 9.0 Hz), 7.35–7.47 (6H, m), 7.74 (1H, d,
triflic anhydride (67 mL, 0.40 mmol) and the reaction mixture was
allowed to warm to room temperature for 1 h 40 min. The reaction
mixture was diluted with EtOAc, washed with water, 1 M KHSO4,
water, and brine, dried over Na2SO4, and concentrated in vacuo. The
residue was purified by silica gel column chromatography (n-hex-
ane/EtOAc¼3/1) to give 26 (166 mg, 71.8%, dr >99/1) as white
J¼9.0 Hz); 13C NMR (100 MHz, CDCl3)
d 21.4, 26.5, 28.2, 32.1, 39.2,
60.6, 70.3, 78.9, 111.1, 122.7, 124.2, 127.5, 127.6, 128.1, 128.5, 128.9,

11576
Y. Yoshitomi et al. / Tetrahedron 64 (2008) 11568–11579
26
amorphous powder: [
a
]
D
þ44.6 (c 0.490, CHCl3, 95.7% ee, dr >99/
dd, J¼2.0, 8.8 Hz), 8.09 (1H, s); 13C NMR (100 MHz, CDCl3)
d 21.5,
1); IR (neat) 3905, 3835, 3751, 3677, 3423, 2978, 1698, 1598, 1509,
1476, 1423, 1363, 1248, 1211, 1165, 1135, 1087, 1007, 859, 758, 706,
25.1, 27.2, 28.3, 28.7, 39.6ꢂ2, 45.6, 52.1, 55.9, 56.1, 79.0, 126.7, 126.9,
127.6, 128.7, 129.7, 130.2, 133.3, 137.1ꢂ2, 143.8, 155.9, 166.5; HRMS
(FAB, NBA) calcd for C28H38N3O6S 544.2481 (MþHþ), found
544.2452.
664 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d 1.28–1.33 (1H, m), 1.41 (9H,
s), 1.44–1.51 (1H, m), 1.61–1.63 (1H, m), 2.32 (1H, dd, J¼10.3,
17.9 Hz), 2.44 (3H, s), 2.55 (1H, dt, J¼5.1, 8.6 Hz), 2.87 (1H, dd, J¼4.8,
17.8 Hz), 3.03–3.11 (1H, m), 3.17–3.24 (1H, m), 4.53 (1H, br), 4.87
(1H, dt, J¼3.7, 11.4 Hz), 7.34 (2H, d, J¼8.1 Hz), 7.53 (1H, dd, J¼2.9,
9.2 Hz), 7.65 (2H, d, J¼8.4 Hz), 7.79 (1H, d, J¼2.9 Hz), 8.14 (1H, d,
4.16. (3aS,4S,9bR)-4-(3-tert-Butoxycarbonylaminopropyl)-5-
(toluene-4-sulfonyl)-2,3,3a,4,5,9b-hexahydro-pyrrolo[3,2-
c]quinoline-1,8-dicarboxylic acid 1-tert-butyl ester 8-methyl
ester (30)
J¼9.2 Hz); 13C NMR (100 MHz, CDCl3)
d 14.2, 21.6, 23.0, 26.7, 28.2,
38.9, 45.1, 58.4, 79.2, 116.9, 119.8, 120.1, 125.1, 126.9, 128.1, 128.1,
130.6, 135.8, 138.9, 145.6, 146.6, 156.1, 189.4; HRMS (FAB, NBA) calcd
for C27H31F3N3O8S2 646.1505 (MþHþ), found 646.1482.
To a stirred solution of 29 (69.2 mg, 0.127 mmol) in CH2Cl2
(2.0 mL) at room temperature were added Et3N (50 mL,
0.361 mmol) and Boc2O (87.8 mg, 0.402 mmol). The solution was
stirred at room temperature for 1 h and diluted with EtOAc. The
mixture was washed with H2O and brine, dried over Na2SO4, fil-
tered, and concentrated in vacuo. The residue was purified by silica
4.14. (2S,3R)-2-(3-tert-Butoxycarbonylaminopropyl)-3-
cyanomethyl-4-oxo-1-(toluene-4-sulfonyl)-1,2,3,4-
tetrahydroquinoline-6-carboxylic acid methyl ester (27)
gel column chromatography (n-hexane/EtOAc¼2/1) to give 30
17
To a stirred solution of 26 (45.8 mg, 0.071 mmol, dr >99/1) in
DMF (0.71 mL) and MeOH (0.35 mL) at room temperature were
(85.1 mg, quant.) as a colorless oil: [
a
]
ꢀ13.1 (c 0.27, CHCl3); IR
D
(neat) 3368, 2975, 1689, 1609, 1516, 1437, 1391, 1364, 1288, 1254,
1161, 1129, 1091, 990, 909, 858, 815, 768, 730, 708, 692, 658 cmꢀ1
1H NMR (400 MHz, 55 ꢁC, CDCl3)
1.07–1.17 (2H, m), 1.42 (9H, s),
added Pd(OAc)2 (1.8 mg, 8.0
mmol), dppp (3.0 mg, 7.3
mmol), and
;
Et3N (0.05 mL, 0.36 mmol), and the reaction mixture was stirred at
70 ꢁC for 2 h under an atmosphere of carbon monoxide. Then, the
reaction mixture was cooled to room temperature, diluted with
brine, and filtered. The filtrate was diluted with EtOAc, washed with
water, 1 M KHSO4, and brine, dried over Na2SO4, and concentrated
in vacuo. The residue was purified by silica gel column chroma-
d
1.62–1.71 (4H, m), 2.38 (3H, s), 2.96 (1H, br s), 3.08–3.19 (2H, m),
3.30 (2H, d, J¼8.0 Hz), 3.48 (1H, d, J¼6.8 Hz), 3.88 (3H, s), 4.51 (1H,
br s), 4.61 (1H, br t, J¼9.6 Hz), 7.19 (2H, d, J¼8.0 Hz), 7.47 (2H, d,
J¼8.4 Hz), 7.65 (1H, d, J¼8.0 Hz), 7.80 (1H, s), 7.97 (1H, d, J¼7.6 Hz);
13C NMR (100 MHz, 55 ꢁC, CDCl3)
d 21.4, 25.6, 27.1, 28.3, 28.4, 29.4,
tography (n-hexane/EtOAc¼2/1) to give 27 (17.9 mg, 45.4%, dr >99/
40.0, 44.6, 45.5, 52.0, 54.3, 55.1, 79.1, 80.0, 126.7, 127.9, 128.7, 128.9,
129.7, 130.0, 134.9, 137.5, 137.7, 143.8, 154.8, 156.0, 166.4; HRMS
(FAB, NBA) calcd for C33H46N3O8S 644.3006 (MþHþ), found
644.2954.
