Preparation of both enantiomers of 1-allyl-1,2,3,4-tetrahydro-β-carboline using allyltin reagents and a chiral auxiliary derived from L-proline

Article abstract of DOI:10.1016/S0040-4020(01)00684-6

β-Carboline, which had an acyl group derived from L-proline at the 9-position, reacted with allyltributyltin and 2,2,2-trichloroethyl chloroformate to afford an 1-allyl-1,2-dihydro-β-carboline derivative in a diastereoselective manner. The chiral acyl group at N-9 was readily eliminated by aqueous alkali to give a corresponding carboxylic acid. The formed 1-allyl-1,2-dihydro-β-carboline was transformed via two reduction steps to 1-allyl-1,2,3,4-tetrahydro-β-carboline in high ee. When the allylation was carried out using tetraallyltin instead of allyltributyltin, the stereoselectivity was reversed, and the antipode of the allyl adduct was obtained in high yield and ee in the presence of tin(IV) tetraiodide. Thus, it was found that both enantiomers of 1-allyl-β-carboline were obtained in good enantioselectivities by the use of the same chiral auxiliary.

Full text of DOI:10.1016/S0040-4020(01)00684-6

TETRAHEDRON
Pergamon
Tetrahedron 57 32001) 7277±7289
Preparation of both enantiomers of
1-allyl-1,2,3,4-tetrahydro-b-carboline using allyltin reagents and
a chiral auxiliary derived from l-proline
p
Ã
Takashi Itoh, Yuji Matsuya, Yasuko Enomoto and Akio Ohsawa
School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan
Received 23 April2001; accepted 26 June 2001
AbstractÐb-Carboline, which had an acyl group derived from l-proline at the 9-position, reacted with allyltributyltin and 2,2,2-trichloro-
ethyl chloroformate to afford an 1-allyl-1,2-dihydro-b-carboline derivative in a diastereoselective manner. The chiral acyl group at N-9 was
readily eliminated by aqueous alkali to give a corresponding carboxylic acid. The formed 1-allyl-1,2-dihydro-b-carboline was transformed
via two reduction steps to 1-allyl-1,2,3,4-tetrahydro-b-carboline in high ee. When the allylation was carried out using tetraallyltin instead of
allyltributyltin, the stereoselectivity was reversed, and the antipode of the allyl adduct was obtained in high yield and ee in the presence of
tin3IV) tetraiodide. Thus, it was found that both enantiomers of 1-allyl-b-carboline were obtained in good enantioselectivities by the use of
the same chiralauxiilary. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
alkaloids, and there are many reports concerning about their
synthesis.6 Pictet±Spengler reaction7 and vinylogous
Mannich reaction8 are among the most representative
methods for the synthesis of the nucleus, and the application
toward asymmetric syntheses has been carried out using
l-tryptophan7,8 or tryptamine9 as a starting material. On
the other hand, asymmetric addition or substitution of
b-carboline or its derivatives at C-1 position has been rarely
reported. Although there have been several papers to claim
that the addition reaction of 3,4-dihydro-b-carboline with
nucleophiles in the presence of an acyl chloride afforded
1-substituted tetrahydro-b-carboline derivatives,10 the
methods were hardly applied to asymmetric syntheses.
Yamaguchi et al., reported only in a review11 that 3,4-dihy-
dro-b-carboline-3-3S)-carboxylate underwent the addition
reaction with tributyl32,4-pentadienyl)tin in the presence
of acryloyl chloride to give a yohimbane derivative in
86% yield 386% de), but the detailed procedure was not
shown yet. Thus, there has been a sole method, that was
developed by Meyers et al., to introduce directly a sub-
stituent on b-carboline framework.12
Introduction of functionalgroups to azaaromatics is one of
the most important issues in organic synthesis, because
products thus formed are versatile starting materials for a
wide variety of complex molecules including pharmaceuti-
cals and alkaloids.1 We have recently been investigating the
reactivity of N-acylated quaternary salts of azaaromatics
toward nucleophiles, and found that allyltributyltin2 and
3
siyllenolethers
react with these salts to form dihydro
adducts which have a substituent at their 2-positions,
namely at the vicinal position of the acyl groups. The results
suggest that an asymmetric addition might be possible if the
N-acyl group is chiral. Thus, we applied the reaction to
the synthesis of optically pure homolaudanosine, one of
the isoquinoline alkaloids via an asymmetric addition reac-
tion using a chiralacylcholride derived from
l-alanine.4
Continuing research of our group revealed that b-carboline
was also a suitable substrate for the asymmetric addition of
allyltributyltin using an auxiliary derived from l-proline
attached at the 9-position, and that 1-allyl-1,2,3,4-tetra-
hydro-b-carboline was obtained in a enantioselective
manner. In addition, the enantiomer of the allyl adduct
was obtained by the reaction with tetraallyltin and tin3IV)
halide using the same chiral auxiliary. This paper describes
these results.5 b-Carboline nucleus having a substituent at
their C-1 position widely exists in nature as a part of indole
2. Results and discussion
In order to develop a new method for asymmetric synthesis
of 1-substituted tetrahydro-b-carboline, we ®rst tried the
reaction of 3,4-dihydro-b-carboline 31) according to the
reported procedure,10 and observed almost no stereo-
selectivity despite of a good chemical yield 3Scheme 1).13
Next, the application of our previous method was carried
out using 1,2-addition of a chiralacylcholride and
Keywords: b-carboline; asymmetric addition; chiral auxliary; l-proline;
allyltributyltin; tetraallyltin; pseudoyohimbane.
Corresponding author. Tel.: 181-3-3784-8183; fax: 181-3-3784-5982;
e-mail: ohsawa@pharm.showa-u.ac.jp
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020301)00684-6

7278
T. Itoh et al. / Tetrahedron 57 )2001) 7277±7289
chemical yields and the same stereoselectivity 3entries
14±16), but neither yields nor stereoselectivity exceeded
that of entry 9.
We next examined the reaction of tetraallyltin and 9-acyl-b-
carboline 8, expecting that the reagent would have the same
stereoselectivity,15 and the results are shown in Table 2.
Unexpectedly, it was found that the opposite con®guration
S was obtained in every case, in spite of using the same
chiral auxiliaries in Table 1.
Scheme 1.
The results prompted us to investigate the reaction
mechanism, and the possibility of selective formation of
both enantiomers with the same chiralauxiilary. At ®rst,
we thought that allyltributyltin and tetraallyltin had the
same stereoselectivity and there must be another species
that really reacted with the substrate. A distinguishing
difference between these two allylic reagents is that tetra-
allyltin can transfer two or more allyl groups to the
substrate. Thus triallyltin chloride formed by the ®rst
Scheme 2.
Scheme 3.
allyltributyltin to 9-phenoxycarbonyl-b-carboline 33), and it
was found that the selectivity became better but the yield
was very low 3Scheme 2). The reason of the low yield was
probably a weaker electron-withdrawing ability of N-acyl
group than that of N-alkoxycarbonyl group. The exchange
of the positions of these two groups, however, was revealed
to improve both chemicalyidel and stereosecl tivity
3Scheme 3).
allylation might have the ability to bring about further
allylation.16 We assumed that the reversalof stereo-
selectivity was induced by the participation of these allyltin
chlorides. Thus it was anticipated that the addition of tin3IV)
halide would change the stereoselectivity.17 The results of
these experiments are shown in Table 3.
Addition of tin3IV) chloride emphasized the S selectivity,
but the chemical yields decreased considerably 3entries 2
and 3). Chlorinated tin3IV) has higher Lewis acidity
than that of tetraallyltin, hence it was supposed that this
Accordingly, in spite of one atom further than N-2 position,
the attachment of the chiralauxial ry to 9-position on
b-carboline was found to be more effective for the asym-
metric addition at C-1. Thus, for the purpose of further
improvement of both chemicaland chiralyields, we studied
the effect of various acylgroups on N-9 derived from
l-proline. Although we tested other amino acids such as
alanine, phenylalanine, and valine as chiral auxiliaries,
they were less effective than proline.14 9-Acyl-b-carbolines
8 were readily prepared by reaction of parent b-carboline 7
with acylchlorides in the presence of triethylamine 3or with
corresponding carboxylic acids and 1-ethyl-3-33-dimethyl-
aminopropyl)-carbodiimide hydrochloride 3EDC´HCl)) in
the yields over 80% 3step A of Scheme 4). Then the addition
of allyl group was carried out using allyltributyltin and
phenylcholroformate to afford 9 in high yields 3step B).
Compounds 9 was hydrolyzed smoothly at N-9 to give an
allyl adduct 10 in quantitative yields accompanied by the
complete recovery of the acyl group as the corresponding
carboxylate 3step C). These results are summarized in Table
1. The data show that the best result was obtained by the use
of N-phenylsulfonyl group which had t-amylgroup at para
position 3entry 9), although the effect of the substituents was
rather slight. The other acyl groups afforded moderate
Scheme 4.

T. Itoh et al. / Tetrahedron 57 )2001) 7277±7289
7279
Table 1. Reaction of 9-acyi-b-carboline with allyltributyltin in the presence of chloroformate
Entry
Ra
R0
Yield of 9 3%)
%eeb,c of 10d
1e
2
3
4
5
6
7
8
C6H5SO2±
C6H5SO2±
C6H5SO2±
Ph
Ph
53
0
74
±
78
CH2CC13
CH2CCl3
CH2CCl3
CH2CCl3
CH2CC13
CH2CC13
CH2CC13
CH2CC13
CH2CCl3
CH2CCl3
CH2CCl3
CH2CCl3
CH2CC13
CH2CCl3
90
60
75
70
74
63
98
72
63
71
62
80
71
85
I±C6H4SO2±
73
74
74
76
83
86
77
70
82
81
57
58
Cl 5H4SO2±
MeO±C6H4SO2±
Me±C6H4SO2±
i-Pr±C6H4SO2±
t-Am±C6H4SO2±
Ph±C6H4SO2±
PhCuC±C6H4±SO2±
neopentyl±C6H4SO2±
cyclohexyl±C6H4SO2±
PhCO±
±C
9
10
11
12
13
14
15
16
MeCO±
CF3CO±
76
a
The substituents of phenylsulfonyl group are at p-position.
Determined by HPLC using CHIRALCEL OD column.
The con®guration of 10 was R in every case.
The yield of 10 and recoveries of 11 were over 90% in every case.
All the reactions were carried out at 2788 C except the entry 1 32408C).
b
c
d
e
Table 2. Reaction of 9-acyl-b-carboline with tetraallyltin in the presence of 2,2,2-trichloroethyl chloroformate
Entry
Compound
R
Yield of 9 3%)
%eea of 10b
Con®g.
1
2
3
4
8a
8b
8c
8d
MeCO
PhCO
C6H5SO2
71
52
54
72
9
S
S
S
S
12
29
36
t-Am±C6H4SO2
a
Determined by HPLC using CHIRALCEL OD column.
The yield of 10 was over 90% in every case.
b
reduction of the yields was caused by the coordination of
chlorinated tin to the nitrogen at 2-position of the substrate.
The coordination could inhibit the quaternarization process
by chloroformate, which is an essential step for succeeding
addition reaction. Thus, tin3IV) bromide or iodide, which
has lower Lewis acidity than that of tin3IV) chloride, was
added to the reaction system. In the cases of tin3IV)
bromide, the high ee was observed despite of low chemical
yields 3entries 4±6). It was found that the decrease of the
amount of tin3IV) bromide resulted in the rise of the chemi-
cal yield without a loss of selectivity 3entry 7 vs entry 4).
Potentialresutls were obtained when tin3IV) iodide was
employed 3entries 9±13), and the best one was gained by
the reaction using 1 equiv. of tetraallyltin and 0.5 equiv. of
tin3IV) iodide 3entry 13). As a result of these data, a method
for preparing 3S)-1-allyl-1,2,3,4-tetrahydro-b-carboline was
established as a counterpart of the reaction which affords the
corresponding R isomer 3Scheme 5).
Compound 10 thus obtained was readily transformed to
Table 3. Asymmetric allylation of 9-[N-3t-Amylphenylsulfonyl)prolinyI]-b-carboline with various allyltins formed in situ
Entry
Conditions of allyltin preparation
Chloroformate 3equiv.)
Yield of 10 3%)
%eea
Tetraallyltin 3equiv.)
Additive 3equiv.)
Total tin 3equiv.)
1
2
3
4
5
6
7
8
3
2.25
1.5
1.5
0.75
0.5
0.75
1.5
0.75
0.5
0.75
0.67
1.0
None
3
3
3
3
1.5
1
1
3
1.5
1
2
2
2
2
2
10
10
2
2
10
2
72
59
4
36
44
74
80
83
88
83
87
90
87
72
85
84
SnCl4 30.75)
SnC14 31.5)
SnBr4 31.5)
SnBr4 30.75)
SnBr4 30.5)
SnBr4 30.25)
SnI4 31.5)
SnI4 30.75)
SnI4 30.5)
SnI4 30.25)
SnI4 30.33)
SnI4 30.5)
13
17
15
43
13
32
50
72
62
91
9
10
11
12
13
1
1
1.5
10
10
a
The con®guration of 10 was S in every case.

