Constrained Cyclic β,γ-Diamino Acids from Glutamic Acid: Synthesis of Both Diastereomers and Unexpected Kinetic Resolution

Article abstract of DOI:10.1002/ejoc.201701477

We describe here an efficient synthesis of both diastereomers of cyclic β,γ-diamino acids starting from l-glutamic acid, based on the Blaise reaction. We show that by changing the protecting group, we can access either the five-membered-ring lactam, which

Full text of DOI:10.1002/ejoc.201701477

A Journal of
Accepted Article
Title: New constrained cyclic beta,gamma-diamino acids from glutamic
acid: synthesis of both diastereomers and unexpected kinetic
resolution.
Authors: Valérie Alezra, Yang Wan, Nicolas Auberger, Sophie Thétiot-
Laurent, Francelin Bouillère, Anaïs Zulauf, Jiefang He,
Stéphanie Courtiol-Legourd, Régis Guillot, Cyrille Kouklovsky,
Sylvain Cote des Combes, Christophe Pacaud, and Ingrid
Devillers
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201701477
Link to VoR: http://dx.doi.org/10.1002/ejoc.201701477
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10.1002/ejoc.201701477
European Journal of Organic Chemistry
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New constrained cyclic -diamino acids from glutamic acid:
synthesis of both diastereomers and unexpected kinetic
resolution.
Yang Wan,[a] Nicolas Auberger,[a] Sophie Thétiot-Laurent,[a] Francelin Bouillère,[a] Anaïs Zulauf,[a]
Jiefang He,[a] Stéphanie Courtiol-Legourd,[a] Régis Guillot,[a] Cyrille Kouklovsky,[a] Sylvain Cote des
Combes,[b] Christophe Pacaud,[b] Ingrid Devillers,[b] and Valérie Alezra*[a]
Abstract: We describe here an efficient synthesis of both
diastereomers of cyclic -diamino acids starting from L-glutamic
acid based on Blaise reaction. We showed that by changing the
protecting group, we could have access to either 5-member ring
lactam, which can be used as -amino acid, or to 6-member ring
lactam, as -amino acid. We also discovered an interesting kinetic
resolution during the synthesis which allowed easier diastereomer
separation. These compounds can be easily used in peptide
synthesis and a tetramer alternating trans cyclic -amino acid and
AIB has been synthesized.
-amino acid or -amino acid building block for foldamers. The
presence of second nitrogen would either allow further
functionalization or supplementary hydrogen bonding or
hydrosolubility enhancement. We have already developed a
strategy based on Blaise reaction[29] and described the
asymmetric synthesis of acyclic -diamino acids and of the
pentacyclic lactam 3 derived from aspartic acid (Scheme 1).
Alternating this -amino acid with AIB led to a family of hybrid
-peptides which were able to adopt stable extended helix
conformation in solution, without any hydrogen bond.[23]
Introduction
Proteinogenic and non proteinogenic amino acids are of great
interest for organic and bioorganic chemists, due to their huge
biological significance. Among these amino acids, cyclic ones
occupy a special place as they are conformationally constrained
and thus are responsible for special conformational features of
peptides. For example, the natural -amino acid, L-proline is
known to form poly-proline helices[1] or to generate turns when
associated with glycine. In the field of foldamers, cyclic -amino
acids or -amino acids have been extensively studied and
incorporated in peptides to induce the folding into new
conformations.[2–9] A large variety of helices,[10–14] turns,[15]
sheets[16] and ribbons[17,18] were thus observed, even in the less
explored domain of -peptides. Moreover, this kind of
preorganization seems to be crucial to get secondary structures
stable in water.[19] In our group, we are interested for a few years
in the synthesis and use of -diamino acids.[20–25] This pattern
is present in some biologically active compounds such as
Scheme 1. Synthesis of -diamino acids from aspartic acid.
Therefore, we were then interested in the synthesis of the 6-
membered analogue of compound 3, starting from glutamic acid
(Scheme 2). We wanted to have access to both diastereomers
to be able to study later the impact of the configuration on the
conformation of peptides.[14] This kind of compounds is highly
functionalized and we needed to pay special attention to
protecting groups. We describe here our results in the synthesis
of the two orthogonally protected diastereomers of compound 4.
We were also able to have access to both diastereomers of the
cyclic -amino acid 6, in a chemodivergent process.
pseudotheonamide
A1,[26]
aminocarnitine[27]
or
deoxyaminostatine[28] but its main interest lies in its use as either
[a]
Laboratoire de Méthodologie, Synthèse et Molécules
Thérapeutiques, ICMMO,
UMR 8182, CNRS,
Univ. Paris-Sud,
Université Paris-Saclay,
Faculté des Sciences d’Orsay Bât 410, Orsay, F-91405 France
Department
Institution
Address 1
E-mail: Valerie.alezra@u-psud.fr
Sanofi Recherche et Développement,
1 avenue Pierre Brossolette, F-91385 Chilly Mazarin cedex, France
[b]
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201701477
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Table 1. Synthesis of monoprotected nitriles 10
Conditions Yield Conditions Yield Conditions Yield
P
Comp.
8 (%)
9 (%)
10 (%)
[a]
Boc Boc2O,
NaHCO3,
H2O/dioxane
Cbz ClCO2Bn,
Na2CO3,
98
ClCO2Et,
-
POCl3,
61 (2 10a
Et3N, THF
then NH4OH
ClCO2Et,
Et3N, THF
then NH4OH
CDI, THF 73
then NH3(g)
or NH4OH
CDI, THF 62
then NH3(g)
CDI, CH2Cl2 88
then NH4OH
pyridine
steps)
[a]
88
79
-
POCl3,
pyridine
69 (2 10b
steps)
H2O/dioxane
Ts
Ns
TsCl, Et3N,
H2O/dioxane
TFAA,
Et3N, THF
95
10c
NsCl, Et3N,
63
65
TFAA,
Et3N, THF
TFAA,
64
10d
10e
H2O/dioxane
Scheme 2. Retrosynthetic scheme of 6-membered ring -diamino acid 4 and
structure of 5-membered ring -diamino acid 6.
SES TMSCl,
CH2Cl2 then
Et3N, SESCl
Alloc AllocCl,
NaHCO3 H2O
100
Et3N, THF
92
ClCO2Et,
Et3N, THF
then NH4OH
84
TFAA,
Et3N, THF
77
10f
Results and Discussion
The first step was the synthesis of protected nitriles 10.
Following our previous work, we first planned to use carbamates.
For aspartic acid, Blaise reaction was performed on
[a] Compounds 9a,b are impure compounds, the yield was reported for the
final compounds 10a,b.
monoprotected nitrile
1
and nucleophilic attack of the
iminozincate intermediate occurred on methylester leading to the
formation of 5-membered compound 2. Only traces of
nucleophilic attack on carbamate moiety were observed, the
ester being more electrophilic than the carbamate. Nevertheless
for glutamic acid derivative 10, there could be competition
between nucleophilic attack onto the ester, leading to a 6-
membered lactam and nucleophilic attack onto the carbamate
leading to a 5-membered cyclic urea (see below, table 2). Thus,
non-electrophilic sulfonyl protecting groups were also used. The
results are gathered in Table 1. Six different monoprotected
nitriles 10 were synthesized in good yield under classical
conditions.
We then used our previously optimized conditions to perform
Blaise reaction on the various nitriles (Table 2). With Cbz and
Boc protecting group cyclic urea 12a,b was not surprisingly
formed but the global yield of lactam 5a,b and urea 12a,b was
disappointingly low. Reaction was efficient for compound 10c
(tosyl protection) affording 5c (along with still some starting
material) but Ns (nosyl) protected derivative 10d was not
compatible with the Blaise reaction conditions and no expected
product could be isolated. The use of SES (2-
(trimethylsilyl)ethanesulfonyl), which is in principle easily cleaved,
led to lactam 5e in a very low yield and further SES-nitrogen
deprotection led to degradation. Unexpectedly, use of Alloc
(allyloxycarbonyl) protecting group led to formation of the lactam
5f from 10f along with the deprotected 5-membered ring lactam
13 with a global yield for these two compounds of 62%. The
structure of compound 13 was unambiguously determined at the
next step. The formation of compound 13 results probably from
in situ Alloc deprotection and subsequent cyclization, the -
amino group (sp3 nitrogen) being more nucleophilic with respect
to the -one (sp2 nitrogen), and 5-membered ring formation
being more rapid than 6-membered ring one.
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10.1002/ejoc.201701477
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Fortunately one of the two diastereomers of 15 crystallized and
allowed the determination of its absolute configuration (Figure 1).
Figure 1. Crystallographic structure of compound (S,S)-15..
Thus we successfully had access to both diastereomers of
compound 15, which can be used as functionalized and
constrained -amino-acids (see the work of Sharma’s
group[30,31]). As our initial target was the 6-membered ring lactam,
we try to either de-tosylate the mixture of diastereomers 14 or to
introduce a second protecting group to be able to separate them.
At this stage, on the mixture of diastereomers, we were not able
to deprotect the -amine function with usual (Mg/MeOH), or
strong reductant (Red-Al) Ts cleavage conditions. On the
contrary, benzylation of the mixture of diastereomers 14 was
achieved in good yield but the diastereomers 16 were again
inseparable. We turned then our attention towards
Table 2. Blaise reaction on nitriles 10a-10f.
Nitrile
P
Lactam
Yield 5 (%)
Urea
Yield 12
(%)
Yield
13 (%)
10a
10b
10c
10d
10e
10f
Boc
Cbz
Ts
Ns
SES
Alloc
5a
5b
5c
5d
5e
5f
18
8
49
12a
12b
12c
12d
12e
13f
13
25
-
-
-
-
-
-
-
degradation
<10%
20
-
42
We then attempted reduction on lactams 5c and 13 (Scheme 3).
Hydrogenation with Pd/(OH)2 of compound 5c gave access to an
inseparable mixture of diastereomers 14 (dr = 70:30) in 85%
yield (just a few amount of the less polar compound, major
diastereomer, whose configuration was further assigned to
(R,S)-14, could be isolated as pure compound by
chromatography). Reduction with sodium cyanoborohydride was
then performed on compound 13. It gave access to both
diastereomers of compound 15 in 86% yield. These
diastereomers are separable by chiral HPLC or after Fmoc
protection by SFC HPLC.
benzylcarbamate protection. Various conditions were tested.[32]
.
We observed in several cases the formation, along with the
expected product, of the benzylated compound 16, arising
probably from degradation of the chloroformate in the reaction
conditions. N-carbamoylation was finally successfully achieved
by using NaH as a base and CbzCl (Scheme 4). In that case, we
observed a kinetic resolution: only diastereomer (R,S) was
carbamoylated whereas the minor one remained unreactive.
These two compounds had then very distinct polarity and were
easily separated by chromatography. Probably the minor
diastereomer is more hindered and therefore more difficult to
carbamoylate. With this method, we had thus obtained
separately both diastereomers of the 6-membered ring lactam.
NOESY experiment allowed us to determine the relative
configuration of both diastereomers 14, which was confirmed by
the crystallographic structure of the isolated minor diastereomer
(Figure 2).
Scheme 4. Kinetic resolution by carbamoylation of compound 14.
Scheme 3. Reduction of enaminoesters 5c and 13.
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10.1002/ejoc.201701477
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we did not find satisfactory explanation for this result.[36]
Hydrogenation gave access to compound 21 as an inseparable
mixture of roughly 1:1 diastereomers. After Cbz protection with
an excess of NaH (no kinetic resolution occurred in that case),
the two diastereomers 22 were easily separated by
chromatography and then compounds (R,S)-21 and (S,S)-
21 were regenerated as separated compounds.
Figure 2. Crystallographic structure of compound (S,S)-14.
The final steps consisted in deprotection of the Ts group.
[33]
Removal was performed with KPPh2 on compounds (R,S)-
17 leading to the constrained -amino acid 18 orthogonally
protected for peptide synthesis (Scheme 5). The isolated minor
diastereomer (S,S)-14 could be protected by a benzyl group in
70% yield with BnBr and K2CO3 in refluxing acetonitrile overnight
(introduction of a benzylcarbamate was not possible, even on
the isolated diastereomer). Unfortunately, for the minor
diastereomer, neither (S,S)-14, nor (S,S)-16 can be de-
tosylated (several conditions for Ts removal were tested: KPPh2,
Sodium or Lithium /naphthalene, CsF-celite, SmI2, DMPU, THF
or SmI2, pyrrolidine/water…).
Scheme 5. Tosyl removal on diprotected lactam (R,S)-16.
Furthermore, the synthesis of a five-membered ring analogue of
compound 2 (Boc protecting group instead of Cbz) was recently
published.[34] the authors used our strategy to get this fragment
of Microsclerodermine B and J and completed the total synthesis.
In their approach, they started from N-Boc-L-aspartic acid 4-
benzyl ester and got the corresponding lactam in higher yield
than we did. We thus decided to investigate again Boc
protection and repeated the synthesis starting from commercially
available L-glutamic acid 4-benzyl ester. The synthesis is
described below (Scheme 6). This strategy was much more
efficient: nitrile 20[35] was obtained in higher yield than before
(compare with compound 10a or 10c with tosyl protection) and
Blaise reaction was also more efficient and afforded expected
compound 5a in comparable yield with respect to the tosylate 5c.
Benzyl ester group obviously favored the nucleophilic attack of
iminozincate on ester group instead of carbamate (and
consequently prevent the degradation of the intermediate,
observed for compound 10a, leading to a better overall yield) but
Scheme 6. Alternative strategy starting from (S)-19.
The relative configuration of compound 22 (and consequently
21) was determined by chemical correlation with compound
(R,S)-18 deriving from (R,S)-16 (see scheme 4): this later
was Boc-protected to get pure compound (R,S)-22.
Comparison with NMR data showed unambiguously that the
more polar isomer of compound 21 corresponded to (R,S)-21
stereochemistry.
We then wanted to check that the -diamino acid is readily
usable for peptide synthesis and we used major trans
diastereomer (R,S)-18 to perform peptide coupling. Alternating
the -diamino acid and AIB, we obtained efficiently tetramer 24
in pure form by a [2+2] strategy (Scheme 7). Proton NMR of this
compound in methanol-d4 showed slow exchange for some
amides NH (NH5, NH8 and NH13) indicating that they may be
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10.1002/ejoc.201701477
European Journal of Organic Chemistry
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involved in hydrogen bonds. Moreover, long distance NOE Conclusions
correlations are also observed in methanol-d3 (Figure 3). This
could be significant of the formation of 12-helical secondary
structure[19] (Hydrogen bonds between NH5 and CO14, and NH8
and CO of Cbz) and not of a 12/10-helix as observed by
Gellman in a similar peptide.[14] In that case, the resistance to
H/D exchange of NH13 could partially be explained by a steric
shield from solvent in a folded conformation. Further elongation
and structural determination are under investigation.
In conclusion, we developed starting from L-glutamic acid a
synthesis of several 5- or 6-membered ring orthogonally
protected constrained -diamino acids. Depending on the N-
protecting group of compound 10, we were able to direct the
reaction toward the six-membered ring (PG = Ts, Boc) or five-
membered ring (PG = Alloc). During our investigation, we
discovered an interesting kinetic resolution of a mixture of
diastereomers allowing easier separation, when starting from 14.
We have also shown that the trans -diamino acid 24 could be
easily coupled with AIB. According to the literature data, these
amino acids either - with 5-member ring substituent[30,31] or -
with 6-member ring[10,12,14] possess a strong potential in inducing
interesting conformations when inserted in peptide sequences
and we are currently investigating this point.
Experimental Section
General
Unless otherwise stated, all reactions were conducted under an
atmosphere of dry argon gas. THF was distilled over
sodium/benzophenone under argon. Dimethylformamide was
purchased from Acros with a peptide synthesis grade. All other
reagents were used as received. Flash chromatography was
performed on Kieselgel 60 (35-70
m) silica gel. Infrared spectra
were recorded in dichloromethane (5mM) on an FT-IR
spectrophotometer. H1 NMR were measured at 250, 300, 360 or
400 MHz using CDCl3, CD3OD and DMSO-d6 as solvents. Chemical
shifts are reported in units to 0.01 ppm precision with coupling
constants reported to 0.1 Hz precision using residual solvent as an
internal reference.
Multiplicities are reported as follows: s = singlet, d = doublet, t =
triplet, q = quadruplet, m = multiplet, bs = broad singlet. 13C NMR
were measured at 63, 75, 90 or 100 MHz using CDCl3, CD3OD and
DMSO-d6 as solvents. Chemical shifts are reported in units to 0.1
ppm precision using residual solvent as an internal reference. Mass
spectra were measured on
a Microtof-Q Bruker Daltonics
spectrometer at the Institut de Chimie Moléculaire et des Matériaux
(ICMMO) Mass Spectrometry Laboratory. For LCMS at Sanofi R&D,
mass spectra were measured for method A on Waters HPLC/ZQ
apparatus with method Acetate Kromasil C18 2.1x50mm 3.5µm
0.8ml/mn 0 to 100% B(CH3CN) in 10mn ; for method B on Waters
UPLC/SQD Acquity apparatus with method BEH C18 2.1X50mm
1.7µm 1.0ml/mn 5 to 100%B(CH3CN) with 0.1% AF in 3mn.
Scheme 7. Synthesis of tetramer 24.
(S)-5-Methoxy-2-(4-methylphenylsulfonamido)-5-oxopentanoic
acid 8c
To a solution of compound
7 H-L-Glu(OMe)-OH (478 mg, 2.96
mmol, 1 equiv.) in a mixture water/1,4-dioxane 1/1 (v/v, 20 mL) was
added triethylamine (1.24 mL, 8.89 mmol, 3 equiv.) and p-toluene
sulfonylchloride (565 mg, 2.96 mmol, 1 equiv.) at 0 °C. The
resulting mixture was stirred for 24 h at room temperature. The
volatile was removed. The aqueous layer was washed with diethyl
ether, acidified to pH=1 with 6N HCl aqueous solution, and then
extracted 3 times with ethyl acetate. These organic layers were
combined, dried on anhydrous MgSO4 and concentrated under
reduced pressure. Purification over silica gel with 50%
cyclohexane/ethyl acetate give pure compound 8c (737 mg) in 79%
Figure 3. NOE signals observed between long range protons (red = medium,
green = weak).
20
yield. [α]D = +16 (c = 0.3, CH3OH). 1H NMR (360 MHz, CDCl3):
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7.73 (d, J = 8.1 Hz, 2H), 7.30 (d, J = 8.1 Hz, 2H), 6.84 (bs, 1H),
5.49 (d, J = 8.7 Hz, 1H), 3.91 (dt, J = 6.9 Hz, J = 8.7 Hz, 1H), 3.68
(s, 3H), 2.55-2.39 (m, 2H), 2.46 (s, 3H), 2.22-2.13 (m, 1H), 1.98-
52.1, 30.3, 27.4. HRMS (m/z, ESI) calcd for C10H15NNaO6
([M+Na]+) 268.0792, found 268.0786.
1.88 (m, 1H). 13C NMR (90 MHz, CDCl3):

