Efficient synthesis of nicotianamine and non-natural analogues

Article abstract of DOI:10.1002/ejoc.201000920

An efficient synthesis of nicotianamine has been achieved by using a new strategy based on N-alkylation. Sulfonamide activation proved to be necessary for the alkylation of the primary amine and the 2-(trimethylsilyl)ethanesulfonyl group was easily introd

Full text of DOI:10.1002/ejoc.201000920

FULL PAPER
DOI: 10.1002/ejoc.201000920
Efficient Synthesis of Nicotianamine and Non-Natural Analogues
M’barek Bouazaoui,[a][‡] Manuel Larrouy,[a] Jean Martinez,[a] and Florine Cavelier*[a]
Keywords: Alkylation / Sulfonamides / Natural products / Nucleophilic substitution
An efficient synthesis of nicotianamine has been achieved
by using a new strategy based on N-alkylation. Sulfonamide
activation proved to be necessary for the alkylation of the
primary amine and the 2-(trimethylsilyl)ethanesulfonyl
group was easily introduced and found to provide the best
compromise for the N-alkylation and deprotection reactions.
This new strategy enabled the preparation of several unnatu-
ral analogues including original molecules that will be useful
as tools for plant physiology studies.
of the molecule. More recently, the reduction of amides
through thioamide bonds followed by subsequent desulfur-
ization has been developed.[9] Owing to the importance of
NA it is desirable to develop new efficient methods for the
synthesis of NA suitable for large-scale production.
The purpose of this research was to develop a new syn-
thetic strategy based on nucleophilic substitution by an
amine as the key reaction.
Introduction
Nicotianamine (NA, 1), which was first isolated from the
leaves of Nicotiana tabacum L.,[1] is a key biosynthetic pre-
cursor of phytosiderophores (Figure 1). This ubiquitous
compound is found in all higher plants and is involved in
the homeostasis of such essential metal ions as Fe, Zn and
Cu.[2] In gramineous plant species, NA is a precursor of the
phytosiderophores, the main role of which is in iron uptake.
In plants, NA is characterized by high mobility and is also
found at low concentrations (micromolar) in the circulating
saps of xylem and phloem.[3] NA has a role in the loading
of Cu in xylem for translocation from the roots to the
shoots and also for the unloading of the Fe in the leaves
from the vascular system. NA is also involved in the loading
of Fe by seeds. Its chelation ability has been studied in vitro
with several metals including Fe, Zn, Ni, Cu and Mn.[4]
Interestingly, it has been discovered that NA exhibits anti-
hypertensive activity in humans by inhibiting the angioten-
sin I converting enzyme.[5]
Results and Discussion
This novel approach to NA involved different building
blocks: a free amine for one moiety and a good leaving
group on the other part with suitable protecting groups on
all other functions. In this way building blocks can be used
twice to construct NA from the left to the right part of the
molecule.
Two successive N-alkylation steps were necessary to as-
semble NA, with noticeable differences between the two, the
first one involving a secondary amine, the second one a
primary amine, which was much more difficult to alkylate
(Scheme 1).
For the first alkylation step, we compared several leaving
groups under standard conditions (Scheme 2, Table 1). We
selected iodine as the most efficient leaving group (entry 4).
Then we optimized the synthesis of the intermediate bear-
ing iodine as the leaving group and chose suitable protec-
tions for the other reactive functions. Then we optimized
the N-alkylation conditions.
tert-Butyl ester and benzyl ester (Z) protection were cho-
sen for the iodine-containing compound. tert-Butoxycarb-
onyl (S)-2-(benzyloxycarbonylamino)-4-iodobutanoate (4),
the key precursor, was prepared in three steps by using
l-tert-butyl aspartate (2) as the starting material
(Scheme 3).
Figure 1. Structure of nicotianamine (NA).
The importance of NA in plant physiology has prompted
synthetic investigations. Two main strategies for the synthe-
sis of NA have been described in the literature:[6] reductive
amination of intermediate protected aldehydes, either from
the left to the right part[7] or from the right to the left part[8]
[a] IBMM, UMR-CNRS 5247, Universités Montpellier 1 and 2,
Place Eugène Bataillon, 34095 Montpellier Cedex 5, France
Fax: +33-4-67144866
E-mail: florine.cavelier@univ-montp2.fr
[‡] Present address: Montpellier SupAgro, 2 place Viala, 34060
Montpellier Cedex 2, France.
Treatment of compound 2 with benzyl chloroformate un-
der the usual conditions (NaHCO3, H2O/dioxane) yielded
the Z derivative, which was readily reduced under McGeary
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000920.
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M. Bouazaoui, M. Larrouy, J. Martinez, F. Cavelier
FULL PAPER
Scheme 1. General strategy for the synthesis of NA by N-alkylation.
Selective deprotection of the N-terminal amino group by
hydrogenolysis of 6 using 10% Pd/C and H2 afforded the
free amine 7 (Scheme 4).
However, the second direct alkylation of the resulting
primary amine with the iodine derivative did not afford the
desired product, but gave only the starting material, thus
proving the poor reactivity of this amine in this reaction
and the need for specific activation. For this experiment, we
used sulfonamide as temporary protection.
Scheme 2. Comparison between leaving groups on a model sub-
strate.
Table 1. Comparison between leaving groups in the N-alkylation
In a first attempt, we introduced onto the free amine the
p-nitrophenylsulfonyl group (nosyl)[13] widely used in poly-
amine synthesis.[14] This activated intermediate was ob-
tained in 78% yield and was subsequently alkylated with
compound 4. The reaction was followed by LC–MS: after
6 hours the expected compound was detected with a conver-
sion of 60%. After 12 hours we observed total conversion
with the appearance of a side-product with a mass of 64
units less than the expected product. A rearrangement, al-
ready observed in the literature,[15] resulted in the loss of
SO2. Under optimized conditions we successfully obtained
the desired compound in 65% yield. The same rearrange-
ment occurred in the deprotection step and cannot be avo-
ided when an electron-withdrawing group flanks the nosyl
sulfonamide.
reaction.
Entry
Leaving group
N-Alkylation yields [%][a]
1
2
3
4
OMs
OTs
Br
32
25
69
78
I
[a] Yields of the isolated product.
conditions[10] (preactivation of the acid with BOP then re-
duction with NaBH4) to afford the desired alcohol 3 in 93%
yield. The use of the tert-butyl ester as protecting group
significantly increased the yield of the desired alcohol by
preventing lactonization. Then the alcohol 3 was converted
into the iodide 4 by using iodine, triphenylphosphane and
imidazole.[11]
We therefore tried different sulfonamide protecting
In the first alkylation step, tert-butyl l-azetidine-2-carb- groups, that is, 2-(trimethylsilyl)ethanesulfonyl (SES)[16] and
oxylate[12] (5) was successfully N-alkylated with the iodide 2,2,5,7,8-pentamethylchromane-6-sulfonyl (Pmc)[17] and we
derivative 4. The optimized alkylation conditions, DIEA evaluated the efficiency of the activation and the N-alk-
(2 equiv.) in acetonitrile at 55 °C, provided 6 in good yield. ylation reactions with several substrates (Scheme 5, Table 2).
