Diastereoselective synthesis of heteroaromatic glycine derivatives

Article abstract of DOI:10.1002/ejoc.200800622

A TMSOTf promoted addition of an N-tert-butanesulfinyl α-imino ester to five-membered aromatic heterocycles furnishes optically active heteroaromatic glycine derivatives with moderate-to-good yield in diastereomeric ratios up to 99%. The absolute configuration of two of the addition products were solved by X-ray analysis. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800622

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200800622
Diastereoselective Synthesis of Heteroaromatic Glycine Derivatives
Trygve Andreassen,[a] Lars-Kristian Hansen,[b] and Odd R. Gautun*[a]
Keywords: Aromatic heterocycles / Electrophilic substitution / Sulfinimine / Diastereoselectivity / Glycine derivatives
A TMSOTf promoted addition of an N-tert-butanesulfinyl α-
imino ester to five-membered aromatic heterocycles fur-
nishes optically active heteroaromatic glycine derivatives
with moderate-to-good yield in diastereomeric ratios up to
99%. The absolute configuration of two of the addition prod-
ucts were solved by X-ray analysis.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
Introduction
Chiral nonracemic N-sulfinyl imines (sulfinimines) have
proven to be an extremely versatile class of imines for asym-
metric synthesis, especially through nucleophilic addition
reactions in the asymmetric synthesis of amines, α-amino
acids, β-amino carbonyl compounds (aldehydes, ketones,
acids), and aziridines.[1] The chiral and electron-with-
drawing sulfinyl group activates the C=N bond for nucleo-
philic addition with high and predictable asymmetric induc-
tion and is easily removed in the product.
Figure 1. Glycine reagents.
yields and in diastereoselectivities ranging from poor for the
activated Danishefsky-type dienes to excellent for unacti-
vated acyclic dienes (up to 99%de).
N-Sulfinylimino esters 1 (see Figure 1) have been de-
scribed in the literature as a chiral glycine cation equivalent
for the asymmetric synthesis of α-amino acids.[2] Excellent
diastereoselective results have been reported by using Grig-
nard and dialkylzinc reagents,[2,3] or by the addition of ke-
tene acetals in combination with Lewis acids[4] to 1. Recent
results involving transition-metal catalysts expand the util-
ity of 1 as a chiral glycine cation equivalent. Addition of
arylboronic acids, either catalyzed by cationic PdII[5] or
RhI,[6] demonstrates efficient and highly diastereoselective
synthesis of arylglycines. The rhodium-catalyzed C–C
bond-forming hydrogenation coupling of conjugated al-
kynes and 1 to β,γ-unsaturated α-amino acid esters,[7] and
the diastereoselective Pd/In-mediated catalytic allylation of
1 to 2-arylallyl-α-amino acids[8] are both impressive exam-
ples of utilizing 1 as a chiral glycine cation equivalent.
We have previously shown that optically active 1a reacts
as a dienophile in the aza-Diels–Alder reaction with both
activated and nonactivated dienes in the presence of Lewis
acids.[9] The heterocyclic adducts were obtained in modest
In this communication, we report our results for the reac-
tions of 1a with aromatic heterocycles bearing one hetero-
atom in the presence of a Lewis acid catalyst.
Results and Discussion
Initially, a mixture of furan (3a, 1 equiv.), 1a (1 equiv.),
and trimethylsilyl trifluoromethanesulfonate (TMSOTf,
1 equiv.) in dry dichloromethane was stirred overnight at
–78 °C under an argon atmosphere. Instead of the expected
aza-Diels–Alder reaction, nucleophilic addition of the furan
α-carbon atom to the imine carbon atom took place as
shown in Scheme 1. A similar result was previously re-
ported by Jørgensen et al. for N-tosyl glyoxylate imine ethyl
ester (2; see Figure 1) in the presence of an optically active
BINAP–CuClO4 catalyst.[10] In their case, the addition
product was isolated in 25–30% yield and up to 54%ee. In
our case, a 5:1 mixture of epimers 4a and 5a, partly separa-
ble by flash chromatography, was obtained in 56% (total
yield of isomers). The absolute configuration of the major
diastereomer was determined by chemical correlation
(cleavage of the sulfinyl group[6] and acetylation) to the
known acetamido compound 6 (see Scheme 1).[11]
[a] Department of Chemistry, Norwegian University of Science
and Technology (NTNU),
7491 Trondheim, Norway
Fax: +47-73594256
Encouraged by the result with 3a, a series of aromatic
heterocycles 3b–e were tested in the presence of 1a and a
stoichiometric amount of TMSOTf. The results are pre-
sented in Table 1. Electron-rich pyrrole 3b (Table 1, En-
E-mail: odd.gautun@chem.ntnu.no
[b] Department of Chemistry, Faculty of Science, University of
Tromsø,
Tromsø, Norway
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T. Andreassen, L.-K. Hansen, O. R. Gautun
SHORT COMMUNICATION
Table 1. Addition of 1a (1 equiv.) to aromatic compounds 3b–f
(1–2 equiv.) promoted by TMSOTf (1 equiv.) in dry CH2Cl2 under
an argon atmosphere.
