Synthesis of enantiopure (S)-indolylglycine by organocatalyzed Friedel-Crafts alkylation of indole

Article abstract of DOI:10.1002/ejoc.200700886

Tritylsulfenyl- and 2-nitrophenylsulfenyl-substituted glyoxyl imines were used in chiral phosphoric acid catalyzed Friedel-Crafts (FC) reactions with indole. High yields and ee values ranging from 86 % for Nps-protected (S)-indolylglycine to 88 % for Trs-

Full text of DOI:10.1002/ejoc.200700886

FULL PAPER
DOI: 10.1002/ejoc.200700886
Synthesis of Enantiopure (S)-Indolylglycine by Organocatalyzed Friedel–Crafts
Alkylation of Indole
Martin J. Wanner,[a] Peter Hauwert,[a] Hans E. Schoemaker,[b] René de Gelder,[c]
Jan H. van Maarseveen,[a] and Henk Hiemstra*[a]
Keywords: Friedel–Crafts reaction / Chirality / Phosphoric acids / Amino acids / Sulfenamides / Organocatalysis
Tritylsulfenyl- and 2-nitrophenylsulfenyl-substituted glyoxyl
imines were used in chiral phosphoric acid catalyzed
Friedel–Crafts (FC) reactions with indole. High yields and ee
values ranging from 86% for Nps-protected (S)-indolylgly-
cine to 88% for Trs-protected (R)-indolylglycine were ob-
tained. On a preparative scale, a FC product with 99.5%ee
and 71% yield was readily obtained by crystallization of the
reaction mixture. Removal of the Nps protecting group under
mild acidic conditions did not affect the stereochemical in-
tegrity of the α-carbon atom and (S)-indolylglycine was af-
forded in Ն98%ee.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
lytic process towards N-tosyl-substituted indolylglycines re-
ported; the Lectka CuITol-binap system was used.[9]
Introduction
Stimulated by the rapidly increasing number of applica-
tions of enantioselective organocatalyzed reactions involv-
ing iminium ions,[10] we explored the use of binolphos-
phoric acids as Brønsted activators in the Friedel–Crafts
substitution of the indole 3-position. Several recent reports
describe highly enantioselective indole alkylation reactions
with imines or equivalents thereof, but an approach to in-
dolylglycine has not yet appeared.[11] An important limita-
tion of almost all examples mentioned here is the presence
of undesirable substituents on both the indole nitrogen
atom and on the amine functionality. Only a few publica-
tions describing deprotection of these Friedel–Crafts prod-
ucts to simple 3-alkylamino-substituted indoles can be
found in the literature.[11a]
The reactive nature of the indole moiety and its 3-substit-
uent renders chemoselective removal of substituents from
the amine difficult; for example, removal of the meth-
oxyphenyl group under oxidative conditions would harm
the indole ring, and strongly hydrogenolytic conditions
would cleave the C–N bond in the substituent. Also, strong
base or acid can easily destroy the stereocentre. Reducing-
metal conditions, successfully applied to remove tosyl or
benzenesulfonyl substituents from 3-alkylaminoindoles,[11a]
cannot be applied safely for sensitive amino acids such as
indolylglycine. N-Sulfenyl-protected amines seemed suitable
for this purpose, because the N–S bond can be hydrolyzed
under mild acidic conditions.[12] Both the 2-nitrophenylsul-
fenyl (Nps) and the triphenylmethylsulfenyl (Trs) groups are
known in the literature, and they are used in particular as
N-protecting groups in amino acid chemistry.[13] Previously,
we introduced the Nps and Trs groups as stabilizing and
protecting substituents in the binolphosphoric acid cata-
Indolylglycines have attracted much attention as nonpro-
teinogenic amino acids in drug development, natural prod-
uct synthesis and in peptide mimetics.[1] The total synthesis
of biologically important bis(indole) alkaloids such as the