Scheme 3. Synthesis of tert-butoxycarbonyl (S)-2-(benzyloxycarbonylamino)-4-iodobutanoate (4).
Scheme 4. Synthesis of the free amine 7.
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Efficient Synthesis of Nicotianamine and Non-Natural Analogues
Table 2. Comparison of the efficacy of the Pmc and SES protecting
groups in the activation and N-alkylation steps with the iodine de-
rivative 4.
Scheme 5. Comparison of the efficacy of the SES and Pmc protect-
ing groups with a model substrate.
With monomeric (entries 1 and 2) and dimeric linear
substrates (entries 3 and 4), Pmc provided better yields for
both reactions, but to a higher extent during the activation
than in the N-alkylation. However, with ring-containing
substrates (entry 6) we were unable to isolate the alkylation
product due to purification difficulties. In addition, the Pmc
protecting group proved to be resistant to final HF depro-
tection.
For these reasons we used the SES group for the synthe-
sis. After introducing the SES protecting group, which af-
forded the sulfonamide 8, the N-alkylation step gave an op-
timal yield when using caesium carbonate (2 equiv.) in ace-
tonitrile at 55 °C. Higher temperatures and a large excess
of caesium carbonate led to the decomposition of 4. The
targeted compound 9 was obtained in 55% yield. Removal
of the SES, Z and tert-butyl protecting groups proceeded
without difficulty on HF treatment to afford NA after lyo-
philization as a white powder in high purity (Scheme 6).
We then extended this strategy to produce three synthetic
analogues (Figure 2) by replacing the carboxy-azetidine
ring with proline (10), silaproline (11)[18] and pyroglutamic
acid (12), thus modifying the physicochemical properties of
the molecules. These compounds were used as probes in
plant experiments.[19] By using the same operational condi-
tions, the NA analogues 10[20] and 11 were synthesized with
overall yields in the same range as that of 1 (Scheme 7).
For the synthesis of the analogue 12, tert-butyl pyroglut-
amate (21) was alkylated in the presence of the iodide deriv-
ative and sodium hydride in DMF at 0 °C to afford the
tertiary amide 22. The pyroglutamate analogue 12 was then
obtained by following the same procedure as described for
the synthesis of 1 (Scheme 8).
[a] Sulfonamide introduction, yields of the isolated products. [b]
Formation of N–C bonds, yields of the isolated products. R = any
alkyl group, n = 1 or 2.
Figure 2. Unnatural nicotianamine analogues.
Scheme 6. Synthesis of nicotianamine (1) from the free amine 7.
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M. Bouazaoui, M. Larrouy, J. Martinez, F. Cavelier
FULL PAPER
Scheme 7. Synthesis of nicotianamine analogues 10 and 11.
Scheme 8. Synthesis of nicotianamine analogue 12.
the apparatus frequency (SF1 = BF1). Low-resolution mass spec-
trometry (MS) was performed with a Micromass Platform II spec-
trometer by using electrospray ionization (ESI). HRMS were re-
Conclusions
An efficient synthesis of NA based on N-alkylation as
the key reaction has been developed. Different sulfonamide corded with a JEOL JMS-SX-102A spectrometer. High-pressure
liquid chromatography (HPLC) was performed with a Waters Al-
liance 2796 apparatus with a Chromolith SpeedROD (50ϫ4.6 mm)
column and a diode array detector. A linear gradient of H2O to
ACN (0.1% TFA) in 3 min was used as eluent in the HPLC analy-
sis. Melting points were measured with a Büchi instrument. Optical
rotations values were measured with a Perkin–Elmer 341 apparatus
(20 °C, sodium discharge lamp).
activations were compared and the SES protecting group
was finally chosen on the basis of the best compromise for
its introduction and the N-alkylation and deprotection reac-
tions. This new strategy enabled the preparation of several
unnatural analogues, including novel structures, that will be
useful tools for plant physiology studies. Their biological
evaluation in plants and in in vitro metal chelation is cur-
rently under progress.
tert-Butyl (S)-2-(Benzyloxycarbonylamino)-4-hydroxybutanoate (3):
Sodium hydrogen carbonate (13 g, 159 mmol) was added to a solu-
tion of compound 2 (10 g, 53 mmol) in water/dioxane (2:1; 170 mL)
and over a period of 2 h, a solution of benzyl chloroformate
(11.8 mL, 69 mmol) in dioxane (70 mL) was added. The reaction
mixture was stirred overnight, then washed with ethyl acetate
(3ϫ200 mL) and the pH was lowered to 2 with 6 n hydrochloric
acid solution at 0 °C. The aqueous phase was extracted with ethyl
acetate (3ϫ200 mL). The organic phases were combined and
washed successively with brine (200 mL) and distilled water
(200 mL), then dried with anhydrous magnesium sulfate and con-
Experimental Section
General: All reactions involving air-sensitive reagents were per-
formed under nitrogen or argon. Solvents and reagents were pur-
chased from Aldrich and Fluka. THF was freshly distilled from
benzophenone/sodium prior to use. Merck silica gel 60 F-254 plates
were used for TLC. Column chromatography was performed by
using silica gel (Merck 60, 230–400 mesh). 1H and 13C NMR spec-
tra were recorded at 300 and 75 MHz, respectively. All chemical centrated to obtain a colourless oil (16.7 g, 97%). Rf (CHCl3/
shifts were recorded as values (ppm) relative to internal tetrameth-
ylsilane when CDCl3 was used as solvent. The 13C standard in D2O
was calculated from the chemical shift of water in 1H NMR and
MeOH/AcOH 37%) = 0.68. HPLC: t = 1.56 min. 1H NMR
(CDCl3, 300 MHz): δ = 1.45 (s, 9 H), 2.95 (dd, J = 4.5, 14 Hz, 2
H), 4.55 (q, J = 4.3 Hz, 1 H), 5.10 (s, 2 H), 5.8 (d, J = 8 Hz, 1 H),
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Efficient Synthesis of Nicotianamine and Non-Natural Analogues
7.35 (m, 5 H), 10.7 (br. s, 1 H) ppm. 13C NMR (CDCl3, 75 MHz):
δ = 27.8, 36.7, 50.8, 67.1, 82.8, 128.1, 128.2, 128.5, 136.1,
156.06, 169.5, 176.3 ppm. MS: m/z = 324.1 [M + H]+, 268.1 [M +
H – tBu]+.
1.45 (s, 9 H), 1.47 (s, 9 H), 1.65–1.78 (m, 1 H), 1.80–1.97 (m, 1 H),
2.14–2.35 (2 m, 2 H), 2.39–2.47 (m, 1 H), 2.71–2.82 (m, 2 H), 3.28–
3.32 (m, 1 H), 3.34–3.5 (m, 1 H), 4.17–4.28 (dd, J = 7.5, 12.5 Hz,
1 H), 5.12 (s, 2 H), 6.21 (d, J = 8.5 Hz, 1 H), 7.32 (m, 5 H) ppm.
13C NMR (CDCl3, 75 MHz): δ = 18.9, 21.1, 28.0, 29.3, 29.7, 50.8,
51.1, 53.8, 55.1, 58.4, 65.9, 66.6, 81.1, 81.7, 127.95, 127.99, 128.2,
128.4, 128.6, 136.7, 156.2, 171.2, 171.8 ppm. MS (ES+): m/z = 449.2
[M + H]+, 393.2 [M – tBu]+, 337.0 [M – 2 tBu]+.
