Straightforward synthesis of non-natural l-chalcogen and l-diselenide N-Boc-protected-γ-amino acid derivatives

Article abstract of DOI:10.1039/c3ob40879e

The synthesis of new chiral seleno-, telluro-, and thio-N-Boc-γ-amino acids is described herein. These new compounds were prepared through a simple and short synthetic route, from the inexpensive and commercially-available amino acid l-glutamic acid. The products, with a highly modular character, were obtained in good to excellent yields, via hydrolysis of chalcogen pyroglutamic derivatives with overall retention of the l-glutamic acid stereochemistry. Also, an l-diselenide-N-Boc-γ-amino acid was prepared in good yield. This new synthetic route represents an efficient method for preparing new l-chalcogen- and l-diselenide-γ-amino acids with biological potential.

Full text of DOI:10.1039/c3ob40879e

Organic &
Biomolecular Chemistry
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Straightforward synthesis of non-natural L-chalcogen
and L-diselenide N-Boc-protected-γ-amino acid
derivatives†
Cite this: Org. Biomol. Chem., 2013, 11,
5173
Cristiane Y. Kawasoko,a Patricia Foletto,a Oscar E. D. Rodrigues,a Luciano Dornelles,a
Ricardo S. Schwab*b and Antonio L. Braga*c
The synthesis of new chiral seleno-, telluro-, and thio-N-Boc-γ-amino acids is described herein. These new
compounds were prepared through a simple and short synthetic route, from the inexpensive and com-
mercially-available amino acid L-glutamic acid. The products, with a highly modular character, were
obtained in good to excellent yields, via hydrolysis of chalcogen pyroglutamic derivatives with overall
retention of the L-glutamic acid stereochemistry. Also, an L-diselenide-N-Boc-γ-amino acid was prepared
in good yield. This new synthetic route represents an efficient method for preparing new L-chalcogen-
and L-diselenide-γ-amino acids with biological potential.
Received 29th April 2013,
Accepted 3rd June 2013
DOI: 10.1039/c3ob40879e
www.rsc.org/obc
key role in the mode of action of such proteins, which cannot
be played by its closest relative, sulfur.6
Introduction
Since the discovery of the biological importance of selenium
Despite the increasing importance of selenium and tellur-
as one of the essential trace elements,1 organochalcogen ium analogues of sulfur amino acids and even though a
compounds have emerged as an exceptional class of struc- number of efficient synthetic methods for the synthesis of sele-
tures that exemplify the role of Se in biochemical processes, nocysteine derivatives have been developed, the introduction
serving as important therapeutic compounds ranging from of a chalcogen atom into an amino acid remains a significant
antiviral and anticancer agents to naturally occurring food challenge.7 In this context, in recent years our group has been
supplements.2
working intensively towards the development of protocols to
In addition, research on amino acids has gained enormous prepare chalcogen α-amino acids, through the ring opening of
popularity and relevance in recent years, particularly with the chiral systems8 and through the O-mesylated L-serine inter-
emergence of unnatural analogs as components of molecules mediate generated in situ and directly substituted with various
with therapeutic potential.3 The most important group of sele- selenolate anions (Scheme 1).9
nium and tellurium compounds with interesting biological
Although the synthesis of chiral chalcogen amino acids
properties is derived from the chalcogen cysteine analogues has been successfully accomplished, all procedures reported
and their derivatives, such as selenocysteine, selenomethio- are restricted to the synthesis of chalcogen α-amino acids.
nine and the analogous tellurium compounds. Many seleno- Over the past few years, pyroglutamic acid (also known as
enzymes have a selenocysteine residue at the active site as a
catalyst for various redox reactions.4 Perhaps the most impor-
tant of these are glutathione peroxidase (GPx) and thioredoxin
reductase (TrxR).5 It is known that the selenium atom plays a
aDepartamento de Química, Universidade Federal de Santa Maria, 97105-900 Santa
Maria, RS, Brazil
bDepartamento de Química, Universidade Federal de São Carlos, 13565-905 São
Carlos, SP, Brazil. E-mail: rschwab@ufscar.br; Tel: +55 (16) 3351-8081
cDepartamento de Química, Universidade Federal de Santa Catarina, 88040-970
Florianópolis, SC, Brazil. E-mail: braga.antonio@ufsc.br; Tel: +55 (48) 3721-6427
†Electronic supplementary information (ESI) available: 1H and 13C NMR spectra
for all new compounds. See DOI: 10.1039/c3ob40879e
Scheme 1 Retrosynthesis of chalcogen α-amino acid derivatives.
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Fig. 1 Examples of important γ-amino acids.
5-oxo-proline)10 derived from glutamic acid has been the
focus of attention as a chiral building block.11 This has been
used as an important starting material for the synthesis of
many natural products12 and for γ-amino acids, easily pre-
pared by hydrolysis under acidic or basic conditions.13 In this
context γ-amino acids have attracted considerable attention
as biologically active compounds. γ-Aminobutyric acid
(GABA) is the major inhibitory neurotransmitter in the
central nervous system of mammals.14 GABA deficiency is
also associated with several important neurological disorders,
such as Huntington’s and Parkinson’s disease, epilepsy,
other psychiatric disorders (e.g., anxiety) and pain.15 Many
other γ-amino acids have been the focus of attention due to
their biological activity, including 4-amino-5-hexenoic acid
(Vigabatrin®), 4-amino-3-(p-chlorophenyl)butyric acid (Baclo-
fen) and (S)-3-aminomethyl-5-methylhexanoic acid (Pregaba-
lin) (Fig. 1).
Stimulated by our recent work on the synthesis of chiral
selenium-containing non-natural amino acids8,9 and pep-
tides,8e,16 selenium- and tellurium-nucleosides17 and, more
recently, chiral selenium- and telluro-amino acids18 and orga-
noselenides and diselenides19 which possess strong gluta-
thione peroxidase-like (GPx-like) activity, we describe herein an
efficient and straightforward synthetic route for the prepa-
ration of novel chiral chalcogen and diselenide γ-amino acids
through the hydrolysis of γ-lactam compounds with a chalco-
gen atom incorporated into their structures, prepared from
L-glutamic acid.
Scheme 2 Synthesis of mesylate γ-lactam 4. Reagents and conditions: (i) H2O,
reflux, 63 h; (ii) MeOH, SOCl2, room temp., 48 h; (iii) NaBH4, EtOH, room temp.,
2 h; (iv) Et3N, MsCl, CH2Cl2, 0 °C, 3 h.
the OMs leaving group (Table 1). Organoselenium anions were
generated through the reaction of diphenyl diselenide with
NaBH4 in a mixture of THF and ethanol, as previously
described.23 Under these conditions, mesylate 4 was cleanly
converted to seleno-γ-lactam and the product was isolated in
80% yield (Table 1, entry 1). Next, we extended our studies to a
broader range of selenium nucleophiles, in order to prepare a
small library of compounds. The reaction was tolerant to a
variety of substituents at the aromatic ring of the organosele-
nium moiety, allowing the preparation of a series of seleno-
γ-lactams. It can be verified that the reaction was not influ-
enced by electronic or steric effects (Table 1, entries 2–4). Ali-
phatic diselenides were also used as a selenium source, with
Bn and Et as R groups, and the compounds were obtained in
good yields showing the versatility of the protocol in terms of
the selenium moiety (Table 1, entries 7 and 8). It is noteworthy
that all reactions proceeded smoothly, with very low by-product
formation.
Due to the success achieved in the preparation of a wide
range of chiral seleno-γ-lactams, we decided to extend our
studies to thio and telluro analogues, in order to prepare a
series of chalcogen-γ-lactam derivatives. In fact, the reduction
of diorganyl ditelluride or diorganyl disulfide with NaBH4, fol-
lowed by reaction with 4, delivered the corresponding telluro-
γ-lactams 5i and 5j and thio-γ-lactams 5l–5p in good yields
(Table 1, entries 9–15).
