Synthesis and diversification of pyridone dipeptide chromophores

Article abstract of DOI:10.1055/s-2006-942546

An improved synthetic protocol transforms D-alduronolactone via a bicyclic dipeptide lactam 2 into pyridone dipeptides with either Boc- or Fmoc-protecting groups 5 or 6. Regioselective bromination of 5 yields dipeptide 10 which is further diversified in P

Full text of DOI:10.1055/s-2006-942546

3224
PAPER
Synthesis and Diversification of Pyridone Dipeptide Chromophores
Pyridone
Dipeptid
a
e
Chromop
r
Fachbereich Chemie der Philipps-Universität Marburg, 35032 Marburg, Germany
Fax +49(6421)2822021; E-mail: geyer@staff.uni-marburg.de
Received 18 May 2006; revised 14 June 2006
Route a to urethane
protected dipeptide
Abstract: An improved synthetic protocol transforms D-aldurono-
OH
O
CH3SO2Cl
in pyridine
lactone via a bicyclic dipeptide lactam 2 into pyridone dipeptides
with either Boc- or Fmoc-protecting groups 5 or 6. Regioselective
bromination of 5 yields dipeptide 10 which is further diversified in
Pd-catalyzed cross coupling reactions. This late diversification of a
common peptide precursor makes a maximum number of rigid
dipeptide chromophores accessible. The dipeptides 11, 12, and 13
exemplify a general strategy of accessing conformationally locked
peptide chromophores as tools for chemical biology.
HO
S
S
Boc
Boc
N
N
N
H
N
CO2Me
CO2Me
H
O
LiOH
> 10 d
Route b to
deprotected dipeptide
OH
HCl, Et2O
S
S
Key words: amino acids, fused-rings, pyridones, thiazolidine lac-
tams, cross-coupling
. HCl
. 2 LiCl
N
N
Boc
H2N
N
H
CO2H
O
CO2Li
O
. LiCl
Side-chain-to-backbone ring structures are incorporated
in oligopeptides as local conformational constraints for
the purpose of altering the bioactivity profile of the pep-
tide.1 In the majority of cases, the suitably protected
mono- or bicyclic dipeptide building blocks are obtained
from two amino acid precursors, whose side-chain func-
tionalities are consumed for the formation of the fused
ring system.2 Decorated bicyclic dipeptide lactams de-
mand an extra functional group on each amino acid mak-
ing their synthesis more laborious.3 Synthetic strategies
which rely on common precursors are desirable but hardly
developed.4 In the example presented here, the side-chain
diversification is achieved by cross-coupling reactions be-
tween a halogenated 2-pyridone and diverse boronic ac-
ids. The fused pyridone chromophore which becomes part
of the peptide backbone has been efficiently accessible by
the elimination of two equivalents of water from the bicy-
clic condensation product between an uronic acid and cys-
teine (Scheme 1).
Scheme 1
Regioselective activation of the a-hydroxy group,6 fol-
lowed by azide substitution (2, 73%) and reduction under
Staudinger conditions7 led to the Boc-protected dipeptide
3 (86%) as a mixture of diastereomers along published
procedures.8 The reduction proceeded with comparable
yields using H2 and Pd/C in methanol or H2S in pyridine.
The remaining two hydroxyls in 2 and in 3 assume pseu-
OH
OH
HO
HO
HO
N3
S
S
a
N
N
CO2Me
CO2Me
O
O
1
2, 73%
c
b
OH
HO
S
S
It was already shown that such a dehydration can be pro-
voked during peptide synthesis without requiring extra
synthetic transformations (route b in Scheme 1).5 Yet, for
the several-fold introduction of this bicyclic 2-pyridone
into a 36mer neuropeptide (Biochemistry Leipzig, A.
Beck-Sickinger) we were urged to develop a building
block which is amenable for solid-phase peptide synthesis
(route a in Scheme 1). The following protocol is more ef-
ficient than the original procedure and additionally allows
the desired side-chain diversification. The precursor 1
(Scheme 2) is available on gram scale in a one-pot proto-
col from commercial D-glucuronic acid and L-cysteine
methyl ester hydrochloride.
N
N
N3
Boc
N
H
CO2Me
CO2Me
3, 86%
O
O
c
4, 81%
d
S
N
S
N
Fmoc
N
H
Boc
N
CO2R
CO2Me
5, 91%
O
H
O
6, R = Me, 62%
7, R = OH, quant.
e
Scheme 2 Reagents and conditions: a) 1. Tf2O, CH2Cl2/Py, 2.
NaN3, DMF; b) Ph3P, THF–H2O, Boc2O; c) MsCl (3 equiv), Et3N,
CH2Cl2/Py; d) 1. H2, Pd/C, MeOH, 2. Fmoc-ONSu, NaHCO3, ace-
tone; e) aq 6 N HCl, AcOH
SYNTHESIS 2006, No. 19, pp 3224–3230
Advanced online publication: 02.08.2006
x
x.
x
x
.
2
0
0
6
DOI: 10.1055/s-2006-942546; Art ID: T08106SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Pyridone Dipeptide Chromophores
3225
do-axial orientations thereby facilitating their elimination, the addition of base must be handled carefully to avoid
independently of the stereochemistry at C-6. The first epimerization of C-3. Nevertheless this is a well-known
elimination could be achieved under basic conditions property in this substance class which should be avoided
leading to the dehydroamino acid which yielded the aro- without big effort.13
matized ring under acidic conditions. Both eliminations
occurred together in a fast and clean transformation in the
S
S
O
O
presence of three equivalents of mesyl chloride and trieth-
ylamine in isolated yields of 81% (4) and 91% (5), respec-
tively. Single crystals of 5 were obtained from ethyl
acetate/petroleum ether.9 The new protocol yields the pro-
tected pyridone in a single synthetic transformation and
avoids the slow first elimination step of the old protocol
(route b in Scheme 1). Syrupy aromatic azide 4 cannot be
stored for longer time. Immediate hydrogenation (H2 and
Pd/C) in methanol led to the corresponding amine which
was subsequently protected with Fmoc-ONSu in acetone
in the presence of NaHCO3 (6, 62% yield). Recrystalliza-
tion from ethanol yielded single crystals which were suit-
able for X-ray analysis (Figure 1).10 The N-protected
carboxylic acid 7 could be generated quantitatively by
acidic ester hydrolysis of 6 in 6 N aqueous HCl/acetic acid
without detectable racemization. Compound 7 is a stor-
able solid as necessary for solid-phase peptide synthesis
and it was used in several Fmoc protocols without prob-
lems.11
N
N
N
N
O
O
H
O
O
H
N
H
O
O
H
N
H
H
H
H
N
N
O
O
N
N
N
N
O
O
S
S
9
8
Figure 2 Hexapeptides 8 and 9
Bromination of 5 by NBS in refluxing CCl4 proceeded
with excellent selectivity to give the substituted 2-pyri-
done 10 (Table 1) in 95% isolated yield. This halogenated
dipeptide is a good starting material for cross-coupling re-
actions, opening a wide range of further derivatization
possibilities at C-8 with the aim of altering the lumines-
cence properties of the dipeptide. Introduction of an io-
dine substituent gave much lower yields, therefore we
concentrated on the cross-coupling reactions of bromide
10.