20
1) as a yellow oil: [
a]
þ25.2 (c 0.480, CHCl3, dr 95/5); IR (neat)
D
3376, 2929, 1698, 1608, 1516, 1426, 1363, 1257, 1163, 1086, 1010, 917,
814, 767, 750, 705, 667 cmꢀ1: 1H NMR (400 MHz, CDCl3)
d
1.25–1.68
(4H, m), 1.40 (9H, s), 2.33 (1H, dd, J¼10.0, 17.6 Hz), 2.42 (3H, s), 2.57
(1H, ddd, J¼4.8, 4.8, 9.2 Hz), 2.90 (1H, dd, J¼4.8, 17.2 Hz), 3.05–3.20
(2H, m), 3.94 (3H, s), 4.53 (1H, s), 4.91 (1H, d, J¼11.2 Hz), 7.30 (2H, d,
J¼8.4 Hz), 7.65 (2H, d, J¼8.4 Hz), 8.11 (1H, d, J¼8.8 Hz), 8.26 (1H, dd,
J¼2.0, 8.8 Hz), 8.55 (1H, d, J¼2.0 Hz); 13C NMR (100 MHz, CDCl3)
4.17. (3aR,4S,9bR)-4-(3-tert-Butoxycarbonylaminopropyl)-
2,3,3a,4,5,9b-hexahydro-pyrrolo[3,2-c]quinoline-1,8-
dicarboxylic acid 1-tert-butyl ester 8-methyl ester (31)
d
14.3, 21.7, 23.1, 26.7, 28.3, 39.1, 45.3, 52.5, 58.4, 79.3, 117.1, 123.5,
To a stirred solution of 30 (70.4 mg, 0.109 mmol) in MeOH
(3 mL) at room temperature was added Mg (136 mg, 0.560 mmol)
and the mixture was stirred for 18 h. The reaction was quenched
with aqueous saturated NH4Cl. The resulting mixture was extracted
with EtOAc. The organic layer was washed with H2O and brine,
dried over Na2SO4, filtered, and concentrated in vacuo. The residue
125.5, 126.9, 127.5, 129.2, 130.6, 136.1ꢂ2, 142.8, 145.5, 156.1, 165.4,
190.1; HRMS (FAB, NBA) calcd for C28H34N3O7S 556.2117 (MþHþ),
found 556.2131.
4.15. (3aS,4S,9bR)-4-(3-tert-Butoxycarbonylaminopropyl)-5-
(toluene-4-sulfonyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-
c]quinoline-8-carboxylic acid methyl ester (29)
was purified by silica gel column chromatography (n-hexane/
15
EtOAc¼1/1) to give 31 (51.5 mg, 97%) as a colorless oil: [
a
]
D
þ82.1 (c
0.38, CHCl3); IR (neat) 3345, 2976, 2249, 1672, 1609, 1513, 1435,
1393, 1365, 1329, 1278, 1245, 1213, 1164, 1104, 992, 907, 770,
To a stirred solution of 27 (83.0 mg, 0.149 mmol, dr 95/5) in
EtOH (2.0 mL) at room temperature was added Raney nickel (W-2,
699 mg). After being stirred for 24 h under an atmosphere of
hydrogen at 50 ꢁC, the reaction mixture was filtered through a pad
of Celite. The filtrate was concentrated in vacuo. The residue was
dissolved in MeOH (1.5 mL) and NaBH3CN (27.8 mg, 0.442 mmol)
was added at room temperature. The resulting mixture was acid-
ified to pH 5 with AcOH and stirred at room temperature for 4.5 h.
After the reaction mixture was concentrated in vacuo, the residue
was dissolved in CH2Cl2, washed with aqueous saturated NaHCO3,
dried over Na2SO4, filtered, and concentrated in vacuo. The residue
was purified by silica gel column chromatography (n-hexane/
727 cmꢀ1; 1H NMR (400 MHz, 55 ꢁC, CDCl3)
d 1.45 (9H, s), 1.49–1.60
(4H, m), 1.85 (2H, t, J¼9.6 Hz), 2.42 (1H, br s), 3.17 (2H, q, J¼6.4 Hz),
3.27–3.33 (1H, m), 3.46 (1H, br s), 3.54 (1H, dt, J¼2.8, 6.4 Hz), 3.81
(3H, s), 4.14 (1H, br s), 4.58 (1H, br s), 5.11 (1H, br s), 6.44 (1H, d,
J¼8.4 Hz), 7.68 (1H, dd, J¼1.6, 8.4 Hz), 8.29 (1H, s); 13C NMR
(100 MHz, 55 ꢁC, CDCl3)
d 21.6, 26.6, 28.4, 28.5, 31.2, 40.6, 41.4, 44.6,
50.9, 51.3, 55.7, 79.4, 80.1, 113.5, 119.8, 121.2, 129.8, 132.4, 147.4,
154.8, 156.1, 167.1; HRMS (FAB, NBA) calcd for C26H39N3O6 489.2839
(MþH), found 489.2820.
4.18. (3aR,4S,9bR)-4-(3-Aminopropyl)-2,3,3a,4,5,9b-
hexahydro-1H-pyrrolo[3.2-c]quinoline-8-carboxylic acid
methyl ester (32)
EtOAc¼1/2 to CHCl3/MeOH¼9/1) to give 29 (69.2 mg, dr >98/2,
19
85%) as a colorless oil: [
a
]
D
ꢀ74.7 (c 0.69, CHCl3); IR (neat) 3385,
2929, 1701, 1609, 1513, 1437, 1341, 1267, 1160, 1088, 1037, 917, 813,
747, 707, 666 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
0.88–1.00 (1H, m),
Hydrogen chloride (2 M) in MeOH (6 mL) was added to 31
1.25 (s, 1H), 1.40 (9H, s), 1.53 (2H, quin, J¼6.8 Hz), 1.60–1.68 (1H,
m), 1.91 (1H, tq, J¼4.4, 8.8 Hz), 2.26 (1H, br s), 2.38 (3H, s), 2.80
(1H, dt, J¼8.0, 10.4 Hz), 2.95–3.01 (1H, m), 3.05 (2H, q, J¼6.4 Hz),
3.41 (1H, d, J¼8.4 Hz), 3.90 (3H, s), 4.40–4.47 (2H, m), 7.17 (2H, d,
J¼8.4 Hz), 7.45 (2H, d, J¼8.4 Hz), 7.85 (1H, d, J¼8.4 Hz), 7.95 (1H,
(44.0 mg, 89.9
m
mol) at ꢀ15 ꢁC and the reaction mixture was
gradually allowed to warm to room temperature. After stirring the
mixture for 23 h, the reaction mixture was concentrated in vacuo.