Following the protocol previously reported,24 the com-
pounds 5a–p were protected with Boc2O, in the presence of tri-
ethylamine and 4-dimethylaminopyridine in CH2Cl2, to afford
the L-chalcogen-N-Boc-γ-lactams 6a–p in excellent yields
(Scheme 3). This protection is necessary in order to render the
“amide” carbonyl more susceptible to nucleophilic attack
under mild conditions.25
Results and discussion
In keeping with our aim, as the starting point of this study we
sought an efficient way to prepare the key chiral mesylate
γ-lactam 4 in a short and high yielding sequence. To accom-
plish this task we used a methodology previously described
in the literature,20 where L-glutamic acid 1 is converted to pyro-
glutamic acid by heating with H2O, followed by esterifica-
tion, in the presence of MeOH and SOCl2 to afford the
corresponding pyroglutamic methyl ester 2 in 95% yield. Sub-
sequent reduction with NaBH4 in EtOH led to alcohol 3 in
70% yield.21 The reaction of the primary hydroxyl group with
methanesulfonyl chloride in CH2Cl2 using triethylamine
as a base delivered the desired mesylate 4 in 85% yield22
(Scheme 2).
With the L-chalcogen-N-Boc-γ-lactams (6a–p) in hand, we
turned our attention to performing the hydrolysis under basic
With the required mesylate 4 in hand we turned our atten-
tion to the introduction of the organoselenium moiety in the
γ-lactam backbone through the nucleophilic substitution of
Scheme 3 Synthesis of L-chalcogen-N-Boc-γ-lactams 6a–p.
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conditions26 in order to prepare a small library of L-chalcogen-
N-Boc-γ-amino acids (Table 2).
Table 1 Synthesis of selenium-, telluro- and thio-γ-lactamsa
As summarized in Table 2, a series of L-chalcogen-N-Boc-
γ-amino acids were obtained in moderate to good yields. It can
be observed that steric effects exerted some influence during
the hydrolysis. Substituents attached to the para-position
of seleno-N-Boc-γ-lactams furnished better yields (Table 2, entries
2 and 4) than the same substituents in the ortho position
(entries 3 and 5). On the other hand, electron-donating (Table 2,
entries 2, 3 and 6) and electron-withdrawing (entries 4 and 5)
groups attached to the aromatic ring did not display any influ-
ence on the yield. Additionally, aliphatic groups attached to the
selenium-γ-lactams showed good results. For instance, the
benzyl group furnished the product 7h in good yield (Table 2,
entry 8), whereas the ethyl group attached to selenium
afforded the product 7g in moderate yield (entry 7). Moreover,
the hydrolysis reaction of telluro- and thio-N-Boc-γ-lactams
provided the corresponding N-Boc-γ-amino acids 7i–p in good
to excellent yields (Table 2, entries 9–15).
Encouraged by the success in the synthesis of L-chalcogen-
N-Boc-γ-amino acids we decided to synthesize an L-diselenide-
N-Boc-γ-amino acid 12. To accomplish this task, we took
advantage of our previous strategy for the synthesis of chiral
β-amino diselenides, which employs the nucleophilic ring
opening of N-Boc aziridines with lithium diselenide.27 The
treatment of mesylate γ-lactam 4 with lithium diselenide,
which is readily accessible through the addition of appropriate
amounts of Super Hydride (1 M solution in THF) to powdered
gray selenium, afforded the product in unacceptably low yield
(34%) with a complex mixture of by-products (Scheme 4). This
result prompted us to look for an alternative approach to
achieve our aim. It is reported in the literature that the for-
mation of diselenides via the cross-coupling of aryl and alkyl
iodides with elemental selenium, under basic conditions
using copper oxide as a catalyst in DMSO, can be accom-
plished efficiently in high yield.28 However, with this approach,
the diselenide-γ-lactam 8 was prepared in only 15% yield and
the results are summarized in Scheme 4. Although the yield
obtained in this reaction was lower compared to that obtained
using lithium diselenide, the product was easily isolated after
purification.
Entry
1
RYYR
Product
Yieldb (%)
80
(PhSe)2
5a
5b
2
3
4
(4-MePhSe)2
(2-MePhSe)2
(4-ClPhSe)2
77
80
75
5c
5d
5
6
(2-ClPhSe)2
5e
5f
80
78
(2-MeOPhSe)2
7
8
(EtSe)2
5g
5h
70
71
(BnSe)2
9
(PhTe)2
5i
5j
75
73
10
(4-ClPhTe)2
11
12
(PhS)2
5l
75
77
(4-MePhS)2
5m
In an alternative approach, we decided to change the
leaving group in the side-chain of γ-lactam 4 to a tosyl group
via treatment of the aminoalcohol 3 with p-toluenesulfonyl
chloride in the presence of triethylamine and using 4-dimethyl-
aminopyridine as a catalyst, providing the corresponding
13
14
15
(4-ClPhS)2
(2-ClPhS)2
(4-MeOPhS)2
5n
5o
5p
69
78
62
a Reactions were performed in the presence of mesylate 4 (2.2 mmol),
diorganyl dichalcogenide (1.1 mmol) and THF–EtOH (3 : 1) at room
temperature under an argon atmosphere overnight. b Isolated yields.
Scheme 4 Synthesis of L-diselenide-γ-lactam 8. Reagents and conditions: (i)
Se0, LiEt3BH, THF, reflux, 30 min, this solution was then added dropwise to mesy-
late γ-lactam 4 under −78 °C, room temp., 12 h, (ii) Se0, 20 mol% CuO, KOH,
DMSO, 90 °C, 24 h.
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Table 2 Synthesis of L-chalcogen-N-Boc-γ-amino acids 7a–pa
Entry
1
Product
Yieldb (%)
70
7a
7b
2
3
4
80
70
75
Scheme 5 Synthesis of L-diselenide-N-Boc-γ-amino acid 12.
7c
tosylate 9 in 90% yield, as depicted in Scheme 5.29 Subsequent
protection with di-tert-butyl dicarbonate afforded the tosylate
N-Boc-γ-lactam 10 in good yield.30 Treatment of tosylate N-Boc-
γ-lactam with elemental selenium under basic conditions,
using 20 mol% of copper oxide as a catalyst, in DMSO, furn-
ished the diselenide 11 in moderate 50% yield. Finally, treat-
ment of L-diselenide-N-Boc-γ-lactam with LiOH 1 N and THF at
room temperature afforded L-diselenide-N-Boc-γ-amino acid 12
in 50% yield.
7d
5
6
7e
7f
50
80
Conclusions
7
7g
7h
7i
55
78
72
80
In summary, we have described herein the preparation of a
new class of chiral selenium-, telluro-, and thio-N-Boc-γ-amino
acid derivatives from L-glutamic acid. These compounds were
prepared via a concise and flexible route, in good to excellent
yields, which permitted the preparation of a wide range of
compounds with a highly modular character. Additionally, the
method was easily adapted to the synthesis of L-diselenide-N-
Boc-γ-amino acid.
8
9
10
7j
We also emphasize that this modular approach may have
significant importance in the design of new L-chalcogen and
L-diselenide N-Boc-γ-amino acid compounds for biological
screening.
11
12
7l
60
98
7m
Experimental section
General
13
7n
84
Hydrogen nuclear magnetic resonance (1H NMR) spectra were
obtained on a Bruker DPX-400 MHz or DPX-200 MHz spectro-
meter. Spectra were recorded in CDCl3 solutions. Chemical
shifts are reported in parts per million, referenced to the
solvent peak of TMS. Data are reported as follows: chemical
shift (d), multiplicity (br = broad, s = singlet, d = doublet, dd =
double doublet, t = triplet, m = multiplet), and coupling con-
stant ( J) in hertz and integrated intensity. Carbon-13 nuclear
magnetic resonance (13C NMR) spectra were obtained at
50 MHz or 100 MHz. Spectra were recorded in CDCl3 solutions.
Chemical shifts are reported in ppm, referenced to the solvent
peak of CDCl3. High-resolution mass spectra (ESI) were
14
15
7o
7p
84
93
a Reactions were performed in the presence of L-chalcogen-N-Boc-
γ-lactams (1.0 mmol), THF (3.0 mL) and a 1.0 M solution of LiOH at
room temperature. b Isolated yields.
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obtained at the Institute of Plant Biochemistry, Halle-Saale, CDCl3): δ = 177.82, 139.57, 132.34, 129.89, 129.65, 127.14,
Germany, using a Bruker BioApex 70 eV spectrometer. Optical 126.35, 53.78, 32.72, 30.01, 26.89, 22.23 ppm. HRMS-ESI: m/z
rotations were carried out on a Perkin Elmer Polarimeter 341. calcd for C12H15NOSe [M + Na]+ 292.0217; found 292.0209.
