Solventless mechanosynthesis of N-protected amino esters

Article abstract of DOI:10.1021/jo500463y

Mechanochemical derivatizations of N- or C-protected amino acids were performed in a ball mill under solvent-free conditions. A vibrational ball mill was used for the preparation of N-protected α- and β-amino esters starting from the corresponding N-unmasked precursors via a carbamoylation reaction in the presence of di-tert-butyl dicarbonate (Boc₂O), benzyl chloroformate (Z-Cl) or 9-fluorenylmethoxycarbonyl chloroformate (Fmoc-Cl). A planetary ball mill proved to be more suitable for the synthesis of amino esters from N-protected amino acids via a one-pot activation/esterification reaction in the presence of various dialkyl dicarbonates or chloroformates. The spot-to-spot reactions were straightforward, leading to the final products in reduced reaction times with improved yields and simplified work-up procedures.

Full text of DOI:10.1021/jo500463y

Article
pubs.acs.org/joc
Solventless Mechanosynthesis of N‑Protected Amino Esters
Laure Konnert, Frederic Lamaty, Jean Martinez, and Evelina Colacino*
́
́
́
Institut des Biomolecules Max Mousseron, UMR 5247 CNRS-UM I-UM II, Place E. Bataillon, cc 1703, 34095 Montpellier, France
S
* Supporting Information
ABSTRACT: Mechanochemical derivatizations of N- or C-
protected amino acids were performed in a ball mill under
solvent-free conditions. A vibrational ball mill was used for the
preparation of N-protected α- and β-amino esters starting from the
corresponding N-unmasked precursors via a carbamoylation
reaction in the presence of di-tert-butyl dicarbonate (Boc2O),
benzyl chloroformate (Z-Cl) or 9-fluorenylmethoxycarbonyl
chloroformate (Fmoc-Cl). A planetary ball mill proved to be
more suitable for the synthesis of amino esters from N-protected
amino acids via a one-pot activation/esterification reaction in the
presence of various dialkyl dicarbonates or chloroformates. The
spot-to-spot reactions were straightforward, leading to the final
products in reduced reaction times with improved yields and
simplified work-up procedures.
acids (PG-NH-AA-OH) are suitable substrates leading to N-
protected amino esters (PG-NH-AA-OR) by esterification
reaction of the C-terminal end with alkyl chloroformates,21
dialkyl dicarbonates,22−25 or imidazole carbamates26 via
carbonic carboxylic anhydride intermediates. To avoid the
drawbacks of time-consuming solution synthesis and to reduce
the environmental impact of reported procedures, new
methodologies need to be developed allowing the eco-friendly
synthesis of peptide building blocks as N- and/or C-protected
amino acids.
We have recently disclosed in this area new strategies for
amide bond formation,27 preparation of peptides28,29 and
amino acid analogues,30,31 or for synthesis of N-protected
amino acids32 (PG-NH-AA-OH) starting from free amino acids
(NH2-AA-OH), under solvent-free conditions using ball-milling
technology. Herein we present how this low-cost, eco-friendly
method can be successfully applied to the solid-state synthesis
of N-protected amino esters (PG-NH-AA-OR) according to
two different approaches: (i) via carbamoylation of amino
esters (NH2-AA-OR) or (ii) via esterification of C-terminal N-
protected amino acids (PG-NH-AA-OH) by using, respectively,
vibrational or planetary ball-mill apparatus (Scheme 1).
Technical and process parameters33 such as type of ball mill
(vibrational or planetary), oscillation (up to 30 Hz) or rotation
frequency (up to 450 rpm), milling time, number of milling
stainless steel balls (up to 50, with a diameter of 5 mm), and
mode of milling (continuous or cycled) were also explored in
some cases.
INTRODUCTION
■
The awareness of environmental problems caused by human
acitivity has led scientists to change their way of “thinking
chemistry”, leading to the rapid growth of alternative methods
to carried out organic synthesis under environmentally friendly
conditions,1 aiming to diminish the generation of toxic and
nontoxic wastes and use safer reagent or solvents. With this
perspective, the employment of mechanical energy to conduct
organic reactions2−7 in the absence of solvent is a strong
emerging field. Our interest was turned toward the
investigation of novel alternatives to solvent-based chemistry,
applied to N- and C-protected amino acids, essential building
blocks in the field of peptide synthesis. Usually, peptide
syntheses (in solution or solid-phase) are carried out from the
C- to N-direction by the assembly of amino acids through
protection/deprotection coupling strategy according to well-
established procedures.8 It is thus necessary to find new
methodologies enabling to prepare protected amino acids
derivatives in a more straightforward manner and environ-
mentally friendly conditions. Usual procedures not only require
dramatic amounts of organic solvents but generally also toxic or
dangerous reactants, extended reaction times, and several
purification steps.9−14 Herein we report our findings on the
solvent-free synthesis of N-protected amino esters under ball
milling conditions.
RESULTS AND DISCUSSION
■
Preparation of N-protected amino esters (PG-NH-AA-OR, R =
Me, t-Bu and PG = protecting group) from the corresponding
precursors (NH2-AA-OR) is usually carried out in solution via
carbamoylation reaction in the presence of catalysts,15
enzymes,16 or additives17−19 or through solid-supported
methodologies.20 On the other hand, N-protected amino
N-Protection of Amino Esters. A few rare examples of
solvent-free procedures were reported for the synthesis of N-
Received: March 1, 2014
Published: April 16, 2014
© 2014 American Chemical Society
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Scheme 1. Mechanochemical Synthesis of N-Protected Amino Esters
a
Table 1. N-Protection of Amino Esters in a Vibrational Ball Mill
b
c
entry
R2
precursor of protecting group
Fmoc-Cl
N-protected amino ester
time (min)
yield (%)
1
Me
Me
Me
Me
t-Bu
Me
t-Bu
t-Bu
t-Bu
t-Bu
Me
Me
Me
Me
Me
Me
Fmoc-Gly-OMe
Fmoc-Phe-OMe
Fmoc-Ala-OMe
Fmoc-Ala-OMe
Fmoc-Leu-OtBu
Z-Gly-OMe
1
90
90
96
95
96
2
2
3
3
90
d
4
3
90
92
5
4
90
87
80
96
80
6
Z-Cl
5
90
e
7
Z-Gly-O-t-Bu
6
120
90
8
Z-Leu-O-t-Bu
Z-Leu-OtBu
7
d
9
7
90
67
10
11
12
13
14
15
16
Z-Glu(O-t-Bu)2
Boc-Phe-OMe
Boc-Phe-OMe
Boc-Pro-OMe
Boc-β-Ala-OMe
Boc-3-Aib-OMe
Boc-Aib-OMe
8
90
quant
91
Boc2O
9
90
d
9
90
57
10
11
12
13
90
81
68
61
68
120
120
120
a
Typical procedure: vibration ball mill, 10 mL stainless steel jar, 2 stainless steel balls (5 mm diameter) at 30 Hz using α-amino ester (1 equiv),
b
NaHCO3 (1 equiv) and Fmoc-Cl, Z-Cl or Boc2O (1 equiv); Configuration of all substrates is L and they are used as hydrochloride salts except
when specified; Yields after work-up; 1 stainless steel ball (5 mm diameter) was used; The acetic acid salt was used instead of the hydrochloride
c
d
e
salt.
Boc-protected amines of nucleosides:34 mainly by using an
excess of Boc2O or a two-step carbonyldiimidazole (CDI)−
DMAP-mediated approach, grinding the reaction media with a
spatula, but only one step was performed without any solvent.35
In the case of amino esters, molecular iodine36 was the catalyst
for Boc-protection. Silica−sulfuric acid (SSA)37 and sulfamic
acid (NH2SO3H)38 were used as catalysts for the chemo-
selective N-protection of various aliphatic and aromatic amines
with Z- and Boc- groups, respectively, under solvent-free
conditions at room temperature.