Scheme 1.
try 1), known to be more active than 3a in aromatic electro-
philic substitution,[12] afforded only one addition product
1
(pure according to H NMR spectroscopy) at –78 °C after
17.5 h, which was identified as 4b and isolated in 92% yield.
The absolute configuration of 4b was assumed to be (SS,2S)
by comparison with results obtained by using two equiva-
lents of 1a (Table 1, Entry 7) discussed below. This result
deviates from the result obtained by Johannsen where chiral
copper(I)/Tol-BINAP-catalyzed addition of tosyl imine 2 to
3b gave the pyrrole N-addition product as the main prod-
uct.[13] Furthermore, Johannsen also reported the catalyzed
addition of 2 to N-methylpyrrole to give approximately a
1:1 mixture of the 2- and 3-substituted products in 84 and
56%ee, respectively.
Thiophene (3c) is known to be somewhat less reactive
than 3a toward electrophiles, and much less reactive than
3b.[12] This we indeed observed in the reaction between 1a
and 3c, where no reaction took place at –78 °C (Table 1,
Entry 2), but at –20 °C, a mixture of epimers 4c was formed
in a 1:1.5 ratio and isolated in 40% combined yield (Table 1,
Entry 3). The configuration of the major compound of 4c
was not determined.
The preferred site for electrophilic substitution at indole
(3d) is known to be C-3 rather than C-2, in contrast to
3b.[12] The reaction between 1a and 3d at –78 °C for 17 h
afforded a mixture of isomers, from which the major 3-sub-
stituted indole derived amino acid 4d was isolated pure by
flash chromatography in 82% yield as a solidified foam
(Table 1, Entry 4). Comparable results are also reported for
the chiral copper(I)–Tol-BINAP-catalyzed addition of 2 to
a variety of 5-substituted indole derivatives.[13] There, the
indoles reacted exclusively at the 3-position giving the N-
tosyl addition products in high yields (61–89%) and
enantioselectivities (78–97%ee). Enantiopure products
were available after one recrystallization. In an attempt to
determine the absolute configuration by X-ray analysis, 4d
was transformed into 8a (see Scheme 2). Recrystallization
of 8a from a mixture of 1-chloropentane and n-hexane af-
forded crystals of sufficient quality for X-ray analysis. The
absolute configuration of 8a was determined to be (2S),[14]
and thus, 4d should have the (SS,2S) configuration. Because
the N-tosyl 3-substituted indole amino acid ethyl ester 8b
had previously been reported with high ee (96%) without
assignment of the configuration,[13] 8b was prepared from
[a] The product ratio was determined by 1H NMR (400 MHz) spec-
troscopic analysis of the crude product. [b] Isolated yield. [c] Rela-
tive configuration was not determined. [d] Total yield of isolated
isomers. [e] Two equivalents of 1a and TMSOTf were added to one
equivalent 3b.
rotation {[α]rD.t. = +105.6 (c = 1, CHCl3)} with the literature
data {[α]2D0 = +102 (c = 1, CHCl3)}[13] verifies that the gentle
acidic removal of the sulfinyl group[6] and the following
tosylation proceeded without notable racemization.
4d (see Scheme 2). Comparison of our data for the optical Scheme 2.
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Diastereoselective Synthesis of Heteroaromatic Glycine Derivatives
In order to explore the feasibility of the reaction further,
The stereochemical outcome of the addition reactions of
1a was treated with pyridine (3e) and anisole (3f) in the 1a to 3a, 3b, and 3d can be rationalized according to the
presence of TMSOTf. As expected, reactions with 3e did open-transition-state model (see Scheme 3) proposed by
not afford addition products at all at –78 °C (Table 1, En- others from calculations on related sulfinimines with and
try 5) or at room temperature (20 h reaction time). This re- without a Lewis acid (LA) present.[15] This model also con-
sult is consistent with the knowledge that the dominance of firms the model proposed for the reaction of sulfinimines
electrophilic substitution, which typifies benzene chemistry, with Grignard reagents in the presence of BF3·ether[2] and
is not apparent in the chemistry of pyridines.[12] For 3f, no the stereochemical outcome observed for the Lewis acid
reaction was observed at –78 °C (17 h reaction time), but at promoted addition of silyl nucleophiles.[16]
–20 °C a mixture of epimers 4f and 5f was formed in a 1:2.6
ratio (65% combined yield; Table 1, Entry 6). The isomers
were partly separable by flash chromatography. The 1H
NMR spectrum of minor isomer 4f was in accordance with
the data reported for the (RS,2R) enantiomer obtained from
cationic PdII catalyzed addition of p-methoxyphenylboronic
acid to ent-1a (ent = enantiomer).[5] The major isomer
should then have (SS,2R) configuration.
