Regioselectivity of larock indole synthesis using functionalized alkynes

Article abstract of DOI:10.1271/bbb.80179

Regioselectivity of Larock indole synthesis, a palladium-catalyzed heteroannulation between o-iodoaniline and internal acetylene, was estimated using acetylenes substituted with ester and/or Boc-protected amine at the homopropargylic position and with perbenzyl- and unprotected glucose. Low to moderate regioselectivities were observed in all the cases, indicating these functional groups do not exert good directing effects, in the Larock indole synthesis.

Full text of DOI:10.1271/bbb.80179

Biosci. Biotechnol. Biochem., 72 (8), 2092–2102, 2008
Regioselectivity of Larock Indole Synthesis Using Functionalized Alkynes
Kumi SUGINO, Hiroshi YOSHIMURA, Toshio NISHIKAWA,y and Minoru ISOBE
Graduate School of Bioagricultural Sciences, Nagoya University, Chikusa, Nagoya 464-8601, Japan
Received March 18, 2008; Accepted April 24, 2008; Online Publication, August 7, 2008
[doi:10.1271/bbb.80179]
Regioselectivity of Larock indole synthesis, a palla-
dium-catalyzed heteroannulation between o-iodoaniline
and internal acetylene, was estimated using acetylenes
substituted with ester and/or Boc-protected amine at
the homopropargylic position and with perbenzyl- and
unprotected glucose. Low to moderate regioselectivities
were observed in all the cases, indicating these func-
tional groups do not exert good directing effects, in the
Larock indole synthesis.
disclose herein full details of our efforts to clarify the
reasons for this reverse regioselectivity.11–13)
Results and Discussions
In order to find factors determining regioselectivity in
the reaction of eq. 1, we planned to investigate the
regioselectivity of the Larock indole synthesis using
acetylenes 7, 10, 13, including Boc-protected amine,
ester, and protected amino acid respectively, and tetra-
O-benzyl-ꢀ-C-glucosylacetylene 18. In addition, unpro-
tected ꢀ-C-glucosylacetylene 19 was synthesized to
evaluate the effect of the benzyl groups of 18 in the
Larock indole synthesis.
Key words: palladium; indole; acetylene; regioselectiv-
ity; Larock indole synthesis
In 1991, Larock and Yum reported palladium-cata-
lyzed heteroannulation between internal acetylene and
o-iodoaniline giving a 2,3-disubsituted indole in a single
step.1,2) This reaction, known as the Larock indole
synthesis,3) has been employed in the synthesis of
biologically interesting natural and unnatural com-
pounds possessing an indole nucleus.4–6) In the course
Synthesis of functionalized acetylenes 7, 10, and 13
N-Boc-hexynylamine 7 was prepared in three steps
*
from 3-hexyne-1-ol 5, as shown in Scheme 1. 3-Hexyn-
1-ol 5 was condensed with phthalimide under the
Mitsunobu conditions to give 6. Removal of the
phthalimide with N-methylhydrazine14) in methanol,
followed by Boc-protection, afforded N-Boc-hexynyl-
amine 7 in a good yield. 4-Heptynoic acid methyl ester
10 was synthesized by malonate ester synthesis;15)
alkylation of diethyl malonate with 1-bromo-2-pentyne
8 gave 9. After alkaline hydrolysis of the ester,
decarboxylation, and esterification yielded 10. Propargyl
glycine derivative 13 was synthesized from Schiff base
11 of glycine methyl ester through alkylation16) with 1-
bromo-2-pentyne 8, hydrolysis of the Schiff base, and
protection with Boc group.
of our synthetic studies on C-mannosyltryptophan,7,8)
a
novel C-glycosylamino acid found in some proteins,9)
we attempted convergent synthesis of ꢀ-C-glucosyltryp-
tophan by means of the Larock indole synthesis between
glucosyl ethynylalanine derivative 1 and tosyl-o-iodo-
aniline 2. We expected that the regioselectivity of the
reaction would be controlled by the steric effect of tetra-
O-benzyl-glucose of acetylene 1 to give a tryptophan
derivative 4 as the desired product (eq. 1), because
Larock suggested that the larger substituent of acetylene
was preferentially introduced into the 2 position of the
indole product. However, the reaction between 1 and 2
under the conditions reported by Larock gave not
tryptophan derivative 4 but iso-tryptophan derivative 3
in a high yield.10) This unexpected result motivated us
to study unknown factors determining the complete
reversed regioselectivity in the Larock indole synthesis.
At the outset, we hypothesized that the protected amino
acid functionality of 1 would determine the regioselec-
tivity, because Larock also suggested that a substituent
containing a hydroxyl group at the propargylic position
was preferentially introduced into the 2 position of
indole, due to coordination of the hydroxyl group with
palladium catalyst in a reaction intermediate. We
Synthesis of sugar acetylene 18 and 19
According to a synthetic method for sugar acetylenes
developed in this laboratory,17,18) we would synthesize
sugar acetylene 18 by means of C-glycosylation of 1-O-
acetyl-2,3,4,6-tetra-O-benzylgluocose 14 (Scheme 2).
However, the reaction of 14 with (but-1-ynyl)tributyl-
stannane 17 in the presence of TMSOTf gave an
inseparable mixture of ꢀ- and ꢁ-C-glucoside 18 in
moderate stereoselectivity (ca. 4:1). This is a contrast to
the result of the reaction of 14 with (trimethylsilyl)-
*
All reactions had not been optimized.
y
To whom correspondence should be addressed. Fax: +81-52-789-4111; E-mail: nisikawa@agr.nagoya-u.ac.jp

Regioselectivity of Larock Indole Synthesis
BocHN COOMe
2093
BocHN
COOMe
N
BocHN COOMe
I
OBn
NTs
OBn
OBn
H
TsHN
H
O
H
2
O
O
Ts
Pd(OAc)2, Ph3P,
n-Bu4NCl, Na2CO3
/ DMF
BnO
OBn
BnO
OBn
BnO
OBn
OBn
OBn
OBn
1
3 (89%)
4 (0%)
100 °C, 24 h
eq. 1. The Complete Reversed Regioselectivity in the Larock Indole Synthesis.
O
O
Et
1) MeNHNH2
MeOH
BocHN
Et
OH
Et
Et
DEAD, Ph3P
THF
+
NH
O
N
2) Boc2O, Na2CO3
H2O-THF
5
O
6 (87%)
7 (71% in 2 steps)
1) NaOH
H2O-EtOH
EtOOC
EtOOC
EtOOC
EtOOC
Et
Et
NaOEt
EtOH
+
+
Br
MeOOC
2) DMF, 100 °C
3) AcCl, MeOH
9 (31%)
8
10 (21% in 3 steps)
Ph
Ph
Et
Ph
MeOOC
N
Et
BocHN
MeOOC
Et
Ph
N
NaH, LiI
THF
1) HCl, Et2O
Br
MeOOC
2) Boc2O, Na2CO3,
THF
11
8
12
Scheme 1. Preparation of Functionalyzed Acetylenes 7, 10, and 13.
13 (33% in 3 steps)
OBn
OBn
Et
O
OAc
OBn
O
Bu3Sn
Et (17)
TMSOTf
CH2Cl2
BnO
BnO
OBn
OBn
OBn
14
18α,β (89%, 4:1)
Bu3Sn
TMS (15)
Ref. 17
TMSOTf, CH2Cl2; K2CO3, MeOH
OBn
H
OBn
Et
OH
Et
H
H
H
O
O
O
i) n-BuLi
ii) EtI, HMPA
OBn
BnO
BnO
OBn
HO
OH
OH
OBn
OBn
18α (70%)
16 (89%)
19
Scheme 2. Synthesis of Sugar Acetylene Protected by Benzyl Groups.
ethynyltributylstannane 15 under the same conditions,
giving ꢀ-C-glucosylacetylene 16 as a single product.
Hence, sugar acetylene 18ꢀ was prepared as a pure form
from 16 by alkylation with ethyl bromide by a conven-
tional method. On the other hand, preparation of
unprotected glucosylacetylene 19 from 18ꢀ by deben-
zylation proved difficult.19) Since all attempted depro-
tection of 18ꢀ were unsuccessful, we explored an
alternative route for unprotected sugar acetylene 19.
After extensive studies, we finally found a new route
for the synthesis of 19, as shown in Scheme 3, on
the basis of C-glycosylation developed in this labora-
tory.20–22) Reaction of 2-acetoxyl-D-glucal 20 with TMS-
butyne 21 in the presence of SnCl4 gave an unstable enol

2094
K. SUGINO et al.
OAc
H
Et
1) Et3N, MeOH
OAc
OTBS
Et
1) SnCl4, CH2Cl2
H
O
O
O
TMS
Et (21)
2) TBSCl, imid
DMF
2) NaBH4, CeCl3
MeOH
(53% in 2 steps)
OH
AcO
OAc
OTBS
OAc
(93% in 2 steps)
20
22
23
OAc
Et
OTBS
Et
OAc
Et
H
H
H
MCPBA,
Na2HPO4
O
O
O
1) TBAF, THF
+
(CH2Cl)2
(62%)
2) 12% HClO4
3) Ac2O, Py.
AcO
OAc
OTBS
AcO
OAc
O
OAc
OAc
(64% from 24)
24
25
26
2 Hz
9 Hz
OH
OH
9 Hz
HO
4
H
5.5 Hz
H
5.5 Hz
H
H
1) Et3N,
MeOH-H2O
4
O
O
H
HO
HO
2
2
H
4.5Hz
H
3
3
OH
H
OH
2) recrystalization
H
OH
H
3.5Hz
10 Hz
Et
27
Et
19 (55%)
Scheme 3. Synthesis of Unprotected Sugar Acetylene 19.