175.0, 173.4, 144.0,
(S)-Methyl 5-amino-4-((tert-butoxycarbonyl)amino)-5-
oxopentanoate 9a[38]
136.3, 129.8, 127.2, 54.6, 52.0, 29.5, 28.0, 21.6. HRMS (m/z, ESI)
calcd for C13H17NNaO6S ([M+Na]+): 338,0674, found 338.0666.
To a stirred solution of Boc-L-Glu(OMe)-OH 8a (1.46g, 5.6 mmol, 1
equiv.) in anhydrous THF (120 mL)was added triethylamine (0.86
mL, 6.15 mmol, 1.1 equiv.) at 0°C. The mixture was stirred at 0°C
for 15 min and ethyl chloroformate (0.59 mL, 6.15 mmol, 1.1 equiv.)
was added. The mixture was stirred for 30 min at 0°C. A 1/1 (v/v)
solution of tetrahydrofuran/ammonium hydroxide (3.58 mL) was
added and the mixture was stirred at 0°C for 30 min. Water was
added to the mixture and the aqueous layer was extracted with
diethyl ether 3 times. The organic layer was dried over magnesium
sulfate, filtered and concentrated, affording 9a (1.071 g) with
impurities (urethane) and engaged without further purification in the
(2S)-5-Methoxy-2-[(4-nitrophenyl)sulfonylamino]-5-oxo-
pentanoic acid 8d
To a solution of compound
7 H-L-Glu(OMe)-OH (14.8 g, 91.8 mmol,
1 equiv.) in a mixture water/1,4-dioxane 1/1 (v/v, 440 mL) was
added triethylamine (38.4 mL, 275.5 mmol, 3 equiv.) and p-
nitrophenyl sulfonylchloride (22.8 g, 101 mmol, 1.1 equiv.) at 0 °C.
The resulting mixture was stirred for 48 h at room temperature. The
reaction mixture was diluted with ethyl acetate (180 mL) and after
addition of 3 spoons of NaCl solid, the aqueous layer was
separated, acidified to pH=2-3 with 6N HCl aqueous solution, and
then extracted 3 times with ethyl acetate. These organic layers
were combined, dried on anhydrous MgSO4 and concentrated
under reduced pressure to yield a yellow solid 8d (20.22 g) in 63%
yield which was used directly in the next step without any further
1
next step. H NMR (360 MHz, CDCl3, 330K): 6.45 (bs, 1H), 6.75
(bs, 1H), 5.40 (d, J = 5.3 Hz, 1H), 4.12 (m, 1H), 3.70 (s, 3H), 2.40-
2.60 (m, 2H), 2.18 (m, 1H), 1.95 (m, 1H), 1.47 (s, 9H). 13C NMR
(90MHz, CDCl3):
27.9.
 174.0, 173.7, 155.7, 80.1, 53.2, 51.8, 30.2, 28.2,
1
purification. H NMR (400 MHz, DMSO-d6): 8.39 (d, J= 9 Hz, 2H),
8.01 (d, J= 8.9 Hz, 2H), 3.85 (m, 1H), 3.56 (s, 3H), 2.32-2.29 (m,
2H), 1.98-1.89 (m, 1H), 1.76-1.69 (m, 1H). LCMS method A Tr=2.13
min ((MH)+=347 ; 99.2%).
(S)-Methyl 5-amino-4-(((benzyloxy)carbonyl)amino)-5-
oxopentanoate 9b[39]
To a stirred solution of Cbz-L-Glu(OMe)-OH 8b (1.2 g, 4.1 mmol, 1
equiv.) in anhydrous THF (90 mL) was added triethylamine (0.63
mL, 4.5 mmol, 1.1 equiv.) at 0°C. The mixture was stirred at 0°C for
15 min and ethyl chloroformate (0.44 mL, 4.5 mmol, 1.1 equiv.) was
added. The mixture was stirred for 30 min at 0°C. A 1/1 (v/v)
solution of tetrahydrofuran/ammonium hydroxide (2.64 mL) was
added and the mixture was stirred at 0°C for 30 min. Water was
added to the mixture and the aqueous layer was extracted with
diethyl ether 3 times. The organic layer was dried over magnesium
sulfate, filtered and concentrated, affording 9b (844 mg) with
impurities (urethane) and engaged without further purification in the
next step. 1H NMR (250 MHz, CDCl3): 7.30-7.50 (m, 5H), 6.30
(bs, 1H), 5.57 (d, J= 7.3 Hz, 1H), 5.50 (bs, 1H), 5.12 (s, 2H), 4.30
(m,1H), 3.30 (s, 3H), 2.35-2.70 (m, 2H), 2.20 (m, 1H), 1.95 (m, 1H).
(S)-5-Methoxy-5-oxo-2-(2-
(trimethylsilyl)ethylsulfonamido)pentanoic acid 8e [37]
Compound
suspended in DCM (1 mL). TMSCl (36
added and the mixture refluxed for 2 h. The mixture was allowed to
stand at room temperature. TEA (80 L, 576 mol, 2 equiv.) and
then SES-Cl (55 L, 288 mol, 1 equiv.) were successively added.
The reaction mixture was vigorously stirred at room temperature for
1h. Methanol (50 L, 1.15 mmol, 4 equiv.) was added. The mixture
7
H-L-Glu(OMe)-OH (47 mg, 288
mol, 1 equiv.) was
L, 288
mol, 1 equiv.) was