7280
T. Itoh et al. / Tetrahedron 57 )2001) 7277±7289
Scheme 5.
In order to determine the absolute con®guration and study
the applicability to the synthesis of natural products, formal
synthesis of pseudoyohimbane20 was carried out from 13,
which was obtained from the reaction with allyltributyltin.
The reaction of 13 with penta-2,4-dienoic acid and
EDC´HCl followed by methoxymethylation with MOM±
Cl and potassium hydride afforded 1-allyl-1,2,3,4-tetra-
hydro-9-methoxymethyl-2-3penta-2,4-dienoyl)-b-carboline
315) 3[a]Dˆ298.6783c 0.31, THF)) in 60% yield 3two steps)
3Scheme 7). Compound 15 is a known intermediate that
Meyers et al., used for the synthesis of 32)-pseudo-
yohimbane.12b The reported con®guration of 15 was S
3[a]Dˆ1100.48). Therefore, the allyl adduct 13 derived
from the reaction with allyltributyltin was determined to
be an R isomer, whereas the reaction with tetraallyltin and
tin3IV) iodide afforded an S isomer. Meyers transformed the
compound S-15 to 32)-pseudoyohimbane in four steps.
Thus the formation of the R isomer in our system was
considered to complete the formal synthesis of 31)-pseudo-
yohimbane 316).
Scheme 6.
1-allyl-1,2,3,4-tetrahydro-b-carboline 313)18 by the sequen-
tialreduction with triethylsilane±TFA and zinc±acetic acid
in the yields of 76 and 85%, respectively 3Scheme 6). No
racemization was observed in these procedures.
Allyl group is known to be transformed to a variety of other
functionalgroups,
19
and most of the previous studies
concerning direct modi®cation of b-carboline moiety
introduced allyl derivatives to the nucleus,10 thus both
enantiomers of the compound 13 are supposed to be
versatile starting materials for diverse kinds of indole
alkaloids.
Though the mechanisms of the asymmetric addition remain
unclear, several experiments were carried out to study the
details of the mechanism 3Scheme 8 and Table 4). It was
supposed at ®rst that allyltributyltin and tetraallyltin had
the same stereoselectivity, and the opposite results were
Scheme 7.

T. Itoh et al. / Tetrahedron 57 )2001) 7277±7289
7281
Scheme 8.
Table 4. Allylation of 8 with allyltributyltin or tetraallyltin under various conditions
Entry
R
X
Allylation reagenta
Additive
Yield 3%)
%eeb
Con®g.
1
2
3
4
5
6
7
8
9
t-AmC6H4SO2
t-AmC6H4SO2
t-AmC6H4SO2
t-AmC6H4SO2
t-AmC6H4SO2
PhSO2
PhSO2
PhCH2
PhCH2
CH2
CH2
CH2
CH2
CH2
CH2
CvO
CvO
CvO
A
A
B
B
B
A
A
A
C
±
98
53
75
69
23c
90
51
15
95
86
49
36
0
R
R
S
±
S
HMPA
±
HMPA
32c
78
79
43
37
±
±
±
±
R
R
S
a
Al1ylation reagent: Aˆallyltributyltin; Bˆtetraallyltin; Cˆtetraallyltin1SnI4.
The ee was measured by HPLC after removalof the chiralauxiilary.
The reaction was stopped at 2 h.
b
c
originated from allylchlorotin3s) which was formed in the
reaction mixture. To con®rm the presumption, the reaction
with tetraallyltin was monitored at different times 3Table 4,
entries 3 and 5). The ee of the product, however, was not
altered by the shortening of the reaction time, thus it was
revealed that tetraallyltin itself had an S selectivity irrespec-
tive of the ligand exchange.21 The addition of HMPA
33 equiv.) reduced the selectivity of both reagents 3entries
1±4), and the effect was larger in the case of tetraallyltin
3entries 3 and 4). These data suggest that the reagents might
coordinate to the substrate for expressing the stereo-
selectivity, and that tetraallyltin was weaker ligand than
allyltributyltin. For specifying the coordination site, other
experiments shown in entries 7±9 were carried out 3Table
4). The use of pyroglutamic acid instead of proline did not
change the selectivity 3entries 6 and 7), but the replacement
of phenylsulfonyl group with benzyl group shifted the
selectivity from R to S in spite of the use of allyltributyltin
or tetraallyltin1SnI4 3entries 7±9). Thus the coordination
site seems to be an oxygen atom of sulfonyl group 3or
acyl group in Table 1, entries 14±16, and Table 2, entries
1 and 2). This supposition seems to be accord with the
results that the p-substituent of phenylsulfonyl groups,
which resides in the outside of a transition state, hardly
affected the stereoselectivity 3Table 1).
totalsyntheses of depalncheine, vincamine, and other
alkaloids, are now under investigation.
3. Experimental
3.1. General
Melting points are uncorrected. 1H and 13C NMR spectra of
CDCl3, CD2Cl2, and DMSO-d6 solutions were recorded at
500 and 125 MHz, respectively, with TMS as an internal
standard. Mass spectra and high-resolution mass spectra
3HRMS) were measured at 70 eV.
3.1.1. 9-Phenoxycarbonyl-b-carboline +3). In the solution
of b-carboline 30.5 mmol) and triethylamine 31 mmol) in
THF 32 ml), phenyl chloroformate 30.5 mmol) was added
dropwise at room temperature, and the mixture was allowed
to stir for 2 h. Then the solvent was evaporated off to leave a
residue, which was chromatographed on silica gel 3AcOEt)
to give 3 in 70% yield. Colorless plates from hexane; mp
125±128.38C; 1H NMR 3CDCl3) d 7.37±7.41 33H, m),
7.49±7.55 33H, m), 7.69 31H, ddd, Jˆ8.5, 7.3, 1.3 Hz),
7.99 31H, dd, Jˆ5.3, 0.9 Hz), 8.12 31H, dt, Jˆ7.7,
0.6 Hz), 8.46 31H, d, Jˆ8.5 Hz), 8.67 31H, d, Jˆ5.3 Hz),
9.68 31H, s); 13C NMR 3CDCl3) d 114.2, 116.6, 121.2,
121.3, 123.7, 124.2, 126.6, 129.6, 130.4, 133.0, 134.3,
137.3, 138.8, 142.3, 149.6, 149.7. Anal. Calcd for
C18H12N2O2: C, 74.99; H, 4.20; N, 9.72. Found: C, 75.06;
H, 4.05; N, 9.79.
In this paper, we disclosed a ®rst asymmetric allylation of
b-carboline using a l-proline derivative as a chiral
auxiliary. Moreover, the selection of the allylation reagents
altered the stereoselectivity in the presence of the same
auxiliary to give both enantiomers of 1-allyl-1,2,3,4-tetra-
hydro-b-carboline. These processes were readily performed
by an inexpensive chiralsource, which coudl be recovered
quantitatively from the reaction mixture. The both enantio-
mers of the 1-allyl adduct might be useful starting material
for asymmetric alkaloids syntheses. The study of the reac-
tion mechanism, and the application of the allyl adducts to
3.2. The formation of 2 and 4
3,4-Dihydro-b-carboline 31) was synthesized according to
the reported method.22 To the solution of N-phenylsulfonyl-
proline 30.25 mmol) in dry benzene 30.5 ml), thionyl
chloride 32.5 mmol) was added and the mixture was heated

