Efficient and practical procedure for the esterification of the free α-carboxylic acid of amino acid residues with β-(trimethylsilyl)ethoxymethyl chloride and triisopropylsilyl chloride

Article abstract of DOI:10.1055/s-0034-1379004

An efficient and practical procedure for the free α-carboxylic acid esterification of amino acid residues with β-(trimethylsilyl)ethoxymethyl chloride and triisopropylsilyl chloride is described. The reaction takes place under mild conditions and the expected protected amino acids are obtained in good to excellent yields. Our method provides a useful alternative for the C-terminal carboxylic acid protection of amino acids and peptides. Moreover, the removal of such protection was also achieved under mild conditions, without affecting either the other protecting groups at the α-amino moiety and side chains or the optical integrity at the α-position of the amino acid residues. Examples of their use in peptide synthesis are also illustrated.

Full text of DOI:10.1055/s-0034-1379004

PAPER
▌3075
paper
Efficient and Practical Procedure for the Esterification of the Free α-Car-
boxylic Acid of Amino Acid Residues with β-(Trimethylsilyl)ethoxymethyl
Chloride and Triisopropylsilyl Chloride
Esterification of the Free α-Carboxylic Acid of Amino Acid Residues
Jean-Simon Suppo,a Danilo Pereira de Sant’Ana,a,b Luiz Carlos Dias,b Renata Marcia de Figueiredo,*a
Jean-Marc Campagne*a
a
Institut Charles Gerhardt Montpellier, UMR 5253 CNRS-UM2-UM1-ENSCM; Ecole Nationale Supérieure de Chimie, 8 Rue de l’Ecole
Normale, 34296 Montpellier Cedex 5, France
Fax +33(4)67144322; E-mail: renata.marcia_de_figueiredo@enscm.fr
b
Institute of Chemistry, University of Campinas, UNICAMP, P. O. Box 6154, 13084-971 Campinas-SP, Brazil
Received: 23.06.2014; Accepted after revision: 29.07.2014
Dedicated to Professor Dr. Dieter Enders
able for this purpose, they are mainly based on alkyl
Abstract: An efficient and practical procedure for the free α-car-
groups (e.g., tBu, Me, Et, Bn, Fm, Allyl)3 and the harsh
boxylic acid esterification of amino acid residues with β-(trimethyl-
conditions required for their introduction and/or removal
are sometimes deleterious to the stereochemical integrity
silyl)ethoxymethyl chloride and triisopropylsilyl chloride is
described. The reaction takes place under mild conditions and the
expected protected amino acids are obtained in good to excellent at the α-position of the amino acid residue as well as to the
yields. Our method provides a useful alternative for the C-terminal
carboxylic acid protection of amino acids and peptides. Moreover,
the removal of such protection was also achieved under mild condi-
acids chemistry. Among the most described groups, we
tions, without affecting either the other protecting groups at the α-
amino moiety and side chains or the optical integrity at the α-posi-
amide bond. However, silyl-containing α-carboxylic acid-
protecting groups are less common, particularly in amino
can cite 2-(trimethylsilyl)ethyl (TMSE),8 which is gener-
ally introduced by using 2-(trimethylsilyl)ethanol in the
presence of a carbodiimide such as N,N-dicyclohexylcar-
bodiimide (DCC),9a diisopropylcarbodiimide (DIC)9b
tion of the amino acid residues. Examples of their use in peptide
synthesis are also illustrated.
Key words: amino acids, protecting groups, carboxylic acids, syn-
thetic methodology, peptides, organic synthesis
or
N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide
(EDCI)9c–e and 4-(N,N-dimethylamino)pyridine (DMAP).
This protecting group is compatible with Cbz-urethane re-
moval conditions (hydrogenolysis) but is unstable to acids
and bases. Other examples are (2-phenyl-2-trimethylsi-
lyl)ethyl (PTMSE)10 esters and 2-(trimethylsilyl)isopro-
pyl (TMSI)11 esters, which are less often reported than the
parent TMSE. These groups can be used either for a
broader stability under urethane-removal conditions (e.g.,
PTMSE) or for preventing diketopiperazine (DKP) for-
mation (e.g., TMSI).3
In peptide chemistry the choice of protecting groups for
both amine and carboxylate moieties is of paramount im-
portance for the development of synthetic strategies and
for the efficient construction of new amide bonds by
means of orthogonal1,2 protection and deprotection. Al-
though the field of amino acid protecting groups is well
established and widely developed,3 it might be taken into
consideration that most peptide syntheses are realized on
the classical C→N direction either in solution or on a solid
phase. This fact makes deprotection of the amine function
mandatory and, consequently, the major developments in
this area are concentrated on the α-amine function and on
side chain protection regime (temporary protections). Rel-
atively few studies have so far been devoted to the protec-
tion of carboxylic acids.4
Although it is well known that O-SEM and O-TIPS esters
are attractive protecting groups for carboxylic acid func-
tions and that they can be easily cleaved under mild con-
ditions,6,7 intriguingly they are not commonly used in
peptide chemistry. In the case of O-SEM-protected amino
acids, the examples found that allow the corresponding
ester to be isolated in moderate to good yields rely on the
utilization of lithium carbonate as base in N,N-dimethyl-
formamide as solvent with SEMCl as electrophile,12,13
and, in some cases, additional amounts of 4-(N,N-dimeth-
ylamino)pyridine are required to reach higher yields.14
Adding a TIPS group to a C-terminal residue of an amino
acid appears to be more troublesome. Whereas it is known
that simple carboxylic acids can be esterified with TIPSCl
in the presence of tetrahydrofuran and triethylamine, these
conditions, when applied on amino acid residues, afford
very low yields, and, to our knowledge, only a few exam-
ples have been described.15,16 The ongoing need for alter-
Within this context, and as part of an ongoing project fo-
cused on new peptide synthesis strategies,5 we sought to
find an accessible and practical way to protect the C-ter-
minal residue of amino acids with β-(trimethylsi-
lyl)ethoxymethyl (SEM) and triisopropylsilyl (TIPS)
esters.6,7 Although very good protecting groups are avail-
SYNTHESIS 2014, 46, 3075–3084
Advanced online publication: 26.08.2014
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0034-1379004; Art ID: ss-2014-t0388-op
© Georg Thieme Verlag Stuttgart · New York

3076
J.-S. Suppo et al.
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native carboxylate protecting groups for amino acid that for peptide chemistry, many amino acids can be pur-
moieties prompted us to develop a practical and straight- chased as their DCA salts, which makes them solids and
forward procedure for their introduction.
thus easier to handle. We then prepared the salt of 1a with
DCA by reaction in methanol at 0 °C for 20 minutes. The
DCA salt of 1a (2a) was isolated by simple filtration in
92% yield. The following step involved the use of 2a for
the SEM-esterification. Gratifyingly, the combination of
2a with SEMCl in dichloromethane at room temperature
for a period of 12 hours and 18 hours afforded the ester in
good yields (65 and 60%, respectively; entries 2 and 3).
We started our studies by using the amino acid Cbz-Ala-
OH (1a) as a model with which to devise the best reaction
conditions that could allow the introduction of the SEM
protecting group. The results are highlighted in Table 1. In
a first experiment, the reaction of 1a in the presence of tri-
ethylamine as base and SEMCl at 0 °C (the classical
protocol for SEM and TIPS esterification) in dichloro-
methane as solvent did not allow isolation of the desired Lowering the temperature to 0 °C for a period of 12 hours
Cbz-Ala-OSEM (3a; entry 1). We then moved to another afforded a similar yield of 62% (Table 1, entry 4). Based
system in which we chose to check the viability of using on these preliminary results, we considered whether for-
secondary encumbered amines such as dicyclohexyl- mation of the DCA salt in situ followed by SEMCl addi-
amine (DCA) to promote the esterification. It is known tion could allow the transformation without the need for
that DCA can mediate alcoholysis under mild conditions17 formation and isolation of the salt. To our delight, the re-
and also facilitate esterifications in the presence of very action of 1a with DCA and SEMCl in dichloromethane
good electrophiles such as benzyl bromide.18 Another ad- for a period of 2 h at room temperature allowed the ester-
vantage of this base, in addition of being inexpensive, is ification to proceed in very good yield (92%; entry 5).
However, longer reaction times at room temperature were
found to be slightly deleterious to the outcome of the re-
action (entry 6). Whereas the kinetics of the reaction was
slightly lower at 0 °C (86% yield after 2 h vs. 98% yield
after 12 h; entries 7 and 8) compared with the reaction at
room temperature, less decomposition or hydrolysis of the
silylating agent was observed. Switching to other second-
ary amines such as diisopropylamine (DIPA) and piperi-
dine afforded the same good reaction outcome (entries 9
and 10). The yield obtained with DIPA (97%) was equiv-
alent to that observed with DCA. Thus, in our hands, the
use of secondary amines gave better results than the use of
tertiary amines.
