A general synthesis of N-reverse-prenyl indoles

Article abstract of DOI:10.1055/s-2004-822390

A general method for the construction of N-reverse-prenyl indoles was established using copper catalyzed N-propargylation, the Lindlar hydrogenation of the acetylenic bond, and dehydrogenation with chemical manganese dioxide as key steps. The antifungal i

Full text of DOI:10.1055/s-2004-822390

1476
PAPER
A General Synthesis of N-Reverse-Prenyl Indoles
A
G
eneral Syn
u
thesis of
N
-
R
m
everse-Prenyl Indo
i
les aki Yokokawa,a Hideyuki Sugiyama,a Toyohiko Aoyama,a Takayuki Shioiri*b
a
Graduate School of Pharmaceutical Sciences, Nagoya City University, Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan
b
Graduate School of Environmental and Human Sciences, Meijo University, Shiogamaguchi, Tempaku, Nagoya 468-8502, Japan
Fax +81(52)8321555; E-mail: shioiri@ccmfs.meijo-u.ac.jp
Received 14 April 2004
Dedicated to Prof. Teruaki Mukaiyama on the occasion of his 77th birthday
Our first targets were simple antifungal N-reverse-prenyl
Abstract: A general method for the construction of N-reverse-pre-
nyl indoles was established using copper catalyzed N-propargyl-
ation, the Lindlar hydrogenation of the acetylenic bond, and
dehydrogenation with chemical manganese dioxide as key steps.
indole alkaloids 1 and 2, isolated from the basidomycete
Aporpium caryae.2 Initially, indole (4) was attempted to
undergo the propargylation with propargyl acetate (5) by
The antifungal indole alkaloids (1 and 2) and N-reverse-prenyl tryp- using copper (I) salts,10 as shown in Scheme 1. The reac-
tophan (3) were efficiently synthesized by this method.
tion did not proceed at all because of the low nucleophi-
licity of indole-nitrogen. However, indoline (7) whose
nitrogen is more nucleophilic easily reacted with propar-
gyl acetate (5) under analogous conditions to give the pro-
pargylated indoline 8 though 0.5 equivalents of CuI were
needed.11 After partial reduction over Lindlar’s catalyst,
the resulting indoline 9 was dehydrogenated by use of
CMD9 to yield the N-reverse-prenyl indole derivative 10.
Bromination of 10 with N-bromosuccinimide (NBS) af-
forded the 3-bromo derivative 11, which was transformed
to the desired indole 1 by lithiation with tert-BuLi fol-
lowed by methoxycarbonylation. In general, the 3-lithiat-
ed indoles are easily rearranged to the corresponding 2-
lithiated derivatives. However, no 2-methyl ester deriva-
tive was detected in the above case, which might be due to
the steric hindrance of the bulky reverse-prenyl func-
tion.12
Key words: N-reverse-prenyl indole, N-propargylation, Lindlar
hydrogenation, dehydrogenation
The N-reverse-prenyl (N-1,1-dimethyl-2-propenyl) indole
skeleton is a constituent of some biologically interesting
natural products that are not commonly found in na-
ture.1–4 In connection with the synthetic studies for cyclo-
marin A,4 isolated from a marine bacterium, we needed to
explore a general entry to the efficient synthesis of the N-
reverse-prenyl indole derivatives. There were no reports
of synthetic efforts directed toward the N-reverse-prenyl
indole skeleton when we initiated our program. After our
work was completed,5 related works6 whose strategies are
quite analogous to ours were reported.7 We now describe
the details of a general method for the construction of this
unique skeleton utilizing copper catalyzed N-propargyl-
ation of indoline, the Lindlar hydrogenation of the acety-
lenic bond,8 and dehydrogenation with chemical
manganese dioxide (CMD).9 The targets are shown in
Figure 1.
Transformation of 1 to the corresponding diol derivative
2 was accomplished by use of Sharpless asymmetric dihy-
droxylation (AD).13 It is known that Sharpless AD of the
terminal olefin proceeds sluggishly with lower enantiose-
lectivity because of no sulfonamide effect. Since Sharp-
less AD of 1 with commercially available AD-mix
proceeded slowly, the quantity of both osmium and the
ligand was increased to 0.1 equivalents to accelerate the
reaction. However, the ligand in AD-mix showed low se-
lectivity as shown in entry 1 (Table 1). So far, pyrimidine
based chiral ligands (DHQD)2PYR and (DHQ)2PYR gave
the best result to give (R)-2 with 89% ee (entry 3) and (S)-
2 with 69% ee (entry 5), respectively. Common lower se-
lectivity in AD was observed by changing the ligand from
DHQD to DHQ (see entries 3 and 5; 4 and 7). Thus we
could achieve the synthesis of the antifungal indole alka-
loids 1 and (S)-2 in an overall yield of about 60% from in-
doline (7).