7282
T. Itoh et al. / Tetrahedron 57 )2001) 7277±7289
for 1 h at 608C. Then the solvent was evaporated off to leave
the acid chloride, which was dissolved in CH2Cl2 30.5 ml).
The solution was added to the mixture of 1 or 3 30.2 mmol)
and allyltributyltin 30.3 mmol) in CH2Cl2 30.5 ml), and the
mixture was allowed to react for 1.5 h for 1, and 48 h for 3 at
room temperature. Thereafter, 3 M KF solution was added,
and the mixture was reacted for 1 h to form a precipitate,
which was ®ltered. The organic layer was separated, dried
over MgSO4, and evaporated. The residue was chromato-
graphed on silica gel to give the product. The des of 2 and 4
were measured as 6 and 38%, respectively, using the HPLC
analysis 3CHIRALCEL OD, hexane±isopropanolˆ1:1).
350 ml) of K2CO3 336 mmol), and the THF solution 310 ml)
of phenylsulfonyl chloride 310.5 mmol) was added. The
mixture was allowed to react for 2±5 h at 608C, then the
pH of the solution was adjusted to 3 by diluted aq. HCl. The
mixture was extracted with CHCl3, which was dried over
MgSO4, then removed by evaporation. Phenylsulfonyl
chlorides which were not commercially available 3p-phenyl,
p-neopentyl, and p-cyclohexyl) were synthesized according
to the reported methods.23
3.3.1. +S)-N-Phenylsulfonyl-l-proline. The mp and 1H
NMR data were identicalwith those of reported ones.
24
3.2.1. 1-Allyl-1,2,3,4-tetrahydro-2-+N-phenylsulfonyl)-
prolinyl-b-carboline +2). Yield 75%; Colorless powder;
mp 100±1048C; The product was obtained as a mixture of
conformationaland diastereomeric isomers. 1H- and 13C
NMR spectra were obtained as those of a mixture of at
3.3.2. +S)-N-+p-Iodophenylsulfonyl)-l-proline. Yield 94%;
Colorless needles from diisopropyl ether; mp 121±1238C;
[a]20 ˆ262.40 3c 1.00, CHCl3); 1H NMR 3CDCl3) d 1.79±
D
1.88 31H, m), 1.95±2.14 33H, m), 3.30 31H, dt, Jˆ9.4,
7.4 Hz), 3.50 31H, ddd, Jˆ9.4, 7.3, 4.5 Hz), 4.33 31H, dd,
Jˆ7.4, 5.2 Hz), 7.61 32H, d, Jˆ8.6 Hz), 7.90 32H, d,
Jˆ8.6 Hz), 9.83 31H, brs); 13C NMR 3CDCl3) d 24.6,
30.8, 48.4, 60.2, 100.3, 128.6, 137.3, 138.1, 176.8. Anal.
Calcd for C11H12INO4S: C, 34.66; H, 3.17; N, 3.67.
Found: C, 34.86; H, 2.78; N, 3.62.
1
least four isomers. H NMR 3CDCl3) d 1.80±2.17 34H,
m), 2.47±2.88 32.94±3.10) 34H, m), 3.43±3.64 33.70±
3.76) 33H, m), 4.23 34.12, 4.65, 4.82) 31H, dd, Jˆ12.9,
4.9 Hz), 4.87±5.24 33H, m), 5.73 35.55) 31H, dd, Jˆ13.5,
6.9 Hz 38.6, 5.0 Hz)), 5.79±5.94 36.00±6.08) 31H, m), 7.06±
7.16 32H, m), 7.24±7.34 32H, m), 7.41±7.57 33H, m), 7.84
31H, dd, Jˆ8.3, 1.2 Hz), 7.96 31H, dd, Jˆ7.0, 1.2 Hz), 8.55
38.48, 8.60, 8.56) 31H, s); 13C NMR 3CDCl3) d 20.8 321.1,
22.2, 22.4), 24.4 324.6, 24.9, 25.2), 30.9 331.1, 31.2, 31.6),
36.9 338.6, 39.0, 39.5), 39.6 340.5, 40.8), 48.2 348.3, 48.8,
49.0), 49.8 352.6, 53.2), 56.8 358.7, 59.2), 107.3 3107.6,
109.0, 109.4), 111.1 3111.2), 117.9 3118.0, 118.1, 118.2),
118.6, 119.40 3119.44, 119.47, 119.58), 121.76 3121.81,
121.9, 122.1), 126.4 3126.5, 126.6), 127.4 3127.46,
127.54), 128.75 3128.77, 128.79, 128.9), 132.4 3132.5,
132.7), 133.2 3133.3, 133.6), 133.8 3134.1, 134.4), 136.07
3136.09, 136.2, 136.3), 139.0 3139.1, 139.3), 170.3 3170.5,
171.2, 171.4). Anal. Calcd for C25H27N3O3S´1/2H2O: C,
65.48; H, 6.15; N, 9.16. Found: C, 65.63; H, 6.13; N, 8.80.
3.3.3. +S)-N-+p-Chlorophenylsulfonyl)proline. Yield 40%;
Colorless needles from hexane±diisopropyl ether; mp 108±
1098C; [a]20 ˆ279.40 3c 1.00, CHCl3); 1H NMR 3CDCl3)
D
d 1.79±1.88 31H, m), 1.95±2.15 33H, m), 3.31 31H, dt,
Jˆ9.5, 7.4 Hz), 3.50 31H, ddd, Jˆ9.5, 7.3, 4.6 Hz), 4.34
31H, dd, Jˆ7.2, 5.2 Hz), 7.52 32H, d, Jˆ8.9 Hz), 7.84
32H, d, Jˆ8.9 Hz), 9.56 31H, brs); 13C NMR 3CDCl3) d
24.7, 30.9, 48.6, 60.3, 128.8, 129.3, 136.3, 139.4, 177.0.
Anal. Calcd for C11H12CINO4S: C, 45.60; H, 4.17; N,
4.83. Found: C, 45.75; H, 3.84; N, 4.83.
3.3.4. +S)-N-+p-Methoxyphenylsulfonyl)proline. Yield
91%; Colorless plates from hexane±AcOEt; mp 108.8±
109.48C; [a]20 ˆ289.81 3c 1.00, CHCl3); 1H NMR
D
3.2.2. 1-Allyl-1,2-dihydro-9-phenoxycarbonyl-2-+N-phenyl-
sulfonyl)prolinyl-b-carboline +4). Yield 18%; Colorless
powder; mp 87±928C; The product was obtained as a
mixture of conformationaland diastereomeric isomers.
1H- and 13C NMR spectra were obtained as those of a
mixture of at least four isomers. 1H NMR 3CDCl3) d
1.72±2.30 34H, m), 2.41±2.63 32H, m), 3.32±3.59 32H,
m), 4.85±5.30 33H, m), 5.72±5.99 31H, m), 6.26 36.25,
6.34) 31H, d, Jˆ7.3 Hz), 6.63 36.70) 31H, t, Jˆ6.5 Hz),
6.94 36.97) 31H, d, Jˆ7.3 Hz), 7.30±7.65 311H, m), 7.83
37.89) 31H, d, Jˆ8.2 Hz), 7.93 31H, d, Jˆ8.2 Hz), 8.05
38.25, 8.28) 31H, d, Jˆ8.4 Hz); 13C NMR 3CDCl3) d 18.3
320.0), 24.5 324.9), 30.9 332.0), 37.7 338.2), 48.2 348.3, 50.6,
50.7), 58.4 359.0, 59.5), 104.9 3105.0), 114.3 3114.5), 116.1,
118.21 3118.23), 121.27 3121.31), 121.8 3121.9, 122.0),
123.8 3123.9), 124.9 3125.0), 125.81 3125.82), 126.52
3126.53), 127.3 3127.4), 127.9, 128.6 3128.7), 128.9, 129.6
3129.7), 131.5 3132.2), 132.4 3132.5), 133.0 3133.8), 136.0
3136.1), 138.7 3139.1), 149.2 3149.7), 169.6 3170.3). Anal.
Calcd for C32H29N3O5S´H2O: C, 65.62; H, 5.33; N, 7.17.
Found: C, 65.86; H, 5.02; N, 6.88.
3CDCl3) d 1.74±1.79 31H, m), 1.92±2.15 33H, m), 3.27
31H, dt, Jˆ9.5, 7.5 Hz), 3.50 31H, ddd, Jˆ9.5, 7.0,
4.6 Hz), 3.88 33H, s), 4.28 31H, dd, Jˆ8.3, 4.0 Hz), 7.01
32H, d, Jˆ8.7 Hz), 7.82 32H, d, Jˆ8.7 Hz), 11.05 31H,
brs); 13C NMR 3CDCl3) d 24.6, 30.6, 48.6, 55.6, 60.2,
114.3, 128.9, 129.6, 163.2, 177.0. Anal. Calcd for
C12H15NO5S: C, 50.52; H, 5.30; N, 4.91. Found: C, 50.52;
H, 5.18; N, 4.84.
3.3.5. +S)-N-+p-Tolylsulfonyl)proline. The mp and NMR
spectra were identicalto those of reported data.
25
3.3.6. +S)-N-+p-Isopropylphenylsulfonyl)proline. Yield
96%; Colorless needles from hexane±AcOEt; mp 94.1±
95.38C; [a]20 ˆ290.20 3c 1.00, CHCl3); 1H NMR
D
3CDCl3) d 1.28 36H, d, Jˆ7.0 Hz), 1.75±1.80 31H, m),
1.94±2.07 32H, m), 2.11±2.14 31H, m), 2.99 31H, sep,
Jˆ7.0 Hz), 3.29 31H, q, Jˆ8.0 Hz), 3.51±3.55 31H, m),
4.31 31H, dd, Jˆ8.3, 3.7 Hz), 7.39 32H, d, Jˆ7.9 Hz),
7.81 32H, d, Jˆ7.9 Hz), 11.17 31H, br); 13C NMR 3CDCl3)
d 23.5, 24.6, 30.7, 34.0, 48.6, 60.2, 127.2, 127.6, 134.7,
154.5, 177.2. Anal. Calcd for C14H19NO4S: C, 56.55; H,
6.44; N, 4.71. Found: C, 56.55; H, 6.29; N, 4.68.
3.3. The synthesis of N-phenylsulfonylprolines
3.3.7. +S)-N-{p-+t-Amyl)phenylsulfonyl}proline. Yield
l-Proline 310 mmol) was dissolved to the aqueous solution

T. Itoh et al. / Tetrahedron 57 )2001) 7277±7289
7283
90%; Colorless needles from hexane±AcOEt; mp 113.6±
bs). 13C NMR 3CDCl3) d 25.2 322.4), 29.0 331.2), 50.2
346.5), 59.4 361.4), 127.0 3126.3), 128.06 3128.12), 130.2
3129.8), 135.2 3133.2), 170.4 3170.6), 174.85 3174.90).
Anal. Calcd for C12H13NO3: C, 65.74; H, 5.98; N, 6.39.
Found: C, 65.67; H, 5.74; N, 6.39. N-Acetyl-l-proline was
obtained from the method shown below: to the acetonitrile
solution 310 ml) of l-proline 310 mmol), acetic anhydride
320 mmol) was added at room temperature, and the mixture
was allowed to react for 1 h, then diluted with water. The
mixture was extracted with CH2Cl2, then the organic layer
was dried over MgSO4 and evaporated. The residue was
suspended in hexane to crystallize the product, which was
separated by ®ltration 311% yield). 3S)-N-Tri¯uoroacetyl-
prolinyl chloride is a commercially available compound.
114.28C; [a]20 ˆ284.83 3c 1.00, CHCl3); 1H NMR
D
3CDCl3) d 0.67 33H, t, Jˆ7.3 Hz), 1.32 36H, s), 1.68 32H,
q, Jˆ7.3 Hz), 1.73±1.81 31H, m), 1.93±2.04 32H, m), 2.10±
2.16 31H, m), 3.27±3.32 31H, m), 3.51±3.55 31H, m), 4.31
31H, dd, Jˆ8.2, 4.0 Hz), 7.49 32H, d, Jˆ8.5 Hz), 7.81 32H,
d, Jˆ8.5 Hz), 10.68 31H, br); 13C NMR 3CDCl3) d 9.0, 24.7,
28.2, 30.7, 36.7, 38.5, 48.8, 60.4, 126.9, 127.4, 134.3, 155.5,
177.0. Anal. Calcd for C16H23NO4S: C, 59.05; H, 7.12; N,
4.30. Found: C, 59.13; H, 6.81; N, 4.32.
3.3.8. +S)-N-+Biphenyl-4-sulfonyl)proline. Yield 79%;
Colorless granules from hexane±AcOEt; mp 133.5±
1
135.58C; H NMR 3CDCl3) d 1.76±1.85 31H, m), 1.92±
2.05 32H, m), 2.13±2.21 31H, m), 3.32 31H, dt, Jˆ9.5,
7.3 Hz), 3.56 31H, ddd, Jˆ9.5, 6.9, 4.0 Hz), 4.33 31H, dd,
Jˆ8.3, 3.6 Hz), 7.43 31H, tt, Jˆ7.2, 1.3 Hz), 7.47±7.51 32H,
m), 7.61±7.63 32H, m), 7.76 32H, d, Jˆ8.7 Hz), 7.95 32H, d,
Jˆ8.7 Hz); 13C NMR 3CDCl3) d 24.8, 30.7, 48.9, 60.5,
127.2, 127.7, 128.0, 128.5, 129.0, 135.7, 139.0, 145.9,
175.2. Anal. Calcd for C17H17NO4S: C, 61.61; H, 5.17; N,
4.23. Found: C, 61.35; H, 4.85; N, 4.26.
3.5. The synthesis of +S)-N-{4-+Phenylethynyl)benzene-
sulfonyl}proline
4-Iodophenylsulfonylproline 32 mmol), tBuOH 32 mmol),
EDC´HCl 32.2 mmol), and DMAP 30.2 mmol) were
dissolved in CH2Cl2 35 ml) and the mixture was allowed
to react at room temperature for 18 h. Thereafter, the solvent
was evaporated off to leave a residue, which was chromato-
graphed on silica gel 3CH2Cl2) to give a t-butylester as
colorless crystals in 76% yield. The recrystallization was
carried out from hexane to give colorless granules 3mp
96±988C). The t-butyl ester 30.98 mmol), phenylacetylene
31.08 mmol), Pd3PPh3)2Cl2 30.02 mmol), CuI 30.04 mmol),
and Et3N 33 ml) were mixed and was allowed to react for 3 h
at room temperature. Then the mixture was diluted with
water 320 ml), and extracted with CH2Cl2. The organic
layer was dried over MgSO4, and evaporated. The residue
was chromatographed on silica gel 3CH2Cl2±AcOEt) to
afford corresponding phenylethynyl derivative in 98%
yield as pale yellow crystals 3mp 100±1028C). To the
CH2Cl2 solution of the compound 30.81 mmol) was added
TFA 34.5 mmol), and the mixture was allowed to react for
4 h at room temperature. Then CH2Cl2 was added, and the
combined organic layer was extracted with sat. NaHCO3.
The aqueous layer was acidi®ed with dil. HCl and extracted
with CH2Cl2. The organic layer was dried over MgSO4, and
evaporated off. The residue was suspended in hexane, and
the solid thus formed was ®ltered. The carboxylic acid was
obtained as colorless powder in 76% yield 3mp 1378C).
3.3.9. +S)-N-+p-Neopentylphenylsulfonyl)proline. Yield
69%; Colorless powder from hexane±CH2Cl2; mp 136±
1378C; [a]20 ˆ280.02 3c 1.00, CHCl3); 1H NMR
D
3CDCl3) d 0.92 39H, s), 1.73±1.80 31H, m), 1.94±2.04
32H, m), 2.11±2.18 31H, m), 2.58 32H, s), 3.26±3.32 31H,
m), 3.50±3.55 31H, m), 4.31 31H, dd, Jˆ8.2, 3.7 Hz), 7.29
32H, d, Jˆ8.2 Hz), 7.79 32H, d, Jˆ8.2 Hz); 13C NMR
3CDCl3) d 24.7, 29.3, 30.7, 32.0, 48.8, 50.0, 60.4, 127.0,
131.1, 134.8, 145.8, 176.6. Anal. Calcd for C16H23NO4S: C,
59.05; H, 7.12; N, 4.30. Found: C, 58.83; H, 7.04; N, 4.31.
3.3.10. +S)-N-+p-Cyclohexylphenylsulfonyl)proline. Yield
77%; Colorless granules from hexane±AcOEt; mp 128.1±
132.88C; [a]20 ˆ280.55 3c 1.20, CHCl3); 1H NMR
D
3CDCl3) d 1.22±1.32 31H, m), 1.36±1.48 34H, m), 1.73±
1.80 32H, m), 1.83±1.91 34H, m), 1.93±2.04 32H, m), 2.06±
2.17 31H, m), 2.55±2.62 31H, m), 3.27 31H, dt, Jˆ9.7,
7.6 Hz), 3.52 31H, ddd, Jˆ9.7, 6.7, 4.3 Hz), 4.29 31H, dd,
Jˆ8.2, 3.7 Hz), 7.37 32H, d, Jˆ8.4 Hz), 7.79 32H, d,
Jˆ8.4 Hz), 9.29 31H, br); 13C NMR 3CDCl3) d 24.7, 26.0,
26.7, 30.6, 34.1, 44.6, 48.8, 60.4, 127.5, 127.7, 134.6, 153.8,
176.5. Anal. Calcd for C17H23NO4S: C, 60.51; H, 6.87; N,
4.15. Found: C, 60.39; H, 6.88; N, 4.15.
3.5.1. t-Butyl +S)-N-+p-Iodophenylsulfonyl)-l-prolinate.
Yield 76%; Colorless granules from hexane; mp 96±988C;
1
3.4. The synthesis of N-acylprolines
[a]20 ˆ250.51 3c 0.40, CHCl3); H NMR 3CDCl3) d 1.45
D
39H, s), 1.78±1.85 31H, m), 1.92±2.00 32H, m), 2.00±2.11
31H, m), 3.32±3.36 31H, m), 3.43±3.47 31H, m), 4.22 31H,
dd, Jˆ8.5, 3.4 Hz), 7.60 32H, d, Jˆ8.5 Hz), 7.87 32H, d,
Jˆ8.5 Hz); 13C NMR 3CDCl3) d 24.5, 27.8, 30.9, 48.2,
61.1, 81.7, 100.0, 128.8, 138.1, 138.6, 171.0. Anal. Calcd
for C15H20INO4S: C, 41.20; H, 4.61; N, 3.20. Found: C,
41.19; H, 4.39; N, 3.17.
N-Acyl-l-prolines were synthesized using the same method
applied to N-phenylsulfonyl-l-prolines. N-Acetylproline:
the mp was identicalto that of reported data.
26
3.4.1. N-Benzoyl-l-proline. Yield 85%; Colorless plates
from isopropylether±AcOEt; mp 155.5±156.5 8C; The
NMR spectra were obtained as those of a mixture of two
isomers 34:1) derived from restricted rotation of the amide
bond. The signals originated from the minor one are shown
3.5.2. t-Butyl +S)-N-{4-+Phenylethynyl)benzenesulfonyl}-
l-prolinate. Yield 98%; Colorless needles from hexane;
in parentheses. [a]20 ˆ2136.34 3c 1.00, CHCl3); 1H NMR
mp 99.5±102.18C; [a]20 ˆ259.99 3c 0.40, CHCl3); 1H
D
D
3CDCl3) d 1.81±1.91 31H, m), 1.95±2.05 31H, m), 2.09±
2.20 31H, m), 2.25±2.34 31H, m), 3.49±3.63 33.71±3.83)
32H, m), 4.72 34.28) 31H, dd, Jˆ8.3, 5.4 Hz), 7.29±7.45
33H, m), 7.56 38.06) 32H, dd, Jˆ7.5, 1.4 Hz), 10.23 31H,
NMR 3CDCl3) d 1.46 39H, s), 1.77±1.82 31H, m), 1.94±
2.07 33H, m), 3.36 31H, dt, Jˆ9.5, 7.2 Hz), 3.49 31H, ddd,
Jˆ9.5, 7.4, 4.9 Hz), 4.23 31H, dd, Jˆ8.4, 3.5 Hz), 7.34±
7.39 33H, m), 7.52±7.57 32H, m), 7.64 32H, d, Jˆ8.5 Hz),