We disclose herein the solvent-free preparation of diverse N-
protected α-,β-amino esters using a vibrational ball mill. The
mechanochemical introduction of the most common carba-
mate-based protecting groups such as Fmoc (9-fluorenylme-
thoxycarbonyl), Z (benzyloxycarbonyl) or Boc (tert-butylox-
ycarbonyl) derivatives was investigated using a 10 mL stainless
steel jar with 2 balls (5 mm diameter) under neat conditions
(Table 1).
Except for β-amino esters (entries 14 and 15) yields were as
high (80% to quantitative) as for the usual synthetic methods in
solution.9,36,39−41 Final products were recovered by a very
simple workup, based on a precipitation/filtration procedure
without need of chromatographic purification for most of cases,
contrary to synthesis in solution, resulting in more environ-
mentally friendly conditions. Starting from our previous
findings,32 equimolar amounts of glycine methyl ester hydro-
chloride and 9-fluorenylmethoxycarbonyl chloroformate
(Fmoc-Cl) were ground without any special precaution in the
presence of NaHCO3 (Table 1, entry 1). We were pleased to
find that the conversion of reactants was quantitative in only 90
min and no other optimization studies were necessary. The
smooth conditions afforded by vibrational ball milling
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Scheme 2. Simplified Mechanism for Decarboxylative Esterification
prevented formation of byproducts observed during solution-
phase synthesis, as dibenzofulvene or its polymer. As a
consequence, no striking workup to eliminate side products
was necessary, and Fmoc-Gly-OMe was recovered by
precipitation after addition of water to the crude. The number
of balls in the jar seems to have influence on the yields as
shown by parallel experiments performed using one or two
balls in the milling jar for the N-protection of alanine (Table 1,
entries 3 and 4), leucine (entries 8 and 9), and phenylalanine
(entries 11 and 12). In the case of Fmoc-Ala-OMe 3 synthesis,
yields were similar (entries 3 and 4), while Z-Leu-O-t-Bu 7 and
Boc-Phe-OMe 9 were obtained in much lower yields in the
presence of only one grinding ball instead of two, the
conversion of the substrates being incomplete in these cases.
The methodology applied so far to the Fmoc derivatization
of amino ester derivatives was extended for the introduction of
Z (entries 6−10) and Boc protecting groups (entries 11−16),
using, respectively, benzyl chloroformate (Z-Cl) and di-tert-
butyl dicarbonate (Boc2O). Z-Cl reacted without any special
precaution, although at lower frequencies (e.g., 20 and 25 Hz),
incomplete reactions were observed even for prolonged
reaction times, probably because of premature Z-Cl hydrolysis
leading to the formation of benzyl alcohol, as also confirmed by
(only for Boc-protection), the use of hazardous solvents (THF
or dioxane), catalysts (ZrCl4 or β-cyclodextrin42), and
39
reagents (e.g., N-hydroxysuccinimide derivatives) was avoided,
and chromatographic purifications were not necessary in most
cases. Planetary ball milling was also explored for the synthesis
of Fmoc-Ala-OMe 3 (Table 1, entry 3), running a similar
experiment on 2 mmol scale at 450 rpm during the same time
(90 min), using a 12 mL stainless steel jar with 25 balls (5
mm). Interestingly, it resulted in poor conversion of the
substrate and recovery of Fmoc-Cl. Together with different
stress phenomena with respect to vibrational ball milling (at 30
Hz), a part of the explanation could be that planetary ball
milling at 450 rpm would not give enough energy to the
reaction. Indeed, 450 rpm corresponded to a frequence of 7.5
Hz, which is much lower than the frequence used in the
experiments with the horizontally vibrating ball mill.
C-Protection/Activation of N-Protected Amino Acids.
Dialkyl dicarbonates were successfully applied as esterification
reagents in solution. Takeda22 used them in the presence of
DMAP in THF or t-BuOH while Gooβen performed a
decarboxylative esterification with Mg(ClO4)2 as catalyst.23
However, this procedure was unsuitable to access amino acid
tert-butyl esters because of their instability in the reaction
medium. Then, the DMAP-catalyzed benzyl esterification using
Boc2O and benzyl alcohol24 was also described by Bartoli,25
who reported a MgCl2-catalyzed process with a combination of
alcohol and the corresponding dialkyl dicarbonates (e.g., t-
BuOH/Boc2O for the synthesis of tert-butyl esters). These
methods presented poor mass efficiency requiring a large
alcohol excess25 or/and expensive dialkyl dicarbonate (up to 3
equiv)22 or catalysis by Lewis acids.23,25 Starting from our
previous findings,32 we demonstrated that di-tert-butyl
dicarbonate (Boc2O) was a very compatible protecting group
within ball milling technology. In our ongoing efforts to set up
new and straightforward eco-friendly methodologies for organic
synthesis, the possibility of realizing the esterification of the C-
terminal position of amino acids under stoichiometric
solventless mechanochemical activation appeared to be
promising and appealing. In this respect, various dialkyl
dicarbonates [(ROCO)2O such as Boc2O, Z2O, Moc2O with
R = O-t-Bu, Bn, Me, respectively], carbonates (RO2CO, R =
succinimide, Me) or alkyl chloroformates (ROCOCl, R = Bn,
Me, Et, allyl) were investigated for the esterification of the C-
terminal of amino acid derivatives (Scheme 2), in the presence
1
LC/MS and H NMR analyses of the crude. In the case of
glycine (entries 1, 6, and 7), the nature of the C-terminal ester
might influence the kinetic of the process, which proved to be
slower when tert-butyl esters were used, and independently of
the incoming protecting group. Pure Z-protected amino esters
precipitated from the solution upon acidification with 0.1 N
HCl, while Boc-protected amino esters were recovered by
extraction. The study was also extended to the protection of β-
(Table 1, entries 14 and 15) and hindered quaternary amino
ester (Table 1, entry 16). The substrates were not completely
converted even after longer reaction times (120 min), but the
yields remained satisfying, although lower than those obtained
for the preparation of β-amino esters in solution.36,39,42
However, an impressive improved yield (three times more
than in solution)43 was obtained with the hindered substrate H-
Aib-OMe (Table 1, entry 16), suggesting that mechanochem-
ical activation could be particularly suitable with poorly reactive
(hindered) substrates. It is worth noting that in all cases the
solvent-free methodology herein reported is environmentally
friendly with respect to more classical protocols in solution or
on supports for Fmoc,9 Boc,12 or Z13 protection. The only
waste was water, sodium chloride, CO2 and t-butyl alcohol
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a
Table 2. C-Protection/Activation of N-Protected Amino Acids in a Planetary Ball Mill
b
c
d
entry
R2
activating agent (equiv)/DMAP (equiv)
cycled milling rpm/n
C-protected amino ester
Z-Phe-O-t-Bu
yield (%)
e
f
1
Z
Boc2O (1) /0.3
300/6
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
79
67
65
56
69
55
35
48
54
59
90
87
84
91
90
83
82
91
2
Z
Z-Pro-O-t-Bu
3
Boc
Boc
Z
Boc-Thr(Bn)-O-t-Bu
Boc-Tyr(2,6-Cl-Bn)-O-t-Bu
Z-Phe-OSu
4
5
DSC (1)/0.3
450/6
6
Boc
Boc
Z
Boc-Thr(Bn)-OSu
Boc-Met-OSu
7
e
f
8
BnOCOCl (1) /1.3
300/6
Z-Phe-OBn
9
Z
Z-Ser(O-t-Bu)-OBn
Boc-Met-OBn
10
11
12
13
14
15
16
17
18
Boc
Z
EtOCOCl (1.2)/1.5
300/9
300/9
Z-Phe-OEt
Z
Z-Ser(t-Bu)-OEt
Boc-Met-OEt
Boc
Boc
Z
Boc-Cys(SBn)-OEt
Z-Phe-OAllyl
AllylOCOCl (1.2)/1.5
Z
Z-Ser(t-Bu)-OAllyl
Boc-Met-OAllyl
Boc-Cys(Bn)-OAllyl
Boc
Boc
a
Typical procedure: planetary, 12 mL stainless steel jar, 50 stainless steel balls (5 mm diameter) at 300 (or 450) rpm using N-protected α-amino acid
(250 mg) and activating agent/DMAP (equivalents as stated in the table) were milled for the specified times under cycled milling of 10 min cycles
b
c
d
followed by 2 min of standby in between, with reverse rotation. n is the number of cycles. All substrates have the L configuration. Yields after
e
f
workup. The activating agent was added in two portions of 0.5 equiv each. The second half of activating agent was added after the third cycle.
of DMAP as catalyst, and a selection of data is reported in
Table 2.