DIEA (10.5 mL, 60.4 mmol) was added to a suspension of the re-
sulting oil (15 g, 46.4 mmol) and BOP (27 g, 60.4 mmol) in anhy-
drous THF was added. The reaction mixture was stirred for 10 min
until it turned yellow, and cooled down to 0 °C for 15 min. Then
NaBH4 (2.3 g, 60.4 mmol) was added portionwise. The reaction
mixture was stirred overnight. The solvent was evaporated in vacuo
and the crude was dissolved in ethyl acetate (250 mL). The organic
layer was washed successively with a 10% citric acid solution
(3ϫ100 mL), a saturated solution of sodium hydrogen carbonate
(3ϫ100 mL) and distilled water (2ϫ100 mL). The organic layer
was dried with anhydrous magnesium sulfate and concentrated to
afford a colourless oil. Compound 3 was purified by chromatog-
raphy on silica gel (petroleum ether/diethyl ether, 3:7) to afford a
colourless oil (13.95 g, 96%).
tert-Butyl (S)-1-[(S)-3-Amino-4-tert-butoxy-4-oxobutyl]azetidine-2-
carboxylate (7): Palladium on charcoal (400 mg, 20% weight) was
added to compound 6 (2 g, 4.46 mmol) in anhydrous THF (35 mL).
The air in the apparatus was eliminated and replaced by argon
through three cycles of vacuum/argon and then by hydrogen with
three cycles of vacuum/hydrogen. The reaction mixture was stirred
vigorously for 10 h, filtered through a pad of Celite and concen-
trated to afford a pale-brown oil (1.38 g, 98%). Rf (CHCl3/MeOH/
1
AcOH 37%, 24:2:1) = 0.3. [α]2D4 = –9.7 (c = 4.4, DCM). H NMR
(CDCl3, 300 MHz): δ = 1.45 (s, 9 H), 1.47 (s, 9 H), 1.51–1.62 (m,
1 H), 1.80–1.93 (m, 1 H), 2.14–2.35 (m, 2 H), 2.42–2.55 (m, 1 H),
2.71–2.82 (m, 2 H), 3.35–3.52 (m, 3 H), 3.64 (br. s, 2 H) ppm. 13C
NMR (CDCl3, 75 MHz): δ = 21.3, 27.99, 28.03, 28.3, 31.1, 50.8,
53.3, 55.2, 62.0, 65.2, 81.0, 81.3, 172.1, 174.2 ppm. MS (ES+): m/z
= 315.3 [M + H]+, 337.2 [M + Na]+.
Rf (petroleum ether/diethyl ether, 3:7) = 0.42. HPLC: t = 1.45 min.
1H NMR (CDCl3, 300 MHz): δ = 1.43 (s, 9 H), 2.09 (dd, J = 4.6,
15.2 Hz, 2 H), 3.48 (s, 1 H), 3.8 (m, 2 H), 4.45 (m, 1 H), 5.10 (s, 2
H), 5.87 (d, J = 8 Hz, 1 H), 7.35 (m, 5 H) ppm. 13C NMR (CDCl3,
75 MHz): δ = 27.9, 35.5, 52.0, 58.4, 67.0, 82.4, 128.07, 128.1, 128.3,
129.0, 136,1, 156.8, 169.5, 171.7 ppm. MS: m/z = 310.2 [M + H]+,
254.1 [M + H – tBu]+.
tert-Butyl (S)-1-{(S)-4-tert-Butoxy-4-oxo-3-[2-(trimethylsilyl)ethyl-
sulfonamido]butyl}azetidine-2-carboxylate (8): The free amine 7
(1.3 g, 4.14 mmol) was dissolved in anhydrous dimethylformamide
(15 mL) and then TEA (1.74 mL, 12.14 mmol) was added and the
mixture was cooled to 0 °C. A solution of 2-(trimethylsilyl)ethane-
sulfonic chloride (1.3 g, 6.6 mmol) in anhydrous dimethylform-
amide (5 mL) was added over a 10 min period. The reaction mix-
ture was stirred overnight. The reaction mixture was concentrated
and dissolved in ethyl acetate (35 mL), washed with brine (20 mL)
and distilled water (20 mL), then dried on anhydrous magnesium
and concentrated. Compound 7 was obtained after silica gel
chromatography (petroleum ether/ethyl acetate, 8:2 to 7:3) as a yel-
low oil (1.25 g, 65%). Rf (petroleum ether/ethyl acetate, 6:4) = 0.52.
tert-Butyl (S)-2-(Benzyloxycarbonylamino)-4-iodobutanoate (4):
Iodine (14.3 g, 56.4 mmol), triphenylphosphane (14.8 g,
56.4 mmol) and, after 10 min, imidazole (9.6 g, 141 mmol) were
added to a solution of compound 3 (5.8 g, 18.8 mmol) in anhydrous
DCM (260 mL) under argon. The reaction mixture was heated at
reflux for 3 h. The reaction mixture was cooled to room tempera-
ture and washed successively with a molar solution of potassium
sulfate (3ϫ150 mL), a saturated solution of sodium hydrogen
carbonate (3ϫ150 mL),
a 5% sodium thiosulfate solution
(3ϫ150 mL) and with brine (3ϫ150 mL). The organic layer was
dried with anhydrous magnesium sulfate and concentrated to af-
ford a yellow oil. Compound 4 was obtained after silica gel
chromatography (petroleum ether/ethyl acetate, 10:0 to 8:2) as a
yellow oil (6.2 g, 78%). Rf (petroleum ether/ethyl acetate, 8:2) =
[α]2D4 = –81.4 (c = 6.7, DCM). H NMR (CDCl3, 300 MHz): δ =
1
0.00 (s, 9 H), 0.91–1.27 (m, 2 H), 1.42 (s, 9 H), 1.44 (s, 9 H), 1.65–
1.89 (m, 2 H), 2.05–2.35 (m, 2 H), 2.42–2.55 (m, 1 H), 2.65–2.83
(m, 2 H), 2.84–3.01 (m, 2 H), 3.36–3.51 (m, 2 H), 4.00–4.15 (m, 1
H), 6.56 (d, J = 8.07 Hz, 1 H) ppm. 13C NMR (CDCl3, 75 MHz):
δ = –0.3, 0.0, 0.3, 12.1, 23.0, 29.8, 30.0, 30.1, 32.2, 52.0, 52.7, 55.4,
56.2, 57.2, 67.5, 83.0, 84.0, 173.1, 173.8 ppm. MS (ES+): m/z =
479.2 [M + H]+. HRMS (ES+): calcd. for C21H43N2O6SSi 479.2611;
found 479.2592.