dragmacidins and hamacanthins rely on indolylglycine and
indolylglycinol units.[2,3] Although indolylglycine itself and
a few of its derivatives are commercially available, no enan-
tioselective synthesis of unprotected indolylglycine or its an-
alogues can be found in the literature. Friedel–Crafts-type
synthetic methods are the path of choice to prepare these
aromatic amino acids and takes advantage of the excellent
nucleophilic properties of the indole 3-position. With glyox-
ylic acid derived imines as counterparts in racemic Friedel–
Crafts reactions, catalysts ranging from simple Brønsted ac-
ids, such as TFA, to lanthanide triflates or complexed palla-
dium readily introduce the amino acid functionality. Even
catalyst-free reactions are reported, although the indole N–
H or even water can take the role of the Brønsted cata-
lyst.[1,4] Several enantioselective syntheses of N-substituted
indolylglycine are reported, and they use chiral amine auxil-
iaries in the imine part,[5,6] enzymatic resolution[7] or chiral
Lewis acidic silanes.[8] Johannsen described the only cata-
[a] Van’t Hoff Institute for Molecular Sciences, Faculty of Science,
University of Amsterdam,
Nieuwe Achtergracht 129, 1018 WS Amsterdam, The Nether-
lands
Fax: +31-20-5255670
E-mail: hiemstra@science.uva.nl
[b] DSM Research, Life Science Products,
P. O. Box 18, 6160 MD Geleen, The Netherlands
[c] Institute for Molecules and Materials, Radboud University
Nijmegen,
Toernooiveld 1, 6525 ED Nijmegen, The Netherlands
180
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 180–185

Organocatalyzed Friedel–Crafts Alkylation of Indole
Table 1. Catalyst screening and reaction optimization.[a]
lyzed Pictet–Spengler reaction, which revealed their excel-
lent behaviour in iminium-ion chemistry.[14] The required
glyoxylic imine precursors 1[15] and 2 were readily prepared
by condensation of methyl glyoxylate with 2-nitrophenyl
sulfenamide (Nps-NH2) and with triphenylmethyl sulfen-
amide (Trs-NH2).
(S)-3 R2 = 2-nitrophenyl
Entry Catalyst Solvent
t [h]
T [°C]
ee [%] MS [Å]
1
2
3
4
5
6
7
8
5a
5b
5c
5d
5e
5f
5g
6a
6b
6c
7
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
PhH
1
r.t.
r.t.
50
r.t.
r.t.
50
50
r.t.
50
r.t.
50
r.t.
r.t.
0
30
69
68
2
49
62
4
35
53
5
61
69
48
90
0.5
0.5
48
48
6
18
24
24
48
24
24
Results and Discussion
Reaction of Nps-imine 1 with indole catalyzed by unsub-
stituted (R)-binolphosphoric acid 5a gave clean production
of Nps-protected indolylglycine 3 in good yield and with
a promising 30%ee (Scheme 1, Table 1). Chloroform was
selected as the solvent for a preliminary optimization study
with 1, and next, a series of (R)-binolphosphoric acids 5,
(R)-octahydrobinol phosphoric acids 6 and (R)-vapol 7 as
a nonbinol-derived catalyst were screened (Table 1). Re-
markably low ee values were obtained from the generally
very selective 3,5-bis(trifluoromethyl)phenyl and 2,4,6-tri-
isopropylphenyl-substituted catalysts 5d and 5g, respec-
tively. 3,3Ј-Triphenylsilyl catalyst 5b gave the highest ee and
although 3,3Ј-(4-biphenyl)-substituted catalyst 5c showed
comparable ee values, the triphenylsilyl catalyst was chosen
for further optimization in view of its availability.[16] The
9
10
11
12
13
14
5b
5b
5b[b]
PhH
78
86
5
5
PhH[c]
(R)-4 R2 = triphenylmethyl
15
16
17
18
19
20
21
22
23
5a
5b
5c
5d
5e
5f
5g
6a
6b
6c
7
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
PhH
1
48[d]
48[e]
2
r.t.
reflux
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
0
0
–
15
21
36
46
72
0
21
77
–12
88
88
88
1
48[e]
24
4
24
4
2
10
10
24
(S) configuration at the newly formed asymmetric carbon 24
centre was deduced from an X-ray structure obtained from
3, which easily crystallized in an enantiopure form (see be-
low).