Column chromatography was performed using Merck Silica
(S)-5-((4-Chlorophenylselanyl)methyl)pyrrolidin-2-one (5d).
Gel (230–400 mesh). Thin layer chromatography (TLC) was per- Pale yellow solid. mp 80–81 °C; yield: 75%; [α]2D0 = +76 (c = 1.0;
formed using Merck Silica Gel GF254, 0.25 mm. For visualiza- CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 7.45 (d, 2 H, J =
tion, TLC plates were either placed under ultraviolet light, or 8.4 Hz), 7.24 (d, 2 H, J = 8.4 Hz), 6.54 (br, 1 H), 3.83–3.77 (m,
stained with iodine vapor, or acidic vanillin. Anhydrous sol- 1 H), 3.01 (dd, 1 H, J1 = 12.6 Hz, J2 = 5.6 Hz), 2.89 (dd, 1 H, J1 =
vents were obtained as follows: THF was distilled from sodium 12.6 Hz, J2 = 7.2 Hz), 2.44–2.22 (m, 3 H), 1.84–1.75 (m, 1 H)
and benzophenone. Dichloromethane and triethylamine were ppm. 13C NMR (100 MHz, CDCl3): δ = 177.99, 134.58, 133.60,
distilled from CaH2. All other solvents were used as purchased. 129.25, 126.91, 53.87, 34.39, 30.15, 26.90 ppm. HRMS-ESI: m/z
CuO nanoparticles (the mean particle size, 33 nm, surface calcd for C11H12ClNOSe [M + Na]+ 311.9670; found 311.9667.
area, 29 m2 g−1 and purity of 99.99%) were purchased from
(S)-5-((2-Chlorophenylselanyl)methyl)pyrrolidin-2-one (5e).
Sigma Aldrich. The pyroglutamic methyl ester20 2, the corres- Yellow oil. Yield: 80%; [α]D20 = +29 (c = 1.0; CH2Cl2). 1H NMR
ponding amino alcohol21 3, mesylate γ-lactam22 4, tosylate (400 MHz, CDCl3): δ = 7.37 (br, 1 H), 7.36–7.29 (m, 2 H),
γ-lactam29 9 and tosylate N-Boc-γ-lactam30 10 have been pre- 7.17–7.15 (m, 2 H), 3.87–3.81 (m, 1 H), 3.02 (d, 2 H, J = 6.4 Hz),
viously prepared and characterized.
2.43–2.24 (m, 3 H), 1.86–1.78 (m, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 177.89, 135.62, 132.01, 130.04, 129.39,
127.85, 127.10, 54.50, 32.47, 29.97, 28.85 ppm. HRMS-ESI: m/z
calcd for C11H12ClNOSe [M + Na]+ 311.9670; found 311.9660.
(S)-5-((2-Methoxyphenylselanyl)methyl)pyrrolidin-2-one (5f).
General procedure for the synthesis of L-chalcogen-γ-lactams
derivatives 5a–p
Under an argon atmosphere, NaBH4 (0.09 g, 2.5 mmol) was
added to a solution of diorganyl dichalcogenide (0.34 g, White solid. mp 112–113 °C; yield: 70%; [α]2D0 = +83 (c = 1.0;
1.1 mmol) in THF (3.3 mL) at room temperature. Ethanol CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 7.45–7.43 (m, 1 H),
(1.1 mL) was added dropwise and the mixture was stirred for 7.30–7.26 (m, 1 H), 6.92–6.86 (m, 2 H), 6.33 (br, 1 H), 3.92 (s, 3
10 minutes. After this time a solution of mesylate γ-lactam 4 in H), 3.80–3.74 (m, 1 H), 3.06 (dd, 1 H, J1 = 12.4 Hz, J2 = 5.2 Hz),
THF (3.0 mL) was added, and the resulting mixture was stirred 2.81 (dd, 1 H, J1 = 12.4 Hz, J2 = 8.4 Hz), 2.45–2.25 (m, 3 H),
at room temperature overnight. The reaction was quenched 1.87–1.77 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
with 10 mL of a NH4Cl solution, and the aqueous layer was 177.51, 158.36, 133.40, 128.94, 121.41, 117.27, 110.71, 55.78,
extracted with CH2Cl2 (3.0 × 20 mL). The combined organic 53.94, 31.86, 30.20, 27.31 ppm. HRMS-ESI: m/z calcd for
extracts were dried over MgSO4, filtered and evaporated to C12H15NO2Se [M + Na]+ 308.0268; found 308.0163.
dryness. The crude products were purified in a silica gel
(S)-5-(Ethylselanylmethyl)pyrrolidin-2-one (5g). Pale yellow
column for chromatographic purification, using hexane–ethyl oil. Yield: 70%; [α]2D0 = +14 (c = 1.0; CH2Cl2). 1H NMR
acetate (10 : 90) as the eluent.
(400 MHz, CDCl3): δ = 6.98 (br, 1 H), 3.89–3.82 (m, 1 H), 2.74
(S)-5-(Phenylselanylmethyl)pyrrolidin-2-one (5a). Yellow oil. (dd, 1 H, J1 = 12.4 Hz, J2 = 6 Hz), 2.64–2.59 (m, 3 H), 2.43–2.29
Yield: 80%; [α]D20 = +73 (c = 1.0; CH2Cl2). H NMR (400 MHz, (m, 3 H), 1.86–1.77 (m, 1 H), 1.40 (t, 3 H, J = 7.6 Hz) ppm. 13C
1
CDCl3): δ = 7.54–7.51 (m, 2 H), 7.28–7.27 (m, 3 H), 6.79 (br, NMR (50 MHz, CDCl3): δ = 178.02, 54.37, 30.28, 29.61, 27.19,
1 H), 3.83–3.76 (m, 1 H), 3.01 (dd, 1 H, J1 = 12.8 Hz, J2 = 6 Hz), 17.94, 15.73 ppm. HRMS-ESI: m/z calcd for C7H13NOSe
2.91 (dd, 1 H, J1 = 12.8 Hz, J2 = 7.6 Hz), 2.44–2.26 (m, 3 H), 230.0060; found 230.0054.
1.85–1.76 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
(S)-5-(Benzylselanylmethyl)pyrrolidin-2-one (5h). Pale yellow
177.75, 133.33, 129.21, 128.62, 127.50, 53.93, 34.10, 30.18, solid. mp 68–69 °C; yield: 71%; [α]2D0 = +50 (c = 1.0; CH2Cl2). 1H
27.14 ppm. HRMS-ESI: m/z calcd for C11H13NOSe [M + Na]+ NMR (200 MHz, CDCl3): δ = 7.35–7.22 (m, 5 H), 6.17 (br, 1H),
278.0060; found 278.0059.
3.81 (s, 2 H), 3.75–3.63 (m, 1 H), 2.63 (dd, 1 H, J1 = 12.6 Hz, J2
(S)-5-(p-Tolylselanylmethyl)pyrrolidin-2-one (5b). Yellow oil. = 5.4 Hz), 2.51 (dd, 1 H, J1 = 12.6 Hz, J2 = 7.6 Hz), 2.39–2.20 (m,
1
Yield: 77%; [α]2D0 = +61 (c = 1.04; CH2Cl2). H NMR (400 MHz, 3 H), 1.76–1.62 (m, 1 H) ppm. 13C NMR (50 MHz, CDCl3): δ =
CDCl3): δ = 7.28 (d, 2 H, J = 8.4 Hz), 7.08 (d, 2 H, J = 8.4 Hz), 178.02, 138.61, 128.65, 128.37, 126.71, 54.05, 30.13, 29.82,
6.80 (br, 1H), 3.80–3.74 (m, 1 H), 2.95 (dd, 1 H, J1 = 12.6 Hz, 27.43, 26.95 ppm. HRMS-ESI: m/z calcd for C12H15NOSe
J2 = 6 Hz), 2.87 (dd, 1 H, J1 = 12.4 Hz, J2 = 7.2 Hz), 2.42–2.21 [M + Na]+ 292.0217; found 292.0212.
(m, 6 H), 1.83–1.74 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3):
(S)-5-(Phenyltellanylmethyl)pyrrolidin-2-one (5i). Dark yellow
δ = 177.74, 137.60, 133.76, 129.97, 124.70, 53.94, 34.30, 30.16, oil. Yield: 75%; [α]2D0 = +39 (c = 1.0; CH2Cl2). 1H NMR
27.09, 20.95 ppm. HRMS-ESI: m/z calcd for C12H15NOSe (400 MHz, CDCl3): δ = 7.78–7.73 (m, 2 H), 7.36–7.17 (m, 3 H),
[M + Na]+ 292.0217; found 292.0213.