The excellent result obtained for 3b by addition of one
Scheme 3. Stereochemical model.
equivalent of 1a and TMSOTf (Table 1, Entry 1) prompted
us to investigate if we were able to introduce two glycine
units into the pyrrole ring. Indeed, we were pleased to ob-
Conclusions
serve that addition of two equivalents of 1a and TMSOTf
afforded only one addition product with two glycine groups
(according to 1H NMR spectroscopy) in 77% yield
(Table 1, Entry 7) and a minor amount of 4b. The NMR
spectra of the former product indicated C2 symmetry in the
molecule. This was also confirmed by X-ray analysis (see
Figure 2).[14] Here, the absolute configuration of product 7
was determined to be (SS,2S) in both glycine parts of the
molecule. From this result we also assume (SS,2S) configu-
ration in the mono glycine pyrrole product 4b (Table 1, En-
try 1).
In conclusion, a simple method for preparation of het-
eroaromatic glycine derivatives from TMSOTf-promoted
addition of an N-tert-butanesulfinyl α-imino ester to aro-
matic heterocycles has been presented. The addition prod-
ucts were obtained in moderate-to-good yields and in dia-
stereoselectivities up to 99%. Acidic cleavage of the sulfinyl
group occurred without notable racemization.
Experimental Section
General: All reactions were performed under an argon atmosphere.
Dichloromethane and pyridine were distilled from calcium hydride.
Sulfinimine 1a was prepared according to the literature.[2] TLC was
performed on Merck silica gel 60 F254 plates by using UV light at
312 nm and a 5% alcoholic molybdophosphoric acid for detection.
Silica gel for flash chromatography was purchased from Merck.
Optical rotations were measured with a Perkin–Elmer 243B Polari-
meter. Enantiomeric excesses were determined by HPLC analysis
by using Daicels column Chiralpak AD (250ϫ4.6 mm). 1H and
13C NMR spectra were obtained with a Bruker Advance DPX in-
strument (400 and 100 MHz, respectively) from solutions of
CDCl3. The chemical shifts are referenced to TMS. The 1H and 13
C
NMR signals were assigned by 2D correlation techniques (COSY,
HSQC). IR spectra were recorded with a Thermo Nicolet FTIR
NEXUS instrument, and only the strongest and structurally most
important peaks are listed. Elemental analyses were performed at
the Mikroanalytisches labor Beller, Göttingen, Germany. Melting
points were determined with a Büchi 535 apparatus and are uncor-
rected.
General Procedure for the Addition of Ethyl (SS)-[(tert-Butylsulfinyl)-
imino]acetate (1a) to Aromatic Heterocycles: The aromatic hetero-
cycle (1 mmol) was dissolved with stirring in dry CH2Cl2 (8 mL)
and cooled to the temperature shown in Table 1 given for the spe-
cific reaction. A solution of 1a in dry CH2Cl2 (1.13–1.24 ,
1 mmol) and TMSOTf (180 µL, 1 mmol) were added by syringe.
After the specified reaction time (see Table 1), the reaction was
Figure 2. X-ray structure of 7.[14]
Eur. J. Org. Chem. 2008, 4871–4876
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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4873

T. Andreassen, L.-K. Hansen, O. R. Gautun
SHORT COMMUNICATION
quenched by addition of phosphate buffer (8 mL, pH = 7), warmed
to room temperature and extracted with CH2Cl2 (4ϫ15 mL). The
combined organic layer was dried (MgSO4) and concentrated. The
crude product was analyzed by 1H NMR spectroscopy to deter-
mine the diastereomeric ratio and, thereafter, purified by flash
chromatography.