7284
T. Itoh et al. / Tetrahedron 57 )2001) 7277±7289
7.86 32H, d, Jˆ8.5 Hz); 13C NMR 3CDCl3) d 24.6, 27.9,
31.0, 48.3, 61.2, 81.8, 87.9, 92.8, 122.4, 127.4, 128.0, 128.5,
129.0, 131.8, 131.9, 138.0, 171.1. Anal. Calcd for
C23H25NO4S: C, 67.13; H, 6.12; N, 3.40. Found: C, 66.96;
H, 5.92; N, 3.41.
31H, d, Jˆ8.6 Hz), 8.24 31H, dd, Jˆ4.9, 0.7 Hz), 8.36 31H,
d, Jˆ7.7 Hz), 8.65 31H, d, Jˆ4.9 Hz), 9.51 31H, s); 13C
NMR 3DMSO-d6) d 24.0, 30.6, 48.1, 62.0, 101.2, 114.5,
116.1, 121.9, 123.9, 124.2, 128.5, 130.1, 131.8, 134.4,
137.4, 137.6, 137.7, 137.9, 143.5, 171.3. Anal. Calcd for
C22H18IN3O3S: C, 49.73; H, 3.41; N, 7.91. Found: C,
49.75; H, 3.18; N, 7.98.
3.5.3. +S)-N-{4-+Phenylethynyl)benzenesulfonyl}-l-proline.
Yield 76%; Colorless needles from hexane±AcOEt; mp
137±1398C; [a]20 ˆ279.77 3c 0.40, CHCl3); 1H NMR
3.6.3. +S)-9-{N-+p-Chlorophenylsulfonyl)prolinyl}-b-car-
boline. Yield 70% by Method A; Colorless powder; mp
D
3CDCl3) d 1.76±1.84 31H, m), 1.94±2.05 32H, m), 2.14±
2.22 31H, m), 3.30 31H, dt, Jˆ9.2, 7.5 Hz), 3.55 31H, ddd,
Jˆ9.2, 6.8, 4.0 Hz), 4.31 31H, dd, Jˆ8.2, 3.6 Hz), 7.37±
7.40 33H, m), 7.53±7.57 32H, m), 7.68 32H, d, Jˆ8.6 Hz),
7.87 32H, d, Jˆ8.6 Hz); 13C NMR 3CDCl3) d 24.6, 30.7,
48.7, 60.3, 87.7, 93.1, 122.3, 127.5, 128.4, 128.5, 129.0,
131.8, 132.1, 136.7, 176.8. Anal. Calcd for C19H17NO4S:
C, 64.21; H, 4.82; N, 3.94. Found: C, 64.11; H, 4.55; N,
3.92.
166±1698C; [a]20 ˆ262.16 3c 1.00, CHCl3); 1H NMR
D
3CDCl3) d 2.06±2.27 33H, m), 2.45±2.56 31H, m), 3.56±
3.66 32H, m), 5.62 31H, dd, Jˆ8.9, 2.1 Hz), 7.43±7.46 33H,
m), 7.62 31H, td, Jˆ8.4, 1.3 Hz), 7.80 32H, d, Jˆ8.8 Hz),
7.88 31H, dd, Jˆ5.1, 0.9 Hz), 8.05 31H, d, Jˆ7.4 Hz), 8.09
31H, d, Jˆ8.4 Hz), 8.63 31H, d, Jˆ5.1 Hz), 9.48 31H, s); 13C
NMR 3CDCl3) d 24.3, 31.3, 48.0, 62.0, 114.0, 116.1, 121.3,
124.3, 124.4, 128.7, 129.0, 129.9, 132.5, 134.8, 137.1,
137.7, 138.2, 139.1, 143.7, 171.0. Anal. Calcd for
C22H18ClN3O3S: C, 60.07; H, 4.12; N, 9.55. Found: C,
60.18; H, 4.12; N, 9.64.
3.6. General procedure for the synthesis of 9-acyl-b-
carbolines
3.6.4. +S)-9-{N-+p-Methoxyphenylsulfonyl)prolinyl}-b-
carboline. Yield 84% by Method A; Colorless powder;
Method A: To the benzene solution 31 ml) of N-acylor
N-sulfonylproline 30.5 mmol), thionyl chloride 3SOCl2)
35 mmol) was added at room temperature, and the mixture
was heated at 608C for 1 h, then the solvent and excess
SOCl2 were evaporated off. The residue was dissolved in
THF 31 ml), and the solution was added to the THF solution
31 ml) of b-carboline 30.5 mmol) and Et3N 31 mmol) at
room temperature. The mixture was allowed to react for
1±4 h at room temperature, then the solvent was evaporated
off to leave the residue, which was chromatographed on
silica gel to give the product.Method B: Ethyl-3N,N-
dimethylaminopropyl)carbodiimide hydrochloride 3EDC´
HCl) 30.6 mmol) was added to the mixture of N-acylor
N-sulfonylproline 30.5 mmol) and b-carboline 30.5 mmol)
in CH2Cl2 31 ml), and the mixture was reacted for 1±3 h.
Then the solvent was evaporated off, and the residue thus
formed was chromatographed on silica gel 3AcOEt) to give
the product.
mp 186±1898C; [a]20 ˆ285.75 3c 1.00, CHCl3); 1H
D
NMR 3CDCl3) d 2.03±2.10 31H, m), 2.17±2.24 32H, m),
2.39±2.48 31H, m), 3.55 31H, q, Jˆ8.4 Hz), 3.65 31H, dt,
Jˆ8.4, 3.5 Hz), 3.83 33H, s), 5.56 31H, dd, Jˆ8.9, 2.1 Hz),
6.92 32H, d, Jˆ9.0 Hz), 7.44 31H, m), 7.61 31H, ddd, Jˆ8.5,
7.3, 1.3 Hz), 7.78 32H, d, Jˆ9.0 Hz), 7.88 31H, dd, Jˆ5.1,
0.9 Hz), 8.04 31H, dd, Jˆ7.7, 0.6 Hz), 8.10 31H, d,
Jˆ8.5 Hz), 8.62 31H, d, Jˆ5.1 Hz), 9.49 31H, s); 13C
NMR 3CDCl3) d 24.4, 31.4, 48.1, 55.5, 61.8, 113.98,
114.0, 116.1, 121.4, 124.2, 124.4, 129.4, 129.93, 129.99,
132.5, 134.9, 137.7, 138.3, 143.6, 162.8, 171.4. Anal.
Calcd for C23H21N3O4S: C, 63.43; H, 4.86; N, 9.65.
Found: C, 63.68; H, 5.13; N, 9.64.
3.6.5. +S)-9-{N-+p-Tolylsulfonyl)prolinyl}-b-carboline.
Yield 78% by Method A; Colorless powder; mp 161±
1628C; [a]20 ˆ2101.3 3c 0.40, CHCl3); 1H NMR
D
3CDCl3) d 2.04±2.10 31H, m), 2.14±2.26 32H, m), 2.40
33H, s), 2.40±2.45 31H, m), 3.56 31H, q, Jˆ8.3 Hz), 3.68
31H, td, Jˆ8.3, 3.5 Hz), 5.56 31H, dd, Jˆ8.8, 1.4 Hz), 7.26
32H, d, Jˆ8.1 Hz), 7.45 31H, t, Jˆ7.7 Hz), 7.62 31H, t,
Jˆ7.7 Hz), 7.72 32H, d, Jˆ8.1 Hz), 7.89 31H, d,
Jˆ5.1 Hz), 8.05 31H, d, Jˆ7.7 Hz), 8.10 31H, d,
Jˆ7.7 Hz), 8.62 31H, d, Jˆ5.1 Hz), 9.47 31H, s); 13C
NMR 3CDCl3) d 21.5, 24.3, 31.4, 48.1, 62.1, 114.1, 116.1,
121.4, 124.2, 124.4, 127.2, 129.5, 130.0, 132.6, 134.9,
135.4, 137.7, 137.8, 138.4, 143.5, 171.2. Anal. Calcd for
C23H21N3O3S: C, 65.85; H, 5.05; N, 10.02. Found: C,
65.59; H, 4.80; N, 9.91.
3.6.1. +S)-9-{N-+Phenylsulfonyl)prolinyl}-b-carboline.
Yield 76% by Method A; Colorless powder; mp 1248C;
[a]20 ˆ±101.38 3c 1.00, CHCl3); 1H NMR 3CDCl3) d
D
2.07±2.15 31H, m), 2.17±2.28 32H, m), 2.43±2.53 31H,
m), 3.58±3.64 31H, m), 3.69 31H, td, Jˆ8.3, 3.5 Hz), 5.63
31H, dd, Jˆ8.8, 2.0 Hz), 7.48±7.52 33H, m), 7.60 31H, tt,
Jˆ7.4, 1.3 Hz), 7.67 31H, ddd, Jˆ8.5, 7.3, 1.3 Hz), 7.85±
7.88 32H, m), 7.97 31H, dd, Jˆ5.1, 0.7 Hz), 8.11±8.15 32H,
m), 8.66 31H, d, Jˆ5.1 Hz), 9.50 31H, s); 13C NMR 3CDCl3)
d 24.4, 31.4, 48.2, 62.0, 114.1, 116.2, 121.5, 124.3, 124.6,
127.3, 128.9, 130.0, 132.66, 132.74, 135.0, 137.9, 138.4,
138.5, 143.8, 171.2. Anal. Calcd for C22H19N3O3S´1/
2H2O: C, 63.75; H, 4.86; N, 10.14. Found: C, 64.01; H,
4.60; N, 9.90.
3.6.6. +S)-9-{N-+p-Isopropylphenylsulfonyl)prolinyl}-b-
carboline. Yield 83% by Method A; Colorless powder;
mp 758C; [a]20 ˆ286.67 3c 1.00, CHCl3); 1H NMR
3.6.2. +S)-9-{N-+p-Iodophenylsulfonyl)prolinyl}-b-carbo-
line. Yield 84% by Method A; Colorless needles from diiso-
D
3CDCl3) d 1.27 36H, d, Jˆ6.9 Hz), 1.99±2.11 31H, m),
2.17±2.25 32H, m), 2.41±2.50 31H, m), 2.97 31H, sep,
Jˆ6.9 Hz), 3.57 31H, q, Jˆ8.5 Hz), 3.69 31H, td, Jˆ8.5,
3.7 Hz), 5.61 31H, dd, Jˆ9.0, 1.5 Hz), 7.34 32H, d,
Jˆ8.4 Hz), 7.47 31H, t, Jˆ7.7 Hz), 7.63 31H, t, Jˆ
7.7 Hz), 7.79 32H, d, Jˆ8.4 Hz), 7.92 31H, d, Jˆ5.0 Hz),
propylether±AcOEt; mp 207±209 8C; [a]20 ˆ228.89 3c
D
1
0.60, CHCl3); H NMR 3DMSO-d6) d 1.97±2.10 32H, m),
2.23±2.27 31H, m), 2.54±2.64 31H, m), 3.33±3.41 31H, m),
3.58±3.63 31H, m), 5.49 31H, dd,Jˆ8.9, 2.5 Hz), 7.53±7.60
33H, m), 7.71±7.75 31H, m), 7.98 32H, d, Jˆ8.6 Hz), 8.21

