Cross-claisen condensation of N-Fmoc-amino acids - A short route to heterocyclic γ-amino acids

Article abstract of DOI:10.1002/ejoc.201500012

4-Amino(methyl)-1,3-thiazole-5-carboxylic acids (ATCs) are a new class of constrained heterocyclic γ-amino acids built around a thiazole ring; these compounds are valuable as design mimics of the secondary structures of proteins such as helices, β-sheets, turns, and β-hairpins. We report herein a short and versatile chemical route to orthogonally protected ATCs. The synthesis is centered on cross-Claisen condensations between N-Fmoc-amino acids and sterically hindered 1,1-dimethylallyl acetate. The optimized conditions are compatible with aliphatic, aromatic, acidic, and basic amino acids. The resulting N-Fmoc-β-keto ester intermediates were engaged in a two-step process to give ATCs in 45-90 % yields. The synthetic protocol provides a highly flexible method for the introduction of a wide variety of lateral chains either on the γ-carbon atom or on the thiazole core of the γ-amino acids.

Full text of DOI:10.1002/ejoc.201500012

Job/Unit: O50012
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FULL PAPER
DOI: 10.1002/ejoc.201500012
Cross-Claisen Condensation of N-Fmoc-Amino Acids – A Short Route to
Heterocyclic γ-Amino Acids
Loïc Mathieu,[a][‡] Clément Bonnel,[a][‡] Nicolas Masurier,[a] Ludovic T. Maillard,*[a]
Jean Martinez,[a] and Vincent Lisowski[a]
Keywords: Peptidomimetics / Amino acids / Heterocycles / Cross-Claisen reactions
4-Amino(methyl)-1,3-thiazole-5-carboxylic acids (ATCs) are
a new class of constrained heterocyclic γ-amino acids built
around a thiazole ring; these compounds are valuable as de-
sign mimics of the secondary structures of proteins such as
helices, β-sheets, turns, and β-hairpins. We report herein a
short and versatile chemical route to orthogonally protected
1,1-dimethylallyl acetate. The optimized conditions are com-
patible with aliphatic, aromatic, acidic, and basic amino
acids. The resulting N-Fmoc-β-keto ester intermediates were
engaged in a two-step process to give ATCs in 45–90%
yields. The synthetic protocol provides a highly flexible
method for the introduction of a wide variety of lateral chains
ATCs. The synthesis is centered on cross-Claisen condensa- either on the γ-carbon atom or on the thiazole core of the γ-
tions between N-Fmoc-amino acids and sterically hindered
amino acids.
chemical route has to be versatile for the deployment of a
wide variety of side chains. In addition, a judicious choice
of orthogonal protecting groups is required for peptide
elongation. In our previous work, 9-fluorenylmethyloxy-
carbonyl (Fmoc) was chosen as the transient protecting
group of the N-terminal position, as it has become the pre-
ferred method for most solid- and solution-phase peptide
synthetic processes. The lateral chains were protected with
acid-labile groups [e.g., tBu, tert-butyloxycarbonyl (Boc),
trityl (Trt), and 2,2,4,6,7-pentamethyldihydrobenzofuran-5-
sulfonyl (Pbf)]. The chemical route for the ATC motif con-
sisted of a six-step synthesis starting from N-Fmoc-pro-
tected α-amino acids to take advantage of their ready avail-
ability, low cost, and high enantiomeric purity (Scheme 1).
However, the major issue of the process was the preparation
of the key N-Fmoc-amino-β-keto ester intermediates, which
were obtained in three steps with 25 to 56% overall
yields.[24–26] Furthermore, a partial racemization of the γ
stereocenter occurred, because the key tin-mediated diazo
coupling reaction involved a N-Fmoc-aminoaldehyde inter-
mediate (Scheme 1, Route A).
To speed up the overall synthesis and avoid racemization,
we reconsidered the chemical route to N-protected γ-
amino-β-keto esters. The most commonly used route
involves a neutral C-acylation of acyl imidazoles with a
magnesium enolate that is generated in situ from a mono-
alkyl malonate and magnesium chloride (Scheme 1,
Route B).[27–29] Although amino acids protected with
carboxybenzyl (Cbz), Boc, and Bz groups are readily con-
verted, Fmoc-protected amino acids degrade slowly during
the acylation. Additionally, the reactions are relatively slow
and usually require 1–2 d of stirring. Reducing the reaction
time by increasing the temperature results in racemiza-
Introduction
Over recent decades, peptidomimetic oligomers have
been pursed to identify potent therapeutic agents, because
they might overcome the poor pharmacokinetic profiles
often attributed to peptides with their potency and selectiv-
ity toward biological targets maintained. In consequence,
synthetic oligomers that adopt stable and predictable con-
formations in solution and are able to mimic the secondary
structures of proteins such as helices, β-sheets, turns, and β-
hairpins have been extensively described.[1–3] A wide range
of scaffolds derived from β-amino acids have been charac-
terized,[4–11] whereas homo- or heterogeneous sequences in-
corporating γ-amino acids have received far less attention,
in part because of the difficulty to access stereochemically
pure γ building blocks.[8,9,12–23] In this context, we recently
described a new class of constrained heterocyclic γ-amino
acids named 4-amino(methyl)-1,3-thiazole-5-carboxylic
acids or ATCs (1), which are built around a thiazole
ring.[24,25] Owing to the low conformational flexibility of
the γ-amino acids, ATC-containing oligomers adopt pre-
dictable secondary structures that are stabilized by C9 intra-
molecular hydrogen-bonding networks.
To modulate the physicochemical properties of the oligo-
mers and to drive molecular recognition, the designed ATC
[a] Institut des Biomolécules Max Mousseron, UMR 5247, CNRS
Universités Montpellier I et II and ENSCM,
15 Avenue Charles Flahault, 34093 Montpellier Cedex 5,
France
E-mail: ludovic.maillard@univ-montp1.fr
http://www.ibmm.univ-montp1.fr
[‡] These authors contributed equally to this work.
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500012.
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L. T. Maillard et al.
FULL PAPER
Scheme 1. Strategies to access N-Fmoc-protected γ-amino-β-keto ester intermediates as precursors for ATCs.
tion.[29] Another classical strategy for the chain extension tetrahydrofuran (THF) at –78 °C. The reaction gave the de-
of amino acid skeletons consists of cross-Claisen condensa- sired β-keto ester 3 in only 33% yield (Table 1, Entry 1).
tions between activated carboxylic acids and a lithium enol- The major product was the N-Fmoc-leucine benzyl ester 4,
ate prepared from an alkyl acetate (Scheme 1, Route C). probably resulting from the reaction of the imidazolide and
Whereas positive results have been obtained for N-Boc-[30]
or N-Cbz-amino acids,[31–34] only one example of a cross-
Table 1. Optimization of the cross-Claisen condensation.
Claisen reaction has been reported to date for N-Fmoc-pro-
tected amino acids.[35] The success of this method highly
depends on functional-group compatibility, harsh reaction
conditions, and longer reaction durations. As a conse-
quence, to the best of our knowledge, effective cross-Claisen
condensations with amino acids with functionalized lateral
chains are exceptional.
As we considered that cross-Claisen condensations be-
tween N-Fmoc-amino acids and alkyl acetates might be
Entry a: Amino acid b: Enolate forma- c: Conden- Ratio 3/4 Yield
activation
tion[b]
sation time
[min]
[%][c]
worthy of investigation, we report herein our efforts to de-
velop compatible conditions for cross-Claisen reactions of
N-Fmoc-amino acids. The optimized methodology was ap-
plied for the preparation of ten N-Fmoc-amino-β-keto es-
ters with diverse lateral chains, including acidic and basic
amino acids. In a second part, these β-keto esters were used
as precursors to prepare a representative set of highly di-
verse orthogonally protected ATC building blocks.
(equiv.)[a]
Acetate
Base
1
2
3
CDI (1.05)
CDI (1.05)
PyBOP (1.1) /
DIEA (1.1)
DIC (1.1) /
HOBt (1.1)
CDI (1.05)
CDI (1.05)
CDI (1.2)
2a
2b
2b
LiHMDS
LiHMDS
LiHMDS
45
45
30
1:3
1:0
1:0
33
55
6
4
2b
LiHMDS
30
1:0
9
5
6
7
8
2b
2b
2b
2b
LDA
LiTMP
LiHMDS
LiHMDS
45
45
90
15
1:0
1:0
1:0
1:0
57
dec.
47
CDI (1.05) /
DMAP (0.03)
73
Results and Discussion
To study the cross-Claisen condensation, N-Fmoc-Leu-
OH was selected as a model amino acid. Considering the
previous work in β-keto ester preparation,[36] N,NЈ-carbon-
yldiimidazole (CDI) was first chosen for the carbonyl acti-
vation. The N-Fmoc-Leu-imidazolide was condensed with
the lithium enolate 2a, which was prepared from benzyl
[a] The activation of Fmoc-Leu-OH (1.0 equiv., 28 mmol) was per-
formed at room temp. in anhydrous THF (50 mL) for 1 h. [b] The
enolate formation was performed at –78 °C for 10 min, then at r.t.
for 10 min, and at –78 °C for 20 min starting from 1,1-dimethylallyl
acetate (4.0 equiv., 112 mmol) and base (3.5 equiv.) in anhydrous
THF (190 mL). The activated amino acid was added dropwise to
the enolate at –78 °C. [c] Determined for the isolated β-keto ester
acetate and lithium bis(trimethylsilyl)amide (LiHMDS) in 3; dec. = decomposition.