1
0.65. HPLC: t = 2.42 min. H NMR (CDCl3, 300 MHz): δ = 1.45
(s, 9 H), 2.15–2.45 (2 m, 2 H), 3.15 (m, 2 H), 4.35 (m, 1 H), 5.10
(s, 2 H), 5.87 (d, J = 8 Hz, 1 H), 7.35 (m, 5 H) ppm. 13C NMR
(CDCl3, 75 MHz): δ = 16.1, 28.4, 38.5, 54.2, 56.2, 67.9, 83.6,
128.95, 129.03, 129.2, 129.3, 129.4, 137.0, 156.7, 171.0 ppm. MS:
m/z = 442.0 [M + Na]+, 420.1 [M + H]+, 364.2 [M + H – tBu]+.
tert-Butyl (S)-1-[(S)-3-(Benzyloxycarbonylamino)-4-tert-butoxy-4- tert-Butyl (S)-1-[(S)-3-{N-[(S)-3-(Benzyloxycarbonylamino)-5,5-di-
oxobutyl]azetidine-2-carboxylate (6): A solution of compound 4
(2.68 g, 6.4 mmol) in anhydrous acetonitrile (2 mL) was added to
compound 5 (1 g, 6.4 mmol) dissolved in anhydrous acetonitrile
(2 mL). The reaction mixture was stirred for 30 min under argon.
Freshly distilled DIEA (2.8 mL, 16 mmol) was added and the re-
action mixture was diluted with anhydrous acetonitrile (13 mL).
The reaction mixture was heated to 55 °C and stirred vigorously
for 16 h. The mixture was concentrated and the crude was dissolved
methyl-4-oxohexyl]-2-(trimethylsilyl)ethylsulfonamido}-4-tert-but-
oxy-4-oxobutyl]azetidine-2-carboxylate (9): Caesium carbonate
(411 mg, 1.26 mmol) was added to a solution of 8 (300 mg,
0.63 mmol) in anhydrous acetonitrile (14 mL). The reaction mix-
ture was heated at 55 °C for 30 min whilst vigorously being stirred.
Then compound 4 (264 mg, 0.63 mmol) in anhydrous acetonitrile
(5 mL) was added dropwise through a syringe pump. The reaction
mixture was stirred overnight at 55 °C. The reaction mixture was
in ethyl acetate (25 mL). The organic layer was washed successively concentrated and dissolved in ethyl acetate (25 mL). The organic
with a 5% hydrochloric acid solution (2ϫ15 mL), brine (15 mL)
and distilled water (20 mL). The organic phase was dried with mag-
nesium sulfate, filtered and concentrated to afford a yellow oil. The
compound was purified by chromatography on silica gel (petroleum
ether/ethyl acetate, 8:2 to 0:1) to afford a yellow oil (2.3 g, 94%).
Rf (petroleum ether/ethyl acetate, 8:2) = 0.3. HPLC: t = 2.17 min.
layer was successively washed with brine (15 mL) and distilled
water (15 mL), then dried with anhydrous magnesium sulfate and
concentrated. Compound
9 was obtained after silica gel
chromatography (petroleum ether/ethyl acetate, 8:2 to 7:3) as a yel-
low oil (266 mg, 55%). Rf (petroleum ether/ethyl acetate, 6:4) =
1
0.62. [α]2D4 = –71.4 (c = 6.7, DCM). H NMR (CDCl3, 300 MHz):
1
[α]2D4 = –10.4 (c = 4.55, DCM). H NMR (CDCl3, 300 MHz): δ =
δ = 0.00 (s, 9 H), 0.91–1.27 (m, 2 H), 1.43 (s, 27 H), 1.56–1.80 (m,
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1 H), 1.92–2.05 (m, 1 H), 2.09–2.15 (m, 3 H), 2.16–2.19 (m, 1 H),
2.4 (dt, J = 4.1, 20.4 Hz, 1 H), 2.6–2.95 (m, 4 H), 3.20–3.31 (m, 2
H), 3.51 (t, J = 8.4 Hz, 1 H), 4.05–4.33 (m, 2 H), 5.08 (s, 2 H), 5.48
(d, J = 7.07 Hz, 1 H), 7.28–7.38 (m, 5 H) ppm. 13C NMR (CDCl3,
75 MHz): δ = –0.3, –0.0, 0.3, 12.1, 23.3, 29.9, 29.95, 30.04, 33.9,
35.7, 45.1, 50.8, 52.7, 54.8, 57.5, 61.7, 67.7, 68.8, 82.9, 84.2, 84.3,
129.9, 130.0, 130.1, 131.00, 138.3, 158.0, 172.3, 172.8, 173.9 ppm.
MS (ES+): m/z = 771.4 [M + H]+. HRMS (ESI+): calcd. for
C37H64N3O10SSi 770.4082; found 770.4099.
brine (15 mL) and distilled water (20 mL). The organic phase was
dried with magnesium sulfate, filtered and concentrated to afford
a yellow oil. The compound was purified by chromatography on
silica gel (petroleum ether/ethyl acetate, 8:2 to 0:1) to afford a yel-
low oil (1.98 g, 92%). Rf (petroleum ether/ethyl acetate, 7:3) = 0.74.
1H NMR (CDCl3, 300 MHz): δ = –0.35–0.10 (m, 6 H), 0.56–0.80
(m, 2 H), 1.35 (s, 18 H), 1.85–2.05 (m, 2 H), 1.92–2.00 (m, 2 H),
2.13–2.29 (m, 1 H), 2.33–2.48 (m, 1 H), 2.83–3.00 (m, 1 H), 3.75–
4.17 (m, 1 H), 5.25 (s, 2 H), 6.50 (d, J = 9.8 Hz, 1 H), 7.19 (m, 5
H) ppm. MS (ES+): m/z = 507.2 [M + H]+. HRMS (ES+): calcd.
for C26H43N3O6Si 507.2890; found 507.2883.
(S)-1-{(S)-3-[(S)-3-Amino-3-carboxypropylamino]-3-carboxy-
propyl}azetidine-2-carboxylic Acid (1): Hydrofluoric acid (1 mL,
large excess) was added with the help of a Teflon® apparatus to a
Teflon® vessel containing 9 (140 mg, 0.18 mmol). The reaction mix-
ture was stirred at 0 °C for 1.5 h. The hydrofluoric acid was evapo-
rated and the remaining was neutralized by addition of potassium
hydroxide. The crude was dissolved in distilled water (3 mL) and
tert-Butyl (S)-1-{(S)-4-tert-Butoxy-4-oxo-3-[2-(trimethylsilyl)ethyl-
sulfonamido]butyl}pyrrolidine-2-carboxylate (17): Palladium on
charcoal (300 mg, 20% weight) was added to compound 15 (1.5 g,
3.25 mmol) dissolved in anhydrous THF (17 mL). The air in the
apparatus was eliminated and replaced by argon with three cycles
the aqueous phase washed with diethyl ether (3 ϫ 3 mL). After of vacuum/argon and then by hydrogen with three cycles of vac-
freeze-drying, compound 1 was obtained as a pure pale-brown solid
(49 mg, 98%); m.p. 218–220 °C. [α]2D4 = –55.6 (c = 0.8, H2O) {ref.[9b]
[α]3D4 = –56.4 (c = 0.81, H2O)}. 1H NMR (D2O, 300 MHz): δ =
1.95–2.28 (m, 4 H), 2.35–2.52 (m, 1 H), 2.6 (qd, J = 9.1, 4.2 Hz, 1
H), 3.1–3.4 (m, 4 H), 3.69 (dd, J = 4.5, 8.2 Hz, 1 H), 3.73 (m, 1
H), 3.85 (t, J = 9.6 Hz, 1 H), 3.96 (dt, J = 9.6, 6.6 Hz, 1 H), 4.92
(td, J = 9.6, 6.5 Hz, 1 H) ppm. 13C NMR (D2O, 75 MHz): δ = 16.3,
uum/hydrogen. The reaction mixture was vigorously stirred for
10 h, filtered through a pad of Celite and concentrated to afford
the free amino compound as a brown oil (1.04 g, 98%). Rf (CHCl3/
MeOH/AcOH 37%, 24:2:1) = 0. [α]2D4 = –5.3 (c = 2.2, DCM). H
1
NMR (CDCl3, 300 MHz): δ = 1.42 (s, 18 H), 1.51–1.65 (m, 1 H),
1.69–2.05 (m, 7 H), 2.19–2.46 (m, 2 H), 2.75–2.88 (m, 1 H), 2.91–
3.05 (m, 1 H), 3.09–3.17 (m, 1 H), 3.41–3.49 (m, 1 H) ppm. 13C
17.8, 21.0, 26.9, 42.5, 44.0, 54.4, 57.9, 65.6, 170.6, 171.4, NMR (CDCl3, 75 MHz): δ = 22.9, 28.01, 28.07, 28.3, 29.2, 33.5,
173.0 ppm. MS (ES+): m/z = 304.2 [M + H]+, 203.1 [M – AzeOH]+.