Ethyl
(SS,2S)-[(tert-Butylsulfinyl)amino](1H-pyrrol-2-yl)acetate
(4b): Addition of 1a to 3b according to the general procedure af-
forded pure 4b according to NMR spectroscopic analysis. Flash
chromatography (EtOAc/hexane, 3:2) of the crude product gave 4b
(0.249 g, 92% yield) as a pale yellow oil. [α]2D0 = +137.2 (c = 1.3,
CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 8.74 (br. s, 1 H, pyrrole
NH), 6.77 (app td, J = 2.6, 1.6 Hz, 1 H, 5-H), 6.18–6.14 (m, 2 H,
3-H/4-H), 5.16 (br. d, J = 6.0 Hz, 1 H, NCH), 4.47 (br. d, J =
6.0 Hz, 1 H, NH), 4.27 (dq, J = 10.8, 7.2 Hz, 1 H, OCH2), 4.21
(dq, J = 10.8, 7.1 Hz, 1 H, OCH2), 1.28 (t, J = 7.1 Hz, OCH2CH3),
1.26 (s, 9 H, tBu) ppm. 13C NMR (100 MHz, CDCl3): δ = 170.6
(CO2Et), 126.2 (2-C), 118.8 (5-C), 108.7 (3-C or 4-C), 107.8 (3-C
or 4-C), 62.3 (OCH2), 56.3 (CMe3), 54.7 (NCH), 22.7 (CMe3), 14.1
Ethyl (SS,2S)-2-[(tert-Butylsulfinyl)amino](2-furyl)acetate (4a) and
Ethyl (SS,2R)-[(tert-Butylsulfinyl)amino](2-furyl)acetate (5a): Ad-
dition of 1a to 3a according to the general procedure afforded a
5:1 mixture of 4a/5a, which were partly separable by flash
chromatography (EtOAc/hexane, 1:2). The mixture was isolated as
a pale yellow oil (total yield 0.153 g, 56%). Analytical data of the
mixture 4a and 5a: IR (thin film, NaCl): ν = 3287, 2980, 1743,
˜
(OCH CH ) ppm. IR (thin film, NaCl): ν = 3279, 2981, 1736, 1473,
˜
2
3
1475, 1367, 1280, 1219, 1076, 1014 cm–1. C12H19NO4S (273.10):
calcd. C 52.73, H 7.01, N 5.12, S 11.73; found C 52.62, H 7.02, N
5.08, S 11.46. Data for 4a: HPLC (Chiralpak AD; iPrOH/hexane,
10:90; 1 mLmin–1; 230 nm): tR = 12.4 min. 1H NMR (400 MHz,
1367, 1229, 1180, 1098 cm–1. C12H20N2O3S (272.12): calcd. C
52.92, H 7.40, N 10.29, S 11.77; found C 52.74, H 7.41, N 10.06,
S 11.49.
CDCl3): δ = 7.39 (dd, J = 1.7, 0.8 Hz, 1 H, 5-H), 6.36 (dd, J = 3.3, Ethyl [(tert-Butylsulfinyl)amino](thien-2-yl)acetate (4c): Addition of
1.8 Hz, 1 H, 4-H), 6.34 (app dt, J = 3.2, 0.7 Hz, 1 H, 3-H), 5.13
(d, J = 5.4 Hz, NCH), 4.46 (br. d, J = 5.2 Hz, 1 H, NH), 4.28 (dq,
J = 10.7, 7.2 Hz, 1 H, OCH2), 4.24 (dq, J = 10.7, 7.1 Hz, 1 H,
1a to 3c according to the general procedure afforded a 1:1.5 mix-
ture of epimeric 4c. Purification of the crude product by flash
chromatography (EtOAc/hexane, 1:2) afforded 4c (0.116 g, 40%) as
OCH2), 1.26 (t, J = 7.2 Hz, 3 H, OCH2CH3), 1.23 (s, 9 H, tBu) a colorless oil. IR (thin film, NaCl): ν = 3283, 3237, 2980, 1740,
˜
ppm. 13C NMR (100 MHz, CDCl3): δ = 169.40 (CO2Et), 149.6 (2- 1474, 1366, 1189, 1074, 1020, 705 cm–1. C12H19NO3S2 (289.08):
C), 143.09 (5-C), 110.5 (4-C), 108.9 (3-C), 62.6 (OCH2), 56.2
(CMe3), 52.2 (NCH), 22.47 (CMe3), 14.0 (OCH2CH3) ppm. HPLC
(Chiralpak AD; iPrOH/hexane, 10:90; 1 mLmin–1; 230 nm) of race-
mic 4a: tR = 7.8, 12.4 min. Data for 5a: HPLC (Chiralpak AD;
iPrOH/hexane, 10:90; 1 mLmin–1; 230 nm): tR = 10.9 min. 1H
calcd. C 49.80, H 6.62, N 4.84; found C 49.86, H 6.80, N 4.80.
Data for the major epimer: RF (EtOAc) = 0.45. HPLC (Chiralpak
AD; iPrOH/hexane, 10:90; 1 mLmin–1; 230 nm): tR = 13.3 min. 1H
NMR (400 MHz, CDCl3): δ = 7.28 (dd, J = 5.1, 1.3 Hz, 1 H, 5-
H), 7.09 (app dt, J = 3.6, 1.1 Hz, 1 H, 3-H), 6.99 (dd, J = 5.1,
NMR (400 MHz, CDCl3): δ = 7.40 (dd, J = 1.9, 0.8 Hz, 1 H, 5- 3.6 Hz, 1 H, 4-H), 5.32 (dd, J = 5.2, 0.9 Hz, 1 H, NCH), 4.66 (br.