Table 1 Optimization of the Reaction Conditions for the SEM-
Esterification of Cbz-Ala-OH (1)
Cbz
OH
Cbz
OSEM
conditionsa
B
N
H
N
H
O
O
1a
3a
MeOH
DCA
conditionsa A
Cbz
O
H2N
N
0 °C
20 min
H
O
2a (92%)
Based on these observations, we decided to continue our
studies by using DCA as base, which is much less expen-
sive than DIPA and piperidine, and also because a large
number of amino acids can be purchased as their corre-
sponding salts. Although the yield obtained at room tem-
perature during 2 hours was good, we chose to work at
0 °C for a period of 12 hours. Delighted by the successful
results obtained with the SEMCl and DCA protection, we
decided to apply these mild conditions to TIPSCl systems.
Indeed, as previously stated, the protection of the carboxyl
moieties of amino acid residues in the presence of this
compound is rather challenging, and low yields are often
observed under classical conditions (e.g., Et3N in THF).
We were pleased to find that when the new conditions
(TIPSCl, DCA) were applied to O-TIPS-esterification of
1a, the required ester 4a was isolated in 92% yield (Table
1, entry 11).
Entry
Base
Conditions Temp
(°C)
Time
(h)
Yield
(%)b of 3a
1
2
Et3N
B
A
A
A
B
B
B
B
B
B
Bd
0
12
12
18
12
2
NR
65
DCAc
DCAc
DCAc
DCA
DCA
DCA
DCA
DIPA
r.t.
r.t.
0
3
60
4
62
5
r.t.
r.t.
0
92
6
12
2
88
7
86
8
0
12
12
12
12
98
9
0
97
10
11
piperidine
DCA
0
84
The scope of this esterification procedure was evaluated
with a range of amino acids 1a–i, which were submitted
to the optimized conditions (Table 1, entry 8). The desired
O-SEM (3a–i) and O-TIPS (4a–h) esters were obtained in
good yields (up to 98%) as shown in Table 2. The most
commonly used Nα-amino acid protection groups (e.g.,
Cbz, Boc and Fmoc)19 are all compatible with the method-
ology.20 The silylated derivatives 3 and 4 proved to be
very stable; they can be stored at +4 °C for long periods
0
92 (4a)
a Reaction conditions: A: 2a (1.0 equiv), CH2Cl2 (c 0.2 M), SEMCl
(1.1 equiv); B: 1a (1.0 equiv), CH2Cl2 (c 0.2 M), base (1.1 equiv), then
after 20 min, SEMCl (1.1 equiv) was added. Reaction time and tem-
perature are indicated in the table.
b Isolated yield after column chromatography. NR = no reaction.
c Previous DCA amino acid salt intermediate formation and isolation
by filtration.
d In this case, TIPSCl (1.1 equiv) was used instead of SEMCl.
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Esterification of the Free α-Carboxylic Acid of Amino Acid Residues
3077
without decomposition, further illustrating the viability (3i) was successfully isolated in a good yield of 75% (en-
and versatility of this O-SEM and O-TIPS protection try 9).
method.21 Side-chain protection groups such as benzyl
(entry 5), tert-butyloxycarbonyl (entry 7), and tert-butyl
(entry 8) are well tolerated during this mild procedure for
The following step was to verify that such esters could be
removed without affecting either the other protecting
groups at the α-amino moiety and side chains or the opti-
esterification. Nonprotected side-chain threonine deriva-
cal integrity at the α-position of the amino acid residues.
tive (entry 4) could also be chemoselectively protected in
Joullié and co-workers have devised an efficient way to
good yields.12 The dipeptide Cbz-Ala-(D)-Phe-OSEM
Table 2 Synthesis of O-SEM and O-TIPS Protected α-Amino Esters 3a–i and 4a–h
R2
R2
i) DCA (1.1 equiv), CH2Cl2 [0.2 M]
0 °C, 20 min
R1
OH
R1
OR3
N
N
H
H
ii) SEMCl or TIPSCl (1.1 equiv)
0 °C, 12 h
O
O
1a–i
(1.0 equiv)
R3 = SEM (3a–i)
R3 = TIPS (4a–h)
Entry
1
Starting material
Product
Yield (%)a
Cbz
N
OR3
3a (98)
4a (92)
Cbz-Ala-OH (1a)
H
O
Fmoc
OR3
3b (82)
4b (98)
2
3
Fmoc-Ala-OH (1b)
Boc-Aib-OH (1c)
N
H
O
Boc
Boc
Boc
OR3
3c (76)
4c (97)
N
H
O
O
HO
3d (83)
4d (93)
OR3
4
5
6
Boc-Thr-OH (1d)
N
H
CO2Bn
OR3
3e (86)
4e (92)
Boc-Asp(Bn)-OH (1e)
Fmoc-Phe-OH (1f)
N
H
O
Ph
3f (86)
4f (75)
Fmoc
OR3
N
H
O
NHBoc
3g (82)
4g (90)
7b
Boc-Lys(Boc)-OH·DCA (1g)
Boc
OR3
N
H
O
t-BuO
3h (93)
4h (73)
Cbz
OR3
8b
Cbz-Thr(tBu)-OH·DCA (1h)
Cbz-Ala-(D)-Phe-OH (1i)
N
H
O
O
O
H
N
Cbz
N
H
OSEM
9
3i (75)
Ph
a Isolated yield after column chromatography.
b The amino acid starting material was purchased as its DCA salt.
© Georg Thieme Verlag Stuttgart · New York
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J.-S. Suppo et al.
PAPER
selectively cleave O-SEM esters from amino acids by us- thesis direction) and inverse (N→C peptide synthesis di-
ing magnesium bromide etherate.14 Their conditions al- rection) conditions.
lowed us to isolate free-acid 1b from 3b in 84% yield
(Scheme 1, eq. 1). The Fmoc-urethane analogue 3b was
chosen to demonstrate that SEM esters can be selectively
removed in the presence of the base-sensitive Fmoc car-
bamate group. With respect to O-TIPS esters, deprotec-
tion was accomplished by using potassium fluoride in
tetrahydrofuran–methanol.22 The required free carboxylic
acids were easily isolated by simple base/acid extraction
(Scheme 1, eqs. 2 and 3).23
a
Fmoc
OH
Fmoc
OSEM
(1)
N
N
H
H
b
O
O
1b (84%)
3b (82%)
c
Fmoc
OH
Fmoc
OTIPS
(2)
N
H
N
H
O
d
O
1b (86%)
4b (98%)
t-BuO
t-BuO
Cbz
e
Cbz
OH•DCA
OTIPS
(3)
(4)
N
N
d, f
H
H
O
O
1h (88%) (2 steps)
4h (73%)
SBn
SBn
OR
a or c
b or d
Boc
OH
Boc
N
N
H
O
H
O
1j
3j (R = SEM)
4j (R = TIPS)
(75%) (steps a,b)
(78%) (steps c,d)
Figure 1 Chiral HPLC chromatograms for the sequence of protec-
tion/deprotection of Boc-Cys(Bn)-OH (see Scheme 1, eq. 4). Analyt-
ical chiral HPLC conditions: column Chiralpak IA (250 × 4.6 mm,
5 μm); n-heptane–CH2Cl2–HCO2H, 50:50:0.1; flow rate: 1.0
mL/min; 25 °C; detection at 230 nm. For more details, see the Sup-
porting Information.
Scheme 1 Reagents and conditions: (a) DCA, SEMCl, CH2Cl2,
0 °C; (b) MgBr2 Et2O, CH2Cl2, –20 to 0 °C, 3 h; (c) DCA, TIPSCl,
CH2Cl2, 0 °C; (d) KF, THF–MeOH (3:1), r.t., 2 h; (e) TIPSCl,
CH2Cl2, 0 °C; (f) DCA, MeOH, 0 °C, 20 min.
.
To perform these studies, we first carried out the chemo-
selective urethane-deprotection (Fmoc, Cbz or Boc) fol-
lowed by coupling with a second amino acid by means of
a coupling agent25,26 (C→N direction). Unfortunately, all
efforts to selectively deprotect carbamate groups in the
presence of the O-TIPS esters were unsuccessful in our
hands.27 Nevertheless, O-SEM esters proved to be more
robust and, to our delight, Fmoc and Cbz-urethane depro-
tections28 could be successfully achieved. Consequently,
we used these groups to proceed with our solution-phase
peptide synthesis studies.