Best conversions (and yields) were obtained using
stoichiometric amounts of Boc2O in the presence of DMAP,
added in a minimum amount of 0.3 equiv, with lower quantities
leading to poor conversions. Vibrational ball mill (up to 30 Hz)
or planetary ball mill under continuous or cycled milling at
100−500 rpm were also explored, with or without NaCl as
additive.32
The common feature of all these decarboxylative ester-
ifications was formation of a mixed carboxylic−carbonic
anhydride, converted into an acylpyridinium species by
nucleophilic attack of catalytic 4-(dimethylamino)pyridine
(DMAP), carbon dioxide evolution providing the driving
force of the reaction. Moreover, DMAP catalyzed the
nucleophilic addition of the alcohol44 leading to the desired
ester (Scheme 2). tert-Butyl esters were prepared first, and N-Z-
protected phenylalanine (Z-Phe-OH) served as a benchmark
for optimization of the method. Synthetic (base, additives,
stoichiometry of reactants) and technical parameters (time,
rotation speed, number of balls, continuous or cycled milling)
needed to be adjusted. Several combinations of bases
(K2CO3,32 Et3N,21 DMAP44) and additives (t-BuOH,24,25
MgSO4, MgCl2,23 or PPh345) were also explored. In opposition
with synthesis in solution, adding catalysts gave no interesting
results, with no or poor conversion of the substrate. Finding
inspiration by Takeda’s work,22 N-Z-Phe-OH was ball milled
with t-BuOH (2 equiv) and Boc2O (1 equiv) in the presence of
DMAP. Z-Phe-O-t-Bu was obtained in low yield (54%, based
on 1H NMR). The yield was increased to the same extent as in
Vibrational ball mill at 30 Hz using 2 stainless steel balls (5
mm diameter) was ineffective: two experiments were run,
following either a one-step procedure where the N-protected
amino acid, Boc2O, and K2CO3 were put altogether in the jar
and ground for 1 h or a two-step procedure consisting of
forming the carboxylate of the amino acid with K2CO3 in the
first step32 and then performing the carbamoylation by adding
Boc2O in the second step. In both cases, no conversion of the
substrate was observed. Reaction of N-Z-Phe-OH under
continuous milling in the planetary apparatus, in the presence
of a stoichiometric amount of Boc2O, afforded a moderate yield
of N-Z-Phe-O-t-Bu (54% conversion based on NMR) propably
because of Boc2O degradation, while with an excess of Boc2O
the yield was hampered by the formation of N-Z,N-Boc-Phe-O-
t-Bu. Cycled mixing at 300 rpm using 50 balls (stainless steel 5
mm diameter) for two steps of three 10 min cycles, with a 2
min pause between each cycle, were the best milling conditions
(Table 2, entry 1), with Boc2O added twice (0.5 equiv each
time to obtain good conversion of the substrate). Environ-
mentally friendly acidic workup with 10% aqueous citric acid
allowed elimination of DMAP and afforded the N-protected
tert-butyl amino ester derivatives (PG-NH-AA-OR) in good
yields without any further purification (Table 2, entries 1−4).
1
solution (66%, based on H NMR) by adding an excess of
Boc2O (1.5 equiv), but N-Z,N-Boc-Phe-O-t-Bu was also
formed. Using an excess of Boc2O alone22−25 was also
detrimental leading to N-Z,N-Boc-Phe-O-t-Bu, along with the
desired ester (Z-Phe-O-t-Bu), even after modulation of the
reaction time (30 min to 3 h) and the amount of energy
transferred during milling.
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Scheme 3. Possible Side Reaction in the Synthesis of Benzyl Esters
The solvent-free synthesis afforded Z-Phe-O-t-Bu in better
yields (79%) (Table 2, entry 1) in shorter reaction times (68
min) with respect to solution synthesis (61% yield after 2
days)22 without using an excess of Boc2O and avoid silica-gel
purification. High-yield Z-Phe-O-t-Bu (84%) in solution could
be obtained only after further increasing the quantity of
dicarbonate and adding large excess of t-BuOH.22 From the
point of view of benign chemistry, the above-described
procedure thus presents many advantages with respect to
literature: (i) the quantity of wastes is reduced, avoiding the use
of an excess of expensive Boc2O, Lewis acids, or solvents or
excess of the suitable alcohol to speed up the reaction; (ii) it is
particularly suitable for the esterification of amino acids in short
reaction times compared to synthesis in solution.
By analogy with the preparation of tert-butyl amino esters
with (Boc2O), dibenzyloxy dicarbonate (Z2O) was used to
prepare the corresponding esters. Unfortunately, the main
product of the reaction was dibenzyl ether 33 (Scheme 3). One
possible explanation may be that catalytic DMAP reacts quickly
on Z2O to form a “Z-DMAP” intermediate 32, releasing CO2
and phenylmethanolate, which in turn acts as a nucleophile at
the benzylic position (pathway (a), Scheme 3) of 32, affording
dibenzyl ether 33 and regenerating DMAP. In order to avoid
the formation of dibenzyl ether 33, and according to the
literature,46 the reaction was repeated by adding dry CO2
(about 1.4 g, corresponding to a quarter of the jar volume); no
conversion of the substrate was observed, and again, dibenzyl
ether 33 was the only product. In addition, we tried to esterify
N-Z-phenylalanine with both Z2O and 2 equiv of benzyl alcohol
in the milling jar, taking inspiration from literature,24 where
Boc2O and benzyl alcohol were used for the synthesis of benzyl
esters. Dibenzyl ether was once again the main reaction
product, confirming the fact that dibenzyl dicarbonate was not
suitable for ball milling.
obtained. N-Phenylmethyl(dimethylamino)pyridinium chloride
34 was also obtained (pathway (b), Scheme 3), probably
through a double-nucleophilic attack of DMAP on Z-Cl, as well
as toluene, a byproduct probably coming from Z-Cl
degradation in the milling jar. Although the elimination of
the two byproducts did not represent a problem (the salt being
water-soluble and the toluene easily evaporated), column
chromatography was necessary to eliminate dibenzyl ether 33.
N-Z-Phenylalanine was also reacted with ethyl- (EtOCOCl)
and allyl- (AllylOCOCl) chloroformates, the last one never
described in solution for the preparation of amino ester
derivatives. The corresponding esters were formed in a
straightforward manner and without any byproducts (Table 2,
entries 11 and 15). The method was general and successfully
used for the synthesis of various amino esters, recovered pure
after addition of aqueous citric acid and extraction with diethyl
ether (Table 2, entries 11−14 and 15−18). Compared to the
synthesis of N-Z-Phe-OEt (entry 11) in solution, the ball-
milling procedure resulted in similar yields, elimination of
chlorinated solvent, and reduced quantity of basic catalysts
allowing synthesis to be performed at room temperature
(instead of 0 °C).
Through a heat transfer lumped mathematical model
describing the vibrational milling apparatus starting from its
mechano-physical properties,47 we previously demonstrated
that during the mechanochemical solvent-free synthesis of
nitrones (at 30 Hz for 30 min) there was a small increase in
temperature (from 30 °C at the beginning of the experiment to
44 °C at the end). In order to rule out that a temperature
increase into the milling jar could be responsible for the good
yields, the temperature of the mixture, after vibrational or
planetary milling, was measured using a thermocouple sensor.