**
acetate, which was treated with a large amount of
NaBH4 in the presence of CeCl3 to afford allylic alcohol
22 in 53% overall yield from 20. In the next epoxidation
with MCPBA, we found that bis-TBS ether 23 derived
from 22 was the best substrate to obtain high yield of
ꢁ-epoxide 24. After removal of the silyl groups of 24,
the epoxide was hydrolyzed with 12% HClO4.23) The
products were purified as a mixture of the corresponding
acetates 25 and 26 in a 7:1 ratio (by 1H NMR).
Deacetylation followed by re-precipitation gave ꢀ-C-
glucosylacetylene 19 as a pure form in 55% isolated
yield. The stereochemistry was determined by three
large coupling constants (J2{3 ¼ 10 Hz, J3{4 ¼ 9 Hz, and
J4{5 ¼ 9 Hz) of the 1H NMR spectra, as shown in
Scheme 3. The structure of isomer 27 was also con-
firmed by NMR analysis.
ited low selectivities, to give 31 and 32 (entries 4 and
5), indicating the tetra-O-benzylglucose moiety was not
recognized as a sterically hindered substituent in this
reaction and none of the four hydroxyl groups of 19 was
involved in the reaction.
Conclusion
Despite our systematic studies, we have not yet
identified the factors determining the regioselectivity of
eq. 1. However, these studies have revealed that the
ester and carbamate group at the homopropargylic
position and glucose moiety did not afford high
regioselectivity, although these functional groups were
seemingly the controlling factors, through coordination
to a palladium catalyst or the steric hindrance. These
results should provide an important guideline as to when
the Larock indole synthesis would be employed in the
syntheses of complex compounds. Further examination
to control the regioselectivity of the Larock indole
synthesis with functionalized acetylene is in progress in
our laboratory.
Regioselectivity in the Larock indole synthesis
The Larock indole synthesis using acetylenes 7, 10,
13, 18, and 19 with N-tosyl-o-iodoaniline 2 were
conducted under the conditions reported by Larock.
The regioselectivities were summarized in Table 1. The
regiochemistries of the products were determined by
NOESY spectra, depicted in eq. 2. Unexpectedly, all the
reactions gave low selectivities (entries 1 to 5). The
slight preferences observed may be attributed to the
steric effect of the substituents. These results indicate
that ester, carbamate, and protected amino acid at the
homopropargylic position have little effect on regiose-
lectivity (entries 1 to 3). More surprisingly, the reaction
with the tetra-O-benzyl-glucosylacetylene 18 and the
corresponding unprotected glucosylacetylene 19 exhib-
Experimental
General procedure. Melting points (Mp) were re-
corded on a Yanaco MP-S3 melting point apparatus.
Optical rotations (½ꢀꢀD) were measured on a JASCO
**
The structure of 32a was confirmed by NMR analysis of the
corresponding acetate 33a, because 1H NMR signals of 32a were
heavily overlapped. For the details, see the experimental.

Regioselectivity of Larock Indole Synthesis
2095
Table 1. Regioselectivity of the Larock Indole Synthesis with o-Iodoaniline 2 and Functionalized Acetylenes
NOESY
NOESY
H
H
Et
R
Pd(OAc)2, Ph3P,
I
R
Et
R
n-Bu4NCl, Na2CO3
+
+
(eq. 2)
DMF, 100 °C
NHTs
N
Et
N
Ts
b
Ts
7, 10, 13, 18, 19
a
2
NOESY
NOESY
entry
1
acetylene
time (h)
2
products
yield (%)
75
ratio (a:b)a
Et
7
28
60:40
MeOOC
BocHN
Et
Et
2
3
10
13
24
40
29
30
90
50
56:44
56:44
BocHN
MeOOC
OR
Et
H
O
R = Bn
4
5
18
19
1
31
32
60
16
65:35
69:31
R = H
48
RO
OR
OR
aRatios were determined by 1H-NMR spectra
DIP-370 digital polarimeter. Infrared spectra (IR) were
recorded on a JASCO FT/IR-8300 spectrophotometer,
and are reported in wave number (cmꢁ1). Proton nuclear
magnetic resonance (1H NMR) spectra were recorded
on a BRUKER ARX-400 (400 MHz), a BRUKER
AVANCE-400 (400 MHz), or a Varian Gemini-2000
(300 MHz) spectrometers. NMR samples were dissolved
in CDCl3 or CD3OD. Measured in CDCl3, chemical sifts
are reported in ppm from tetramethylsilane (ꢂ ¼ 0:00
ppm), or in ppm relative to the residual undeuterated
CHCl3 (ꢂ ¼ 7:26 ppm) for compounds containing the Si
group. Measured in CD3OD, chemical sifts are reported
in ppm relative to residual undeuterated CD2HOD
(ꢂ ¼ 3:30 ppm). The data are reported as follows:
chemical shift, integration, multiplicity (s = singlet,
d = doublet, t = triplet, q = quartet, br = broadening,
m = multiplet), coupling constant, and assignment.
Carbon nuclear magnetic resonance (13C NMR) spectra
were recorded on a BRUKER ARX-400 (100 MHz),
a BRUKER AVANCE-400 (100 MHz), or a Varian
Gemini-2000 (75 MHz) spectrometers. NMR samples
were dissolved in CDCl3 or CD3OD, and chemical sifts
are reported in ppm relative to the solvent (CDCl3 as
ꢂ ¼ 77:0, CD3OD as ꢂ ¼ 49:3 ppm). 2D NMR (COSY,
ses were performed by the Analytical Laboratory at the
Graduate School of Bioagricultural Sciences of Nagoya
University. The reactions were monitored by thin-layer
chromatography (TLC) on 0.25 mm silica gel-coated
glass plates 60 F254 (Merck, #1.05715). Visualization
was achieved using UV light and an appropriate reagent
(7% ethanolic phosphomolybdic acid or p-anisaldehyde
solution), followed by heating. Silica gel (spherical,
particle size 0.063–0.2 mm, Merck, # 1.07734.9929) and
silica gel (N) (spherical, neutral, particle size 0.063–
0.210 mm, Kanto, # 37565-84) were used for open-
column chromatography. Silica gel (spherical, particle
size 40–50 mm, Kanto, # 37562-84) and silica gel (N)
(spherical, neutral, particle size 40–50 mm, Kanto,
# 37563-79) were used for flash-column chromatogra-
phy. Preparative thin-layer chromatographic separations
were carried out on 0.5 mm silica gel plates 60 F254
(Merck, #1.05774). Non-aqueous reactions were carried
out in oven-dried (120 ꢂC) or flame-dried glassware
under nitrogen or argon atmosphere. Anhydrous THF
and CH2Cl2 were purchased from Kanto Chemical Co.,
Inc. Anhydrous DMF was purchased from Wako Pure
Chemical Industries, Ltd. Et3N was distilled from CaH2.
All other commercially available reagents were used as
received.
NOESY, HMBC, HMQC) were measured on
a
BRUKER AVANCE-400 (400 MHz) spectrometer. All
NMR were measured at 300 K. High resolution mass
spectra (HRMS) were recorded on a JEOL JMS-LCmate
spectrometer, and are reported in m=z. Elemental analy-
2-(Hex-3-ynyl)isoindoline-1,3-dione (6). To a solution
of phthalimide (4.19 g, 20.0 mmol), Ph3P (5.34 g,
20.0 mmol), and 3-hexyne-1-ol (5) (2.2 ml, 20 mmol)

2096
K. SUGINO et al.
in anhydrous THF (162 ml) was added DEAD (9.3 ml,
20 mmol) dropwise under N2 atmosphere. The mixture
was stirred at room temperature for 1.5 h, and then
concentrated. The Ph3PO in the residue was recrystal-
lized from Et2O-hexane and removed by filtration. The
mother liquor was evaporated, and the residue was
purified by open-column chromatography (silica gel
190 g, AcOEt:hexane = 1:5) to afford 6 (3.93 g, 87%) as
yellow crystals. Mp: 75–77 ꢂC. IR (KBr) ꢃmax 3460,
1465, 1371, 1155, 1036 cmꢁ1 1H NMR (CDCl3,
.
300 MHz) ꢂ 1.08 (3H, t, J ¼ 7:5 Hz, CCH2CH3), 1.28
(6H, t, J ¼ 7 Hz, COOCH2CH3), 2.13 (2H, qt, J ¼ 7:5,
2.5 Hz, CCH2CH3), 2.73 (2H, dt, J ¼ 8, 2.5 Hz,
CHCH2), 3.51 (1H, t, J ¼ 8 Hz, CHCH2), 4.22 (2H, q,
J ¼ 7 Hz, COOCH2CH3). 13C NMR (CDCl3, 75 MHz) ꢂ
12.2, 13.9(x2), 18.7, 51.8, 61.5, 74.9, 83.8, 168.3. Anal.
Calcd. for C12H18O4: C, 63.70; H, 8.02. Found: C,
63.49; H, 7.84.
1
2974, 1771, 1705, 1401, 1112 cmꢁ1. H NMR (CDCl3,
300 MHz) ꢂ 1.02 (3H, t, J ¼ 7:5 Hz, CH2CH3), 2.08
(2H, qt, J ¼ 7:5, 2.5 Hz, CH2CH3), 2.54 (2H, tt, J ¼ 7,
2.5 Hz, NCH2CH2), 3.83 (2H, t, J ¼ 7 Hz, NCH2CH2),
7.68–7.75 (2H, m, aromatic), 7.81–7.88 (2H, m, aro-
matic). 13C NMR (CDCl3, 75 MHz) ꢂ 12.1, 13.8, 18.5,
37.0, 75.2, 83.7, 123.2, 132.1, 134.0, 168.1. Anal. Calcd.
for C14H13NO2: C, 73.99; H, 5.77; N, 6.16. Found: C,
73.85; H, 5.52; N, 6.11.