was stirred for 5 minutes and then evaporated. An aqueous solution
of saturated K2CO3 was added until pH=8. The aqueous solution
was extracted with diethylether (3 x 5 mL). The aqueous layer was
acidified with a 1 N aqueous hydrochloric solution until pH = 1 and
then extracted with ethyl acetate (3 x 5 mL). The organic layers
were gathered, dried over MgSO4, filtered and concentrated. The
residue was purified by chromatography (SiO2, 25/75,
Cyclohexane/AcOEt, v/v) to afford 61 mg of a yellow oil (65 %
yield). 1H NMR (250MHz, CDCl3): 5.75 (bs, 1H), 5.29 (d, J = 9.4
Hz, 1H), 4.22 (m, 1H), 3.37 (s, 3H), 2.98 (t, J = 9.4 Hz, 2H), 2.60-
2.55 (m, 2H), 2.29 (m, 1H), 2.05 (m, 1H), 1.09-1.01 (m, 2H), 0.08 (s,
(S)-Methyl 5-amino-4-(4-methylphenylsulfonamido)-5-
oxopentanoate 9c
To a solution of compound 8c (500 mg, 1.6 mmol, 1 equiv.) in
anhydrous THF (30 mL) was added 1,1'-Carbonyldiimidazole (260
mg, 1.6 mmol, 1 equiv.) at 0 °C under argon. The resulting mixture
was stirred for 1
h at 0 ℃. Then a 1/1 (v/v) solution of
THF/ammonium hydroxide (1.0 mL) was added. The resulting
solution was stirred for 30 minutes at room temperature. Then the
volatile was removed and aqueous layer was extracted with diethyl
ether. The gathered organic layers are dried on magnesium sulfate,
filtered and concentrated. The residue was purified by
chromatography (SiO2, 95/5, DCM/MeOH, v/v) to afford 247 mg of a
colorless oil in 50% yield. Alternative protocol: To a solution of
compound 8c (13.8 g, 43.9 mmol, 1 equiv.) in anhydrous THF (145
mL) was added 1,1'-Carbonyldiimidazole (7.8 g, 48.3 mmol, 1.1
equiv.) at 0 °C under argon. The resulting mixture was stirred for 1
9H). 13C NMR (90MHz, CDCl3):
 175.5, 173.7, 55.3, 52.3, 50.2,
30.0, 28.4, 10.6, -1.8. HRMS (m/z, ESI) calcd for C11H23NNaO6SSi
([M+Na]+): 348.0908, found 348.0899.
(S)-2-(((Allyloxy)carbonyl)amino)-5-methoxy-5-oxopentanoic
acid 8f
Compound
7 H-L-Glu(OMe)-OH (10.0 g, 62.0 mmol, 1 equiv.) was
dissolved in 5% aqueous sodium hydrogen carbonate solution (200
mL). Allyl chloroformate (8 mL, 74.5 mmol, 1.2 equiv.) was added
and the reaction mixture was stirred for 16 h at room temperature. 1
N aqueous hydrochloric acid solution was added until pH 1 and the
mixture was extracted twice with ethyl acetate. The organic layer
was dried over sodium sulfate, filtered and concentrated, affording
8f (14.06 g, 92%) as a colorless oil. 1H NMR (400 MHz, CDCl3):
5.95-5.86 (m, 1H), 5.46 (bd, J = 7.3 Hz, 1H), 5.31 (m, 1H), 5.23
(m, 1H), 4.59 (bd, J = 5.4 Hz, 2H), 4.46-4.38 (m, 1H), 3.69 (s, 3H),
2.57-2.40 (m, 2H), 2.33-2.22 (m, 1H), 2.11-2.00 (m, 1H). 13C NMR
h at 0
℃. Then gazeous NH3 was bubbled during 10 minutes until
the reaction mixture precipitated). The precipitated reaction mixture
was diluted with ethyl acetate and washed twice with brine, dried on
sodium sulfate, filtrated and concentrated. The obtained solid was
triturated in 150 mL of diisopropylether, filtrated and concentrated
under vacuum to yield to 9c (10.1 g, 73%) as a white solid powder.
20
[α]D = +1.3 (c = 2.1, CH3OH). 1H NMR (360 MHz, CD3OD): 
7.74 (d, J= 8.1 Hz, 2H), 7.37 (d, J= 8.1 Hz, 2H), 3.81 (m, 1H), 3.63
(62.5 MHz, CDCl3):

175.5, 173.8, 156.4, 132.6, 118.2, 66.3, 53.4,
(s, 3H), 2.43 (s, 3H), 2.28 (m, 2H), 2.02-1.93 (m, 1H), 1.82-1.71 (m,
1H). 13C NMR (90 MHz, CD3OD):
 174.5, 173.4, 143.5, 137.4,
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10.1002/ejoc.201701477
European Journal of Organic Chemistry
FULL PAPER
129.3, 126.8, 55.5, 50.8, 29.2, 28.0, 20,1. HRMS (m/z, ESI) calcd
To a stirred solution of crude compound 9a (1.071 g, 4.11 mmol, 1
equiv.) in pyridine (13.3 mL, 40 equiv.) at 0 °C under argon was
added POCl3 (0.58 mL, 6.18 mmol, 1.5 equiv.). The reaction
mixture became orange. After 3.5 h, a hydrochloric acid solution
(2N, 3.2 mL/mmol) is added and the aqueous layer was extracted
with diethyl ether 3 times. The organic layer was then successively
washed with NaHCO3 5% aqueous solution, water and brine. The
organic layer was dried over magnesium sulfate, filtered and
concentrated, affording pure compound 10a (833 mg, 61%, 2 steps
yield). [α]D20 = - 48.2 (c = 0.98, CH2Cl2). 1H NMR (360 MHz, CDCl3,
330K): 5.10 (bs, 1H), 4.70 (bs, 1H), 3.70 (s, 3H), 2.50-2.57 (m,
for C13H18N2NaO5S ([M+Na]+): 337.0834, found 337.0820.
(S)-Methyl -5-amino-4-[(4-nitrophenyl)sulfonylamino]-5-oxo-
pentanoate 9d
Compound 8d (1.28 g, 3.7 mmol, 1 equiv.) was dissolved in THF
(12 mL). CDI (659 mg, 4 mmol, 1.1 equiv) was added and the
mixture stirred at room temperature for 1h (slight bubbling).
Ammonia was bubbled in the reaction mixture over 15 min until
saturation. Precipitation occurred. The reaction mixture was diluted
with ethyl acetate and washed twice with brine. The organic layers
were gathered, dried over MgSO4, filtered and concentrated. The
solid was recrystallized in 20 mL of hot diisopropyl ether, filtrated at
RT and dried to obtain 800 mg of 9d (62% yield). 1H NMR (400
MHz, DMSO-d6): 8.38 (d, J= 9 Hz, 2H), 8.34 (br s, 1H), 8.02 (d, J=
9 Hz), 7.30 (s, 1H), 6.98 (s, 1H), 3.76 (ddd, J=5.6 Hz, 5.6 Hz, 8.3
Hz), 3.54 (s, 3H), 2.33-2.17 (m, 2H), 1.86-1.65 (m, 2H). LCMS
method B Tr=0.76 min ((MH)-=344 ; 100%).
2H), 2.10-2.19 (m, 2H), 1.45 (s, 9H). 13C NMR (90 MHz, CDCl3):