T. Itoh et al. / Tetrahedron 57 )2001) 7277±7289
7285
8.08 31H, d, Jˆ7.7 Hz), 8.15 31H, d, Jˆ7.7 Hz), 8.64 31H, d,
Jˆ5.0 Hz), 9.49 31H, s); 13C NMR 3CDCl3) d 23.6, 24.3,
31.3, 34.1, 48.1, 61.8, 114.0, 116.2, 121.3, 124.2, 124.4,
126.9, 127.3, 130.0, 132.6, 134.9, 135.7, 137.6, 138.4,
143.4, 154.0, 171.3. Anal. Calcd for C25H25N3O3S´1/
2H2O: C, 65.77; H, 5.74; N, 9.20. Found: C, 66.17; H,
5.68; N, 8.98.
Jˆ8.7 Hz), 3.69 31H, td, Jˆ8.7, 3.9 Hz), 5.59 31H, dd,
Jˆ8.8, 1.8 Hz), 7.23 32H, d, Jˆ8.3 Hz), 7.43 31H, t,
Jˆ7.3 Hz), 7.60 31H, ddd, Jˆ8.5, 7.3, 1.3 Hz), 7.77 32H,
d, Jˆ8.3 Hz), 7.87 31H, dd, Jˆ5.1, 0.9 Hz), 8.03 31H, d,
Jˆ7.3 Hz), 8.10 31H, d, Jˆ8.5 Hz), 8.61 31H, d,
Jˆ5.1 Hz), 9.49 31H, s); 13C NMR 3CDCl3) d 22.6, 24.3,
29.2, 31.3, 31.9, 49.9, 61.7, 114.0, 116.1, 121.3, 124.1,
124.4, 126.6, 129.9, 130.7, 132.5, 134.8, 135.8, 137.7,
138.3, 143.6, 145.2, 171.2. Anal. Calcd for C27H29N3O3S:
C, 68.18; H, 6.15; N, 8.84. Found: C, 67.83; H, 6.16; N,
8.46.
3.6.7. +S)-9-[N-{p-+t-Amyl)phenylsulfonyl}prolinyl]-b-
carboline. Yield 86% by Method B; Colorless powder
from hexane±diisopropylether; mp 100±102 8C;
[a]20 ˆ284.24 3c 1.00, CHCl3); 1H NMR 3CD2Cl2) d
D
0.68 33H, t, Jˆ7.3 Hz), 1.31 36H, s), 1.68 32H, q,
Jˆ7.3 Hz), 2.00±2.06 31H, m), 2.13±2.24 32H, m), 2.37±
2.45 31H, m), 3.49 31H, q, Jˆ7.6 Hz), 3.69 31H, td, Jˆ7.6,
3.1 Hz), 5.52 31H, dd, Jˆ9.9, 2.5 Hz), 7.46±7.49 33H, m),
7.64 31H, ddd, Jˆ8.5, 7.6, 1.2 Hz), 7.75 32H, d, Jˆ8.5 Hz),
7.93 31H, dd, Jˆ5.2, 0.9 Hz), 8.11 31H, d, Jˆ7.6 Hz), 8.14
31H, d, Jˆ8.5 Hz), 8.61 31H, d, Jˆ5.2 Hz), 9.46 31H, s); 13C
NMR 3CD2Cl2) d 9.2, 24.7, 28.3, 31.7, 37.0, 38.8, 48.7,
62.5, 114.6, 116.7, 121.9, 124.7, 125.1, 127.2, 127.4,
130.4, 133.0, 135.6, 135.9, 138.3, 139.1, 144.2, 155.7,
172.1. Anal. Calcd for C27H29N3O3S´1/2H2O: C, 66.92; H,
6.24; N, 8.67. Found: C, 66.89; H, 6.20; N, 8.70.
3.6.11. +S)-9-{N-+p-Cyclohexylphenylsulfonyl)prolinyl-
b-carboline. Yield 32% by Method A; Colorless powder;
1
mp 83±868C; [a]20 ˆ268.05 3c 0.60, CHCl3); H NMR
D
3CDCl3) d 1.21±1.31 32H, m), 1.35±1.45 33H, m), 1.74±
1.79 31H, m), 1.82±1.90 34H, m), 2.03±2.10 31H, m), 2.16±
2.24 32H, m), 2.40±2.48 31H, m), 2.52±2.60 31H, m), 3.56
31H, q, Jˆ8.5 Hz), 3.68 31H, td, Jˆ8.5, 3.7 Hz), 5.59 31H,
dd, Jˆ9.0, 1.9 Hz), 7.31 32H, d, Jˆ8.4 Hz), 7.44 31H, t,
Jˆ7.1 Hz), 7.61 31H, ddd, Jˆ8.5, 7.1, 1.2 Hz), 7.77 32H,
d, Jˆ8.4 Hz), 7.89 31H, dd, Jˆ5.2, 0.9 Hz), 8.05 31H, d,
Jˆ7.1 Hz), 8.12 31H, d, Jˆ8.5 Hz), 8.62 31H, d,
Jˆ5.2 Hz), 9.49 31H, s); 13C NMR 3CDCl3) d 24.4, 26.0,
26.7, 31.4, 34.0, 44.5, 48.2, 61.9, 114.2, 116.4, 121.6, 124.4,
124.6, 127.5, 127.6, 130.2, 132.8, 135.1, 135.9, 138.0,
138.6, 143.8, 153.5, 171.6. Anal. Calcd for
C28H29N3O3S´1/4H2O: C, 68.34; H, 6.04; N, 8.54. Found:
C, 68.46; H, 6.32; N, 8.23.
3.6.8. +S)-9-{N-+Biphenyl-4-sulfonyl)prolinyl}-b-carbo-
line. Yield 47% by Method A; Colorless powder; mp
185±1878C; 1H NMR 3CDCl3) d 2.09±2.17 31H, m),
2.20±2.29 32H, m), 2.47±2.55 31H, m), 3.63 31H, q,
Jˆ8.5 Hz), 3.72 31H, td, Jˆ8.5, 3.7 Hz), 5.66 3dd, Jˆ9.0,
2.3 Hz), 7.42 31H, tt, Jˆ7.3, 1.2 Hz), 7.47±7.50 33H, m),
7.60±7.62 32H, m), 7.65 31H, ddd, Jˆ8.3, 7.3, 1.4 Hz), 7.70
32H, d, Jˆ8.5 Hz), 7.93 32H, d, Jˆ8.5 Hz), 7.95 31H, dd,
Jˆ5.7, 0.9 Hz), 8.10 31H, d, Jˆ8.0 Hz), 8.16 31H, d,
Jˆ8.3 Hz), 8.65 31H, d, Jˆ5.7 Hz), 9.54 31H, s); 13C
NMR 3CDCl3) d 24.4, 31.4, 48.2, 62.0, 114.4, 116.4,
121.7, 124.57, 124.63, 127.4, 127.7, 128.0, 128.5, 129.0,
130.4, 133.2, 135.2, 137.3, 137.6, 138.8, 139.3, 143.5,
145.8, 171.6. Anal. Calcd for C28H23N3O3S: C, 69.83; H,
4.81; N, 8.73. Found: C, 69.85; H, 4.45; N, 8.66.
3.6.12. +S)-9-{N-+Benzoyl)prolinyl}-b-carboline. Yield
86% by Method B; Colorless powder; mp 72±758C; The
1H NMR spectrum was obtained as that of a mixture of
two isomers 39:1) derived from restricted rotation of the
amide bond. The signals originated from the minor one
are shown in parentheses. [a]20 ˆ225.96 3c 0.40,
D
1
CHCl3); H NMR 3CDCl3) d 2.04±2.13 31H, m), 2.22±
2.33 32H, m), 2.51±2.63 31H, m), 3.73 34.09) 31H, dt,
Jˆ10.1, 6.9 Hz), 3.88±3.95 31H, m), 5.84 35.36) 31H, dd,
Jˆ8.5, 3.4 Hz), 7.42±7.47 36.84±6.91) 34H, m), 7.61±7.67
37.23±7.24) 33H, m), 7.92 37.84) 31H, dd, Jˆ5.1, 0.9 Hz),
8.08 38.01) 31H, d, Jˆ7.7 Hz), 8.32 31H, d, Jˆ8.4 Hz), 8.63
38.59) 31H, d, Jˆ5.1 Hz), 9.65 31H, s); 13C NMR 3CDCl3) d
25.1, 29.7, 50.1, 60.9, 114.0, 116.5, 121.2, 123.9, 124.4,
127.1, 128.1, 129.8, 130.1, 132.5, 135.1, 135.6, 138.1,
138.7, 143.4, 169.4, 171.8. Anal. Calcd for C23H19N3O2´1/
4H2O: C, 73.88; H, 5.26; N, 11.24. Found: C, 73.76; H, 5.18;
N, 11.01.
3.6.9. +S)-9-[N-{4-+Phenylethynyl)benzenesulfonyl}pro-
linyl]-b-carboline. Yield 78% by Method A; Colorless
needles from hexane±AcOEt; mp 202±2038C; [a]20
ˆ
D
1
17.32 3c 0.05, CHCl3); H NMR 3CDCl3) d 2.07±2.14
31H, m), 2.16±2.26 32H, m), 2.44±2.52 31H, m), 3.59
31H, q, Jˆ8.5 Hz), 3.69 31H, td, Jˆ8.5, 3.5 Hz), 5.62 31H,
dd, Jˆ8.8, 2.1 Hz), 7.37±7.39 33H, m), 7.46 31H, t,
Jˆ8.2 Hz), 7.55±7.57 32H, m), 7.61±7.65 33H, m), 7.84
32H, d, Jˆ8.8 Hz), 7.90 31H, dd, Jˆ5.1, 0.9 Hz), 8.07
31H, d, Jˆ7.0 Hz), 8.12 31H, d, Jˆ8.2 Hz), 8.64 31H, d,
Jˆ5.1 Hz), 9.51 31H, s); 13C NMR 3CDCl3) d 24.3, 31.3,
48.1, 62.1, 87.8, 92.9, 114.2, 116.3, 121.6, 122.3, 124.4,
124.6, 127.4, 128.2, 128.4, 128.9, 130.2, 131.7, 131.9,
132.8, 135.0, 137.7, 137.9, 138.6, 143.9, 171.3. Anal.
Calcd for C30H23N3O3S: C, 71.27; H, 4.59; N, 8.31.
Found: C, 71.14; H, 4.27; N, 8.31.
3.6.13. +S)-9-{N-+Acetyl)prolinyl}-b-carboline. Yield
quant. by Method B; Colorless powder; mp 144±1478C;
The H NMR spectrum was obtained as that of a mixture
1
of two isomers 37:1) derived from restricted rotation of the
amide bond. The signals originated from the minor one are
1
shown in parentheses. H NMR 3CDCl3) d 2.09±2.27 33H,
m), 2.16 33H, s), 2.41±2.48 31H, m), 3.64 31H, q,
Jˆ8.5 Hz), 3.86 33.94) 31H, td, Jˆ8.5, 3.3 Hz), 5.61
35.43) 31H, dd, Jˆ8.7, 2.5 Hz), 7.35 37.43) 31H, t,
Jˆ7.5 Hz), 7.53 37.61) 31H, m), 7.81 31H, dd, Jˆ5.2,
0.9 Hz), 7.96 37.88) 31H, d, Jˆ7.5 Hz), 8.13 38.04) 31H, d,
Jˆ8.2 Hz), 8.55 38.62) 31H, d, Jˆ5.2 Hz), 9.56 31H, s); 13C
NMR 3CDCl3) d 22.2 322.4), 24.4 331.5), 29.7 331.8), 48.0
346.8), 60.4 362.3), 114.0, 116.5, 121.3, 124.1, 124.5
3.6.10. +S)-9-{N-+p-Neopentylphenylsulfonyl)prolinyl}-
b-carboline. Yield 43% by Method A; Colorless powder;
1
mp 82±858C; [a]20 ˆ248.51 3c 0.47, CHCl3); H NMR
D
3CDCl3) d 0.90 39H, s), 2.03±2.09 31H, m), 2.16±2.24
32H, m), 2.38±2.47 31H, m), 2.54 32H, s), 3.57 31H, q,