Phenylboronic acid was chosen in order to investigate the
reactivity of 10 in Suzuki–Miyaura cross-coupling reac-
tions. We tried several coupling conditions with different
Pd
species
[tetrakispalladiumtriphenylphosphine,
Pd(OAc)2, PdCl2 together with triphenylphosphine], dif-
ferent bases (Na2CO3, NaHCO3, DIPEA), and different
solvents (dioxane, DME, THF) without satisfactory re-
sults. Finally, the conditions published by Buchwald et
al.14 seemed adequate for bromide 10 using 2-dicyclohex-
ylphosphino-2¢,6¢-dimethoxybiphenyl (S-Phos) as ligand,
Pd(OAc)2 as Pd source, K3PO4·H2O as base in THF
(Table 1). Water was added in the case of thiophene-2-bo-
ronic acid to the reaction mixture to increase the solubility
of the boronic acid. The required ligand was obtained
according to literature procedures from 1,3-dimethoxy-
benzene, 2-bromochlorobenzene and dicyclohexyl-
phosphoryl chloride.15 The advantage of this method over
the above-named is the complete conversion of the start-
ing material 10, formation of less by-product 5 and thus an
easier work-up procedure. Thienyl-substituted 2-pyridone
12 was introduced in a 36mer peptide by solid-phase pep-
tide synthesis11 (Biochemistry Leipzig, M. Haack, A.
Beck-Sickinger) without loss of stereochemical informa-
tion after aqueous acidic cleavage of the methyl ester to-
gether with the Boc group and subsequent introduction of
the Fmoc protecting group under standard conditions us-
ing Fmoc chloroformate. NMR spectra of pyrene substi-
tuted 13 recorded at 300 K showed a double signal set
because of its axial chirality. Coalescence of the methyl
Figure 1 Crystal structure of 6
In order to examine the handling of the building block
with the Boc strategy, we assembled a cyclic peptide in
solution with standard coupling and deprotection cycles
using 5 as starting compound. During this synthesis the
methyl esters were saponified under basic conditions (1 N
LiOH/MeOH) and the Boc group was cleaved under acid-
ic conditions with HCl/Et2O. Acylation of the amino
group which has a low basicity because of its aniline-like
character was achieved with the coupling reagent (benzo-
triazol-1-yloxy)tripyrrolidinophosphonium hexafluoro-
phosphate (PyBOP), NMM as base and DMF as solvent in
93% yield. Cyclization was carried out with 1-hydroxy-7-
azabenzotriazole (HOAT), O-(7-azabenzotriazol-1-yl)-
N,N,N¢,N¢-tetramethyluronium
hexafluorophosphate
1
ester H NMR signals occurred between 350 and 360 K
(500 MHz, Dd = 20 Hz at 300 K).
(HATU) and 1,3,5-collidine in DMF applying the dilution
method12 (yield: 57%). Ci (8) and C2-symmetric (9)
hexapeptides were obtained (Figure 2), thus showing that
Synthesis 2006, No. 19, 3224–3230 © Thieme Stuttgart · New York

3226
H. Seger, A. Geyer
PAPER
Table 1 Suzuki–Miyaura Cross-Coupling of Pyridone Bromide 10a
O–
S+
O–
S+
R
O
R-B(OH)2
Pd(OAc)2
S-Phos
Br
O
S
S
N
N
Boc
Boc
N
H
N
H
K3PO4⋅H2O
N
N
CO2Me
Boc
CO2Me
N
H
Boc
O
N
H
O
CO2Me
14
15
CO2Me
O
O
Product
Boronic acid
Conditions,
yield (%)b
S
N
Boc
N
H
THF, 80 °C,
4.25 h
CO2Me
B(OH)2
O
11
16
86
S
Figure 3 Compounds 14–16
N
Boc
N
H
CO2Me
O
are under study. This new synthetic entry to highly substi-
tuted fused 2-pyridones could find applications in the
fields of cytotoxic alkaloids,17a acetylcholine receptor
ligands17b or other enzyme inhibitors.17c
THF/H2O,
80 °C, 5.5 h
95
S
12
B(OH)2
S
N
S
Solvents were purified according to standard procedures. Flash
chromatography was performed on Merck silica gel 60 (0.040–
0.063 mm) at a pressure of 0.4 bar. TLC was performed on Merck
silica gel aluminum plates, 60F254. Compounds were visualized by
treatment with a solution of (NH4)6Mo7O24·4H2O (20 g) and
Ce(SO4)2 (0.4 g) in 10% sulfuric acid (400 mL) or ninhydrin (2 g)
in MeOH (200 mL) and heating at 150 °C. All compounds were of
white to yellowish color unless stated otherwise indicated. NMR
spectra were recorded with Bruker Avance 400, 500 or 600 spec-
trometers. TMS, or the resonance of the residual solvent (DMSO-
d6: d = 2.49), was used as internal standard. Diastereomeric groups
Boc
N
H
CO2Me
O
THF, 95 °C,
8.5 h
B(OH)2
71c
13
S
N
Boc
N
H
CO2Me
are marked with t (low-field shift) and h (high-field shift). All 13
C
O
assignments are based on inverse CH correlations (HMQC and HM-
BC). Mass spectra were taken on a Finnigan MAT 95 spectrometer.
FT-IR spectra were recorded on a Bruker IFS 88 spectrometer. Ele-
mental analyses were obtained with an Elementar Vario III analyz-
er. Melting points were measured on a Büchi 530 apparatus.
a Reaction conditions: 10 (1 equiv), boronic acid (3 equiv),
K3PO4·H2O (3 equiv), Pd(OAc)2 (5 mol%) and S-Phos (10 mol%).
b Isolated yield.
c 2 equiv of boronic acid and K3PO4·H2O were used.