Methyl hept-4-ynoate (10). To a solution of 9 (2.10 g,
9.28 mmol) in EtOH (26 ml) was added 2 N NaOH
aq. (26.0 ml, 46.4 mmol), and stirring was continued at
room temperature for 1 h. After removal of ethanol by
evaporation, the solution was acidified to pH 2 with 1 N
HCl, and extracted with AcOEt (x3). The combined
organic layers were dried over anhydrous Na2SO4 and
concentrated. The resulting white crystals (dicarboxylic
acid, 1.52 g) were dissolved in DMF (30 ml), and the
solution was heated at 100 ꢂC for 1 h. After dilution with
AcOEt, the mixture was washed with 1 N HCl solution,
dried over anhydrous Na2SO4, and concentrated to give
hept-4-ynoic acid (1.13 g) as yellow crystals. A solution
of the crude carboxylic acid (1.13 g) in MeOH (45 ml)
was treated with AcCl (64 ml, 0.90 mmol) and stirred at
room temperature for 10.5 h. The solution was diluted
with Et2O, quenched with sat. NaHCO3 solution, and
extracted with Et2O (x3). The combined organic layers
were washed with H2O (x2) and brine (x1), dried over
anhydrous Na2SO4, and concentrated under reduced
pressure (>20 mmHg). The residue was distilled (96–
97 ꢂC under 50 mmHg) to afford methyl hept-4-ynoate
10 (242 mg, 21% in 3 steps) as a colorless oil. IR (KBr)
tert-Butyl hex-3-ynylcarbamate (7). A solution of 6
(2.27 g, 10.0 mmol) and MeNHNH2 (5.2 ml, 0.10 mol) in
MeOH (42.0 ml)-THF (42.0 ml) was stirred at 70 ꢂC for
3 h under N2 atmosphere. The solution was diluted with
H2O and extracted with AcOEt (x3). The combined
organic layers were concentrated, and the residue was
dissolved in THF (21.0 ml) and H2O (21.0 ml). To the
solution were added Na2CO3 (4.24 g, 40.0 mmol) and
Boc2O (8.72 g, 40.0 mmol). After stirring at room
temperature for 1 h, the reaction mixture was extracted
with AcOEt (x3). The combined organic layers were
dried over anhydrous Na2SO4 and concentrated. The
residue was purified by open-column chromatography
(silica gel 80 g, AcOEt:hexane = 1:10 ! 1:7) to afford
Boc hexynylamine 7 (1.41 g, 71%) as a yellow oil. IR
(KBr) ꢃmax 3419, 3312, 2978, 1699, 1522, 1367, 1252,
ꢃmax 2977, 1742, 1438, 1367, 1169 cmꢁ1 1H NMR
.
(CDCl3, 400 MHz) ꢂ 1.10 (3H, t, J ¼ 7:5 Hz, CH2CH3),
2.14 (2H, qt, J ¼ 7:5, 2 Hz, CH2CH3), 2.43–2.55
(4H, m, CH2CH2), 3.70 (3H, s, COOCH3). 13C NMR
(CDCl3, 100 MHz) ꢂ 12.3, 14.1, 14.8, 33.9, 51.8, 82.3
(x2), 172.6. Anal. Calcd. for C8H12O2: C, 68.54; H,
8.63. Found: C, 68.43; H, 8.55.
1173, 965, 870 cmꢁ1 1H NMR (CDCl3, 300 MHz) ꢂ
.
1.10 (3H, t, J ¼ 7:5 Hz, CH2CH3), 1.43 (9H, s, CH3 of
Boc), 2.14 (2H, qt, J ¼ 7:5, 2.5 Hz, CH2CH3), 2.31 (2H,
tt, J ¼ 6:5, 2.5 Hz, NCH2CH2), 3.21 (2H, br s,
NHCH2CH2), 4.81 (1H, br s, NH). 13C NMR (CDCl3,
100 MHz) ꢂ 12.3, 14.1, 20.2, 28.4, 39.7, 76.3, 79.2, 83.3,
155.7. Anal. Calcd. for C11H19NO2: C, 66.97; H, 9.71;
N, 7.10. Found: C, 66.88; H, 9.92; N, 7.23.
t-Butyl-1-(methoxycarbonyl)hex-3-ynylcarbamate (13).
A solution of ketimine 11 (1.27 g, 5.00 mmol) in
anhydrous THF (23 ml) was added to a flask charged
with NaH (0.2 g, 5 mmol, 60% dispersion in oil, washed
with hexane) and LiI (67 mg, 0.50 mmol). The suspen-
sion was stirred at room temperature for 20 min, and then
1-bromo-2-pentyne 8 (0.6 ml, 6 mmol) was added drop-
wise via a cannular tubing. The mixture was stirred
vigorously at room temperature for 85 h and evaporated.
The residue was dissolved in sat. NH4Cl solution at 0 ꢂC,
and the solution was extracted with Et2O (x2). The
combined organic layers were dried over anhydrous
Na2SO4 and concentrated to give propargyl ketimine 12
as a yellow oil. The crude product was dissolved in Et2O
(10.0 ml), and 1 N HCl (3.0 ml, 3.0 mmol) was added.
The mixture was stirred at room temperature for 22.5 h
and then partitioned. The aqueous layer was diluted with
Diethyl pent-2-ylmalonate (9). To a solution of
EtONa (33 mmol, prepared from 0.75 g of Na in 25 ml
EtOH) was added diethyl malonate (4.6 ml, 30 mmol).
After stirring at room temperature for 10 min, a solution
of 1-bromopent-2-yne (8) (3.0 ml, 30 mmol) in EtOH
(25 ml) was added dropwise. The mixture was stirred
at room temperature for 2 h and then evaporated. To
the residue was added H2O and the mixture was ex-
tracted with CH2Cl2 (x3). The combined organic layers
were washed with brine (x1), dried over anhydrous
Na2SO4, and concentrated. The residue was purified by
flash-column chromatography (silica gel (N) 150 g,
AcOEt:hexane 1:10) to afford 9 (2.10 g, 31%) as a pale
yellow oil. IR (KBr) ꢃmax 3652, 3462, 2981, 2239, 1736,

Regioselectivity of Larock Indole Synthesis
2097
THF (12.5 ml), and then Boc2O (1.4 ml, 6.0 mmol) and
Na2CO3 (636 mg, 6.00 mmol) were added. The mixture
was stirred at room temperature for 12 h, and then
extracted with Et2O (x3). The combined organic layers
were dried over anhydrous Na2SO4 and concentrated.
The residue was purified by open-column chromatog-
raphy (silica gel 30 g, AcOEt:hexane = 1:20 ! 1:7) to
afford 13 (422 mg, 33% in 3 steps) as low-melting white
crystals. Mp: 31–32 ꢂC. IR (KBr) ꢃmax 3553, 3482, 2979,
1:10 ! 1:5) to afford glucosylacetylene 18ꢀ (121 mg,
28
70%) as a pale yellow oil. ½ꢀꢀD 65.5ꢂ (c 1.70, CHCl3).
IR (KBr) ꢃmax 2869, 2230, 1497, 1455, 1364, 1092
1
cmꢁ1. H NMR (CDCl3, 300 MHz) ꢂ 1.18 (3H, t, J ¼
7:5 Hz, CH2CH3), 2.29 (2H, qd, J ¼ 7:5, 2 Hz,
CH2CH3), 3.62 (1H, dd, J ¼ 9:5, 5.5 Hz, H-2), 3.62
(1H, dd, J ¼ 10, 9.5 Hz, H-4), 3.67 (1H, dd, J ¼ 11,
2 Hz, H-6), 3.75 (1H, dd, J ¼ 11, 3.5 Hz, H-60), 3.94
(1H, t, J ¼ 9:5 Hz, H-3), 4.00 (1H, ddd, J ¼ 10, 3.5,
2 Hz, H-5), 4.49 (1H, d, J ¼ 12 Hz, OCHaHbPh), 4.49
(1H, d, J ¼ 10:5 Hz, OCHcHdPh), 4.61 (1H, d,
J ¼ 12 Hz, OCHaHbPh), 4.70 (2H, s, OCH2Ph), 4.80
(1H, dt, J ¼ 5:5, 2 Hz, H-1), 4.82 (1H, d, J ¼ 11 Hz,
OCHeHfPh), 4.83 (1H, d, J ¼ 10:5 Hz, OCHcHdPh),
4.99 (1H, d, J ¼ 11 Hz, OCHeHfPh), 7.13–7.17 (2H, m,
aromatic), 7.25–7.40 (18H, m, aromatic). 13C NMR
(CDCl3, 75 MHz) ꢂ 12.6, 13.7, 66.7, 68.6, 72.6, 73.1,
73.4, 73.8, 75.2, 75.5, 77.5, 79.1, 83.0, 91.6, 127.6,
127.7, 127.8 (x2), 127.9, 128.0 (x2), 128.1, 128.4 (x2),
138.0, 138.1, 138.2, 138.9. Anal. Calcd. for C38H40O5:
C, 79.14; H, 6.99. Found: C, 79.01; H, 6.78.
1
1749, 1717, 1508, 1367, 1168 cmꢁ1. H NMR (CDCl3,
400 MHz) ꢂ 1.08 (3H, t, J ¼ 7:5 Hz, CH2CH3), 1.44 (9H,
s, CH3 of Boc), 2.12 (2H, qt, J ¼ 7:5, 2.5 Hz, CH2CH3),
2.60 (1H, ddt, J ¼ 17, 5, 2.5 Hz, CHCHaHb), 2.69 (1H,
br d, J ¼ 17 Hz, CHCHaHb), 3.74 (3H, s, COOCH3),
4.41 (1H, m, CHCHaHb), 5.26 (1H, br s, NHBoc).