CO2Me
CO2Me
N
N
OH
OH
2
1
CO2Me
NHCbz
N
3
Figure 1
Our next target was the tryptophan derivative 3, which is
the constituent of rufomycins. After methyl esterification
of carbobenzoxy-L-tryptophan (12), reduction of the in-
dole nucleus with (CF3CO2)2BH·THF14 afforded the indo-
line 13. Propargylation followed by dehydrogenation of
14 with CMD afforded the indole 15 in good yield, which
smoothly underwent the Lindlar reduction to give the
SYNTHESIS 2004, No. 9, pp 1476–1480
Advanced online publication: 26.05.2004
DOI: 10.1055/s-2004-822390; Art ID: C02804SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
0
4

PAPER
A General Synthesis of N-Reverse-Prenyl Indoles
1477
Table 1 Sharpless Asymmetric Dihydroxylation
OAc
K2[OsO2(OH)4]
5
H
(10 mol%)
Ligand
CO2Me
CO2Me
N
CuX, base
N
H
(10 mol%)
several conditions
4
N
N
6
H
K3Fe(CN)6
K2CO3
OH
t-BuOH/H2O
4 °C, 24 h
> 90% yield
OH
(S)-2
1
OAc
5
H
N
CuI, i-Pr2NEt
THF, 50 °C, 90%
Entry Liganda
ee (%)b
Absolute
configuration
[a]D
N
H
8
7
H
1
2
3
4
5
6
7
8
(DHQD)2PHAL
30
2
R
R
R
R
S
S
S
S
H2
CMD
Lindlar's catalyst
(DHQD)2AQN
(DHQD)2PYR
DHQD-PHN
(DHQ)2PYR
DHQ-MEQ
DHQ-PHN
N
toluene
r.t., 86%
MeOH, r.t.
91%
89
79
69
66
66
12
+6.2
+5.6
–5.3
9
Br
NBS
N
N
DMF, 0 °C
95%
10
11
–3.9
CO2Me
t-BuLi
DHQ-CLB
THF, –78 °C;
a See Figure 2 for abbreviation of ligands.
b Determined by chiral HPLC.
N
ClCO2Me
–78 to 0 °C
89%
1
Scheme 1
Incidentally, direct attachment of the side chain to 10 with
the aziridine derivative 16 by use of scandium triflate15
was attempted but failed to give 3 (Scheme 2).
tryptophan derivative 3. In this case, the reduction of the
propargyl derivative 14, followed by dehydrogenation
with CMD afforded 3 in lower yield. Corey and co-work-
ers synthesized the Boc derivative of 3 utilizing our meth-
od for the total synthesis of okaramine N.6a
Thus, we were able to establish a general entry into the
construction of the N-reverse-prenyl indole skeleton. The
method will be useful for the synthesis of other com-
Et
N
Et
N
RO
H
OR
H
MeO
OMe
N
N
DHQ R = H
DHQD R = H
(Dihydroquinine)
(Dihydroquinidine)
N
N
O
ODHQ
Ph
Ph
Ph
DHQDO
ODHQD
DHQO
ODHQ
DHQDO
ODHQD
N
N
N
N
(DHQD)2PHAL
Cl
DHQ-CLB
Ph
(DHQD)2PYR
(DHQ)2PYR
ODHQ
DHQDO
ODHQD
ODHQD
ODHQ
N
O
O
DHQ-MEQ
DHQ-PHN
DHQD-PHN
(DHQD)2AQN
Figure 2 Ligands in Table 1
Synthesis 2004, No. 9, 1476–1480 © Thieme Stuttgart · New York

1478
F. Yokokawa et al.
PAPER
1-(1,1-Dimethyl-2-propynyl)-2,3-dihydro-1H-indole (8); Typi-
cal Procedure
1) MeI, KHCO3
DMF
CO2H
To a stirred solution of 510 (2.80 g, 20 mmol) in THF (40 mL) were
added indoline (7) (2.24 mL, 20 mmol), CuI (380 mg, 2.0 mmol),
and i-Pr2NEt (7.0 mL, 40 mmol) at r.t., and the mixture was stirred
at 50 °C for 13 h. To the reaction mixture was added CuI (380 mg,
2.0 mmol) since TLC indicated that the reaction had not gone to
completion. After 5 h, additional CuI (380 mg, 2.0 mmol) was add-
ed, and the mixture was stirred at 50 °C for 3 h. Upon cooling, the
mixture was filtered through a pad of Celite® (washed with Et2O).
