Synthesis of new functionalized aziridine-2- and azetidine-3-carboxylic acid derivatives of potential interest for biological and foldameric applications

Article abstract of DOI:10.1007/s00726-011-0879-1

A short synthesis of alkyl 2-(bromomethyl)aziridine-2-carboxylates and alkyl 3-bromoazetidine-3-carboxylates was developed involving amination, bromination, and base-induced cyclization of alkyl 2-(bromomethyl)acrylates. The aziridines are the kinetically

Full text of DOI:10.1007/s00726-011-0879-1

Amino Acids (2011) 41:541–558
DOI 10.1007/s00726-011-0879-1
ORIGINAL ARTICLE
Synthesis of new functionalized aziridine-2- and azetidine-3-
carboxylic acid derivatives of potential interest
for biological and foldameric applications
ˇ
Asta Zukauskaite Sven Mangelinckx
•
•
_
ˇ
•
•
_
ˇ
Vida Buinauskaite Algirdas Sackus
Norbert De Kimpe
Received: 14 January 2011 / Accepted: 1 March 2011 / Published online: 22 March 2011
Ó Springer-Verlag 2011
Abstract A short synthesis of alkyl 2-(bromomethyl)azi-
ridine-2-carboxylates and alkyl 3-bromoazetidine-3-carbox-
ylates was developed involving amination, bromination, and
base-induced cyclization of alkyl 2-(bromomethyl)acrylates.
The aziridines are the kinetically favored cyclization products
and could be transformed into 3-bromoazetidine-3-car-
boxylic acid derivatives via thermal isomerization. The
new small-membered azaheterocyclic a- and b-amino acid
derivatives contain a bromo-substituted carbon center as a
useful moiety for functionalization. Transformation of these
functionalized azaheterocycles via nucleophilic substitution
with carbon, sulfur, oxygen, and nitrogen nucleophiles and
via elaboration of the amino and carboxyl group provided a
broad range of new conformationally constrained aziridine-2-
and azetidine-3-carboxylic acid derivatives, which are of
interest from a biological point-of-view as well as for appli-
cations in the field of foldamers.
Introduction
Aziridine-2-carboxylic acid derivatives are biologically
important constrained amino acid derivatives and versatile
building blocks in the preparation of proteinogenic and non-
proteinogenic amino acids and biologically active nitrogen-
containing compounds (Cardillo et al. 2003, 2006; Lee and
Ha 2003; Lucarini and Tomasini 2001; Ide et al. 2005; Vicik
et al. 2006). The latter is nicely exemplified by the ring
opening of (2R)-N-(acetyl)aziridine-2-carboxylates 1 in the
synthesis of lacosamide (2, VimpatÒ; UCB), approved in
2008 for the adjunctive treatment of partial onset seizures in
patients with epilepsy (Fig. 1) (Morieux et al. 2008; Hughes
2009b). The different isomers of 2-(4-amino-4-carboxybu-
tyl)aziridine-2-carboxylate 3 (AziDAP) are irreversible
inhibitors and substrate mimics of diaminopimelate (DAP)
epimerase, a key enzyme for the biosynthesis of lysine
in plants (Pillai et al. 2006, 2009). In view of the analogy
with constrained b2,2-amino acids such as b2-HAib 5,
314-helix- and sheet-breaking in b-peptides (Seebach
and Gardiner 2008; Cheng et al. 2001), and 1-(amino-
methyl)cyclopropanecarboxylic acid 6, which forms b-oli-
gopeptides with a ribbon- or stair-like structure (Abele et al.
1999), the unknown 2-(aminomethyl)aziridine-2-carboxylic
acids 4 are of significant interest as potential foldameric
building blocks. Alternatively, derivatives of azetidine-
3-carboxylic acid disclose gametocidal activity (Zhang
et al. 2004; Verbrugge and De Waal 1989; Orr and Clifford
1984; Devlin 1981), have found application as b-proline
analogues (Mazzini et al. 1997), and have been used for
the preparation of a variety of pharmaceutically active
compounds (Miller et al. 2003). More specifically, a
3-aminoazetidine-3-carboxylic acid derivative has been
incorporated in CE-178,253 (7, Pfizer), a CB1 antagonist for
the treatment of obesity (Brandt et al. 2009). Furthermore,
Keywords Aziridine-2-carboxylic acids Á Azetidine-3-
carboxylic acids Á b-Amino acids Á a-Amino acids Á
Conformational constraint
Sven Mangelinckx is the Postdoctoral Fellow of the Research
Foundation-Flanders (FWO).
ˇ
_
A. Zukauskaite Á S. Mangelinckx Á N. De Kimpe (&)
Department of Sustainable Organic Chemistry and Technology,
Faculty of Bioscience Engineering, Ghent University,
Coupure Links 653, 9000 Ghent, Belgium
e-mail: norbert.dekimpe@ugent.be
ˇ
ˇ
ˇ
_
_
A. Zukauskaite Á V. Buinauskaite Á A. Sackus
Institute of Synthetic Chemistry, Kaunas University
of Technology, 50270 Kaunas, Lithuania
123