172.4, 154.3, 118.3, 81.2, 51.9, 41.5, 29.6, 28.1. IR (cm-1) : 3358,
2306, 1720. MS (M + Na+) : 265. HRMS (m/z, ESI) calcd for
C11H18N2NaO4 ([M+Na]+) 265.1164, found 265.11699.
(S)-Methyl 4-(((benzyloxy)carbonyl)amino)-4-cyanobutanoate
10b[41]
To a stirred solution of crude compound 9b (844 mg, 2.87 mmol, 1
equiv.) in pyridine (9.28 mL, 40 equiv.) at 0 °C under argon was
added POCl3 (0.4 mL, 4.33 mmol, 1.5 equiv.). The reaction mixture
became orange. After 3h30, a hydrochloric acid solution (2N, 9.2
mL) is added and the aqueous layer was extracted with diethyl
ether 3 times. The organic layer was then successively washed with
NaHCO3 5% aqueous solution, water and brine. The organic layer
(S)-Methyl 5-amino-5-oxo-4-(2-
(trimethylsilyl)ethylsulfonamido)pentanoate 9e[40]
Compound 8e (61 mg, 188
mL). CDI (27 mg, 140 mol, 1.3 equiv) was added and the mixture
stirred at room temperature for 1h. A commercial solution of NH4OH
(50 L) was added and the mixture stirred for 3 h. Ethyl acetate (10
mol, 1 equiv.) was dissolved in DCM (1


mL) and water (10 mL) were added. The aqueous layer was
extracted with ethyl acetate (3 x 5 mL). The organic layers were
gathered, washed with a 1N aqueous hydrochloric solution (3 x 10
mL), dried over MgSO4, filtered and concentrated. The residue was
filtered over a short SiO2-column (100 % ethyl acetate) to afford 30
was dried over magnesium sulfate, filtered and concentrated,
20
affording pure compound 10b (547 mg, 69%, 2 steps yield). [α]D
=
1
- 36.8 (c = 0.9, MeOH). H NMR (250 MHz, CDCl3): 7.30-7.50 (m,
5H), 5.76 (d, J= 7.9 Hz, 1H), 5.12 (s, 2H), 4.70 (m,1H), 3.70 (s, 3H),
2.48-2.56 (m, 2H), 2.06-2.20 ( m, 2H). 13C NMR (90 MHz, CDCl3):

1
mg of a yellow oil (88 % yield). H NMR (250MHz, CDCl3): 6.68
172.6, 155.4, 135.6, 128.6, 128.5, 128.3, 118.1, 67.7, 52.1, 42.2,
29.7, 28.0. IR (cm-1) : 3331, 2245, 1732. MS : (M + Na+) : 299.
HRMS (m/z, ESI) calcd for C14H16N2NaO4 ([M+Na]+) 299.1008,
found 299.1002.
(bs, 1H), 6.06 (bs, 1H), 5.65 (d, J = 8.4 Hz, 1H), 4.05 (m, 1H), 3.74
(s, 3H), 2.96 (t, J = 8.8 Hz, 2H), 2.68-2.52 (m, 2H), 2.19-2.10 (m,
1H), 2.02-1.94 (m, 1H), 1.10-1.02 (m, 2H), 0.07 (s, 9H). 13C NMR
(90MHz, CDCl3):
 174.2, 174.0, 55.6, 52.1, 49.4, 29.7, 28.9, 10.4, -
2.0. HRMS (m/z, ESI) calcd for C11H24N2NaO5SSi ([M+Na]+):
(S)-Methyl 4-cyano-4-(4-methylphenylsulfonamido) butanoate
10c
347.1067, found 347.1068.
Compound 9c (120 mg, 0.38 mmol, 1 equiv.) was dissolved in dry
(S)- Methyl-4-(((allyloxy)carbonyl)amino)-5-amino-5-
THF (7 mL). TEA (40
L, 0.76 mmol, 2 equiv.) and trifluoroacetic
oxopentanoate 9f
anhydride (110 L, 0.76 mmol, 2 equiv.) were added. The mixture

At 0°C, to a stirred solution of Alloc-Glu(OMe)-OH 8f (14.06 g, 57.3
mmol, 1 equiv.) in anhydrous tetrahydrofuran (120 mL) was added
triethylamine (8.8 mL, 63.1 mmol, 1.1 equiv). The mixture was
stirred at 0°C for 15 min and ethyl chloroformate (6.1 mL, 63.1
mmol, 1.1 equiv) was added. The mixture was stirred for 30 min at
0°C. A 1/1 (v/v) solution of tetrahydrofuran/ammonium hydroxide
(120 mL) was added and the mixture was stirred at 0°C for 30 min.
The mixture was diluted with ethyl acetate and washed with brine.
The organic layer was dried over sodium sulfate, filtered and
concentrated, affording 9f (11.73 g, 84%) as a colorless oil. 1H
NMR (400 MHz, CDCl3): 6.34 (bs, 1H), 5.90 (ddt, J = 17.3 Hz, J =
10.5 Hz, J = 5.6 Hz, 1H), 5.72-5.65 (m, 2H), 5.30 (ddd, J = 17.3 Hz,
J = 1.5 Hz, J = 1.5 Hz, J = 1.4 Hz, 1H), 5.21 (ddd, J = 10.5 Hz, J =
1.4 Hz, J = 1.4 Hz, J = 1.1 Hz, 1H), 4.56 (bd, J = 5.6 Hz, 2H), 4.30-
4.22 (m, 1H), 3.69 (s, 3H), 2.55 (ddd, J = 16.8 Hz, J = 7.7 Hz, J =
7.0 Hz, 1H), 2.43 (dt, J = 16.8 Hz, J = 6.7 Hz, 1H), 2.18 (dddd, J =
14.4 Hz, J = 7.7 Hz, J = 6.7 Hz, J = 5.2 Hz, 1H), 1.96 (dddd, J =
14.4 Hz, J = 7.9 Hz, J = 7.0 Hz, J = 6.7 Hz, 1H). 13C NMR (62.5
was stirred at room temperature for 1h and concentrated. The
residue was dissolved in DCM (15 mL). The solution was washed
with a 6N aqueous solution of hydrochloric acid (10 mL) and then
with a saturated aqueous solution of NaHCO3 (2 x 10 mL). The
organic layer was dried over MgSO4, filtered and concentrated. The
residue was purified by chromatography (SiO2, 30/70, ethyl
acetate/petroleum ether, v/v) to afford 107 mg of a white solid in 95%
yield. [α]D = - 39.3 (c = 1.9, CH3OH). H NMR (360 MHz, CDCl3):
7.78 (d, J= 8.1 Hz, 2H), 7.35 (d, J=8,1 Hz, 2H), 6.16 (d, J= 9.8
Hz, 1H), 4.36 (ddd, J= 6.8 Hz, 7.9 Hz, 9.8 Hz, 1H), 3.69 (s, 3H),
2.48-2.56 (m, 2H), 2.43 (s, 3H), 2.08-2.16 (m, 2H). 13C NMR (90
20
1
MHz, CDCl3):
 172.8, 144.6, 135.9, 130.1, 127.3, 117.1, 52.3,
43.6, 29.3, 28.7, 21.7. HRMS (m/z, ESI) calcd for C13H16N2NaO4S
([M+Na]+) 319.0729, found 319.0723.
(S)-Methyl 4-cyano-4-[(4-nitrophenyl)sulfonylamino] butanoate
10d
Compound 9d (1.1 g, 3.19 mmol, 1 equiv.) was dissolved in THF
(60 mL). TEA (890 µL, 6.37 mmol, 2 equiv.) and trifluoroacetic
MHz, CDCl3):
 174.1, 156.4, 132.7, 118.2, 66.2, 54.0, 52.1, 30.4,
28.2. HRMS (m/z, ESI) calcd for C10H16N2NaO5 ([M+Na]+):
anhydride (890 L, 6.37 mmol, 2 equiv.) were added. The mixture
267.0951, found 267.0944.
was stirred at room temperature for 1h and concentrated. The
residue was dissolved in ethyl acetate. The solution was washed
with a 1N aqueous solution of hydrochloric acid and then with a
saturated aqueous solution of NaHCO3 (2 x 10 mL). The organic
layer was dried over MgSO4, filtered and concentrated. Purification
(S)-Methyl 4-((tert-butoxycarbonyl)amino)-4-cyanobutanoate
10a
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10.1002/ejoc.201701477
European Journal of Organic Chemistry
FULL PAPER
over silica gel eluted with 4% of methanol in dichloromethane give
white solid 670 mg in 64% yield. 1H NMR (400 MHz, DMSO-d6):
9.18 (bs, 1H), 8.46 (d, J=8.9 Hz, 2H), 8.10 (d, J=9 Hz, 2H), 4.54
(ddd, J=6.8 Hz, 6.9 Hz, 7.9 Hz, 1H), 3.58 (s, 3H), 2.42-2.37 (m, 2H),
2.04-1.89 (m, 2H). LCMS method A Tr=3.27 min ((MH)-=326 ;
100%).
Method B (starting from 20
)
[35]: To a stirred suspension of Zn dust
(432 mg, 6.62 mmol, 7 equiv.) in refluxing THF (12 mL) were added
1,2-dibromoethane (0.6 ml, 3.31 mmol, 3.5 equiv.) and few drops of
tert-butyl bromoacetate. To the resulting greenish suspension was
then rapidly added a solution of 20 (311 mg, 0.95 mmol, 1 equiv.) in
THF (4 mL). A solution of tert-butylbromoacetate (0.57 mL, 3.78
mmol, 4 equiv.) in dry THF (5 mL) was added dropwise in 10 min.
and the mixture was stirred for additional 1 h at reflux. After cooling
to room temperature, the reaction was quenched with 50% K2CO3
aqueous solution (12 mL). After stirring for 15 min, the resulting
mixture was filtered through Celite, and the precipitate was washed
with Et2O, and the combined extracts were dried (MgSO4), filtered
and concentrated under reduced pressure. The residue was purified
by chromatography (SiO2, petroleum ether /ethyl acetate, 7/3, v/v)
(S)-Methyl 4-cyano-4-(2-(trimethylsilyl)ethylsulfonamido)
butanoate 10e
Compound 9e (150 mg, 460
(4 mL). TEA (129 L, 925
anhydride (131 L, 925 mol, 2 equiv.) were added. The mixture
mol, 1 equiv.) was dissolved in THF

mol, 2 equiv.) and trifluoroacetic


was stirred at room temperature for 1h and concentrated. The
residue was dissolved in DCM (15 mL). The solution was washed
with a 6N aqueous solution of hydrochloric acid (3 x 15 mL) and
then with a saturated aqueous solution of NaHCO3 (3 x 15 mL). The
organic layer was dried over MgSO4, filtered and concentrated. 140
mg of a yellow pale oil were obtained (quant. yield). 1H NMR
(250MHz, CDCl3): 5.90 (d, J = 8.8 Hz, 1H), 4.42 (q, J = 7.9 Hz,
1H), 3.72 (s, 3H), 3.13-3.05 (m, 2H), 2.63-2.56 (m, 2H), 2.24-2.18
(m, 2H), 1.09-1.01 (m, 2H), 0.07 (s, 9H). 13C NMR (90MHz, CDCl3):
20
to afford 135 mg of compound 5a as a white solid (44%). [α]D = -
99.8 (c = 1.8, CH3OH). 1H NMR (360 MHz, CDCl3): 10.48 (s, 1H),
6.34 (s, 1H), 5.37 (dd, J = 3.4 Hz, J = 8.7 Hz, 1H), 5.15 (s, 1H),
2.74-2.62 (m, 1H), 2.46-2.26 (m, 2H), 2.08-2.00 (m, 1H), 1.49 (s,
18H). 13C NMR (90 MHz, CDCl3):
 178.9, 169.0, 157.5, 151.7,
92.9, 81.7, 80.9, 53.3, 28.8, 28.4, 28.3, 27.9. HRMS (m/z, ESI)
calcd for C16H26N2NaO5 ([M+Na]+): 349.1739, found 349.1729.