The filtrate was washed with 1 M aq KHSO4 (2 ×) and sat. brine,
dried over MgSO4, filtered and concentrated in vacuo. The residue
was purified by column chromatography (silica gel BW-820MH,
150 g, hexane–Et2O, 200:1→50:1→30:1) to give 8 (3.34 g, 90%) as
a pale yellow oil.
NHCbz
2) BH3·Me2S, TFA
THF, 0 °C
96% in 2 steps
N
H
12
CO2Me
OAc
5
H
NHCbz
N
H
CuCl, i-Pr2NEt
THF, 50 °C, 75%
13
CO2Me
MnO2 (CMD)
NHCbz
N
toluene
r.t., 86%
14
H
IR (neat): 3291, 1605, 1485, 1256, 1225, 747 cm–1.
CO2Me
1H NMR (CDCl3): d = 1.59 [s, 6 H, (CH3)2], 2.37 (s, 1 H, C≡CH),
2.90 (t, J = 8.1 Hz, 2 H, indoline-3-CH2), 3.37 (t, J = 8.1 Hz, 2 H,
indoline-2-CH2), 6.70 (t, J = 7.3 Hz, 1 H, Ar), 7.02–7.20 (m, 3 H,
Ar).
H2, Lindlar's cat.
EtOAc, r.t., 96%
NHCbz
N
15
H
HRMS (EI): m/z calcd for C13H15N: 185.1204; found: 185.1195.
CO2Me
1-(1,1-Dimethylallyl)-2,3-dihydro-1H-indole (9); Typical Proce-
dure
NHCbz
N
To a solution of 8 (2.68 g, 14.44 mmol) in MeOH (40 mL) was add-
ed Lindlar’s catalyst (260 mg) under Ar, and hydrogen gas was in-
troduced (balloon with needle through three-way stop-cock). The
black slurry was stirred under 1 atm of H2 at r.t. for 10 h. The mix-
ture was filtered through a pad of Celite® and the filtrate was con-
centrated in vacuo. The residue was purified by column
chromatography (silica gel BW-820MH, 120 g, hexane–Et2O,
100:1–50:1) to give 9 (2.46 g, 91%) as a pale yellow oil.
3
CO2Me
Sc(OTf)3
3
+
N
N
Cbz
16
10
IR (neat): 1607, 1483, 1381, 1256, 1196, 914, 745 cm–1.
Scheme 2
1H NMR (CDCl3): d = 1.32 [s, 6 H, (CH3)2], 2.88 (t, J = 8.1 Hz, 2
H, indoline-3-CH2), 3.41 (t, J = 8.2 Hz, 2 H, indoline-2-CH2), 5.10
(d, J = 10.9 Hz, 1 H, CH=CH2), 5.20 (d, J = 17.5 Hz, 1 H, CH=CH2),
6.10 (dd, J = 17.7, 10.9 Hz, 1 H, CH=CH2), 6.60 (t, J = 7.3 Hz, 1 H,
Ar), 6.76 (d, J = 8.1 Hz, 1 H, Ar), 6.93 (d, J = 7.8 Hz, 1 H, Ar), 7.03
(d, J = 7.0 Hz, 1 H, Ar).
13C NMR (CDCl3): d = 23.88 (2 × CH3), 27.92 (CH2), 48.86 (CH2),
57.07 (C), 111.00 (CH), 111.90 (CH2), 117.07 (CH), 124.01 (CH),
126.31 (CH), 131.14 (C), 146.83 (CH), 150.49 (C).
pounds having the N-reverse-prenyl indole and indoline
moieties.16
Melting points were determined on a YANAGIMOTO micro melt-
ing point apparatus (hot plate) and are uncorrected. IR spectra were
measured on salt plate with a SHIMADZU FTIR-8100 spectrome-
ter. Optical rotations were measured on a JASCO DIP-1000 digital
polarimeter with sodium lamp (l = 589 nm, D line) and are ex-
Anal. Calcd for C13H17N: C, 83.37; H, 9.15; N, 7.48. Found: C,
83.07; H, 9.13; N, 7.50.
1
pressed as follows: [a]DT (C g/100 mL, solvent). H and 13C NMR
spectra were recorded on a JEOL EX-270 spectrometer at 270 MHz
and 67.8 MHz, respectively, and were obtained at the indicated field
in CDCl3 unless otherwise indicated. Chemical shifts (d) are report-
ed in ppm from TMS or CHCl3 as internal standard. Mass spectra
were obtained on a JEOL JMS-SX 102A (EI) and JMS-AX 505HA
(FAB) spectrometer. Analytical TLC was performed on a Merck
Art. 5715 with Kieselgel 60 F254/0.25 mm thickness plates. Visual-
ization was accomplished with UV light, phosphomolybdic acid, or
ninhydrin solution followed by heating. Column chromatography
was peformed with silica gel BW-820 MH (Fuji Silysia). HPLC was
carried out with a JASCO UV-970 detector and PU-980 pump. Sol-
vents for extraction and chromatography were reagent grade and
distilled from the indicated drying agents. THF was dried by distil-
lation from sodium/benzophenone ketyl. CH2Cl2 and toluene were
dried by distillation from CaH2. MeOH was distilled from CaH2 and
stored over 4Å molecular sieves. All other commercially available
reagents were used as received.