2
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Cross-Claisen Condensation of N-Fmoc-Amino Acids
the benzyl alcoholate, which was released because of acetate Table 2. Scope of the cross-Claisen condensation between N-Fmoc-
protected α-amino acids and 1,1-dimethylallyl acetate.[a]
autocondensation. Usually, the autocondensation side reac-
Yield [%][b]
tion can be avoided by using the sterically hindered tert-
butyl acetate.[32,37,38] However, as the resulting tert-butyl es-
ter is sensitive to acidic conditions, the orthogonality of the
Fmoc-AA-OH
β-Keto ester
Fmoc-(l)-Leu-OH
Fmoc-Gly-OH
3a
3b
3c
3d
3e
3f
73
59
80
66
55
53
72
45
49
34
protections would not be preserved. Thus, we considered Fmoc-(l)-Ala-OH
Fmoc-(l)-Phe-OH
the use of another sterically hindered acetate, that is, 1,1-
Fmoc-(l)-Lys(Boc)-OH
dimethylallyl acetate (2b); the resulting 1,1-dimethylallyl es-
Fmoc-(l)-Glu(tBu)-OH
ter could be selectively deprotected under mild conditions
Fmoc-(l)-Asp(tBu)-OH
3g
3h
3i
with a palladium catalyst.
Fmoc-(l)-Cys(Trt)-OH
Fmoc-(l)-Trp(Boc)-OH
Fmoc-(l)-Arg(Pbf)-OH
Compound 2b was synthesized from 2-methyl-3-buten-2-
ol by the procedure of Watson et al.[39] The 1,1-dimeth-
ylallyl acetate was isolated by distillation in 71% yield. Af-
ter the generation of the enolate and subsequent condensa-
tion with the Fmoc-Leu-imidazolide, the N-Fmoc-amino-
β-keto ester 3 was recovered in 55% yield. Despite the use
of a large excess of reagent, we did not detect the formation
of N-Fmoc-Leucine ester 4.
3j
[a] Experimental conditions: the activation of Fmoc-AA-OH
(1.0 equiv.) was performed at room temp. in anhydrous THF
(50 mL) for 1 h. The enolate was prepared from 1,1-dimethylallyl
acetate (4.0 equiv.) and base (3.5 equiv.) in anhydrous THF at
–78 °C for 10 min, then at 20 °C for 10 min, and at –78 °C for
20 min. The cross-Claisen condensation was performed at –78 °C.
[b] Determined for isolated compound.
To optimize the cross-Claisen reaction, we explored some
other conditions for amino acid activation, that is, (benzo-
triazol-1-yloxy)tripyrrolidinophosphonium
phosphate/N,N-diisopropylethylamine (PyBOP/DIEA) and
diisopropylcarbodiimide/1-hydroxybenzotriazole (DIC/
hexafluoro-
Such a result was surprising as no dichlorinated compound
was detected for the reaction of a benzyl β-keto ester. This
suggested that overchlorination did not occur at the malo-
nic position. Consequently, we reinvestigated the conditions
for selective monohalogenation (Table 3). Confirmation
that the dimethylallyl protecting group was very sensitive to
halogenation was achieved by isolation of the byproduct
6a (see Supporting Information). Bromodimethylsulfonium
bromide (BDMS) was tested according to the procedure de-
scribed by Khan et al.[40] but did not give any reaction. We
found that the bromination conditions reported by Yang et
al.,[41] that is Mg(ClO4)2 Lewis acid catalysis combined with
N-bromosuccinimide (NBS) afforded mild, fast mono-
halogenation of the β-keto ester. An improvement of the
selectivity was obtained by decreasing the temperature to
–45 °C.
HOBt), but these conditions led to drastic decreases in the
yield (Table 1, Entries 3–4). Therefore, CDI was kept as the
best activation reagent. We also tested the influence of the
base used for the enolate formation. Although lithium di-
isopropylamide (LDA) and LiHMDS gave similar results,
lithium 2,2,6,6-tetramethylpiperidine (LiTMP) yielded a
complex mixture (Table 1, Entries 2, 5, and 6). Finally, the
best-identified conditions consisted of activation of the N-
Fmoc-protected amino acid with CDI (1.10 equiv.) and 4-
dimethylaminopyridine (DMAP; 3 mol-%) at room temp. in
anhydrous THF. At the same time, the enolate was gener-
ated from 1,1-dimethylallyl acetate and LiHMDS. The acti-
vated amino acid was then added dropwise to the enolate
solution. A strict control of the temperature and the reac-
tion time was essential to avoid any Fmoc deprotection.
After 15 min of stirring, the reaction mixture was quenched
with an aqueous citric acid solution to afford the N-Fmoc-
amino-β-keto ester 3, which was isolated in 73% yield by
chromatography. The scope of the reaction was extended
to nine other N-Fmoc-amino acids, namely, Fmoc-Gly-OH,
Table 3. Results of halogenation of the N-Fmoc-amino-β-keto ester
3a.[a]
Fmoc-Ala-OH,
Fmoc-Phe-OH,
Fmoc-Lys(Boc)-OH,
Fmoc-Glu(tBu)-OH, Fmoc-Asp(tBu)-OH, Fmoc-Cys(Trt)-
OH, Fmoc-Trp(Boc)-OH, and Fmoc-Arg(Pbf)-OH, to af-
ford the N-Fmoc-amino-β-keto esters 3b–3j in overall yields
of 34–80% (Table 2). The conditions were compatible with
aliphatic and aromatic as well as acidic and basic amino
acids. Finally, the reaction was scaled up to almost 10 g for
3a without the yield decreasing.
Monohalogenation of the malonic position of the N-
Fmoc-amino-β-keto esters 3a–3j was another important is-
sue for accessing ATCs. As supported by Honda et al.[32]
and by our previous studies on ATC synthesis, sulfuryl
chloride was first considered as the halogenating reagent.
The desired α-chloro-β-keto ester 5a was isolated in 67%
X
Reagent (equiv.)
Conditions
Ratio 5a/6
Cl SO2Cl2 (1.1)
Br BDMS (1.25)
CH2Cl2, 0–20 °C
CH2Cl2, 0–20 °C
67:33
–
Br NBS (1.05)/Mg(ClO4)2 (1.05) CH3CN, 20 °C
Br NBS (1.05)/Mg(ClO4)2 (0.5) CH3CN, 20 °C
Br NBS (1.05)/Mg(ClO4)2 (0.3) CH3CN, 20 °C
Br NBS (1.05)/Mg(ClO4)2 (0.3) CH3CN, –35 °C
Br NBS (1.05)/Mg(ClO4)2 (0.3) iBuCN, –65 °C
Br NBS (1.05)/Mg(ClO4)2 (0.3) CH3CN, –45 °C
86:14
85:15
85:15
89:11
93:7
97:3[b]
[a] Yields determined by HPLC. [b] Determined for isolated com-
yield, but we also observed 33% overchlorination (Table 3). pound.
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L. T. Maillard et al.
FULL PAPER
Scheme 2. Scope of the ATC synthesis (yields determined for isolated compounds).
Finally, the optimized bromination conditions were used
Experimental Section
to convert the N-Fmoc-amino-β-keto esters 3 into α-
bromo-β-keto esters 5, which were engaged without any pu-
rification in Hantzsch heterocyclizations. Thiazole rings
were formed after 2 h in ethanol at 40 °C. Starting from
a representative set of primary thioamides, thiourea, and
thiosemicarbazones, the ATCs 7a–7m were isolated in 45–
86% yields over the last two steps (Scheme 2). The enantio-
selectivity of the overall synthesis was ascertained by chiral
HPLC. The compounds are usually stocked as fully pro-
tected ATC 7. The removal of the dimethylallyl ester is clas-
sically done under Tsuji–Trost conditions with palladium
tetrakis(triphenylphosphine) (3 mol-%) and phenylsilane
(1.2 equiv.) just before ATC oligomerization (see Support-
ing Information).
General: Commercially available reagents and solvents were used
without any further purification. Reactions were monitored by
HPLC with an analytical Chromolith Speed Rod RP-C18 185 Pm
column (50ϫ4.6 mm, 5 μm) and 100:0 to 0:100 A/B gradient elu-
tion over 3 (conditions A) or 5 min (conditions B) at a flow rate of
5.0 mL/min; eluent A is H2O/trifluoroacetic acid 0.1% (H2O/TFA
0.1%) and eluent B is CH3CN/TFA 0.1%. Detection was per-
formed at λ = 214 and 254 nm with a photodiode array detector.
The retention times are reported as follows: LC: tR = [min]. The
1H and 13C NMR spectra were recorded at room temperature with
samples in deuterated solvents. The chemical shifts (δ) are given in
parts per million relative to tetramethylsilane (TMS) or relative to
the solvent [1H: δ (CDCl3) = 7.24 ppm; 13C: δ (CDCl3) = 77.2 ppm].