In the case of N-protection (30 Hz for 2 h, vibrational milling),
the final temperature was 23 °C, while for planetary milling
(450 rpm for 90 min), the value was 25 °C. From this
perspective, the C-protection was performed under cycled
milling mostly to avoid the degradation of precursors of
protecting groups instead of controlling a possible temperature
increase due to the mechanical energy entry. During the ball
milling, the combination of pressure and grinding phenomena
(and not necessarily heat!) were responsible for the successful
outcome of the reactions, creating conditions otherwise difficult
to obtain.
Due to the high reactivity of Z2O, benzyl chloroformate (Z-
Cl) was selected to perform the decarboxylative esterification.
Starting from N-Z-phenylalanine, the best results were obtained
under the same milling conditions as for the preparation of tert-
butyl esters (Table 2, entry 8) but using a DMAP excess. The
two-step cycled milling was executed by addition of Z-Cl in two
equivalent portions, so as to consume the chloroformate and
reduce the formation of the undesired byproducts. Although
dibenzyl ether 33 was still present as a byproduct, its amount
was dramatically reduced. In this case, after the addition of dry
CO2 as additive,46 a similar yield (53% instead of 48%) was
We then turned our attention toward the solvent-free
preparation of succinimide esters, one of the most popular
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family of active esters for peptide coupling.48 They are usually
prepared in solution through two reaction pathways: (i) by
esterification of the N-protected amino acid with N-
hydroxysuccinimide in the presence of dicyclohexylcarbodii-
mide (DCC)48 or (ii) N,N′-disuccinimidyl carbonate49 (DSC)
or a succinimidyl carbonate derivative,50 in basic medium
(pyridine or triethylamine). The second approach was selected
for the mechanochemical synthesis of succinimide ester
derivatives, using DMAP. However, the DSC carbonate was
difficult to handle via mechanosynthesis: the reaction mixture
became sticky from the beginning of the mixing, preventing the
balls from moving into the jar, independent of the milling
conditions (reaction time and rotation speed). The use of DSC
carbonate in excess was also unsuccessful (the more carbonate
used, the stickier the crude was), and the addition of NaCl32 to
make the mixture more powdery did not help. Evoking a liquid-
assisted grinding (LAG) in the presence of AcOEt or
acetonitrile did not produce any improvement. For these
reasons, only moderate yields of succinimide esters were
obtained (Table 2, entries 5−7). However, the workup
remained simple and fast: N-hydroxysuccinimide precipitated
by addition of AcOEt, and it was filtered. The residual
unreacted amino acid was removed by washings with aqueous
citric acid, followed by a saturated solution of NaHCO3, leading
to the desired compounds without any other purification steps.
An attempt to synthesize Z-Phe-OSu (Table 2, entry 5) in the
presence of Boc2O with an excess of hydroxysuccinimide
(HOSu) (like for the synthesis of tert-butyl esters with Boc2O/
t-BuOH in excess)24 was also performed, but neither the
succinimidyl nor the tert-butyl ester was obtained, confirming
our previous trials. We then became interested in the possibility
of preparing the methyl ester derivatives from N-protected
amino acids. Highly reactive dimethyldicarbonate (Moc2O),
dimethyl carbonate (DMC), and methyl chloroformates
(MeOCOCl), known to produce very good results in solution,
were tested in the presence of DMAP or 1,8-diazabicycloundec-
7-ene (DBU).51,52 In particular, dimethyl carbonate (DMC)
has recently attracted interest as a valuable green methylating
agent51−56 as it showed stability, nontoxicity, and biodegrad-
ability. Unfortunately, our attempts with any of these
methylation sources were unsuccessful, principally due to
their degradation during the milling, always affording unreacted
starting material. Moc2O degraded itself as soon as added in the
jar. Although methyl chloroformate seemed to be the most
promising reactant, leading to Z-L-Phe-OMe (300 rpm, 9 cycles
of 10 min) in good yield (60% determined by 1H NMR), when
the reaction was tested with other amino acids, the mixture
became sticky and prevented the balls from moving, thus
stopping the reaction.
chemist and especially useful for applications in combinatorial
chemistry and drug discovery.
EXPERIMENTAL SECTION
■
General Remarks. All reagents were commercially available and
used without any further purification. NMR spectra were recorded at
room temperature with the appropriate deuterated solvent (CDCl3,
CD3OD, or DMSO-d6). Chemical shifts (δ) of H NMR and 13C
1
NMR spectra are reported in ppm relative to residual solvent signals
1
(CHCl3 in CDCl3: δ = 7.27 ppm for H and CDCl3: δ = 77.04 ppm
1
for 13C NMR. J values are given in hertz. H and 13C NMR spectra
were registered at 300 or 400 MHz. The identity of analytically pure
1
final products was assessed by comparison of their H NMR data
previously described in the literature and by their fragmentation in
LC/MS. Analytical high-performance liquid chromatography (HPLC)
was performed with a variable wavelength diode detector using a
CHROMOLITH RP18 column (50 × 4,6 mm), flow 5 mL/min, linear
gradient CH3CN in water 0−100% (+ 0.1% TFA) in 4.5 min. LC-MS
analysis were performed using an Onyx C18 HPLC column (25 × 4.6
mm), flow 3 mL/min linear gradient CH3CN in water 0−100% (+
0.1% HCO2H) in 2.5 min. The ball milling experiments were
performed in a MM200 vibrational ball (Retsch GmbH, Haan,
Germany) using 10 mL mill steel jar (2 stainless steel balls, 5 mm Ø),
or PM100 planetary mill (Retsch GmbH, Haan, Germany) 12 mL
steel jar (12, 24, 36, or 50 stainless steel balls, 5 mm Ø). All
compounds displayed identical spectral data compared to authentic
commercial sample.
General Experimental Procedures and Characterizations.
General Procedure for the Synthesis of N-Fmoc- (Table 1, Entries
1−4) and N-Z-α-Amino Esters (Table 1, Entries 6−10). The amino
ester hydrochloride (0.238 mmol), NaHCO3 (0.476 mmol), and the
suitable protecting group (Fmoc-Cl or Z-Cl) (0.238 mmol) were
introduced into a 10 mL stainless grinding jar with two stainless balls
(5 mm diameter). The reaction mixture was ground at 30 Hz with a
vibrational ball mill for 90 min (120 min from the tert-butyl esters).
CH2Cl2 was then added to the crude product, and the water-soluble
side products were filtered on cotton. The organic phase was dried
over MgSO4, filtered, and concentrated to give the pure compound
after drying over P2O5.
1
Fmoc-Gly-OMe 1. CAS [121616-32-8] (70.5 mg, 95% yield). H
NMR (300 MHz, CDCl3)57 δ (ppm): 3.78−4.44 (m, 6H), 5.42 (m,
2H), 7.36−7.79 (m, 8H). 13C{1H} NMR (300 MHz, CDCl3) δ
(ppm): 40.3, 44.8, 50.0, 64.8, 117.7, 122.7, 124.7, 125.4, 138.9, 141.4,
153.9, 168.2. MS ESI-(+): m/z 312 [M + H]+, 334 [M + Na]+, 623
[2M + H]+, 179 [C14H11]+, 134.
Fmoc-Phe-OMe 2. CAS [129397-81-5]58 (90.2 mg, 95% yield). 1H
NMR (300 MHz, CDCl3) δ (ppm): 2.93−5.37 (m, 10H), 7.82−7.16
(m, 13H). 13C{1H} NMR (300 MHz, CDCl3) δ (ppm): 36.2, 45.2,
50.3, 52.8, 64.9, 117.9, 123.0, 124.6, 125.0, 125.7, 126.6, 127.3, 139.3,
140.4, 141.7, 153.5, 169.9. MS ESI-(+): m/z 402 [M + H]+, 424 [M +
Na]+, 803 [2M + H]+, 825 [2M + Na]+, 224, 180 [C14H11 + H]+.