1-(1,1-Dimethylallyl)-1H-indole (10); Typical Procedure
To a stirred solution of 9 (1.21 g, 6.47 mmol) was added MnO2
(CMD,9 5.63 g, 64.8 mmol) at r.t., and the mixture was stirred for 1
h. The mixture was filtered through a pad of Celite® and the filtrate
was concentrated in vacuo. The residue was purified by column
chromatography (silica gel BW-820MH, 60 g, hexane–Et2O,
200:1→100:1→50:1) to give 10 (1.04 g, 86%) as a pale yellow oil.
IR (neat): 1456, 1316, 1293, 1222, 1210, 922, 734 cm–1.
1H NMR (CDCl3): d = 1.75 [s, 6 H, (CH3)2], 5.26–5.37 (m, 2 H,
CH=CH2), 6.14 (dd, J = 17.3, 10.7 Hz, 1 H, CH=CH2), 6.48 (d, J =
3.0 Hz, 1 H, indole-3-H), 7.10–7.14 (m, 2 H, Ar), 7.29 (d, J = 3.1
Hz, 1 H, indole-2-H), 7.52 (d, J = 7.6 Hz, 1 H, Ar), 7.61 (d, J = 6.9
Hz, 1 H, Ar).
13C NMR (CDCl3): d = 27.74 (2 × CH3), 58.83 (C), 100.54 (CH),
113.29 (CH2), 113.65 (CH), 119.00 (CH), 120.52 (CH), 120.83
(CH), 124.85 (CH), 129.98 (C), 135.17 (C), 144.03 (CH).
HRMS (EI): m/z calcd for C13H15N: 185.1204; found: 185.1211.
Synthesis 2004, No. 9, 1476–1480 © Thieme Stuttgart · New York

PAPER
A General Synthesis of N-Reverse-Prenyl Indoles
1479
3-Bromo-1-(1,1-dimethylallyl)-1H-indole (11); Typical Proce-
dure
1H NMR (CDCl3): d = 1.71 [s, 6 H, (CH3)2], 2.47 (s, 1 H, disap-
peared with D2O, OH), 3.09 (s, 1 H, disappeared with D2O, OH),
3.34–3.41 (m, 2 H, CH2OH), 3.80 (s, 3 H, CO2CH3), 4.40 (br s, 1 H,
CHOH), 7.13–7.25 (m, 2 H, Ar), 7.60 (d, J = 8.2 Hz, 1 H), 7.95 (s,
1 H, indole-2-H), 8.16 (d, J = 7.6 Hz, 1 H, Ar).
13C NMR (CDCl3): d = 24.00 (CH3), 24.19 (CH3), 50.98 (CH3),
62.26 (C), 62.34 (CH2), 74.90 (CH), 106.22 (C), 113.85 (CH),
121.77 (CH), 121.97 (CH), 122.24 (CH), 128.10 (C), 133.41 (CH),
135.45 (C), 165.74 (C=O).
To a stirred solution of 10 (444 mg, 2.40 mmol) in DMF (8.0 mL)
was added NBS (427 mg, 2.40 mmol) at 0 °C, and the mixture was
stirred for 30 min. The reaction was quenched with H2O, and the
mixture was extracted with Et2O. The extract was washed with 1 M
aq KHSO4 (2 ×) and sat. brine, dried over MgSO4, filtered, and con-
centrated in vacuo. The residue was purified by column chromatog-
raphy (silica gel BW-820MH, 25 g, hexane–Et2O,
200:1→150:1→120:1) to give 11 (600 mg, 95%) as a colorless oil.
HRMS (EI): m/z calcd for C15H19NO4: 277.1314; found: 277.1275.
IR (neat): 1451, 1414, 1368, 1312, 1231, 1183, 924, 741 cm–1.
HPLC analysis of 2 was carried out as follows. Column: Daicel
CHIRALPAK AD; Solvent: hexane–i-PrOH, 9:1; Flow Rate: 1.0
mL/min; Detector: 254 nm; Retention Time: 16.3 min [(S)-isomer]
and 18.2 min [(R)-isomer). The enantiomeric purity of 2 was deter-
mined to be 69% ee.