The following abbreviations are used to designate the signal multi-
plicities: s (singlet), d (doublet), dd (doublet doublet), t (triplet),
q (quartet), m (multiplet), and br. (broad). Analytical TLC was
performed with aluminium-backed silica gel plates coated with a
0.2 mm thickness of silica gel or with aluminium oxide 60 F254,
neutral. LC–MS spectra (ESI) were recorded with an HPLC instru-
Conclusions
We have developed an efficient and stereoselective
method for the preparation of ATCs in 34 to 52% overall ment with an analytical Chromolith Speed Rod RP-C18 185 Pm
column (50ϫ4.6 mm, 5 μm) and 100:0 to 0:100 A/B gradient elu-
tion over 2.5 min at a flow rate of 3.0 mL/min; eluent A is H2O/
HCOOH 0.1% and eluent B is CH3CN/HCOOH 0.1%. High-reso-
lution mass spectrometric analyses were performed with a time-of-
flight (TOF) mass spectrometer fitted with an electrospray ioniza-
tion source (ESI). All measurements were performed in the posi-
tive-ion mode. Melting points were recorded with a capillary melt-
ing point apparatus. Enantiomeric excesses were determined by chi-
ral HPLC analysis with a Chiracel OD-R column (250ϫ4.6 mm)
with H2O, TFA 0.1%/CH3CN, TFA 0.1% (40:60) as eluent and a
flow rate of 1 mL/min.
yield starting from N-Fmoc-amino acids. The three-step
synthesis is based on a cross-Claisen condensation between
N-Fmoc-amino acids and 1,1-dimethylallyl acetate to pro-
vide N-Fmoc-γ-amino-β-keto ester intermediates. We dem-
onstrated that the choice of the sterically hindered 1,1-di-
methylallyl acetate was crucial to improve the condensation
yield and maintain orthogonal protection. The synthetic
protocol provides a highly versatile and flexible method for
the introduction of a wide variety of lateral chains either
on the γ-carbon atom or on the thiazole core of the ATC.
4
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Cross-Claisen Condensation of N-Fmoc-Amino Acids
General Procedure for Synthesis of β-Keto Ester 3
3.50 (AB, J = 16.0 Hz, 1 H), 4.22 (t, J = 6.9 Hz, 1 H), 4.38–4.50
(m, 3 H), 5.10 (d, J = 11.0 Hz, 1 H), 5.20 (d, J = 17.5 Hz, 1 H),
5.47 (d, J = 7.2 Hz, 1 H), 6.08 (dd, J = 11.0, 17.5 Hz, 1 H), 7.32
(td, J = 0.7, 7.5 Hz, 2 H), 7.40 (t, J = 7.5 Hz, 2 H), 7.59 (d, J =
7.4 Hz, 2 H), 7.75 (d, J = 7.5 Hz, 2 H) ppm. 13C NMR (CDCl3,
100 MHz): δ = 17.4, 26.4 (2 C), 47.0, 47.3, 56.0, 67.1, 82.8, 113.6,
120.1 (2 C), 125.1 (2 C), 127.2 (2 C), 127.9 (2 C), 141.5, 141.8 (2
Imidazolide Formation: In a 250 mL two-neck flask under a nitro-
gen atmosphere was dissolved the Fmoc-AA-OH (28.57 mmol) in
dry THF. Then, CDI (5.096 g, 31.41 mmol, 1.1 equiv.) was added
in three portions.
A catalytic amount of DMAP (105 mg,
0.8571 mmol, 3 mol-%) was added 2–3 min later, and the solution
was stirred for 1 h at room temp.
C), 143.9 (2 C), 155.8, 165.6, 202.2 ppm. LC (conditions A): tR
=
Enolate Formation: Under a nitrogen atmosphere, a 500 mL three-
neck flask was charged with LiHMDS (100 mL, 100 mmol, 1 m
solution in THF) followed by dry THF (100 mL). After cooling at
–78 °C 1,1-dimethylallyl acetate (14.650 g, 114.3 mmol) was added
dropwise over 10 min. The solution was stirred at –78 °C for 5–
10 min, then at room temp. for 10 min, and finally at –78 °C for
20 min.
2.25 (major) and 2.48 min (minor; keto–enol equilibrium). LC–MS
(ESI+): m/z (%) = 422.3 (100) [M + H]+, 444.2 (70) [M + Na]+.
HRMS (ESI): calcd. for C25H28NO5 [M + H]+ 422.1972; found
422.1967. FTIR: ν
= 3309, 2983, 2939, 1717, 1685, 1533, 1450,
˜
max
1316, 1254, 1123, 1048, 923, 833, 757, 737 cm–1.
1,1-Dimethylprop-2-en-1-yl
(4S)-4-(Fmoc-amino)-3-oxo-5-phenyl-
pentanoate (3d): Pale pink solid, yield 66%, m.p. 101–102 °C.
[α]2D0 °C = +0.55 (c = 1.00, CHCl3). H NMR (CDCl3, 400 MHz):
1
Condensation: The imidazolide solution was added dropwise to the
enolate solution at –78 °C over 5–10 min. After stirring for 15 min
(HPLC monitoring), the mixture was removed from the cold bath
and poured onto a solution of 10% aqueous citric acid (200 mL)
until pH 7. The crude was extracted with EtOAc (2ϫ 100 mL).
The combined organic layers were washed with saturated NaHCO3
solution (1ϫ 100 mL) and brine (3ϫ 150 mL), dried, filtered, and
evaporated under reduced pressure to yield the crude product. Puri-
fication by flash column chromatography afforded the pure β-keto
ester.
δ = 1.52 (s, 6 H), 3.01 (ABX, J = 7.0, 14.0 Hz, 1 H), 3.18 (ABX, J
= 7.0, 14.0 Hz, 1 H), 3.40 (d, J = 5.3 Hz, 2 H), 4.17 (t, J = 6.9 Hz,
1 H), 4.40 (m, 2 H), 4.67 (m, 1 H), 5.10 (d, J = 10.8 Hz, 1 H), 5.19
(d, J = 17.5 Hz, 1 H), 5.34 (d, J = 7.6 Hz, 1 H), 6.07 (dd, J = 10.8,
17.5 Hz, 1 H), 7.14 (d, J = 7.0 Hz, 1 H), 7.23–7.33 (m, 6 H), 7.40
(t, J = 7.4 Hz, 2 H), 7.53 (t, J = 7.4 Hz, 2 H), 7.77 (d, J = 7.4 Hz,
2 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 26.4 (2 C), 37.1, 47.3,
48.0, 60.9, 67.1, 82.8, 113.5, 120.1 (2 C), 125.2 (2 C), 127.2 (2 C),
127.3, 127.9 (2 C), 128.9 (2 C), 129.4 (2 C), 135.9, 141.4 (2 C),
141.8, 143.8 (2 C), 155.8, 165.6, 201.7 ppm. LC (conditions A): tR
= 2.04 (major) and 2.19 min (minor; keto–enol equilibrium).
LC–MS (ESI+): m/z (%) = 498.2 (100) [M + H]+, 520.2 (10) [M +
Na]+. HRMS (ESI): calcd. for C31H31NO5Na [M + Na]+ 520.2100;
1,1-Dimethylprop-2-en-1-yl (4S)-4-(Fmoc-amino)-6-methyl-3-oxo-
heptanoate (3a): White solid, yield 73%, m.p. 117–118 °C. [α]2D0 °C
1
= –10.2 (c = 1.00, CHCl3). H NMR (CDCl3, 400 MHz): δ = 0.95
(t, J = 6.2 Hz, 6 H), 1.41 (m, 2 H), 1.53 (s, 6 H), 1.68 (m, 1 H),
3.41 (AB, J = 15.6 Hz, 1 H), 3.49 (AB, J = 15.6 Hz, 1 H), 4.22 (t,
J = 6.6 Hz, 1 H), 4.42 (s, 1 H), 4.45 (d, J = 6.6 Hz, 2 H), 5.09 (d,
J = 10.8 Hz, 1 H), 5.19 (d, J = 17.4 Hz, 1 H), 5.19 (s, 1 H), 6.08
(dd, J = 10.9, 17.4 Hz, 1 H), 7.32 (t, J = 7.4 Hz, 2 H), 7.40 (t, J =
7.4 Hz, 2 H), 7.59 (m, 2 H), 7.78 (d, J = 7.4 Hz, 2 H) ppm. 13C
NMR (CDCl3, 100 MHz): δ = 21.7, 23.4, 25.0, 26.5 (2 C), 40.3,
47.5 (2 C), 58.8, 67.0, 82.7, 113.5, 120.2 (2 C), 125.1 (2 C), 127.2
(2 C), 127.9 (2 C), 141.5 (2 C), 142.0, 143.9 (2 C), 156.2, 165.7,
202.7 ppm. LC (conditions A): tR = 2.29 (major) and 2.52 min
(minor; keto–enol equilibrium). LC–MS (ESI+): m/z (%) = 464.3
(100) [M + H]+, 486.3 (10) [M + Na]+. HRMS (ESI): calcd. for
found 520.2098. FTIR: ν
= 3313, 2984, 1738, 1713, 1692, 1534,
˜
max
1323, 1254, 1124, 1031, 929, 836, 755, 741, 703 cm–1.