25
26
27
28
6c
6c
6c[b]
3
3
3
CH2Cl2
CH2Cl2
The Friedel–Crafts reaction between bulky tritylsulfenyl
[a] Reaction conditions: 1 or 2 (0.05 mmol), indole (1.1 equiv.), cata-
lyst (2 mol-%) and optionally powdered MS (75 mg) in 0.5 mL of
solvent (MS = molecular sieves). The reaction was continued until
Ͼ95% conversion. Isolated yields were Ͼ85%. [b] 5 mol-%. [c] Mix-
ture of PhH/PhMe, 4:1. [d] No conversion. [e] Ͻ10% Conversion.
imine 2 (Scheme 1) and indole was also readily catalyzed by
binolphosphoric acids, but it displayed a completely dif-
ferent catalyst preference in comparison with 2-nitrophen-
ylsulfenyl imine 1. Triphenylsilyl catalyst 5b and 3,3Ј-bi-
Scheme 1.
Eur. J. Org. Chem. 2008, 180–185
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181

H. Hiemstra et al.
FULL PAPER
phenyl catalyst 5c, previously found as most successful with yield based on 1, Ͼ99.5%ee. N-STr amino ester 4 was ob-
the 2-nitrophenyl substituent, were virtually incapable of tained from 1 (3 mmol) in 88% yield and 88%ee (63% yield
catalyzing the reaction. Only 3,3Ј-benzhydryl-substituted and Ͼ99.5%ee after crystallization).
octahydrobinol phosphoric acid 6c was acceptable as a cata-
lyst with respect to ee values (77%) and conversion rate,
and thus, it was selected for further optimization studies.
Surprisingly, all catalysts except vapol-phosphate[17] gave
product 4 with the (R) configuration at the newly formed
centre. This is opposite to Nps-product 3, which was ob-
tained without exception with the (S) configuration. Obvi-
ously, the substituent on sulfur in combination with the
3,3Ј-R groups on the binol ring system determine the bind-
ing of the imine to the catalyst and not the configuration
of the binolphosphoric acid [exclusively catalysts with the
(R) configuration were used during this investigation]. In
a recent publication, Terada and coworkers described an
inversion of the sense of enantioselection during indole al-
kylation by different 3,3Ј-substitution on the (R)-binaphthyl
ring system. Calculations gave some insight into the 3D
structures that are responsible for these observations.[18]
Figure 1. X-ray structure of (S)-3.
Further optimization studies showed that both reactions
were insensitive towards solvent changes. Addition of pow-
dered molecular sieves and replacement of chloroform by
Deprotection of tritylsulfenylindolylglycine 4 turned out
benzene as the solvent gave a significant improvement in to be complicated owing to a combination of the electron-
both the reaction time and the enantiomeric excess. Imine donating properties of the indole ring and the shielding ef-
1 showed a slight preference for 5 Å (Table 1, Entry 13; fect of the trityl substituent on the sulfur atom (Scheme 2).
78%ee) over 3-Å molecular sieves (73%ee). Surprisingly, 4- Standard conditions with the use of hydrochloric acid in
Å molecular sieves almost completely inhibited the reaction methanol gave deaminated racemic methyl 2-methoxyindo-
with the 2-nitrophenylsulfenyl-substituted imine 1. Lower- loacetate (9) (77%) and amino ester (R)-8 (14% yield,
ing the temperature to 0 °C further increased of the ee value 82%ee). Triphenylmethylsulfenyl scavengers such as eth-
to 86%, although increasing the catalyst loading to 5 mol- anethiol or thiophenol in combination with trifluoroacetic
% was necessary to obtain acceptable reaction times. In the acid or hydrochloric acid[14] gave the corresponding 2-mer-
tritylsulfenyl reaction with imine 2, an optimum ee value of captoindoloacetics in low yield together with unidentified
88% was reached upon combination of dichloromethane decomposition products. Undesirable reaction conditions
with 3-Å molecular sieves. Again, 4-Å molecular sieves such as tributyltin hydride/AIBN were not investigated.
showed a strong inhibitory effect on the reaction. These ee
Removal of the 2-nitrophenylsulfenyl substituent in 3 was
values were reproducible on a preparative scale: starting readily accomplished under acidic conditions and amino es-
from 1 (2 mmol) and catalyst 5b (2 mol-%), amino ester 3 ter (S)-8 was obtained in 74% yield with complete retention
was obtained in 97% yield and 79%ee. Enantiopure prod- of configuration of the stereocentre. Hydrolysis of the
uct was obtained by two simple crystallizations from methyl ester cleanly afforded unprotected (S)-(3)-indolylgly-
EtOAc/petroleum ether mixtures: (S)-3 (Figure 1): 71% cine (10) with good ee and yield.