The residue was dissolved in H2O, washed with EtOAc, and con-
centrated in vacuo to give 32 (33.6 mg, 94%) as a yellow oil: [
16
a]
D

Y. Yoshitomi et al. / Tetrahedron 64 (2008) 11568–11579
11577
ꢀ73.7 (c 0.34, MeOH); IR (neat) 3376, 3261, 2947, 2066, 1698, 1607,
1518, 1436, 1322, 1285, 1233, 1195, 1134, 1049, 1018, 986, 940, 880,
838, 769 cmꢀ1 1H NMR (400 MHz, CD3OD)
1.64–1.86 (4H, m),
1163, 1127, 909, 769, 729 cmꢀ1
;
1H NMR (400 MHz, CDCl3, 55 ꢁC)
d
1.44 (9H, s), 1.51–1.62 (4H, m), 1.59 (9H, s), 1.94 (2H, t, J¼8.4 Hz),
;
d
2.34–2.40 (1H, m), 3.04–3.17 (2H, m), 3.26–3.32 (2H, m), 3.45 (1H,
q, J¼9.2 Hz), 3.81 (3H, s), 4.52–4.59 (2H, br m), 5.00 (1H, br s), 6.43
(1H, d, J¼8.4 Hz), 7.68 (1H, dd, J¼2.0, 8.4 Hz), 8.26 (1H, s); 13C NMR
2.00–2.17 (2H, m), 2.88–2.95 (1H, m), 3.01 (2H, t, J¼7.2 Hz), 3.25–
3.35 (2H, m), 3.47 (1H, dt, J¼2.8, 6.8 Hz), 3.84 (3H, s), 4.57 (1H, s),
5.05 (d, 1H, J¼9.2 Hz), 6.80 (1H, d, J¼8.4 Hz), 7.77 (1H, dd, J¼1.6,
(100 MHz, CDCl3, 55 ꢁC)
d 27.0, 27.4, 28.4, 28.5, 33.2, 40.2, 41.1, 44.5,
8.4 Hz), 7.96 (1H, d, J¼1.2 Hz); 13C NMR (100 MHz, CD3OD)
d
23.6,
51.2, 51.5, 52.4, 79.4, 80.0, 113.6, 119.1, 120.1, 130.0, 132.4, 145.6,
155.2, 156.1, 167.1; HRMS (FAB, NBA) calcd for C26H39N3O6 489.2839
(Mþ), found 489.2868.
24.8, 30.9, 40.7, 42.3, 45.5, 52.2, 52.3, 58.8, 116.1, 116.2, 120.5, 132.2,
132.7 152.2, 168.2; HRMS (FAB, glycerol) calcd for C16H24N3O2
290.1869 (MþHþ), found 290.1843.
4.21. (3aS,4S,9bS)-4-(3-Aminopropyl)-2,3,3a,4,5,9b-
hexahydro-1H-pyrrolo[3.2-c]quinoline-8-carboxylic acid
methyl ester (3)
4.19. (2S,3R)- and (2S,3S)-2-(3-tert-Butoxycarbonyl
aminopropyl)-3-cyanomethyl-4-oxo-1,2,3,4-tetrahydroquino
line-6-carboxylic acid methyl ester (34)
The protected pyrroloquinoline 35 (57.6 mg, 117 mmol) was
A solution of sodium naphthalenide was prepared from sodium
(113 mg, 4.89 mmol) and naphthalene (637 mg, 4.97 mmo) in DME
(4 mL) by stirring the mixture at ꢀ78 ꢁC for 1 h under an argon
atmosphere. A solution of 27 (278 mg, 0.500 mmol, dr 94/6) in DME
(6 mL) was added dropwise to the solution via cannula over 20 min.
After stirring the mixture at ꢀ78 ꢁC for 1 h, the reaction mixture
was treated with MeOH and allowed to warm to room temperature.
The resulting mixture was extracted with EtOAc. The organic layer
was washed with H2O and brine, dried over Na2SO4, filtered, and
concentrated in vacuo. The residue was purified by silica gel column
treated with 2 M HCl/MeOH (7.8 mL) at ꢀ15 ꢁC. After being stirred
at room temperature for 14 h, the reaction mixture was concen-
trated in vacuo. The residue was dissolved in H2O, washed with
EtOAc, and concentrated in vacuo to give martinelline core 3
18
(33.1 mg, 71%) as a yellow oil: [
a]
ꢀ54.4 (c 0.290, MeOH); IR (neat)
D
3204, 2904, 2736, 2667, 2580, 2468, 1681, 1609, 1528, 1434, 1418,
1334, 1289, 1255, 1229, 1147, 1024, 960, 844, 769 cmꢀ1 1H NMR
(400 MHz, CD3OD) 1.69–1.87 (m, 4H), 2.11–2.17 (m, 1H), 2.40–2.44
;
d
(2H, m), 3.00–3.13 (m, 3H), 3.30–3.40 (3H, m), 3.84 (3H, s), 4.67 (d,
1H, J¼5.6 Hz), 6.82 (1H, d, J¼8.8 Hz), 7.78 (1H, dd, J¼2.0, 8.8 Hz),
chromatography (CH2Cl2/EtOAc¼2/1) to give quinolone 34
7.98 (1H, d, J¼2.0 Hz); 13C NMR (100 MHz, CD3OD)
d 23.9, 27.9, 30.4,
17
(80.2 mg, 40%, dr 57/43) as a yellow oil: [
a]
ꢀ170 (c 0.22, CHCl3, dr
39.3, 40.8, 43.5, 50.8, 52.2, 59.2, 113.4,115.7,119.3,132.8,133.9,151.1,
168.4; HRMS (FAB, glycerol) calcd for C16H24N3O2 290.1869
(MþHþ), found 290.1843.