1,1-Dimethylprop-2-en-1-yl (4S)-4-(Fmoc-amino)-8-[(tert-butyloxy-
carbonyl)amino]-3-oxooctanoate (3e): Yellow gel, yield 55%. [α]
20 °C
1
= –4.7 (c = 1.00, CHCl3). H NMR (CDCl3, 400 MHz): δ =
D
1.35 (br., 2 H), 1.43 (s, 9 H), 1.53 (s, 6 H), 1.62 (br., 2 H), 1.92 (m,
2 H), 3.11 (br., 2 H), 3.42 (AB, J = 15.7 Hz, 1 H), 3.49 (AB, J =
15.7 Hz, 1 H), 4.21 (t, J = 6.6 Hz, 1 H), 4.42 (br., 1 H), 4.46 (br.,
2 H), 4.58 (br., 1 H), 5.10 (d, J = 10.9 Hz, 1 H), 5.19 (d, J =
17.4 Hz, 1 H), 5.51 (br., 1 H), 6.08 (dd, J = 10.9, 17.4 Hz, 1 H),
7.32 (t, J = 7.6 Hz, 2 H), 7.40 (t, J = 7.6 Hz, 2 H), 7.60 (d, J =
7.6 Hz, 2 H), 7.76 (d, J = 7.6 Hz, 2 H) ppm. 13C NMR (CDCl3,
100 MHz): δ = 22.3, 26.5, 27.1, 28.6 (3 C), 29.8, 30.6, 40.0, 47.4 (2
C), 60.0, 67.1, 79.4, 82.8, 113.6, 120.1 (2 C), 125.2 (2 C), 127.2 (2
C), 127.9 (2 C), 141.5 (2 C), 141.9, 143.9 (2 C), 156.2, 156.3, 165.7,
202.1 ppm. LC (conditions A): tR = 2.29 (major) and 2.46 min
(minor; keto–enol equilibrium). LC–MS (ESI+): m/z (%) = 579.3
(100) [M + H]+, 601.3 (10) [M + Na]+. HRMS (ESI): calcd. for
C28H34NO5 [M + H]+ 464.2437; found 464.2416. FTIR: ν
=
˜
max
3375, 3041, 2958, 1739, 1717, 1536, 1452, 1353, 1249, 1237, 1222,
1126, 1098, 1038, 942, 760, 737, 730 cm–1.
1,1-Dimethylprop-2-en-1-yl (Fmoc-amino)-3-oxobutanoate (3b):
White solid, yield 59%, m.p. 99–100 °C. 1H NMR (400 MHz,
CDCl3): δ = 1.55 (s, 6 H), 3.43 (s, 2 H), 4.23 (m, 3 H), 4.41 (d, J
= 7.0 Hz, 2 H), 5.12 (dd, J = 0.6, 10.9 Hz, 1 H), 5.21 (d, J =
17.5 Hz, 1 H), 5.46 (br., 1 H), 6.08 (dd, J = 10.9, 17.5 Hz, 1 H),
7.30 (t, J = 7.4 Hz, 2 H), 7.40 (t, J = 7.4 Hz, 2 H), 7.59 (d, J =
7.4 Hz, 2 H), 7.76 (d, J = 7.4 Hz, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 26.4 (2 C), 47.3, 47.8, 51.0, 67.3, 83.0, 113.7, 120.1 (2
C), 125.2 (2 C), 127.2 (2 C), 127.9 (2 C), 141.5, 141.7 (2 C), 143.9
(2 C), 156.3, 165.4, 198.5 ppm. LC (conditions A): tR = 2.19
(major) and 2.40 min (minor; keto–enol equilibrium). LC–MS
(ESI+): m/z (%) = 408.2 (17) [M + H]+, 430.1 (100) [M + Na]+.
HRMS (ESI): calcd. for C24H26NO5 [M + H]+ 408.1811; found
C33H43N2O7 [M + H]+ 579.3039; found 579.3031. FTIR: ν
=
˜
max
3375, 3041, 2958, 2934, 1739, 1717, 1695, 1511, 1450, 1364, 1247,
1165, 1084, 974, 759, 740, 708 cm–1.
1-(1,1-Dimethylprop-2-en-1-yl) 7-tert-Butyl (4S)-4-(Fmoc-amino)-3-
oxoheptan-1,7-dioate (3f): Orange oil, yield 53%. [α]2D0 °C = +4.72 (c
= 2.00, CHCl3). 1H NMR (CDCl3, 400 MHz): δ = 1.44 (s, 9 H),
1.53–1.57 (m, 6 H), 1.82–1.90 (m, 1 H), 2.17–2.38 (m, 3 H), 3.47
(AB, J = 16.0 Hz, 1 H), 3.54 (AB, J = 16.0 Hz, 1 H), 4.21 (t, J =
6.6 Hz, 1 H), 4.38–4.47 (m, 3 H), 5.09 (d, J = 11.3 Hz, 1 H), 5.18
(d, J = 17.4 Hz, 1 H), 5.60 (d, J = 7.4 Hz, 1 H), 6.08 (dd, J = 11.3,
17.4 Hz, 1 H), 7.32 (t, J = 7.4 Hz, 2 H), 7.40 (t, J = 7.4 Hz, 2 H),
7.59 (d, J = 7.4 Hz, 2 H), 7.76 (d, J = 7.4 Hz, 2 H) ppm. 13C NMR
(CDCl3, 100 MHz): δ = 26.1, 26.4, 26.5, 28.2 (3 C), 31.2, 47.4 (2
C), 59.7, 67.1, 81.1, 82.8, 113.5, 120.2 (2 C), 125.2 (2 C), 127.2 (2
C), 127.9 (2 C), 141.5, 141.9 (2 C), 143.8, 143.9, 156.2, 165.6, 172.3,
408.1811. FTIR: ν
= 3357, 3041, 2979, 1724, 1704, 1449, 1436,
˜
max
1394, 1306, 1288, 1252, 1109, 1073, 1050, 988, 969, 760, 739 cm–1.
1,1-Dimethylprop-2-en-1-yl (4S)-4-(Fmoc-amino)-3-oxo-5-pentano-
ate (3c): Pale orange solid, yield 80%, m.p. 68–70 °C. [α]2D0 °C
=
+6.61 (c = 2.00, CHCl3). 1H NMR (CDCl3, 400 MHz): δ = 1.39
(d, J = 7.1 Hz, 3 H), 1.54 (s, 6 H), 3.45 (AB, J = 16.0 Hz, 1 H),
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5

Job/Unit: O50012
/KAP1
Date: 16-02-15 14:28:09
Pages: 10
L. T. Maillard et al.
FULL PAPER
201.7 ppm. LC (conditions A): tR = 2.54 (major) and 2.73 min
(minor; keto–enol equilibrium). LC–MS (ESI+): m/z (%) = 558.3
(100) [M + Na]+. HRMS (ESI): calcd. for C31H38NO7 [M + H]+
1
[α]2D0 °C = –0.5 (c = 1.00, CHCl3). H NMR (CDCl3, 400 MHz): δ
= 1.43 (s, 6 H), 1.49 (s, 6 H), 1.58 (br., 3 H), 1.90 (br., 1 H), 2.07
(s, 3 H), 2.49 (s, 3 H), 2.56 (s, 3 H), 2.91 (s, 2 H), 3.20 (br., 2 H),
3.48 (d, J = 3.8 Hz, 2 H), 4.16 (t, J = 6.8 Hz, 1 H), 4.35 (m, 3 H),
536.2648; found 536.2648. FTIR: ν
= 3334, 2979, 1714, 1515,
˜
max
1450, 1367, 1320, 1243, 1150, 1123, 1042, 927, 844, 759, 739 cm–1. 5.06 (d, J = 10.9 Hz, 1 H), 5.15 (d, J = 17.6 Hz, 1 H), 6.02 (m, 1
H), 6.55 (br., 1 H), 7.26 (m, 2 H), 7.36 (t, J = 7.5 Hz, 2 H), 7.57 (d,
1-(1,1-Dimethylprop-2-en-1-yl) 7-tert-Butyl (4S)-4-(Fmoc-amino)-3-
J = 7.5 Hz, 2 H), 7.73 (d, J = 7.5 Hz, 2 H) ppm; the HN Guanidine
oxoheptan-1,7-dioate (3g): Brown oil, yield 72%. [α]2D0 °C = –11.0 (c
resonance was not observed. 13C NMR (CDCl3, 100 MHz): δ =
= 1.00, CHCl3). 1H NMR (CDCl3, 400 MHz): δ = 1.44 (s, 9 H),
12.6, 18.1, 19.5, 25.0, 26.5 (2 C), 28.1, 28.7 (2 C), 41.0, 43.2, 47.0,
1.53 (s, 6 H), 2.71 (ABX, J = 5.0, 17.1 Hz, 1 H), 2.90 (ABX, J =
47.2, 60.5, 67.2, 82.9, 86.8, 113.5, 118.0, 120.1 (2 C), 125.1 (2 C),
5.0, 17.1 Hz, 1 H), 3.50 (s, 2 H), 4.23 (t, J = 6.7 Hz, 1 H), 4.47 (m,
125.2 (2 C), 127.2 (2 C), 127.9 (2 C), 133.0, 139.1, 141.4 (2 C),
2 H), 4.57 (m, 1 H), 5.08 (d, J = 10.9 Hz, 1 H), 5.18 (d, J = 17.5 Hz,
141.8, 143.8 (2 C), 155.7, 156.7, 159.5, 166.3, 202.4 ppm. LC (con-
1 H), 5.89 (br., 1 H), 6.08 (dd, J = 10.9, 17.5 Hz, 1 H), 7.32 (t, J
ditions A): tR = 2.07 (major) and 2.18 min (minor; keto–enol equi-
= 7.5 Hz, 2 H), 7.41 (t, J = 7.5 Hz, 2 H), 7.59 (d, J = 7.5 Hz, 2 H),
librium). LC–MS (ESI+): m/z (%) = 759.4 (100) [M + H]+, 781.5
7.76 (d, J = 7.5 Hz, 2 H) ppm. 13C NMR (CDCl3, 100 MHz): δ =
(10) [M + Na]+. HRMS (ESI): calcd. for C41H51N4O8S [M + H]+
26.4 (2 C), 28.2 (3 C), 36.7, 47.1, 47.4, 56.9, 67.3, 82.2, 82.6, 113.4,
759.3428; found 759.3434. FTIR: ν
= 2990, 2940, 1716, 1455,
˜
max
120.2 (2 C), 125.2 (2 C), 127.2 (2 C), 127.9 (2 C), 141.5 (2 C), 142.0,
143.8 (2 C), 156.1, 165.7, 170.5, 201.2 ppm. LC (conditions A): tR
= 2.44 (major) and 2.60 min (minor; keto–enol equilibrium). LC–
MS (ESI+): m/z (%) = 522.1 (100) [M + H]+, 544.2 (100) [M +
Na]+. HRMS (ESI): calcd. for C30H36NO7 [M + H]+ 522.2491;
1384, 1312, 1259, 1155, 1087, 761, 742, 731 cm–1.