Scheme 2. Deprotection.
182
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Eur. J. Org. Chem. 2008, 180–185

Organocatalyzed Friedel–Crafts Alkylation of Indole
added in portions to a stirred homogeneous mixture of NH4OH
(25%, 150 mL), THF (300 mL) and MeOH (55 mL) at 0 °C. After
stirring for 2 h at room temperature, saturated NH4Cl and diethyl
ether were added. The layers were separated, the organic layer was
dried with Na2SO4 and the solvents were evaporated. The remain-
ing solid was dissolved in hot EtOAc and after cooling, diethyl
ether was added slowly, followed by PE 40/65. 2-Nitrobenzenesul-
fenamide (14.95 g, 88%) was obtained in two fractions. Note: Small
amounts of a less-polar compound can cocrystallize. M.p. 120–
124 °C (ref.[15a] 122–125 °C). 1H NMR (400 MHz, CDCl3): δ = 8.30
(dd, J = 1.0, 8.3 Hz, 1 H), 8.15 (dd, J = 1.2, 8.3 Hz, 1 H), 7.70 (m,
1 H), 7.26 (m, 1 H), 2.74 (br. s, 2 H) ppm.
Conclusions
We developed a practical, organocatalytic Friedel–Crafts
process with catalyst loadings as low as 2 mol-% for the
synthesis of Trs- and Nps-protected indolylglycine. The al-
kylation products of indole were obtained with opposite
configuration depending on the sulfur substituent when bi-
nolphosphoric acids with the (R) configuration were used
exclusively. Only two recrystallization steps were required to
obtain the enantiomerically pure compounds in good yield.
Unprotected (S)-indolylglycine (10; Ն98%ee) was readily
prepared by mild, acid catalyzed removal of the 2-ni-
trophenylsulfenyl substituent followed by ester saponifica-
tion.
Methyl 2-(2-Nitrophenylsulfenimino)acetate (1):[15b,15c] A solution
of NpsNH2 (0.680 g, 4.0 mmol), methyl glyoxylate methanol hemi-
acetal (0.528 g, 4.4 mmol) and PPTS (10 mg) in EtOAc (15 mL)
was heated at reflux for 4 h. PE 40/65 (7.5 mL) and silica gel (0.5 g)
were added and after stirring for 5 min the mixture was filtered
through Celite. The solids were washed with EtOAc/PE (2:1,
3ϫ10 mL) and the solvents were evaporated. Crystallization from
EtOAc/PE mixtures gave imine 1 (0.785 g, 3.27 mmol, 82%). M.p.
120–121 °C (ref.[15] 120 °C). 1H NMR (400 MHz, CDCl3): 4:1 mix-
ture of rotamers: imine protons at 8.28 (major) and 8.02 ppm. In
the literature[15] these rotamers are ascribed to the existence of E/
Z isomers. Instead, a high temperature experiment in DMSO
clearly shows rotamers: 1H NMR (400 MHz, [D6]DMSO, 25 °C,
3:1 mixture of rotamers): δ = 8.52 (s, major), 8.37 (m, 2 H, Ar),
8.17 (s, 1 H, minor), 7.96 (m, 1 H Ar), 7.57 (m, 1 H Ar), 3.87 (s, 3
H, minor), 3.83 (s, 3 H, major) ppm. Upon increasing the tempera-
ture to 80 °C a single rotamer is left: δ = 8.4 (br., 1 H, imine), 8.35
(m, 2 H), 7.93 (m, 1 H), 7.56 (m, 1 H), 3.87 (s, 3 H) ppm. After
cooling to room temperature, the initial 3:1 ratio reformed.