Methyl (3R,6R,7R,8S,8aS)-6-Azido-7,8-dihydroxy-5-oxo-
hexahydro-5H-[1,3]thiazolo[3,2-a]pyridine-3-carboxylate (2)
Compound 1 (6.43 g, 24.4 mmol) was dissolved in a mixture of an-
hyd CH2Cl2 (125 mL) and anhyd pyridine (25 mL). At a reaction
temperature of –50 °C, a solution of Tf2O (4.6 mL, 26.9 mmol) in
CH2Cl2 (4.6 mL) was added over a period of 15 min. The mixture
In order to diversify the chromophores of this class of 2-
pyridones, the thiaproline 5 was oxidized either with an
equimolar amount or with an excess of m-chloroperben-
zoic acid. The former yielded a mixture of crystalline 14
and light pink oily 15 in a ratio of 1:2.3, which is ex-
plained with coordination of the reagent to the carbonyl was allowed to warm up to r.t. over 1 h 45 min and stirred for an-
other 45 min at r.t. After the addition of a solution of Tf2O (0.4 mL,
2.4 mmol) in CH2Cl2 (0.4 mL) and keeping at r.t. for 45 min, the
mixture was treated with ice (75 mL). The product was extracted
oxygen of the methyl ester of 5. The latter resulted in the
corresponding sulfone 16 (Figure 3). Suitable crystals for
X-ray analysis could be obtained from 14 by recrystalliza-
with EtOAc (3 × 100 mL) and the combined organic phases were
tion from ethanol so that 14 and 15 could be identified re-
dried (Na2SO4). After evaporation of the solvent, the brown residue
liably (14).16 The fluorescence quantum yield of each
oxidized product was five to six times higher than for 5,
was taken up in DMF (200 mL) and NaN3 (3.18 g, 49.7 mmol) was
added. The mixture was stirred at r.t. for 18 h, concentrated under
probably because of the missing quenching of the S1 lone vacuum and partitioned between H2O and EtOAc (1:2, 150 mL).
pairs. Further details are discussed elsewhere.11
The aqueous phase was extracted with EtOAc (2 × 100 mL, 6 × 50
mL). The combined organic phases were dried (Na2SO4) and the
solvent was evaporated. The residue was purified by flash chroma-
tography (EtOAc–toluene, 3:1) to afford 2 (5.15 g, 73%) as a pale-
In conclusion, an efficient protocol is presented here to-
wards bicyclic dipeptide lactams wherein a pyridone
chromophore is an integral part of the peptide backbone. brown syrup; Rf 0.43. For analytical data, see lit.8
This rigid pyridone dipeptide can anchor various chro-
mophores at the peptide backbone in a predictable relative
orientation. The peptides depicted in Table 1 are UV-la-
bels with selected CD-absorption and luminescence prop-
Methyl (3R,6R/S,7R,8S,8aS)-6-tert-Butoxycarbonylamino-7,8-
dihydroxy-5-oxohexahydro-5H-[1,3]thiazolo[3,2-a]pyridine-3-
carboxylate (3)
Diastereomeric 2 (4.21 g, 14.6 mmol) and Ph3P (5.75 g, 21.9 mmol)
were dissolved in THF–H2O (10:1, 110 mL). The solution was
erties. The photochemical properties of bioactive peptides
Synthesis 2006, No. 19, 3224–3230 © Thieme Stuttgart · New York

PAPER
Pyridone Dipeptide Chromophores
3227
stirred for 20 h at r.t. and Boc2O (3.82 g, 21.9 mmol) was added.
Stirring at r.t. was continued for 12 h, the solution was concentrated
under vacuum and the product was isolated by flash column chro-
matography (EtOAc–toluene, 3:1) to yield 4.54 g (86%) of diaste-
reomeric 3 as a pale-yellow solid. For analytical data, see ref.8
Methyl (3R)-6-{[(9H-Fluoren-9-ylmethoxy)carbonyl]amino}-5-
oxo-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]pyridine-3-carboxylate
(6)
Compound 5 (1.42 g, 5.6 mmol) was dissolved in MeOH (80 mL).
Pd/C (0.15 g) was added and the suspension was stirred for 20 h un-
der a H2 atmosphere (1 atm). The mixture was filtered through a pad
of Kieselguhr and the solvent was evaporated. 1H NMR of the crude
product confirmed the quantitative reduction of 4. The formed
amine (260 mg, 1.15 mmol) was dissolved in acetone (40 mL) fol-
lowed by the addition of Fmoc-N-oxysuccinimide (590 mg, 1.73
mmol) and NaHCO3 (96 mg, 1.15 mmol). The mixture was stirred
at r.t. for 5 d. Aq 1 N HCl was added until pH 5, acetone was evap-
orated and the aqueous phase was extracted with CH2Cl2 (2 ×). The
combined organic phases were dried (Na2SO4) and the solvent was
evaporated. Flash chromatography (EtOAc–toluene, 1:1, Rf 0.59)
yielded 6 as a yellowish oil. Recrystallization from EtOH gave 320
mg (62%) of colorless crystals; mp 158 °C; [a]D24 –204.6 (c = 1,
MeOH).
Methyl (3R)-6-Azido-5-oxo-2,3-dihydro-5H-[1,3]thiazolo[3,2-
a]pyridine-3-carboxylate (4)
Compound 2 (2.6 g, 9.0 mmol) was dissolved in a mixture of anhyd
CH2Cl2 and anhyd pyridine (1:1, 100 mL). Et3N (3.8 mL, 27 mmol)
was added and the solution was cooled to 0 °C in an ice-bath.
MeSO2Cl (2.1 mL, 27 mmol) was injected via syringe under vigor-
ous stirring over ca. 5 min. The ice-bath was removed after 20 min
and the mixture was stirred at r.t. for additional 40 min. Excess re-
agent was quenched with ice (75 mL), and after addition of NaCl
(1.5 g), the aqueous phase was extracted with CH2Cl2 (2 ×). The
combined organic phases were dried (Na2SO4) and the solvent
evaporated. Purification by flash chromatography (EtOAc–toluene,
1:3) yielded 4 (1.84 g, 81%) as a brown oil; Rf 0.5; [a]D24 –270
(c = 1, MeOH).
IR (KBr): 3377, 3038, 2961, 1734, 1650, 1599, 1506, 1448, 1356,
1301 1202, 1078, 758, 737 cm–1.