General Procedure for ATC Synthesis 7
Synthesis of Bromo-β-keto Esters 5: To a solution of the β-keto
ester 3 (2.87 mmol) in acetonitrile (20 mL) was added magnesium
perchlorate (210 mg, 0.95 mmol, 0.3 equiv.). The solution was
found 522.2492. FTIR: ν
= 3335, 2979, 1714, 1505, 1451, 1367,
˜
max
1319, 1238, 1151, 1123, 1047, 927, 844, 759, 738 cm–1.
stirred at –45 °C for 10 min.
A solution of NBS (537 mg,
3.01 mmol, 1.1 equiv.) in acetonitrile (15 mL) was then added drop-
wise over 5 min. The reaction was complete after a few minutes of
stirring at –45 °C (HPLC monitoring). The mixture was diluted
with Et2O (40 mL) and washed with water (2ϫ 40 mL) and brine
(3ϫ 20 mL). The organic layer was dried with MgSO4 and filtered,
and the solvent was removed under vacuum to give the crude prod-
uct, which was used in the next step without further purification.
1,1-Dimethylprop-2-en-1-yl (4S)-4-(Fmoc-amino)tritylthio-3-oxopen-
tanoate (3h): Orange solid, yield 45%, m.p. 70–71 °C. [α]2D0 °C
=
–0.24 (c = 1.00, CHCl3). 1H NMR (CDCl3, 400 MHz): δ = 1.51
(m, 6 H), 2.52 (ABX, J = 7.4, 13.1 Hz, 1 H), 2.78 (ABX, J = 4.3,
13.1 Hz, 1 H), 3.15 (AB, J = 16.0 Hz, 1 H), 3.21 (AB, J = 16.0 Hz,
1 H), 4.22 (br., 2 H), 4.41 (br., 2 H), 5.06 (d, J = 10.9 Hz, 1 H),
5.14 (d, J = 17.6 Hz, 1 H), 5.23 (br., 1 H), 6.05 (m, 1 H), 7.18–7.31
(m, 12 H), 7.39 (br., 7 H), 7.61 (d, J = 7.2 Hz, 2 H), 7.75 (m, 2 H)
ppm. 13C NMR (CDCl3, 100 MHz): δ = 26.4, 26.8, 32.8, 47.1, 47.3,
59.1, 67.1, 67.4, 82.6, 113.4, 120.1 (2 C), 125.2 (2 C), 127.1 (3 C),
127.2 (2 C), 127.9 (2 C), 128.2 (6 C), 129.6 (6 C), 141.4 (2 C), 141.9,
143.8 (2 C), 144.3 (3 C), 155.8, 165.4, 200.3 ppm. LC (conditions
A): tR = 2.38 (major) and 2.53 min (minor; keto–enol equilibrium).
LC–MS (ESI+): m/z (%) = 718.3 (100) [M + Na]+. HRMS (ESI):
calcd. for C44H41NO5SNa [M + Na]+ 718.2603; found 718.2589.
Hantzsch Cyclization: To a solution of α-monobrominated β-keto
ester (2 mmol) in absolute ethanol was added a solution of the
thioamide (6.0 mmol, 3 equiv.) dissolved in absolute ethanol. The
solution was heated for 2 h at 40 °C until completion of the reac-
tion (HPLC and TLC monitoring). The EtOH was evaporated, and
the yellowish solid was partitioned between EtOAc (25 mL) and
water (25 mL). The organic layer was washed with water (3ϫ
20 mL) and brine (1ϫ 20 mL). The combined organic layers were
dried with magnesium sulfate and filtered, and the solvents were
evaporated under vacuum to yield the crude product. Purification
by silica gel column chromatography afforded ATC 7.
FTIR: νmax = 3391, 3058, 2980, 2927, 1714, 1490, 1446, 1412, 1319,
˜
1239, 1121, 1033, 926, 845, 739, 699 cm–1.
1,1-Dimethylprop-2-en-1-yl
(4S)-4-(Fmoc-amino)-5-(N-Boc-1H-
indol-3-yl)-3-oxopentanoate (3i): Orange solid, yield 49%, m.p. 64–
67 °C. [α]2D0 °C = –3.6 (c = 1.00, CHCl3). 1H NMR (CDCl3,
400 MHz): δ = 1.50 (m, 6 H), 1.64 (s, 9 H), 3.17 (ABX, J = 6.8,
14.8 Hz, 1 H), 3.28 (ABX, J = 6.8, 14.8 Hz, 1 H), 3.39 (AB, J =
16.0 Hz, 1 H), 3.45 (AB, J = 16.0 Hz, 1 H), 4.18 (t, J = 6.6 Hz, 1
H), 4.39 (d, J = 6.9 Hz, 2 H), 4.78 (m, 1 H), 5.08 (d, J = 10.9 Hz,
1 H), 5.16 (d, J = 17.5 Hz, 1 H), 5.46 (d, J = 7.8 Hz, 1 H), 6.04
(dd, J = 10.9, 17.5 Hz, 1 H), 7.23–7.35 (m, 4 H), 7.39 (t, J = 7.5 Hz,
2 H), 7.45 (s, 1 H), 7.51 (t, J = 7.5 Hz, 2 H), 7.59 (d, J = 7.5 Hz,
1 H), 7.75 (d, J = 7.5 Hz, 2 H), 8.13 (br., 1 H) ppm. 13C NMR
(CDCl3, 100 MHz): δ = 26.4 (2 C), 26.9, 28.3 (3 C), 47.3, 48.0,
59.8, 67.2, 82.8, 83.9, 113.5, 115.1, 115.5, 119.0, 120.1 (2 C), 123.0,
124.4, 124.9, 125.2 (2 C), 127.2 (2 C), 127.9 (2 C), 130.3, 135.6,
141.4 (2 C), 141.8, 143.8 (2 C), 149.6, 155.9, 165.7, 201.9 ppm. LC
(conditions A): tR = 2.28 (major) and 2.43 min (minor; keto–enol
equilibrium). LC–MS (ESI+): m/z (%) = 637.3 (100) [M + H]+,
659.3 (10) [M + Na]+. HRMS (ESI): calcd. for C38H41N2O7 [M +
1,1-Dimethylprop-2-en-1-yl 4-[(Fmoc-amino)methyl]–2-methyl-1,3-
thiazole-5-carboxylate (7a): White solid, yield 76%, m.p. 102–
1
105 °C. H NMR (CDCl3, 400 MHz): δ = 1.65 (s, 6 H), 2.69 (s, 3
H), 4.25 (m, 1 H), 4.38 (d, J = 7.2 Hz, 2 H), 4.75 (d, J = 5.7 Hz, 2
H), 5.16 (d, J = 10.9 Hz, 1 H), 5.26 (d, J = 17.5 Hz, 1 H), 5.86
(br., 1 H), 6.17 (dd, J = 10.9, 17.5 Hz, 1 H), 7.30 (t, J = 7.5 Hz, 2
H), 7.39 (t, J = 7.5 Hz, 2 H), 7.61 (d, J = 7.5 Hz, 2 H), 7.76 (d, J
= 7.5 Hz, 2 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 19.6, 26.7
(2 C), 40.8, 47.4, 67.1, 83.2, 113.6, 120.1 (2 C), 124.2, 125.3 (2 C),
127.1 (2 C), 127.8 (2 C), 141.4, 142.0 (2 C), 144.2 (2 C), 156.4,
158.5, 160.7, 169.6 ppm. LC (conditions A): tR = 2.39 min. LC–
MS (ESI+): m/z (%) = 463.2 (100) [M + H]+, 485.2 (10) [M +
Na]+. HRMS (ESI): calcd. for C26H27N2O4S [M + H]+ 463.1682;
found 463.1692. FTIR: ν
= 3213, 3047, 1710, 1541, 1451, 1280,
˜
max
1241, 1191, 1158, 1133, 1082, 1056, 926, 825, 734 cm–1.