H), 6.39 (app dt, J = 3.3, 0.7 Hz, 1 H, 3-H), 6.36 (dd, J = 3.2,
1.8 Hz, 1 H, 4-H), 5.15 (d, J = 8.6 Hz, 1 H, NCH), 4.32 (br. d, J
d, J = 5 Hz, 1 H, NH), 4.28 (dq, J = 10.8, 7.2 Hz, 1 H, OCH2),
4.23 (dq, J = 10.8, 7.1 Hz, 1 H, OCH2), 1.29 (s, 9 H, tBu), 1.28 (t,
= 7.8 Hz, 1 H, NH), 4.25 (dq, J = 10.7, 7.1 Hz, 1 H, OCH2), 4.23 J = 7.1 Hz, 3 H, OCH2CH3) ppm. 13C NMR (100 MHz, CDCl3):
(dq, J = 10.7, 7.1 Hz, 1 H, OCH2), 1.26 (t, J = 7.1 Hz, 3 H,
δ = 170.4 (CO2Et), 140.7 (2-C), 127.1 (4-C), 126.2 (3-C), 126.0 (5-
OCH2CH3), 1.22 (s, 9 H, tBu) ppm. 13C NMR (100 MHz, CDCl3): C), 62.6 (OCH2), 56.8 (NCH), 56.3 (CMe3), 22.6 (CMe3), 14.0
δ = 169.45 (CO2Et), 149.7 (2-C), 143.08 (5-C), 110.7 (4-C), 108.8
(OCH2CH3) ppm. Data for the minor epimer: RF (EtOAc) = 0.52.
(3-C), 62.2 (OCH2), 57.0 (CMe3), 53.8 (NCH), 22.45 (CMe3), 14.0 HPLC (Chiralpak AD; iPrOH/hexane, 10:90; 1 mLmin–1; 230 nm):
1
(OCH2CH3) ppm. HPLC (Chiralpak AD; iPrOH/hexane, 10:90;
tR = 11.5 min. H NMR (400 MHz, CDCl3): δ = 7.28 (dd, J = 5.1,
1.3 Hz, 1 H, 5-H), 7.13 (app dt, J = 3.6, 1.0 Hz, 1 H, 3-H), 6.98
(dd, J = 5.1, 3.6 Hz, 1 H, 4-H), 5.36 (dd, J = 7.1, 0.8 Hz, 1 H,
NCH), 4.37 (br. d, J = 7.1 Hz, 1 H, NH), 4.24 (dq, J = 10.7, 7.1 Hz,
1 H, OCH2), 4.22 (dq, J = 10.7, 7.1 Hz, 1 H, OCH2), 1.27 (t, J =
7.1 Hz, 3 H, OCH2CH3), 1.23 (s, 9 H, tBu) ppm. 13C NMR
(100 MHz, CDCl3): δ = 170.6 (CO2Et), 139.8 (2-C), 127.1 (4-C),
126.5 (3-C), 126.1 (5-C), 62.2 (OCH2), 57.1 (CMe3), 54.6 (NCH),
22.5 (CMe3), 14.0 (OCH2CH3) ppm.
1 mLmin–1; 230 nm) of racemic 5a: tR = 9.5, 10.9 min.
Ethyl (2S)-(Acetylamino)(2-furyl)acetate [(S)-6]: A mixture of 4a
and 5a (ratio 5:1, 37 mg, 0.135 mmol) was dissolved with stirring in
methanol (1 mL) and treated with 4.0  HCl in dioxane (0.170 mL,
5.0 equiv. HCl) at room temperature for 4 h.[6] The reaction mixture
was concentrated in vacuo, and the crude amine hydrochloride
(white solid) was dissolved with stirring in dry pyridine (1 mL) and
cooled to 0 °C. Acetic acid anhydride (55 µL, 0.58 mmol) was
added by syringe, and the mixture was stirred for 4 h at 0 °C before
being diluted with diethyl ether (20 mL) and washed with water
(4 mL) and 10% CuSO4 (aq. 10 mL). The combined aqueous phase
was extracted with diethyl ether (20 mL). The combined organic
layer was washed successively with water (10 mL), saturated
NaHCO3 (aq. 10 mL), and brine (10 mL) and then dried (MgSO4).
The solvent was removed to yield a residue, which was purified by
flash chromatography (EtOAc/hexane, 1:1). Acetamido compound
(S)-6 was obtained as a yellow oil (19.3 mg, 68%), which solidified
in the freezer. [α]rD.t. = +96.4 (c = 1.2, abs. EtOH) {ref.[11] for (R)-6:
[α]2D0 = –69.6 (c = 1, EtOH)}. HPLC (Chiralpak AD; iPrOH/hex-
ane, 10:90; 1 mLmin–1; 230 nm) 64%ee, tR = 8.5 (R), 9.5 (S) min.