6.64 (br, 1 H), 3.92–3.79 (m, 1 H), 3.06 (dd, 1 H, J1 = 12 Hz, J2 =
(S)-5-(o-Tolylselanylmethyl)pyrrolidin-2-one (5c). Pale yellow 6 Hz), 2.90 (dd, 1 H, J1 = 12 Hz, J2 = 6.8 Hz), 2.43–2.22 (m, 3 H),
1
solid. mp 42–44 °C; yield: 80%; [α]2D0 = +73 (c = 1.0; CH2Cl2). H 1.84–1.66 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
NMR (200 MHz, CDCl3): δ = 7.46–7.42 (m, 1 H), 7.32 (br, 1 H), 177.34, 139.03, 129.44, 128.21, 110.41, 55.04, 30.50, 28.85,
7.20–7.04 (m, 3 H), 3.85–3.73 (m, 1 H), 2.93 (d, 2 H, J = 6.4 Hz), 15.86 ppm. HRMS-ESI: m/z calcd for C11H13NOTe [M + Na]+
2.44–2.23 (m, 6 H), 1.89–1.71 (m, 1 H) ppm. 13C NMR (100 MHz, 327.9957; found 327.9960.
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(S)-5-((4-Chlorophenyltellanyl)methyl)pyrrolidin-2-one (5j). 2.0 mmol), and DMAP (0.12 g, 1.0 mmol) were added. The
Pale yellow solid. mp 74–75 °C; yield: 73%; [α]2D0 = +23 (c = 1.0; solution was stirred at room temperature under an argon
1
CH2Cl2). H NMR (400 MHz, CDCl3): δ = 7.67 (d, 2 H, J = 8.4 atmosphere overnight. The solvent was removed and the
Hz), 7.19 (d, 2 H, J = 8.4 Hz), 6.68 (br, 1 H), 3.88–3.82 (m, 1 H), residue was purified by chromatography on silica gel. Elution
3.05 (dd, 1 H, J1 = 12.4 Hz, J2 = 6.4 Hz), 2.90 (dd, 1 H, J1
=
with hexane–ethyl acetate (50 : 50) afforded the desired
12.4 Hz, J2 = 6.8 Hz), 2.46–2.27 (m, 3 H), 1.80–1.70 (m, 1 H) products.
ppm. 13C NMR (100 MHz, CDCl3): δ = 177.70, 140.41, 134.85,
(S)-tert-Butyl 2-oxo-5-(phenylselanylmethyl)pyrrolidine-1-car-
129.69, 107.81, 54.86, 30.56, 28.64, 16.51 ppm. HRMS-ESI: m/z boxylate (6a). Pale yellow oil. Yield: 95%; [α]2D0 = −42 (c = 1.0;
calcd for C11H12ClNOTe [M + Na]+ 361.9567; found 361.9555.
CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 7.56–7.53 (m, 2 H),
(S)-5-(Phenylthiomethyl)pyrrolidin-2-one (5l). Colorless oil. 7.26–7.24 (m, 3 H), 4.35–4.30 (m, 1 H), 3.33 (dd, 1 H, J1 = 12.5
1
Yield: 75%; [α]2D0 = +90 (c = 1.0; CH2Cl2). H NMR (400 MHz, Hz, J2 = 2.8 Hz), 2.97 (dd, 1 H, J1 = 12.5 Hz, J2 = 9 Hz),
CDCl3): δ = 7.38–7.35 (m, 2 H), 7.29–7.18 (m, 3 H), 7.15 (br, 2.67–2.58 (m, 1 H), 2.43–2.36 (m, 1 H), 2.18–2.08 (m, 1 H),
1 H), 3.80–3.74 (m, 1 H), 3.00–2.97 (m, 2 H), 2.40–2.20 (m, 3 H), 2.01–1.95 (m, 1 H), 1.41 (s, 9 H) ppm. 13C NMR (100 MHz,
1.87–1.78 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = CDCl3): δ = 173.64, 149.16, 132.93, 128.89, 128.66, 127.13,
177.89, 134.69, 130.02, 128.88, 126.55, 53.29, 40.11, 29.81, 82.56, 57.24, 31.24, 30.78, 27.54, 22.11 ppm. HRMS-ESI: m/z
26.09 ppm. HRMS-ESI: m/z calcd for C11H13NOS [M + Na]+ calcd for C16H21NO3Se [M + Na]+ 378.0584; found 378.0573.
230.0616; found 230.0609.
(S)-tert-Butyl 2-oxo-5-(p-tolylselanylmethyl)pyrrolidine-1-car-
(S)-5-(p-Tolylthiomethyl)pyrrolidin-2-one (5m). White solid. boxylate (6b). Yellow oil. Yield: 80%; [α]2D0 = −22 (c = 1.0;
mp 86–87 °C; yield: 77%; [α]2D0 = +92 (c = 1.0; CH2Cl2). 1H NMR CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 7.45–7.40 (m, 2 H),
(400 MHz, CDCl3): δ = 7.28 (d, 2 H, J = 8.4 Hz), 7.09 (d, 2 H, J = 7.08–7.05 (m, 2 H), 4.34–4.29 (m, 1 H), 3.29 (dd, 1 H, J1 = 12.5
8.4 Hz), 6.47 (br, 1 H), 3.77–3.71 (m, 1 H), 2.98 (dd, 1 H, J1 = Hz, J2 = 2.8 Hz), 2.95 (dd, 1 H, J1 = 12.5 Hz, J2 = 9.4 Hz),
13.6 Hz, J2 = 5.6 Hz), 2.88 (dd, 1 H, J1 = 13.6 Hz, J2 = 7.4 Hz), 2.64–2.57 (m, 1 H), 2.42–2.34 (m, 1 H), 2.30 (s, 3 H), 2.15–2.07
2.40–2.20 (m, 6 H), 1.86–1.76 (m, 1 H) ppm. 13C NMR (m, 1 H), 2.01–1.93 (m, 1 H), 1.41 (s, 9 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 177.50, 137.19, 131.23, 131.06, 129.88, (100 MHz, CDCl3): δ = 173.57, 149.40, 137.33, 133.49, 129.81,
53.52, 41.36, 29.86, 26.49, 20.86 ppm. HRMS-ESI: m/z calcd for 125.12, 82.64, 57.50, 31.76, 30.95, 27.70, 22.34, 20.74 ppm.
C12H15NOS [M + Na]+ 244.0772; found 244.0764.
HRMS-ESI: m/z calcd for C17H23NO3Se [M + Na]+ 392.0843;
(S)-5-((4-Chlorophenylthio)methyl)pyrrolidin-2-one (5n). found 392.0734.
White solid. mp 51–53 °C; yield: 69%. [α]2D0 = +80 (c = 1.0;
(S)-tert-Butyl 2-oxo-5-(o-tolylselanylmethyl)pyrrolidine-1-car-
CH2Cl2). NMR 1H (400 MHz, CDCl3): δ = 7.32–7.26 (m, 4 H), boxylate (6c). Pale yellow oil. Yield: 90%; [α]D20 = −63 (c = 1.0;
5.80 (br, 1 H), 3.79–3.78 (m, 1 H), 3.06 (dd, 1 H, J1 = 13.6 Hz, J2 CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 7.55–7.53 (m, 1 H),
= 5 Hz), 2.87 (dd, 1 H, J1 = 13.6 Hz, J2 = 8.2 Hz), 2.42–2.26 (m, 3 7.19–6.07 (m, 3 H), 4.34–4.29 (m, 1 H), 3.31 (dd, 1 H, J1 = 12.5
H), 1.88–1.69 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = Hz, J2 = 2.8 Hz), 2.91 (dd, 1 H, J1 = 12.5 Hz, J2 = 9.6 Hz),
177.67, 133.56, 133.04, 131.78, 129.22, 53.41, 41.00, 29.86, 2.66–2.57 (m, 1 H), 2.43 (s, 3 H), 2.38–2.22 (m, 1 H), 2.18–1.99
26.41 ppm. HRMS-ESI: m/z calcd for C11H12ClNOS [M + Na]+ (m, 2 H), 1.43 (s, 9 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
264.0226; found 264.0221.