To confirm that the conditions for the O-SEM and O-TIPS
esterification together with the deprotection steps proceed
through an epimerization-free process, we chose to work
with sensitive cysteine residues (Scheme 1, eq. 4), which
are known for being highly prone to racemization.24 Thus,
the starting material Boc-Cys(Bn)-OH (1j) was engaged
in a sequence of O-SEM and O-TIPS protection/deprotec-
tion, and it could be successfully recovered in good yields
after two steps. The chiral purity of both samples was con-
firmed by using chiral HPLC analysis (Figure 1). Impor-
tantly, in both cases similar chromatograms were
obtained, with no detectable epimerization.
The first results obtained are summarized in Scheme 2.
Removal of the Fmoc-amine protecting group from 3b
was successfully performed in the presence of acetonitrile
and diethylamine (90:10) at room temperature without
concurrent deprotection of the O-SEM ester. Indeed, by
using classical N,N-dimethylformamide–piperidine
(80:20) conditions, simultaneous deprotection of O-SEM
ester and Fmoc-group was observed. The intermediate 5,
Having shown that the O-SEM and O-TIPS esterification
followed by selective deprotection in the presence of Nα-
urethane protecting groups proceed in a mild and straight-
forward manner, we next investigated the use of such es-
ters in solution-phase peptide couplings. The idea was to
illustrate their behavior over classical (C→N peptide syn-
Synthesis 2014, 46, 3075–3084
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PAPER
Esterification of the Free α-Carboxylic Acid of Amino Acid Residues
3079
PyBOP-mediated dipeptide
SEM deprotection14
MgBr2•OEt2
O
O
synthesis29
H
N
H
N
Boc
N
CO2SEM
Boc
N
CO2H
H
H
CH2Cl2
Boc-Phe-OH
PyBOP, DIPEA
CH2Cl2, r.t., 2 h
Ph
Ph
6 (91%)
(2 steps)
7 (90%)
Fmoc removal
MeCN–Et2NH
(90:10)
Fmoc
N
CO2SEM
H2N
CO2SEM
H
[0.1 M]
r.t., 90 min
3b
5
Cbz-Met-OH
(1.5 equiv)
conditions A or B
O
CDI
CH2Cl2–THF
overnight
O
H
N
Cbz
N
H
CO2SEM
N
N
H
CO2SEM
N
CH2Cl2, r.t., 20 h
8 (79%)
(2 steps)
CDI-mediated activation
A: HOBt/CuBr2 (10 mol%)
B: HOBt (10 mol%)
SMe
of α-amino ester5
9
conditions A (24%)
conditions B (70%)
Scheme 2 Synthesis of dipeptides with O-SEM α-amino esters
thus obtained, was engaged in a condensation step with
Boc-Phe-OH through PyBOP-mediated29 activation. The
desired dipeptide 6 was isolated in 91% yield after two
steps. Its deprotection was achieved by applying Joullié’s
conditions14 (e.g., MgBr2·Et2O in CH2Cl2), affording di-
peptide carboxylic acid 7.
O
O
H
N
Boc
N
H
CO2H
+
N
N
CO2SEM
N
H
Ph
7
8
HOBt (10 mol%)
CH2Cl2
r.t., 20 h
Very recently, we have reported that α-amino esters can
be successfully activated with commercially available
N,N′-carbonyldiimidazole (CDI) and engaged under very
mild and neutral conditions in amide bonds formation
through an inverse peptide synthesis strategy.5 Having il-
lustrated the preparation of dipeptide 6 by means of Py-
BOP carboxylate activation, we then investigated whether
intermediate 5 could be activated with CDI to afford an
activated α-amino ester, thus enabling the carboxyl func-
tionality of a second amino acid to react with it and form
the peptide bond (Scheme 2). For this purpose, 5 was
treated with CDI and the required activated α-amino ester
(Imi-Ala-OSEM; 8) was isolated in 79% yield after
straightforward purification through a short plug of silica
gel. We then used this intermediate to perform the cou-
pling reaction with Cbz-Met-OH under our optimized
conditions.5 The dual addition of copper(II) bromide and
1-hydroxybenzotriazole (HOBt) as additives (10 mol% of
each) in dichloromethane at room temperature afforded
only the expected dipeptide 9 in 24% yield. We believe
that the addition of a Lewis acid could be deleterious to
the O-SEM ester integrity. Indeed, it turned out that in the
absence of copper(II) bromide, the amide bond was suc-
cessfully formed, and 9 was isolated in 70% yield.
O
H
N
H
N
CO2SEM
Boc
N
H
O
Ph
10 (48%)
Scheme 3 Activated α-amino ester-mediated tripeptide synthesis
With the synthesis of 10 achieved, and through the
straightforward preparation of activated α-amino-OSEM
esters, we revealed that an iterative process can be envis-
aged to perform inverse peptide bond synthesis by means
of O-SEM deprotection and subsequent coupling with
Imi-AA-OSEM activated esters. Accordingly, the mild
and epimerization-free procedures to realize the protec-
tion and deprotection steps of O-SEM esters can be ap-
plied to the challenging and less developed N→C peptide
synthesis.5
In conclusion, we have devised an efficient, mild, and
practical procedure for the O-SEM and O-TIPS esterifica-
tion of amino acids residues. We showed that the combi-
nation of stoichiometric amounts of the readily available
dicyclohexylamine salts (or other secondary amines such
as piperidine and DIPA) with SEMCl or TIPSCl allow es-
terification in a selective and straightforward manner. The
O-TIPS and O-SEM esters were obtained in good to ex-
cellent yields (up to 98% yield). The extremely simple op-
erational procedure and the synthetic versatility of the
products obtained, render this approach highly appealing
for amino acid and peptide chemistry. In addition, their
simple and selective removal makes these two esters a vi-
able alternative for the protection of C-terminal carboxyl-
We then investigated whether this protocol could be ex-
tended to longer targets and, as a proof of concept, the
synthesis of a tripeptide was undertaken. As shown in
Scheme 3, the dipeptide free carboxylic acid 7 was treated
with activated α-amino ester 8 to give the desired tripep-
tide Boc-Phe-Ala-Ala-OSEM 10 in a respectable 48%
yield.
© Georg Thieme Verlag Stuttgart · New York
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1H NMR (400 MHz, CDCl3): δ = 7.36–7.31 (m, 5 H), 5.37 (br d, J =
7.4 Hz, 1 H), 5.10 (d, JAB = 12.1 Hz, 2 H), 4.38 (q, J = 7.3 Hz, 1 H),
1.46 (d, J = 10.2 Hz, 3 H), 1.35–1.25 (m, 3 H), 1.07 (d, J = 7.4 Hz,
18 H).
13C NMR (100 MHz, CDCl3): δ = 172.7, 155.5, 136.3, 128.4 (3C),
128.0 (2C), 66.7, 50.5, 18.7, 17.6 (6C), 11.7 (3C).
ic acids of amino acids and peptides. Additionally, we
could show that Fmoc-urethane protection can be readily
removed in the presence of O-SEM esters, allowing the
free-amines to undergo either condensation with a second
amino acid in the presence of PyBOP coupling agent or
they can be used for the preparation of activated α-amino-
OSEM esters so that an iterative process for inverse pep-
tide synthesis (N→C direction) could be performed.
HRMS (ESI+): m/z [M + H]+ calcd for C20H34NO4Si: 380.2257;
found: 380.2244.
Fmoc-Ala-OSEM (3b)
To Fmoc-Ala-OH (1b; 200 mg, 0.64 mmol) in CH2Cl2 (2.25 mL) at
0 °C were added DCA (140 μL, 0.70 mmol) and SEMCl (124 μL,
0.70 mmol). Purification by flash chromatography (PE–EtOAc,
85:15).
Commercial reagents and solvents were used without purification.
Reactions were carried out in round-bottomed flasks of 10 mL
equipped with a magnetic stirring bar. TLC analysis was performed
on silica gel 60 F254 TLC plates (using KMnO4 solution stain for
all compounds). Flash chromatography was carried out on silica gel
60 A (35–70 µm). FTIR spectra were recorded with a Perkin–Elmer
20
Yield: 231 mg (82%); colorless viscous oil; [α]D –4.3 (c 1.40,
CHCl3).
1
Spectrum 1000. H and 13C NMR spectra were recorded with a
IR (film): 3337, 2952, 1722, 1525, 1450, 1247, 1103, 1060, 936,
856, 834, 757, 653 cm–1.