51.1, 53.1, 53.3, 66.5, 80.4, 80.8, 173.1, 175.2 ppm. MS (ES+): m/z
= 329.5 [M + H]+, 273.3 [M – tBu]+, 217.2 [M – 2tBu]+.
HRMS (FAB+): calcd. for C12H22N3O6 304.1509; found 304.1502.
tert-Butyl (S)-1-[(S)-3-(Benzyloxycarbonylamino)-4-tert-butoxy-4- TEA was added (1.8 mL, 12.8 mmol) to a solution of the resulting
oxobutyl]pyrrolidine-2-carboxylate (15): Compound 4 (2 g,
4.78 mmol) was added to 13 (0.98 g, 5.75 mmol) dissolved in anhy-
drous acetonitrile (4 mL). The reaction mixture was kept under ar-
gon and stirred for 30 min. Anhydrous DIEA (2 mL, 11.95 mmol)
was added and the reaction mixture was diluted with anhydrous
acetonitrile (12 mL). The reaction mixture was heated to 55 °C and
vigorously stirred for 16 h. The mixture was concentrated and the
crude was dissolved in ethyl acetate (25 mL). The organic layer was
successively washed with a 5 % hydrochloric acid solution
(2ϫ15 mL), brine (15 mL) and distilled water (20 mL). The or-
ganic phase was dried with magnesium sulfate, filtered and concen-
trated to afford a yellow oil. The compound was purified by
chromatography on silica gel (petroleum ether/ethyl acetate, 8:2 to
0:1) to afford a yellow oil (2.15 g, 95%). Rf (petroleum ether/ethyl
amino compound (1.4 g, 4.26 mmol) in anhydrous dimethylform-
amide (14 mL). The reaction mixture was cooled to 0 °C. A solu-
tion of 2-(trimethylsilyl)ethanesulfonyl chloride (1.4 g, 7.26 mmol)
in anhydrous dimethylformamide (5 mL) was added over a 10 min
period. The reaction mixture was stirred overnight at 0 °C. The
dimethylformamide was evaporated and the crude was partitioned
between ethyl acetate (15 mL) and water (20 mL). The aqueous
phase was extracted with ethyl acetate (2ϫ10 mL). The combined
organic phases were washed with brine (20 mL), dried with anhy-
drous sodium sulfate, filtered and concentrated to afford a yellow
oil, which was purified by chromatography on silica gel (petroleum
ether/ethyl acetate, 8:2 then 7:3) to afford 17 as a yellow oil (1.34 g,
64 %). Rf (petroleum ether/ethyl acetate, 6:4) = 0.52.
[α]2D4 = –35.4 (c = 1.53, DCM). H NMR (CDCl3, 300 MHz): δ =
1
acetate, 7:3) = 0.74. HPLC: t = 2.27 min. [α]2D4 = –27.9 (c = 1.95,
0.00 (s, 9 H), 0.91–1.22 (m, 2 H), 1.43 (s, 18 H), 1.65–1.89 (m, 4
1
DCM). H NMR (CDCl3, 300 MHz): δ = 1.35 (s, 18 H), 1.6–1.84 H), 1.91–2.09 (m, 2 H), 2.29 (q, J = 8.01 Hz, 1 H), 2.45–2.56 (m,
(m, 4 H), 1.85–2.05 (m, 2 H), 2.13–2.29 (m, 1 H), 2.33–2.48 (m, 1
H), 2.69–2.80 (m, 1 H), 2.89–2.98 (m, 1 H), 3.00–3.11 (m, 1 H),
4.17–4.28 (dd, J = 7.5, 13.5 Hz, 1 H), 5.04 (s, 2 H), 6.4 (d, J =
1 H), 2.74–2.85 (m, 1 H), 2.87–2.96 (m, 2 H), 2.99–3.08 (m, 1 H),
3.12–3.21 (m, 1 H), 4.05–4.15 (m, 1 H), 6.59 (br. s, 1 H) ppm. 13C
NMR (CDCl3, 75 MHz): δ = –0.3, –0.0, 0.3, 12.2, 25.2, 29.94,
8.6 Hz, 1 H), 7.29 (m, 5 H) ppm. 13C NMR (CDCl3, 75 MHz): δ 30.05, 31.5, 31.6, 32.3, 32.4, 52.1, 53.2, 54.9, 58.3, 68.5, 82.7, 83.8,
= 23.1, 27.7, 27.9, 29.3, 30.2, 51.0, 53.0, 53.8, 66.3, 66.5, 81.1, 81.6,
126.7, 127.3, 127.8, 127.9, 128.1, 128.3, 136.7, 156.2, 171.2,
173.2 ppm. MS (ES+): m/z = 463.2 [M + H]+. HRMS (ES+): calcd.
for C25H39N2O6 463.2848; found 463.2825.
173.1, 175.2 ppm. MS (ES+): m/z = 493.26 [M + H]+.
tert-Butyl 1-{(S)-4-tert-Butoxy-4-oxo-3-[2-(trimethylsilyl)ethyl-
sulfonamido]butyl}-3,3-dimethyl-1,3-azasilolidine-5-carboxylate
(18): Palladium on charcoal (300 mg, 20% weight) was added to a
solution of 16 (1.5 g, 3.25 mmol) in anhydrous THF (30 mL). The
air in the apparatus was eliminated and replaced by argon with
tert-Butyl 1-[(S)-3-(Benzyloxycarbonylamino)-4-tert-butoxy-4-oxo-
butyl]-3,3-dimethyl-1,3-azasilolidine-5-carboxylate (16): Compound
4 (2 g, 4.78 mmol) was added to 14 (1.23 g, 5.74 mmol) dissolved three cycles of vacuum/argon and then by hydrogen with three cy-
in anhydrous acetonitrile (2 mL). The reaction mixture was kept
under argon and stirred for 30 min. Anhydrous DIEA (2 mL,
11.95 mmol) was added and the reaction mixture was diluted with
anhydrous acetonitrile (12 mL). The reaction mixture was heated
to 55 °C and vigorously stirred for 16 h. The mixture was concen-
trated and the crude was dissolved in ethyl acetate (25 mL), suc-
cessively washed with a 5% hydrochloric acid solution (2ϫ15 mL),
cles of vacuum/hydrogen. The reaction mixture was stirred vigor-
ously for 10 h, filtered through a pad of Celite and concentrated to
afford the free amino compound as a pale-brown oil (1.04 g, 98%).