7286
T. Itoh et al. / Tetrahedron 57 )2001) 7277±7289
3124.7), 129.9 3130.4), 132.5, 135.2, 138.3, 138.6, 143.6
3144.2), 169.4 3169.3), 171.9 3171.4). Anal. Calcd for
C18H17N3O2: C, 70.34; H, 5.57; N, 13.67. Found: C,
70.12; H, 5.44; N, 13.49.
31H, m), 5.77±5.85 31H, m), 6.16 36.22) 31H, d, Jˆ7.6 Hz),
6.72 36.73) 31H, d, Jˆ7.6 Hz), 7.14±7.20 32H, m), 7.33 31H,
t, Jˆ7.2 Hz), 7.59 31H, d, Jˆ7.6 Hz), 7.93 38.00) 31H, bs);
13C NMR 3CDCl3) d 38.9 339.9), 53.4 353.7), 75.46 375.52),
95.2 395.1), 104.20 3104.19), 107.3 3107.6), 111.4 3111.3),
118.3 3117.9), 118.4 3118.9), 119.3 3119.6), 120.5, 122.2
3122.3), 123.7, 130.8 3130.6), 133.00 3133.03), 136.0,
152.0 3151.9). HRMS 3FAB1): Calcd for C17H16Cl3N2O2
3M1H)1: 385.0277. Found: 385.0298.
3.6.14. +S)-9-{N-+Tri¯uoroacetyl)prolinyl}-b-carboline.
Yield 73% by Method A; Colorless powder; mp 148±
1
1518C; The H NMR spectrum was obtained as that of a
mixture of two isomers 37:1) derived from restricted rotation
of the amide bond. The signals originated from the minor
one are shown in parentheses. [a]20 ˆ2112.6 3c 0.05,
3.7.2. 1-Allyl-1,2-dihydro-2-phenoxylcarbonyl-b-carbo-
line. Yield.90%; Colorless viscous oil; The NMR spectra
were obtained as those of a mixture of three conformational
isomers. The signals originated from the minor ones are
D
1
CHCl3); H NMR 3CDCl3) d 2.03±2.38 33H, m), 2.41±
2.65 31H, m), 3.79 31H, q, Jˆ8.5 Hz), 4.00±4.06 31H, m),
5.62 35.68) 31H, dd, Jˆ8.8, 1.6 Hz), 7.31 37.40) 31H, t,
Jˆ7.6 Hz), 7.48 37.56) 31H, m), 7.77 37.83) 31H, d,
Jˆ4.9 Hz), 7.92 31H, d, Jˆ7.6 Hz), 8.05 38.01) 31H, d,
Jˆ8.1 Hz), 8.52 38.57) 31H, d, Jˆ4.9 Hz), 9.44 31H, s);
13C NMR 3CDCl3) d 24.4 320.5), 28.7 331.6), 47.4 348.6)
3q, Jˆ3 Hz), 62.0 361.3), 114.1, 116.1 3q, Jˆ288 Hz), 116.4,
121.4, 124.4, 124.6, 130.0, 132.8, 135.0, 138.1, 138.4, 144.0
3144.4), 155.9 3q, Jˆ38 Hz), 169.7 3169.9). Anal. Calcd for
C18H14F3N3O2: C, 59.84; H, 3.91; N, 11.63. Found: C,
59.92; H, 3.56; N, 11.59.
1
shown in parentheses. H NMR 3CDCl3) d 2.51±2.63 32H,
m), 5.03±5.15 32H, m), 5.75±5.86 32H, m), 6.19 36.23) 31H,
d, Jˆ7.6 Hz), 6.81 36.79) 31H, d, Jˆ7.6 Hz), 7.12±7.19 35H,
m), 7.26±7.30 31H, m), 7.39±7.44 32H, m), 7.58±7.61 31H,
m), 8.01 38.36, 8.38) 31H, s); 13C NMR 3CDCl3) d 39.0
340.0), 53.2 353.6), 104.38 3104.2, 104.35), 107.1 3107.7),
111.50 3111.34, 111.48), 118.09 3118.13, 118.14), 118.4
3118.9), 119.1 3119.4), 120.3 3120.4), 121.7 3121.6),
121.91 3121.94, 122.2), 123.7 3123.8), 125.85 3125.93),
129.52 3129.50, 129.55), 131.3 3130.8), 133.28 3133.26,
133.06), 136.08 3136.10), 151.1 3150.9), 152.6 3152.3).
HRMS 3FAB1): Calcd for C21H18N2O2 3M1H)1:
331.1447. Found 331.1468.
3.7. Asymmetric addition of allyltributyltin to 8 in the
presence of 2,2,2-trichloroethyl chloroformate +the
synthesis of 9 and 10, and the recovery of 11)
To the CH2Cl2 solution 31 ml) of 9-acyl-b-carboline
30.1 mmol) and allyltributyltin 30.3 mmol), 2,2,2-trichloro-
ethyl chloroformate 30.2 mmol) was added at 2788C under
Ar atmosphere, and the reaction was continued for 24 h at
the same temperature. Then 3 M aqueous KF solution was
added to the solution, and the mixture was allowed to stir
vigorously for 1 h. The organic layer was separated, dried
over MgSO4, and evaporated off. The residue was chroma-
tographed on silica gel 3CH2Cl2±AcOEt) to afford the
adduct 9 as a colorless oil. The adduct 9 was rather unstable,
and the NMR spectrum is complicated because of the
existence of diastereomeric and conformationalisomers.
Accordingly, the adduct 9 was treated with alkaline
hydrolysis without further puri®cation. Thus, to the THF
solution 31 ml) of 9, 1 M aqueous NaOH solution 32 ml)
was added and the mixture was allowed to stand for
30 min at room temperature. Then H2O was added to the
mixture, which was extracted with CH2Cl2. The organic
layer thus obtained was dried over MgSO4, and evaporated
to leave a residue, which was con®rmed to be almost pure 10
3.8. Asymmetric addition of 8 with tetraallyltin
The same procedure mentioned above was applied to the
case of tetraallyltin. The estimation of the ee was performed
similarly.
3.9. Typical procedure for the asymmetric addition of 8
with tetraallyltin and SnX4
To the CH2Cl2 solution 30.5 ml) of SnI4 30.05 mmol), tetra-
allyltin 30.1 mmol) was added, and the mixture was allowed
to react for 10 min at room temperature. Then the mixture
was cooled to 2788C, and the CH2Cl2 solution 30.5 ml) of 8
3p-t-Amylderivative, 0.1 mm)o,l and ClO
2CH2CCl3
31 mmol) were added successively. The mixture was reacted
for 48 h at 2788C, then treated with 3M aqueous KF solu-
tion for 1 h at room temperature. The organic layer was
separated and dried over MgSO4, and evaporated off. The
residue was chromatographed on silica gel 3CH2Cl2±
AcOEt) to afford the adduct 9, which was hydrolyzed
using the above method to afford 10 in 91% yield 384%ee).
1
by H- and 13C NMR. The aqueous layer was treated with
dil. HCl to be acidic, and extracted with CH2Cl2. The
evaporation of the CH2Cl2 afforded pure 11. The yields of
10 and 11 were quantitative in every case. The ee of 10
was measured with HPLC 3CHIRALCEL OD, hexane±
isopropanolˆ1:1), which is shown in Table 1.
3.10. The formation of 12 by the reduction of 10
To the CH2Cl2 solution 31 ml) of 10 344 mmol), Et3SiH
3200 ml) and tri¯uoroacetic acid 3TFA, 100 ml) were
added sequentially. The solution color was turned to
glaucous instantaneously by the addition of TFA, but
changed to pale yellow after 15 min, and the starting
materialwas entireyl consumed by the time, which was
con®rmed by TLC. The mixture was diluted with CH2Cl2,
and washed with aqueous Na2CO3. The organic layer was
separated, dried over MgSO4, and evaporated off to leave a
residue, which was chromatographed on silica gel to give an
3.7.1. 1-Allyl-1,2-dihydro-2-+2,2,2-trichloroethoxycar-
bonyl)-b-carboline. Yield.90%; Colorless viscous oil;
The NMR spectra were obtained as those of a mixture of
two conformationalisomers. The signasl originated from
the minor one are shown in parentheses. 86%ee 3R);
[a]20 ˆ2184.6 3c 1.50, CHCl3); 1H NMR 3CDCl3) d
D
2.49±2.67 32H, m), 4.75 34.78) 31H, d, Jˆ11.9 Hz), 4.99
35.00) 31H, d, Jˆ11.9 Hz), 5.05±5.14 32H, m), 5.63±5.69