Bruker Ultra shield 400 plus. 1H and 13C chemical shifts are report-
ed in delta (δ) units in parts per million (ppm) relative to the singlet
at δ = 7.26 ppm and to the triplet at δ = 77.0 ppm for CDCl3 (residual
CHCl3). Optical rotations were measured with a Perkin–Elmer 341
Polarimeter. Low-resolutions mass spectra were recorded with a
Waters QTof-I spectrometer using electrospray ionization. High-
resolution mass spectra were obtained by using the mass spectrom-
eters operated by the Laboratoire de Mesures Physiques (LMP) of
University Montpellier 2.
1H NMR (400 MHz, CDCl3): δ = 7.77 (d, J = 7.6 Hz, 2 H), 7.59–
7.52 (m, 2 H), 7.41 (t, J = 7.2 Hz, 2 H), 7.32 (td, J = 7.6, 1.2 Hz,
2 H), 5.37–5.41 (m, 2 H), 5.30–5.33 (m, 1 H), 4.35–4.46 (m, 3 H),
4.23 (t, J = 7.0 Hz, 1 H), 3.70–3.75 (m, 2 H), 1.47 (d, J = 7.2 Hz,
3 H), 0.97 (t, J = 8.0 Hz, 2 H), 0.02 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 172.7, 155.6, 143.9, 143.7, 141.3
(2C), 127.7 (2C), 127.0 (2C), 125.1 (2C), 120.0 (2C), 89.8, 68.1,
67.0, 49.7, 47.1, 18.7, 18.0, –1.5 (3C).
O-SEM and O-TIPS Esterification of Amino Acids 1a–i; Gener-
al Procedure
HRMS (ESI+): m/z [M + Na]+ calcd for C24H31NO5NaSi: 464.1869;
found: 464.1873.
To a solution of the amino acid derivative (1.00 equiv) in CH2Cl2 at
0 °C, was added DCA (1.10 equiv) and the mixture was stirred at
0 °C for 20 min. SEMCl or TIPSCl was added (1.10 equiv), and stir-
ring was continued at 0 °C for 12 h. THF was then added to the sus-
pension and the mixture was filtered over a plug of Celite, eluting
with additional THF (10 mL). The filtrate was concentrated under
vacuum and the crude product was purified by flash chromatogra-
phy [petroleum ether (PE)–EtOAc] to afford the title compounds as
viscous colorless oils.
Fmoc-Ala-OTIPS (4b)
To Fmoc-Ala-OH (1b; 200 mg, 0.64 mmol) in CH2Cl2 (2.25 mL) at
0 °C were added DCA (140 μL, 0.70 mmol) and TIPSCl (150 μL,
0.70 mmol). Purification by flash chromatography (PE–EtOAc,
95:5).
20
Yield: 293 mg (98%); colorless viscous oil; [α]D +4.2 (c 1.19,
CHCl3).
IR (film): 3299, 2944, 2867, 1717, 1683, 1540, 1451, 1343, 1265,
1208, 1052, 883, 756, 651 cm–1.
Cbz-Ala-OSEM (3a)
To Cbz-Ala-OH (1a; 200 mg, 0.90 mmol) in CH2Cl2 (3.00 mL) at
0 °C were added DCA (197 μL, 0.99 mmol) and SEMCl (175 μL,
0.99 mmol). Purification by flash chromatography (PE–EtOAc,
85:15).
1H NMR (400 MHz, CDCl3): δ = 7.78 (d, J = 7.6 Hz, 2 H), 7.60–
7.62 (m, 2 H), 7.41 (t, J = 7.2 Hz, 2 H), 7.32 (td, J = 7.6, 1.2 Hz,
2 H), 5.46–5.48 (m, 1 H), 4.38–4.43 (m, 3 H), 4.21–4.24 (m, 1 H),
1.49 (d, J = 8.0 Hz, 1 H), 1.33 (q, J = 8.0 Hz, 3 H), 1.09 (d, J =
8.0 Hz, 18 H).
13C NMR (100 MHz, CDCl3): δ = 172.8, 155.5, 143.9, 143.8, 141.2
(2C), 127.6 (2C), 127.0 (2C), 125.1 (2C), 119.9 (2C), 66.9, 50.6,
47.1, 18.9, 17.6 (6C), 11.8 (3C).
20
Yield: 311 mg (98%); colorless viscous oil; [α]D –6.0 (c 1.17,
CHCl3).
IR (film): 3342, 2953, 1722, 1523, 1454, 1248, 1209, 1103, 1060,
1028, 912, 857, 834, 735, 696 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.37–7.33 (m, 5 H), 5.39–5.29 (m,
3 H), 5.10 (dd, J = 15.8, 12.2 Hz, 2 H), 4.41 (q, J = 7.3 Hz, 1 H),
3.73–3.66 (m, 2 H), 1.44 (d, J = 7.2 Hz, 3 H), 0.96 (t, J = 8.4 Hz,
2 H), 0.02 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 172.7, 155.5, 136.2, 128.5 (2C),
128.2, 128.1 (2C), 89.8, 68.1, 66.9, 49.6, 18.6, 18.0, –1.5 (3C).
HRMS (ESI+): m/z [M + H]+ calcd for C17H28NO5Si: 354.1737;
HRMS (ESI+): m/z [M + H]+ calcd for C27H38NO4Si: 468.2570;
found: 468.2581.
Boc-Aib-OSEM (3c)
To Boc-Aib-OH (1c; 200 mg, 0.99 mmol) in CH2Cl2 (3.45 mL) at
0 °C were added DCA (217 μL, 1.09 mmol) and SEMCl (193 μL,
1.09 mmol). Purification by flash chromatography (PE–EtOAc,
80:20).
found: 354.1748.
Yield: 251 mg (76%); colorless viscous oil.
Cbz-Ala-OTIPS (4a)
IR (film): 2978, 1713, 1503, 1366, 1249, 1163, 1076, 857, 834,
755 cm–1.
1H NMR (400 MHz, CDCl3): δ = 5.34 (s, 2 H), 3.70–3.74 (m, 2 H),
1.52 (s, 6 H), 1.43 (s, 9 H), 0.93–0.98 (m, 2 H), 0.02 (s, 9 H).
To Cbz-Ala-OH (1a; 200 mg, 0.90 mmol) in CH2Cl2 (3.00 mL) at
0 °C were added DCA (197 μL, 0.99 mmol) and TIPSCl (212 μL,
0.99 mmol). Purification by flash chromatography (PE–EtOAc,
95:5).
20
Yield: 314 mg (92%); colorless viscous oil; [α]D +5.0 (c 1.20,
CHCl3).
13C NMR (100 MHz, CDCl3): δ = 174.4, 154.4, 89.9, 79.6, 67.8,
56.1, 28.3 (3C), 25.2 (2C), 18.0, –1.5 (3C).
IR (film): 2946, 2868, 1705, 1455, 1341, 1240, 1213, 1189, 1065,
882, 750, 687, 667 cm–1.
HRMS (ESI+): m/z [M + H]+ calcd for C15H32NO5Si: 334.2050;
found: 334.2054.
Synthesis 2014, 46, 3075–3084
© Georg Thieme Verlag Stuttgart · New York

PAPER
Esterification of the Free α-Carboxylic Acid of Amino Acid Residues
3081
Boc-Aib-OTIPS (4c)
HRMS (ESI+): m/z [M + H]+ calcd for C22H36NO7Si: 454.2261;
found: 454.2273.
To Boc-Aib-OH (1c; 200 mg, 0.99 mmol) in CH2Cl2 (3.45 mL) at
0 °C were added DCA (217 μL, 1.09 mmol) and TIPSCl (233 μL,
1.09 mmol). Purification by flash chromatography (PE–EtOAc,
95:5).
Boc-Asp(Bn)-OTIPS (4e)
To Boc-Asp(Bn)-OH (1e; 200 mg, 0.62 mmol) in CH2Cl2 (2.15 mL)
at 0 °C were added DCA (150 μL, 0.68 mmol) and TIPSCl (146 μL,
0.62 mmol). Purification by flash chromatography (PE–EtOAc,
95:5).
Yield: 345 mg (97%); colorless viscous oil.
IR (film): 2946, 2869, 1704, 1497, 1454, 1384, 1366, 1306, 1249,
1156, 1069, 882, 732, 684, 648 cm–1.
1H NMR (400 MHz, CDCl3): δ = 5.30 (br s, 1 H), 1.53 (s, 6 H), 1.40
20
Yield: 273 mg (92%); colorless viscous oil; [α]D +17.8 (c 1.01,
CHCl3).