173.69, 149.28, 139.41, 132.51, 129.84, 129.67, 127.16, 126.36,
(S)-5-((2-Chlorophenylthio)methyl)pyrrolidin-2-one (5o). Pale 82.71, 57.20, 30.78, 29.99, 27.60, 22.25, 22.19 ppm. HRMS-ESI:
yellow oil. Yield: 78%. [α]D20 = +70 (c = 1.0; CH2Cl2). 1H NMR m/z calcd for
(400 MHz, CDCl3): δ = 7.45–7.34 (m, 2 H), 7.17–7.15 (m, 2 H), 392.0738.
C17H23NO3Se [M +
Na]+ 392.0741; found
6.97 (br, 1 H), 3.87–3.81 (m, 1 H), 3.07–2.96 (m, 2 H), 2.43–2.24
(S)-tert-Butyl 2-((4-chlorophenylselanyl)methyl)-5-oxopyrroli-
(m, 3 H), 1.86–1.78 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3): dine-1-carboxylate (6d). Pale yellow oil. Yield: 95%; [α]D20 = −32
δ = 177.62, 134.93, 133.99, 130.66, 129.73, 127.54, 127.07, (c = 1.0; CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 7.48 (d, 2 H, J
53.13, 39.35, 29.67, 26.22 ppm. HRMS-ESI: m/z calcd for = 8.4 Hz), 7.23 (d, 2 H, J = 8.4 Hz), 4.36–4.31 (m, 1 H), 3.33 (dd,
C11H12ClNOS [M + Na]+ 264.0226; found 264.0219.
1 H, J1 = 12.6 Hz, J2 = 2.6 Hz), 3.01 (dd, 1 H, J1 = 12.6 Hz, J2 =
(S)-5-((4-Methoxyphenylthio)methyl)pyrrolidin-2-one (5p). 8.6 Hz), 2.68–2.58 (m, 1 H), 2.45–2.37 (m, 1 H), 2.21–2.13 (m, 1
1
Colorless oil. Yield: 62%. [α]2D0 = +98 (c = 1.0; CH2Cl2). H NMR H), 1.98–1.91 (m, 1 H), 1.44 (s, 9 H) ppm. 13C NMR (100 MHz,
(400 MHz, CDCl3): δ = 7.34 (d, 2 H, J = 8.8 Hz), 7.13 (br, 1 H), CDCl3): δ = 173.24, 149.64, 134.44, 133.68, 129.25, 127.25,
6.81 (d, 2 H, J = 8.8 Hz), 3.74 (s, 3 H), 3.71–3.67 (m, 1 H), 2.87 82.93, 57.30, 32.02, 31.06, 27.81, 22.59 ppm. HRMS-ESI: m/z
(d, 1 H, J = 6.4 Hz), 2.37–2.15 (m, 3 H), 1.82–1.73 (m, 1 H) ppm. calcd for C16H20ClNO3Se [M + Na]+ 412.0195; found 412.0186.
13C NMR (100 MHz, CDCl3): δ = 177.44, 158.91, 133.23, 124.87,
(S)-tert-Butyl 2-((2-chlorophenylselanyl)methyl)-5-oxopyrroli-
114.39, 54.82, 53.17, 41.70, 29.51, 25.80 ppm. HRMS-ESI: m/z dine-1-carboxylate (6e). Pale yellow oil. Yield: 95%; [αD] = −38
calcd for C12H15NO2S [M + H]+ 238.0902; found 238.0896.
(c = 1.0; CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 7.38–7.36 (m,
1 H), 7.33–7.30 (m, 1 H), 7.20–7.17 (m, 2 H), 4.40–4.35 (m, 1
H), 3.44 (dd, 1 H, J1 = 12.3 Hz, J2 = 2.6 Hz), 2.99 (dd, 1 H, J1 =
12.3 Hz, J2 = 9.6 Hz), 2.69–2.59 (m, 1 H), 2.47–2.39 (m, 1 H),
General procedure for the synthesis of L-chalcogen-N-Boc-
γ-lactams 6a–p
To a 0.50 M solution of L-chalcogen-γ-lactam 5 (1.0 mmol) 2.22–2.13 (m, 1 H), 2.07–2.00 (m, 1 H), 1.48 (s, 9 H) ppm. 13C
in CH2Cl2, Et3N (0.14 mL, 1.0 mmol), Boc2O (0.27 mL, NMR (100 MHz, CDCl3): δ = 173.72, 149.77, 135.75, 132.38,
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130.23, 129.68, 128.12, 127.40, 83.29, 57.17, 31.08, 29.80,
(S)-tert-Butyl 2-oxo-5-(phenylthiomethyl)pyrrolidine-1-car-
27.93, 22.68 ppm. HRMS-ESI: m/z calcd for C16H20ClNO3Se boxylate (6l). Colorless oil. Yield: 90%; [α]2D0 = −35 (c = 1.0;
[M + Na]+ 412.0195; found 412.0190.
CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 7.42–7.17 (m, 5 H),
(S)-tert-Butyl 2-((2-methoxyphenylselanyl)methyl)-5-oxopyr- 4.33–4.28 (m, 1 H), 3.41 (dd, 1 H, J1 = 13.5 Hz, J2 = 3.2 Hz),
rolidine-1-carboxylate (6f). Yellow oil. Yield: 85%; [α]2D0 = −64 2.98 (dd, 1 H, J1 = 13.5 Hz, J2 = 9 Hz), 2.67–2.57 (m, 1 H),
(c = 1.0; CH2Cl2). 1H NMR (200 MHz, CDCl3): δ = 7.54–7.50 (m, 2.44–2.36 (m, 1 H), 2.15–2.01 (m, 2 H), 1.46 (s, 9 H) ppm. 13C
1 H), 7.29–7.21 (m, 1 H), 6.95–6.83 (m, 2 H), 4.41–4.30 (m, 1 NMR (100 MHz, CDCl3): δ = 173.43, 149.73, 135.26, 130.11,
H), 3.88 (s, 3 H), 3.37 (dd, 1 H, J1 = 12.4 Hz, J2 = 2.9 Hz), 2.90 129.00, 126.64, 82.97, 57.06, 37.52, 31.05, 27.93, 21.77.
(dd, 1 H, J1 = 12.4 Hz, J2 = 10 Hz), 2.70–2.56 (m, 1 H), 2.49–2.34 HRMS-ESI: m/z calcd for C16H21NO3S [M + Na]+ 330.1140;
(m, 1 H), 2.18–2.00 (m, 2 H), 1.47 (s, 9 H) ppm. 13C NMR found 330.1131.
(100 MHz, CDCl3): δ = 173.99, 157.96, 149.71, 132.44, 128.48,
(S)-tert-Butyl 2-oxo-5-(p-tolylthiomethyl)pyrrolidine-1-car-
121.47, 118.06, 110.60, 83.04, 57.57, 55.80, 31.14, 28.55, 27.91, boxylate (6m). White solid. mp 51–53 °C; yield: 91%. [α]D20
=
22.58 ppm. HRMS-ESI: m/z calcd for C17H23NO3Se [M + Na]+ −43 (c = 1.0; CH2Cl2). NMR H (400 MHz, CDCl3): δ = 7.32 (d,
1
408.0690; found 408.0681.
2 H, J = 8 Hz), 7.09 (d, 2 H, J = 8 Hz), 4.31–4.25 (m, 1 H), 3.33
(S)-tert-Butyl 2-(ethylselanylmethyl)-5-oxopyrrolidine-1-car- (dd, 1 H, J1 = 13.5 Hz, J2 = 2.8 Hz), 2.94 (dd, 1 H, J1 = 13.5 Hz,
boxylate (6g). Yellow oil. Yield: 80%; [α]2D0 = −57 (c = 1.0; J2 = 9 Hz), 2.67–2.57 (m, 1 H), 2.44–2.36 (m, 1 H), 2.30 (s, 3 H),
CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 4.35–4.30 (m, 1 H), 2.15–2.02 (m, 2 H), 1.45 (s, 9 H) ppm. 13C NMR (100 MHz,
2.96 (dd, 1 H, J1 = 12.5 Hz, J2 = 3 Hz), 2.74 (dd, 1 H, J1 = 12.5 CDCl3): δ = 173.45, 149.80, 137.03, 131.58, 130.95, 129.91,
Hz, J2 = 9.2 Hz), 2.68–2.63 (m, 3 H), 2.46–2.38 (m, 1 H), 83.07, 57.30, 38.20, 31.21, 28.01, 21.84, 20.92 ppm. HRMS-ESI:
2.21–2.15 (m, 1 H), 2.00–1.92 (m, 1 H), 1.54 (s, 9 H), 1.42 (t, 3 m/z calcd for C17H23NO3S [M + Na]+ 344.1296; found 344.1302.