13C NMR (CDCl3, 100 MHz) ꢂ 12.3, 14.0, 23.1, 28.3,
52.3, 52.4, 73.2, 80.0, 85.3, 155.2, 171.5. Anal. Calcd.
for C13H21NO4: C, 61.16; H, 8.29; N, 5.49. Found: C,
61.38; H, 8.34; N, 5.54.
(2,3,4,6-Tetra-O-benzyl-ꢀ-D-glucopyranosyl)but-1-yne
(18ꢀ,ꢁ). Glucosylacetate 14 (1.46 g, 2.50 mmol, azeo-
tropically dried with toluene) was placed in a flask
connected to a vacuum/N2 line. The flask was evacuated
and filled with N2. After this evacuated/filling cycle was
repeated three times, anhydrous CH2Cl2 (45 ml) and
stannylacetylene 17 (1.6 ml, 5.0 mmol) were added. To
the solution cooled to 0 ꢂC was added TMSOTf (0.5 ml,
2.5 mmol). After stirring at 4 ꢂC for 12 h, additional
TMSOTf (0.3 ml, 2.5 mmol) was added. The mixture
was stirred for 23 h, and then quenched with sat.
Na2CO3 solution. After extraction with CH2Cl2 (x3),
the combined organic layers were washed with H2O (x2)
and brine (x1), dried over anhydrous Na2SO4, and
concentrated. The residue was purified by flash-chro-
matography (silica gel 70 g, AcOEt:hexane = 0:1 !
1:5) to afford glucosylacetylene 18ꢀ,ꢁ (1.46 g, 89%,
6-O-Acetyl-1-(but-1-ynyl)-3,4-dideoxy-ꢀ-D-(2S,5S)-hex-
3-enopyranose (22). To a solution of 2-acetoxy-D-glucal
20 (5.0 g, 15 mmol) and TMS-butyne 21 (4.8 ml,
30 mmol) in anhydrous CH2Cl2 (100 ml) was added
SnCl4 (3.5 ml, 30 mmol) at ꢁ10 ꢂC. After stirring at
ꢁ10 ꢂC for 5 min, the reaction was quenched with sat.
Na2CO3 solution and sat. potassium sodium (+)-tartrate
solution. After filtration through a pad of Super-Cel, the
filtrate was extracted with CH2Cl2 (x3). The combined
organic layers were washed with brine (x1), dried over
anhydrous Na2SO4, and concentrated. The residue
(enol acetate) was dissolved in MeOH (100 ml), and
.
CeCl3 7H2O (11.2 g, 30.0 mmol) and NaBH4 (0.28 g,
7.5 mmol) were added at 0 ꢂC. After stirring at 0 ꢂC for
30 min, additional NaBH4 (5.10 g, 135 mmol) was added
portionwise over 5 h, until the enol acetate was
consumed [judged by TLC (Et2O:hexane = 4:1)]. The
reaction was quenched with sat. Na2CO3 solution
and extracted with AcOEt (x3). The combined organic
layers were washed with brine (x1), dried over anhy-
drous Na2SO4, and concentrated. The residue was
purified by column chromatography (silica gel 100 g,
AcOEt:hexane = 1:5 ! 1:4 ! 1:3) to afford allylic
alcohol 22 (1.79 g, 53%) as white crystals. Mp: 67.0 ꢂC–
1
ꢀ:ꢁ = 4:1 by H NMR spectra) as a yellow oil.
(2,3,4,6-Tetra-O-benzyl-ꢀ-D-glucopyranosyl)but-1-yne
(18ꢀ). Glucosylacetylene 16 (165 mg, 0.300 mmol,
azeotropically dried with toluene) and a trace of Ph3CH
(as an indicator) were placed in a flask that was
connected to a vacuum/N2 line. The flask was evacuated
and filled with N2. After this evacuation/filling cycle
was repeated 3 times, anhydrous THF (4.9 ml) was
added, and the flask was cooled to ꢁ78 ꢂC. n-BuLi
(0.5 ml, 0.8 mmol) was added dropwise until the color of
the solution turned to orange. After stirring for 1 h, EtI
(0.11 ml, 1.2 mmol) and HMPA (0.12 ml, 0.80 mmol)
were added. The reaction mixture was allowed to warm
to room temperature, and stirring was continued for an
additional 8 h. The reaction was quenched with sat.
NaHCO3 solution, and the mixture was extracted with
AcOEt (x3). The combined organic layers were washed
with H2O (x2) and brine (x1), dried over anhydrous
Na2SO4, and concentrated. The residue was purified by
flash-chomatography (silica gel 15 g, AcOEt:hexane =
25
67.1 ꢂC. ½ꢀꢀD ꢁ116:0ꢂ (c 0.15, CHCl3). IR (KBr) ꢃmax
3524, 2978, 2242, 1743, 1456, 1369, 1239, 1039 cmꢁ1
.
1H NMR (CDCl3, 300 MHz) ꢂ 1.17 (3H, t, J ¼ 7:5 Hz,
CH2CH3), 1.96 (1H, d, J ¼ 11 Hz, OH), 2.10 (3H, s,
CH3 of Ac), 2.27 (2H, qd, J ¼ 7:5, 2 Hz, CH2CH3), 4.15
(2H, d, J ¼ 5 Hz, H-6), 4.26 (1H, m, H-2), 4.56 (1H, m,
H-5), 4.89 (1H, dt, J ¼ 5:5, 2 Hz, H-1), 5.73 (1H, dt,
J ¼ 10:5, 2 Hz, H-3), 5.87 (1H, dtd, J ¼ 10:5, 2.5,
0.5 Hz, H-4). 13C NMR (CDCl3, 75 MHz) ꢂ 12.3, 13.6,
20.8, 63.5, 65.1, 67.4, 69.0, 73.1, 91.1, 127.1, 129.8,
171.0. Anal. Calcd. for C12H16O4: C, 64.27; H, 7.19.
Found: C, 64.28; H, 7.28.

2098
K. SUGINO et al.
2,6-O-bis-(t-Butyldimethylsilyl)-1-but-1-ynyl-3,4-di-
18.0, 18.3, 25.6, 25.8, 50.8, 55.4, 62.4, 65.7, 65.8, 68.9,
73.9, 90.1. Anal. Calcd. for C22H42O4Si2: C, 61.92; H,
9.92. Found: C, 61.92; H, 10.12.
deoxy-ꢀ-D-(2S,5S)-hex-3-enopyranose (23). A solution
of allylic alcohol 22 (1.79 g, 7.99 mmol) in MeOH
(25 ml), Et3N (5 ml), and H2O (5 ml) was stirred at room
temperature for 16 h and evaporated. The residue was
dissolved in DMF (45 ml), and imidazole (3.26 g,
48.0 mmol) and TBSCl (3.61 g, 24.0 mmol) were added.
After stiring at room temperature for 4 h, the reaction
was quenched with ice-cold H2O and extracted with
AcOEt (x3). The combined extract was washed with
H2O (x2) and brine (x1), dried over anhydrous Na2SO4,
and concentrated. The residue was purified by column
chromatography (silica gel 150 g, AcOEt:hexane =
1:20) to afford bis-TBS ether 23 (3.06 g, 93%) as a
(2,3,4,6-Tetra-O-acetyl-ꢀ-D-glucopyranosyl)but-1-yne
(25) and (2,3,4,6-tetra-O-acetyl-ꢀ-D-gulopyranosyl)but-
1-yne (26). To a solution of epoxide 24 (0.28 g,
0.64 mmol) in THF (5.5 ml) was added TBAF (1.0 m
in THF, 2.6 ml, 2.6 mmol). After stirring at room
temperature for 1.5 h, the solution was concentrated.
The residue was dissolved in a 12% HClO4 solution
(13 ml), and stirring was continued at room temperature
for 12 h. After the reaction mixture was filtered through
a cotton plug, an additional 12% HClO4 solution (6 ml)
was added, and stirring was continued for 34 h. The
reaction was quenched with NaHCO3 solid and con-
centrated azeotropically with EtOH. The residue (18.8 g)
was dissolved in Ac2O (6 ml) and pyridine (6 ml), and
the solution was stirred at room temperature for 21 h.
The reaction was quenched with ice-H2O, and the
mixture was extracted with AcOEt (x3). The combined
organic layers were washed with sat. NH4Cl solution
(x1), sat. NaHCO3 solution (x1), and brine (x1), dried
over anhydrous Na2SO4, and concentrated. The residue
was purified by flash-chromatography (AcOEt:hexane =
1:3 ! 1:2 ! 1:1) to afford a mixture of 25 and 26
(157 mg, 64%, 25:26 = 7:1).
28
colorless oil. ½ꢀꢀD ꢁ62:8ꢂ (c 0.60, CHCl3). IR (KBr)
1
ꢃmax 2930, 1473, 1256, 1117 cmꢁ1. H NMR (CDCl3,
300 MHz) ꢂ 0.06 (6H, s, SiCH3), 0.10 (6H, s, SiCH3),
0.89 (9H, s, CH3 of t-Bu), 0.91 (9H, s, CH3 of t-Bu),
1.13 (3H, t, J ¼ 7:5 Hz, CH2CH3), 2.23 (2H, qd,
J ¼ 7:5, 2 Hz, CH2CH3), 3.57 (1H, dd, J ¼ 10, 6 Hz,
H-6), 3.62 (1H, dd, J ¼ 10, 5 Hz, H-60), 4.31–4.41 (2H,
m, H-2 and 5), 4.74 (1H, br d, J ¼ 5 Hz, H-1), 5.70 (1H,
br d, J ¼ 11 Hz, olefinic), 5.82 (1H, br d, J ¼ 11 Hz,
olefinic).13C NMR (CDCl3, 75 MHz) ꢂ ꢁ5:4, ꢁ4:8,
12.5, 13.7, 18.1, 18.3, 25.7, 25.8, 65.1, 65.4, 67.7, 70.9,
74.7, 88.5, 127.9, 129.0. Anal. Calcd. for C22H42O3Si2:
C, 64.33; H, 10.31. Found: C, 64.20; H, 10.56.