(s, 9 H), 1.27–1.34 (m, 3 H), 1.06 (d, J = 7.2 Hz, 18 H).
13C NMR (100 MHz, CDCl3): δ = 175.0, 154.3, 79.1, 56.9, 28.4
(3C), 25.0 (2C), 17.7 (6C), 11.9 (3C).
HRMS (ESI+): m/z [M + H]+ calcd for C18H38NO4Si: 360.2570;
found: 360.2568.
IR (film): 2946, 2868, 1716, 1497, 1366, 1352, 1214, 1162, 883,
735, 694 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.28–7.38 (m, 5 H), 5.57 (d, J =
5.6 Hz, 1 H), 5.13 (dd, JAB = 12.3 Hz, 2 H), 4.55–4.60 (m, 1 H), 3.06
(dd, J = 17.2, 4.3 Hz, 1 H), 2.88 (dd, J = 17.2, 4.6 Hz, 1 H), 1.43 (s,
9 H), 1.25–1.32 (m, 3 H), 1.05 (d, J = 7.6 Hz, 18 H).
13C NMR (100 MHz, CDCl3): δ = 171.0, 170.8, 155.3, 135.4, 128.5
(2C), 128.3 (3C), 79.8, 66.7, 50.7, 36.8, 28.3 (3C), 17.6 (6C), 11.9
(3C).
Boc-Thr-OSEM (3d)12
To Boc-Thr-OH (1d; 200 mg, 0.91 mmol) in CH2Cl2 (3.17 mL) at
0 °C were added DCA (199 μL, 1.00 mmol) and SEMCl (177 μL,
1.00 mmol). Purification by flash chromatography (PE–EtOAc,
75:25).
HRMS (ESI+): m/z [M + H]+ calcd for C25H42NO6Si: 480.2781;
20
found: 480.2805.
Yield: 264 mg (83%); colorless viscous oil; [α]D –11.9 (c 1.18,
CHCl3).
Fmoc-Phe-OSEM (3f)
1H NMR (400 MHz, CDCl3): δ = 5.41 (d, J = 9.2 Hz, 1 H), 5.34 (d,
J = 6.0 Hz, 1 H), 5.31 (d, J = 6.0 Hz, 1 H), 4.23–4.31 (m, 2 H),
3.67–3.71 (m, 2 H), 2.6 (br s, 1 H), 1.42 (s, 9 H), 1.23 (d, J = 6.8 Hz,
3 H), 0.91–0.93 (m, 2 H), –0.01 (s, 9 H).
To Fmoc-Phe-OH (1f; 200 mg, 0.52 mmol) in CH2Cl2 (1.80 mL) at
0 °C were added DCA (113 μL, 0.57 mmol) and SEMCl (100 μL,
0.57 mmol). Purification by flash chromatography (PE–EtOAc,
80:20).
20
HRMS (ESI+): m/z [M + H]+ calcd for C15H32NO6Si: 350.1999;
Yield: 231 mg (86%); colorless viscous oil; [α]D +19.7 (c 0.91,
found: 350.2003.
CHCl3).
IR (film): 2953, 1717, 1507, 1248, 908, 857, 834, 729, 699 cm–1.
Boc-Thr-OTIPS (4d)
1H NMR (400 MHz, CDCl3): δ = 7.78 (d, J = 7.5 Hz, 2 H), 7.58 (t,
J = 6.8 Hz, 2 H), 7.43 (t, J = 7.4 Hz, 2 H), 7.27–7.35 (m, 5 H), 7.16
(d, J = 6.6 Hz, 2 H), 5.39 (d, J = 6.0 Hz, 1 H), 5.34 (br s, 1 H), 5.33
(d, J = 6.0 Hz, 1 H), 4.71–4.76 (m, 1 H), 4.44–4.49 (m, 1 H), 4.33–
4.37 (m, 1 H), 4.23 (t, J = 7.1 Hz, 1 H), 3.67–3.72 (m, 2 H), 3.12–
3.24 (m, 2 H), 0.97 (t, J = 8.4 Hz, 2 H), 0.05 (s, 9 H).
To Boc-Thr-OH (1d; 200 mg, 0.91 mmol) in CH2Cl2 (3.17 mL) at
0 °C were added DCA (199 μL, 1.00 mmol) and TIPSCl (214 μL,
1.00 mmol). Purification by flash chromatography (PE–EtOAc,
90:10).
20
Yield: 318 mg (93%); colorless viscous oil; [α]D –2.7 (c 1.10,
CHCl3).
13C NMR (100 MHz, CDCl3): δ = 171.2, 155.5, 143.7, 143.6, 141.2
(2C), 135.5, 129.3 (2C), 128.6 (2C), 127.6 (2C), 127.1, 127.0 (2C),
125.1, 125.0, 119.9 (2C), 90.0, 68.3, 66.9, 54.7, 47.0, 38.0, 17.9,
–1.5 (3C).
HRMS (ESI+): m/z [M + H]+ calcd for C30H36NO5Si: 518.2363;
found: 518.2358.
IR (film): 3443, 2946, 2869, 1698, 1504, 1464, 1367, 1297, 1164,
1066, 882, 731, 672 cm–1.
1H NMR (400 MHz, CDCl3): δ = 5.26 (d, J = 9.0 Hz, 1 H), 4.24–
4.34 (m, 2 H), 1.45 (s, 9 H), 1.25–1.36 (m, 6 H), 1.08 (d, J = 7.3 Hz,
18 H).
13C NMR (100 MHz, CDCl3): δ = 171.3, 156.1, 79.8, 68.3, 59.6,
28.3 (3C), 20.2, 17.7 (6C), 11.9 (3C).
Fmoc-Phe-OTIPS (4f)
To Fmoc-Phe-OH (1f; 200 mg, 0.52 mmol) in CH2Cl2 (1.80 mL) at
0 °C were added DCA (113 μL, 0.57 mmol) and TIPSCl (122 μL,
0.57 mmol). Purification by flash chromatography (PE–EtOAc,
95:5).
HRMS (ESI+): m/z [M + H]+ calcd for C18H38NO5Si: 376.2519;
found: 376.2509.
Boc-Asp(Bn)-OSEM (3e)
To Boc-Asp(Bn)-OH (1e; 200 mg, 0.62 mmol) in CH2Cl2 (2.15 mL)
at 0 °C were added DCA (150 μL, 0.68 mmol) and SEMCl (121 μL,
0.68 mmol). Purification by flash chromatography (PE–EtOAc,
80:20).
20
Yield: 212 mg (75%); colorless viscous oil; [α]D +14.6 (c 1.03,
CHCl3).
IR (film): 2946, 2867, 1705, 1506, 1450, 1353, 1213, 1049, 908,
883, 728, 698 cm–1.
Yield: 242 mg (86%); colorless viscous oil; [α]D20 +9.4 (c 0.85, CH-
Cl3).
1H NMR (400 MHz, CDCl3): δ = 7.79 (d, J = 7.5 Hz, 2 H), 7.59 (t,
J = 7.5 Hz, 2 H), 7.43 (t, J = 7.4 Hz, 2 H), 7.23–7.35 (m, 7 H), 5.41
(d, J = 8.1 Hz, 1 H), 4.71–4.46 (m, 1 H), 4.44–4.48 (m, 1 H), 4.30–
4.35 (m, 1 H), 4.23 (t, J = 7.2 Hz, 1 H), 3.30 (dd, J = 13.9, 5.7 Hz,
1 H), 3.13 (dd, J = 14.0, 6.5 Hz, 1 H), 1.30–1.39 (m, 3 H), 1.09–
1.03 (m, 18 H).
13C NMR (100 MHz, CDCl3): δ = 171.3, 155.5, 143.7 (2C), 141.2
(2C), 136.0, 129.3 (2C), 128.5 (3C), 127.6 (2C), 126.9 (2C), 125.1,
125.0, 119.9 (2C), 66.9, 55.7, 47.0, 38.0, 17.7 (6C), 11.8 (3C).
IR (film): 2954, 1716, 1498, 1249, 1158, 1114, 908, 835, 729,
696 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.33–7.37 (m, 5 H), 5.49 (d, J =
8.7 Hz, 1 H), 5.34–5.28 (m, 2 H), 5.12 (dd, JAB = 12.3 Hz, 2 H),
4.57–4.63 (m, 1 H), 3.65–3.70 (m, 2 H), 3.07 (dd, J = 17.2, 4.8 Hz,
1 H), 2.88 (dd, J = 17.2, 4.8 Hz, 1 H), 1.44 (s, 9 H), 0.92–0.96 (m,
2 H), 0.01 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 170.7 (2C), 155.3, 135.3, 128.6
(2C), 128.4, 128.2 (2C), 90.1, 80.1, 68.0, 66.8, 50.0, 36.7, 28.2
(3C), 17.9, –1.5 (3C).