1
Rf (CHCl3/MeOH/AcOH 37%, 24:2:1) = 0.41. H NMR (CDCl3,
300 MHz): δ = –0.31–0.15 (m, 6 H), 0.61–0.83 (m, 2 H), 1.35 (s, 18
H), 1.85–2.05 (m, 2 H), 1.92–2.00 (m, 2 H), 2.13–2.29 (m, 1 H),
2.33–2.48 (m, 1 H), 2.83–3.00 (m, 1 H), 3.35–3.61 (m, 1 H), 4.97
6614
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 6609–6617

Efficient Synthesis of Nicotianamine and Non-Natural Analogues
(sl, 2 H) ppm. MS (ES+): m/z = 373.25 [M + H]+, 317.25 [M –
tBu]+, 261.24 [M – 2 tBu]+.
ether/ethyl acetate, 9:1 to 8:2) as a yellow oil (145 mg, 51%). Rf
(petroleum ether/ethyl acetate, 8:2) = 0.44. HPLC: t = 2.85 min. 1H
NMR (CDCl3, 300 MHz): δ = –0.10 (s, 9 H), 0.10–0.39 (2 m, 6 H),
0.75–1.20 (m, 4 H), 1.42 (s, 27 H), 1.75–2.39 (m, 6 H), 2.51–3.00
(m, 5 H), 3.21–3.50 (m, 3 H), 4.05–4.18 (m, 1 H), 5.05 (s, 2 H),
5.50 (d, J = 7.40 Hz, 1 H), 7.28–7.38 (m, 5 H) ppm. MS (ES+): m/z
= 829.4 [M + H]+.
TEA was added (1.45 mL, 10.47 mmol) to a solution of the re-
sulting free amino compound (1.3 g, 3.49 mmol) in anhydrous di-
methylformamide (14 mL). The reaction mixture was cooled to
0 °C in an ice bath. A solution of 2-(trimethylsilyl)ethanesulfonyl
chloride (1.12 g, 5.58 mmol) in anhydrous dimethylformamide
(5 mL) was added over a 10 min period. The reaction mixture was
stirred overnight at 0 °C. The dimethylformamide was evaporated
and the crude was partitioned between ethyl acetate (15 mL) and
water (20 mL). The aqueous phase was extracted with ethyl acetate
(2ϫ10 mL). The combined organic phases were washed with brine
(20 mL), dried with anhydrous sodium sulfate, filtered and concen-
trated to afford a yellow oil, which was purified by chromatography
on silica gel (petroleum ether/ethyl acetate, 8:2 then 7:3) to afford
18 as a yellow oil (1.25, 65%). Rf (petroleum ether/ethyl acetate,
6:4) = 0.56. 1H NMR (CDCl3, 300 MHz): δ = –0.10 (s, 9 H), 0.05–
(S)-1-{(S)-3-[(S)-3-Amino-3-carboxypropylamino]-3-carboxyprop-
yl}pyrrolidine-2-carboxylic Acid (10): Hydrofluoric acid (2 mL,
large excess) was added with the help of a Teflon® apparatus to
a Teflon® vessel containing 19 (140 mg, 0.18 mmol). The reaction
mixture was stirred at 0 °C for 1.5 h. The hydrofluoric acid was
evaporated and the remaining neutralized by addition of potassium
hydroxide. The crude was dissolved in distilled water (5 mL) and
the aqueous phase washed with diethyl ether (3ϫ 5 mL). After
freeze-drying, compound 10 was obtained as a pure white solid
(39 mg, 98%); m.p. 203–205 °C. 1H NMR (D2O, 300 MHz): δ =
0.35 (m, 6 H), 0.81–1.20 (m, 4 H), 1.42 (s, 18 H), 1.75–2.05 (m, 4 1.95–2.28 (m, 6 H), 2.35–52 (m, 1 H), 2.6 (qd, J = 9.1, 4.2 Hz, 1
H), 2.51–3.00 (m, 4 H), 3.31–3.51 (m, 1 H), 4.05–4.18 (m, 1 H),
H), 3.1–3.4 (m, 4 H), 3.69 (dd, J = 4.5, 8.2 Hz, 1 H), 3.73 (m, 1
H), 3.85 (t, J = 9.6 Hz, 1 H), 3.96 (dt, J = 9.6, 6.6 Hz, 1 H), 4.92
(td, J = 9.6, 6.5 Hz, 1 H) ppm. 13C NMR (D2O, 75 MHz): δ = 22.4,
25.1, 26.7, 28.5, 43.5, 51.5, 55.1, 59.2, 68.8, 171.6, 172.4,
173.0 ppm. MS (ES+): = 318.2 [M + H]+, 220.1 [M – Pro]+. HRMS
(FAB+): calcd. for C13H24N3O7 318.1665; found 318.1675.
6.75 (br. s, 1 H) ppm. MS (ES+): m/z = 537.1 [M + H]+.
tert-Butyl (S)-1-[(S)-3-{N-[(S)-3-(Benzyloxycarbonylamino)-5,5-di-
methyl-4-oxohexyl]-2-(trimethylsilyl)ethylsulfonamido}-4-tert-but-
oxy-4-oxobutyl]pyrrolidine-2-carboxylate (19): Caesium carbonate
(166 mg, 1.62 mmol) was added to a solution of 17 (400 mg,
0.81 mmol) in anhydrous acetonitrile (15 mL). The reaction mix-
ture was heated at 55 °C for 30 min whilst being stirred vigorously.
A solution of 4 (339 mg, 0.81 mmol) in anhydrous acetonitrile
(5 mL) was then added dropwise through a syringe pump. The reac-
tion mixture was stirred overnight at 55 °C. The reaction mixture
was concentrated and the crude was partitioned between ethyl acet-
ate (12 mL) and distilled water (17 mL). The aqueous layer was
extracted with ethyl acetate (3ϫ7 mL). The combined organic lay-
ers were successively washed with brine (15 mL) and distilled water
(15 mL), then dried with anhydrous magnesium sulfate and concen-
trated. Compound 19 was obtained after silica gel chromatography
(petroleum ether/ethyl acetate, 8:2 to 7:3) as a yellow oil (349 mg,
1-{(S)-3-[(S)-3-Amino-3-carboxypropylamino]-3-carboxypropyl}-
3,3-dimethyl-1,3-azasilolidine-5-carboxylic Acid (11): Hydrofluoric
acid (2 mL, large excess) was added with the help of a Teflon®
apparatus to a Teflon® vessel containing 20 (140 mg, 0.17 mmol).