1H NMR (400 MHz, CDCl3): δ = 7.36 (dd, J = 1.7, 1.0 Hz, 1 H,
5-H), 6.40 (br. d, J = 6 Hz, 1 H, NH), 6.37–6.35 (m, 2 H, 3-H/4-
Ethyl (SS,2S)-[(tert-Butylsulfinyl)amino](1H-indol-3-yl)acetate (4d):
Addition of 1a to 3d according to the general procedure afforded
a complex mixture of isomers. Purification of the crude product
by flash chromatography (EtOAc/hexane, 3:2) afforded 4d (0.140 g,
82%) as a white foam. Analytical data for 4d: [α]rD.t. = +146.8 (c =
0.8, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 8.42 (br. s, 1 H,
indol NH), 7.65 (app d, J = 8 Hz, 1 H, 4-H), 7.38 (app dt, J = 8.2,
0.9 Hz, 1 H, 7-H), 7.23–7.18 (m, 2 H, 2-H/6-H), 7.12 (ddd, J = 8.1,
7.1, 0.9 Hz, 1 H, 5-H), 5.33 (app dd, J = 4.6, 0.4 Hz, 1 H, NCH),
4.51 (br. d, J = 4.6 Hz, 1 H, NH), 4.25 (dq, J = 10.7, 7.1 Hz, 1 H,
OCH2), 4.14 (dq, J = 10.7, 7.1 Hz, 1 H, OCH2), 1.21 (s, 9 H, tBu),
1.19 (t, J = 7.1 Hz, OCH2CH3) ppm. 13C NMR (100 MHz,
CDCl3): δ = 171.9 (CO2Et), 136.6 (7a-C), 125.6 (3a-C), 124.0 (C-2
or C-6), 122.5 (C-2 or C-6), 120.0 (5-C), 119.7 (4-C), 111.8 (3-C),
H), 5.75 (d, J = 7.9 Hz, 1 H, NCH), 4.25 (dq, J = 10.8, 7.2 Hz, 1 111.4 (7-C), 62.0 (OCH2), 55.8 (CMe3), 54.3 (NCH), 22.7 (CMe3),
H, OCH2), 4.21 (dq, J = 10.8, 7.1 Hz, 1 H, OCH2), 2.05 (s, 3 H, 14.1 (OCH CH ) ppm. IR (KBr tablet): ν = 3406, 3250, 3059, 2979,
˜
2
3
Ac), 1.25 (t, J = 7.2 Hz, 3 H, OCH2CH3) ppm.
1732, 1458, 1367, 1232, 1185, 1052, 744 cm–1. C16H22N2O3S
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Diastereoselective Synthesis of Heteroaromatic Glycine Derivatives
(322.14): calcd. C 59.60, H 6.88, N 8.69, S 9.95; found C 59.22, H
6.99, N 8.46, S 9.69.
55.3 (OCH3), 22.5 (CMe3), 14.0 (OCH2CH3) ppm. IR (thin film,
NaCl): ν = 3269, 3214, 2979, 1736, 1611, 1513, 1464, 1389, 1304,
˜
1249, 1178, 1070, 1031, 836 cm–1. C15H23NO4S (313.13): calcd. C
57.48, H 7.40, N 4.47, S 10.23; found C 57.08, H 7.53, N 4.43, S
10.23.
Ethyl (2S)-{[(4-Bromophenyl)sulfonyl]amino}(1H-indol-3-yl)acetate
(8a): N-Sulfinyl indolylglycine derivative 4d (0.233 g, 0.722 mmol)
was dissolved with stirring in MeOH (6 mL) and treated with 4.0 
HCl in dioxane (0.900 mL, 3.60 mmol) at room temperature for
4 h.[6] The reaction mixture was concentrated under reduced pres-
sure, and the precipitated amine hydrochloride was dissolved with
stirring by addition of dry CH2Cl2 (2 mL) and triethylamine
(0.320 mL, 2.30 mmol), and then cooled to 0 °C. A solution of 4-
bromobenzenesulfonyl chloride (0.182 g, 0.712 mmol) in dry
CH2Cl2 (3 mL) was cannulated into the mixture. The resultant mix-
ture was stirred at 0 °C for 2 h and then warmed to room tempera-
ture. The reaction mixture was concentrated under reduced pres-
sure, and the residue was purified by flash chromatography
(EtOAc/hexane, 3:7 to 1:1) affording 8a (0.256, 82% yield) as a