H, J = 7.2 Hz) ppm. 13C NMR (100 MHz, CDCl3): δ = 173.45,
(S)-tert-Butyl 2-((4-chlorophenylthio)methyl)-5-oxopyrroli-
149.77, 82.77, 57.75, 31.07, 27.90, 27.10, 22.62, 17.95, dine-1-carboxylate (6n). Colorless oil. Yield: 94%. [α]2D0 = −30
15.71 ppm. HRMS-ESI: m/z calcd for C12H21NO3Se [M + Na]+ (c = 1.0; CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 7.35 (d, 2 H, J
330.0584; found 330.0577.
= 8.8 Hz), 7.25 (d, 2 H, J = 8.8 Hz), 4.33–4.27 (m, 1 H), 3.38 (dd,
(S)-tert-Butyl 2-(benzylselanylmethyl)-5-oxopyrrolidine-1-car- 1 H, J1 = 13.8 Hz, J2 = 2.4 Hz), 2.98 (dd, 1 H, J1 = 13.8 Hz, J2 =
boxylate (6h). Pale yellow oil. Yield: 90%; [α]2D0 = −44 (c = 1.0; 8.8 Hz), 2.68–2.57 (m, 1 H), 2.46–2.38 (m, 1 H), 2.19–1.99 (m, 2
CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 7.30–7.19 (m, 5 H), H), 1.47 (s, 9 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 173.28,
4.33–4.28 (m, 1 H), 3.86–3.78 (m, 2 H), 2.94 (dd, 1 H, J1 = 12.4 149.96, 133.89, 132.94, 131.42, 129.27, 83.25, 56.98, 37.82,
Hz, J2 = 2.8 Hz), 2.69 (dd, 1 H, J1 = 12.4 Hz, J2 = 9.2 Hz), 31.19, 28.02, 21.89 ppm. HRMS-ESI: m/z calcd for
2.57–2.50 (m, 1 H), 2.39–2.32 (m, 1 H), 2.14–2.01 (m, 1 H), C16H20ClNO3S [M + Na]+ 364.0750; found 364.0738.
1.85–1.79 (m, 1 H), 1.51 (s, 9 H) ppm. 13C NMR (100 MHz,
(S)-tert-Butyl
2-((2-chlorophenylthio)methyl)-5-oxopyrroli-
CDCl3): δ = 173.37, 149.91, 138.85, 128.78, 128.45, 126.83, dine-1-carboxylate (6o). Yellow oil. Yield: 84%. [α]2D0 = −44 (c =
82.94, 57.63, 31.17, 27.99, 27.88, 27.81, 22.76 ppm. HRMS-ESI: 1.0; CH2Cl2). H NMR (400 MHz, CDCl3): δ = 7.52 (dd, J1 = 7.9
1
m/z calcd for
392.0732.
C
17H23NO3Se [M
+
Na]+ 392.0741; found Hz, J2 = 1.6 Hz), 7.37 (dd, 1 H, J1 = 7.9 Hz, J2 = 1.4 Hz),
7.25–7.20 (m, 1 H), 7.17–7.13 (m, 1 H), 4.35–4.29 (m, 1 H), 3.44
(S)-tert-Butyl 2-oxo-5-(phenyltellanylmethyl)pyrrolidine-1- (dd, 1 H, J1 = 13.6 Hz, J2 = 2.4 Hz), 2.98 (dd, 1 H, J1 = 13.6 Hz,
carboxylate (6i). Pale yellow oil. Yield: 90%; [α]2D0 = −45 J2 = 9.6 Hz), 2.70–2.60 (m, 1 H), 2.47–2.39 (m, 1 H), 2.20–2.07
(c = 1.0; CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 7.78–7.76 (m, 2 H), 1.48 (s, 9 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
(m, 2 H), 7.30–7.17 (m, 3 H), 4.42–4.36 (m, 1 H), 3.37 (dd, 1 H, 173.40, 149.84, 134.84, 134.32, 130.60, 129.94, 127.61, 127.30,
J1 = 14 Hz, J2 = 3.2 Hz), 3.03 (dd, 1 H, J1 = 14 Hz, J2 = 9.6 Hz), 83.21, 56.75, 36.32, 31.03, 27.96, 21.96 ppm. HRMS-ESI: m/z
2.63–2.53 (m, 1 H), 2.42–2.35 (m, 1 H), 2.21–2.11 (m, 1 H), calcd for C16H20ClNO3S [M + Na]+ 364.0750; found 364.0745.
1.88–1.81 (m, 1 H), 1.43 (s, 9 H) ppm. 13C NMR (100 MHz,
(S)-tert-Butyl 2-((4-methoxyphenylthio)methyl)-5-oxopyrroli-
CDCl3): δ = 171.54, 149.77, 138.98, 129.34, 128.09, 110.63, dine-1-carboxylate (6p). Pale yellow solid. mp 94–95 °C; yield:
1
82.94, 59.92, 31.22, 27.97, 24.08, 13.58 ppm. HRMS-ESI: m/z 85%. [α]2D0 = −43 (c = 1.0; CH2Cl2). H NMR (400 MHz, CDCl3):
calcd for C16H21NO3Te [M + Na]+ 428.0481; found 428.0475.
δ = 7.38 (d, 2 H, J = 8 Hz), 6.84 (d, 2 H, J = 8 Hz); 4.28–4.22 (m,
(S)-tert-Butyl 2-((4-chlorophenyltellanyl)methyl)-5-oxopyrroli- 1 H), 3.78 (s, 3 H), 3.27 (dd, 1 H, J1 = 13.5 Hz, J2 = 3.2 Hz), 2.90
dine-1-carboxylate (6j). Yellow oil. Yield: 88%; [α]D20 = −47 (dd, 2 H, J1 = 13.5 Hz, J2 = 9 Hz), 2.68–2.59 (m, 1 H), 2.45–2.38
1
(c = 1.0; CH2Cl2). H NMR (400 MHz, CDCl3): δ = 7.70 (d, 2 H, (m, 1 H), 2.14–2.03 (m, 2 H), 1.42 (s, 9 H) ppm. 13C (100 MHz,
J = 8.4 Hz), 7.18 (d, 2 H, J = 8.4 Hz), 4.44–4.33 (m, 1 H), 3.33 CDCl3): δ = 173.84, 159.56, 149.74, 133.78, 125.57, 114.94,
(dd, 1 H, J1 = 12.1 Hz, J2 = 2.6 Hz), 3.00 (dd, 1 H, J1 = 12.1 Hz, 83.00, 57.40, 55.37, 39.44, 31.25, 28.00, 21.82 ppm. HRMS-ESI:
J2 = 9.6 Hz), 2.73–2.34 (m, 2 H), 2.28–2.08 (m, 1 H), m/z calcd for C17H23NO4S [M + Na]+ 360.1245; found 360.1257.
1.91–1.77 (m, 1 H), 1.41 (s, 9 H) ppm. 13C NMR (100 MHz,
General procedure for the synthesis of L-chalcogen-N-Boc-
CDCl3): δ = 173.69, 149.48, 140.30, 134.66, 129.49, 107.88,
γ-amino acids 7a–p
82.94, 58.57, 31.10, 27.73, 23.80, 14.04 ppm. HRMS-ESI:
m/z calcd for C16H20ClNO3Te [M + Na]+ 462.0092; found To a 0.2 M solution of L-chalcogen-N-Boc-γ-lactam (1.0 mmol)
462.0092.
in THF, 3.0 mL (3.0 mmol) of a 1.0 N solution of LiOH was
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added. This mixture was stirred at room temperature and the
(S)-4-(tert-Butoxycarbonylamino)-5-(2-methoxyphenylselanyl)-
product formation was monitored by TLC. After removal of pentanoic acid (7f). White solid. mp 102–103 °C; yield: 80%;
1
THF under vacuum, the basic aqueous residue was acidified by [α]2D0 = +8.0 (c = 1.0; CH2Cl2). H NMR (400 MHz, CDCl3): δ =
addition of 1.0 M HCl and extracted with diethyl ether. 7.45–7.43 (m, 1 H), 7.27–7.19 (m, 1 H), 6.89–6.81 (m, 2 H), 3.87
The combined organic layers were dried with MgSO4, filtered (s, 3 H), 3.83–3.78 (m, 1 H), 3.10–3.00 (m, 2 H), 2.36 (t, 2 H, J =
and the solvent was removed under vacuum. The crude 7.2 Hz), 2.03–1.90 (m, 1 H), 1.84–1.77 (m, 1 H), 1.39 (s, 9 H)
products were purified in a silica gel column for chromato- ppm. 13C NMR (100 MHz, CDCl3): δ = 178.91, 157.95, 155.36,
graphic purification, using hexane–ethyl acetate (20 : 80) as the 133.46, 128.89, 121.42, 118.87, 110.63, 79.41, 55.71, 50.04,
eluent.