D
57/43); IR (ATR) 3354, 2949, 2249, 1674, 1612, 1517, 1435,1421, 1391,
1365, 1345, 1275, 1234, 1166, 1108, 1041, 968, 836, 750, 666 cmꢀ1
1H NMR (400 MHz, CDCl3, major isomer)
1.25–1.30 (1H, m), 1.46
;
d
(9H, s), 1.54–1.79 (3H, m), 2.70–2.90 (3H, m), 3.20 (2H, q, J¼6.4 Hz),
3.76–3.81 (1H, m), 3.87 (3H, s), 4.82 (1H, br s), 6.04 (1H, br s), 6.79
(1H, d, J¼8.8 Hz), 7.97 (1H, dd, J¼2.0, 8.8 Hz), 8.50 (1H, d, J¼2.0 Hz);
4.22. 3-Bromo-4-(toluene-4-sulfonylamino)-benzoic acid
methyl ester (36)
13C NMR (100 MHz, CDCl3, major isomer)
d
15.1, 25.6ꢂ2, 28.4, 39.5,
To a stirred solution of methyl p-aminobenzoate (500 mg,
3.31 mmol) in pyridine (10 mL) at 0 ꢁC was added p-toluenesulfonyl
chloride (761 mg, 3.99 mmol) and the mixture was allowed to
gradually warm to room temperature. After stirring the mixture for
37 h, the mixture was quenched with H2O (5 mL) and the resulting
mixture was extracted with EtOAc. The organic layer was washed
with brine, dried over Na2SO4, filtered, and concentrated in vacuo
to give tosylamide (1.34 g) as pink solids, which was used for next
reaction without further purification.
46.5, 51.9, 54.7, 79.8, 115.8, 115.9, 117.5, 119.8, 130.7, 136.4, 153.1,
156.7, 166.4, 190.7; HRMS (FAB, NBA) calcd for C26H39N3O6 401.1951
(Mþ), found 401.1941.
4.20. (3aS,4S,9bS)-4-(3-tert-Butoxycarbonylaminopropyl)-
2,3,3a,4,5,9b-hexahydro-pyrrolo[3,2-c]quinoline-1,8-
dicarboxylic acid 1-tert-butyl ester 8-methyl ester (35)
To a stirred solution of 34 (80.2 mg, 0.200 mmol, dr 57/43) in
EtOH (2.5 mL) at room temperature was added Raney nickel (W-2,
699 mg). After being stirred at 50 ꢁC for 29 h under an atmosphere
of hydrogen, the reaction mixture was cooled to room temperature
and filtered through a pad of Celite. The filtrate was concentrated in
vacuo.
The residue was dissolved in MeOH (2.0 mL) and NaBH3CN
(38.5 mg, 0.613 mmol) was added at room temperature. The
resulting mixture was acidified to pH 5 with AcOH and stirred at
room temperature for 3 h. After the reaction mixture was concen-
trated in vacuo, the residue was dissolved in CH2Cl2, washed with
aqueous saturated NaHCO3, dried over Na2SO4, filtered, and con-
centrated in vacuo.
Bromine (0.17 mL, 3.32 mmol) was slowly added to a stirred
solution of the above tosylamide (1.34 g) and NaOAc (1.09 g,
13.3 mmol) in AcOH (15 mL) at room temperature. After stirring for
24 h, the reaction was quenched with aqueous 50% NaOH at 0 ꢁC.
The resulting mixture was extracted with EtOAc, washed with
aqueous 2 M NaOH and brine, dried over Na2SO4, filtered, and
concentrated in vacuo. The residue was purified by silica gel column
chromatography (n-hexane/EtOAc¼4/1 to 2/1) to give 36 (1.21 g, 95
%) as white solids: mp 124–126 ꢁC; IR (neat) 3342, 3274, 1711, 1597,
1492, 1432, 1375, 1333, 1285, 1264, 1217, 1161, 1115, 1088, 1038, 972,
894, 814, 759, 653 cmꢀ1 1H NMR (400 MHz, CDCl3)
; d 2.38 (3H, s),
3.88 (3H, s), 7.25 (2H, d, J¼8.4 Hz), 7.30 (1H, s), 7.69 (1H, d,
J¼8.8 Hz), 7.71 (2H, d, J¼8.8 Hz), 7.90 (1H, dd, J¼2.0, 8.4 Hz), 8.11
The residue was dissolved in 1,4-dioxane (1.5 mL) and H2O
(3.0 mL). NaHCO3 (228 mg, 1.04 mmol) and Boc2O (55.0 mg,
0.252 mmol) were added to the solution at 0 ꢁC. After stirring the
mixture at room temperature for 42 h, the reaction mixture was
extracted three times with CH2Cl2. The combined organic layers
were dried over Na2SO4, filtered, and concentrated in vacuo. The
residue was purified by silica gel column chromatography (n-hex-
ane/EtOAc¼2/1) to give 35 (58.0 mg, 59%) and 35 with impurity,
(1H, d, J¼2.0 Hz); 13C NMR (100 MHz, CDCl3)
d 21.5, 52.3, 113.8,
119.7, 127.2, 127.3, 129.8, 129.9, 134.0, 135.5, 138.7, 144.7, 165.1;
HRMS (FAB, NBA) calcd for C15H14BrNO4S 382.9827 (Mþ), found
382.9808.
4.23. 4-(Toluene-4-sulfonylamino)-3-vinyl-benzoic acid
methyl ester (37)
which was subjected to preparative TLC (n-hexane/EtOAc¼1/1) to
To a stirred solution of bromide 36 (10.0 g, 28.7 mmol), 2,6-di-
tert-butyl-4-methylphenol (BHT) (632 mg, 2.87 mmol), and
(PPh3)4Pd (1.65 g, 1.43 mmol) in toluene (140 mL) was added
15
give 35 (11.1 mg, 11%) as a colorless oil: [
a
]
ꢀ156 (c 0.467, CHCl3);
D
IR (neat) 3345, 2974, 2935, 1673, 1607, 1518, 1393, 1365, 1276, 1247,

11578
Y. Yoshitomi et al. / Tetrahedron 64 (2008) 11568–11579
tributyl(vinyl)tin (12.5 mL, 42.8 mmol) at room temperature under
argon atmosphere and the mixture was heated to reflux for 5.5 h.
The mixture was cooled to room temperature, filtered through
a short pad of silica gel, and concentrated in vacuo. The residue was
dissolved in EtOAc, filtered, and concentrated in vacuo. The residue
was crystallized and purified by recrystallization from n-hexane/
EtOAc to give 37 (4.37 g, 46%) as yellow solids. The mother liquor
was concentrated in vacuo and the residue was purified by silica gel
column chromatography (n-hexane/EtOAc¼6/1 to 2/1) to give 37
(2.46 g, 26%) as yellow solids: mp >200 ꢁC (decomp.); IR (neat)
3288, 1714, 1594, 1490, 1434, 1400, 1336, 1301, 1263, 1163, 1118,
1087, 915, 883, 815, 761, 704, 664 cmꢀ1; 1H NMR (400 MHz, CDCl3)
567.1589. HPLC analysis: CHIRALCEL AD-H, n-hexane/i-PrOH (80/
20, 1.0 mL/min), tR: 22.7 min (major) and 26.6 min (minor).