1,1-Dimethylprop-2-en-1-yl 4-[(1S)-1-(Fmoc-amino)ethyl]-2-methyl-
1,3-thiazole-5-carboxylate (7b): White solid, yield 69%, m.p. 51–
53 °C. [α]2D0 °C = +8.37 (c = 1.00, CHCl3). 1H NMR (CDCl3,
400 MHz): δ = 1.48 (d, J = 6.5 Hz, 3 H), 1.66 (s, 6 H), 2.68 (s, 3
H), 4.23 (t, J = 7.8 Hz, 1 H), 4.36 (d, J = 6.5 Hz, 2 H), 5.15 (d, J
H]+ 637.2914; found 637.2918. FTIR: ν
= 2981, 2936, 1718,
˜
max
1508, 1451, 1368, 1310, 1252, 1226, 1154, 1122, 1083, 1044, 929,
855, 739 cm–1.
1,1-Dimethylprop-2-en-1-yl (4S)-4-(Fmoc-amino)-7-(N-Pbf-guanid- = 10.9 Hz, 1 H), 5.27 (d, J = 17.4 Hz, 1 H), 5.68 (m, 1 H), 6.01 (d,
ino)-3-oxooctanoate (3j): Yellow solid, yield 34%, m.p. 86–88 °C. J = 8.7 Hz, 1 H), 6.18 (dd, J = 10.9, 17.4 Hz, 1 H), 7.30 (t, J =
6
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Job/Unit: O50012
/KAP1
Date: 16-02-15 14:28:09
Pages: 10
Cross-Claisen Condensation of N-Fmoc-Amino Acids
7.5 Hz, 2 H), 7.39 (t, J = 7.5 Hz, 2 H), 7.61 (d, J = 7.5 Hz, 2 H),
400 MHz): δ = 1.62 (d, J = 5.7 Hz, 6 H), 2.67 (s, 3 H), 3.13 (d, J
7.76 (d, J = 7.5 Hz, 2 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = = 6.8 Hz, 2 H), 4.21 (m, 2 H), 4.39 (m, 1 H), 5.14 (d, J = 11.0 Hz,
19.5, 22.1, 26.7 (2 C), 46.6, 47.4, 66.8, 83.2, 113.5, 120.0 (2 C),
123.1, 125.3 (2 C), 127.1 (2 C), 127.7 (2 C), 141.4, 142.0 (2 C),
144.1, 144.2, 155.7, 160.3, 162.6, 169.8 ppm. LC (conditions A): tR
= 2.49 min. LC–MS (ESI+): m/z (%) = 477.2 (100) [M + H]+.
1 H), 5.23 (d, J = 17.5 Hz, 1 H), 5.98 (m, 1 H), 6.11 (m, 2 H), 7.09
(m, 2 H), 7.18–7.23 (m, 3 H), 7.29 (t, J = 7.4 Hz, 2 H), 7.39 (t, J
= 7.4 Hz, 2 H), 7.55 (m, 2 H), 7.76 (d, J = 7.4 Hz, 2 H) ppm. 13C
NMR (CDCl3, 100 MHz): δ = 19.4, 26.5, 26.6, 42.2, 47.2, 51.2,
HRMS (ESI): calcd. for C27H29N2O4S [M + H]+ 477.1844; found 66.8, 83.2, 113.4, 120.0 (2 C), 124.4, 125.2, 125.3, 126.6, 127.0 (2
477.1848. FTIR: ν
= 3317, 2980, 1705, 1499, 1448, 1366, 1315,
C), 127.7 (2 C), 128.2 (2 C), 129.4, 129.6, 137.2, 141.3 (2 C), 141.9,
144.1 (2 C), 155.7, 160.0 (2 C), 169.8 ppm. LC (conditions A): tR
= 2.18 min. LC–MS (ESI+): m/z (%) = 553.3 (100) [M + H]+, 575.3
(10) [M + Na]+. HRMS (ESI): calcd. for C33H33N2O4S [M + H]+
˜
max
1233, 1192, 1132, 1082, 923, 830, 758 cm–1.
1,1-Dimethylprop-2-en-1-yl 4-[(1S)-1-(Fmoc-amino)-3-methylbutyl]-
2-methyl-1,3-thiazole-5-carboxylate (7c): White solid, yield 81%,
m.p. 98–99 °C. [α]2D0°C = –0.6° (c = 1.00, CHCl3). 1H NMR (CDCl3,
400 MHz): δ = 0.95 (d, J = 6.4 Hz, 3 H), 0.99 (d, J = 6.4 Hz, 3 H),
1.56 (m, 2 H), 1.66 (s, 6 H), 1.75 (m, 1 H), 2.67 (s, 3 H), 4.21 (t, J
= 7.4 Hz, 1 H), 4.35 (m, 2 H), 5.14 (d, J = 10.5 Hz, 1 H), 5.26 (d,
J = 17.5 Hz, 1 H), 5.70 (m, 1 H), 5.83 (m, 1 H), 6.19 (dd, J = 17.5,
10.5 Hz, 1 H), 7.29 (m, 2 H), 7.39 (t, J = 7.4 Hz, 2 H), 7.60 (m, 2
H), 7.75 (d, J = 7.4 Hz, 2 H) ppm. 13C NMR (CDCl3, 100 MHz):
δ = 19.5, 22.3, 23.3, 25.1, 26.7, 26.8, 45.1, 47.4, 48.8, 66.7, 83.3,
113.5, 120.0 (2 C), 123.8, 125.3 (2 C), 127.1 (2 C), 127.7 (2 C),
141.4 (2 C), 142.1, 144.1, 144.2, 155.9, 160.4, 162.2, 169.8 ppm. LC
(conditions A): tR = 2.45 min. LC–MS (ESI+): m/z (%) = 519.3
(100) [M + H]+, 541.3 (10) [M + Na]+. HRMS (ESI): calcd. for
553.2161; found 553.2166. FTIR: ν
= 2925, 2310, 1703, 1501,
˜
max
1449, 1319, 1245, 1131, 1083, 738, 699 cm–1.
1,1-Dimethylprop-2-en-1-yl
2-Amino-4-[(1S)-1-(Fmoc-amino)-2-
phenethyl]-1,3-thiazole-5-carboxylate (7g): White solid, yield 90%,
m.p. 119–120 °C. [α]2D0 °C = +0.07 (c = 1.00, CHCl3). 1H NMR
(CDCl3, 400 MHz): δ = 1.56 (m, 6 H), 3.10 (d, J = 7.2 Hz, 2 H),
4.20 (m, 2 H), 4.29 (m, 1 H), 5.10 (d, J = 11.0 Hz, 1 H), 5.19 (d, J
= 17.5 Hz, 1 H), 5.71 (q, J = 8.0 Hz, 1 H), 6.07 (br., 2 H), 6.10
(dd, J = 17.5, 11 Hz, 1 H), 6.16 (d, J = 9.2 Hz, 1 H), 7.13–7.26 (m,
5 H), 7.27 (t, J = 7.5 Hz, 2 H), 7.38 (t, J = 7.5 Hz, 2 H), 7.53 (d,
J = 7.5 Hz, 2 H), 7.74 (d, J = 7.5 Hz, 2 H) ppm. 13C NMR (CDCl3,
100 MHz): δ = 26.7, 26.8, 41.4, 47.3, 51.4, 66.9, 82.8, 113.2, 120.0
(2 C), 125.3, 125.4 (2 C), 126.7, 127.1 (2 C), 127.7 (2 C), 128.3 (2
C), 129.7 (2 C), 137.2, 141.4 (2 C), 142.3, 144.1 (2 C), 155.9, 158.1,
160.5, 169.8 ppm. LC (conditions A): tR = 1.96 min. LC–MS
(ESI+): m/z (%) = 554.2 (100) [M + H]+, 576.2 (10) [M + Na]+.
HRMS (ESI): calcd. for C32H32N3O4S [M + H]+ 554.2114; found
C30H35N2O4S [M + H]+ 519.2305; found 519.2318. FTIR: ν
=
˜
max
3326, 2956, 1699, 1507, 1450, 1327, 1278, 1251, 1191, 1082, 1044,
923, 830, 759, 736 cm–1.
1,1-Dimethylprop-2-en-1-yl
2-Amino-4-[(1S)-1-(Fmoc-amino)-3-
methylbutyl]-1,3-thiazole-5-carboxylate (7d): White solid, yield
85%, m.p. 113–114 °C. [α]2D0 °C = –16.0 (c = 1.00, CHCl3). 1H NMR
(CDCl3, 400 MHz): δ = 0.95 (m, 6 H), 1.53 (m, 2 H), 1.61 (s, 3 H),
1.62 (s, 3 H), 1.73 (m, 1 H), 4.21 (m, 1 H), 4.32 (dd, J = 10.3,
7.0 Hz, 1 H), 4.40 (dd, J = 10.3, 7.0 Hz, 1 H), 5.12 (d, J = 10.9 Hz,
1 H), 5.23 (d, J = 17.6 Hz, 1 H), 5.42 (m, 1 H), 5.82 (br., 2 H),
6.04 (m, 1 H), 6.17 (dd, J = 17.6, 10.9 Hz, 1 H), 7.29 (t, J = 7.4 Hz,
2 H), 7.38 (t, J = 7.4 Hz, 2 H), 7.59 (d, J = 7.4 Hz, 2 H), 7.75 (d,
J = 7.4 Hz, 2 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 22.3,
23.3, 25.1, 26.7, 27.0, 44.4, 47.4, 49.2, 66.7, 82.5, 113.1, 120.0 (2
C), 125.3 (3 C), 127.1 (2 C), 127.7 (3 C), 141.4 (2 C), 142.5, 144.1
(2 C), 156.1, 161.6, 170.1 ppm. LC (conditions A): tR = 2.23 min.