T. Itoh et al. / Tetrahedron 57 )2001) 7277±7289
7287
oily substance. When it was dispersed in hexane, the crystal-
line product 12 was obtained in 76% yield.
was slowly decomposed at ambient temperature, and the
NMR spectra were obtained as those of a mixture of two
conformationalisomers. The signasl originated from the
1
3.10.1. 1-Allyl-1,2,3,4-tetrahydro-2-+2,2,2-trichloroethoxy-
carbonyl)-b-carboline +12). Yield 76%; Colorless plates
from hexane±AcOEt; mp 111.5±112.08C; The NMR spec-
tra were obtained as those of a mixture of two conforma-
tionalisomers. The signasl originated from the minor one
minor one are shown in parentheses., H NMR 3CDCl3) d
2.65±2.75 32H, m), 2.75±2.89 32H, m), 3.50±3.57 31H, m),
4.19±4.24 31H, m), 5.08±5.28 32H, m), 5.45 31H,
d,Jˆ9.9 Hz), 5.59 31H, d, Jˆ16.9 Hz), 5.85 31H, t,
Jˆ6.7 Hz), 5.93±6.05 31H, m), 6.39±6.57 32H, m), 7.10
31H, t, Jˆ7.0 Hz), 7.16 31H, t, Jˆ7.0 Hz), 7.28±7.35 32H,
m), 7.45±7.52 31H, m), 8.15 37.93) 31H, bs); 13C NMR
3CDCl3) d 22.5 321.2), 38.9 337.0), 41.0 339.9), 49.4
350.3), 107.7, 110.9, 117.8, 118.3, 119.3 3119.5), 121.4,
121.7 3122.0), 124.2, 126.3, 133.7 3133.4), 134.3, 135.0,
135.9, 143.1, 165.7.
are shown in parentheses. 86%ee; [a]20 ˆ264.75 3c 0.82,
D
CHCl3); 1H NMR 3CDCl3) d 2.63±2.91 34H, m), 3.23±3.36
31H, m), 4.49±4.56 31H, m), 4.82 34.67) 31H, d, Jˆ11.9 Hz),
4.82 34.94) 31H, d, Jˆ11.9 Hz), 5.15±5.24 32H, m), 5.31±
5.38 31H, m), 5.90±6.06 31H, m), 7.11 31H, td, Jˆ7.4,
2.8 Hz), 7.17 31H, td, Jˆ7.4, 1.4 Hz), 7.30±7.32 31H, m),
7.48 37.50) 31H, d, Jˆ7.4 Hz), 7.94 37.90) 31H, s); 13C NMR
3CDCl3) d 21.6 321.1), 38.9 339.26), 39.4 339.30), 51.6
351.5), 75.1 375.2), 95.7 395.5), 108.5 3109.0), 110.9
3111.0), 118.3 3118.1), 118.8 3119.2), 119.6 3119.7), 122.1
3122.0), 126.5 3126.4), 133.1 3132.8), 133.9 3134.1), 135.94
3135.92), 153.9 3153.5). Anal. Calcd for C17H17Cl3N2O2: C,
52.67; H,4.42; N, 7.23. Found: C, 52.86; H, 4.70; N, 7.16.
3.13. The synthesis of 15
The excess amount of KH, which was washed with pentane,
was suspended in THF 30.5 ml), then the THF solution
31 ml) of 14 30.12 mmol) was added and the mixture was
allowed to stir for 5 min at 08C. After the addition of
methoxymethylcholride 30.48 mmo),l the reaction was
continued for 30 min at 08C. Then water was added, and
the mixture was extracted with CH2Cl2, which was dried
over MgSO4, and evaporated. The residue was chromato-
graphed on silica gel 3CH2Cl2±AcOEtˆ3:1) to afford color-
3.11. The synthesis of 13 via the reduction of 12 with Zn
The compound 12 30.1 mmol) and AcOH 330 ml) were
dissolved in THF 30.5 ml)±H2O 30.5 ml) solution, and Zn
powder 30.5 mmol) was added to the mixture, then the reac-
tion was continued for 30 min at room temperature. Then
the excess Zn was ®ltered off, and the ®ltrate was diluted
with H2O. The solution was alkalized with K2CO3, and
extracted with CH2Cl2. The organic layer was extracted
with 1 M HCl, then the layer was alkalized again by
K2CO3, and extracted with CH2Cl2. The organic layer was
dried over MgSO4, and evaporated to leave colorless
crystals, which was almost pure 13 385%).
1
less oil in 80% yield. The H and 13C NMR of the product
were in accord with those reported by Meyers et al.,12b,27
The [a]20 was 298.67 3c 0.31, THF) 3lit.12b [a]20
1100.4 3c 0.24, THF) for the S isomer) thus the con®gura-
tion of 15 was determined as R.
ˆ
D
D
3.14. The synthesis of chiral auxiliaries dserived from
pyroglutamic acid +Table 4, entries 7±9)
The N-sulfonyl derivative 3entry 7): Sodium hydride
30.6 mmol) was suspended in THF 31 ml), and t-butylpyro-
glutamate 30.5 mmol) was added at room temperature, then
the mixture was allowed to stir for 5 min. After the gas
evolution, phenylsulfonyl chloride 30.55 mmol) was added
and the reaction was continued for another 30 min. Then the
mixture was quenched with water, and extracted with
CH2Cl2. The organic layer was dried over MgSO4 and
evaporated off to leave a residue, which was chromato-
graphed on silica gel 3CH2Cl2±AcOEt) to give the t-butyl
N-3phenylsulfonyl)pyroglutamate as a viscous oil 369%).
The ester 30.07 mmol) was dissolved in CH2Cl2 31.5 ml),
and the reaction was started by the addition of tri¯uoroacetic
acid 30.35 mmol), and continued for 15 h at room tempera-
ture. The mixture was diluted with CH2Cl2 and extracted
with sat. NaHCO3. The aqueous layer was acidi®ed by dil.
HCl, and extracted with CH2Cl2, which was dried over
MgSO4, and evaporated. The oily residue was suspended
in hexane to crystallize, and the solid thus formed was
®ltered, and had a melting point of 158±1608C 376%).
The addition of the carboxylic acid to b-carboline was
carried out according to the Method B applied to the
synthesis of 8.
3.11.1. 1-Allyl-1,2,3,4-tetrahydro-b-carboline +13). Yield
85%; Colorless granules from hexane; mp 118±1198C;
86%ee; [a]20 ˆ1110.0 3c 0.64, CHCl3); 1H NMR
D
3CDCl3) d 1.72±1.85 31H, bs), 2.54±2.59 32H, m), 2.68±
2.81 32H, m), 3.03 31H, ddd, Jˆ12.8, 8.6, 5.3 Hz), 3.37 31H,
ddd, Jˆ12.8, 5.0, 3.7 Hz), 4.16 31H, tt, Jˆ6.3, 1.8 Hz),
5.20±5.29 32H, m), 5.92 31H, ddt, Jˆ17.1, 10.2, 7.0 Hz),
7.09 31H, td, Jˆ7.0, 1.1 Hz), 7.15 31H, td, Jˆ7.0, 1.3 Hz),
7.29 31H, d, Jˆ7.0 Hz), 7.48 31H, d, Jˆ7.0 Hz), 7.96 31H,
bs); 13C NMR 3CDCl3) d 22.7, 39.5, 42.9, 51.6, 109.1,
110.6, 117.9, 118.4, 119.2, 121.4, 127.1, 134.6, 135.4,
135.6. Anal. Calcd for C14H16N2: C, 79.21; H,7.60; N,
13.20. Found: C, 79.01; H, 7.71; N, 13.21.
3.12. The synthesis of 14
To the CH2Cl2 solution 32 ml) of 13 30.26 mmol) and 2,4-
pentadienoic acid 30.78 mmol), EDC´HCl 30.78 mmol) was
added, and the mixture was allowed to react for 3 h at room
temperature. The solution was diluted with CH2Cl2, and
washed with 1 M HCland 1 M NaOH, successiveyl. The
organic layer was dried with MgSO4, and evaporated off to
leave a residue, which was chromatographed on silica gel
3CH2Cl2 to AcOEt) to give the product 14 in 75% yield.
3.14.1. t-Butyl pyroglutamate. Yield 32%; Colorless
powder; mp 99.8±102.58C; H NMR 3CDCl3) d 1.48 39H,
1
3.12.1. 1-Allyl-2-+penta-2,4-dienoyl)-1,2,3,4-tetrahydro-
b-carboline +14). Yield 75%; Colorless oil. The product
s), 2.14±2.22 31H, m), 2.31±2.48 33H, m), 4.14 31H, dd,
Jˆ7.6, 5.5 Hz), 6.31 31H, bs); 13C NMR 3CDCl3) d 24.9,