4.26. (2S)-2-(3-tert-Butoxycarbonylaminopropyl)-3-hydroxy
methyl-1-(toluene-4-sulfonyl)-1,2-dihydroquinoline-6-
carboxylic acid methyl ester (40)
To
a stirred solution of 39 (523 mg, 0.988 mmol) and
CeCl3$7H2O (557 mg, 1.50 mmol) in MeOH (5 mL) at 0 ꢁC was added
NaBH4 (77.4 mg, 2.05 mmol) and the mixture was allowed to
gradually warm to room temperature. After stirring the mixture for
1 h, the reaction was quenched with aqueous 1 M KHSO4 at 0 ꢁC.
The resulting mixture was concentrated in vacuo to half volume
and then diluted with EtOAc. The organic layer was washed with
H2O and brine, dried over Na2SO4, filtered, and concentrated in
vacuo. The residue was purified by silica gel column chromatogra-
d
2.39 (3H, s), 3.89 (3H, s), 5.43 (1H, dd, J¼0.6, 11.4 Hz), 5.60 (1H, dd,
J¼0.8, 17.6 Hz), 6.50 (1H, dd, J¼11.0, 17.6 Hz), 6.72 (1H, s), 7.24 (2H,
d, J¼8.4 Hz), 7.50 (1H, d, J¼8.4 Hz), 7.66 (2H, d, J¼8.4 Hz), 7.87 (1H,
dd, J¼1.8, 8.4 Hz), 7.96 (1H, d, J¼2.0 Hz); 13C NMR (100 MHz, CDCl3)
d
21.5, 52.1, 119.9, 121.9, 126.9, 127.1, 128.8, 129.7, 129.7, 130.5, 130.8,
phy (n-hexane/EtOAc¼1/1) to give dihydroquinoline 40 (533 mg,
25
136.0, 137.5, 144.2, 166.3; HRMS (FAB, NBA) calcd for C17H18NO4S
quant.) as white amorphous powder: [
a
]
D
þ104 (c 0.45, CHCl3); IR
332.0957 (MþHþ), found 332.0956.
(neat) 3393, 2932, 1685, 1598, 1518, 1437, 1392, 1348, 1274, 1200,
1160, 1089, 1033, 915, 853, 810, 768, 726, 704, 684, 659 cmꢀ1 1H
NMR (400 MHz, CDCl3) 1.22–1.60 (3H, m), 1.44 (9H, s), 1.47–1.60
;
4.24. 3-Formyl-4-(toluene-4-sulfonylamino)-benzoic acid
methyl ester (38)
d
(2H, m), 1.84 (1H, br s), 2.33 (3H, s), 3.08 (1H, dt, J¼5.0, 14.8 Hz),
3.17–3.20 (1H, m), 3.62–3.64 (1H, m), 3.91 (3H, s), 3.92–4.06 (2H,
m), 4.66 (1H, s), 5.16 (1H, d, J¼9.2 Hz), 5.94 (1H, s), 7.07 (2H, d,
J¼8.4 Hz), 7.35 (2H, d, J¼8.0 Hz), 7.63 (1H, s), 7.83 (1H, d, J¼8.4 Hz),
The styrene derivative 37 (2.00 g, 6.03 mmol) was dissolved in
CH2Cl2 (30 mL) and cooled to ꢀ78 ꢁC. Ozone was bubbled through
the solution at ꢀ78 ꢁC until the solution turned blue. Oxygen was
then bubbled through the solution until it turned colorless. The
reaction was quenched with dimethyl sulfide (2.2 mL) and was
allowed to warm to room temperature. The mixture was extracted
with EtOAc. The organic layer was washed with aqueous 0.5 M
Na2S2O3 and brine, dried over Na2SO4, filtered, and concentrated in
vacuo. The residue was purified by silica gel column chromatog-
raphy (n-hexane/EtOAc¼2/1) to give 38 (1.84 g, 92 %) as white
solids: mp 140–142 ꢁC; IR (neat) 3126, 1710, 1667, 1614, 1492, 1444,
1392, 1343, 1294, 1269, 1185, 1159, 1133, 1087, 978, 924, 872, 851,
7.92 (1H, dd, J¼2.0, 8.4 Hz); 13C NMR (100 MHz, CDCl3)
d 21.4, 25.5,
27.5, 28.3, 38.4, 52.1, 54.2, 62.9, 79.4, 118.7, 127.0, 127.1, 127.5, 127.9,
128.7, 128.8, 129.0, 135.7, 136.2, 142.4, 143.7, 156.9, 166.5; HRMS
(FAB, NBA) calcd for C27H35N2O7S 531.2165 (MþHþ), found
531.2188.
4.27. (1R,2S,7bR)- and (1S,2S,7bS)-2-(3-tert-Butoxycarbonyl
aminopropyl)-1a-hydroxymethyl-3-(toluene-4-sulfonyl)-
1a,2,3,7b-tetrahydro-1-oxa-3-aza-cyclopropa
[a]naphthalene-6-carboxylic acid methyl ester (41)
802, 764, 734, 694, 658 cmꢀ1 1H NMR (400 MHz, CDCl3)
; d 1.55 (s,
9H), 2.38 (3H, s), 3.91 (3H, s), 7.27 (2H, d, J¼8.8 Hz), 7.73 (1H, d,
J¼8.8 Hz), 7.81 (2H, d, J¼8.0 Hz), 8.14 (1H, dd, J¼2.0, 8.8 Hz), 8.31
(1H, d, J¼2.4 Hz), 9.90 (1H, s), 11.07 (1H, s); 13C NMR (100 MHz,
To a stirred solution of 40 (250 mg, 0.472 mmol) in CH2Cl2
(1.9 mL) at 0 ꢁC was added m-CPBA (77%, 211 mg, 0.943 mmol) and
the mixture was allowed to gradually warm to room temperature.
After stirring the mixture for 19.5 h, the reaction was quenched
with saturated aqueous Na2SO3. The resulting mixture was
extracted with EtOAc. The organic layer was washed with H2O and
brine, dried over Na2SO4, filtered, and concentrated in vacuo. The
residue was purified by silica gel column chromatography (n-hex-
CDCl3)
d 21.5, 52.4, 116.8, 120.9, 124.5, 127.3, 129.9, 135.9, 136.5,
137.8, 143.5, 144.7, 165.2, 194.5; HRMS (FAB, NBA) calcd for
C16H16NO5S 334.0749 (MþHþ), found 334.0746.