HRMS (ESI+): m/z [M + H]+ calcd for C33H42NO4Si: 544.2883;
found: 544.2892.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 3075–3084

3082
J.-S. Suppo et al.
PAPER
Boc-Lys(Boc)-OSEM (3g)
IR (film): 2945, 2869, 1717, 1498, 1465, 1283, 1200, 1067, 883,
733, 686 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.31–7.40 (m, 5 H), 5.55 (d, J =
9.6 Hz, 1 H), 5.13 (dd, JAB = 12.2 Hz, 2 H), 4.18–4.30 (m, 2 H),
1.26–1.33 (m, 3 H), 1.22 (d, J = 4.2 Hz, 3 H), 1.14 (s, 9 H), 1.08 (d,
J = 7.9 Hz, 18 H).
To Boc-Lys(Boc)-OH·DCHA (1g; 400 mg, 0.76 mmol) in CH2Cl2
(2.65 mL) at 0 °C was added SEMCl (149 μL, 0.84 mmol). Purifi-
cation by flash chromatography (PE–EtOAc, 80:20).
20
Yield: 297 mg (82%); colorless viscous oil; [α]D –2.7 (c 1.48,
CHCl3).
13C NMR (100 MHz, CDCl3): δ = 171.0, 156.6, 136.3, 128.5 (2C),
128.2 (2C), 128.1, 73.9, 67.2, 66.9, 61.1, 28.7, 17.7 (9C), 11.9 (3C).
IR (film): 3355, 2954, 1693, 1513, 1457, 1391, 1365, 1248, 1165,
1102, 857, 835 cm–1.
1H NMR (400 MHz, CDCl3): δ = 5.35–5.36 (m, 1 H), 5.28–5.29 (m,
1 H), 5.12 (br s, 1 H), 4.59 (br s, 1 H), 4.28 (br s, 1 H), 3.68–3.72
(m, 2 H), 3.08–3.11 (m, 2 H), 1.81–1.88 (m, 1 H), 1.61–1.70 (m,
1 H), 1.43 (s, 18 H), 1.36–1.52 (m, 4 H), 0.93–0.97 (m, 2 H), 0.01
(s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 172.5, 156.0, 155.5, 89.6, 79.9,
79.1, 68.1, 53.3, 40.0, 32.2, 29.5, 28.4 (3C), 28.3 (3C), 22.4, 18.0,
–1.5 (3C).
HRMS (ESI+): m/z [M + H]+ calcd for C25H44NO5Si: 466.2989;
found: 466.2991.
Cbz-Ala-(D)-Phe-OSEM (3i)
To Cbz-Ala-(D)-Phe-OH (1i; 100 mg, 0.27 mmol) in CH2Cl2 (1.70
mL) at 0 °C were added DCA (59 μL, 0.30 mmol) and SEMCl (53
μL, 0.30 mmol). Purification by flash chromatography (PE–EtOAc,
80:20).
20
Yield: 101 mg (75%); colorless viscous oil; [α]D –28.6 (c 0.84,
HRMS (ESI+): m/z [M + H]+ calcd for C22H45N2O7Si: 477.2996;
found: 477.2987.
CHCl3).
IR (film): 3313, 2953, 1723, 1662, 1498, 1454, 1247, 1100, 857,
834, 742, 702 cm–1.
Boc-Lys(Boc)-OTIPS (4g)
To Boc-Lys(Boc)-OH·DCHA (1g; 400 mg, 0.76 mmol) in CH2Cl2
(2.65 mL) at 0 °C was added TIPSCl (180 μL, 0.84 mmol). Purifi-
cation by flash chromatography (PE–EtOAc, 90:10).
1H NMR (400 MHz, CDCl3): δ = 7.22–7.35 (m, 10 H), 7.12 (d, J =
6.6 Hz, 1 H), 5.42 (d, J = 6.8 Hz, 1 H), 5.30 (dd, JAB = 6.0 Hz, 2 H),
5.09 (dd, JAB = 4.5 Hz, 2 H), 4.88 (m, 1 H), 4.25 (m, 1 H), 3.62–3.76
(m, 2 H), 3.06–3.20 (m, 2 H), 1.29 (d, J = 7.1 Hz, 3 H), 0.96 (m,
2 H), 0.03 (s, 9 H).
20
Yield: 344 mg (90%); colorless viscous oil; [α]D +1.2 (c 0.82,
CHCl3).
13C NMR (100 MHz, CDCl3): δ = 171.8, 171.0, 155.8, 136.1, 135.5,
129.3 (2C), 128.5 (4C), 128.1, 128.0 (2C), 127.1, 90.0, 68.3, 66.9,
52.9, 50.4, 37.6, 18.7, 17.9, –1.5 (3C).
HRMS: m/z [M + H]+ calcd for C26H37N2O6Si: 501.2421; found:
501.2421.
IR (film): 3357, 2944, 2868, 1692, 1512, 1461, 1365, 1248, 1165,
883, 733, 674 cm–1.
1H NMR (400 MHz, CDCl3): δ = 5.07 (br d, J = 7.8 Hz, 1 H), 4.55
(m, 1 H), 4.28 (m, 1 H), 3.10 (m, 2 H), 1.83–1.90 (m, 1 H), 1.62–
1.72 (m, 1 H), 1.45–1.60 (m, 3 H), 1.44 (s, 18 H), 1.25–1.36 (m,
5 H), 1.09 (d, J = 7.2 Hz, 18 H).
13C NMR (100 MHz, CDCl3): δ = 172.6, 156.0, 155.5, 79.6, 79.0,
54.2, 40.2, 32.4, 29.5, 28.4 (3C), 28.3 (3C), 22.5, 17.7 (6C), 11.8
(3C).
H2N-Ala-OSEM (5)
To Fmoc-Ala-OSEM (3b; 500 mg, 1.13 mmol) was added a solu-
tion of MeCN–Et2NH (90:10, c 0.1 M), and the mixture was stirred
for 1.5 h at 22 °C. Upon completion of the reaction (TLC monitor-
ing), the solvent and diethylamine were removed under vacuum and
the free amine 5 was keep under vacuum for 1 h before being used,
without further purification, to synthesize compounds 6 and 8 (see
below).
HRMS (ESI+): m/z [M + H]+ calcd for C25H51N2O6Si: 503.3516;
found: 503.3524.
Cbz-Thr(tBu)-OSEM (3h)
To Cbz-Thr(tBu)-OH·DCHA (1h; 600 mg, 1.22 mmol) in CH2Cl2
(7.00 mL) at 0 °C was added SEMCl (244 μL, 1.38 mmol). Purifi-
cation by flash chromatography (PE–EtOAc, 85:15).
Boc-Phe-Ala-OSEM (6)
To a solution of Boc-Phe-OH (451 mg, 1.70 mmol) in CH2Cl2 (c 0.5
M) were successively added DIPEA (787 μL, 4.52 mmol), PyBOP
(884 mg, 1.70 mmol) and H2N-Ala-OSEM (5; 248 mg, 1.13 mmol),
and the reaction was stirred at r.t. for 2 h. Upon completion of the
reaction (TLC monitoring), the mixture was washed with HCl (0.1
M; 5 mL) and the resulting aqueous phase was extracted with CH2-
Cl2 (3 × 5 mL). The organic phases were combined and washed
with a sat. aq NaHCO3 (2 × 10 mL), and the aqueous phase was fur-
ther extracted with CH2Cl2 (3 × 10 mL). The organic phases were
combined, washed with brine (20 mL), dried over MgSO4, and
evaporated under reduced pressure. Purification was performed by
column chromatography on silica gel (pentane–EtOAc, 80:20) to
give the desired dipeptide.
20
Yield: 498 mg (93%); colorless viscous oil; [α]D +4.6 (c 1.31,
CHCl3).
IR (film): 2976, 1726, 1505, 1249, 1195, 1087, 1066, 857, 834, 751,
695 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.31–7.40 (m, 5 H), 5.59 (d, J =
9.6 Hz, 1 H), 5.37 (d, J = 6.0 Hz, 1 H), 5.26 (d, J = 6.0 Hz, 1 H),
5.13 (dd, JAB = 12.0 Hz, 2 H), 4.21–4.26 (m, 2 H), 3.70–3.74 (m,
2 H), 1.22 (d, J = 6.0 Hz, 3 H), 1.11 (s, 9 H), 0.94–0.98 (m, 2 H),
0.02 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 170.9, 156.7, 136.3, 128.5 (2C),
128.2 (2C), 128.1, 90.2, 74.0, 68.3, 67.2, 67.0, 59.9, 28.4 (3C), 21.0,
17.9, –1.4 (3C).