Experimental Section
General: All reactions were carried out in flame-dried glassware
with magnetic stirring under an atmosphere of nitrogen. Solvents
were dried and distilled by standard procedures. Powdered molecu-
lar sieves (Aldrich) were dried at 200 °C and 0.1 mbar. Flash
chromatography was performed by using silica gel (Biosolve 60 Å).
400 MHz 1H NMR and 100 MHz 13C NMR spectra were obtained
1
with a Bruker Avance 400 spectrometer. H NMR chemical shifts
(δ) are given in ppm downfield from tetramethylsilane. 13C NMR
chemical shifts were calibrated to internal CDCl3 (δ = 77 ppm).
Optical rotations ([α]2D5) were measured with a Perkin–Elmer 241
polarimeter. HPLC was performed by using LKB equipment (2150
HPLC-pump and 2140 rapid spectral detector) and a Daicel Chi-
ralcel OD- or an AD-column with the use of 2-propanol/heptane
as the eluent. Chromatograms were measured at 254 nm. Chroma-
tograms were processed by using Borwin software version 1.22
(build 0.3). (R)-3,3Ј-Bis(triphenylsilyl)-1,1Ј-binaphthyl phosphate
5b was prepared according to MacMillan.[16] (R)-3,3Ј-Bis[3,5-bis-
(trifluoromethyl)phenyl]-1,1Ј-binaphthyl phosphate 5d, (R)-3,3Ј-
bis(4-nitrophenyl)-1,1Ј-binaphthyl phosphate 5e, 3,3Ј-bis(9-an-
thryl)-1,1Ј-binaphthyl phosphate 5f, 3,3Ј-bis(2,4,6-triisopro-
pylphenyl)-1,1Ј-binaphthyl phosphate 5g and 3,3Ј-diphenyl-octahy-
dro-1,1Ј-binaphthyl phosphate 6b were prepared according to Aki-
yama et al.;[19] (R)-3,3Ј-bis(p-biphenylyl)-1,1Ј-binaphthyl phosphate
5c was prepared according to Terada et al.;[20,21] (R)-1,1Ј-binaph-
thyl phosphate 5a, (R)-VAPOL 7, triphenylmethanesulfenamide
and 2-nitrobenzenesulfenyl chloride were obtained from Aldrich.
Methyl 2-(Triphenylmethanesulfenimino)acetate (2): Triphenylmeth-
anesulfenamide (1.746 g, 6.0 mmol), methyl glyoxylate methanol
hemiacetal (0.720 g, 6.6 mmol), PPTS (76.4 mg, 0.30 mmol) and
MgSO4 (1.25 g, 10 mmol) were stirred in dichloromethane (10 mL)
for 3 h at room temperature. The mixture was filtered through silica
and washed with a 1:1 mixture of EtOAc and PE 60/80 to remove
the catalyst. Evaporation and trituration of the solid residue gave
imine 2 (1.86 g, 5.14 mmol, 86%). M.p. 145–147 °C. 1H NMR
(400 MHz, CDCl3): δ = 7.74 (br., 1 H, imine), 7.2–7.4 (15 H, Ar),
3.81 (br., 3 H, CH3) ppm. 1H NMR (400 MHz, [D6]DMSO, 80 °C):
δ = 7.78 (s, 1 H), 7.3–7.4 (m, 9 H); 7.2 (m, 6 H), 3.74 (s, 3 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 52.1, 126.7, 127.2, 127.9,
130.5 ppm, S-CPh3 and carbonyl not observed due to line broaden-
ing. HRMS (FAB): calcd. for C22H20NO2S [M + H] 362.1208;
found 362.1219.
(R)-3,3Ј-Bis(benzhydryl)-octahydro-1,1Ј-binaphthyl Phosphate 6c:
(R)-3,3Ј-Bis(benzhydryl)-octahydro-1,1Ј-binaphthol (11) was pre-
pared by reaction of (R)-octahydro-1,1Ј-binaphthol[22] with benzhy-
dryl chloride.[23] Phosphorylation of 11 (0.120 g, 0.19 mmol) was
performed with POCl3 (37 mL, 0.40 mmol) in pyridine (0.6 mL)
over 1 h at 90 °C. After cooling to room temperature, water
(0.12 mL) was added and heating was continued at 95 °C for 1.5 h.