LC–MS (ESI+): m/z (%) = 520.2 (100) [M + H]+, 542.2 (10) [M +
Na]+. HRMS (ESI): calcd. for C29H34N3O4S [M + H]+ 520.2270;
554.2123. FTIR: ν
= 3316, 3198, 2982, 1691, 1614, 1494, 1450,
˜
max
1317, 1280, 1251, 1076, 1046, 923, 827, 758, 739, 699 cm–1.
1,1-Dimethylprop-2-en-1-yl 4-{(1S)-1-(Fmoc-amino)-[(tert-butoxy-
carbonyl)amino]pentyl}-2-methyl-1,3-thiazole-5-carboxylate
(7h):
White solid, yield 81%, m.p. 128–129 °C. [α]2D0 °C = –1.4 (c = 1.00,
1
CHCl3). H NMR (CDCl3, 400 MHz): δ = 1.36 (br., 2 H), 1.41 (s,
9 H), 1.52 (br., 2 H), 1.65 (s, 6 H), 1.80 (m, 2 H), 2.75 (s, 3 H),
3.08 (br., 2 H), 4.21 (t, J = 7.6 Hz, 1 H), 4.34 (m, 2 H), 4.60 (br.,
1 H), 5.16 (d, J = 10.7 Hz, 1 H), 5.26 (d, J = 17.3 Hz, 1 H), 5.62
(m, 1 H), 6.16–6.19 (m, 2 H), 7.29 (m, 2 H), 7.38 (t, J = 7.6 Hz, 2
H), 7.60 (br., 2 H), 7.75 (d, J = 7.6 Hz, 2 H) ppm. 13C NMR
(CDCl3, 100 MHz): δ = 19.3, 23.1, 26.6 (2 C), 28.5 (3 C), 29.7,
35.7, 40.4, 47.3, 50.1, 66.9, 79.2, 83.5, 113.7, 120.0 (2 C), 123.6,
125.3 (2 C), 127.1 (2 C), 127.8 (2 C), 141.4 (2 C), 141.8, 144.0 (2
found 520.2274. FTIR: ν
= 3313, 2955, 1695, 1615, 1496, 1450,
˜
max
1316, 1257, 1075, 1043, 923, 827, 758, 738 cm–1.
C), 156.1, 156.2, 160.2, 161.3, 170.1 ppm. LC (conditions A): tR
=
2.04 min. LC–MS (ESI+): m/z (%) = 634.3 (100) [M + H]+, 656.3
1,1-Dimethylprop-2-en-1-yl 4-[(1S)-1-(Fmoc-amino)-3-(tert-butyl)-
propionate]-2-isopropyl-1,3-thiazole-5-carboxylate (7e): Yellow gel,
yield 70%. [α]2D0 °C = –1.9 (c = 1.00, CHCl3). 1H NMR (CDCl3,
400 MHz): δ = 1.38 (s, 6 H), 1.40 (s, 9 H), 1.67 (s, 6 H), 2.82 (m,
2 H), 3.29 (m, 1 H), 4.24 (br., 1 H), 4.33 (br., 2 H), 5.15 (d, J =
10.7 Hz, 1 H), 5.27 (d, J = 17.3 Hz, 1 H), 5.98 (br., 1 H), 6.19–6.25
(m, 2 H), 7.29 (t, J = 7.4 Hz, 2 H), 7.38 (t, J = 7.4 Hz, 2 H), 7.60
(d, J = 7.4 Hz, 2 H), 7.75 (d, J = 7.4 Hz, 2 H) ppm. 13C NMR
(CDCl3, 100 MHz): δ = 23.0 (2 C), 26.7 (2 C), 28.1 (3 C), 33.7,
41.5, 47.3, 47.8, 67.1, 81.0, 83.6, 113.7, 120.0 (2 C), 123.7, 125.4 (2
C), 127.1 (2 C), 127.8 (2 C), 141.4 (2 C), 141.9, 144.2 (2 C), 155.7,
159.2, 160.3, 169.5, 181.7 ppm. LC (conditions A): tR = 2.81 min.
LC–MS (ESI+): m/z (%) = 605.3 (100) [M + H]+. HRMS (ESI):
calcd. for C34H41N2O6S [M + H]+ 605.2685; found 605.2690.
(10) [M + Na]+. HRMS (ESI): calcd. for C35H44N3O6S [M + H]+
634.2951; found 634.2955. FTIR: ν
= 3298, 3069, 2978, 2934,
˜
max
1695, 1511, 1450, 1364, 1247, 1165, 1084, 974, 831, 759, 740, 708
cm–1.
1,1-Dimethylprop-2-en-1-yl 2-Amino-4-{(1S)-1-(Fmoc-amino)-[(tert-
butoxycarbonyl)amino]pentyl}-1,3-thiazole-5-carboxylate (7i): White
solid, yield 82%, m.p. 147–148 °C. [α]2D0 °C = –15.4 (c = 1.00,
1
CHCl3). H NMR (CDCl3, 400 MHz): δ = 1.36 (br., 2 H), 1.43 (s,
9 H), 1.51 (br., 2 H), 1.62 (s, 6 H), 1.75 (m, 2 H), 3.09 (br., 2 H),
4.19 (t, J = 7.0 Hz, 1 H), 4.35 (d, J = 7.0 Hz, 2 H), 4.62 (br., 1 H),
5.12 (d, J = 10.9 Hz, 1 H), 5.23 (d, J = 17.6 Hz, 1 H), 5.39 (m, 1
H), 6.03 (br., 3 H), 6.16 (dd, J = 17.6, 10.9 Hz, 1 H), 7.28 (m, 2
H), 7.37 (t, J = 7.5 Hz, 2 H), 7.59 (br., 2 H), 7.74 (d, J = 7.5 Hz,
2 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 23.0, 26.8 (2 C), 28.6
(3 C), 29.7, 35.1, 40.3, 47.4, 50.5, 66.9, 79.3, 82.6, 113.2, 118.6,
FTIR: νmax = 2975, 1711, 1506, 1450, 1438, 1367, 1246, 1150, 1121,
˜
1084, 1043, 845, 759, 738, 723, 695 cm–1.
1,1-Dimethylprop-2-en-1-yl 4-[(1S)-1-(Fmoc-amino)-2-phenethyl]-2- 120.0 (2 C), 125.3 (2 C), 127.2 (2 C), 127.7 (2 C), 141.4 (2 C), 142.4,
methyl-1,3-thiazole-5-carboxylate (7f): White solid, yield 75%, m.p.
144.2 (2 C), 156.1 (2 C), 156.3, 160.9, 170.1 ppm. LC (conditions
A): tR = 2.08 min. LC–MS (ESI+): m/z (%) = 635.3 (100) [M +
50–51 °C. [α]2D0 °C = +2.9 (c = 1.00, CHCl3). 1H NMR (CDCl3,
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O50012
/KAP1
Date: 16-02-15 14:28:09
Pages: 10
L. T. Maillard et al.
FULL PAPER
H]+, 657.3 (10) [M + Na]+. HRMS (ESI): calcd. for C34H43N4O6S
7.38 (m, 5 H), 7.57 (m, 2 H), 7.75 (m, 2 H) ppm. 13C NMR (CDCl3,
[M + H]+ 635.2903; found 635.2908. FTIR: ν
= 3316, 2933, 100 MHz): δ = 12.6, 18.0, 19.4, 19.5, 25.3, 26.5, 26.9, 28.7 (2 C),
˜
max
1685, 1498, 1450, 1364, 1248, 1165, 1077, 926, 858, 828, 758, 739
33.8, 40.6, 43.4, 47.3, 49.2, 67.0, 83.5, 86.4, 113.6, 117.5, 120.1 (2
C), 122.7, 124.6 (2 C), 125.2 (2 C), 127.2 (2 C), 127.8 (2 C), 132.4,
133.3, 138.5, 141.4, 142.0, 143.8, 144.0, 156.2, 156.6, 158.7, 160.6,
161.8, 170.1 ppm. LC (conditions A): tR = 2.54 min. LC–MS
(ESI+): m/z (%) = 814.4 (100) [M + H]+. HRMS (ESI): calcd. for
cm–1.
1,1-Dimethylprop-2-en-1-yl 4-[(1S)-1-(Fmoc-amino)-2-(N-Boc-1H-
indol-3-yl)ethyl]-2-methyl-1,3-thiazole-5-carboxylate (7j): Yellow so-
lid, yield 72%, m.p. 149–150 °C. [α]2D0 °C = +0.56 (c = 1.00, CHCl3).