2,6-O-bis-(t-Butyldimethylsilyl)-1-(but-1-ynyl)-3,4-an-
hydro-ꢀ-D-galactose (24). To a solution of bis-TBS ether
23 (1.97 g, 4.80 mmol) in (CH2Cl)2 (48 ml) were
successively added Na2HPO4 (1.36 g, 9.60 mmol) and
MCPBA (0.83 g, 4.80 mmol). After stirring at room
temperature for 36 h, the reaction mixture was filtered
through a cotton plug, and additional NaH2PO4 (2.72 g,
19.2 mmol) and MCPBA (1.66 g, 9.60 mmol) were
added. After stirring for 24 h, the mixture was treated
with sat. NaHCO3 solution and sat. NaHSO3 solution,
and then filtered through a pad of Super-Cel. The filtrate
was extracted with AcOEt (x2). The combined organic
layers were washed with brine (x1), dried over anhy-
drous Na2SO4, and concentrated. The residue was
suspended in hexane and then filtered through a
Kiriyama-funnel to remove the m-chlorobenzoic acid.
The filtrate was concentrated and then purified by flash-
chromatography (silica gel 60 g, AcOEt:hexane =
0:1 ! 1:100) to afford epoxide 24 (1.44 g, 70%) as a
(ꢀ-D-Glucopyranosyl)but-1-yne (19) and (ꢀ-D-gulo-
pyranosyl)but-1-yne (27). A solution of a mixture of
25 and 26 (157 mg) in MeOH (2.5 ml), Et3N (0.5 ml),
and H2O (0.5 ml) was stirred at room temperature for
12 h, and then concentrated azeotropically with toluene.
Recrystallization from AcOEt and MeOH afforded
glucosyl acetylene 19 (48 mg, 55%) as a white solid.
Isomer 27 was obtained by flash-chromatography
(MeOH:AcOEt = 1:20) of the mother liquor for spec-
troscopic analysis. 19: ½ꢀꢀD 116.1ꢂ (c 2.65, CH3OH).
30
IR (KBr) ꢃmax 3463, 2928, 2654, 2520, 2228, 1733,
1564, 1460, 1319, 1243, 1062 cmꢁ1. 1H NMR (CD3OD,
300 MHz) ꢂ 1.15 (3H, t, J ¼ 7:5 Hz, CH2CH3), 2.26
(2H, qd, J ¼ 7:5, 2 Hz, CH2CH3), 3.26 (1H, dd, J ¼ 10,
9 Hz, H-3), 3.45 (1H, dd, J ¼ 10, 5.5 Hz, H-2), 3.63 (1H,
t, J ¼ 9 Hz, H-4), 3.66 (1H, dd, J ¼ 12, 5 Hz, H-6), 3.76
(1H, ddd, J ¼ 9, 5, 2 Hz, H-5), 3.79 (1H, dd, J ¼ 12,
2 Hz, H-60), 4.63 (1H, dt, J ¼ 5:5, 2 Hz, H-1). 13C NMR
(CD3OD, 75 MHz) ꢂ 14.0, 15.0, 63.7, 70.8, 72.6, 73.3,
76.2, 77.0, 77.3, 93.2. Anal. Calcd. For C10H16O5: C,
26
colorless oil. ½ꢀꢀD ꢁ16:9ꢂ (c 0.70, CHCl3). IR (KBr)
30
ꢃmax 2931, 2859, 1473, 1362, 1258, 1118 cmꢁ1
.
55.55; H, 7.46. Found: C, 55.59; H, 7.45. 27: ½ꢀꢀD
1H NMR (CDCl3, 300 MHz) ꢂ 0.08 (6H, s, SiCH3),
0.10 (3H, s, SiCH3), 0.13 (3H, s, SiCH3), 0.90 (9H, s,
CH3 of t-Bu), 0.92 (9H, s, CH3 of t-Bu), 1.14 (3H, t,
J ¼ 7:5 Hz, CH2CH3), 2.24 (2H, qd, J ¼ 7:5, 2 Hz,
CH2CH3), 3.24 (1H, d, J ¼ 4 Hz, H-3), 3.32 (1H, dd,
J ¼ 4, 1.5 Hz, H-4), 3.74 (2H, d, J ¼ 7 Hz, H-6), 3.87
(1H, d, J ¼ 5:5 Hz, H-2), 4.28 (1H, td, J ¼ 7, 1.5 Hz,
H-5), 4.45 (1H, dt, J ¼ 5:5, 2 Hz, H-1). 13C NMR
(CDCl3, 75 MHz) ꢂ ꢁ5:6, ꢁ5:5, ꢁ5:0, ꢁ4:9, 12.4, 13.7,
63.1ꢂ (c 2.00, CH3OH). IR (KBr) ꢃmax 3334, 2940, 2239,
1508, 1457, 1245, 1074 cmꢁ1
.
1H NMR (CD3OD,
300 MHz) ꢂ 1.14 (3H, t, J ¼ 7:5 Hz, CH2CH3), 2.24
(2H, qd, J ¼ 7:5, 2 Hz, CH2CH3), 3.68 (1H, dd,
J ¼ 6 Hz, H-6), 3.69 (1H, dd, J ¼ 6:5 Hz, H-60), 3.79
(1H, dd, J ¼ 4, 2 Hz, H-4), 3.85 (1H, dd, J ¼ 4:5,
3.5 Hz, H-3), 3.93 (1H, dd, J ¼ 5:5, 3.5 Hz, H-2), 4.20
(1H, ddd, J ¼ 6:5, 6, 2 Hz, H-5), 4.61 (1H, dt, J ¼ 5:5,
2 Hz, H-1). 13C NMR (CD3OD, 75 MHz) ꢂ 14.1, 14.9,

Regioselectivity of Larock Indole Synthesis
2099
63.1, 67.5, 68.7, 71.7, 72.1, 73.6, 77.8, 91.6. Anal.
Calcd. For C10H16O5: C, 55.55; H, 7.46. Found: C,
55.55; H, 7.49.
2-(tert-Buthoxycarbamoyl)ethyl-3-ethyl-1-tosyl-indole
(29a) and 3-(tert-buthoxycarbamoyl)ethyl-2-ethyl-1-to-
syl-indole (29b). Purification by flash-chromatogra-
phy (AcOEt:hexane = 1:2) afforded a mixture of re-
gioisomer of indole (41 mg, 75%, 29a:29b = 56:44 by
1H NMR spectra [Anal. Calcd. for C24H30N2O4 S: C,
65.13; H, 6.83; N 6.33. Found: C, 65.22; H, 7.04; N,
6.27.]), which was further separated by preparative TLC
for spectroscopic analysis. 29a: IR (film) ꢃmax 3422,
General procedure for the Larock indole synthesis as
in Table 1. N-Tosyl-o-iodoanilide (2) (37 mg, 0.10
mmol), acetylene (0.20 mmol), Pd(OAc)2 (6.7 mg, 30
mmol), Ph3P (7.9 mg, 30 mmol), Na2CO3 (53 mg, 0.50
mmol), and n-Bu4NCl (27 mg, 0.10 mmol) were placed
in a flask, which was evacuated and filled with N2. After
this evacuation/filling cycle was repeated 3 times,
anhydrous DMF (10 ml) was added. The reaction
mixture was stirred at 100 ꢂC, and then cooled to 0 ꢂC.
After the addition of sat. NH4Cl solution, the mixture
was extracted with AcOEt (x3). The combined organic
layers were washed with H2O (x2) and brine (x1), dried
over anhydrous Na2SO4, and concentrated. The residue
was purified by flash-chromatography to afford a
mixture of regioisomer.
2975, 1699, 1455, 1367, 1251, 1173 cmꢁ1 1H NMR
.
(CDCl3, 400 MHz) ꢂ 1.16 (3H, t, J ¼ 7:5 Hz, CH2CH3),
1.43 (9H, s, CH3 of Boc), 2.31 (3H, s, CH3 of Ts), 2.64
(2H, q, J ¼ 7:5 Hz, CH2CH3), 3.19 (2H, br t, J ¼
6:5 Hz, CH2CH2NH), 3.44 (2H, br q, J ¼ 6:5 Hz,
CH2CH2NH), 4.75 (1H, br t, J ¼ 6 Hz, NHBoc), 7.14
(2H, d, J ¼ 8:5 Hz, aromatic of Ts), 7.24 (1H, td, J ¼ 7,
1 Hz, H-5 or 6), 7.28 (1H, td, J ¼ 7, 1.5 Hz, H-5 or 6),
7.43 (1H, br d, J ¼ 7 Hz, H-4 or 7), 7.53 (2H, d,
J ¼ 8:5 Hz, aromatic of Ts), 8.17 (1H, br d, J ¼ 7 Hz,
H-4 or 7). 13C NMR (CDCl3, 75 MHz) ꢂ 14.7, 17.4,
21.4, 27.0, 28.3, 40.9, 79.1, 115.4, 118.8, 123.5, 124.4,
125.5, 126.2, 129.8, 130.5, 133.3, 135.8, 137.1, 144.6,
156.0. HRMS (FAB) (Mþ): Calcd for C24H30N2O4S:
442.1926. Found: 442.1918. 29b: IR (KBr) ꢃmax 3429,
3-Ethyl-2-(methoxycarbonyl)ethyl-1-Ts-indole (28a)
and 2-ethyl-3-(methoxycarbonyl)ethyl-1-Ts-indole (28b).