Fmoc-Ala-OMe 3. CAS [146346-88-5]59 (74.8 mg, 96%). 1H NMR
(300 MHz, CDCl3) δ (ppm): 1.46 (d, 3H, J = 7.1 Hz), 3.79 (s, 3H),
4.25 (t, 1H, J = 7.0 Hz), 4.38−4.43 (m, 3H), 5.43 (d, 1H, J = 6.6 Hz),
7.43 (t, 4H, J = 7.3 Hz), 7.63 (d, 2H, J = 6.6 Hz), 7.79 (d, 2H, J = 7.4
Hz). 13C{1H} NMR (300 MHz, CDCl3) δ (ppm): 16.7, 45.2, 47.7,
50.6, 65.0, 118.1, 123.5, 125.1, 125.8, 139.4, 141.8, 153.7, 171.6. MS
ESI-(+): m/z 326 [M + H]+, 348 [M + Na]+, 651 [2M + H]+, 179
[C14H11 + H]+, 148, 104.
CONCLUSION
■
Two different methodologies to prepare N-protected amino
esters were developed under solvent-free conditions via
mechanosynthesis: the N-protection approach using free
amino esters as substrates was straightforward and more
adaptable to mechanochemistry. In the case of the C-terminal
esterification via carbonates or chloroformates, the success of
the reaction was strictly dependent on the nature and stability
of the activating agent in milling conditions. In all cases, the
pure products were recovered in good to excellent yields after
simple and clean workup procedures reducing the environ-
mental impact with respect to the syntheses in solution. The
transformations here reported are attractive for the synthetic
Fmoc-Leu-O-t-Bu 4. CAS [129460-20-4] (78.1 mg, 87%). 1H NMR
(300 MHz, CDCl3)60 δ (ppm): 0.78 (d, 3H, J = 5.4 Hz), 0.81 (d, 3H, J
= 5.4 Hz), 1.41 (s, 9H), 1.62 (pseudo-s, 2H), 4.01−4.05 (m, 1H),
4.40−4.60 (m, 3H), 4.81−4.95 (m, 2H), 7.33−7.69 (m, 8H). 13C{1H}
NMR (300 MHz, CDCl3) δ (ppm): 22.2, 23.2, 25.2, 28.2, 42.3, 47.4,
53.2, 67.0, 82.0, 120.1, 125.3, 127.2, 127.8, 141.4, 143.9, 144.1, 156.1,
172.81. MS ESI-(+): m/z 224 [M + H]+, 417 [M + H2O]+, 432 [M +
Na]+, 354 [M − t-Bu + H]+, 217.
1
Z-Gly-OMe 5. CAS [1212-53-9] (42.4 mg, 80%). H NMR (300
MHz, CDCl3)61 δ (ppm): 3.75 (s, 3H), 3.98 (d, 2H, J = 5.6 Hz), 5.13
4013
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Article
(s, 2H, CH2O), 5.38 (sbroad, 1H, NH), 7.3 (s, 5H, ArH). 13C{1H}
NMR (300 MHz, CDCl3) δ (ppm): 42.7, 52.4, 67.2, 128.2, 128.3,
128.6, 136.3, 156.4, 170.6. MS ESI-(+): m/z 410 [M + H]+, 246 [M +
Na]+, 180.
with reverse rotation. Then, Boc2O (0.5 equiv) was added to the jar
and the mixture was milled again for 3 cycles of 10 min (2 min pause
in between, with reverse rotation). Aqueous citric acid (10% aq, 10
mL) was added, and the crude was mixed with a spatula. The mixture
was extracted with diethyl ether (3 × 5 mL). The organic phase was
washed with a saturated aqueous solution of NaHCO3, dried over
MgSO4, filtered, and concentrated under vacuum.
1
Z-Gly-O-t-Bu 6. CAS [16881-32-6] (61 mg, 96% yield). H NMR
(300 MHz, CDCl3)62 δ (ppm): 1.39 (s, 9H), 3.79 (d, 2H, J = 5.4 Hz),
5.04 (s, 2H), 5.22 (pseudo-s, 1H), 7.26 (s, 5H). 13C{1H} NMR (300
MHz, CDCl3) δ (ppm): 28.2, 43.4, 66.9, 82.2, 128.08, 128.13, 128.5,
140.9, 156.3, 169.1. MS ESI-(+): m/z 266 [M + H]+, 288 [M + Na]+,
210 [M − t-Bu + H]+, 166 [M − Boc + H]+, 132.
Z-Phe-O-t-Bu 14. CAS [7670-20-4] (236.6 mg, 79% yield). 1H
NMR (300 MHz, CDCl3)22 δ (ppm): 1.40 (s, 9H, O-t-Bu), 2.22 (d,
2H, J = 6.0 Hz), 4.53−4.60 (m, 1H, CHα), 5.06 (s, 2H, CH2O), 7.03−
7.36 (m, 10H, ArH). 13C{1H} NMR (300 MHz, CDCl3) δ (ppm):
28.1, 38.6, 55.3, 66.9, 82.5, 127.1, 128.2, 128.3, 128.5, 128.6, 129.7,
136.2, 136.5, 155.8, 170.7. MS ESI-(+): m/z 356 [M + H]+, 378 [M +
Na]+, 300 [M − t-Bu + H]+, 256 [M − CO2-t-Bu + H]+.
Z-Leu-O-t-Bu 7. CAS [16881-37-1]16 (61.3 mg, 80% yield). 1H
NMR (300 MHz, DMSO-d6) δ (ppm): 0.84−0.90 (m, 6H), 1.64−1.25
(m, 11H), 3.89−3.92 (m, 1H, CHα), 5.04 (s, 2H, CH2O), 7.31−7.35
(m, 5H), 7.61 (d, 1H, J = 7.9 Hz). 13C{1H} NMR (300 MHz, DMSO-
d6) δ (ppm): 21.2, 22.7, 24.2, 27.6, 39.5, 52.9, 65.3, 80.3, 127.6, 127.7,
127.9, 142.5, 156.1, 171.9. MS ESI-(+): m/z 322 (9) [M + H]+, 344
[M + Na]+, 266 [M − t-Bu + H]+, 222 [M − Boc + H]+, 132.
1
Z-Pro-O-t-Bu 15. CAS [16881-39-3] (205.1 mg, 67% yield). H
NMR (300 MHz, CDCl3)68 δ (ppm): 1.36/1.46 (2s, 9H), 1.81−1.95
(m, 3H), 2.15−2.21 (m, 1H), 3.48−3.61 (m, 2H), 4.21−4.29 (m, 1H),
5.07−5.21 (m, 2H), 7.28−7.37 (m, 5H). 13C{1H} NMR (300 MHz,
CDCl3) δ (ppm): 23.5, 24.3, 27.9, 28.1, 30.0, 31.0, 46.5, 47.0, 59.7,
60.0, 66.9, 81.3, 81.3, 127.8, 127.9, 128.0, 128.5, 128.5, 136.8, 137.0,
154.6, 154.9, 171.9, 172.1. MS ESI-(+): m/z 306 [M + H]+, 328 [M +
Na]+, 250 [M − t-Bu + H]+, 206 [M − CO2t-Bu + H]+.
Z-Glu(O-t-Bu)2 8. CAS [16881-41-7]63 (94 mg, quant). H NMR
1
(300 MHz, DMSO-d6) δ (ppm): 1.39 (s, 18H), 1.60−1.80 (m, 1H),
1.80−2.00 (m, 1H), 2.27−2.28 (m, 2H), 3.90−4.00 (m, 1H), 5.04 (s,
2H), 7.31−7.36 (m, 5H), 7.63 (d, 1H, J = 7.9 Hz). 13C{1H} NMR
(300 MHz, DMSO-d6) δ (ppm): 27.1, 28.6, 28.7, 32.2, 54.6, 66.4, 80.9,
81.6, 128.7, 128.8, 129.3, 138.0, 157.1, 172.2, 172.4. MS ESI-(+): m/z
394 [M + H]+, 416 [M + Na]+, 809 [2M + Na]+, 338 [M − t-Bu +
H]+, 282 [M − (tBu)2 + H]+, 238 [M − Boc-t-Bu + H]+.