white solid. M.p. 141–142 °C (abs EtOH). [α]rD.t. = +101.5 (c = 1,
Diethyl (SS,2S,2ЈS)-2,2Ј-(1H-Pyrrole-2,5-diyl)bis({[(S)-tert-butyl-
sulfinyl]amino}acetate) (7): Addition of 1a (2 equiv.) and TMSOTf
(2 equiv.) to 3b (1 equiv.) according to the general procedure af-
forded a mixture of 7 and a minor amount of 4b. Purification of
the crude product by flash chromatography (EtOAc) gave 7
(0.368 g, 77%) as a white solid. M.p. 103–104 °C (10% iPrOH in
hexane). [α]rD.t. = +162.4 (c = 1, CH2Cl2). 1H NMR (400 MHz,
CDCl3): δ = 8.90 (br. s, 1 H, pyrrole NH), 6.09 (d, J = 2.7 Hz, 2
H, 3-H/4-H), 5.11 (br. d, J = 6.0 Hz, 2 H, 2ϫNCH), 4.41 (br. d,
J = 6.0 Hz, 2 H, 2ϫNH), 4.27 (dq, J = 10.7, 7.2 Hz, 2 H, OCH2),
4.22 (dq, J = 10.7, 7.1 Hz, 2 H, OCH2), 1.29 (t, J = 7.1 Hz, 6 H,
2ϫOCH2CH3), 1.26 (s, 18 H, 2ϫtBu) ppm. 13C NMR (100 MHz,
CDCl3): δ = 170.3 (2ϫCO2Et), 127.4 (2-C/5-C), 108.3 (3-C/4-C),
62.4 (2ϫOCH2), 56.3 (2ϫCMe3), 54.7 (2ϫNCH), 22.6
1
CHCl3). H NMR (400 MHz, CDCl3): δ = 8.05 (br. s, 1 H, indol
NH), 7.49 (app d, J = 8.8 Hz, 2 H, 4-BrC6H4, 2-H/6-H), 7.49–7.46
(m, 1 H, 4-H), 7.35 (app d, J = 8.8 Hz, 2 H, 4-BrC6H4, 3-H/5-H),
7.29 (dt, J = 8.2, 0.9 Hz, 1 H, 7-H), 7.19 (app ddd, J = 8.2, 7.1,
1.1 Hz, 1 H, 6-H), 7.09–7.05 (m, 2 H, 2-H/5-H), 5.67 (br. d, J =
7.3 Hz, 1 H, NH), 5.36 (app dd, J = 7.3, 0.4 Hz, 1 H, NCH), 4.13
(dq, J = 10.8, 7.1 Hz, 1 H, OCH2), 4.03 (dq, J = 10.7, 7.1 Hz, 1
H, OCH2), 1.14 (t, J = 7.1 Hz, 3 H, OCH2CH3) ppm. 13C NMR
(CDCl3, 100 MHz): δ = 170.2 (CO2Et), 139.0 (4-BrC6H4, 1-C),
136.2 (7a-C), 131.6 (4-BrC6H4, 3-C/5-C), 128.5 (4-BrC6H4, 2-C/6-
C), 127.2 (3a-C or 1-C in 4-BrC6H4), 124.9 (3a-C or 1-C in 4-
BrC6H4), 123.7 (2-C), 122.9 (6-C), 120.5 (5-C), 119.0 (4-C), 111.4
(7-C), 110.1 (3-C), 62.3 (OCH2), 53.2 (NCH), 13.9 (OCH2CH3)
(2ϫCMe ), 14.1 (2ϫOCH CH ) ppm. IR (KBr tablet): ν = 3444,
˜
3
2
3
3275, 2981, 1739, 1474, 1367, 1299, 1233, 1186, 1057 cm–1.
C20H35N3O6S2 (477.20): calcd. C 50.29, H 7.39, N 8.80, S 13.43;
found C 50.09, H 7.50, N 8.68, S 13.29. The absolute configuration
of 7 was corroborated by X-ray crystallographic analysis.[14]
Acknowledgments
We thank the Norwegian Research Council (Grant 160099 to T.A.)
for generous financial support.
ppm. IR (KBr tablet): ν = 3408, 3251, 3129, 3058, 2998, 1731,
˜
1575, 1471, 1458, 1420, 1344, 1304, 1197, 1168, 1101, 1087, 1009,
919, 830, 750 cm–1. The absolute configuration of 8a was corrobo-
rated by X-ray crystallographic analysis.[14]
[1] For reviews covering asymmetric synthesis with the use of sulfi-
nimines, see: a) F. A. Davis, P. Zhou, B.-C. Chen, Chem. Soc.
Rev. 1998, 27, 13–18; b) J. A. Ellman, T. D. Owens, T. P. Tang,
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[3] L. P. Jayathilaka, M. Deb, R. F. Standaert, Org. Lett. 2004, 6,
3659–3662.