Purification by flash-chromatography (Et2O:hexane =
1:2) afforded a mixture of regioisomer of indole (29 mg,
75%, 28a:28b = 60:40 by 1H NMR spectra), which was
separated by preparative TLC for spectroscopic analysis.
28a: IR (KBr) ꢃmax 3068, 2970, 2931, 2875, 1739, 1598,
1455, 1437, 1365, 1188, 1172, 1122, 1090, 1008,
3339, 2977, 1706, 1599, 1508, 1366, 1174 cmꢁ1
.
1H NMR (CDCl3, 400 MHz) ꢂ 1.30 (3H, t, J ¼ 7:5 Hz,
CH2CH3), 1.43 (9H, s, CH3 of Boc), 2.31 (3H, s, CH3 of
Ts), 2.81 (2H, t, J ¼ 7 Hz, CH2CH2NH), 3.00 (2H, q,
J ¼ 7:5 Hz, CH2CH3), 3.27 (2H, br q, J ¼ 6:5 Hz,
CH2CH2NH), 4.42 (1H, br s, J ¼ 6 Hz, NHBoc), 7.15
(2H, d, J ¼ 8 Hz, aromatic of Ts), 7.22 (1H, td, J ¼ 7,
1.5 Hz, H-5 or 6), 7.27 (1H, td, J ¼ 7, 1.5 Hz, H-5 or 6),
7.40 (1H, br d, J ¼ 7 Hz, H-4 or 7), 7.55 (2H, d,
J ¼ 8 Hz, aromatic of Ts), 8.17 (1H, br d, J ¼ 8 Hz, H-4
or 7). HRMS (FAB) (Mþ): Calcd for C24H30N2O4S:
442.1926. Found: 442.1905.
1
988 cmꢁ1. H NMR (CDCl3, 400 MHz) ꢂ 1.13 (3H, t,
J ¼ 7:5 Hz, CH2CH3), 2.31 (3H, s, CH3 of Ts), 2.64
(2H, q, J ¼ 7:5 Hz, CH2CH3), 2.78 (2H, m,
CH2CH2CO), 3.28 (2H, m, CH2CH2CO), 3.70 (3H, s,
COOCH3), 7.15 (2H, d, J ¼ 8 Hz, aromatic of Ts), 7.23
(1H, td, J ¼ 7:5, 1 Hz, H-5 or 6), 7.28 (1H, td, J ¼ 7:5,
1 Hz, H-5 or 6), 7.41 (1H, br d, J ¼ 7:5 Hz, H-4 or 7),
7.56 (2H, d, J ¼ 8 Hz, aromatic of Ts), 8.17 (1H, br d,
J ¼ 7:5 Hz, H-4 or 7). 13C NMR (CDCl3, 75 MHz) ꢂ
15.7, 19.7, 19.8, 21.6, 34.3, 51.6, 115.3, 118.2, 118.8,
123.4, 124.1, 126.2, 129.7, 130.2, 136.2, 136.8, 139.9,
144.5, 173.1. Anal. Calcd. for C21H23NO4 S: C, 65.43;
H, 6.01; N, 3.63. Found: C, 65.38; H, 5.75; N, 3.76.
HRMS (FAB) (Mþ): Calcd for C21H23NO4S: 385.1348.
Found: 385.1353. 28b: IR (film) ꢃmax 2967, 1737, 1598,
3-Ethyl-2-[2-(methoxycarbonyl)-(tert-buthoxycarba-
moyl)ethyl]-1-tosyl-indole (30a) and 2-ethyl-3-[2-(me-
thoxycarbonyl)-(tert-buthoxycarbamoyl)ethyl]-1-tosyl-
indole (30b). Purification by flash-chromatography
(AcOEt:hexane = 1:5) afforded a mixture of regio-
isomer of indole (25 mg, 50%, 30a:30b = 56:44 by
1H NMR spectra [Anal. Calcd. for C26H32N2O6 S: C,
62.38; H, 6.44; N, 5.60. Found: C, 62.28; H, 6.40; N,
5.49.]), which was separated by flash-chromatography
for spectroscopic analysis. 30a: IR (film) ꢃmax 3398,
1
1455, 1365, 1172 cmꢁ1. H NMR (CDCl3, 400 MHz) ꢂ
1.29 (3H, t, J ¼ 7:5 Hz, CH2CH3), 2.31 (3H, s, CH3 of
Ts), 2.53 (2H, m, CH2CH2CO), 2.94 (2H, m,
CH2CH2CO), 3.02 (2H, q, J ¼ 7:5 Hz, CH2CH3), 3.62
(3H, s, COOCH3), 7.15 (2H, d, J ¼ 8 Hz, aromatic of
Ts), 7.22 (1H, td, J ¼ 7, 1.5 Hz, H-5 or 6), 7.26 (1H, td,
J ¼ 7:5, 1.5 Hz, H-5 or 6), 7.39 (1H, br d, J ¼ 7 Hz, H-4
or 7), 7.55 (2H, d, J ¼ 8 Hz, aromatic of Ts), 8.17 (1H,
br d, J ¼ 7:5 Hz, H-4 or 7). 13C NMR (CDCl3, 75 MHz)
ꢂ 15.8, 19.7, 19.8, 21.5, 34.3, 51.7, 115.3, 118.2, 118.8,
123.5, 124.2, 126.2, 129.7, 130.2, 136.1, 136.7, 139.8,
144.4, 173.2. Anal. Calcd. for C21H23NO4 S: C, 65.43;
H, 6.01; N, 3.63. Found: C, 65.56; H, 5.80; N, 3.69.
HRMS (FAB) (Mþ): Calcd for C21H23NO4S: 385.1348.
Found: 385.1325.
2977, 1717, 1508, 1456, 1367, 1172 cmꢁ1 1H NMR
.
(CDCl3, 400 MHz) ꢂ 1.16 (3H, t, J ¼ 7:5 Hz, CH2CH3),
1.26 (3H, br s, CH3 of Boc), 1.33 (6H, br s, CH3 of Boc),
2.31 (3H, s, CH3 of Ts), 2.66 (2H, br q, J ¼ 7:5 Hz,
CH2CH3), 3.45–3.57 (2H, m, CH2CH), 3.76 (3H, s,
COOCH3), 4.62 (1H, br s, CHNH), 5.36 (1H, br d,
J ¼ 8 Hz, NHBoc), 7.13 (2H, d, J ¼ 8 Hz, aromatic of
Ts), 7.23 (1H, td, J ¼ 7:5, 1 Hz, H-5 or 6), 7.28 (1H, br
t, J ¼ 7:5 Hz, H-5 or 6), 7.43 (1H, br d, J ¼ 8 Hz, H-4 or
7), 7.52 (2H, d, J ¼ 8 Hz, aromatic of Ts), 8.15 (1H, br
d, J ¼ 8 Hz, H-4 or 7). HRMS (FAB) (Mþ): Calcd for

2100
K. SUGINO et al.
C26H32N2O6S: 500.1981. Found: 500.2003. 30b: IR
(film) ꢃmax 3412, 2977, 1716, 1507, 1367, 1172 cmꢁ1
OCHeHfPh), 4.52 (1H, d, J ¼ 12 Hz, OCHcHdPh), 4.55
(1H, d, J ¼ 11:5 Hz, OCHeHfPh), 4.59 (1H, d,
J ¼ 11 Hz, OCHgHhPh), 4.75 (1H, d, J ¼ 11 Hz,
OCHgHhPh), 5.28 (1H, d, J ¼ 3 Hz, H-1), 6.58 (2H, d,
J ¼ 8 Hz, aromatic), 7.00–7.09 (4H, m, aromatic), 7.12–
7.18 (2H, m, aromatic), 7.22–7.37 (16 H, m, aromatic),
7.57 (2H, d, J ¼ 8 Hz, aromatic of Ts), 7.78 (1H, d,
J ¼ 8 Hz, H-40), 8.19 (1H, d, J ¼ 8 Hz, H-70). 13C NMR
(CDCl3, 100 MHz) ꢂ 15.7, 20.2, 21.3, 69.7, 69.9, 72.5,
72.9, 73.4(x2), 73.9, 76.7, 81.2, 82.3, 114.6, 118.8,
122.5, 123.4, 123.9, 126.2, 127.5, 127.6, 127.7, 127.8,
127.9, 128.0, 128.1, 128.2, 128.3, 128.5, 129.6, 130.1,
136.2, 136.6, 137.3, 138.0, 138.3, 138.4, 139.6, 144.5.
HRMS (FAB) ðM þ HÞþ: Calcd for C51H52NO7S:
822.3644. Found: 822.3474.
.