7288
T. Itoh et al. / Tetrahedron 57 )2001) 7277±7289
28.0, 29.4, 56.1, 82.3, 170.8, 177.6. Anal. Calcd for
C9H15NO3: C, 58.36; H, 8.16; N, 7.56. Found: C, 58.12;
H, 8.14; N, 7.77.
85±888C). The addition to b-carboline was performed by
the Method B, and the colorless needles were obtained.
3.15.2. N-Benzylpyroglutamic acid. The mp and 1H NMR
data were identicalwith those of reported ones.
28
3.14.2. t-Butyl N-+phenylsulfonyl)pyroglutamate. Yield
69%; Colorless viscous oil; [a]20 ˆ249.40 3c 0.10,
D
1
CHCl3); H NMR 3CDCl3) d 1.49 39H, s), 2.01±2.08 31H,
3.15.3. 9-+N-Benzylpyroglutamyl)-b-carboline. Yield
71%; Colorless needles from ether±AcOEt; mp 175±
m), 2.33±2.45 32H, m), 2.46±2.59 31H, m), 4.74 31H, dd,
Jˆ9.0, 2.6 Hz), 7.52 32H, t, Jˆ8.0 Hz), 7.64 31H, tt, Jˆ8.0,
1.3 Hz), 8.08 32H, dd, Jˆ8.0, 1.3 Hz); 13C NMR 3CDCl3) d
23.2, 27.7, 30.3, 60.0, 82.7, 128.3, 128.5, 133.8, 137.7,
169.4, 172.4. HRMS 3FAB1): Calcd for C15H20NO5S
3M1H)1: 326.1062. Found 326.1031.
1788C; [a]20 ˆ2125.4 3c 0.40, CHCl3); 1H NMR
D
3CDCl3) d 2.26±2.32 31H, m), 2.55±2.64 32H, m), 2.66±
2.75 31H, m), 4.00 31H, d, Jˆ14.8 Hz), 5.01 31H, dd, Jˆ8.9,
1.9 Hz), 5.22 31H, d, Jˆ14.8 Hz), 7.12±7.18 35H, m), 7.48
31H, t, Jˆ8.4 Hz), 7.60 31H, t, Jˆ8.4 Hz), 7.85±8.20 31H,
br), 7.91 31H, dd, Jˆ5.1, 0.9 Hz), 8.09 31H, d, Jˆ8.4 Hz),
8.64 31H, d, Jˆ5.1 Hz), 9.31 31H, brs); 13C NMR 3CDCl3) d
23.8, 29.3, 45.9, 60.2, 114.2, 116.1, 121.5, 124.5, 124.6,
127.7, 128.2, 128.7, 130.3, 132.9, 134.6, 135.3, 137.4,
138.3, 143.9, 170.6, 174.8. Anal. Calcd for C23H19N3O2:
C, 74.78; H, 5.18; N, 11.37. Found: C, 74.47; H, 4.79;
N,11.46.
3.14.3. N-+Phenylsulfonyl)pyroglutamic acid. Yield 76%;
Colorless powder; mp 158.0±160.58C; [a]20 ˆ251.33 3c
D
1
0.10, CHCl3); H NMR 3CDCl3) d 2.20±2.29 31H, m),
2.43±2.70 33H, m), 4.94 31H, dd, Jˆ9.2, 2.5 Hz), 5.72
31H, br), 7.56 32H, t, Jˆ8.0 Hz), 7.68 31H, t, Jˆ8.0 Hz),
8.11 32H, dd, Jˆ8.0, 1.3 Hz); 13C NMR 3CDCl3) d 23.4,
30.5, 59.0, 128.7, 128.8, 134.3, 137.5, 172.3, 175.0. Anal.
Calcd for C11H11NO5S: C,49.06; H, 4.12; N, 5.20. Found: C,
48.97; H, 3.74; N, 5.15.
References
3.14.4. 9-{N-+Phenylsulfonyl)pyroglutamyl}-b-carbo-
line. Yield 91%; Colorless plates from diisopropyl ether±
1. 3a) Comins, D. L.; O'Conner, S. Advances in Heterocyclic
Chemistry; Katritzky, A. R., Ed.; Academic: San Diego,
1988; Vol. 44, pp. 199±267. 3b) Rozwadowska, M. D.
Heterocycles 1994, 39, 903±931.
AcOEt; mp 203.1±204.08C; [a]20 ˆ282.31 3c 0.18,
D
1
CHCl3); H NMR 3CDCl3) d 2.32±2.40 31H, m), 2.57±
2.66 31H, m), 2.71±2.85 32H, m), 6.07 31H, dd, Jˆ9.2,
1.5 Hz), 7.53±7.60 33H, m), 7.69±7.75 32H, m), 8.01 31H,
d, Jˆ4.9 Hz), 8.03±8.16 31H, br), 8.09±8.12 32H, m), 8.16
31H, d, Jˆ7.5 Hz), 8.71 31H, d, Jˆ4.9 Hz), 9.59 31H, brs);
13C NMR 3CDCl3) d 23.9, 30.2, 60.7, 114.3, 115.9, 121.8,
124.8, 128.5, 129.3, 130.4, 133.1, 134.3, 134.9, 137.1,
138.0, 144.2, 169.5, 172.1. Anal. Calcd for C22H17N3O4S:
C, 63.00; H, 4.09; N, 10.02. Found: C, 62.94; H, 3.74; N,
9.96.
2. 3a) Itoh, T.; Hasegawa, H.; Nagata, K.; Ohsawa, A. J. Org.
Chem. 1994, 59, 1319±1325. 3b) Itoh, T.; Hasegawa, H.;
Nagata, K.; Okada, M.; Ohsawa, A. Tetrahedron 1994, 50,
13089±13100.
3. 3a) Itoh, T.; Miyazaki, M.; Hasegawa, H.; Nagata, K.; Ohsawa,
A. Chem. Commun. 1996, 1217±1218. 3b) Itoh, T.; Miyazaki,
M.; Nagata, K.; Ohsawa, A. Tetrahedron 2000, 56, 4383±
4395.
4. 3a) Itoh, T.; Miyazaki, M.; Nagata, K.; Hasegawa, H.; Ohsawa,
A.; Nakamura, K. T. Heterocycles 1998, 47, 125±128.
3b) Itoh, T.; Nagata, K.; Miyazaki, M.; Ohsawa, A. Synlett
1999, 1154±1156.
3.15. The N-benzyl derivatives +entries 8 and 9)
5. Preliminary communications: 3a) Itoh, T.; Matsuya, Y.;
Enomoto, Y.; Nagata, K.; Miyazaki, M.; Ohsawa, A. Synlett
1999, 1799±1801. 3b) Matsuya, Y.; Itoh, T.; Enomoto, Y.;
Ohsawa, A. Heterocycles 2000, 53, 2357±2361.
The above procedure was applied with the use of benzyl
bromide instead of phenylsulfonyl chloride and after the
same work-up procedure, the colorless crystals were
obtained by recrystallization.
6. Saxton, J. E., Ed.; The Chemistry of Heterocyclic Compounds
Part 4; Wiley: Chichester, 1994; Suppl. of Vol. 25.
7. 3a) Cox, E. D.; Cook, J. M. Chem. Rev. 1995, 95, 1797±1842.
3b) Li, J.; Wang, T.; Yu, P.; Peterson, A.; Weber, R.; Soerens,
D.; Grubisha, D.; Bennet, D.; Cook, J. M. J. Am. Chem. Soc.
1999, 121, 6998±7010. 3c) Yu, S.; Berner, M.; Cook, J. M.
J. Am. Chem. Soc. 2000, 122, 7827±7828 and references cited
therein.
3.15.1. t-Butyl N-benzylpyroglutamate. Yield 81%;
Colorless needles from diisopropyl ether±AcOEt; mp
1
51.0±58.98C; [a]20 ˆ238.08 3c 0.20, CHCl3); H NMR
D
3CDCl3) d 1.44 39H, s), 1.99±2.06 31H, m), 2.16±2.26
31H, m), 2.40 31H, ddd, Jˆ13.6, 9.6, 4.0 Hz), 2.51±2.60
31H, m), 3.83 31H, dd, Jˆ9.2, 3.3 Hz), 3.96 31H, d,
Jˆ14.7 Hz), 5.06 31H, d, Jˆ14.7 Hz), 7.20±7.23 32H, m),
7.26±7.35 33H, m); 13C NMR 3CDCl3) d 22.9, 28.0, 29.7,
45.6, 59.6, 82.2, 127.6, 128.4, 128.6, 135.8, 170.6, 174.9.
Anal. Calcd for C16H21NO3: C, 69.79; H, 7.69; N, 5.09.
Found: C, 69.65; H, 7.55; N, 5.09.
8. Martin, S. F.; Chen, K. X.; Eary, C. T. Org. Lett. 1999, 1, 79±
81 and references cited therein.
9. 3a) Waldmann, H.; Schmidt, G.; Henke, H.; Burkard, M.
Angew. Chem., Int. Ed. Engl. 1995, 34, 2402±2403. 3b) Tietze,
L. F.; Zhou, Y.; Topken, E. Eur. J. Org. Chem. 2000, 2247±
2252.
To the CH2Cl2 solution 32 ml) of the obtained compound
30.81 mmol) was added TFA 30.5 ml), and the mixture was
allowed to react for 7 h at room temperature. The same
work-up procedure mentioned above was carried out, and
the product was obtained as colorless crystals 391%, mp
10. 3a) Martin, S. F.; Benage, B.; Hunter, J. E. J. Am. Chem. Soc.
1988, 110, 5925±5927. 3b) Martin, S. F.; Benage, B.; Geraci,
L. S.; Hunter, J. E.; Mortimore, M. J. Am. Chem. Soc. 1991,
113, 6161±6171. 3c) Yamaguchi, R.; Hamasaki, T.; Sasaki, T.;
Ohta, T.; Utimoto, K.; Kozima, S.; Takaya, H. J. Org. Chem.

T. Itoh et al. / Tetrahedron 57 )2001) 7277±7289
7289
1993, 58, 1136±1143. 3d) Birman, V. B.; Rawal, V. H. J. Org.
Chem. 1998, 63, 9146±9147.
17. Wardell, J. L. In Chemistry of Tin; Harrison, P. G., Ed.;
Blackie & Sons: Glasgow, 1989; pp. 145±186.
18. The compound 15 was recently synthesized by Nakamura et
al., but the characterization was carried out as N-tri¯uoro-
acetylderivative, see:Nakamura, M.; Hirai, A.; Nakamura,
E. J. Am. Chem. Soc. 1996, 118, 8489±8490.
11. Yamaguchi, R. Yuki Gosei Kagaku Kyokaishi 1991, 49, 128±
137 3Chem. Abstr., 1991, 114 185149u).
12. 3a) Meyers, A. I.; Miller, D. B.; White, F. H. J. Am. Chem. Soc.
1988, 110, 4778±4787. 3b) Meyers, A. I.; Highsmith, T. K.;
Buonora, P. T. J. Org. Chem. 1991, 56, 2960±2964.
13. Comins et al., reported that non-aromatic N-acyliminium salts
resulted in a lower degree of stereocontrol than the aromatic
ones when a-attack of nucleophiles was controlled by the
chiralacylgroup, see: Comins, D. L.; Thakker, P. M.;
Baevsky, M. F.; Badawa, M. M. Tetrahedron 1997, 53,
16327±16340.
19. Yamamoto, Y.; Asao, N. Chem. Rev. 1993, 93, 2207±2293
and references cited therein.
20. 3a) Naito, T.; Miyata, O.; Tada, Y.; Nishiguchi, Y.; Kiguchi,
T.; Ninomiya, I. Chem. Pharm. Bull. 1986, 34, 4144±4149.
3b) Yamaguchi, R.; Otsuji, A.; Utimoto, K.; Kozima, S. Bull.
Chem. Soc. Jpn 1992, 65, 298±300.
21. When allyltrimethyltin was used under the same conditions,
the R isomer was obtained in 52% yield 371%ee). Thus, the
change of alkyl groups 3methyl or butyl) to allyl group caused
the reversalof the stereoseelctivity.
14. For example, when N-protected alanine or phenylalanine was
used for the chiralauxiliary, the de of the addition product was
lower than 10%.
22. Whittaker, N. J. Chem. Soc. C 1969, 85±89.
23. Roemmele, R. C.; Rapoport, H. J. Org. Chem. 1988, 53,
2367±2371.
15. Pereyre, M.; Quintard, J.-P.; Rahm, A. Tin in Organic
Synthesis; Butterworths: London, 1987 pp 185±258.
16. There are some reports to claim that allyltin halides and
methoxides are more reactive to carbonylcompounds than
tetraallyltin or allyltributyltin, see: 3a) Boaretto, A.; Marton,
D.; Tagliavini, G.; Ganis, P. J. Organomet. Chem. 1987, 321,
199±207. 3b) Marshall, R. L.; Young, D. J. Tetrahedron Lett.
1992, 33, 2369±2370. 3c) Miyake, H.; Yamamura, K. Chem.
Lett. 1992, 1369±1372. 3d) Yanagisawa, A.; Inoue, H.; Moro-
dome, M.; Yamamoto, H. J. Am. Chem. Soc. 1993, 115,
10356±10357. 3e) Colkey, T. M.; Marshall, R. L.; McCluskey,
A.; Young, D. J. Tetrahedron Lett. 1996, 37, 1905±1908. 3f)
Yanagisawa, A.; Morodome, M.; Nakashima, H.; Yamamoto,
H. Synlett 1997, 1309±1311.
24. Cupps, T. L.; Boutin, R. H.; Rapoport, H. J. Org. Chem. 1985,
50, 3972±3979.
25. Evans, D. A.; Nelson, J. V.; Vogel, E.; Taber, T. J. Am. Chem.
Soc. 1981, 103, 3099±3111.
26. Yamada, K.; Takeda, M.; Iwakuma, T. J. Chem. Soc., Perkin
Trans. 1 1983, 265±270.
27. The 13C NMR showed that 15 was obtained as a mixture of
two conformers.
28. 3a) Petersen, J. S.; Fels, G.; Rapoport, H. J. Am. Chem. Soc.
1984, 106, 4539±4547. 3b) Campaigne, E.; Matthews, D. P.
Heterocycl. Chem. 1975, 12, 391±392.