1H NMR (600 MHz, DMSO-d6): d = 8.63 (br, 1 H, NH), 7.89 (m,
2 H, Fmoc-Harom), 7.78 (m, 2 H, Fmoc-Harom), 7.67 (br, 1 H, 7-H),
7.41 (m, 2 H, Fmoc-Harom), 7.33 (m, 2 H, Fmoc-Harom), 6.27 (d,
1H NMR (400 MHz, DMSO-d6): d = 7.05 (d, 3J7-H,8-H = 7.8 Hz, 1 H,
7-H), 6.31 (d, 3J8-H,7-H = 7.8 Hz, 1 H, 8-H), 5.61 (dd, 3J3-H,2-Ht = 9.0
3
2
t
Hz, J3-H,2-Hh = 2.0 Hz, 1 H, 3-H), 3.94 (dd, J2-H ,2-Hh = 12.0 Hz,
3J2-H ,3-H = 9.0 Hz, 1 H, 2-Ht), 3.74 (s, 3 H, OCH3), 3.65 (dd,
t
3
t
3J8-H,7-H = 7.3 Hz, 1 H, 8-H), 5.60 (dd, J3-H,2-H = 8.9 Hz,
2J2-H ,2-Ht = 12.0 Hz, 3J2-H ,3-H = 2.0 Hz, 1 H, 2-Hh).
h
h
3J3-H,2-Hh = 2.0 Hz, 1 H, 3-H), 4.37 (d, 3JFmoc-H
tert = 6.9 Hz, 2
sec
, Fmoc-H
13C NMR (100 MHz, DMSO-d6): d = 168.1 (CO2CH3), 156.9 (5-
CO), 143.9 (8a-C), 127.4 (7-C), 123.1 (6-C), 99.5 (8-C), 62.7 (3-C),
53.0 (OCH3), 31.7 (2-C).
H, Fmoc-Hsec), 4.27 (t, JFmoc-H
H
sec = 7.0 Hz, 1 H, Fmoc-
3
tert
,
Fmoc-H
3
tert), 3.92 (dd, J2-H ,2-Hh = 11.9 Hz, J2-H ,3-H = 8.9 Hz, 1 H, 2-Ht),
2
t
t
3.72 (s, 3 H, OCH3), 3.62 (dd, 2J2-H , 2-Ht = 11.9 Hz, 3J2-H , 3-H = 2.1
h
h
Hz, 1 H, 2-Hh).
MS (EI, 70 eV): m/z = 252.0 [M]+.
13C NMR (150 MHz, DMSO-d6): d = 168.4 (CO2CH3), 156.5 (5-
CO), 153.5 (Fmoc-CO), 143.6, 140.7 (4 C, fluorenyl-Cquat), 140.0
(8a-C), 127.7 (2 C, fluorenyl), 127.1 (2 C, fluorenyl), 125.4 (fluore-
nyl), 125.3 (fluorenyl), 125.3 (7-C), 124.3 (6-C), 120.1 (2 C, fluo-
renyl), 99.0 (8-C), 66.3 (Fmoc-Csec), 62.8 (3-C), 52.9 (OCH3), 46.4
(Fmoc-Ctert), 31.6 (2-C).
Methyl (3R)-6-[(tert-Butoxycarbonyl)amino]-5-oxo-2,3-dihy-
dro-5H-[1,3]thiazolo[3,2-a]pyridine-3-carboxylate (5)
Compound 3 (5.03 g, 13.8 mmol) was dissolved in a mixture of an-
hyd CH2Cl2 and anhyd pyridine (1:1, 60 mL). Et3N (6.7 mL, 48.6
mmol) was added and the solution was cooled to 0 °C in an ice-bath.
MeSO2Cl (3.2 mL, 41.6 mmol) was injected via syringe under vig-
orous stirring over ca. 5 min. The ice-bath was removed after 20 min
and the mixture was stirred at r.t. for additional 20 h. Excess reagent
was quenched with ice (75 mL), and after the addition of NaCl (2
g), the aqueous phase was extracted CH2Cl2 (2 ×). The combined or-
ganic phases were dried (Na2SO4) and the solvent evaporated. Puri-
fication by flash chromatography (EtOAc–toluene, 1:1) yielded 5
(4.12 g, 91%) as an oil; Rf 0.58. Recrystallization from EtOAc–pe-
troleum ether (bp 40–60 °C) gave colorless crystals; mp 117 °C;
[a]D24 –268 (c = 1, MeOH).
CI-MS (positive): m/z = 449.0 [M + H]+.
Anal. Calcd for C24H20N2O5S: C, 64.27; H, 4.49; N, 6.25. Found: C,
63.53; H, 4.45; N, 6.17.
(3R)-6-{[(9H-Fluoren-9-ylmethoxy)carbonyl]amino}-5-oxo-2,3-
dihydro-5H-[1,3]thiazolo[3,2-a]pyridine-3-carboxyic Acid (7)
Compound 6 (572 mg, 1.28 mmol) was dissolved in AcOH (120
mL) and aq 6 N HCl (75 mL). The solution was stirred for 7 d at r.t.
and was heated 5 times for 6 h to 50 °C. The solvent was evaporated
1
and the residue was co-evaporated 3 times with aq 1 N HCl. H
IR (KBr): 3270, 3113, 2984, 1750, 1737, 1712, 1638, 1586, 1508,
1357, 1220, 1153, 1071, 767, 725 cm–1.
NMR showed quantitative cleavage of the methyl ester; mp 235 °C
(dec.); [a]D24 –141 (c = 1, MeOH).
1H NMR (600 MHz, DMSO-d6): d = 7.74 (d, 3J7-H,8-H = 7.7 Hz, 1 H,
IR (KBr): 3331, 2950, 2605, 1722, 1632, 1576, 1509 1205, 1185,
7-H), 7.72 (s, 1 H, NH), 6.30 (d, 3J8-H,7-H = 7.8 Hz, 1 H, 8-H), 5.61
1073, 756 cm–1.