After evaporation of the pyridine, hydrochloric acid (6 , 3 mL)
was added and heating was continued for 2 h at 110 °C. Pure 6c
(0.120 g, 0.174 mmol, 92%) was obtained by extraction with DCM
and drying of the solid residue at 50 °C/0.05 mbar. M.p. 204–
207 °C. 1H NMR (400 MHz, CDCl3): δ = 7.0–7.25 (m, 20 H), 6.63
(s, 2 H), 6.16 (s, 2 H), 2.4–2.75 (m, 6 H), 2.2 (m, 4 H), 1.4–1.8 (m,
6 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 144.6, 143.8, 143.4,
135.9, 134.5, 133.0, 130.8, 129.9, 128.9, 128.2, 127.0, 126.0, 49.60,
29.71, 29.28, 22.45 ppm. HRMS (FAB): m/z calcd. for C46H42O4P
[M + H] 689.2818; found 689.2821.
Catalytic Experiments with Methyl 2-(2-Nitrophenylsulfenimino)-
acetate (1): Indole (6.5 mg, 0.055 mmol) and methyl 2-(2-ni-
trophenylsulfenimino)acetate (1; 12.0 mg, 0.050 mmol) and molec-
ular sieves if appropriate, were mixed with CHCl3 (0.5 mL), and
the catalyst (0.002 mmol, 2 mol-%) was added to the stirred suspen-
sion. The progress of the reaction was monitored with TLC on
silica (PE/EtOAc, 1:1). After disappearance of the starting mate-
rial, the reaction mixture was diluted with DCM (0.5 mL) and PE
(1 mL) and immediately applied to a silica column packed with PE/
EtOAc (2:1). If racemate had precipitated from the reaction mix-
ture, this was first dissolved by adding more DCM and heating.
Product 3 was obtained in 92–97% yield. Spectroscopic data: see
synthesis of 3. HPLC (OD-column; heptane/2-propanol, 75:25;
0.8 mLmin–1): tR = 19.4 (minor), 27.8 min.
2-Nitrobenzenesulfenamide
(o-Nitrophenylsulfenamide,
Nps-
Catalytic Experiments with Methyl 2-Tritylsulfeniminoacetate (2):
The same conditions described for the nitrophenyl derivative were
NH2):[15a] 2-Nitrobenzenesulfenyl chloride (18.0 g, 0.10 mol) was
Eur. J. Org. Chem. 2008, 180–185
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183

H. Hiemstra et al.
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applied for purification (silica; PE/EtOAc, 3:1). Spectroscopic data:
see synthesis of 4. HPLC (AD-column; heptane/2-propanol, 80:20;
1 mLmin–1): tR = 4.9 (major), 8.7 min.
Methyl 3-Indolylglycinate [(S)-8]: TFA (0.385 mL, 5.0 mmol) was
added to a solution of (S)-3 (0.357 g, 1.0 mmol) and PhSH
(0.308 mL, 3.0 mmol) in DCM (15 mL) at 0 °C. After stirring for
1 h PE (15 mL) was added, and the reaction mixture was directly
applied to a silica column. Elution with PE/EtOAc (5:1 and 1:1),
EtOAc containing 3% TEA and finally EtOAc/MeOH (95:5) af-
forded (S)-8 (0.151 g, 0.74 mmol, 74%) as colourless crystals after
crystallization from EtOAc/PE. M.p. 114–115 °C; m.p. (racemate)
118 °C.[24] [α]D = +163 (c = 0.51, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 8.18 (br., 1 H); 7.74 (d, J = 8.0 Hz, 1 H); 7.39 (d, J =
8.1 Hz, 1 H), 7.23 (d, J = 1.5 Hz, 1 H), 7.15–7.25 (m, 2 H), 4.96,
(br., 1 H), 3.73 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
174.6, 136.4, 125.4, 122.7, 122.4, 120.0, 119.0, 114.2, 111.6, 52.43,
51.54 ppm. The ee was determined by integration of the methyl
Methyl N-(2-Nitrobenzenesulfenyl)(3-indolyl)glycinate [(S)-3]:
A
solution of 1 (0.480 g, 2.0 mmol), indole (0.257 g, 2.2 mmol), 5-
Å molecular sieves (3.0 g) and triphenylsilyl catalyst 5b (34.6 mg,
0.04 mmol, 2 mol-%) in benzene (20 mL) was stirred under an at-
mosphere of N2 at room temperature for 24 h. DCM (20 mL) and
silica (3 g) were added. The mixture was stirred for 5 min and PE
60/80 (30 mL) was added. The mixture was immediately applied to
a silica column packed with PE/EtOAc (2:1). Elution with PE/
EtOAc (2:1 Ǟ 3:2) gave pure (S)-3 (0.691 g, 1.94 mmol, 97%) as a
solid. This product had an ee value of 79.3%. The crude product
was stirred with EtOAc and filtered to give racemic 3. Evaporation
of the filtrate and crystallization by dissolving the residue in hot
EtOAc followed by the addition of PE gave (S)-3 with 96–99%ee.