Boc-Thr(Bzl)-O-t-Bu 16. CAS [174872-58-3]69 (200.3 mg, 65%
yield). 1H NMR (300 MHz, CDCl3) δ (ppm): 1.29 (d, 3H, J = 6.3 Hz,
CH3), 1.49 (pseudo-s, 18H, 2 × C(CH3)3), 4.04−4.10 (m, 1H, CHα),
4.14−4.46 (1H, CH−O), 4.32−4.63 (m, 2H, CH2O), 5.28 (d, 1H, J =
9.5 Hz, NH), 7.30−7.37 (m, 5H, ArH). 13C{1H} NMR (300 MHz,
CDCl3) δ (ppm)16.5, 16.4,28.2, 28.5,58.8, 71.0, 71.2, 75.2, 75.5, 79.7,
81.9, 82.2, 127.7, 127.8, 128.4, 128.7, 138.2, 156.4, 170.3. MS ESI-(+):
m/z 366 [M + H]+, 388 [M + Na]+, 254 [M − t-Bu + H]+, 210 [M −
CO2 − t-Bu + H]+; HRMS ESI-(+) calcd for C20H31NO5 [M + Na]+
388.2100, found 388.2098.
General Procedure for the Synthesis of N-Boc-α- and β-Amino
Esters (Table 1, Entries 11−16). The amino ester hydrochloride (50
mg, 1 equiv), NaHCO3 (2 equiv), and Boc2O (1 equiv) were
introduced into a 5 mL stainless grinding jar with two stainless balls (5
mm diameter). The reaction mixture was ground at 30 Hz for 90 min
in a vibrational ball mill. The crude was extracted with H2O/Et2O, and
the organic phase was dried over MgSO4, filtered, and concentrated to
give the pure compound after drying over P2O5.
Boc-Tyr(2,6-dichlorobenzyl)-O-t-Bu 17. CAS [1253041-18-7]70
Boc-Phe-OMe 9. CAS [51987-73-6]64 (58,2 mg, 91% yield). H
1
1
(159.1 mg, 56% yield). H NMR (300 MHz, CDCl3) δ (ppm): 1.43
NMR (300 MHz, DMSO-d6) δ (ppm): 1.32 (s, 9H), 2.81−3.03 (m,
2H), 3.60 (s, 3H), 4.14−4.22 (m, 1H), 7.18−7.30 (m, 5H). 13C{1H}
NMR (300 MHz, DMSO-d6) δ (ppm): 28.1, 36.5, 51.8, 55.2, 78.3,
126.4, 128.2, 129.1, 137.6, 146.2, 155.4, 172.6. MS ESI-(+): m/z 230
[M + H]+, 252 [M + Na]+, 174 [M − t-Bu + H]+, 130 [M −Boc +
H]+.
(s, 18H), 3.02 (d, 2H, J = 5.9 Hz), 4.40−4.46 (m, 1H), 4.99 (pseudo-
d, 1H, J = 8.1 Hz), 5.25 (s, 2H), 6.94−7.62 (m, 7H). 13C{1H} NMR
(300 MHz, CDCl3) δ (ppm): 27.9, 28.3, 37.7, 54.9, 65.3, 79.6, 81.9,
114.9, 128.5, 129.1, 130.4, 130.6, 132.2, 137.0, 155.2, 157.9, 171.0. MS
ESI-(+): m/z 496 [M + H]+, 518 [M + Na]+, 340 [H-AA-OH]+.
HRMS ESI-(+): calcd for C25H31NO5Cl2 [M + H]+ 496.1658, found
496.1660.
Boc-Pro-OMe 10. CAS [51987-73-6] (55,5 mg, 81% yield). 1H
NMR (300 MHz, CDCl3)64 δ (ppm): 1.36 (2s, 9H), 1.71−2.22 (m,
4H), 3.37−3.48 (m, 2H), 3.65 (s, 3H), 4.13−4.26 (m, 1H). 13C{1H}
NMR (300 MHz, CDCl3) δ (ppm): 23.8, 24.4, 28.4, 28.5, 30.0, 30.9,
46.4, 46.6, 52.0, 52.1, 58.8, 59.2, 79.86, 79.91, 153.9, 154.5, 173.6,
173.8. MS ESI-(+): m/z 230 [M + H]+, 252 [M + Na]+, 174 [M − t-
Bu + H]+, 130 [M − Boc + H]+.
General Procedure for the Synthesis of N-Protected Succinimidyl
Esters (Table 2, Entries 5−7). The N-protected amino acid (250 mg, 1
equiv), DSC (1 equiv), and DMAP (0.3 equiv) were added in a 12 mL
stainless steel jar with 50 stainless steel balls (diameter 5 mm). The
mixture was milled at 450 rpm for 6 cycles of 10 min each, with a 2
min pause in between, with reverse rotation. Aqueous citric acid (10%
aq, 10 mL) was added, and the crude was mixed with a spatula. The
mixture was then extracted with diethyl ether (3 × 5 mL). The organic
phase was washed with a saturated aqueous solution of NaHCO3 dried
over MgSO4, filtered, and concentrated under vacuum.
1
Boc-β-Ala-OMe 11. CAS [42116-55-2] (50,1 mg, 68% yield). H
NMR (300 MHz, CDCl3)65 δ (ppm): 1.41 (s, 9H, O-t-Bu), 2.50 (t,
2H, J = 6.1 Hz, CH2CO), 3.33−3.42 (m, 2H, CH2N), 3.69 (s, 3H,
OMe). 13C{1H} NMR (300 MHz, CDCl3) δ (ppm): 28.5, 34.5, 36.2,
51.8, 79.4, 155.9, 172.9. MS ESI-(+): m/z 204 [M + H]+, 226 [M +
Na]+, 148 [M − t-Bu + H]+.
1
Z-Phe-OSu 18. CAS [3397-32-8] (228.7 mg, 69% yield). H NMR
(300 MHz, CDCl3)71 δ (ppm): 2.86 (s, 4H), 3.27 (dd, 1H, J = 5.7 Hz,
J = 13.9 Hz), 3.36 (dd, 1H, J = 5.7 Hz, J = 13.9 Hz), 5.02−5.16 (m,
4H), 7.28−7.40 (m, 10H). 13C{1H} NMR (300 MHz, CDCl3) δ
(ppm): 25.6, 38.0, 52.9, 67.4, 127.5, 128.2, 128.3, 128.5, 128.6, 128.8,
129.4, 129.7, 134.3, 135.9, 155.3, 167.5, 168.5. MS ESI-(+): m/z 300
[M + H]+, 322 [M + Na]+, 256.
1
Boc-3-Aib-OMe 12. CAS [182486-32-4] (43.7 mg, 61% yield). H
NMR (300 MHz, CDCl3)66 δ (ppm): 1.17 (d, 3H, J = 7.2 Hz, CH3),
1.43 (s, 9H, O-t-Bu), 2.67−2.71 (m, 1H, CHCO), 3.24−3.31 (m, 2H,
CH2N), 3.70 (s, 3H, OMe). 13C{1H} NMR (300 MHz, CDCl3) δ
(ppm): 14.8, 28.5, 40.1, 43.1, 51.9, 85.3, 156.0, 175.9. MS ESI-(+): m/
z 218 [M + H]+, 240 [M + Na]+, 162 [M − t-Bu + H]+.
Boc-Thr(Bzl)-OSu 19. CAS [32886-43-4]50 (179.4 mg, 55% yield).
1
Boc-Aib-OMe 13. CAS [84758-55-4] (48.9 mg, 68% yield). 1H
NMR (300 MHz, CDCl3)67 δ (ppm): 1.42 (s, 9H), 1.48 (s, 6H), 3.72
(s, 3H). 13C{1H} NMR (300 MHz, CDCl3) δ (ppm): 25.5, 28.4, 52.6,
56.3, 79.9, 154.7, 175.5. MS ESI-(+): m/z 218 [M + H]+, 240 [M +
Na]+, 203 [M − Me + H]+.