1H NMR (CDCl3, 400 MHz) ꢂ 1.30 (3H, br t, J ¼
7:5 Hz, CH2CH3), 1.55 (9H, br s, CH3 of Boc), 2.32 (3H,
s, CH3 of Ts), 2.91–3.05 (2H, m, CH2CH3), 3.10 (2H, br
d, J ¼ 6:5 Hz, CH2CH), 3.43 (3H, s, COOCH3), 4.50
(1H, m, CHNH), 4.93 (1H, br d, J ¼ 7:5 Hz, NHBoc),
7.16 (2H, d, J ¼ 8 Hz, aromatic of Ts), 7.18–7.26 (2H,
m, H-5, 6), 7.35 (1H, br d, J ¼ 7 Hz, H-4 or 7), 7.51
(2H, d, J ¼ 8 Hz, aromatic of Ts), 8.14 (1H, d, J ¼ 8 Hz,
H-4 or 7). HRMS (FAB) (Mþ): Calcd for C26H32N2O6S:
500.1981. Found: 500.1991.
2-(2,3,4,6-Tetra-O-benzyl-ꢀ-D-glucopyranosyl)-3-eth-
yl-1-tosyl-indole (31a) and 3-(2,3,4,6-tetra-O-benzyl-ꢀ-
D-glucopyranosyl)-2-ethyl-1-tosyl-indole (31b). Purifica-
tion by flash-chromatography (AcOEt:hexane = 1:7)
afforded a mixture of regioisomer of indole and glucosyl
acetylene 18 (117 mg, 64%, 31a:31b = 67:33 by
1H NMR spectra [Anal. Calcd. for C51H51NO7 S: C,
74.52; H, 6.25; N, 1.70. Found: C, 74.50; H, 6.31; N,
1.80.]), which was separated by flash-chromatography
2-(ꢀ-D-Glucopyranosyl)-3-ethyl-1-tosyl-indole (32a)
and 3-(ꢀ-D-glucopyranosyl)-2-ethyl-1-tosyl-indole (32b).
Purification by flash-chromatography (AcOEt:hexane =
1:7) afforded recovered iodoaniline 2 (17 mg, 57%) and
a mixture of regioisomer of indole (6 mg, 16%,
1
32a:32b = 69:31 by H NMR spectra [Anal. Calcd. for
C23H27NO7 S: C, 59.85; H, 5.90; N, 3.03. Found: C,
59.97; H, 5.76; N, 3.03.]), which was separated by flash-
28
for spectroscopic analysis. 31a: ½ꢀꢀD 107.3ꢂ (c 0.45,
CHCl3). IR (film) ꢃmax 3032, 2868, 1455, 1367, 1218,
1
30
1172, 1090 cmꢁ1. H NMR (CDCl3, 400 MHz) ꢂ 1.12
chromatography for spectroscopic analysis. 32a: ½ꢀꢀD
(3H, t, J ¼ 7:5 Hz, CHAHBCH3), 2.22 (3H, s, CH3 of
Ts), 2.79 (1H, dq, J ¼ 14, 7.5 Hz, CHAHBCH3), 3.03
(1H, dq, J ¼ 14, 7.5 Hz, CHAHBCH3), 3.69 (1H, dd,
J ¼ 11, 3 Hz, H-6), 3.75 (1H, dd, J ¼ 11, 4.5 Hz, H-60),
3.91 (1H, dd, J ¼ 5, 2.5 Hz, H-3), 3.93 (1H, dd, J ¼ 8:5,
5 Hz, H-4), 4.17 (1H, d, J ¼ 12 Hz, OCHaHbPh), 4.26
(1H, d, J ¼ 12 Hz, OCHaHbPh), 4.26 (1H, ddd, J ¼ 8:5,
4.5, 3 Hz, H-5), 4.30 (1H, t, J ¼ 2:5 Hz, H-2), 4.41 (1H,
d, J ¼ 11:5 Hz, OCHcHdPh), 4.47 (1H, d, J ¼ 12 Hz,
OCHeHfPh), 4.54 (1H, d, J ¼ 12 Hz, OCHeHfPh), 4.56
(1H, d, J ¼ 11:5 Hz, OCHgHhPh), 4.71 (1H, d,
J ¼ 11:5 Hz, OCHgHhPh), 4.72 (1H, d, J ¼ 11:5 Hz,
OCHcHdPh), 5.98 (1H, d, J ¼ 2:5 Hz, H-1), 6.98 (4H,
m, aromatic), 7.05–7.18 (4H, d, aromatic), 7.23–7.40
(16H, aromatic), 7.46 (1H, br d, J ¼ 7 Hz, H-40 or 70),
7.54 (2H, d, J ¼ 8:5 Hz, aromatic of Ts), 8.20 (1H, br d,
J ¼ 8 Hz, H-40 or 70). 13C NMR (CDCl3, 100 MHz) ꢂ
14.9, 18.4, 21.4, 69.6, 70.3, 71.7, 72.8(x2), 73.2, 73.7,
76.9, 77.7, 80.7, 115.6, 118.8, 123.4, 124.4, 126.3,
127.4(x2), 127.5(x2), 127.7, 127.8, 127.9, 128.1, 128.2,
128.3, 128.4, 128.5, 128.8, 129.6, 131.6, 132.0, 135.6,
137.0, 137.7, 138.1, 138.5(x2), 144.4. MS (FAB) m=z
82.7ꢂ (c 0.55, CHCl3). IR (KBR) ꢃmax 3688, 3318, 3318,
3070, 2406, 1906, 1727, 1595, 1455, 1367, 1171 cmꢁ1
.
1H NMR (CD3OD, 400 MHz) ꢂ 1.14 (3H, t, J ¼ 7:5 Hz,
CHAHBCH3), 2.31 (3H, s, CH3 of Ts), 2.89 (1H, dq,
J ¼ 13:5, 7.5 Hz, CHAHBCH3), 3.09 (1H, dq, J ¼ 13:5,
7.5 Hz, CHAHBCH3), 3.76 (1H, ddd, J ¼ 4:5, 3, 1 Hz,
H-5), 3.81 (1H, dd, J ¼ 14:5, 7.5 Hz, H-6), 3.78 (1H, dd,
J ¼ 4:5, 3.5 Hz, H-3), 3.94–4.08 (4H, m, H-2, 3, 4, 60),
6.09 (1H, d, J ¼ 1:5 Hz, H-1), 7.17–7.27 (4H, m,
aromatic of Ts, H-50, 60), 7.43 (1H, br d, J ¼ 7 Hz,
H-40), 7.60 (2H, d, J ¼ 8:5 Hz, aromatic of Ts), 8.10 (1H,
br d, J ¼ 7:5 Hz, H-70). 13C NMR (CDCl3, 100 MHz) ꢂ
16.2, 21.2, 21.4, 61.3, 68.3, 70.1, 72.0, 75.2, 81.1, 115.5,
120.5, 123.5, 124.1, 124.7, 127.4, 130.9, 131.7, 137.5,
137.9, 141.3, 146.3. HRMS (FAB) (Mþ): Calcd for
27
C23H27NO7S: 461.1508. Found: 461.1518. 32b: ½ꢀꢀD
68.0ꢂ (c 0.10, CHCl3). IR (KBr) ꢃmax 3568, 3335, 2933,
1451, 1364 cmꢁ1. H NMR (CD3OD, 400 MHz) ꢂ 1.31
1
(3H, t, J ¼ 7:5 Hz, CHAHBCH3), 2.32 (3H, s, CH3 of Ts),
3.09 (1H, dq, J ¼ 14:5, 7.5 Hz, CHAHBCH3), 3.19 (1H,
dq, J ¼ 14:5, 7.5 Hz, CHAHBCH3), 3.59 (1H, m, H-2),
3.70 (1H, dd, J ¼ 12, 3.5 Hz, H-6), 3.78 (1H, dd, J ¼ 4:5,
3.5, 1 Hz, H-3), 3.93 (1H, br t, J ¼ 4 Hz, H-4), 4.02 (1H,
dt, J ¼ 7:5, 3.5 Hz, H-5), 4.09 (1H, dd, J ¼ 12, 7.5 Hz,
H-60), 5.34 (1H, d, J ¼ 2 Hz, H-1), 7.13 (1H, td, J ¼ 7:5,
1 Hz, H-50), 7.18 (1H, td, J ¼ 7:5, 1.5 Hz, H-60), 7.24 (2H,
d, J ¼ 8:5 Hz, aromatic of Ts), 7.59 (2H, d, J ¼ 8:5 Hz,
aromatic of Ts), 7.84 (1H, br d, J ¼ 8 Hz, H-40), 8.07 (1H,
br d, J ¼ 8 Hz, H-70). 13C NMR (CDCl3, 100 MHz) ꢂ
15.3, 19.7, 21.4, 61.8, 69.6, 70.0, 72.3, 73.8, 81.4, 116.7,
120.0, 124.7, 125.3, 127.6, 130.2, 130.7, 133.2, 133.8,
136.6, 138.6, 146.3. HRMS (FAB) (Mþ): Calcd for
C23H27NO7S: 461.1508. Found: 461.1508.
28
821 (Mþ). 31b: ½ꢀꢀD 40.7ꢂ (c 0.15, CHCl3). IR (film)
ꢃmax 2870, 1598, 1454, 1364, 1175, 1091 cmꢁ1
.
1H NMR (CDCl3, 400 MHz) ꢂ 1.14 (3H, t, J ¼ 7:5 Hz,
CHAHBCH3), 2.16 (3H, s, CH3 of Ts), 2.93 (1H, dq,
J ¼ 14, 7.5 Hz, CHAHBCH3), 2.99 (1H, dq, J ¼ 14,
7.5 Hz, CHAHBCH3), 3.59 (1H, t, J ¼ 3 Hz, H-2), 3.72
(2H, d, J ¼ 3 Hz, H-6), 3.82 (1H, d, J ¼ 12 Hz,
OCHaHbPh), 3.91 (1H, dd, J ¼ 6:5, 3 Hz, H-3), 4.00
(1H, d, J ¼ 12 Hz, OCHaHbPh), 4.02 (1H, dd, J ¼ 9,
6.5 Hz, H-4), 4.16 (1H, dt, J ¼ 9, 3 Hz, H-5), 4.41 (1H,
d, J ¼ 12 Hz, OCHcHdPh), 4.50 (1H, d, J ¼ 12 Hz,

Regioselectivity of Larock Indole Synthesis
2101
of (ꢃ)-lotthanongine, a novel natural product with a
flavan-indole hybrid structure. Synlett, 1311–1315
(2005).