3
3
h
(dd, J3-H,2-Ht = 8.7 Hz, J3-H,2-H = 1.9 Hz, 1 H, 3-H), 3.92 (dd,
1H NMR (600 MHz, DMSO-d6): d = 8.24 (br s, 1 H), 7.89 (m, 2 H,
Fmoc-Harom), 7.75 (m, 2 H, Fmoc-Harom), 7.6 (br s, 1 H), 7.41 (m, 2
H, Fmoc-Harom), 7.33 (m, 2 H, Fmoc-Harom), 6.10 (br s, 1 H, 8-H),
2J2-H ,2-Hh = 12.0 Hz, J2-H ,3-H = 8.7 Hz, 1 H, 2-Ht), 3.71 (s, 3 H,
t
3
t
OCH3), 3.61 (dd, 2J2-H ,2-Ht = 12.0 Hz, 3J2-H ,3-H = 1.9 Hz, 1 H, 2-Hh),
1.44 (s, 9 H, t-C4H9).
h
h
5.15 (d, 3J3,2-Ht = 8.2 Hz, 1 H, 3-H), 4.41 (br s, 2 H, Fmoc-CH2), 4.28
13C NMR (150 MHz, DMSO-d6): d = 168.4 (CO2CH3), 165.3 (5-
CO), 152.4 (t-BuOCO), 138.9 (8a-C),124.6 (6-C), 123.3 (7-C),
99.3 (8-C), 79.9 [C(CH3)3], 62.8 (3-C), 52.9 (OCH3), 31.6 (2-C),
27.9 [3 C, C(CH3)3].
3
(pt, JFmoc-CH,
= 6.9 Hz, 2 H, Fmoc-CH), 3.71 (dd,
Fmoc-CH2
2
t
3J2-H ,3 = 8.2 Hz, J2-Hgem = 11.0 Hz, 1 H, 2-Ht), 3.63 (d,
2J2-Hgem = 11.0 Hz, 1 H, 2-Hh).
13C NMR (HMQC, DMSO-d6): d = 127.4, 126.8, 124.9, 119.8
(Fmoc-CHarom), 97.7 (C-8), 66.0 (Fmoc-CH2), 65.7 (C-3), 46.4
(Fmoc-CH), 33.3 (C-2).
EI-MS (70 eV, positive): m/z = 326.2 [M]+.
Anal. Calcd for C14H18N2O5S: C, 51.52; H, 5.56; N, 8.58; S, 9.82.
Found: C, 51.61; H, 5.39; N, 8.42; S, 9.37.
MS (ESI): m/z = 433.0 [M – H]–, 867.4 [2 M – H]–.
Cyclic Hexapeptides 8 and 9
The linear deprotected hexapeptide H2N-gly-(thiazolopyridone)-
gly-(thiazolopyridone)-CO2H·2LiCl hydrochloride (80 mg, 0.154
Synthesis 2006, No. 19, 3224–3230 © Thieme Stuttgart · New York

3228
H. Seger, A. Geyer
PAPER
Methyl (3R)-8-Phenyl-6-[(tert-butoxycarbonyl)amino]-5-oxo-
mmol) was dissolved in DMF (800 mL) and treated with HOAT (32
mg, 0.23 mmol), HATU (88 mg, 0.23 mmol), 1,3,5-collidine (0.2
mL, 188 mg, 1.5 mmol) and stirred for 4 days at r.t. Evaporation of
the solvent and purification of the crude product by flash column
chromatography (CHCl3–MeOH, 5:1, Rf 0.45) yielded a mixture of
8 and 9 (44 mg, 57%). The mixture could be separated by prepara-
tive HPLC. The [a]D values could not be specified exactly because
of the very bad solubility of both products in all of the tested sol-
vents. Nevertheless the measured values could be taken qualitative-
ly to identify 8 as a meso compound and 9 as the expected chiral
product.
2,3-dihydro-5H-[1,3]thiazolo[3,2-a]pyridine-3-carboxylate (11)
Compound 10 (200 mg, 0.494 mmol), phenylboronic acid (180 mg,
1.48 mmol), K3PO4·H2O (340, mg, 1.48 mmol), Pd(OAc)2 (5.6 mg,
0.025 mmol) and S-Phos (21 mg, 0.051 mmol) were filled into a dry
5 mL flask under argon. The flask was evacuated and backfilled
with argon three times before anhyd THF (2 mL) was added. The
flask was sealed, and the mixture was heated to 80 °C for 4.25 h.
H2O (10 mL) was added, the aqueous phase extracted with EtOAc
(2 ×) and the combined organic phases dried (Na2SO4). The solvent
was evaporated and flash chromatography [toluene–EtOAc (4:1); Rf
0.22 (8:1)] yielded 170 mg (86%) of 11 as a colorless solid; mp
169 °C; [a]D22 –40 (c = 1, CHCl3).
MS (ES, positive, product mixture): m/z = 503.2 [M + H]+, 509.0
[M + Li]+, 520.2 [M + NH4]+.
IR (KBr): 3409, 2977, 1751, 1723, 1649, 1599, 1505, 1487, 1402,
8
1368, 1227, 1151, 1088, 165, 701 cm–1.
IR (KBr): 3371, 3268, 1679, 1635, 1585, 1522, 1235, 764 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 7.94 (s,1 H, 7-H), 7.88 (s, 1 H,
1H NMR (600 MHz, DMSO-d6): d = 9.22 (dd, JGly-NH,Gly-Ht = 7.7
NH), 7.50–7.33 (m, 5 H, C6H5), 5.71 (dd, J3-H,2-H = 8.9 Hz,
3
3
t
Hz, JGly-NH,Gly-Hh = 5.0Hz, 2 H, Gly-NH), 8.89 (s, 2 H, Bic-NH),
3J3-H,2-H = 1.9 Hz, 1 H, 3-H), 3.87 (dd, J2-H ,2-H = 11.9 Hz,
3
h
2
t
h
7.95 (d, 3J7-H,8-H = 8.0 Hz, 2 H, 7-H), 6.33 (d, 3J8-H,7-H = 8.0 Hz, 2 H,
8-H), 5.19 (dd, 3J3-H,2-Ht = 8.8 Hz, 3J3-H,2-Hh = 7.7 Hz, 2 H, 3-H), 4.18
3J2-H ,3-H = 8.8 Hz, 1 H, 2-Ht), 3.74 (s, 3 H, OCH3), 3.62 (dd,
t
h
3
h
2J2-H ,2-Ht = 11.9 Hz, J2-H ,3-H = 1.8 Hz, 1 H, 2-Hh), 1.44 (s, 9 H, t-
(dd, JGly-H ,Gly-Hh = 16.6 Hz, JGly-H ,Gly-NH = 7.7 Hz, 2 H, Gly-Ht),
C4H9).