Two rotamers were present in the spectrum. H NMR (300 MHz,
acetone-d6) δ (ppm):1.23/1.31 (2d, 6H, J = 6.3 Hz, 2 × CH3 two
rotamers), 1.38 (pseudo-s, 9H), 2.62 (s, 2H), 2.87 (s, 2H), 4.15−4.30
(m, 1H), 4.55−4.69 (m, 3H), 7.20−7.37 (m, 5H). 13C{1H} NMR
(300 MHz, acetone-d6) δ (ppm): 15.3, 16.9, 26.1, 26.3, 28.4, 42.9,
57.9, 71.5, 72.0, 75.8, 79.5, 80.0, 128.2, 128.8, 128.9, 139.5, 156.4,
167.9, 170.3, 171.6, 172.5. MS ESI-(+): m/z 407 [M + H]+, 425 [M +
Na]+, 351 [M − t-Bu + H]+, 307 [M − Boc + H]+. HRMS ESI-(+):
calcd for C20H26N2O7 [M + H]+ 407.1818, found 407.1822.
General Procedure for the Synthesis of N-Protected tert-Butyl
Esters (Table 2, Entries 1−4). The N-protected amino acid (250 mg, 1
equiv), Boc2O (0.5 equiv), and DMAP (0.3 equiv) were added
together in a 12 mL stainless steel jar with 50 stainless steel balls
(diameter 5 mm). The mixture was milled in a planetary ball mill at
300 rpm for 3 cycles of 10 min each, with a 2 min pause in between,
Boc-Met-OSu 20. CAS [3845-64-5]50 (121.2 mg, 35% yield). H
1
NMR (300 MHz, acetone-d6) δ (ppm): 1.35 (s, 9H), 2.09−2.25 (m,
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1
4H), 2.58−2.73 (m, 3H), 2.88 (s, 1H), 4.69−4.76 (m, 1H). 13C{1H}
NMR (300 MHz, acetone-d6) δ (ppm): 14.9, 26.2, 32.0, 42.9, 51.8,
73.4, 79.8, 156.1, 169.3, 170.2, 171.5, 174.8. MS ESI-(+): m/z 306 [M
+ H]+, 328 [M + Na]+, 250 [M − t-Bu + H]+. HRMS ESI-(+): calcd
for C14H22N2O6S [M + Na]+ 369.1096, found 369.1091.
Boc-Met-OEt 26. CAS [76220-80-9] (232.1 mg, 84% yield). H
NMR (300 MHz, CDCl3)77 δ (ppm): 1.27 (t, 3H, J = 7.1 Hz), 1.43 (s,
9H), 1.84−1.96 (m, 1H), 2.08 (s, 3H), 2.08−2.17 (m, 1H), 2.52 (t,
2H, J = 7.0 Hz), 4.19 (q, 2H, J = 7.1 Hz), 4.36 (pseudo-s, 1H), 5.13
(pseudo-s, 1H). 13C{1H} NMR (300 MHz, CDCl3) δ (ppm):14.3,
15.6, 28.4, 30.1, 32.4, 52.9, 61.6, 80.1, 155.4, 172.4. MS ESI-(+): m/z
278 [M + H]+, 300 [M + Na]+, 221 [M − t-Bu + H]+, 219 [M −
(CH2)2SCH3 + H]+, 178 [M − Boc + H]+.
General Procedure for the Synthesis of N-Protected Benzyl Esters
(Table 2, Entries 8−10). The N-protected amino acid (250 mg, 1
equiv), Z-Cl (0.5 equiv), and DMAP (1.3 equiv) were added in a 12
mL stainless steel jar with 50 stainless steel balls (diameter 5 mm).
The mixture was milled in a planetary mill at 300 rpm for 3 cycles of
10 min each, with a 2 min pause in between. Then, Z-Cl (0.5 equiv)
was added into the jar and the mixture was milled again for 3 cycles of
10 min (2 min pause in between, with reverse rotation). Aqueous citric
acid (10% aq., 10 mL) was added and the crude mixed with a spatula.
The mixture was extracted with diethyl ether (3 × 5 mL). The organic
phase was washed with a saturated aqueous solution of NaHCO3,
dried over MgSO4, filtered, and concentrated under vacuum.
Boc-Cys(Bzl)-OEt 27. CAS [110694-58-1]78 (246.1 mg, 91% yield).
1H NMR (300 MHz, CDCl3) δ (ppm): 1.27 (t, 3H, J = 7.1 Hz), 1.46
(s, 9H), 2.84 (m, 2H, CH2−S), 3.73 (s, 2H), 4.18 (q, 2H, J = 7.1 Hz),
4.53 (pseudo-s, 1H), 5.31 (pseudo-d, 1H, J = 7.6 Hz), 7.22−7.35 (m,
5H). 13C{1H} NMR (300 MHz, CDCl3) δ (ppm): 14.3, 28.4, 33.8,
36.8, 53.3, 61.8, 80.2, 127.3, 128.7, 129.1, 137.9, 155.5, 171.2. MS ESI-
(+): m/z 340 [M + H]+, 362 [M + Na]+, 284 [M − t-Bu + H]+, 240
[M − Boc + H]+, 223. HRMS ESI-(+): calcd for C17H25NO4S [M +
Na]+ 362.1402, found 362.1404.
Z-Phe-OBn 21. CAS [60379-01-3] (155.4 mg, 48% yield). 1H NMR
(300 MHz, CDCl3)72 δ (ppm): 3.13 (pseudo-s, 2H), 4.73 (q, 1H, J =
5.9 Hz), 5.07−5.27 (m, 5H), 7.01−7.39 (m, 15H). 13C{1H} NMR
(300 MHz, CDCl3) δ (ppm): 38.3, 54.9, 67.1, 67.4, 127.2, 128.2,
128.3, 128.65, 128.69, 128.74, 129.5, 135.2, 135.6, 136.4, 155.7, 171.5.
MS ESI-(+): m/z 390 [M + H]+, 412 [M + Na]+, 346.
Z-Phe-OAllyl 28. CAS [64286-85-7] (257.6 mg, 90% yield). 1H
NMR (300 MHz, CDCl3)64 δ (ppm): 3.14 (t, 2H, J = 5.6 Hz, CH2Ar),
4.62 (d, 2H, J = 5.8 Hz, allyl CH2−O), 4.67−4.72 (m, 1H, CHα), 5.11
(s, 2H, OCH2Ph), 5.19−5.28 (m, 3H, allyl CH2 and NH), 5.80−5.93
(m, 1H, allyl CH), 7.10−7.37 (m, 10H, ArH). 13C{1H} NMR (300
MHz, CDCl3) δ (ppm): 38.4, 54.9, 66.2, 67.1, 119.2, 127.3, 128.2,
128.3, 128.67, 128.74, 129.5, 131.5, 135.8, 136.4, 155.8, 171.3. MS ESI-
(+): m/z 340 [M + H]+, 362 [M + Na]+, 296.
Z-Ser(O-t-Bu)-OBn 22. CAS [20700-93-0]73 (175.3 mg, 54% yield).
1H NMR (300 MHz, CDCl3) δ (ppm): 1.08 (s, 9H), 3.58 (dd, 1H, J =
3.1 Hz, J = 8.9 Hz), 3.85 (dd, 1H, J = 2.6 Hz, J = 8.9 Hz), 4.43 (dt, 1H,
J = 2.8 Hz, J = 8.9 Hz), 5.05−5.18 (m, 1H), 7.34−7.36 (m, 5H).
13C{1H} NMR (300 MHz, CDCl3) δ (ppm): 27.3, 54.8, 62.1, 67.1,
128.25, 128.27, 128.31, 128.4, 128.6, 135.7, 136.4, 156.3, 170.7. MS
ESI-(+): m/z 386 [M + H]+, 408 [M + Na]+, 330 [M − t-Bu + H]+,
286 [M − CO2 − t-Bu + H]+. HRMS ESI-(+): calcd for C22H27NO5
[M + H]+ 386.1967, found 386.1973.