1H NMR (CDCl3, 400 MHz): δ = 1.53 (m, 6 H), 1.62 (s, 9 H), 2.67
(s, 3 H), 3.26 (m, 2 H), 4.20 (t, J = 7.1 Hz, 1 H), 4.25–4.35 (m, 2
H), 5.09 (d, J = 10.8 Hz, 1 H), 5.17 (d, J = 17.4 Hz, 1 H), 5.99–
6.06 (m, 2 H), 6.11 (m, 1 H), 7.16 (t, J = 7.3 Hz, 1 H), 7.24–7.40
(m, 6 H), 7.56 (m, 3 H), 7.75 (d, J = 7.7 Hz, 2 H), 8.08 (br., 1 H)
ppm. 13C NMR (CDCl3, 100 MHz): δ = 19.3, 26.5 (2 C), 28.3 (3
C), 31.5, 47.3, 50.3, 67.0, 83.5 (2 C), 113.6, 115.2, 116.1, 119.0,
120.0 (2 C), 122.5, 124.3, 124.9, 125.5 (2 C), 127.2 (2 C), 127.7 (2
C), 127.9, 130.9, 135.4, 141.4 (2 C), 141.8, 144.1 (2 C), 149.8, 155.8,
159.9 (2 C), 170.0 ppm. LC (conditions B): tR = 2.98 min. LC–MS
(ESI+): m/z (%) = 692.4 (100) [M + H]+, 714.4 (10) [M + Na]+.
HRMS (ESI): calcd. for C40H42N3O6S [M + H]+ 692.2794; found
C43H52N5O7S2 [M + H]+ 814.3308; found 814.3312. FTIR: ν
˜
max
= 2921, 2853, 1719, 1539, 1452, 1370, 1251, 1135, 1083, 759, 740
cm–1.
Acknowledgments
The authors thank the Institut des Biomolécules Max Mousseron
(IBMM, UMR5247 CNRS, UM1, UM2, ENSCM) and the Ag-
ence Nationale de la Recherche (ANR), FragSPIN, for financial
support. The Laboratory for Physical Measurements of the
Montpellier 2 University is thanked for providing analysis facilities.
692.2798. FTIR: ν
= 3376, 2978, 2932, 1718, 1504, 1451, 1368,
˜
max
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1331, 1252, 1155, 1082, 936, 855, 833, 758, 739 cm–1.
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J. Org. Chem. 2005, 70, 10753.
Compound 7k: White solid, yield 51%, m.p. 134–135 °C. [α]2D0 °C
=
–0.98 (c = 1.00, CHCl3). 1H NMR (CDCl3, 400 MHz): δ = 0.91
(br., 6 H), 1.25 (s, 6 H), 1.42 (m, 1 H), 1.57 (m, 2 H), 1.62 (br., 9
H), 3.23 (m, 2 H), 4.21 (br., 1 H), 4.33 (m, 2 H), 4.98 (br., 1 H),
5.09 (m, 2 H), 5.12 (s, 2 H), 5.97 (br., 1 H), 6.00 (m, 1 H), 6.07
(br., 2 H), 7.07–7.39 (m, 12 H), 7.50–7.61 (m, 3 H), 7.75 (d, J =
7.8 Hz, 2 H), 8.06 (br., 1 H) ppm. 13C NMR (CDCl3, 100 MHz):
δ = 22.9 (2 C), 26.6 (2 C), 28.3 (3 C), 29.9 (2 C), 32.1, 45.8, 47.4,
50.7, 67.1, 67.4, 83.5, 83.6, 113.6, 115.3, 116.1, 117.6, 120.1 (2 C),
122.7, 124.3, 124.4, 125.3 (2 C), 127.2 (2 C), 127.8 (2 C), 128.2 (2
C), 128.4, 128.7 (2 C), 129.8, 130.4, 132.2, 136.2, 141.4 (2 C), 142.0,
144.2 (2 C), 149.8, 155.8, 155.9, 161.5, 161.9, 165.4 ppm. LC (con-
ditions B): tR = 3.16 min. LC–MS (ESI+): m/z (%) = 897.1 (100)
[M + H]+, 919.1 (10) [M + Na]+. HRMS (ESI): calcd. for
C52H57N4O8S [M + H]+ 897.3897; found 897.3899. FTIR: ν
=
˜
max
2917, 2851, 1728, 1593, 1522, 1451, 1368, 1254, 1191, 1143, 1081,
937, 831, 758, 740, 721 cm–1.
Compound 7l: White solid, yield 45%, m.p. 121–122 °C. [α]2D0 °C
=
–0.80 (c = 1.00, CHCl3). 1H NMR (CDCl3, 400 MHz): δ = 1.26 (s,
6 H), 1.66 (s, 9 H), 2.12 (m, 3 H), 2.47 (s, 3 H), 2.95 (m, 4 H), 3.27
(m, 2 H), 4.16 (br., 1 H), 4.25 (m, 2 H), 5.17 (d, J = 10.8 Hz, 1 H),
5.25 (d, J = 17.4 Hz, 1 H), 6.04 (m, 1 H), 6.12 (m, 1 H), 6.24 (br.,
1 H), 7.21–7.38 (m, 7 H), 7.46–7.58 (br., 4 H), 7.64–7.76 (m, 4 H),
8.13 (br., 1 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 14.3, 25.6,
26.6, 28.3 (3 C), 29.9 (2 C), 30.3, 33.0, 47.1, 49.0, 67.6, 84.0, 84.6,
114.2, 114.6, 115.5, 118.6, 120.0 (2 C), 122.8, 122.9, 124.5, 124.6,
124.8, 124.9, 125.2, 125.5 (2 C), 127.2 (2 C), 127.8 (2 C), 130.0 (2
C), 135.5, 141.3, 143.7, 143.9 (2 C), 145.1 (2 C), 147.8, 149.7, 155.8,
157.6, 159.1, 163.3, 169.6 ppm. LC (conditions A): tR = 2.84 and
2.87 min. LC–MS (ESI+): m/z (%) = 850.7 (100) [M + H]+, 872.7
(10) [M + Na]+. HRMS (ESI): calcd. for C50H52N5O6S [M + H]+
[17] A. Sengupta, S. Aravinda, N. Shamala, K. M. Raja, P. Bala-
ram, Org. Biomol. Chem. 2006, 4, 4214.
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Shamala, P. Balaram, J. Am. Chem. Soc. 2007, 129, 4039.
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Shamala, P. Balaram, J. Org. Chem. 2008, 73, 6595.
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nan, N. Shamala, P. Balaram, J. Am. Chem. Soc. 2009, 131,
5956.
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tens, C. Kouklovsky, E. Miclet, V. Alezra, Org. Biomol. Chem.
2012, 10, 9660.
850.3638; found 850.3633. FTIR: ν
= 2917, 2850, 1728, 1594,
˜
max
1522, 1451, 1368, 1252, 1191, 1143, 1081, 938, 832, 758, 740, 721
[22] S. K. Maji, R. Banerjee, D. Velmurugan, A. Razak, H. K. Fun,
A. Banerjee, J. Org. Chem. 2002, 67, 633.
cm–1.
[23] Y. K. Kang, B. J. Byun, Biopolymers 2012, 97, 1018.
[24] L. Mathieu, B. Legrand, C. Deng, L. Vezenkov, E. Wenger, C.
Didierjean, M. Amblard, M. C. Averlant-Petit, N. Masurier, V.
Lisowski, J. Martinez, L. T. Maillard, Angew. Chem. Int. Ed.
2013, 52, 6006; Angew. Chem. 2013, 125, 6122.
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sowski, N. Masurier, S. Zirah, Y. K. Kang, J. Martinez, L. T.
Maillard, Chem. Eur. J. 2014, 20, 6713.
Compound 7m: White solid, yield 70%, m.p. 140–142 °C. [α]2D0 °C
=
–0.99 (c = 1.00, CHCl3). 1H NMR (CDCl3, 400 MHz): δ = 1.44 (s,
6 H), 1.60 (d, J = 8.1 Hz, 6 H), 1.72 (br., 2 H), 1.92 (br., 2 H), 2.08
(s, 3 H), 2.51 (s, 3 H), 2.57 (s, 3 H), 2.67 (s, 3 H), 2.92 (s, 2 H),
3.23 (br., 2 H), 4.19 (t, J = 7.0 Hz, 1 H), 4.39 (m, 2 H), 5.14 (d, J
= 10.9 Hz, 1 H), 5.28 (d, J = 17.6 Hz, 1 H), 5.54 (br., 1 H), 6.04
(br., 1 H), 6.12 (dd, J = 17.6, 10.9 Hz, 1 H), 7.15–7.32 (m, 2 H),
8
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O50012
/KAP1
Date: 16-02-15 14:28:09
Pages: 10
Cross-Claisen Condensation of N-Fmoc-Amino Acids
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R. V. Hoffman, N. Maslouh, F. Cervantes-Lee, J. Org. Chem.
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J. A. Turner, W. S. Jacks, J. Org. Chem. 1989, 54, 4229.
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Received: January 6, 2015
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Published Online: ᭿
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9

Job/Unit: O50012
/KAP1
Date: 16-02-15 14:28:09
Pages: 10
L. T. Maillard et al.
FULL PAPER
Amino Acids
L. Mathieu, C. Bonnel, N. Masurier,
L. T. Maillard,* J. Martinez,
V. Lisowski ...................................... 1–10
Cross-Claisen Condensation of N-Fmoc-
Amino Acids – A Short Route to Hetero-
cyclic γ-Amino Acids
Keywords: Peptidomimetics / Amino acids /
Heterocycles / Cross-Claisen reactions
Cross-Claisen condensations between N-
Fmoc-amino acids and sterically hindered
1,1-dimethylallyl acetate provide a short
route to 4-amino(methyl)-1,3-thiazole-5-
carboxylic acids (ATCs), a new class of
constrained heterocyclic γ-amino acids
built around a thiazole ring. A wide variety
of lateral chains can be introduced on the
γ-carbon atom or on the thiazole core.
10
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Eur. J. Org. Chem. 0000, 0–0