Ethyl (2S)-1H-Indol-3-yl{[(4-methylphenyl)sulfonyl]amino}acetate
(8b): N-Tosyl indolylglycine derivative 8b was prepared according
to the procedure described for the preparation of 8a. Purification
of the crude product by flash chromatography (EtOAc/hexane, 3:7
to 8:2) afforded 8b (0.214 g, 80%) as a white solid. [α]rD.t. = +105.6
(c = 1, CHCl3) {ref.[13] 96%ee, [α]rD.t. = +102 (c = 1, CHCl3), abso-
lute configuration was not given in the reference}. 1H and 13C
NMR spectra were in accordance with the data reported in the
literature.[13]
Ethyl (SS,2S)-[(tert-Butylsulfinyl)amino](4-methoxyphenyl)acetate
(4f) and Ethyl (SS,2R)-[(tert-Butylsulfinyl)amino](4-methoxyphenyl)-
acetate (5f): Addition of 1a to 3f according to the general pro-
cedure afforded a 1:2.6 mixture of 4f/5f, which were partly separa-
ble by flash chromatography (EtOAc/hexane, 1:2). The mixture was
isolated as a pale yellow oil (total yield: 0.201 g, 65%). Analytical
data for 4f: RF (EtOAc) = 0.34. HPLC (Chiralpak AD; iPrOH/
hexane, 10:90; 1 mLmin–1; 230 nm): tR = 20.9 min. 1H NMR spec-
troscopic data was in accordance with data reported for the
(RS,2R)-enantiomer.[5] Analytical data for 5f: RF (EtOAc) = 0.44.
[α]2D0 = –52.7 (c = 1, CHCl3). HPLC (Chiralpak AD; iPrOH/hexane,
10:90; 1 mLmin–1; 230 nm): tR = 22.2 min. 1H NMR (400 MHz,
CDCl3): δ = 7.34 (app d, J = 8.8 Hz, 2 H, aryl), 6.88 (app d, J =
8.8 Hz, 2 H, aryl), 5.05 (br. d, J = 5.9 Hz, 1 H, NCH), 4.20 (dq, J
= 10.8, 7.1 Hz, 1 H, OCH2), 4.13 (dq, J = 10.8, 7.1 Hz, 1 H,
OCH2), 4.12 (br. d, J = 6 Hz, 1 H, NH), 3.80 (s, 3 H, OCH3), 1.21
(s, 9 H, tBu), 1.208 (t, J = 7.1 Hz, 3 H, OCH2CH3) ppm. 13C NMR
(100 MHz, CDCl3): δ = 171.5 (CO2Et), 159.8 (aryl), 129.3 (aryl),
128.8 (aryl), 114.3 (aryl), 61.7 (OCH2), 58.8 (NCH), 56.7 (CMe3),
[4] M. F. Jacobsen, T. Skrydstrup, J. Org. Chem. 2003, 68, 7112–
7114.
[5] H. Dai, X. Lu, Org. Lett. 2007, 9, 3077–3080.
[6] M. Beenen, D. J. Weix, J. A. Ellman, J. Am. Chem. Soc. 2006,
128, 6304–6305.
[7] J.-R. Kong, C.-W. Cho, M. Krische, J. Am. Chem. Soc. 2005,
127, 11269–11276.
[8] R. Grigg, S. McCaffrey, V. Sridharan, C. W. G. Fishwick, C.
Kilner, S. Korn, K. Baiely, J. Blacker, Tetrahedron 2006, 62,
12159–12171.
[9] T. Andreassen, T. Håland, L. K. Hansen, O. R. Gautun, Tetra-
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[10] S. Yao, S. Saaby, R. G. Hazell, K. A. Jørgensen, Chem. Eur. J.
2000, 6, 2435–2448.
[11] H. Kohn, K. N. Sawhney, P. LeGall, J. D. Conley, D. W. Rob-
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[12] T. L. Gilchrist, Heterocyclic Chemistry, Pitman Publishing Ltd,
London, UK, 1985.
[13] M. Johannsen, Chem. Commun. 1999, 2233–2234.
[14] Inquiries concerning X-ray analysis should be addressed to
L. K. H. (E-mail: lars-kristian.hansen@chem.uit.no). CCDC-
Eur. J. Org. Chem. 2008, 4871–4876
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4875

T. Andreassen, L.-K. Hansen, O. R. Gautun
SHORT COMMUNICATION
688243 (for 7) and -692534 (for 8a) contain the supplementary
Chem. Soc. Perkin Trans. 2 2000, 43–50; c) L. F. Tietze, A.
Schuffenhauer, Eur. J. Org. Chem. 1998, 1629–1637.
crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data [16] G. K. S. Prakash, M. Mandal, G. A. Olah, Org. Lett. 2001, 3,
Centre via www.ccdc.cam.ac.uk/data_request/cif.
2847–2850.
[15] a) J. Cz. Dobrowolski, R. Kawe˛cki, J. Mol. Struct. 2005, 734,
Received: June 24, 2008
Published Online: September 2, 2008
235–239; b) P. V. Bharatam, P. Uppal, A. Kaur, D. Kaur, J.
4876
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 4871–4876