1H NMR (CDCl3): d = 1.68 [s, 6 H, (CH3)2], 5.12 (d, J = 17.5 Hz, 1
H, CH=CH2), 5.18 (d, J = 10.7 Hz, 1 H, CH=CH2), 6.06 (dd, J =
17.5, 10.7 Hz, 1 H, CH=CH2), 7.11–7.15 (m, 2 H, Ar), 7.27 (s, 1 H,
indole-2-H), 7.46–7.49 (m, 1 H, Ar), 7.53–7.56 (m, 1 H, Ar).
13C NMR (CDCl3): d = 27.80 (2 × CH3), 59.62 (C), 89.32 (C),
113.85 (CH + CH2), 119.27 (CH), 119.88 (CH), 121.73 (CH),
124.21 (CH), 128.55 (C), 134.78 (C), 143.49 (CH).
Methyl (2S,4RS)-2-Benzyloxycarbonylamino-3-(2,3-dihydro-
1H-indol-3-yl)propionate (13); Typical Procedure
To a stirred solution of Cbz-L-Trp-OH (12, 3.38 g, 10 mmol) in
DMF (20 mL) were added MeI (935 mL, 15.0 mmol) and KHCO3
(2.0 g, 20 mmol) at 0 °C. The mixture was stirred at r.t. for 6 h. After
dilution with Et2O, the mixture was washed with H2O (2 ×), 1 M aq
KHSO4 and sat. brine, dried over MgSO4, filtered, and concentrated
in vacuo to give the crude Cbz-L-Trp-OMe (3.73 g, quantitative) as
a white wax.
HRMS (EI): m/z calcd for C13H14BrN: 263.0310; found: 263.0311.
Methyl 1-(1,1-Dimethylallyl)-1H-indole-3-carboxylate (1); Typ-
ical Procedure
To a stirred solution of 11 (507 mg, 1.92 mmol) in THF (12.8 mL)
was added dropwise t-BuLi (1.62 M in pentane, 2.49 mL, 4.03
mmol) at –78 °C under N2, and the mixture was stirred for 30 min.
To this solution was added ClCO2Me (223 mL, 2.88 mmol) at –78
°C, and the mixture was stirred at –78 °C for 30 min and at 0 °C for
1 h. The reaction was quenched with sat. aq NH4Cl, and the mixture
was extracted with Et2O. The extract was washed with sat. brine,
dried over MgSO4, filtered, and concentrated in vacuo. The residue
was purified by column chromatography (silica gel BW-820MH, 20
g, hexane–Et2O, 12:1) to give 1 (415 mg, 89%) as a colorless oil.
To a stirred solution of Cbz-L-Trp-OMe (421 mg, 1.20 mmol) in
THF–TFA (2.0 mL/2.0 mL) was added dropwise BH3·Me2S (ca. 10
M in Me2S, 360 mL, 3.60 mmol) at 0 °C under Ar. The mixture was
stirred for 10 min, and H2O (4.0 mL) was added. The mixture was
stirred at r.t. for 10 min, and the solvent was removed in vacuo. Ex-
cess TFA in the residue was removed azeotropically with toluene (3
×), and the resulting residue was diluted with EtOAc. The organic
layer was washed with 1 N aq NaOH (3 ×), H2O and sat. brine, dried
over Na2SO4, filtered, and concentrated in vacuo. The residue was
purified by column chromatography (silica gel BW-820MH, 20 g,
hexane–EtOAc, 2:1→1:1) to give 13 (420 mg, 96% from Cbz-L-
Trp-OH) as a white wax; [a]D24 +27.62 (c = 1.0, CHCl3).
IR (neat): 1703, 1538, 1456, 1381, 1215, 1181, 1117, 1069, 750
cm–1.
1H NMR (CDCl3): d = 1.78 [s, 6 H, (CH3)2], 3.91 (s, 3 H, CO2CH3),
5.17 [d, J = 17.5 Hz, 1 H, CH=CH2), 5.26 (d, J = 10.7 Hz, 1 H,
CH=CH2), 6.12 (dd, J = 17.5, 10.7 Hz, 1 H, CH=CH2), 7.15–7.26
(m, 2 H, Ar), 7.53 (d, J =7 .7 Hz, 1 H), 8.03 (s, 1 H, indole-2-H),
8.19 (d, J = 7.3 Hz, 1 H, Ar).
13C NMR (CDCl3): d = 27.75 (2 × CH3), 50.62 (CH3), 59.94 (C),
106.16 (C), 114.28 (CH + CH2), 121.44 (CH), 121.52 (CH), 121.79
(CH), 127.83 (C), 131.90 (CH), 135.72 (C), 142.79 (CH), 165.48
(C).
IR (neat): 3375, 1717, 1215, 1047, 733 cm–1.