2-(2,3,4,6-Tetra-O-acetyl-ꢀ-D-glucopyranosyl)-3-eth-
yl-1-tosyl-indole (33a). A solution of 2-glucopyranosyl-
3-ethyl-1-tosyl-indole 32a (4 mg) in Ac2O (0.5 ml) and
pyridine (0.5 ml was stirred at room temperature for
5 h and concentrated azeotropically with toluene. The
residue was purified by column chromatography
(AcOEt:hexane = 1:2 ! 2:1) to afford the 33a (3 mg,
7) Nishikawa, T., Ishikawa, M., and Isobe, M., Synthesis of
a ꢀ-C-mannosyltryptophan derivative, naturally occur-
ring C-glycosyl amino acid found in human ribonu-
clease. Synlett, 123–125 (1999).
8) Nishikawa, T., Ishikawa, M., Wada, K., and Isobe, M.,
Total synthesis of ꢀ-C-mannosyltryptophan, a naturally
occurring C-glycosyl amino acid. Synlett, 945–947
(2001).
9) Furmanek, A., and Hofsteenge, J., Protein C-mannosy-
lation: facts and questions. Acta Biochimica Polonica,
47, 781–789 (2000).
10) Nishikawa, T., Wada, K., and Isobe, M., Synthesis of
novel ꢀ-C-glycosylamino acids and reverse regioselec-
tivity in Larock’s heteroannulation for the synthesis of
the indole nucleus. Biosci. Biotechnol. Biochem., 66,
2273–2278 (2002).
11) Konno, T., Chae, J., Ishihara, T., and Yamanaka, H., A
facile regiocontrol in the palladium-catalyzed annulation
of fluorine-containing internal alkynes with variously
substituted 2-iodoanilines: a new regioselective syn-
thesis of 2- or 3-fluoroalkylated indole derivatives.
J. Org. Chem., 69, 8258–8265 (2004).
12) Shen, M., Li, G., Lu, B. Z., Hossain, A., Roschangar, F.,
Farina, V., and Senanayake, C. H., The first regioselec-
tive palladium-catalyzed indolization of 2-bromo- or
2-chloroanilines with internal alkynes: a new approach
to 2,3-disubstituted indoles. Org. Lett., 6, 4129–4132
(2004).
27
55%) as a yellow oil. ½ꢀꢀD 111.3ꢂ (c 0.15, CHCl3). IR
(KBr) ꢃmax 2963, 1748, 1371, 1228, 1047 cmꢁ1
.
1H NMR (CDCl3, 400 MHz) ꢂ 1.17 (3H, t, J ¼ 7:5 Hz,
CHAHBCH3), 1.90 (3H, s, CH3 of Ac), 2.05 (3H, s, CH3
of Ac), 2.12 (3H, s, CH3 of Ac), 2.21 (3H, s, CH3 of Ac),
2.32 (3H, s, CH3 of Ts), 2.71 (1H, dq, J ¼ 13, 7.5 Hz,
CHAHBCH3), 3.15 (1H, dq, J ¼ 13, 7.5 Hz,
CHAHBCH3), 4.29–4.36 (2H, m, H-5 & H-6), 4.50
(1H, m, H-60), 5.03 (1H, td, J ¼ 4, 0.5 Hz, H-4), 5.22
(1H, ddd, J ¼ 4, 3, 0.5 Hz, H-3), 5.41 (1H, ddd, J ¼ 3,
2, 0.5 Hz, H-2), 6.15 (1H, d, J ¼ 2 Hz, H-1), 7.17 (2H, d,
J ¼ 8 Hz, aromatic of Ts), 7.21 (1H, td, J ¼ 7:5, 1 Hz,
H-50 or 60), 7.26 (1H, td, J ¼ 7:5, 1.5 Hz, H-50 or 60),
7.43 (1H, br d, J ¼ 7:5 Hz, H-40 or 70), 7.57 (2H, d,
J ¼ 8 Hz, aromatic of Ts), 8.04 (1H, br d, J ¼ 7:5 Hz,
H-40 or 70). 13C NMR (CDCl3, 100 MHz) ꢂ 15.1, 18.4,
20.6, 20.7, 20.9, 21.5, 61.4, 66.6, 67.4, 68.7, 69.4, 73.4,
115.5, 118.9, 123.5, 125.0, 126.4, 128.5, 129.7(2),
130.8, 135.5, 136.8, 144.7, 168.7, 169.0, 169.6, 170.5.
HRMS (FAB) (Mþ): Calcd for C31H35NO11S: 629.1931.
Found: 629.1930.
13) Roschangar, F., Liu, J., Estanove, E., Dufour, M.,
Rodriguez, S., Farina, V., Hickey, E., Hossain, A.,
Acknowledgment
Jones, P.-J., Lee, H., Lu, B. Z., Varsolona, R., Schroder,
¨
This work was supported financially by PRESTO, the
Japan Science and Technology Agency (JST), and the
Global-COE program from MEXT. Elemental analyses
were performed by Mr. M. Kitamura (the analytical
laboratory of this school), whom we thank.
J., Beaulieu, P., Gillard, J., and Senanayake, C. H.,
Preparation of 3-substituted-2-pyridin-2-ylindoles: re-
gioselectivity of Larock’s indole annulation with 2-
alkynylpyridines. Tetrahedron Lett., 49, 363–366 (2008).
14) Kendrick, D. A., Danzin, C., and Kolb, M., 2,2-Difluoro-
5-hexyne-1,4-diamine. A potent enzyme-activated in-
hibitor of ornithine decarboxylase. J. Med. Chem., 32,
170–173 (1989).
References
1) Larock, R. C., and Yum, E. K., Synthesis of indoles
via palladium-catalyzed heteroannulation of internal
alkynes. J. Am. Chem. Soc., 113, 6689–6690 (1991).
2) Larock, R. C., Yum, E. K., and Refvik, M. D., Synthesis
of 2,3-disubstituted indoles via palladium-catalyzed
annulation of internal alkynes. J. Org. Chem., 63,
7652–7662 (1998).
15) Wu, Z., Minhas, G. S., Wen, D., Jiang, H., Chen, K.,
Zimniak, P., and Zheng, J., Design, synthesis, and
structure-activity relationships of haloenol lactones: site-
directed and isozyme-selective glutathione S-transferase
inhibitors. J. Med. Chem., 47, 3282–3294 (2004).
16) Aguilera, B., Wolf, L. B., Nieczypor, P., Rutjes, F. P. J.
T., Overkleeft, H. S., van Hest, J. C. M., Schoemaker,
´
3) Kurti, L., and Czako, B., ‘‘Strategic Applications of
¨
H. E., Wang, B., Mol, J. C., Furstner, A., Overhand, M.,
¨
Named Reactions in Organic Synthesis,’’ ELSEVIER,
Burlington, p. 260 (2005).
4) Ma, C., Liu, X., Li, X., Flippen-Anderson, J., Yu, S.,
and Cook, J. M., Efficient asymmetric synthesis of
van der Marel, G. A., and van Boom, J. H., Synthesis of
diaminosuberic acid derivatives via ring-closing alkyne
metathesis. J. Org. Chem., 66, 3584–3589 (2001).
17) Nishikawa, T., Koide, Y., Kajii, S., Wada, K., Ishikawa,
M., and Isobe, M., Stereocontrolled syntheses of ꢀ-C-
mannosyltryptophan and its analogues. Org. Biomol.
Chem., 3, 687–700 (2005).
biologically important tryptophan analogues via
a
palladium-mediated heteroannulation reaction. J. Org.
Chem., 66, 4525–4542 (2001).
5) Zhou, H., Liao, X., and Cook, J. M., Regiospecific,
enantiospecific total synthesis of the 12-alkoxy-substi-
tuted indole alkaloids, (+)-12-methoxy-Na-methylvello-
simine, (+)-12-methoxyaffinisine, and (ꢁ)-fuchsiaefo-
line. Org. Lett., 6, 249–252 (2004).
18) Nishikawa, T., Koide, Y., Kanakubo, A., Yoshimura, H.,
and Isobe, M., Synthesis of ꢁ-analogues of C-mannosyl-
tryptophan, a novel C-glycosylamino acid found in
proteins. Org. Biomol. Chem., 4, 1268–1277 (2006).
19) Lowary, T., Meldal, M., Helmboldt, A., Vasella, A., and
Bock, K., Novel type of rigid C-linked glycosylacety-
6) Hatakeyama, K., Ohmori, K., and Suzuki, K., Synthesis

2102
K. SUGINO et al.
ˆ
biscobalthexacarbonyl complex (1). Yukigouseikagaku
Kyoukaishi (in Japanese), 58, 23–30 (2000).
lene-phenylalanine building blocks for combinatorial
synthesis of C-linked glycopeptides. J. Org. Chem., 63,
9657–9668 (1998).
22) Isobe, M., and Kira, K., New synthesis with acetylene
ˆ
20) Isobe, M., Nishizawa, R., Hosokawa, S., and Nishikawa,
T., Stereocontrolled synthesis and reactivity of sugar
acetylenes. Chem. Commun., 2665–2676 (1998).
biscobalthexacarbonyl complex (2). Yukigouseikagaku
Kyoukaishi (in Japanese), 58, 99–107 (2000).
23) Fieser, L. F., and Goto, T., Oxido alcohols and
ketoxides. J. Am. Chem. Soc., 82, 1693–1697 (1960).
21) Isobe, M., and Kira, K., New synthesis with acetylene