4.25. (2S)-2-(3-tert-Butoxycarbonylamino)-3-formyl-1-
(toluene-4-sulfonyl)-1,2-dihydroquinoline-6-carboxylc acid
methyl ester (39)
ane/EtOAc¼1/2) to give 41 (272 mg, quant., dr 85/15) as orange
21
amorphous powder: [
a
]
ꢀ0.1 (c 0.58, CHCl3, dr 79/21); IR (ATR)
D
3394, 2951, 1685, 1615, 1519, 1436, 1393, 1346, 1277, 1205, 1160,
1088, 1035, 929, 882, 808, 751, 721, 703, 673 cmꢀ1 1H NMR
(400 MHz, CDCl3, major isomer) 1.01–1.09 (1H, m), 1.43 (9H, s),
To a stirred solution of 38 (1.53 g, 4.59 mmol) and 6 (2.87 g,
13.5 mmol) in CH3CN (4.2 mL) at ꢀ20 ꢁC under an argon atmo-
sphere was slowly added via cannula a solution of (R)-14 (337 mg,
0.916 mmol) in CH3CN (5 mL). After stirring the mixture for 24 h,
the reaction mixture was diluted with EtOAc. The organic layer was
washed with H2O and brine, dried over Na2SO4, filtered, and con-
centrated in vacuo. The residue was purified by silica gel column
;
d
1.46–1.70 (3H, m), 2.34 (3H, s), 3.05–3.12 (2H, m), 3.43–3.56 (2H,
m), 3.61 (1H, s), 3.91 (3H, s), 4.10 (1H, d, J¼13.2 Hz), 4.70 (1H, s),
5.02 (1H, d, J¼11.2 Hz), 7.16 (2H, d, J¼8.4 Hz), 7.48 (2H, d, J¼8.4 Hz),
7.91 (1H, d, J¼2.4 Hz), 7.92 (1H, d, J¼8.8 Hz), 8.01 (1H, dd, J¼2.0,
8.4 Hz); 13C NMR (100 MHz, CDCl3, major isomer)
d 21.6, 25.6, 26.7,
chromatography (n-hexane/EtOAc¼2/1 to 1/1) to give 39 (2.42 g,
28.4, 38.7, 52.2, 52.5, 53.7, 62.1, 71.9, 79.6, 126.6, 126.9, 127.3, 128.0,
129.0, 130.7ꢂ2, 135.1, 138.0, 143.7, 156.8, 166.0; HRMS (FAB, NBA)
calcd for C27H35N2O8S 547.2114 (MþHþ), found 547.2106.
25
quant., 99 %ee) as brown amorphous powder: [
a
]
þ305 (c 0.414,
D
CHCl3); IR (neat) 3402, 2976, 1674, 1633, 1511, 1439, 1363, 1276,
1246, 1203, 1159, 1107, 1088, 862, 808, 751, 705, 692, 662 cmꢀ1; 1H
NMR (400 MHz, CDCl3)
d
1.24–1.38 (3H, m), 1.40 (9H, s), 1.56–1.77
4.28. (2S,4R)- and (2S,4S)-2-(3-tert-Butoxycarbonyl-
aminopropyl)-4-hydroxy-3-methylene-1-(toluene-4-
sulfonyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid
methyl ester (43)
(m, 3H), 2.32 (3H, s), 3.11 (2H, dd, J¼6.6, 13.2 Hz) 3.96 (3H, s), 4.58
(1H, s), 5.31 (1H, dd, J¼4.4, 10.0 Hz), 6.80 (1H, s), 7.05 (2H, d,
J¼8.0 Hz), 7.20 (2H, d, J¼8.4 Hz), 7.92 (2H, d, J¼8.8 Hz), 8.13 (1H, dd,
J¼2.0, 8.4 Hz), 9.22 (1H, s); 13C NMR (100 MHz, CDCl3)
d 21.5, 25.6,
28.4, 29.9, 39.8, 44.0, 52.1, 52.5, 126.6, 126.7, 128.0, 128.6, 129.4,
130.1, 132.5, 135.5, 138.7, 138.7, 139.2, 144.2, 155.9, 165.8, 189.3;
HRMS (FAB, NBA) calcd for C27H32N2O7SK 567.1567 (MþKþ), found
To a stirred solution of 41 (698 mg, 1.28 mmol, dr 81/19), PPh3
(765 mg, 2.91 mmol), and imidazole (200 mg, 2.94 mmol) in ben-
zene (5.8 mL) at room temperature was added iodine (596 mg,

Y. Yoshitomi et al. / Tetrahedron 64 (2008) 11568–11579
11579
2.35 mmol). After stirring the mixture for 1 h, the reaction was
quenched with saturated aqueous Na2SO3. The resulting mixture
was extracted with EtOAc. The organic layer was washed with H2O
and brine, dried over Na2SO4, filtered, and concentrated in vacuo to
give crude 42 as a yellow oil, which was used for next reaction
without further purification.
J¼8.8 Hz), 8.11 (1H, d, J¼8.8 Hz), 8.26 (1H, dd, J¼2.0, 8.8 Hz), 8.55
(1H, d, J¼2.0 Hz); 13C NMR (100 MHz, CDCl3)
d 14.3, 21.7, 23.1, 26.7,
28.3, 39.1, 45.3, 52.5, 58.4, 79.3, 117.1, 123.5, 125.5, 126.9, 127.5,
129.2, 130.6, 136.1ꢂ2, 142.8, 145.5, 156.1, 165.4, 190.1; HRMS (FAB,
NBA) calcd for C28H34N3O7S 556.2117 (MþHþ), found 556.2131.
The residue was dissolved in MeOH (4.7 mL) and AcOH
(0.47 mL) at room temperature and Zn (636 mg, 9.73 mmol) was
added. After stirring the mixture for 75 min, the reaction was
quenched with aqueous 0.5 M Na2S2O3. The resulting mixture was
extracted with EtOAc. The organic layer was washed with H2O and
brine, dried over Na2SO4, filtered, and concentrated in vacuo. The
residue was purified by silica gel column chromatography (n-hex-
Acknowledgements
This work was financially supported in part by a Grant-in-Aid for
Scientific Research (B) from the Ministry of Education, Culture,
Sports, Science and Technology, Japan.