ˇ
A. Zukauskaite et al.
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542
Fig. 1 Several aziridine-2- and
azetidine-3-carboxylic acid
derivatives and related
compounds with biological or
foldameric applications
HOOC
HN
COOH
O
O
H
NH2
N
N
Ph
N
LL-Azi-DAP (3)
H
O
COOR
OMe
HOOC
HN
COOH
®
1
Lacosamide (2) (Vimpat , UCB)
NH2
epilepsy
DL-Azi-DAP (3)
R1
N
NH2
COOH
NH2
COOH
NH2
COOH
4
β2-HAib (5)
6
Me
Cl
R1
N
N
N
N
N
N
CONH2
NHEt
HOOC NH2
HOOC NH2
HOOC NH2
Cl
CE-178,253 (7) (Pfizer)
8
Aib (9)
Ac4c (10)
3-aminoazetidine-3-carboxylic acid derivatives 8 also rep-
resent interesting conformationally constrained functional-
ized Ca-tetrasubstituted a-amino acids, which have not been
studied in the foldameric field. Related Ca-tetrasubstituted
a-amino acids such as Aib (9) and 1-aminocyclobutane-1-
carboxylic acid (10, Ac4c) are known to form short peptides
with a conformational preference for b-turns and 310-helices
functionalization. Allylamines have proven to be suitable
substrates for the synthesis of 2-(bromomethyl)aziridines
and/or 3-bromoazetidines via bromination of the C–C
double bond to the corresponding b,c-dibromo amines
followed by intramolecular ring closure (Abbaspour
Tehrani et al. 2002; De Smaele et al. 1998; De Kimpe et al.
1997; Hayashi et al. 2004; Gensler 1948), or via electro-
phile-induced bromocyclization (Robin and Rousseau
2000, 2002). This ring closure usually has high selectivity
towards the formation of aziridines instead of azetidines.
¨
(Toniolo et al. 2006; Maity and Konig 2008; Soloshonok and
Sorochinsky 2010).
In view of the importance of the aforementioned classes
of amino acids, the development of pathways to new three-
and four-membered azaheterocyclic a- and b-amino acid
derivatives is a challenging research field in modern syn-
thetic chemistry at the biological interface (Hughes 2009a;
Materials and methods
¨
¨ ¨
Kiss and Fu¨lop 2010; Fulop et al. 2006; Kuhl et al. 2005;
´
Miller and Nguyen 2005; Cativiela and Ordon˜ez 2009;
Reagents and solvents were purchased from commercial
suppliers and used without further purification, unless
indicated otherwise. Dichloromethane was distilled from
calcium hydride before use. The purification of reaction
mixtures was performed through flash chromatography
using a glass column with silica gel (0.035–0.070 nm, pore
diameter ca. 6 nm) or by preparative thin layer chroma-
tography on silica gel (silica gel GF preparative layer with
UV 254, 2 mm). Solvent systems were evaluated via TLC
analysis (silica gel 2–25 lm, thickness 0.25 mm, medium
Komarov et al. 2004; Cowell et al. 2004; Gelmi and Pocar
2003; Park and Kurth 2002).
Following a preliminary communication (Mangelinckx
et al. 2008), in the present paper, in-depth results are
described on the synthesis and study of the reactivity of
2-(bromomethyl)aziridine-2-carboxylic esters and 3-bro-
moazetidine-3-carboxylic esters, the structures of which
incorporate the synthetically important 2-(halomethyl)azi-
ridine (Abbaspour Tehrani et al. 2002; De Smaele et al.
1998; De Kimpe et al. 1997; D’hooghe et al. 2006a;
Mangelinckx et al. 2009; Vervisch et al. 2010), or
3-haloazetidine structural motif (Van Driessche et al. 2006;
Van Brabandt et al. 2009). The bromo-substituted car-
bon atom can be advantageously used as a moiety for
1
˚
pore diameter 60 A with UV 254). H NMR (300 MHz),
13C NMR (75 MHz) spectra were recorded on a JEOL
ECLIPSE FT 300 NMR spectrometer at room temperature.
The compounds were dissolved in deuterated solvents as
indicated for each compound. Tetramethylsilane (TMS)
was used as an internal standard. IR spectra were recorded
123