172.8, 118.0, 52.3, 49.9, 43.8, 29.4, 28.8, 10.4, -2.0. HRMS (m/z,
ESI) calcd for C11H22N2NaO4SSi ([M+Na]+): 329.0962, found
329.0957.
(S,Z)-tert-Butyl 2-(3-(((benzyloxy)carbonyl)amino)-6-
oxopiperidin-2-ylidene)acetate 5b
Zinc dust (249 mg, 3.8 mmol, 7 equiv.) was suspended in
anhydrous tetrahydrofuran (2.27 mL) and the mixture was refluxed
for 5 minutes. Drops of 1,2-dibromoethane (0.09 mL) and tert-
butylbromoacetate were added and the mixture was stirred at
reflux. Nitrile 10b (150 mg, 0.54 mmol, 1 equiv.) in tetrahydrofuran
(1.13 mL) was added in one portion while maintaining the reflux. A
solution of tert-butylbromoacetate (0.30 mL, 2.04 mmol, 3.75 equiv.)
in tetrahydrofuran (1.13 mL) was added dropwise over 20 min. The
mixture was refluxing for 2 h, and then allowed to cool at room
temperature. A 50% aqueous potassium carbonate solution (3.6
mL) was added and the mixture stirred at room temperature for 30
min. The mixture was filtered over a Dicalite pad. The filtrate was
extracted with diethyl ether and the organic layer was dried over
sodium sulfate, filtered and concentrated. The residue was purified
by chromatography (SiO2, heptane/ethyl acetate, 3/7 to 0/1, v/v) to
afford enaminoester 5b (16 mg, 8%) and enaminoester 12 (38 mg,
25%). 1H NMR (250 MHz, CDCl3):  9.09 (bs, 1H), 7.30-7.60 (m,
5H), 5.87 (bs, 1H), 5.12 (s, 2H), 4.82 (s, 1H), 4.45 (m, 1H), 2.46 (t, J
= 7.5 Hz, 2H), 2.13 (m, 1H), 1.93 (m, 1H), 1.47 (s, 9H). 13C NMR
(S)-Methyl 4-(((allyloxy)carbonyl)amino)-4-cyanobutanoate 10f
At 0°C, to a stirred solution of amide 9f (11.73 g, 48 mmol, 1 equiv.)
in anhydrous tetrahydrofuran (200 mL) were added triethylamine
(13.5 mL, 96 mmol, 2 equiv.) and trifluoroacetic anhydride (13.5 mL,
96 mmol, 2 equiv.). The mixture was warmed to room temperature,
stirred for 3 h and concentrated. The residue was dissolved in ethyl
acetate and successively washed with a 1 N aqueous hydrochloric
acid solution, with a saturated aqueous sodium hydrogen carbonate
solution and with brine. The organic layer was dried over sodium
sulfate, filtered and concentrated. The residue was purified by
chromatography (SiO2, cyclohexane/ethyl acetate, 10/0 to 60/40,
1
v/v) affording nitrile 10f (8.45 g, 77%) as a yellow oil. H NMR (400
MHz, CDCl3):
 5.91 (ddt, J = 17.3 Hz, J = 10.5 Hz, J = 5.6 Hz, 1H),
5.46-5.35 (m, 1H), 5.33 (bd, J = 17.3 Hz, 1H), 5.25 (bd, J = 10.5 Hz,
1H), 4.76-4.66 (m, 1H), 4.65-4.58 (m, 2H), 3.72 (s, 3H), 2.60 (dt, J =
17.2 Hz, J = 7.1 Hz, 1H), 2.53 (dt, J = 17.2 Hz, J = 6.8 Hz, 1H), 2.18
(ddd, J = 7.1 Hz, J = 7.0 Hz, J = 6.8 Hz, 2H). 13C NMR (90MHz,
CDCl3):
 172.7, 155,0, 131.9, 118.6, 117.9, 67.6, 52.2, 42.2, 29.7,
28.1. HRMS (m/z, ESI) calcd for C10H14N2NaO4 ([M+Na]+):
(90 MHz, CDCl3):

172.5, 167.7, 157.9, 155.7, 135.5, 128.6,
249.0846, found 249.0833
128.5, 128.4, 88.1, 80.3, 66.8, 55.9, 29.9, 28.9, 28.2. MS : (M +
Na+) : calcd for C19H24N2NaO5 383, found 383.
(S,Z)-tert-Butyl 2-(3-((tert-butoxycarbonyl)amino)-6-
oxopiperidin-2-ylidene)acetate 5a
(S,Z)-Methyl 3-(5-(2-(tert-butoxy)-2-oxoethylidene)-2-
oxoimidazolidin-4-yl)propanoate 12
Method A (starting from 10a): Zinc dust (284 mg, 4.34 mmol, 7
equiv.) was suspended in anhydrous tetrahydrofuran (2 mL) and the
mixture was refluxed for 5 minutes. Drops of 1,2-dibromoethane
(0.11 mL) and tert-butylbromoacetate were added and the mixture
was stirred at reflux. Nitrile 10a (150 mg, 0.62 mmol, 1 equiv.) in
tetrahydrofuran (1 mL) was added in one portion while maintaining
the reflux. A solution of tert-butylbromoacetate (0.34 mL, 2.32
mmol, 3.75 equiv.) in tetrahydrofuran (1 mL) was added dropwise
over 20 min. The mixture was refluxing for 2 h, and then allowed to
cool at room temperature. A 50% aqueous potassium carbonate
solution (4.15 mL) was added and the mixture stirred at room
temperature for 30 min. The mixture was filtered over a Dicalite
pad. The filtrate was extracted with diethyl ether and the organic
layer was dried over sodium sulfate, filtered and concentrated. The
residue was purified by chromatography (SiO2, heptane/ethyl
acetate, 3/7 to 1/1, v/v) to afford enaminoester 5a ( 38mg, 18%) and
enaminoester 12 (23 mg, 13%).
1H NMR (250 MHz, CDCl3): 9.09 (s, 1H), 7.02 (s, 1H), 4.83 (s,
1H), 4.45 (m, 1H), 3.67 (s, 3H), 2.42 (t, J = 7.5 Hz, 2H), 2.13 (m,
1H), 1.93 (m, 1H), 1.46 (s, 9H). 13C NMR (90 MHz, CDCl3):
173.1, 167.7, 158.5, 155.8, 88.1, 80.2, 56.1, 51.9, 30.1, 28.7, 28.3.
MS : (M + Na+) : 307. HRMS (m/z, ESI) calcd for C13H20N2NaO5
([M+Na]+): 307.1264, found 307.1250.

(S,Z)-tert-Butyl 2-(3-(4-methylphenylsulfonamido)-6-
oxopiperidin-2-ylidene)acetate 5c
Zinc dust (37.1 g, 0.57 mol, 7 equiv.) was suspended in anhydrous
tetrahydrofuran (150 mL) and the mixture was refluxed for 5
minutes. Drops of 1,2-dibromoethane (0.7 mL) and tert-
butylbromoacetate were added and the mixture was stirred at
reflux. Nitrile 10c (24 g, 0.081 mol, 1 equiv.) in tetrahydrofuran (50
mL) was added in one portion while maintaining the reflux. A
solution of tert-butylbromoacetate (48.6 mL, 0.32 mol, 4 equiv.) in
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701477
European Journal of Organic Chemistry
FULL PAPER
tetrahydrofuran (100 mL) was added dropwise over 1 h. The
mixture was refluxing for 2 h, and then allowed to cool at room
temperature. A 50% aqueous potassium carbonate solution (50 mL)
was added and the mixture stirred at room temperature for 30 min.
The mixture was filtered over a celite pad. The filtrate was extracted
with diethyl ether and the organic layer was dried over sodium
sulfate, filtered and concentrated. The residue was purified by
chromatography (SiO2, petroleum ether/ethyl acetate, 3/7, v/v) to
9.7 Hz, J = 6.0 Hz, 1H), 2.31 (ddd, J = 16.9 Hz, J = 8.4 Hz, J = 8.4
Hz, 1H), 2.20-2.10 (m, 1H), 2.16 (dd, J = 15.4 Hz, J = 8.9 Hz, 1H),
1.79 (m, 1H), 1.44 (s, 9H). 13C NMR Jmod (100 MHz, CDCl3):