2
t
3
t
3.84 (dd, J2-H ,2-Hh = 11.5 Hz, J2-H ,3-H = 9.0 Hz, 2 H, 2-Ht), 3.62
2
t
3
t
13C NMR (125 MHz, DMSO-d6): d = 168.3 (CO2CH3), 155.6 (5-
CO), 152.4 (t-BuOCO), 137.5 (Carom), 136.7 (8a-C), 128.9, 127.5,
127.3 (CHarom), 125.5 (6-C), 124.1 (7-C), 113.1 (8-C), 80.1
[C(CH3)3], 63.1 (3-C), 53.0 (OCH3), 31.2 (2-C), 27.9 [3 C,
C(CH3)3].
(dd, JGly-H ,Gly-Ht = 16.5 Hz, JGly-H ,Gly-NH = 4.7 Hz, 2 H, Gly-Hh),
2
h
3
h
3.45 (dd, 2J2-H ,2-Ht = 11.5 Hz, 3J2-H ,3-H = 7.7 Hz, 2 H, 2-Hh).
h
h
13C NMR (HMQC, DMSO-d6): d = 127.5 (7-C), 98.7 (8-C), 65.7
(3-C), 43.7 (Gly-C), 30.7 (2-C).
HRMS (ESI): m/z calcd for C20H22N2O5S + Na: 425.1142; found:
425.1145.
9
IR (KBr): 3459, 3339, 3288, 1639, 1589, 1513, 1237, 769 cm–1.
1H NMR (600 MHz, DMSO-d6): d = 9.17 (pt, 3J = 5.9 Hz, 2 H, Gly-
Methyl (3R)-8-(2-Thienyl)-6-[(tert-butoxycarbonyl)amino]-5-
oxo-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]pyridine-3-carboxylate
(12)
3
NH), 8.94 (s, 2 H, Bic-NH), 8.23 (d, J7-H,8-H = 8.0 Hz, 2 H, 7-H),
6.27 (d, 3J8-H,7-H = 8.0 Hz, 2 H, 8-H), 5.35 (dd, 3J3-H,2-Ht = 8.8 Hz,
3J3-H,2-Hh = 5.9 Hz, 2 H, 3-H), 3.95 (dd, JGly-H ,Gly-Hh = 17.3 Hz,
Compound 10 (400 mg, 0.988 mmol), thiophene-2-boronic acid
(379 mg, 2.96 mmol), K3PO4·H2O (680 mg, 2.96 mmol), Pd(OAc)2
(11.8 mg, 0.05 mmol) and S-Phos (44.5 mg, 0.099 mmol) were
filled into a Schlenk tube under argon. Degassed THF (3 mL) and
H2O (1 mL) were added. The tube was sealed and the mixture was
heated to 80 °C for 4 h. H2O (10 mL) was added, the aqueous phase
extracted with EtOAc (2 ×) and the combined organic phases were
dried (Na2SO4). The crude mixture was purified by flash chroma-
tography [toluene–EtOAc (4:1), Rf 0.18 (8:1)] to afford 383 mg
(95%) of 12 as a colorless solid; mp 182 °C; [a]D20 –227 (c = 1,
CHCl3).
2
t
t
t
3JGly-H ,Gly-NH = 6.6 Hz, 2 H, Gly-Ht), 3.86 (dd, 2J2-H ,2-Hh = 11.5 Hz,
3J2-H ,3-H = 8.9 Hz, 2 H, 2-Ht), 3.79 (dd, JGly-H
t = 17.3 Hz,
t
2
h
,Gly-H
h
h
3JGly-H ,Gly-NH = 5.5 Hz, 2 H, Gly-Hh), 3.45 (dd, 2J2-H ,2-Ht = 11.5 Hz,
3J2-H ,3-H = 6.0 Hz, 2 H, 2-Hh).
h
13C NMR (HMQC, DMSO-d6): d = 124.4 (7-C), 98.7 (8-C), 64.9
(3-C), 43.7 (Gly-C), 30.7 (2-C).
Methyl (3R)-8-Bromo-6-[(tert-butoxycarbonyl)amino]-5-oxo-
2,3-dihydro-5H-[1,3]thiazolo[3,2-a]pyridine-3-carboxylate (10)
Compound 5 (1.30 g, 3.99 mmol) was dissolved in CCl4 and NBS
(781 mg, 4.39 mmol) was added. The mixture was refluxed for 8 h,
the solvent evaporated and the product purified by flash column
chromatography (EtOAc–toluene, 2:3, Rf 0.52); yield: 1.533 g
(95%); colorless solid; mp 171 °C (dec.); [a]D24 –262.6 (c = 1,
MeOH).
IR (KBr): 3407, 3116, 2976, 1754, 1725, 1642, 1603, 1490, 1439,
1368, 1219, 1152, 1087, 695 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 8.06 (s,1 H, 7-H), 7.92 (s, 1 H,
NH), 7.58 (dd, 3Jthienyl-5-H,thienyl-4-H = 5.1 Hz, 3Jthienyl-5-H,thienyl-3-H = 1.2
3
Hz, 1 H, thienyl-5-H), 7.18 (dd, Jthienyl-3-H,thienyl-4-H = 3.6 Hz,
IR (KBr): 3412, 3348, 2978, 1755, 1730, 1647, 1586, 1490, 1365,
1221, 1149, 1091, 762 cm–1.
3Jthienyl-3-H,thienyl-5-H = 1.2 Hz, 1 H, thienyl-3-H), 7.15 (dd,
3
3Jthienyl-4-H,thienyl-5-H = 5.1 Hz, Jthienyl-4-H,thienyl-3-H = 3.6 Hz, 1 H, thie-
nyl-4-H), 5.73 (dd, 3J3-H,2-Ht = 8.9 Hz, 3J3-H, 2-Hh = 1.8 Hz, 1 H, 3-H),
1H NMR (400 MHz, DMSO-d6): d = 8.0 (s, 1 H, NH), 7.87 (s, 1 H,
t
t
3.94 (dd, 2J2-H , 2-Hh = 11.9 Hz, 3J2-H , 3-H = 8.9 Hz, 1 H, 2-Ht), 3.75 (s,
7-H), 5.76 (dd, 3J3-H,2-Ht = 8.9 Hz, 3J3-H,2-Hh = 2.0 Hz, 1 H, 3-H), 3.97
3 H, OCH3), 3.69 (dd, 2J2-H ,2-Ht = 11.9 Hz, 3J2-H ,3-H = 1.8 Hz, 1 H,
h
h
t
t
(dd, 2J2-H ,2-Hh = 12.0 Hz, 3J2-H ,3-H = 8.9 Hz, 1 H, 2-Ht), 3.72 (s, 3 H,
2-Hh), 1.47 (s, 9 H, t-C4H9).