1H NMR (CDCl3, 1.8:1 mixture of diastereomers): d = 1.86–2.33
(m, 2 H, C3-CH2), 3.21–3.72 (m, 4 H, indoline, CH2, CH, NH),
3.70, 3.72 (s, 3 H, CO2CH3), 4.44–4.49 (m, 1 H, CHNH), 5.11 (s, 2
H, CH2Ph), 5.38, 5.46 (2 × br d, 0.64 H + 0.36 H, NHZ), 6.61–6.75
(m, 2 H, Ar), 7.00–7.15 (m, 2 H, Ar), 7.34–7.36 (m, 5 H, Ar).
13C NMR (CDCl3, 1.8:1 mixture of diastereomers, minor diastereo-
mer in parentheses): d = 37.30 (37.21), 38.54 (38.66), 52.40 (52.30),
52.81 (52.58), 53.48, 67.04, 109.57 (109.67), 118.61 (118.77),
123.57 (124.12), 127.78 (127.83), 128.02, 128.14, 128.46, 131.48
(131.27), 136.05, 151.11 (150.96), 156.01, 172.87.
HRMS (EI): m/z calcd for C15H17NO2: 243.1259; found: 243.1245.
Anal. Calcd for C15H17NO2: C, 74.05; H, 7.04; N, 5.76. Found: C,
74.05; H, 7.12; N, 6.00.
Methyl 1-[(2S)-2,3-Dihydroxy-1,1-dimethylpropyl]-1H-indole-
3-carboxylate [(S)-2, Entry 5 in Table 1]; Typical Procedure
To a well-stirred solution of (DHQ)2PYR (12.8 mg, 0.0145 mmol),
K2CO3 (60.1 mg, 0.435 mmol), K3Fe(CN)6 (143 mg, 0.435 mmol)
and 1 (35.3 mg, 0.145 mmol) in t-BuOH–H2O (0.75/0.75 mL) was
added K2[OsO2(OH)4] (5.3 mg, 0.0145 mmol) at 0 °C. The mixture
was stirred at 4 °C for 24 h, and then Na2SO3 (250 mg) was added.
The suspension was warmed up to r.t. EtOAc and sat. brine were
added, and the aqueous layer was further extracted with EtOAc (2
×). The combined extracts were dried over Na2SO4, filtered and
concentrated in vacuo. The residue was purified by column chroma-
tography (silica gel BW-820MH, 10 g, hexane–EtOAc, 1:1–1:3) to
HRMS (EI): m/z calcd for C20H22N2O4: 354.1580; found: 354.1579.
Anal. Calcd for C20H22N2O4: C, 67.78; H, 6.26; N, 7.90. Found: C,
67.73; H, 6.54; N, 7.63.
Methyl (2S)-2-Benzyloxycarbonylamino-3-[1-(1,1-dimethyl-
prop-2-ynyl)-1H-indol-3-yl]propionate (15); Typical Procedure
A round-bottom flask was charged with 13 (136 mg, 0.384 mmol)
and a solution of 510 (59.0 mg, 0.422 mmol) in THF (3.8 mL) under
N2. To this stirred solution were added CuCl (11.0 mg, 0.11 mmol),
and i-Pr2NEt (134 mL, 0.768 mmol) at r.t., and the mixture was
stirred at 50 °C for 2 h. To the reaction mixture was added CuCl
(11.0 mg, 0.11 mmol) since TLC indicated that the reaction had not
gone to completion. After 3 h additional CuCl (11.0 mg, 0.11 mmol)
was added, and the mixture was stirred at 50 °C for 2 h. After cool-
ing, the mixture was concentrated in vacuo. The residue was puri-
fied by column chromatography (silica gel BW-820MH, 15 g,
23
give (S)-2 (40.5 mg, quantitative) as a colorless oil; [a]D –5.27
(c = 1.0, CHCl3).
IR (neat): 3418, 1694, 1539, 1456, 1385, 1210, 1163, 1120, 1092,
1067, 909, 735 cm–1.
Synthesis 2004, No. 9, 1476–1480 © Thieme Stuttgart · New York

1480
F. Yokokawa et al.
PAPER
(2) Levy, L. M.; Cabrera, G. M.; Wright, J. E.; Seldes, A. M.
hexane–EtOAc, 5:1–4:1–3:1) to give 14 (121 mg, 75%) as a green
oil. Because 14 was labile, this material was immediately used for
the next step without further purification.
Phytochemistry 2000, 54, 941.
(3) (a) Takita, T.; Ohi, K.; Okami, K.; Maeda, K.; Umezawa, H.