178.4, 171.1, 81.3, 59.3, 53.6, 40.9, 30.7, 28.2, 24.4. HRMS (m/z,
ESI) calcd for C11H20N2NaO3 ([M+Na]+): 251.1201, found 251.1208.
Diastereomer (R,S)-15:
1H NMR (400 MHz, CDCl3):  6.42 (s,
1H), 3.60 (ddd, J = 8.0 Hz, J = 5.5 Hz, J = 5.3 Hz, 1H), 3.23 (ddd, J
= 9.0 Hz, J = 5.3 Hz, J = 3.6 Hz, 1H), 2.37 (ddd, J = 17.2 Hz, J = 9.8
Hz, J = 6.3 Hz, 1H), 2.35 (dd, J = 15.4 Hz, J = 3.6 Hz, 1H), 2.31
(ddd, J = 17.2 Hz, J = 9.5 Hz, J = 7.2 Hz, 1H), 2.22 (dd, J = 15.4
Hz, J = 9.0 Hz, 1H), 2.15, (m, 1H), 1.96 (m, 1H), 1.45 (s, 9H).
HRMS (m/z, ESI) calcd for C11H20N2NaO3 ([M+Na]+): 251.1201,
found 251.1208.
20
afford enaminoester 5c (15.1 g, 49%) as a yellow solid. [α]D = -
52.0 (c = 2.7, CH3OH). 1H NMR (300 MHz, CDCl3): 10.57 (bs,
1H), 7.79 (d, J= 8.3 Hz, 2H), 7.35 (d, J= 8.3 Hz, 2H), 5.14 (d; J=
7.9, 1H), 4.87 (d, J= 1.1 Hz, 1H), 4.15-4.06 (m, 1H), 2.68-2.51 (m,
2H), 2.46 (s, 3H), 1.83-2.01 (m, 2H), 1.45 (s, 9H). 13C NMR (90
MHz, CDCl3):
 168.6, 167.4, 150.4, 144.0, 137.3, 130.0, 127.1,
95.6, 81.1, 50.3, 28.9, 28.2, 26.4, 21.5. HRMS (m/z, ESI) calcd for
tert-Butyl (S)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-
C18H24N2NaO5S ([M+Na]+): 403.1304, found 403.1209.
((S)-5-oxopyrrolidin-2-yl)propanoate (
(R)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-((S)-5-
oxopyrrolidin-2-yl)propanoate ( R, S)-6
S,S)-6 and tert-butyl
tert-Butyl (S,Z)-3-amino-3-(5-oxopyrrolidin-2-yl)acrylate 13
Zinc dust was first suspended in a saturated aqueous ammonium
chloride solution and stirred for 5 min. Zinc was then filtered and
washed with water, ethanol and diethyl ether, then dried in vacuo
for 3 h. Activated zinc dust (9.37 g, 143 mmol, 7 equiv.) was
suspended in anhydrous tetrahydrofuran (50 mL). Drops of 1,2-
dibromoethane and tert-butylbromoacetate were added and the
mixture was stirred at reflux. Nitrile 10f (4.63 g, 20.5 mmol, 1 equiv.)
in tetrahydrofuran (30 mL) was added in one portion while
maintaining the reflux. A solution of tert-butylbromoacetate (11.3
mL, 76.7 mmol, 3.75 equiv.) in tetrahydrofuran (10 mL) was added
dropwise over 1 h. The mixture was refluxing for 2 h, and then
allowed to cool at room temperature. A 50% aqueous potassium
carbonate solution (50 mL) was added and the mixture stirred at
room temperature for 30 min. The mixture was filtered over a
Dicalite pad. The filtrate was extracted with diethyl ether and the
organic layer was dried over sodium sulfate, filtered and
concentrated. The residue was purified by chromatography (SiO2,
 
At 0°C, to a stirred solution of β,γ-diamino ester 15 (1.88 g, 8.23
mmol, 1 equiv.) in a 2/2/1 mixture of water/1,4-dioxane/diethyl ether
(100 mL) was added potassium carbonate (2.79 g, 8.23 mmol, 1
equiv.). The reaction mixture was stirred at 0°C for 15 min and
Fmoc-OSu (3.40 g, 24.7 mmol, 3 equiv.) was added. The reaction
mixture was stirred at 0°C for 1 h and a 2 N aqueous hydrochloric
acid solution was added until pH 1. The aqueous layer was
extracted with ethyl acetate and combined organic layers were
dried over magnesium sulfate filtered and concentrated. The
residue was purified by chromatography (SiO2, cyclohexane/ethyl
acetate, 7/3, then ethyl acetate/methanol, 95/5, v/v) affording
(3.01 g, 81%) as a mixture of epimers. Separation by chiral HPLC
afforded S, S)-6 and R, S)-6 in a 45/55 ratio.
Diastereomer S, S)-6: H NMR (400 MHz, DMSO-d6):  7.88 (d,
6
(

( 
1
( 
J = 7.5 Hz, 2H), 7.70 (d, J = 7.5 Hz, 1H), 7.69 (d, J = 7.5 Hz, 1H),
7.60 (s, 1H), 7.41 (dd, J = 7.5 Hz, J = 7.5 Hz, 2H), 7.35-7.28 (m,
3H), 4.35 (dd, J = 10.4 Hz, J = 7.2 Hz, 1H), 4.28 (dd, J = 10.4 Hz, J
= 6.8 Hz, 1H), 4.20 (dd, J = 7.2 Hz, J = 6.8 Hz, 1H), 3.95-3.87 (m,
1H), 3.61-3.53 (m, 1H), 2.37 (dd, J = 15.7 Hz, J = 5.2 Hz, 1H), 2.31
(dd, J = 15.7 Hz, J = 9.6 Hz, 1H), 2.05-1.91 (m, 3H), 1.79-1.67 (m,
cyclohexane/ethyl acetate, 7/3 to 0/1, v/v) to afford enaminoester 13
1
(1.95 g, 42%) as a white powder. H NMR (400 MHz, DMSO-d6):

7.83 (s, 1H), 7.44 (bs, 1H), 6.84 (bs, 1H), 4.35 (s, 1H), 4.02 (dd, J =
8.5 Hz, J = 5.3 Hz, 1H), 2.34 (dddd, J = 12.6 Hz, J = 9.6 Hz, J = 8.5
Hz, J = 6.4 Hz, 1H), 2.16 (ddd, J = 16.7 Hz, J = 9.4 Hz, J = 6.4 Hz,
1H), 2.10 (ddd, J = 16.7 Hz, J = 9.6 Hz, J = 6.8 Hz, 1H), 1.80 (dddd,
J = 12.6 Hz, J = 9.4 Hz, J = 6.8 Hz, J = 5.3 Hz, 1H), 1.39 (s, 9H).
1
1H), 1.34 (s, 9H). H NMR (360 MHz, Methanol-d4):  7.74 (d, J =
7.3 Hz, 2H), 7.61 (d, J = 7.7 Hz, 2H), 7.35 (t, J = 7.6 Hz, 2H), 7.27
(t, J = 7.3 Hz, 2H), 4.40 (dd, J = 10.5 Hz, J = 7.0 Hz, 1H), 4.33 (dd,
J = 10.5 Hz, J = 6.3 Hz, 1H), 4.14 (t, J = 6.7 Hz, 1H), 4.09-4.02 (m,
1H), 3.75-3.67 (m, 1H), 2.45 (dd, J = 15.4 Hz, J = 4.6 Hz, 1H), 2.35
(dd, J = 15.4 Hz, J = 10.0 Hz, 1H), 2.24-2.06 (m, 3H), 1.87-1.77 (m,
1H), 1.39 (s, 9H). 13C NMR (90 MHz, Methanol-d4): 181.3, 171.9,
158.7, 145.4, 145.3, 142.7, 128.9, 128.2, 126.3, 126.2, 121.2, 82.3,
67.8, 59.2, 53.6, 48.7, 38.9, 31.2, 28.5, 24.4. HRMS (m/z, ESI)
13C NMR (90MHz, CDCl3):
 179.5, 169.9, 161.7, 83.8, 78.7, 57.4,
29.8, 28.5, 27.9. HRMS (m/z, ESI) calcd for C11H18N2NaO3
([M+Na]+): 249.1210, found 249.1207.
tert-Butyl (S)-3-amino-3-((S)-5-oxopyrrolidin-2-yl)propanoate
(

S,

S)-15 and tert-butyl (R)-3-amino-3-((S)-5-oxopyrrolidin-2-
R, S)-15
calcd for C26H30N2NaO5 ([M+Na]+): 473.2047, found 473.2031.
1
yl)propanoate (