OCH3), 3.67 (dd, 2J2-H ,2-Ht = 12.0 Hz, 3J2-H ,3-H = 2.0 Hz, 1 H, 2-Hh),
h
h
1.44 (s, 9 H, t-C4H9).
13C NMR (125 MHz, DMSO-d6): d = 168.3 (CO2CH3), 155.4 (5-
CO), 152.4 (t-BuOCO), 139.1 (thienyl-Cquat), 136.5 (8a-C), 127.9
(thienyl-4-C), 125.38, 125.45 (6-C, thienyl-5-C), 124.8 (thienyl-3-
C), 123.0 (7-C), 107.0 (8-C), 80.2 [C(CH3)3], 63.1 (3-C), 53.0
(OCH3), 31.5 (2-C), 27.9 [3 C, C(CH3)3].
13C NMR (100 MHz, DMSO-d6): d = 168.0 (CO2CH3), 155.1 (5-
CO), 152.2 (t-BuOCO), 139.0 (8a-C), 125.8 (6-C), 124.7 (7-C),
90.3 (8-C), 80.3 [C(CH3)3], 64.5 (3-C), 53.0 (OCH3), 31.4 (2-C),
27.8 [3 C, C(CH3)3].
MS (ESI): m/z = 409.0 [M + H]+, 431.1 [M + Na]+.
MS (PI-DCI): m/z = 405.0 [M1 + H]+, 407.0 [M2 + H]+.
HRMS (ESI): m/z calcd for C18H20N2O5S2 + Na: 431.0706; found:
431.0701.
Anal. Calcd for C14H17BrN2O5S: C, 41.49; H, 4.23; N, 6.91. Found:
C, 41.46; H, 4.23; N, 6.95.
Synthesis 2006, No. 19, 3224–3230 © Thieme Stuttgart · New York

PAPER
Pyridone Dipeptide Chromophores
3229
Methyl (3R)-8-(1-Pyrenyl)-6-[(tert-butoxycarbonyl)amino]-5-
oxo-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]pyridine-3-carboxylate
(13)
IR (KBr): 3384, 2955, 2929, 1728, 1650, 1607, 1505, 1368, 1217,
1155, 1052, 957, 771 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 8.18 (s, 1 H, NH), 8.00 (d,
Compound 10 (300 mg, 0.74 mmol), pyrene-1-boronic acid (364
mg, 1.48 mmol), K3PO4·H2O (340 mg, 1.48 mmol), Pd(OAc)2 (8.3
mg, 0.037 mmol) and S-Phos (30.4 mg, 0.074 mmol) were filled
into a dry Schlenk tube under argon. The tube was evacuated and
backfilled with argon before anhyd THF (1.5 mL) was added. The
tube was sealed, and the mixture was heated to 85 °C for 3.5 h and
another 5 h at 100 °C. H2O was added and the aqueous phase was
extracted with EtOAc (4 ×). The combined organic phases were
dried (Na2SO4) and the crude mixture was purified by flash chroma-
tography [toluene–EtOAc (4:1); Rf 0.27 (8:1)] to give 278 mg (71%)
of 13 as a colorless solid; mp 236 °C; [a]D24 –201 (c = 1, CDCl3).
3
3J7-H,8-H = 7.6 Hz, 1 H, 7-H), 7.16 (d, J8-H,7-H = 7.6 Hz, 1 H, 8-H),
5.83 (dd, 3J3-H,2-Hh = 1.2 Hz, 3J3-H,2-Ht = 8.7 Hz, 1 H, 3-H), 3.75 (dd,
2J2-H ,2-Hh = 14.4 Hz, J2-H ,3-H = 8.7 Hz, 1 H, 2-Ht), 3.68 (s, 3 H,
t
3
t
OCH3), 3.62 (dd, 2J2-H ,2-Ht = 14.4 Hz, 3J2-H ,3-H = 1.2 Hz, 1 H, 2-Hh),
1.47 (s, 9 H, t-C4H9).
h
h
13C NMR (125 MHz, DMSO-d6): d = 167.9 (CO2CH3), 154.5, 152.0
(5-CO, t-BuOCO), 141.7 (8a-C), 132.2 (6-C), 119.1 (7-C), 108.2
(8-C), 80.8 [C(CH3)3], 61.3 (3-C), 52.8, 52.3 (OCH3, 2-C), 27.8
[C(CH3)3].
MS (ESI): m/z = 365.0 [M + Na]+.
IR (KBr): 3264, 2976, 1746, 1716, 1635, 1587, 1496, 1438, 1397,
1366, 1218, 1151, 1080, 852 cm–1.
HRMS (ESI): m/z calcd for C14H18N2O6S + Na: 365.0778; found:
365.0782.
1H NMR (500 MHz, 370 K, DMSO-d6): d = 8.38–7.65 (m, 10 H),
t
t
5.79 (m, 1 H, 3-H), 3.94 (dd, 2J2-H ,2-Hh = 11.9 Hz, 3J2-H ,3-H = 8.6 Hz,
Methyl (3R)-6-[(tert-Butoxycarbonyl)amino]-5-oxo-2,3-dihy-
dro-5H-[1,3]thiazolo[3,2-a]pyridine-3-carboxylate 1,1-Dioxide
(16)
2
h
t
1 H, 2-Ht), 3.84 (s, 3 H, OCH3), 3.58 (dd, J2-H
= 11.9 Hz,
,2-H
h
3J2-H ,3-H = 2.3 Hz, 1 H, 2-Hh), 1.45 (s, 9 H, t-C4H9).
To a solution of 5 (320 mg, 0.99 mmol) in EtOAc (20 mL) was add-
ed MCPBA (70%, 970 mg, 3.95 mmol). The solution was stirred at
r.t. for 18 h and neutralized with Et3N while the color changed from
red to blue. The solvent was evaporated and after flash chromatog-
raphy [EtOAc–toluene (3:2), Rf 0.56] to give 349 mg (98%) of 16 as
a pale-pink solid; mp 106 °C; [a]D24 –219.1 (c = 1, MeOH).
13C NMR (125 MHz, 298 K, CDCl3, double signal set): d = 168.4
(CO2CH3), 156.7 (5-CO), 152.8 (t-BuOCO), 136.7 (8a-C), 133–
124.5 (28 signals), 114.4 (8-C), 81 [C(CH3)3], 64.0, 63.9 (3-C), 53.6
(OCH3), 32.2, 32.2 (2-C), 28.4 [3 C, C(CH3)3].