The reaction mixture was stirred at 0 °C for 1.5 h. The hydrofluoric
acid was evaporated and the remaining neutralized by addition of
potassium hydroxide. The crude was dissolved in distillate water
(5 mL) and the aqueous phase washed with diethyl ether
(3ϫ5 mL). After freeze-drying, compound 11 was obtained as a
1
pure white solid (59 mg, 98%); m.p. 176–178 °C. H NMR (D2O,
300 MHz): δ = 0.26–0.42 (m, 6 H), 0.78–1.78 (m, 2 H), 2.12–2.51
(m, 5 H), 2.97–3.28 (m, 4 H), 3.35–3.62 (m, 1 H), 3.66–3.97 (m, 3
55 %). Rf (petroleum ether/ethyl acetate, 6:4) = 0.62. HPLC H) ppm. MS (ES+): m/z = 362.0 [M + H]+, 384.0 [M + Na]+, 203.5
2.95 min. [α]2D4 = –13.4 (c = 1.25, DCM). 1H NMR (CDCl3,
[M – Sip]+. HRMS (ES+): calcd. for C14H28N3O6Si 362.1747;
300 MHz): δ = 0.00 (s, 9 H), 0.91–1.09 (m, 2 H), 1.41 (s, 27 H), found 362.1770.
1.62–1.90 (m, 4 H), 1.92–2.20 (m, 4 H), 2.26–2.35 (m, 1 H), 2.39–
tert-Butyl (S)-1-[(S)-3-(Benzyloxycarbonylamino)-4-tert-butoxy-4-
2.48 (m, 1 H), 2.6–2.95 (m, 4 H), 3.20–3.31 (m, 2 H), 3.45 (t, J =
8.4 Hz, 1 H), 4.05–4.33 (m, 2 H), 5.08 (s, 2 H), 5.48 (d, J = 7.07 Hz,
1 H), 7.28–7.38 (m, 5 H) ppm. 13C NMR (CDCl3, 75 MHz): δ =
–0.3, –0.0, 0.3, 12.1, 23.3, 29.87, 29.95, 30.04, 33.9, 35.7, 45.1, 50.8,
52.7, 54.8, 57.5, 61.7, 67.7, 68.8, 82.9, 84.2, 84.3, 129.9, 130.0,
130.01, 131.0, 138.3, 158.0, 17.3, 172.8, 173.9 ppm. MS (ES+): m/z
= 784.4 [M + H]+, 728.8 [M – tBu]+, 672.6 [M + 2 tBu]+, 616.5
[M – 3 tBu]+. HRMS (ES+): calcd. for C38H66N3O10SSi 784.4238;
found 784.4256.
oxobutyl]-5-oxopyrrolidine-2-carboxylate (22): Sodium hydride at
60% in mineral oil (1.45 g, 3.6 mmol) was added portionwise to a
solution of 21 (670 mg, 3.6 mmol) in anhydrous dimethylform-
amide (2 mL) at 0 °C under argon. After 30 min of vigorous stir-
ring, a solution of 4 (1 g, 2.4 mmol) in dimethylformamide (2 mL)
was added dropwise over a 15 min period. The reaction mixture
was stirred vigorously under argon at room temperature overnight.
After evaporation of the dimethylformamide, the crude was taken
up in ethyl acetate (10 mL) and washed with a 5% hydrochloric
acid solution (2ϫ5 mL), brine (10 mL) and distilled water (10 mL).
The organic phase was dried with magnesium sulfate, filtered and
concentrated. Compound 22 was obtained after silica gel flash
chromatography (petroleum ether/ethyl acetate, 7:3 to 6:4) as a
white solid (628 mg, 54%). Rf (petroleum ether/ethyl acetate, 6:4)
= 0.34. [α]2D4 = –1.4 (c = 1.5, DCM). 1H NMR (CDCl3, 300 MHz):
δ = 1.39 (s, 18 H), 1.75–2.05 (m, 3 H), 2.08–2.23 (m, 2 H), 2.25–
2.48 (m, 1 H), 2.86–3.04 (m, 1 H), 3.50–3.19 (m, 1 H), 3.89–4.09
(m, 1 H), 4.11–4.3 (m, 1 H), 5.06 (s, 2 H), 5.41 (d, J = 8.5 Hz, 1
H), 7.32 (m, 5 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 19.2,
23.1, 27.90, 27.93, 29.4, 29.6, 31.6, 45.5, 52.3, 60.8, 63.7, 67.1, 68.6,
71.1, 82.3, 127.95, 127.99, 128.2, 128.4, 128.6, 136.3, 155.8, 170.8,
171.1, 175.4 ppm. MS (ES+): m/z = 477.1 [M + H]+, 421.1 [M +
tert-Butyl 1-[(S)-3-{N-[(S)-3-(Benzyloxycarbonylamino)-5,5-di-
methyl-4-oxohexyl]-2-(trimethylsilyl)ethylsulfonamido}-4-tert-but-
oxy-4-oxobutyl]-3,3-dimethyl-1,3-azasilolidine-5-carboxylate (20):
Caesium carbonate (166 mg, 0.51 mmol) was added to a solution of
18 (180 mg, 0.34 mmol) in anhydrous DMF (3 mL). The reaction
mixture was heated at 55 °C for 30 min whilst being stirred vigor-
ously. A solution of 4 (172 mg, 0.41 mmol) in anhydrous DMF
(1 mL) was then added dropwise through a syringe pump. The reac-
tion mixture was stirred overnight at 60 °C then concentrated and
taken up in ethyl acetate (10 mL). The organic layer was success-
ively washed with brine (7 mL) and distilled water (7 mL), then
dried with anhydrous magnesium sulfate and concentrated. Com-
pound 20 was obtained after silica gel chromatography (petroleum
Eur. J. Org. Chem. 2010, 6609–6617
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6615

M. Bouazaoui, M. Larrouy, J. Martinez, F. Cavelier
FULL PAPER
H – tBu]+, 377.1 [M + H – CO2tBu]+, 499.1 [M + Na]+. HRMS
2.40–2.51 (m, 1 H), 2.75–2.99 (m, 4 H), 3.20–3.31 (m, 2 H), 3.51–
3.79 (m, 1 H), 3.81–4.35 (m, 2 H), 4.39–4.55 (m, 2 H), 5.08 (d, J
= 5.11 Hz, 2 H), 5.48 (d, J = 7.07 Hz, 1 H), 7.28–7.38 (m, 5
H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 0.0, 12.1, 24.0, 25.3,
29.9, 30.7, 31.5, 31.6, 32.7, 36.9, 41.6, 45.1, 50.8, 54.7, 60.5, 62.75,
68.8, 84.3, 84.77, 84.83, 129.8, 130.0, 130.1, 138.3, 158.01, 171.5,
172.3, 173.8, 177.9 ppm. MS (ES+): m/z = 798.3 [M + H]+, 820.2
[M + Na]+, 742.2 [M – tBu]+, 686.1 [M – 2 tBu]+, 630.0 [M –
CO2tBu – tBu]+. HRMS (ES+): calcd. for C38H64N3O11SSi
798.4031; found 798.4038.