Diastereomer
(
R,
S)-6: H NMR (400 MHz, DMSO-d6):  7.88 (d,
At -78°C, to a stirred solution of enaminoester 13 (5.68 g, 25.1
mmol, 1 equiv.) in a 1/1 (v/v) mixture of dichloromethane/methanol
(200 mL) was added dropwise acetyl chloride (8 mL). Sodium
cyanoborohydride (2.37 g, 37.6 mmol, 1.5 equiv.) was added and
the mixture stirred at -78°C for 30 minutes. The mixture was
allowed to warm to room temperature and stirred for one additional
hour. The reactional mixture was cooled to 0°C and a 10% aqueous
sodium hydroxide solution was added until pH 11. The aqueous
layer was extracted with dichloromethane and combined organic
layers were dried over sodium sulfate, filtered and concentrated.
J = 7.5 Hz, 2H), 7.68 (d, J = 7.5 Hz, 1H), 7.66 (d, J = 7.5 Hz, 1H),
7.60 (s, 1H), 7.41 (dd, J = 7.5 Hz, J = 7.5 Hz, 2H), 7.32 (dd, J = 7.5
Hz, J = 7.5 Hz, 1H), 7.31 (dd, J = 7.5 Hz, J = 7.5 Hz, 1H), 7.26 (d, J
= 9.4 Hz, 1H), 4.35 (dd, J = 10.5 Hz, J = 6.9 Hz, 1H), 4.27 (dd, J =
10.5 Hz, J = 6.6 Hz, 1H), 4.19 (dd, J = 6.9 Hz, J = 6.6 Hz, 1H), 3.86-
3.76 (m, 1H), 3.47-3.39 (m, 1H), 2.53 (dd, J = 15.1 Hz, J = 3.6 Hz,
1H), 2.20 (dd, J = 15.1 Hz, J = 10.7 Hz, 1H), 2.16-1.88 (m, 3H),
1.81-1.72 (m, 1H), 1.34 (s, 9H). 1H NMR (300 MHz, Methanol-d4): 
7.76 (d, J = 7.4 Hz, 2H), 7.62 (dd, J = 6.9 Hz, J = 4.3 Hz, 2H), 7.36
(t, J = 7.4 Hz, 2H), 7.28 (t, J = 7.2 Hz, 2H), 4.37 (dd, J = 10.6 Hz, J
= 7.0 Hz, 1H), 4.32 (dd, J = 10.5 Hz, J = 6.6 Hz, 1H), 4.17 (t, J = 6.8
Hz, 1H), 4.11-4.03 (m, 1H), 3.70-3.63 (m, 1H), 2.51 (dd, J = 15.1
Hz, J = 4.2 Hz, 1H), 2.36-2,23 (m, 3H), 2.15-2.03 (m, 1H), 1.94-1.82
(m, 1H), 1.39 (s, 9H). 13C NMR (75 MHz, Methanol-d4): 181.0,
171.9, 158.7, 145.4, 142.7, 128.9, 128.3, 126.3, 126.2, 121.0, 82.3,
The
residue
was
purified
by
chromatography
(SiO2,
dichloromethane/methanol, 10/0 to 9/1, v/v) to afford 15 (4.95 g,
86%) as a mixture of epimers.
Diastereomer (S,S)-15:
1H NMR (400 MHz, CDCl3):  7.03 (s,
1H), 3.49 (ddd, J = 7.1 Hz, J = 7.1 Hz, J = 6.6 Hz, 1H), 2.95 (m, 1H)
2.41 (dd, J = 15.4 Hz, J = 3.7 Hz, 1H), 2.37 (ddd, J = 16.9 Hz, J =
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701477
European Journal of Organic Chemistry
FULL PAPER
67.9, 59.3, 53.2, 48.6, 38.7, 30.8, 28.4, 23.3. HRMS (m/z, ESI)
To a solution of (2R,3S)-176 (2.14 g, 4.147 mmol, 1 equiv.) in THF
(15 mL) was added potassium diphenylphosphide (0.5 M in THF, 25
mL, 3 equiv.) at -78 °C under argon atmosphere. The resulting
mixture was stirred for 3h. Then, the solution was treated with 2N
HCl aqueous (10 mL) for 15 min. The volatile was removed and the
residue was dissolved in ethyl acetate (200 mL), washed with
saturated NaHCO3 and brine, dried with anhydrous MgSO4, filtered,
and concentrated under reduced pressure. The residue was purified
by chromatography (SiO2, petroleum ether/ethyl acetate, 6 /4, v/v)
calcd for C26H30N2NaO5 ([M+Na]+): 473.2047, found 473.2031.
tert-Butyl 2-((3S)-6-oxo-3-(phenylsulfonamido)piperidin-2-
yl)acetate 14
A solution of compound 5c (56 mg, 0.15 mmol, 1 equiv.) in dry
methanol (3 mL) was hydrogenated at 1 bar for 12 h in the
presence of 10% Pd/(OH)2 (32 mg, 0.29 mmol, 2 equiv.). Filtration
of the catalyst through Celite pad and concentration under reduced
pressure gave compound 14 as a mixture of diastereomers (dr =
70/30). The residue was purified by chromatography (SiO2, CH2Cl2
/MeOH, 95 /5, v/v) to afford compound 14 (purified mixture of
diastereomers) as clear oil (48 mg, 85%).
to afford 1.25 g (83%) of (2R,3S)-18
.
[α]D20 = +10.1 (c = 1.8, CH3OH). 1H NMR (360 MHz, CDCl3): 7.34-
7.31 (m, 5H), 6.58 (s, 1H), 5.67 (d, J = 8.6 Hz, 1H), 5.12 (d, J = 12.6
Hz, 1H) 5.08 (d, J = 12.6 Hz, 1H), 3.74-3.65 (m, 1H), 3.63-3.51 (m,
1H), 2.64 (dd, J = 2.5 Hz, J = 16.6 Hz, 1H), 2.42-2.32 (m, 3H), 1.99-
1.89 (m, 1H), 1.87-1.71 (m, 1H), 1.42 (s, 9H). 13C NMR (90 MHz,
CDCl3): 170.9, 170.7, 156.1, 136.3, 129.9, 128.7, 128.4, 128.2,
126.9, 82.0, 67.1, 54.1, 49.3, 40.2, 29.1, 28.1, 25.9. HRMS (m/z,
ESI) calcd for C19H26N2NaO5 ([M+Na]+): 385.1734, found 385.1717.
tert-Butyl 2-((2R,3S)-3-(4-methylphenylsulfonamido)-6-
oxopiperidin-2-yl)acetate (R,S)-14
A small quantity of this stereoisomer could be obtained by
20
chromatography to perform analyses. [α]D = -13.7 (c = 2.3,
CH3OH). 1H NMR (360 MHz, CDCl3): 7.76 (d, J = 8.3 Hz, 2H),
7.31 (d, J = 8.3 Hz, 2H), 6.57 (s, 1H), 6.31 (d, J = 8.6 Hz, 1H), 3.62-
3.57 (m, 1H), 3.29-3.21 (m, 1H), 2.72 (dd, J = 2.5 Hz, J = 17.3 Hz,
1H), 2.41 (s, 3H), 2.38-2.15 (m, 3H), 1.69-1.62 (m, 2H), 1.41 (s,
9H). 13C NMR (62.25 MHz, CDCl3): 170.8 , 170.4, 143.7, 137.9,
129.9, 126.9, 81.9, 54.2, 51.4, 39.7, 28.7, 28.1, 25.5, 21.5. HRMS
(m/z, ESI) calcd for C18H26N2NaO5S ([M+Na]+): 405.1455, found
405.1440.
tert-Butyl 2-((2R,3S)-3-(N-benzyl-4-methylphenylsulfonamido)-
6-oxopiperidin-2-yl)acetate (R,S)-16
To a solution of (2S,3S)-14 (0.24 g, 0.6280 mmol) with K2CO3
(0.1736 g, 1.2560 mmol) in MeCN (5 ml) was added BnBr (0.2143
g, 1.2560 mmol) under reflux. The resulting solution was stirred for
12 h. Then the volatile was removed and the residue was diluted
with ethyl acetate (50 ml), washed with brine, dried with anhydrous
MgSO4 and concentrated under reduced pressure. The residue was
purified by chromatography (SiO2, petroleum ether/ethyl acetate,
1 /1, v/v) to afford 0.226 g (70%) of (2S,3S)-16. 1H NMR (300 MHz,
CDCl3): 7.68 (d, J = 8.4 Hz, 2H); 7.34-7.26 (m, 7H), 6.16 (d, J =
3.0 Hz, 1H), 4.45 (s, 2H), 4.24-4.17 (m, 1H), 3.93-3.84 (m, 1H),
2.41 (s, 3H), 2.34-2.02 (m, 4H), 1.98-1.82 (m, 1H), 1.78-1.65 (m,
1H), 1.37 (s, 9H). 13C NMR (90 MHz, CDCl3): 170.4, 169.8, 143.9,
137.4, 130.0, 128.7, 127.9, 127.0, 81.6, 55.9, 51.0, 50.5, 36.7, 30.5,
28.0, 21.6, 21.5. HRMS (m/z, ESI) calcd for C25H32N2NaO5S
([M+Na]+): 495.1930, found 495.1915.
tert-Butyl 2-((2S,3S)-3-(4-methylphenylsulfonamido)-6-
oxopiperidin-2-yl)acetate (S,S)-14
[α]D20 = - 14.2 (c = 1.8, CH3OH). 1H NMR (250 MHz, CDCl3): 7.81
(d, J = 7.9 Hz, 2H), 7.31 (d, J = 7.9 Hz, 2H), 6.81 (d, J = 9.4 Hz,
1H), 6.71 (s,1H) 3.91-3.84 (m, 1H), 3.76-3.68 (m, 1H), 2.69 (dd, J =
5.0 Hz, J = 17.3 Hz, 1H) 2.52 (dd, J = 8,6 Hz, J = 17.3 Hz, 1H),
2.44-2.39 (m, 1H), 2.43 (s, 3H), 2.36-2.26 (m, 1H), 1.72-1.57 (m,
2H), 1.47 (s, 9H). 13C NMR (62.5 MHz, CDCl3): 171.7, 170.4,
143.3, 138.4, 129.7, 126.8, 81.8, 52.7, 49.3, 37.6, 28.1, 26.6, 25.1,
21.5. HRMS (m/z, ESI) calcd for C18H26N2NaO5S ([M+Na]+):
405.1455, found 405.1440.
tert-Butyl 2-((2R,3S)-3-(N-((benzyloxy)carbonyl)-4-
methylphenylsulfonamido)-6-oxopiperidin-2-yl)acetate
tert-Butyl 2-(3-((tert-butoxycarbonyl)amino)-6-oxopiperidin-2-
yl)acetate 21
(

R,

S)-17
A solution of compound 5a (0.6 g, 1.84 mmol, 1 equiv.) in dry
methanol(20 mL) was stirred for 12 h in the presence of 10%
Pd/(OH)2 (200 mg) under H2 atmosphere in room temperature.
Then the solution was filtered on celite and the filtrate was
concentrated under reduced pressure to give crude compound
(0.58 g). Then to the crude compound (0.58 g) in THF (10 mL)
under argon at 0°C was added a suspension of NaH (60%
dispersion in mineral oil, 0.22 g, 5.52 mmol, 3 equiv.) in THF (2 mL)
and allowed to stir for 30 min. Then benzyl chloroformate (0.79 mL,
5.52 mmol, 3 equiv.) was added, the mixture was allowed to stir for
12 h, and the reaction was quenched with crushed ice. The volatile
was removed, the residue was dissolved in ethyl acetate (50 mL),
washed with brine, dried with anhydrous MgSO4, filtered, and
concentrated under reduced pressure. The residue was purified by
chromatography (SiO2, petroleum ether/ethyl acetate, 1 /1, v/v) to
To a solution of a mixture of 14 (0.68 g, 1.779 mmol, 1 equiv.) in
THF (10 mL) under argon at 0°C was added a suspension of NaH
(60% dispersion in mineral oil, 213.5 mg, 5.337 mmol, 3 equiv.) in
THF (2mL) and allowed to stir for 30 min. Benzyl chloroformate
(0.76 mL, 5.337 mmol, 3 equiv.) was added, the mixture was
allowed to stir for 12h, and the reaction was quenched with crushed
ice. The volatile was removed, and the residue was dissolved in
ethyl acetate (50 mL), washed with brine, dried with anhydrous
MgSO4, filtered, and concentrated under reduced pressure. The
residue was purified by chromatography (SiO2, petroleum
ether/ethyl acetate, 1 /1, v/v) to afford 0.53 g (58%) of (2R,3S)-17
and 0.17 g (25%) of (2S,3S)-14. [α]D = +27 (c = 1.0, CH3OH). H
NMR (360 MHz, CDCl3): 7.63 (d, J = 8.6 Hz, 2H), 7.37-7.32 (m,
3H), 7.20 (dd, J = 1.8 Hz, J = 7.2 Hz, 2H), 7.16 (d, J = 8.6 Hz, 2H),
6.54 (s, 1H), 5.11 (s, 2H), 4.58-4.50 (m, 1H), 4.49-42 (m, 1H), 2.75
(dd, J = 1.8 Hz, J = 16.9 Hz, 1H), 2.70-2.61 (m, 1H), 2.50-2.36 (m,
3H), 2.40 (s, 3H), 1.86-1.82 (m, 1H), 1.46 (s, 9H). 13C NMR (90
MHz, CDCl3): 170.5, 170.4, 151.5, 145.0, 136.2, 133.9, 129.5,
128.9, 128.7, 128.7, 128.3, 82.1, 69.6, 57.7, 50.2, 39.2, 31.1, 28.1,
24.8, 21.6. HRMS (m/z, ESI) calcd for C26H32N2NaO7S ([M+Na]+):
539.1822, found 539.1809.
20
1
afford a yellow solid 0.26 g (30%) of
S, S)-22 as separated diastereomers. Then the Cbz group was
removed with Pd/C (0.05g and 0.04g respectively) in MeOH (5 mL
and 4 mL respectively) under H2 (1 bar) atmosphere to give R, S)-
21 and S, S)-21 in quantitative yield.
tert-Butyl 2-((2R,3S)-3-(N-((benzyloxy)carbonyl)- tert-
butoxycarbonyl)-6-oxopiperidin-2-yl)acetate R, S)-22
(R,S)-22 and 0.20 g (24%) of
( 
( 
( 
(
 