MS (ESI): m/z = 549.2 [M + Na]+.
HRMS (ESI): m/z calcd for C30H26N2O5S + Na: 549.1455; found:
549.1457.
1H NMR (600 MHz, DMSO-d6): d = 8.36 (s, 1 H, NH), 8.04 (d,
3
3J7-H,8-H = 7.7 Hz, 1 H, 7-H), 7.05 (d, J8-H,7-H = 7.7 Hz, 1 H, 8-H),
5.67 (dd, 3J3-H,2-Hh = 9.4 Hz, 3J3-H,2-Ht = 1.7 Hz, 1 H, 3-H), 4.26 (dd,
t
h
3
t
(1R,3R)-Methyl 6-tert-Butoxycarbonylamino-1,5-dioxo-2,3-di-
hydro-5H-1,3-thiazolo[3,2-a]pyridine-3-carboxylate (14) and
(1S,3R)-Methyl 6-tert-Butoxycarbonylamino-1,5-dioxo-2,3-di-
hydro-5H-1,3-thiazolo[3,2-a]pyridine-3-carboxylate (15)
Compound 5 (1.33 g, 4.07 mmol) was dissolved in EtOAc (50 mL).
The solution was cooled in an ice-bath and MCPBA (70%, 1 g, 4.07
mmol) was added. The cooling bath was removed after 3 h and the
solution was extracted with aq 1 N NaHCO3 and with H2O (2 ×).
The combined aqueous phases were extracted with EtOAc. The
combined organic phases were dried (Na2SO4) and the solvent
evaporated. Flash chromatography (EtOAc–toluene, 3:1) yielded
447 mg (32%) of crystalline 14 and 968 mg (69%) of pale-pink syr-
up 15.
2J2-H ,2-H = 13.9 Hz, J2-H ,3-H = 1.7 Hz, 1 H, 2-Ht), 4.13 (dd,
h
3
h
2J2-H ,2-Ht = 13.9 Hz, J2-H ,3-H = 9.4 Hz, 1 H, 2-Hh), 3.73 (s, 3 H,
OCH3), 1.46 (s, 9 H, t-C4H9).
13C NMR (150 MHz, DMSO-d6): d = 168.7 (CO2CH3), 153.9, 152.1
(5-CO, t-BuOCO), 133.6 (8a-C), 133.0 (6-C), 119.3 (7-C), 101.9
(8-C), 80.9 [C(CH3)3], 45.2 (3-C), 53.3 (OCH3), 50.5 (2-C), 27.8 [3
C, C(CH3)3]; mp 106 °C; [a]D24 –219.1 (c = 1, MeOH).
EI-MS (70 eV, positive): m/z = 358.0 [M]+.
Anal. Calcd for C14H18N2O7S: C, 46.92; H, 5.06; N, 7.82; S, 8.95.
Found: C, 46.81; H, 4.93; N, 7.44; S, 8.06.
Acknowledgment
14
The authors thank Dr. M. Zabel (Fachbereich Chemie, Universität
Regensburg) for crystal structure analysis of compounds 5 and 6.
This work was supported by the Deutsche Forschungsgemeinschaft
and the Fonds der Chemischen Industrie.
Mp 198 °C (dec.); [a]D24 –243 (c = 1, MeOH).
IR (KBr): 3325, 3107, 2979, 1758, 1722, 1648, 1598, 1506, 1366,
1340, 1248, 1219, 1148, 1058, 960, 776, 688 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 8.20 (s, 1 H, NH), 8.03 (d,
3J7-H,8-H = 7.7 Hz, 1 H, 7-H), 7.1 (d, J8-H,7-H = 7.7 Hz, 1 H, 8-H),
3
References
5.61 (dd, 3J3-H,2-Ht = 6.3 Hz, 3J3-H,2-Hh = 7.4 Hz, 1 H, 3-H), 3.89 (dd,
3J2-H ,3-H = 6.3 Hz, J2-H ,2-H = 13.6 Hz, 1 H, 2t-H), 3.72 (dd,
t
3
t
h
(1) Freidinger, R. M.; Perlow, D. S.; Veber, D. F. J. Org. Chem.
1982, 47, 104.
3J2-H ,3-H = 7.4 Hz, J2-H ,2-Ht = 13.6 Hz, 1 H, 2h-H), 3.71 (s, 3 H,
h
3
h
OCH3), 1.46 (s, 9 H, t-C4H9).
(2) Nagai, U.; Sato, K. Tetrahedron Lett. 1985, 26, 647.
(3) (a) Hanessian, S.; McNaughton-Smith, G.; Lombart, H.-G.;
Lubell, W. D. Tetrahedron 1997, 53, 12789. (b) Cluzeau,
J.; Lubell, W. D. Biopolymers 2005, 80, 98. (c)Maison,W.;
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2869.
13C NMR (125 MHz, DMSO-d6): d = 168.3 (CO2CH3), 154.6, 152.0
(5-CO, t-BuOCO), 142.4 (8a-C), 131.8 (6-C), 119.9 (7-C), 107.9
(8-C), 80.8 [C(CH3)3], 61.2 (3-C), 53.0 (OCH3), 52.4 (2-C), 27.8 [3
C, C(CH3)3].
MS (ESI): m/z = 343.1 [M + H]+, 365.1 [M + Na]+.
HRMS (ESI): m/z calcd for C14H18N2O6S + Na: 365.0778; found:
365.0779.
15
[a]D24 –196 (c = 1, MeOH).
(7) Vaultier, M.; Knouzi, M.; Carri, R. Tetrahedron Lett. 1983,
24, 763.
Synthesis 2006, No. 19, 3224–3230 © Thieme Stuttgart · New York

3230
H. Seger, A. Geyer
PAPER
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Chem. 2003, 878.
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A.; Harms, K. Acta Crystallogr. 2005, E61, o2576.
(10) CCDC number 607190. Crystallographic data can be
obtained free of charge from the Cambridge
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L. Angew. Chem. Int. Ed. 2004, 43, 1871.
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S. L. J. Am. Chem. Soc. 2005, 127, 4685. (b) Becht, J.;
Ngouela, S.; Wagner, A.; Mioskowski, C. Tetrahedron
2004, 60, 6853.
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; Fax: +44(1223)336033; E-mail:
deposit@ccdc.cam.ac.uk.
(16) Seger, H.; Marsch, M.; Geyer, A.; Harms, K. Acta
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Synthesis 2006, No. 19, 3224–3230 © Thieme Stuttgart · New York