Recrystallization of this product from EtOAc/PE gave enantiopure
product. Repeating this process with the filtrate gave a total yield
of 0.505 g (71%) of enantiopure (S)-3 (Ͼ99.5%ee). M.p. 142.5–
143 °C; m.p. (racemate) 172.5–174 °C. HPLC: (OD-column; hep-
tane/2-propanol, 75:25; 0.8 mLmin–1): (S)-enantiomer not ob-
served. [α]D = +106 (c = 0.54, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 8.27 (dd, J = 1, J = 8.3 Hz, 1 H), 8.22 (br. s, 1 H),
8.11 (d, J = 7.5 Hz, 1 H), 7.74 (d, J = 7.8 Hz, 1 H), 7.53 (m, 1 H),
7.42 (d, J = 8.3 Hz, 1 H), 7.20–7.26 (m, 4 H), 4.92 (d, J = 7.5 Hz,
1 H), 3.78 (s, 3 H), 3.73 (d, J = 7.5 Hz, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 173.1, 144.8, 142.7, 136.4, 133.6, 125.64,
125.61, 124.9, 124.7, 123.3, 122.9, 120.5, 119.0, 112.6, 111.5, 60.5,
52.6 ppm. HRMS (FAB): calcd. for C17H16N3O4S [M + H]
358.0862; found 358.0863. C17H15N3O4S (357.38): calcd. C 57.13,
H 4.23, N 11.76; found C 57.18, H 4.27, N 11.75.
1
ester signals in the H NMR spectrum taken from a 2-mg sample
after addition of 8 mg (R)-(–)-2,2,2-trifluoro-1-(9-anthryl)ethanol
(Pirkle alcohol).[14,25] From a racemic mixture the methyl esters ap-
peared at δ = 3.70 and 3.67 ppm. Only the methyl ester at δ =
3.67 ppm was observed (Ͼ99%ee).
Methyl (3-Indolyl)glycinate [(R)-8] and Methyl 2-Methoxyindo-
loacetate (9): Concentrated HCl (0.1 mL) was added to a solution
of (R)-4 (48.0 mg, 0.10 mmol) in a mixture of THF (3 mL) and
MeOH (2 mL) at 0 °C. After stirring for 2 h at 0 °C and 30 min
at room temperature, an excess amount of a saturated solution of
Na2CO3 was added, and the products were extracted with EtOAc.
Chromatography (PE/EtOAc, 3:1; then EtOAc; then EtOAc/
MeOH, 88:12) gave (R)-8 and racemic 9. (R)-8: 2.9 mg,
1
0.014 mmol, 14%, glass. [α]D = –126 (c = 0.1, CHCl3). H NMR
(400 MHz, CDCl3): δ = 8.21 (br., 1 H), 7.74 (d, J = 8.0 Hz, 1 H),
7.40 (d, J = 8.1 Hz, 1 H), 7.1–7.3 (m, 3 H), 4.96, (br., 1 H), 3.74
(s, 3 H) ppm. The ee was determined as described for (S)-8:
3.70 ppm (major) and 3.67 ppm (82%ee). 9: 19.0 mg, 0.077 mmol,
77%, solid, m.p. 124–126 °C. [α]D = 0 (c = 0.2, CHCl3). HPLC
(AD; 2-propanol/heptane, 80:20): 0% ee. 1H NMR (400 MHz,
CDCl3): δ = 8.32 (br. s, 1 H), 7.81, (d, J = 8.0 Hz, 1 H); 7.15–7.40
(m, 4 H); 5.16 (s, 1 H); 3.76 (s, 3 H); 3.56 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 171.5, 136.1, 125.6, 123.9, 122.5, 120.1,
119.5, 111.15, 56.77, 52.08 ppm. HRMS (FAB): calcd. for
C12H14NO3 [M + H] 220.0996; found 220.0967.