(ES+): calcd. for C25H37N2O7 477.2601; found 477.2603.
tert-Butyl (S)-1-{(S)-4-tert-Butoxy-4-oxo-3-[2-(trimethylsilyl)-
ethylsulfonamido]butyl}-5-oxopyrrolidine-2-carboxylate (23): Palla-
dium on charcoal (110 mg, 20% weight) was added to a solution
of 22 (550 mg, 1.16 mmol) in anhydrous ethyl acetate (15 mL). The
air in the apparatus was eliminated and replaced by argon with
three cycles of vacuum/argon and then by hydrogen with three cy-
cles of vacuum/hydrogen. The reaction mixture was stirred vigor-
ously for 10 h, filtered through a pad of Celite and concentrated to
afford the free amino compound as a colourless oil (388 mg, 98%).
Rf (CHCl3/MeOH/AcOH 37%, 24:2:1) = 0.25. [α]2D4 = –2.9 (c = 1.5,
DCM). 1H NMR (CDCl3, 300 MHz): δ = 1.39 (s, 18 H), 1.50–1.69
(m, 3 H), 1.75–2.03 (m, 2 H), 2.11–2.45 (m, 3 H), 2.86–3.04 (m, 1
H), 3.11–3.14 (m, 1 H), 3.68–3.81 (m, 1 H), 3.89–4.09 (m, 1
H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 22.98, 23.08, 27.8, 27.9,
29.4, 31.9, 32.2, 38.6, 39.2, 52.3, 60.8, 61.2, 80.9, 82.3, 171.8, 174.1,
175.4 ppm. MS (ES+): m/z = 343.1 [M + H]+, 287.0 [M – tBu]+.
(S)-1-{(S)-3-[(S)-3-Amino-3-carboxypropylamino]-3-carboxyprop-
yl}-5-oxopyrrolidine-2-carboxylic Acid (12): Hydrofluoric acid
(2 mL, large excess) was added with the help of a Teflon® apparatus
to a Teflon® vessel containing 24 (110 mg, 0.14 mmol). The reac-
tion mixture was stirred at 0 °C for 1.5 h. The hydrofluoric acid was
evaporated and the remaining neutralized by addition of potassium
hydroxide. The crude was dissolved in distilled water (5 mL) and
the aqueous phase washed with diethyl ether (3 ϫ 5 mL). After
freeze-drying, compound 12 was obtained as a pure white solid
(45 mg, 98%); m.p. 210–212 °C. [α]2D4 = –35.4 (c = 1.2, H2O). 1H
NMR (D2O, 300 MHz): δ = 1.95–2.28 (m, 4 H), 2.35–2.52 (m, 3
H), 3.05–3.29 (m, 3 H), 3.51–3.71 (m, 3 H), 3.79–3.90 (m, 1 H),
4.20–4.39 (m, 1 H) ppm. 13C NMR (D2O, 75 MHz): δ = 22.4, 26.6,
27.0, 29.5, 38.1, 43.5, 52.2, 59.6, 61.6, 172.6, 177.4, 179.0,
179.8 ppm. MS (ES+): m/z = 332.2 [M + H]+. HRMS (FAB+):
calcd. for C13H22N3O7 332.1458; found 332.1447.
TEA was added (0.4 mL, 2.97 mmol) to a solution of the resulting
amino compound (369 mg, 1.1 mmol) in anhydrous dimethylform-
amide (7 mL). The reaction mixture was cooled to 0 °C. A solution
of 2-(trimethylsilyl)ethanesulfonyl chloride (396 mg, 1.76 mmol) in
anhydrous dimethylformamide (2 mL) was added over a 10 min
period. The reaction mixture was stirred overnight at 0 °C. The
dimethylformamide was evaporated and the crude was partitioned
between ethyl acetate (5 mL) and water (10 mL). The aqueous
phase was extracted with ethyl acetate (2ϫ5 mL). The combined
organic phases were washed with brine (10 mL), dried with anhy-
drous sodium sulfate, filtered and concentrated to afford a yellow
oil, which was purified by chromatography on silica gel (petroleum
ether/ethyl acetate, 8:2 then 7:3) to afford 23 as a yellow oil
(323 mg, 58 %). Rf (petroleum ether/ethyl acetate, 6:4) = 0.52.
Supporting Information (see also the footnote on the first page of
1
this article): H and 13C NMR and mass spectra of all described
compounds.
Acknowledgments
1
[α]2D4 = –5.4 (c = 3.24, DCM). H NMR (CDCl3, 300 MHz): δ =
This work was supported by the funded by the Commissariat
à l’Energie Atomique (CEA), Centre National de la Recherche Sci-
entifique (CNRS), Institut National de la Recherche Agronomique
(INRA), and Institut National de la Santé et de la Recherche
Médicale (INSERM) (sponsors of the Program Toxicologie
Nucléaire Environnementale) (www.toxnuc-e.org; grant to M. B.)
and by the Agence Nationale de la Recherche (ANR) (grant to
M. L.).
–0.10 (s, 9 H), 0.89–1.15 (m, 2 H), 1.39 (s, 9 H), 1.45 (s, 9 H), 1.80–
2.08 (m, 3 H), 2.13–2.49 (m, 3 H), 2.76–2.97 (m, 2 H), 2.99–3.15
(m, 1 H), 3.05–3.21 (m, 1 H), 3.80–3.98 (m, 1 H), 4.01–4.13 (m, 1
H), 5.35 (d, J = 9.01 Hz, 1 H) ppm. 13C NMR (CDCl3, 75 MHz):
δ = –0.34, –0.00, 0.34, 12.26, 25.08, 29.80, 29.93, 31.44, 32.59,
40.65, 51.31, 56.77, 62.66, 84.32, 84.93, 173.09, 173.13, 177.40 ppm.
MS (ES+): m/z = 507.2 [M + H]+, 529.0 [M + Na]+, 451.0 [M –
tBu]+. HRMS (ES+): calcd. for C22H43N2O7SSi 507.2560; found
507.2558.
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oxy-4-oxobutyl]-5-oxopyrrolidine-2-carboxylate (24): Caesium carb-
onate (147 mg, 0.45 mmol) was added to a solution of 23 (150 mg,
0.31 mmol) in anhydrous acetonitrile (4 mL). The reaction mixture
was heated at 55 °C for 30 min whilst being stirred vigorously. A
solution of 4 (151 mg, 0.36 mmol) in anhydrous acetonitrile (2 mL)
was then added dropwise through a syringe pump. The reaction
mixture was stirred overnight at 55 °C. The reaction mixture was
concentrated and the crude was partitioned between ethyl acetate
(4 mL) and distilled water (6 mL). The aqueous layer was extracted
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(petroleum ether/diethyl ether, 4:6) as a yellow oil (129 mg, 52%).
Rf (petroleum ether/ethyl acetate, 6:4) = 0.62. HPLC: t = 3.18 min.
1
[α]2D4 = –17.4 (c = 1.9, DCM). H NMR (CDCl3, 300 MHz): δ =
0.00 (s, 9 H), 0.91–1.27 (m, 2 H), 1.43 (s, 27 H), 1.56–1.80 (m, 1
H), 1.92–2.05 (m, 1 H), 2.09–2.15 (m, 2 H), 2.16–2.19 (m, 1 H),
6616
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Received: June 28, 2010
Published Online: October 28, 2010
Eur. J. Org. Chem. 2010, 6609–6617
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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