J. Antibiot. Ser. A 1962, 15, 46. (b) Takita, T.; Naganawa,
H.; Maeda, K.; Umezawa, H. J. Antibiot. Ser. A 1964, 17,
264. (c) Fujino, M.; Kamiya, T.; Iwasawa, H.; Ueyanagi, J.;
Miyake, A. Chem. Pharm. Bull. 1964, 12, 1390.
(4) (a) Fenical, W. H.; Jacobs, R. S.; Jensen, P. R. US Patent
5444043, 1995; Chem. Abstr. 1995, 123, 246824v.
(b) Pazoles, C. J.; Siegel, S. A. WO Patent 9809640, 1998;
Chem. Abstr. 1998, 128, 226226b. (c) Renner, M. K.; Shen,
Y.-C.; Cheng, X.-C.; Jensen, P. R.; Frankmoelle, W.;
Kauffman, C. A.; Fenical, W.; Lobkovsky, E.; Clardy, J. J.
Am. Chem. Soc. 1999, 121, 11273.
(5) For preliminary accounts of this work, see: Sugiyama, H.;
Yokokawa, F.; Aoyama, T.; Shioiri, T. Tetrahedron Lett.
2001, 42, 7277.
(6) (a) Baran, P. S.; Guerrero, C. A.; Corey, E. J. J. Am. Chem.
Soc. 2003, 125, 5628. (b) Roe, J. M.; Webster, R. A. B.;
Genesan, A. Org. Lett. 2003, 5, 2825.
To a stirred solution of 14 (35 mg, 0.083 mmol) was added MnO2
(CMD,9 36.2 mg, 0.416 mmol) at r.t., and the mixture was stirred for
12 h. The mixture was filtered through a pad of Celite® and the fil-
trate was concentrated in vacuo. The residue was purified by col-
umn chromatography (silica gel BW-820MH, 9 g, hexane–EtOAc,
6:1→5:1→4:1) to give 15 (30 mg, 86%) as a colorless oil; [a]D
+39.89 (c = 0.9, CHCl3).
IR (neat): 3302, 1723, 1513, 1456, 1215, 739 cm–1.
1H NMR (CDCl3): d = 1.90 [s, 6 H, (CH3)2], 2.55 (s, 1 H, C≡CH),
3.27 (d, J = 5.2 Hz, 2 H, C-3-CH2), 3.67 (s, 3 H, CO2CH3), 4.68–
4.74 (m, 1 H, C-2-CH), 5.07 (d, J = 12.3 Hz, 1 H, CH2Ph), 5.14 (d,
J = 12.2 Hz, 1 H, CH2Ph), 5.31 (br d, J = 7.8 Hz, 1 H, NHCbz),
7.05–7.33 (m, 8 H, Ar), 7.50 (d, J = 7.9 Hz, 1 H, Ar), 7.82 (d, J =
8.2 Hz, 1 H, Ar).
13C NMR (CDCl3): d = 27.94 (CH2), 29.85 (2 × CH3), 51.99 (C),
52.21 (CH3), 54.59 (CH), 66.83 (CH2), 72.38 (CH), 108.32 (C),
113.07 (CH), 118.83 (CH), 119.43 (CH), 121.38 (CH), 123.07
(CH), 128.05 (CH), 128.08 (CH), 128.46 (CH), 129.60 (C), 135.07
(C), 136.29 (C), 155.71 (C=O), 172.35 (C=O).
26
(7) See the alternative method: Wen, S.-J.; Zhang, H.-W.; Yao,
Z.-J. Tetrahedron Lett. 2002, 43, 5291.
(8) N-Reverse-prenyl valine was prepared by this reaction
sequence. See: (a) Wipf, P.; Venkatraman, S. J. Org. Chem.
1996, 61, 6517. (b) Muir, J. C.; Pattenden, G.; Thomas, R.
M. Synthesis 1998, 613.
HRMS (EI): m/z calcd for C25H26N2O4: 418.1893; found: 418.1895.
Methyl (2S)-2-Benzyloxycarbonylamino-3-[1-(1,1-dimethylal-
lyl)-1H-indol-3-yl]propionate (3); Typical Procedure
(9) CMD is produced for battery manufacture. It is quite active
and useful for various oxidations and dehydrogenations.
See: (a) Aoyama, T.; Sonoda, N.; Yamauchi, M.; Toriyama,
K.; Anzai, M.; Ando, A.; Shioiri, T. Synlett 1998, 35; and
references therein. (b) Yokokawa, F.; Sameshima, H.;
Shioiri, T. Synlett 2001, 986; and references therein. (c)
CMD is commercially available from Wako Pure Chemical
Industries, Ltd. [Fax: +81(6)62015964].