31.61, 30.84, 29.74, 28.19 ppm. HRMS-ESI: m/z calcd for
(S)-4-(tert-Butoxycarbonylamino)-5-(phenylselanyl)pentanoic C17H25NO5Se [M + Na]+ 426.0796; found 426.0792.
acid (7a). Pale yellow solid. mp 82–83 °C; yield: 70%; [α]D20
=
(S)-4-(tert-Butoxycarbonylamino)-5-(ethylselanyl)pentanoic
+6.0 (c = 1.0; CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = acid (7g). White solid. mp 67–68 °C; yield: 55%; [α]D20 = +16 (c
1
7.53–7.51 (m, 2 H), 7.25–7.22 (m, 3 H), 3.88–3.78 (m, 1 H), = 1.0; CH2Cl2). H NMR (400 MHz, CDCl3): δ = 3.82–3.74 (m, 1
3.18–3.00 (m, 2 H), 2.38 (t, 2 H, J = 7.2 Hz), 1.99–1.90 (m, 1 H), H), 2.78–2.66 (m, 2 H), 2.63–2.57 (m, 2 H), 2.42 (t, 2 H, J =
1.81–1.73 (m, 1 H), 1.40 (s, 9 H) ppm. 13C NMR (100 MHz, 7.2 Hz), 2.02–1.93 (m, 1 H), 1.80–1.72 (m, 1 H), 1.44 (s, 9 H),
CDCl3): δ = 178.11, 155.40, 132.80, 129.94, 129.08, 127.03, 1.39 (t, 3 H, J = 7.6 Hz) ppm. 13C NMR (100 MHz, CDCl3): δ =
79.56, 50.09, 34.12, 30.75, 29.55, 28.21 ppm. HRMS-ESI: m/z 177.92, 155.49, 79.46, 51.96, 30.82, 29.51, 28.21, 26.89, 18.04,
calcd for C16H23NO4Se [M + Na]+ 396.0792; found 396.0683.
15.66 ppm. HRMS-ESI: m/z calcd for C12H23NO4Se [M + Na]+
348.0690; found 348.0684.
(S)-4-(tert-Butoxycarbonylamino)-5-(p-tolylselanyl)pentanoic
acid (7b). White solid. mp 72–73 °C; yield: 80%; [α]2D0 = +23
(S)-5-(Benzylselanyl)-4-(tert-butoxycarbonylamino)pentanoic
1
(c = 1.0; CH2Cl2). H NMR (400 MHz, CDCl3): δ = 7.41 (d, 2 H, acid (7h). Pale yellow oil. Yield: 78%; [α]2D0 = +3 (c = 1.0;
J = 8 Hz), 7.03 (d, 2 H, J = 8 Hz), 3.83–3.77 (m, 1 H), 3.01–2.97 CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 7.29–7.24 (m, 4 H),
(m, 2 H), 2.35 (t, 2 H, J = 7.2 Hz), 2.28 (s, 3 H), 2.01–1.89 (m, 7.20–7.16 (m, 1 H), 3.79 (s, 2 H), 3.79 (s, 2 H), 3.79–3.70 (m,
1 H), 1.80–1.73 (m, 1 H), 1.39 (s, 9 H) ppm. 13C NMR 1 H), 2.64–2.61 (m, 2 H), 2.36 (t, 2 H, J = 7.6 Hz), 1.94–1.86 (m,
(100 MHz, CDCl3): δ = 179.05, 155.41, 137.81, 134.00, 130.09, 1 H), 1.74–1.65 (m, 1 H), 1.44 (s, 9 H) ppm. 13C NMR
124.63, 79.46, 50.12, 34.17, 30.81, 29.67, 28.22, 20.99 ppm. (100 MHz, CDCl3): δ = 178.06, 155.53, 138.91, 128.84, 128.47,
HRMS-ESI: m/z calcd for C17H25NO4Se [M + Na]+ 410.0846; 126.76, 79.60, 49.83, 30.82, 29.79, 29.72, 28.29, 27.74 ppm.
found 410.0846.
HRMS-ESI: m/z calcd for C17H25NO4Se [M + Na]+ 410.0846;
(S)-4-(tert-Butoxycarbonylamino)-5-(o-tolylselanyl)pentanoic found 410.0844.
acid (7c). Colorless oil. Yield: 70%; [α]2D0 = +12 (c = 1.0;
(S)-4-(tert-Butoxycarbonylamino)-5-(phenyltellanyl)pentanoic
CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 7.48–7.46 (m, 1 H), acid (7i). White solid. mp 86–88 °C; yield: 72%; [α]D20 = +66 (c =
1
7.17–7.05 (m, 3 H), 3.94–3.78 (m, 1 H), 3.01–2.99 (m, 2 H), 2.42 1.0; CH2Cl2). H NMR (400 MHz, CDCl3): δ = 7.74–7.73 (m, 2
(s, 3 H), 2.36 (t, 2 H, J = 7.2 Hz), 2.02–1.97 (m, 1 H), 1.81–1.73 H), 7.27–7.14 (m, 3 H), 3.83–3.75 (m, 1 H), 3.07–3.06 (m, 2 H),
(m, 1 H), 1.40 (s, 9 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 2.36 (t, 2 H, J = 7.2 Hz), 1.96–1.88 (m, 1 H), 1.80–1.70 (m, 1 H),
177.47, 155.37, 139.24, 132.71, 130.87, 129.90, 127.47, 126.84, 1.40 (s, 9 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 177.82,
79.45, 54.44, 32.83, 30.73, 29.63, 28.14, 22.28 ppm. HRMS-ESI: 155.32, 138.52, 129.19, 127.73, 111.37, 79.52, 50.53, 31.19,
m/z calcd for
410.0839.
C
17H25NO4Se [M
+
Na]+ 410.0949; found 30.81, 28.22, 16.93 ppm. HRMS-ESI: m/z calcd for
C16H23NO4Te [M + Na]+ 446.0587; found 446.0587.
(S)-4-(tert-Butoxycarbonylamino)-5-(4-chlorophenylselanyl)-
(S)-4-(tert-Butoxycarbonylamino)-5-(4-chlorophenyltellanyl)-
pentanoic acid (7d). Pale yellow solid. mp 104–105 °C; yield: pentanoic acid (7j). Dark yellow oil. Yield: 80%; [α]2D0 = +11 (c =
1
1
75%; [α]2D0 = +15 (c = 1.0; CH2Cl2). H NMR (400 MHz, CDCl3): 1.0; CH2Cl2). H NMR (400 MHz, CDCl3): δ = 7.65 (d, 2 H, J =
δ = 7.45 (d, 2 H, J = 8.4 Hz), 7.23 (d, 2 H, J = 8.4 Hz), 3.87–3.78 8.4 Hz), 7.14 (d, 2 H, J = 8.4 Hz), 3.83–3.72 (m, 1 H), 3.10–3.04
(m, 1 H), 3.08–3.00 (m, 2 H), 2.39 (t, 2 H, J = 7.2 Hz), 2.02–1.92 (m, 2 H), 2.36 (t, 2 H, J = 7.6 Hz), 1.96–1.84 (m, 1 H), 1.77–1.68
(m, 1 H), 1.81–1.71 (m, 1 H), 1.41 (s, 9 H). 13C NMR (100 MHz, (m, 1 H), 1.38 (s, 9 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
CDCl3): δ = 177.79, 155.30, 134.30, 133.39, 129.24, 128.14, 177.25, 155.42, 140.11, 134.51, 129.53, 108.88, 79.75, 50.80,
79.63, 50.44, 34.32, 30.70, 29.59, 28.23 ppm. HRMS-ESI: m/z 31.27, 30.78, 28.30, 17.29 ppm. HRMS-ESI: m/z calcd for
calcd for C16H22ClNO4Se [M + Na]+ 430.0300; found 430.0297.