1H NMR (360 MHz, CDCl3) : δ 7.45 (d, J = 6.8 Hz, 2H), 7.41-7.27
(m, 3H), 5.38-5.28 (ABq, J = 12.3 Hz, 2H), 5.16 (d, J = 9.3 Hz, 1H),
4.46-4.37 (m, 1H), 4.31-4.23 (m, 1H), 2.82 – 2.61 (m, 1H), 2.44
(ddd, J = 17.9, 9.7, 2.6 Hz, 2H), 2.32 (dd, J = 15.2, 7.6 Hz, 1H),
tert-Butyl 2-((2R,3S)-3-(((benzyloxy)carbonyl)amino)-6-
oxopiperidin-2-yl)acetate (R,S)-18
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701477
European Journal of Organic Chemistry
FULL PAPER
2.10 – 1.89 (m, 2H), 1.49 (s, 9H), 1.36 (s, 9H). 13C NMR (360 MHz,
CDCl3): δ 173.6, 170.2, 155.7, 155.1, 135.4, 129.6, 129.2, 129.1,
81.5, 79.8, 68.2, 60.7, 49.1, 37.7, 31.7, 28.1, 19.6. HRMS (m/z,
ESI) calcd for C24H34N2NaO7 ([M+Na]+) 485.2264, found 485.2250.
tert-Butyl 2-((2S,3S)-3-(N-((benzyloxy)carbonyl)- tert-
1 eq.) in dry MeOH (5 mL) was stirred for 30 min in the presence of
10 wt. % Pd/C (24 mg, 0.23 mmol, 0.5 eq.) at room temperature
under H2 (1 bar). Filtration of the catalyst through celite pad and
concentration under reduced pressure gave compound 23b (147
mg ) as a white solid in quantitative yield. Compound 23a (175 mg,
0.45 mmol, 1 eq.) was preactivated with HATU (170 mg, 0.45 mmol,
1 eq.) and DiPEA (0.15 ml, 0.90 mmol, 2 eq.) in DMF (3 mL) for 15
min at room temperature under argon before a solution of 23b (147
mg, 0.47 mmol, 1.1 eq.) in DMF (2 mL) was added. The resulting
mixture was then stirred for 12 h then diluted with ethyl acetate (100
mL) and washed with 10% aqueous citric acid, saturated NaHCO3
aqueous and brine. The organic layer was dried with anhydrous
MgSO4, filtered and concentrated under reduced pressure. Crude
product was purified by chromatography (SiO2, MeOH/DCM = 5/95,
v/v) to give compound 24 (146 mg) as a white solid in 48% yield.
1H NMR (360 MHz, CD3OH): δ 8.14 (d, J = 9.1 Hz, 1 H), 7.96 (s, 1H),
7.91 (d, J = 9.1 Hz, 1H), 7.44 (s, 1H), 7.38-7.27 (m, 5H), 7.15 (s, H28, 1H),
5.06 (s, 2H), 4.11-3.99 (m, 1H), 3.93-3.82 (m, 1H), 3.73-3.63 (m, 1H),
3.57-3.47 (m, 1H), 2.77 (dd, J1 = 2.3 Hz, J2 = 17.0 Hz, 1H), 2.48-2.35 (m,
6H), 2.19 (dd, J1 = 14.9 Hz, J2 = 7.1 Hz, 1H), 2.01-1.77 (m, 4H), 1.46 (s,
9H), 1.44 (s, 6H), 1.40 (s, 6H). 13C NMR (90 MHz, CDCl3): δ 177.5, 177.0,
174.2, 173.6, 172.4, 172.1, 157.4, 138.2, 129.6, 129.2, 129.0, 82.6, 67.7,
57.9, 57.7, 55.4, 54.7, 48.5, 39.7, 38.8, 30.7, 30.4, 28.5, 27.0, 26.5, 26.3,
24.9, 24.4. HRMS (m/z, ESI) calcd for C34H50N6NaO9 ([M+Na]+) 709.3537,
found 709.3528
butoxycarbonyl)-6-oxopiperidin-2-yl)acetate (S,S)-22
1H NMR (360 MHz, CDCl3): δ 7.45 (d, J = 7.1 Hz, 2H), 7.39-7.27
(m, 3H), 5.32-5.24 (ABq, J = 12.3, 2H), 5.00 (d, J = 9.5 Hz, 1H),
4.40-4.34 (m, 1H), 4.27 – 4.13 (m, 1H), 2.85-2.59 (m, 1H), 2.59-
2.34 (m, 2H), 2.28 (dd, J = 15.4, 7.8 Hz, 1H), 2.16 (tt, J = 11.9, 9.4
Hz, 1H), 1.97 (dd, J = 14.6, 7.5 Hz, 1H), 1.42 (s, 9H), 1.37 (s, 9H).
13C NMR (360 MHz, CDCl3): δ 174.0, 169.8, 155.4, 152.2, 135.1,
128.6, 128.4, 128.3, 128.0, 81.5, 79.9, 68.4, 59.9, 51.4, 38.6, 31.4,
28.3, 28.0, 22.5. HRMS (m/z, ESI) calcd for C24H34N2NaO7
([M+Na]+) 485.2264, found 485.2250.
tert-Butyl 2-((2R,3S)-3-((tert-butoxycarbonyl)amino)-6-
oxopiperidin-2-yl)acetate (R,S)-21
[α]D20 = - 62.4 (c = 2.5, CH3OH). 1H NMR (360 MHz, CDCl3) : δ 6.65
(s, 1H), 5.29 (d, J = 8.8 Hz, 1H), 3.99-3.81 (m, 1H), 3.77-3.60 (m,
1H), 2.46-2.20 (m, 4H), 2.20-2.01 (m, 1H), 1.88-1.79 (m, 1H), 1.38
(s, 9H), 1.36 (s, 9H). 13C NMR (90 MHz, CDCl3): δ 178.7, 170.6,
155.6, 81.4, 79.5, 57.8, 51.1, 36.6, 29.7, 29.3, 27.9, 23.2. HRMS
(m/z, ESI) calcd for C16H27N2O5 ([M-H]-) 327.1920, found 327.1914.
tert-Butyl 2-((2S,3S)-3-((tert-butoxycarbonyl)amino)-6-
oxopiperidin-2-yl)acetate (S,S)-21
[α]D20 = - 30.0 (c = 2.4, CH3OH). 1H NMR (360 MHz, CDCl3): δ 6.99
(s, 1H), 5.17 (d, J = 9.4 Hz, 1H), 4.08-3.96 (m, 1H), 3.83-3.76 (m,
1H), 2.52-2.29 (m, 4H), 2.25 - 2.13 (m, 1H), 1.93-1.85 (m, 1H), 1.43
(s, 9H), 1.42 (s, 9H). 13C NMR (90 MHz, CDCl3): δ 179.1, 170.1,
155.4, 80.9, 79.7, 57.4, 51.2, 38.6, 30.2, 28.3, 28.0, 24.2. HRMS
(m/z, ESI) calcd for C16H27N2O5 ([M-H]-) 327.1920, found 327.1914.
Acknowledgements
We thank the CSC (China Scholarship Council, doctoral grant
for Y.W.) and M.E.S.R. (doctoral grant to F.B.) for financial
support.
Dipeptide 23
A solution of compound (R, S)-18 (51 mg, 0.14 mmol, 1 eq.) in
dry MeOH (3 mL) was stirred for 30 min in the presence of 10 wt. %
Pd/C (15 mg, 0.14 mmol, 1 eq.) at room temperature under H2 (1
bar). Filtration of the catalyst through celite pad and concentration
under reduced pressure gave expected compound (31 mg) as a
white solid in quantitative yield. Z-AIB-OH (35 mg, 0.15 mmol, 1.1
eq.) was preactivated with HATU (57 mg, 0.15 mmol, 1.1 eq.) and
DiPEA (52 μL, 0.30 mmol, 2 eq.) in DMF (2 mL) at room
temperature under argon for 15 min before a solution of NH2-LAC-
OtBu (31 mg, 0.14 mmol, 1 eq.) in DMF (1 mL) was added. The
resulting mixture was then stirred for 12 h then diluted with ethyl
acetate (50 mL) and washed with 10% aqueous citric acid,
saturated aqueous NaHCO3 and brine. The organic layer was dried
with anhydrous MgSO4, filtered and concentrated under reduced
pressure. Crude product was purified by chromatography (SiO2,
MeOH/DCM = 3/97, v/v) to give compound 23 (44 mg) as a white
solid in 77% yield.
1H NMR (360 MHz, CDCl3): δ 7.36-7.30 (m, 5H), 6.77 (d, J = 8.7
Hz, 1H), 6.48 (s, 1H), 5.52 (s, 1H), 5.10-5.03 (m, 2H), 3.97-3.89 (m,
1H), 3.54-3.50 (m, 1H), 2.65 (d, J = 17.9 Hz, 1H), 2.41-2.31 (m,
3H), 1.90-1.82 (m, 1H), 1.74-1.66 (m, 1H), 1.50 (s, 3H), 1.49 (s,
3H), 1.44 (s, 9H). 13C NMR (90 MHz, CDCl3): δ 174.7, 171.0, 170.9,
155.4, 136.2, 128.8, 128.5, 128.4, 82.0, 67.1, 57.2, 54.0, 47.3, 40.0,
29.1, 28.2, 25.7, 25.6, 25.4. HRMS (m/z, ESI) calcd for
C23H33N3NaO6 ([M+Na]+) 470.2267, found 470.2247.
Keywords: Amino acid • Blaise reaction • kinetic resolution • -
lactam • -lactam
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Entry for the Table of Contents (Please choose one layout)
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Non natural amino acids *
Y. Wan, N. Auberger, S. Thétiot-Laurent,
F. Bouillère, A. Zulauf, J. He, S. Courtiol-
Legourd, R. Guillot, C. Kouklovsky, S.
Cote des Combes, C. Pacaud, I.
Devillers, and V. Alezra*
New constrained cyclic -diamino acids were synthesized starting from L-glutamic
acid. The key steps are a Blaise reaction and a reduction which gave access to
both diastereomers. Changing the protecting group can lead to either 5-member
ring lactam, which can be used as -amino acid, or to 6-member ring lactam, as -
amino acid. An interesting kinetic resolution was observed during the synthesis
which allowed easier diastereomer separation.
Page No. – Page No.
New constrained cyclic -diamino
acids from glutamic acid: synthesis
of both diastereomers and
unexpected kinetic resolution
*one or two words that highlight the emphasis of the paper or the field of the study
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