1
Z-Ser(O-t-Bu)-OAllyl 29. (236.1 mg, 83% yield, colorless oil). H
NMR (300 MHz, CDCl3) δ (ppm): 1.12 (s, 9H), 3.58 (dd, 1H, J = 3.1
Hz, J = 8.9 Hz), 3.85 (dd, 1H, J = 2.8 Hz, J = 8.9 Hz), 4.48 (dt, 1H, J =
2.9 Hz, J = 8.9 Hz), 4.65 (d, 2H, J = 5.6 Hz), 5.14 (s, 2H), 5.21−5.36
(m, 2H), 5.63 (d, 1H, J = 8.8 Hz), 5.83−5.96 (m, 1H), 7.30−7.38 (m,
7H). 13C{1H} NMR (300 MHz, CDCl3) δ (ppm): 27.4, 54.8, 62.2,
66.0, 67.2, 73.6, 118.5, 128.3, 128.7, 131.8, 136.5, 156.3, 170.5. MS
ESI-(+): m/z 336 [M + H]+, 358 [M + Na]+, 280 [M − t-Bu + H]+,
236. HRMS ESI-(+): calcd for C18H25NO5 [M + Na]+ 358.1630,
found 358.1629.
1
Boc-Met-OBn 23. CAS [87746-57-4] (201.6 mg, 59% yield). H
NMR (300 MHz, CDCl3)74 δ (ppm): 1.43 (s, 9H), 1.89−1.99 (m,
1H), 2.04 (s, 3H), 2.09−2.14 (m, 1H), 2.45−2.51 (m, 2H), 4.42−4.48
(m, 1H), 5.12−5.23 (m, 2H), 7.35 (s, 5H). 13C{1H} NMR (300 MHz,
CDCl3) δ (ppm): 15.6, 28.4, 29.9, 32.3, 52.9, 67.3, 80.2, 128.5, 128.6,
128.7, 135.4, 155.4, 172.3. MS ESI-(+): m/z 340 [M + H]+, 462 [M +
Na]+, 284 [M − t-Bu + H]+, 240 [M − CO2 − t-Bu + H]+, 146.
General Procedure for the Synthesis of N-Protected Ethyl (Table
2, Entries 11−14) and Allyl Esters (Table 2, Entries 15−18). The N-
protected amino acid (250 mg, 1 equiv), the suitable alkyl
chloroformate (ethylchloroformate or allylchloroformate, 1.2 equiv),
and DMAP (1.5 equiv) were added to a 12 mL stainless steel jar with
50 stainless steel balls (diameter 5 mm). The mixture was milled at
300 rpm for 9 cycles of 10 min each, with a 2 min pause in between,
with reverse rotation. Aqueous citric acid (10% aq., 10 mL) was added
and the crude was mixed with a spatula. The mixture was extracted
with diethyl ether (3 × 5 mL) (except for Boc-L-Cys(Bzl)-OAllyl 31,
which precipitated when aqueous citric acid was added and it was
filtered and dried under vacuum). The organic phase was washed with
a saturated aqueous solution of NaHCO3, dried over MgSO4, filtered,
and concentrated under vacuum.
Boc-Met-OAllyl 30. CAS [887646-46-0] (232.1 mg, 84% yield): 1H
NMR (300 MHz, CDCl3)79 δ (ppm): 1.42 (s, 9H), 1.84−2.02 (m,
1H), 2.07 (s, 3H), 2.08−2.18 (m, 1H), 2.52 (t, 2H, J = 7.4 Hz), 4.40
(pseudo-s, 1H), 4.62 (dd, 2H, J = 1.2 Hz, J = 5.8 Hz), 5.15 (pseudo-s,
1H), 5.27 (qd, 2H, J = 1.2 Hz, J = 10.4 Hz), 5.83−5.96 (m, 1H).
13C{1H} NMR (300 MHz, CDCl3) δ (ppm): 15.6, 26.9, 28.4, 30.1,
32.3, 52.9, 66.1, 80.1, 119.0, 131.6, 155.4, 172.1. MS ESI-(+): m/z 290
[M + H]+, 234 [M − t-Bu + H]+, 190 [M − Boc + H]+.
Boc-Cys(Bzl)-OAllyl 31. CAS [848779-96-4]80 (255.6 mg, 91%
yield). 1H NMR (300 MHz, DMSO-d6) δ (ppm): 1.39 (s, 9H), 2.57−
2.73 (m, 2H), 3.71 (s, 2H), 4.19 (q, 1H, J = 5.1 Hz), 4.57 (d, 1H, J =
4.8 Hz), 5.19−5.33 (m, 2H), 5.75−5.89 (m, 1H), 7.19−7.34 (m, 5H).
13C{1H} NMR (300 MHz, DMSO-d6) δ (ppm): 26.4, 28.2, 31.9, 35.2,
53.4, 64.9, 78.5, 117.6, 126.9, 128.4, 128.9, 132.3, 138.1, 155.4, 170.2.
MS ESI-(+): m/z 352 [M + H]+, 374 [M − t-Bu + H]+, 252 [M − Boc
+ H]+, 235. HRMS ESI-(+): calcd for C18H25NO4S [M + Na]+
374.1402, found 374.1400.
Z-Phe-OEt 24. CAS [28709-70-8] (247.9 mg, 90% yield). 1H NMR
(300 MHz, CDCl3)75 δ (ppm): 1.26 (t, 3H, J = 7.1 Hz), 3.15 (pseudo-
t, 2H, J = 5.5 Hz), 4.20 (q, 2H, J = 7.1 Hz), 4.65−4.71 (m, 1H), 5.14
(s, 2H), 5.27 (d, 1H, J = 7.8 Hz), 7.13−7.42 (m, 10H). 13C{1H} NMR
(300 MHz, CDCl3) δ (ppm): 14.2, 38.4, 54.9, 61.6, 67.1, 127.2, 128.2,
128.3, 128.65, 128.68, 129.5, 135.9, 136.4, 155.7, 171.6. MS ESI-(+):
m/z 328 [M + H]+, 350 [M + Na]+, 284.
ASSOCIATED CONTENT
■
S
* Supporting Information
NMR spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
Z-Ser(O-t-Bu)-OEt 25. CAS [130192-13-1]76 (238.4 mg, 87%
1
yield). H NMR (300 MHz, CDCl3) δ (ppm): 1.13 (s, 9H), 1.28 (t,
AUTHOR INFORMATION
■
3H, J = 7.1 Hz), 3.58 (dd, 1H, J = 3.1 Hz, J = 8.9 Hz), 3.83 (dd, 1H, J
= 2.8 Hz, J = 8.9 Hz), 4.21 (q, 2H, J = 7.1 Hz), 4.45 (dt, 1H, J = 2.9
Hz, J = 8.9 Hz), 5.14 (s, 2H), 5.63 (d, 1H, J = 8.7 Hz), 7.32−7.39 (m,
5H). 13C{1H} NMR (300 MHz, CDCl3) δ (ppm): 14.3, 27.4, 54.8,
61.5, 62.2, 67.1, 73.5, 128.3, 128.6, 136.5, 156.3, 170.7. MS ESI-(+):
m/z 324 [M + H]+, 346 [M + Na]+, 268 [M − t-Bu + H]+, 224.
HRMS ESI-(+): calcd for C17H25NO5 [M + Na]+ 346.1630, found
346.1635.
Corresponding Author
*E-mail: evelina.colacino@univ-montp2.fr. Web page: http://
www.greenchem.univ-montp2.fr/. Tel: +33 (0)4 67 14 42 85.
Fax: +33 (0)467 14 48 66.
Notes
The authors declare no competing financial interest.
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Article
(36) Varala, R.; Nuvula, S.; Adapa, S. R. J. Org. Chem. 2006, 71,
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