Yield: 721 mg (91%); colorless oil; [α]D20 –4.0 (c 0.99, CHCl3).
IR (film): 3294, 2953, 1646, 1528, 1250, 1168, 1102 cm–1.
HRMS (ESI+): m/z [M + H]+ calcd for C22H38NO6Si: 440.2468;
1H NMR (400 MHz, CDCl3): δ = 7.19–7.31 (m, 5 H), 6.51 (br d, J =
6.8 Hz, 1 H), 5.34 (d, J = 6.1 Hz, 1 H), 5.27 (d, J = 6.1 Hz, 1 H),
5.00 (br s, 1 H), 4.49–4.56 (m, 1 H), 4.37–4.38 (m, 1 H), 3.65–3.74
(m, 2 H), 3.07 (d, J = 6.4 Hz, 2 H), 1.40 (s, 9 H), 1.37 (s, J = 7.2 Hz,
3 H), 0.93–0.97 (m, 2 H), 0.02 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 172.1, 170.8, 155.4, 136.5 (2C),
129.3, 128.5, 126.8 (2C), 89.7, 80.1, 68.0, 55.4, 48.1, 38.3, 28.2
(3C), 18.1, 17.9, –1.5 (3C).
found: 440.2462.
Cbz-Thr(tBu)-OTIPS (4h)
To Cbz-Thr(tBu)-OH·DCHA (1h; 500 mg, 1.02 mmol) in CH2Cl2
(5.85 mL) at 0 °C was added TIPSCl (240 μL, 1.12 mmol). Purifi-
cation by flash chromatography (PE–EtOAc, 95:5).
20
Yield: 346 mg (73%); colorless viscous oil; [α]D –16.0 (c 1.31,
CHCl3).
Synthesis 2014, 46, 3075–3084
© Georg Thieme Verlag Stuttgart · New York

PAPER
Esterification of the Free α-Carboxylic Acid of Amino Acid Residues
3083
HRMS (ESI+): m/z [M + H]+ calcd for C23H39N2O6Si: 467.2577;
found: 467.2572.
Boc-Phe-Ala-Ala-OSEM (10)
This tripeptide was prepared from Imi-Ala-OSEM 8 (176 mg, 0.56
mmol) and Boc-Phe-Ala-OH 7 (126 mg, 0.37 mmol) by following
the procedure described for 9.
Boc-Phe-Ala-OH (7)
This deprotection step was carried out by using Joullié’s condi-
tions.14 To a solution of dipeptide 6 (210 mg, 0.45 mmol) in CH2Cl2
(c 0.0178 M) at –20 °C was added MgBr2·OEt2 (349 mg, 1.35
mmol). After 30 min at this temperature, the solution was held for
an additional 2.5 h at 0 °C, then for 30 min at r.t. to allow complete
deprotection (TLC monitoring). The solution was extracted with
sat. aq NaHCO3 (15 mL), and the organic phase was discarded at
this stage. The basic aqueous layer was acidified with HCl (1 M)
and extracted with EtOAc (3 × 20 mL). The desired dipeptide free
carboxylic acid 7 (90% yield) was isolated as a white foam and used
without additional purification (see preparation of tripeptide 10).
Yield: 95 mg (48%); pale oil; [α]D20 –11.8 (c 1.02, CHCl3).
IR (film): 3304, 2953, 1660, 1532, 1248, 1099, 1046, 834 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.16–7.29 (m, 5 H), 6.93 (br d, J =
7.2 Hz, 1 H), 6.72 (br d, J = 6.8 Hz, 1 H), 5.37 (d, J = 6.0 Hz, 1 H),
5.28 (d, J = 6.0 Hz, 1 H), 5.10 (br d, J = 7.6 Hz, 1 H), 4.47–4.55 (m,
2 H), 4.38–4.39 (m, 1 H), 3.65–3.75 (m, 2 H), 3.00–3.10 (m, 2 H),
1.40 (d, J = 7.2 Hz, 3 H), 1.38 (s, 9 H), 1.32 (d, J = 7.0 Hz, 3 H),
0.92–0.97 (m, 2 H), 0.01 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 172.2, 171.3, 171.1, 141.0, 136.3,
129.3 (2C), 128.6 (2C), 127.0, 89.8, 80.4, 68.1, 55.7, 48.8, 48.2,
38.2, 28.2 (3C), 18.3, 18.0, 18.0, –1.5 (3C).
Imi-Ala-OSEM (8)5
The free amine product H2N-Ala-OSEM (5; 248 mg, 1.13 mmol)
was solubilized in CH2Cl2–THF (5:1 v/v, c 0.5 M) at r.t. Then, CDI
(272 mg, 1.68 mmol) was added and the reaction was stirred over-
night. Upon completion of the reaction, the mixture was washed
with H2O (10 mL), the organic phase was separated and the aqueous
phase was further extracted with CH2Cl2 (2 × 15 mL). The organic
layers were combined, dried over MgSO4, and evaporated under re-
duced pressure. Imi-Ala-OSEM 8 was purified through a short plug
of silica gel (EtOAc–pentane, 70:30) and isolated.
HRMS (ESI+): m/z [M + H]+ calcd for C26H44N3O7Si: 538.2949;
found: 538.2952.
Acknowledgment
R.M.F. thanks the Agence Nationale de la Recherche (ANR) Pro-
gram JCJC Edition 2012 (PhD grant of J.S.S., project NIPS ANR-
12-JS07-0008-01) and the CAPES-FAPESP (PhD grant of D.P.S.,
project FAPESP 2012/11220-9).
Yield: 279 mg (79%); pale oil; [α]D20 +11.2 (c 0.89, CHCl3).
IR (film): 3216, 2953, 1721, 1548, 1249, 1098 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.17 (s, 1 H), 7.41 (br t, J = 1.4 Hz,
1 H), 7.17 (br d, J = 7.1 Hz, 1 H), 7.07 (s, 1 H), 5.41 (d, J = 6.0 Hz,
1 H), 5.34 (d, J = 6.0 Hz, 1 H), 4.62–4.70 (m, 1 H), 3.67–3.77 (m,
2 H), 1.55 (d, J = 7.2 Hz, 3 H), 0.93–0.97 (m, 2 H), 0.01 (s, 9 H).
Supporting Information for this article is available online
at
http://www.thieme-connect.com/products/ejournals/journal/
10.1055/s-00000084.SunogIpimrfiantoSuIpg
n
fonirtat
ori
13C NMR (100 MHz, CDCl3): δ = 172.2, 148.6, 136.1, 129.6, 116.4,
89.9, 68.1, 49.6, 17.9, 17.4, –1.6 (3C).
HRMS (ESI+): m/z [M + H]+ calcd for C13H24N3O4Si: 314.1536;
References
(1) Barany, G.; Merrifield, R. B. J. Am. Chem. Soc. 1977, 99,
7363.
(2) Barany, G.; Albericio, F. J. Am. Chem. Soc. 1985, 107, 4936.
(3) Isidro-Llobet, A.; Álvarez, M.; Albericio, F. Chem. Rev.
2009, 109, 2455; and references cited therein.
found: 314.1535.
Cbz-Met-Ala-OSEM (9)5
To a solution of Imi-Ala-OSEM (8; 131 mg, 0.42 mmol) in CH2Cl2
(c 1.0 M) at r.t. were successively added HOBt (6.40 mg, 0.042
mmol) followed by Cbz-Met-OH (178 mg, 0.63 mmol), and the
mixture was stirred at r.t. for 20 h. Upon completion of the reaction
(TLC monitoring), the mixture was washed with aq HCl (0.1 M;
5 mL) and the aqueous phase was extracted with CH2Cl2
(2 × 10 mL). The organic layers were combined, washed with sat.
aq NaHCO3 (2 × 10 mL) and brine (20 mL), dried over MgSO4, and
the solvent was evaporated under reduced pressure. Purification
was performed by column chromatography on silica gel (pentane–
EtOAc, 80:20) to give the desired dipeptide.
(4) For selected examples, see: (a) Arrieta, A.; Garcia, T.;
Palomo, C. Synth. Commun. 1982, 12, 1139.
(b) Balasubramaniyan, V.; Bhatia, V. G.; Wagh, S. B.
Tetrahedron 1983, 39, 1475. (c) Widmer, U. Synthesis 1983,
135. (d) Brook, M. A.; Chan, T. H. Synthesis 1996, 201.