References and notes
ane/EtOAc¼2/1 to 1/1) to give iodide 43 (620 mg, 91%, dr 80/20) as
20
1. Witherup, K. M.; Ranson, R. W.; Graham, A. C.; Bernard, A. M.; Salvature, M. J.;
Lumma, W. C.; Anderson, R. P. S.; Pitzewberger, S. M.; Verga, S. L. J. Am. Chem.
Soc. 1995, 117, 6682–6685.
orange amorphous powder: [
a]
ꢀ6.76 (c 0.63 CHCl3, dr 81/19); IR
D
(neat) 3391, 2977, 1687, 1609, 1517, 1436, 1346, 1265, 1160, 1088,
1036, 913, 856, 813, 769, 729, 703, 672 cmꢀ1 1H NMR (400 MHz,
CDCl3) 1.41–1.61 (4H, m), 1.41 (9H, s), 2.34 (3H, s), 3.10 (2H, br s),
;
2. (a) Ho, T. C. T.; Jones, K. Tetrahedron 1997, 53, 8287–8294; (b) Gurjar, M. K.; Pal,
S.; Rama Rao, A. V. Heterocycles 1997, 45, 231–234; (c) Snider, B. B.; Ahn, Y.;
Foxman, B. M. Tetrahedron Lett. 1999, 40, 3339–3342; (d) Lovey, C. J.; Mahmud,
H. Tetrahedron Lett. 1999, 40, 2079–2082; (e) Hadden, M.; Stevenson, P. J. Tet-
rahedron Lett. 1999, 40, 5615–5624; (f) Bately, R. A.; Simoncic, P. D.; Lin, D.;
Smyj, R. P.; Lough, A. J. Chem. Commun. 1999, 651–652; (g) Frank, K. E.; Aube, J.
J. Org. Chem. 2000, 65, 655–666; (h) Nieman, J. A.; Ennis, M. D. Org. Lett. 2000, 2,
1395–1397; (i) Nyerges, M.; Fejes, I.; Toke, L. Tetrahedron Lett. 2000, 41, 7951–
7954; (j) Mahmud, H.; Lovely, C. J.; Dias, H. V. R. Tetrahedron 2001, 57, 4095–
4105; (k) Hadden, M.; Nieuwenhuyzen, M.; Potts, D.; Stevenson, P. J.; Thomp-
son, N. Tetrahedron 2001, 57, 5615–5624; (l) Bately, R. A.; Powell, D. A. Chem.
Commun. 2001, 2362–2363; (m) Nyerges, M.; Fejes, I.; Toke, L. Synthesis 2002,
1823–1828; (n) He, Y.; Mahmud, H.; Wayland, B. R.; Dias, H. V. R.; Lovely, C. J.
Tetrahedron Lett. 2002, 43, 1171–1174; (o) Malassene, R.; Sanchez, B. L.; Toupet,
L.; hurvois, J.-P.; Moinet, C. Synlett 2002, 1500–1504; (p) Nyerges, M. Hetero-
cycles 2004, 63, 1685–1712; (q) Yadav, J. S.; Subba, R. B.; Sunitha, V.; Srinivasa,
R. K.; Ramakrishna, K. V. S. Tetrahedron Lett. 2004, 45, 7947–7950; (r) Hara, O.;
Sugimoto, K.; Makino, K.; Hamada, Y. Synlett 2004, 1625–1627; (s) Hara, O.;
Sugimoto, K.; Makino, K.; Hamada, Y. Tetrahedron 2004, 60, 9381–9390; (t) Ng,
P. Y.; Masse, C. E.; Shaw, J. T. Org. Lett. 2006, 8, 3999–4002; (u) Zhang, Z.; Zhang,
Q.; Yan, Z.; Liu, Q. J. Org. Chem. 2007, 72, 9808–9810; (v) Comesse, S.; Sanselme,
M.; Daich, A. J. Org. Chem. 2008, 73, 5566–5569.
d
3.93 (3H, s), 4.48 (1H, s), 5.00–5.22 (4H, m), 7.14 (2H, d, J¼8.0 Hz),
7.32 (2H, d, J¼8.4 Hz), 7.85 (1H, d, J¼8.8 Hz), 7.98 (1H, dd, J¼2.0,
8.8 Hz), 8.13 (1H, d, J¼2.0 Hz); 13C NMR (100 MHz, CDCl3, major
isomer)
d 21.4, 26.3, 28.2, 30.3, 39.6, 52.1, 62.5, 66.5, 79.0, 113.2,
125.9, 127.7, 127.8, 129.1, 129.6, 130.7, 132.5, 135.1, 138.5, 142.0, 144.1,
155.9, 166.2; HRMS (FAB, NBA) calcd for C27H35N2O7SK 569.1724
(MþKþ), found 569.1708.
4.29. (2S)-2-(3-tert-Butoxycarbonylaminopropyl)-3-
methylene-4-oxo-1-(toluene-4-sulfonyl)-1,2,3,4-
tetrahydroquinoline-6-carboxylic acid methyl ester (44)
To a stirred solution of 43 (291 mg, 0.549 mmol, dr 77/23) in
CH2Cl2 (5 mL) at room temperature was added activated MnO2
(2.42 g) and the reaction mixture was stirred for 21 h. The mixture
was filtered through a pad of Celite. The filtrate was concentrated in
vacuo. The residue was purified by silica gel column chromatog-
3. For diastereoselective syntheses of martinellic acid, see: (a) Ma, D.; Xia, C.;
Jiang, J.; Zhang, J. Org. Lett. 2001, 3, 2189–2191; (b) Ma, D.; Xia, C.; Jiang, J.;
Zhang, J.; Tang, W. J. Org. Chem. 2003, 68, 442–451; (c) Badarinarayana, V.;
Lovely, C. J. Tetrahedron Lett. 2007, 48, 2607–2610; (d) Shirai, A.; Miyata, O.;
Tohnai, N.; Miyata, M.; Procter, D. J.; Sucunza, D.; Naito, T. J. Org. Chem. 2008, 73,
4464–4475.
raphy (n-hexane/EtOAc¼2/1) to give 44 (289 mg, quant.) as white
21
amorphous powder: [
a
]
D
þ143 (c 0.36, CHCl3); IR (neat) 3394,
2925, 1684, 1607, 1684, 1607, 1508, 1424, 1361, 1255, 1164, 1088, 963,
4. For a synthesis of (rac)-martinellic acid, see: Snider, B. B.; Ahn, Y.; O’Hare, S. M.
Org. Lett. 2001, 3, 4217–4220.