X-ray Crystal Structure Analysis of [(S)-3]: C17H15N3O4S, formula
weight: 357.38 gmol–1, crystal size 0.16ϫ0.12ϫ0.04 mm, T =
208(2) K, λ = 0.71073 Å, orthorhombic, P212121, a = 7.4639(2) Å,
b = 14.686(6) Å, c = 14.867(8) Å, V = 1629.6(12) Å3, Z = 4, Dcalcd.
= 1.457 Mgm–3, µ = 0.227 mm–1, F(000) = 744; final R indices
[IϾ2σ(I)] R1 = 0.0568, wR2 = 0.0769, R indices (all data): R1
=
0.0876, wR2 = 0.0849, absolute structure parameter: 0.00(10),
largest diff. peak and hole: 0.267 and –0.303 eÅ–3. CCDC-660890
[for (S)-3] contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
3-(Indolyl)glycine [(S)-10]: LiOH·H2O (25.2 mg, 0.60 mmol) in
water (0.4 mL) was added to a solution of (S)-8 (61.5 mg,
0.30 mmol) in MeOH (1.5 mL). After stirring at room temperature
for 2 h, acetic acid (45 µL, 0.8 mmol) was added, and the mixture
was kept at 4 °C overnight. Filtration and drying in vacuo gave (S)-
10 (53.6 mg, 0.282 mmol, 94%). M.p. 204–206 °C; m.p. (racemate)
221 °C (decomp.).[24] [α]D = +111 (c = 0.20, H2O). HPLC (Chirobi-
otic T; methanol/water, 60:40): tR = 4.20 (major), 5.85 min;
Ն98%ee. 1H NMR (400 MHz, D2O): δ = 7.58 (d, J = 8.0 Hz, 1
H), 7.44 (d, J = 8.2 Hz, 1 H), 7.40 (s, 1 H), 7.19 (m, 1 H), 7.10 (m,
1 H), 5.03 (s, 1 H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ =
169.6, 136.5, 126.5, 125.0, 121.6, 120.1, 118.9, 111.8, 111.7,
51.59 ppm.
Methyl N-(Triphenylmethanesulfenyl)(3-indolyl)glycinate [(R)-4]: A
mixture of 2 (1.085 g, 3.0 mmol), indole (0.369 g, 3.15 mmol), 3-Å
molecular sieves (4.5 g) and benzhydryl catalyst 6c (41.3 mg,
0.06 mmol, 2 mol-%) in CH2Cl2 (30 mL) was stirred under an at-
mosphere of N2 at room temperature for 24 h. PE 60/80 (50 mL)
and silica (4 g) were added, and the suspension was directly applied
to a silica column packed with PE/EtOAc (3:1). The product was
obtained as a syrup (88%ee), which was crystallized from EtOAc
and some PE to remove racemic 4. The filtrate was dissolved in a
small amount of EtOAc, and the enantiopure product [(R)-4,
0.907 g, 1.90 mmol, 63%] was crystallized by the addition of PE.
M.p. 142–144 °C; M.p. (racemate) 88–95 °C. HPLC (AD-column;
heptane/2-propanol, 80:20; 1 mLmin–1): tR = 4.9 (major), 8.7 min.
(S) enantiomer not observed (Ͼ99.5%ee). [α]D = –122 (c = 0.76,
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Received: September 18, 2007
Published Online: November 15, 2007
Eur. J. Org. Chem. 2008, 180–185
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
185