(e) Arai, I.; Muramatsu, I. J. Org. Chem. 1983, 48, 121.
(f) Koŧodziejczyk, A. M.; Slebjoda, M. Synthesis 1984, 866.
(g) Lalezari, I.; Lalezari, P. U.S. Pat. Appl. Publ US
20140142279 A1, 2014.
(5) Suppo, J.-S.; Subra, G.; Bergès, M.; Marcia de Figueiredo,
R.; Campagne, J.-M. Angew. Chem. Int. Ed. 2014, 53, 5389.
(6) For a general review on the use or organosilicon reagents as
protecting groups in organic synthesis, see: Lalonde, M.;
Chan, T. H. Synthesis 1985, 817.
(7) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 4th ed.; John Wiley and Sons: Hoboken, 2007.
(8) (a) Sieber, P. Helv. Chim. Acta 1977, 60, 2711. (b) Sieber,
P.; Andreatta, R. H.; Eisler, K.; Kamber, B.; Riniker, B.;
Rink, H. In Peptides, Proceedings of the 5th American
Peptide Symposium; Goodman, M.; Meienhofer, J., Eds.;
Wiley: New York, 1977, 543.
(9) (a) With DCC: Schmidt, U.; Zäh, M.; Lieberknecht, A.
J. Chem. Soc., Chem. Commun. 1991, 1002. (b) With DIC:
Fécourt, F.; Sapi, J.; Bourguet, E. Synlett 2010, 399. With
EDCI: (c) Boger, D. L.; Yohannes, D. J. Org. Chem. 1990,
55, 6000. (d) Wang, T.; Danishefsky, S. J. J. Am. Chem. Soc.
2012, 134, 13244. (e) Banala, S.; Ensle, P.; Süssmuth, R. D.
Angew. Chem. Int. Ed. 2013, 52, 9518.
Yield: 142 mg (70%); white solid; [α]D20 –3.80 (c 1.04, CHCl3).
IR (film): 3302, 2953, 1661, 1536, 1249, 1103, 1051 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.29–7.34 (m, 5 H), 6.79 (br d, J =
7.1 Hz, 1 H), 5.63 (br d, J = 8.2 Hz, 1 H), 5.37 (d, J = 6.0 Hz, 1 H),
5.28 (d, J = 6.0 Hz, 1 H), 5.06–5.13 (m, 2 H), 4.51–4.60 (m, 1 H),
4.39–4.49 (m, 1 H), 3.65–3.75 (m, 2 H), 2.59 (t, J = 7.2 Hz, 2 H),
1.97–2.09 (m, 5 H), 1.42 (d, J = 7.2 Hz, 3 H), 0.93–0.97 (m, 2 H),
0.01 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 172.1, 170.8, 156.0, 136.1, 128.4
(2C), 128.1, 128.0 (2C), 89.8, 68.0, 67.0, 53.5, 48.1, 31.8, 29.3,
18.8, 17.9, 15.0, –1.5 (3C).
HRMS (ESI+): m/z [M + H]+ calcd for C22H37N2O6SiS: 485.2142;
found: 485.2147.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 3075–3084

3084
J.-S. Suppo et al.
PAPER
order to reach higher yields, but there is no need for
(10) Wagner, M.; Kunz, H. Synlett 2000, 400.
(11) Borsuk, K.; van Delft, F. L.; Eggen, I. F.; ten Kortenaar, P.
B. W.; Petersen, A.; Rutjes, P. J. T. Tetrahedron Lett. 2004,
45, 3585.
(12) Li, W.-R.; Ewing, W. R.; Harris, B. D.; Joullié, M. M. J. Am.
Chem. Soc. 1990, 112, 7659.
(13) Jou, G.; Gonzàlez, I.; Albericio, F.; Lloyd-Williams, P.;
Giralt, E. J. Org. Chem. 1997, 62, 354.
(14) Chen, W.-C.; Vera, M. D.; Joullié, M. M. Tetrahedron Lett.
1997, 38, 4025.
(15) Soto-Cairoli, B.; Kock, I.; de Pomar, J. J.; Yang, G.;
Guzmán, J. M.; González, J. R.; Antomattei, A.; Soderquist,
J. A. Heterocycles 2010, 80, 409.
(16) Bridoux, A.; Cui, H.; Dyskin, E.; Schmitzer, A.-R.; Yalcin,
M.; Mousa, S. A. Bioorg. Med. Chem. Lett. 2010, 20, 3394.
(17) Nefkens, G. H. L.; Thuring, J. W. J. F.; Zwanenburg, B.
Synthesis 1997, 290.
(18) Selected examples: (a) Schnabel, E.; Klostermeyer, H.;
Berndt, H. Justus Liebigs Ann. Chem. 1971, 749, 90.
(b) Akaji, K.; Fujii, N.; Yajima, H. Chem. Pharm. Bull.
1985, 33, 173. (c) Huffman, G. W.; Gesellchen, P. D.;
Turner, J. R.; Rothenberger, R. B.; Osborne, H. E.; Miller, F.
D.; Chapman, J. L.; Queener, S. W. J. Med. Chem. 1992, 35,
1897. (d) Bachi, M. D.; Breiman, R. J. Chem. Soc., Perkin
Trans. 1 1980, 11.
pretreatment of the SiO2 with Et3N.
(22) Paterson, I.; Britton, R.; Delgado, O.; Gardner, N. M.;
Meyer, A.; Naylor, G. J.; Poullennec, K. G. Tetrahedron
2010, 66, 6534.
(23) For compound 1h (Novabiochem Merck Millipore
Corporation): described [α]D25 +7.7 (c 1.0, EtOH); found
after protection and deprotection with TIPSCl [α]D20 +9.3 (c
1.07, EtOH). For compound 1b (Sigma–Aldrich): described
[α]D20 –18 (c 1.0, DMF); found after protection and
deprotection with SEMCl [α]D20 –19.2 (c 1.0, DMF), and
with TIPSCl [α]D20 –19.8 (c 1.0, DMF). For compound 1j
(Sigma–Aldrich): described [α]D20 –44±1 (c 1.0, HOAc);
20
found after protection and deprotection with SEMCl [α]D
–45.3 (c 1.0, HOAc) and with TIPSCl [α]D20 –44.9 (c 1.0,
HOAc).
(24) Li, H.; Jiang, X.; Ye, Y.-h.; Fan, C.; Romoff, T.; Goodman,
M. Org. Lett. 1999, 1, 91.
(25) Joullié, M. M.; Lassen, K. M. ARKIVOC 2010, (viii), 189.
(26) El-Faham, A.; Albericio, F. Chem. Rev. 2011, 111, 6557.
(27) We have tried without success: Boc case: TFA–CH2Cl2
(50:50), HCl (4 M) in dioxane at r.t. or 0 °C. Fmoc case:
DMF–piperidine (80:20, 90:10, or 95:5), MeCN–Et2NH
(90:10). Cbz case: H2, Pd/C (10 mol%) in EtOAc or
methanol.
(19) Bodansky, M. In Principles of Peptide Synthesis; Hafner, K.;
Lehn, J.-M.; Rees, C. W.; Schleyer, P. v. R.; Trost, B. N.;
Zahradnik, R., Eds.; Springer-Verlag: Berlin, 1994.
(20) It might be mentioned that Fmoc-protected amino acids were
robust to the optimized reaction conditions. When only 1.1
equiv of DCA was used as the base to promote our
esterification, no Fmoc-cleavage was observed.
(21) It should be noted that O-SEM derivatives are less robust
than their O-TIPS parents towards long column
chromatography purification on silica gel. With O-SEM
analogues, short pad column purifications are suggested in
(28) For examples of chemoselective Cbz-urethane deprotection
in the presence of O-SEM amino esters, see:
(a) Pfizenmayer, A. J.; Ramanjulu, J. M.; Vera, M. D.; Ding,
X.; Xiao, D.; Chen, W.-C.; Joullié, M. M. Tetrahedron 1999,
55, 313. (b) See also ref. 12. (c) For one example of
chemoselective OBn ether deprotection, see ref. 13.
(29) (a) Coste, J.; Le-Nguyen, D.; Castro, B. Tetrahedron Lett.
1990, 31, 205. (b) Frérot, E.; Coste, J.; Pantaloni, A.;
Dufour, M.-N.; Jouin, P. Tetrahedron 1991, 47, 259.
(c) Campagne, J.-M.; Coste, J.; Jouin, P. Tetrahedron Lett.
1993, 34, 6743.
Synthesis 2014, 46, 3075–3084
© Georg Thieme Verlag Stuttgart · New York