813, 766, 727, 704, 673 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
1.38–1.68
(4H, m),1.41 (9H, s), 2.33 (3H, s), 3.08–3.24 (2H m), 3.95 (3H, s), 4.49
(1H, s), 5.17 (1H, s), 5.34 (1H, s), 6.03 (1H, s), 7.10 (2H, d, J¼8.0 Hz),
7.29 (2H, d, J¼8.0 Hz), 7.94 (1H, d, J¼8.8 Hz), 8.27 (1H, dd, J¼2.0,
5. For syntheses of (rac)-martinelline, see: (a) Powell, D. A.; Bately, R. A. Org. Lett.
2002, 4, 2913–2916; (b) Xia, C.; Heng, L.; Ma, D. Tetrahedron Lett. 2002, 43,
9405–9409.
6. For a diastereoselective synthesis of martinelline, see: Ikeda, S.; Shibuya, M.;
Iwabuchi, Y. Chem. Commun. 2007, 504–506.
7. For formal syntheses of martinelline, see: (a) Hadden, M.; Nieuwenhuyzen, M.;
Osborne, D.; Stevenson, P. J.; Thompson, N. Tetrahedron Lett. 2001, 42, 6417–
6419; (b) Takeda, Y.; Nakabayashi, T.; Shirai, A.; Fukumoto, D.; Kiguchi, T.; Naito,
T. Tetrahedron Lett. 2004, 45, 3481–3484; (c) He, Yong.; Moningka, R.; Lovely, C.
J. Tetrahedron Lett. 2005, 46, 1251–1254; (d) Miyata, O.; Shirai, A.; Yoshino, S.;
Nakabayashi, T.; Takeda, Y.; Kiguchi, T.; Fukumoto, D.; Ueda, M.; Naito, T. Tet-
rahedron 2007, 63, 10092–10117; (e) Miyata, O.; Shirai, A.; Yoshino, S.; Takeda,
Y.; Sugiura, M.; Naito, T. Synlett 2006, 893–896; (f) He, Y.; Mahmud, H.; Mon-
ingka, R.; Lovely, C. J.; Dias, H. V. R. Tetrahedron 2006, 62, 8755–8769; (g)
Hadden, M.; Nieuwenhuyzen, M.; Osborne, D.; Stevenson, P. J.; Thompson, N.;
Walker, A. D. Tetrahedron 2006, 62, 3977–3984.
8.8 Hz), 8.58 (1H, d, J¼8.8 Hz); 13C NMR (100 MHz, CDCl3)
d 21.5,
26.6, 28.3, 32.2, 39.3, 52.4, 60.9, 79.2, 124.7, 127.3, 127.4, 127.7, 128.6,
129.7,134.7,135.1,140.7,143.2, 144.6,155.9,165.6, 181.1; HRMS (FAB,
NBA) calcd for C27H33N2O7S 529.2008 (MþHþ), found 529.1995.
4.30. (2S,3R)-2-(3-tert-Butoxycarbonylaminopropyl)-3-
cyanomethyl-4-oxo-1-(toluene-4-sulfonyl)-1,2,3,4-
tetrahydroquinoline-6-carboxylic acid methyl ester (27)
To a stirred solution of 44 (1.29 g, 2.45 mmol) in EtOH (12 mL) at
0 ꢁC were added KCN (331 mg, 5.08 mmol) in H2O (1.2 mL) and
AcOH (0.2 mL, 3.49 mmol) and the reaction mixture was stirred for
1 h. The reaction mixture was concentrated in vacuo and the resi-
due was diluted with EtOAc. The organic layer was washed with
H2O and brine, dried over Na2SO4, filtered, and concentrated in
vacuo. The residue was purified by silica gel column chromatog-
8. Makino, K.; Hara, O.; Takiguchi, Y.; Katano, T.; Asakawa, Y.; Hatano, K.; Hamada,
Y. Tetrahedron Lett. 2003, 44, 8925–8929.
9. For reviews on tandem reactions and Michael-aldol reactions, see: (a) Tietze, L.
F. Chem. Rev. 1996, 96, 115–136; (b) Takasu, K. Yakugaku Zasshi 2001, 121, 887–
898.
10. Hamada, Y.; Kunimune, I.; Hara, O. Heterocycles 2002, 56, 97–100.
11. (a) Li, H.; Wang, J.; Xie, H.; Zu, L.; Jiang, W.; Duesler, E. N.; Wang, W. Org. Lett.
2007, 9, 965–968; (b) Sunden, H.; Rios, R.; Ibrahem, I.; Zhao, G.-L.; Eriksson, L.;
Cordova, A. Adv. Synth. Catal. 2007, 349, 827–832.
12. For reviews on organocatalysts, see: (a) Pellissier, H. Tetrahedron 2007, 63, 9267–
9331; (b) Kotsuki, H.; Ikishima, H.; Okuyama, A. Heterocycles 2008, 75, 493–529;
Heterocycles 2008, 75, 757–797; (c) Mielgo, A.; Palomo, C. Chem.dAsian J. 2008, 3,
922–948.
13. Yamaguchi, M.; Shiraishi, T.; Hirama, M. Angew. Chem., Int. Ed. Engl. 1993, 32,
1176–1178.
14. Yoshitomi, Y.; Makino, K.; Hamada, Y. Org. Lett. 2007, 9, 2457–2460.
15. Overman, L. E. Acc. Chem. Res. 1980, 13, 218–224.
16. Ichikawa, Y.; Tsuboi, K.; Isobe, M. J. Chem. Soc., Perkin Trans. 1 1994, 2791–2796.
17. Gerlach, U.; Wollmann, T. Tetrahedron Lett. 1992, 33, 5499–5502.
raphy (n-hexane/EtOAc¼2/1) to give tetrahydroquinolone 27
20
(1.22 g, 90%, dr 94/6) as yellow amorphous powder: [
a
]
þ25.2 (c
D
0.480, CHCl3, dr 94/6); IR (neat) 3376, 2929, 1698, 1608, 1516, 1426,
1363, 1257, 1163, 1086, 1010, 917, 814, 767, 750, 705, 667 cmꢀ1 1H
NMR (400 MHz, CDCl3) 1.25–1.68 (4H, m), 1.40 (9H, s), 2.33 (1H,
:
d
dd, J¼10.0, 17.6 Hz), 2.42 (3H, s), 2.57 (1H, ddd, J¼4.8, 4.8, 9.2 Hz),
2.90 (1H, dd, J¼4.8, 17.2 Hz), 3.05–3.20 (2H, m), 3.94 (3H, s), 4.53
(1H, s), 4.91 (1H, d, J¼11.2 Hz), 7.30 (2H, d, J¼8.4 Hz), 7.65 (2H, d,