C16H22ClNO4Te [M + Na]+ 480.0197; found 480.0201.
(S)-4-(tert-Butoxycarbonylamino)-5-(2-chlorophenylselanyl)-
(S)-4-(tert-Butoxycarbonylamino)-5-(phenylthio)pentanoic
pentanoic acid (7e). Orange oil. Yield: 50%; [α]2D0 = +8.0 (c = acid (7l). White solid. mp 73–74 °C; yield: 60%; [α]D20 = +15 (c =
1
1
1.0; CH2Cl2). H NMR (400 MHz, CDCl3): δ = 7.31–7.13 (m, 4 1.0; CH2Cl2). H NMR (400 MHz, CDCl3): δ = 7.39–7.36 (m, 2
H), 3.96–3.78 (m, 1 H), 3.18–2.97 (m, 2 H), 2.40 (t, J = 7.2 Hz, 2 H), 7.28–7.24 (m, 2 H), 7.20–7.16 (m, 1 H), 3.88–3.73 (m, 1 H),
H), 2.06–1.94 (m, 1 H), 1.88–1.74 (m, 1 H), 1.40 (s, 9 H) ppm. 3.11–3.00 (m, 2 H), 2.39 (t, 2 H, J = 7.2 Hz), 2.06–1.96 (m, 1 H),
13C NMR (100 MHz, CDCl3): δ = 177.78, 155.43, 135.70, 132.12, 1.83–1.73 (m, 1 H), 1.40 (s, 9 H) ppm. 13C NMR (100 MHz,
130.63, 129.57, 127.74, 127.28, 79.67, 50.04, 32.59, 30.77, CDCl3): δ = 177.65, 155.67, 136.07, 129.93, 129.03, 126.45,
29.70, 28.25 ppm. HRMS-ESI: m/z calcd for C16H22ClNO4Se 79.61, 50.10, 39.71, 30.75, 29.04, 28.32 ppm. HRMS-ESI: m/z
[M + Na]+ 430.0300; found 430.0292.
calcd for C16H23NO4S [M + Na]+ 348.1245; found 348.1238.
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(S)-4-(tert-Butoxycarbonylamino)-5-(p-tolylthio)pentanoic 1 H), 2.49–2.42 (m, 1 H), 2.22–2.14 (m, 1 H), 2.07–2.00 (m, 1
acid (7m). White solid. mp 89–91 °C; yield: 98%. [α]D20 = +18 (c H), 1.54 (s, 9 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 173.49,
= 1.0; CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 7.28 (d, 2 H, J = 149.74, 83.24, 58.18, 32.92, 31.13, 28.06, 22.39 ppm.
8.4 Hz), 7.08 (d, 2 H, J = 8.4 Hz), 3.83–3.74 (m, 1 H), 3.06–2.94 HRMS-ESI: m/z calcd for C20H32N2O6Se2 [M + Na]+ 579.0489;
(m, 2 H), 2.38 (t, 2 H, J = 7.2 Hz), 2.30 (s, 3 H), 2.03–1.95 (m, 1 found 579.0486.
H), 1.82–1.73 (m, 1 H), 1.40 (s, 9 H) ppm. 13C NMR (100 MHz,
(4S,4′S)-5,5′-Diselanediylbis(4-(tert-butoxycarbonylamino)-
CDCl3): δ = 177.38, 155.92, 136.71, 132.32, 130.79, 129.84, pentanoic acid) (12). Prepared according to the procedure
79.96, 50.48, 40.45, 30.71, 29.12, 28.34, 20.91 ppm. HRMS-ESI: described for chalcogen-N-Boc-γ-amino acids 7a–p. Dark
m/z calcd for C17H25NO4S [M + Na]+ 362.1402; found 362.1397.
yellow oil. Yield: 50%; [α]2D0 = +17 (c = 1.0; CH2Cl2). 1H NMR
(S)-4-(tert-Butoxycarbonylamino)-5-(4-chlorophenylthio)pen- (400 MHz, CDCl3): δ = 3.94–3.76 (m, 1 H), 3.33–3.11 (m, 2 H),
tanoic acid (7n). White solid. mp 106–107 °C; yield: 84%. 2.47–2.43 (m, 2 H), 2.04–1.97 (m, 1 H), 1.83–1.73 (m, 1 H), 1.45
1
[α]2D0 = +20 (c = 1.0; CH2Cl2). H NMR (400 MHz, CDCl3): δ = (s, 9 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 177.12, 156.20,
7.32–7.23 (m, 4 H), 3.88–3.69 (m, 1 H), 3.12–2.91 (m, 2 H), 80.09, 51.03, 34.21, 30.73, 29.64, 28.43 ppm. HRMS-ESI: m/z
2.45–2.36 (m, 2 H), 2.07–1.93 (m, 1 H), 1.81–1.71 (m, 1 H), 1.41 calcd for C20H36N2O8Se2 [M + Na]+ 615.0700; found 615.0700.
(s, 9 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 177.81, 155.47,
134.48, 132.45, 131.12, 129.14, 79.82, 49.87, 39.77, 30.70,
28.85, 28.27 ppm. HRMS-ESI: m/z calcd for C16H22ClNO4S
[M + Na]+ 382.0856; found 382.0865.
Acknowledgements
(S)-4-(tert-Butoxycarbonylamino)-5-(2-chlorophenylthio)pen-
The authors gratefully acknowledge CAPES, CNPq, INCT-Catá-
lise and FAPESP for financial support. C. Y. K. is grateful to
CAPES for a PhD fellowship.
tanoic acid (7o). White solid. mp 73–75 °C; yield: 84%. [α]D20
=
+12 (c = 1.0; CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 7.42–7.34
(m, 2 H), 7.22–7.09 (m, 2 H), 3.90–3.76 (m, 1 H), 3.16–2.97 (m,
2 H), 2.41 (t, 2 H, J = 7.2 Hz), 2.06–2.02 (m, 1 H), 1.86–1.78 (m,
1 H), 1.40 (s, 9 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
177.59, 155.76, 135.17, 134.52, 130.07, 129.83, 127.22, 127.17,
80.09, 49.88, 38.51, 30.73, 28.99, 28.28 ppm. HRMS-ESI: m/z
calcd for C16H22ClNO4S [M + Na]+ 382.0958; found 382.0862.
(S)-4-(tert-Butoxycarbonylamino)-5-(4-methoxyphenylthio)-
Notes and references
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1
pentanoic acid (7p). Colorless oil. Yield: 93%. [α]2D0 = +116. H
NMR (400 MHz, CDCl3): δ = 7.36 (d, 2 H, J = 8.4 Hz), 6.82 (d,
2 H, J = 8.4 Hz), 3.77 (s, 3 H), 3.74–3.66 (m, 1 H), 3.05–2.93 (m,
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pyrrolidine-1-carboxylate) (11). To a 0.5 M solution of tosylate
γ-lactam 9 (0.269 g, 1.0 mmol) in CH2Cl2, Et3N (0.14 mL,
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room temperature under an argon atmosphere. The solvent
was removed and the residue was purified by chromatography
on silica gel using hexane–ethyl acetate (50 : 50) as the eluent
to afford tosylate N-Boc-γ-lactam 10 in 90% yield. To a stirred
solution of Se0 (0.158 g, 2.0 mmol) and tosylate N-Boc-γ-lactam
10 (0.369 g, 1.0 mmol) in dry DMSO (2.0 mL), CuO nanoparti-
cles (0.016 g, 20 mol%) and KOH (0.11 g, 2.0 mmol) were
added under an argon atmosphere at room temperature. The
reaction was monitored by TLC. After the reaction was com-
plete, the resulting mixture was purified by flash chromato-
graphy, first eluting with hexane and then with a hexane–ethyl
acetate (50 : 50) mixture to give the product in 50% yield;
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3 Hz), 3.06 (dd, 1 H, J1 = 12.2 Hz, J2 = 9.4 Hz), 2.67–2.58 (m,
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