To a solution of 15 (32.8 mg, 0.0784 mmol) in EtOAc (40 mL) was
added Lindlar’s catalyst (9.3 mg) under Ar, and hydrogen gas was
introduced (balloon with needle through three-way stopcock). The
black slurry was stirred under 1 atm of H2 at r.t. for 2 h. The mixture
was filtered through a pad of Celite® and the filtrate was concentrat-
ed in vacuo. The residue was purified by column chromatography
(silica gel BW-820MH, 9 g, hexane–EtOAc, 6:1→5:1) to give 3
(31.5 mg, 96%) as a colorless oil; [a]D26 +39.02 (c = 0.8, CHCl3).
(10) Imada, Y.; Yuasa, M.; Nakamura, I.; Murahashi, S. J. Org.
Chem. 1994, 54, 2282.
(11) According to the ref.10 the propargylation reaction
proceeded with 0.1 equiv of CuCl. In our case, the reaction
proceeded with CuCl but with less efficiency.
IR (neat): 3345, 1725, 1510, 1456, 1211, 1059, 734 cm–1.
1H NMR (CDCl3): d = 1.69 [s, 6 H, (CH3)2], 3.28 (d, J = 5.0 Hz,
C-3-CH2, 2 H), 3.91 (s, 3 H, CO2CH3), 4.71 (br d, J = 7.3 Hz, 1 H),
5.03–5.20 (m, 4 H, CH2Ph + CH=CH2), 5.32 (br d, J = 7.7 Hz,
NHCbz, 1 H), 6.09 (dd, J = 17.3, 10.6 Hz, 1 H, CH=CH2), 7.01–7.11
(m, 3 H, Ar), 7.26–7.39 (m, 5 H, Ph), 7.44–7.51 (m, 2 H, Ar).
(12) See: (a) Amat, M.; Sathyanarayana, S.; Hadida, S.; Bosch, J.
Heterocycles 1996, 43, 1713; and references therein.
(b) Matsuzono, M.; Fukuda, T.; Iwao, M. Tetrahedron Lett.
2001, 42, 7621.
13C NMR (CDCl3): d = 27.94 (2 × CH3), 28.12 (CH2), 52.18 (CH3),
54.74 (CH), 58.94 (C), 66.81 (CH2), 107.66 (C), 113.37 (CH),
113.70 (CH), 118.54 (CH), 120.79 (CH), 123.69 (CH), 127.91
(CH), 127.95 (CH), 128.34 (CH), 129.35 (C), 135.37 (C), 136.21
(C), 143.83 (CH), 155.54 (C, C=O), 172.22 (C=O).
(13) (a) Kolbe, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B.
Chem. Rev. 1994, 94, 2483. (b) Crispino, G. A.; Jeong, K.-
S.; Kolbe, H. C.; Wang, Z.-M.; Xu, D.; Sharpless, K. B. J.
Org. Chem. 1993, 58, 3785. (c) Becker, H.; Sharpless, K. B.
Angew. Chem., Int. Ed. Engl. 1996, 35, 448. (d) For recent
reviews, see: Johnson, R. A.; Sharpless, K. B. In Catalytic
Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-VCH:
New York, 2000, Chap. 6D, 357–398. (e) See also: Bolm,
C.; Hildebrand, J. P.; Muniz, K. In Catalytic Asymmetric
Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-VCH: New York,
2000, Chap. 6E, 399–428.
HRMS (EI): m/z calcd for C25H28N2O4: 420.2049; found: 420.2036.
Acknowledgment
This work was financially supported in part by Grants-in-Aid from
the Uehara Memorial Foundation (to F. Y.), the Fujisawa Foundati-
on (to F. Y.), and the Ministry of Education, Science, Sports and
Culture, Japan. H. S. is grateful to the Japan Society for the Promo-
tion of Science (JPPS) for a postgraduate fellowship.
(14) (a) Gribble, G. W. In Comprehensive Organic Synthesis,
Vol. 8; Trost, B. M.; Fleming, I., Eds.; Pergamon Press: New
York, 1991, 604. (b) Maryanoff, B. E.; McComsey, D. F.;
Nortey, S. O. J. Org. Chem. 1981, 46, 355.
(15) Bennani, Y. L.; Zhu, G.-D.; Freeman, J. C. Synlett 1998,
754.
(16) Utilizing this methodology as a key step, we succeeded in
synthesizing a b-hydroxytryptophan derivative of a
component of cyclomarin A. See: Sugiyama, H.; Shioiri, T.;
Yokokawa, F. Tetrahedron Lett. 2002, 43, 3489.
References
(1) Yamamoto, Y.; Nishimura, K.; Kiriyama, N. Chem. Pharm.
Bull. 1976, 24, 1853.
Synthesis 2004, No. 9, 1476–1480 © Thieme Stuttgart · New York