Synthesis of new functionalized aziridine-2- and azetidine-3-carboxylic acid derivatives
543
Methyl 2-[(tert-butylamino)methyl]acrylate (12c)
on a Perkin–Elmer Spectrum BX FT-IR spectrometer in
neat form with an attenuated total reflectance (ATR)
accessory. Alternatively, IR spectra were recorded on a
Perkin–Elmer Spectrum One spectrometer. For liquid
samples, the spectra were collected by preparing a thin film
of compound between two sodium chloride plates. Mass
spectra were recorded on an Agilent 1100 series mass
spectrometer using either a direct inlet system (electron
spray, 4,000 V) or LC–MS coupling (UV detector).
Colorless oil, yield 94%, Rf = 0.48 (petroleum ether/
1
EtOAc 7/3). H NMR (300 MHz, CDCl3): d 1.14 (9H, s,
C(CH3)3), 3.41 (2H, br s, NCH2), 3.77 (3H, s, COOCH3),
5.80 (1H, dt, J = 1.5 Hz, 1.7 Hz, C=CH(H)), 6.23 (1H, d,
J = 1.1 Hz, C=CH(H)). 13C NMR (75 MHz, CDCl3):
d 29.1, 43.8, 50.6, 51.8, 125.5, 139.9, 167.4. IR (NaCl,
cm-1): tNH = 3,327, tC=O = 1,719, tC=C = 1,635. MS
(ES, pos. mode): m/z (%): 172 (M ? H?, 100). Anal. Calcd
for C9H17NO2 (%): C, 63.13; H, 10.01; N, 8.18. Found (%):
C, 63.35; H, 10.34; N, 7.96.
Synthesis of alkyl 2-[(alkylamino)methyl]acrylates
12a–d
Methyl 2-[(tert-pentylamino)methyl]acrylate (12d)
As a representative example, the synthesis of methyl
2-[(tert-pentylamino)methyl]acrylate (12d) is described
here. To a solution of tert-pentylamine (175 mg, 2 mmol)
and triethylamine (210 mg, 2.08 mmol) in CH2Cl2
(10 mL), a solution of methyl 2-(bromomethyl)acrylate
(11b) (358 mg, 2 mmol) in CH2Cl2 (5 mL) was added
dropwise while stirring at 0°C. After the reaction was
stirred for 30 min at 0°C, water (20 mL) was added to the
reaction mixture, which was extracted with CH2Cl2
(3 9 20 mL). Drying (MgSO4), filtration and evaporation
of the solvent under reduced pressure afforded methyl
2-[(tert-pentylamino)methyl]acrylate (12d) in 98% yield
which was used without further purification.
Yellow oil, yield 98%, Rf = 0.50 (petroleum ether/EtOAc
7/3). 1H NMR (300 MHz, CDCl3): d 0.86 (3H, t,
J = 7.4 Hz, CH2CH3), 1.07 (6H, s, C(CH3)2), 1.44 (2H, q,
J = 7.4 Hz, CH2CH3), 3.35 (2H, s, CH2NH), 3.77 (3H, s,
OCH3), 5.81 (1H, dt, J = 1.7 Hz, 1.4 Hz, C=CH(H)), 6.23
(1H, d, J = 1.4 Hz, C=CH(H)). 13C NMR (75 MHz,
CDCl3): d 8.3, 26.7, 33.2, 43.2, 51.9, 52.8, 125.7, 139.9,
167.5. IR (neat, cm-1): tNH = 3,336 (weak), tC=O = 1,718,
tC=C = 1,634. MS (ES, pos. mode): m/z (%): 186 (M ? H?,
100). Anal. Calcd for C10H19NO2 (%): C, 64.83; H, 10.34; N,
7.56. Found (%): C, 64.60; H, 10.41; N, 7.34.
Bromination of alkyl 2-[(alkylamino)methyl]acrylates
Ethyl 2-[(tert-butylamino)methyl]acrylate (12a)
12a–d
Yellow oil, yield 97%, Rf = 0.50 (petroleum ether/EtOAc
7/3). The 1H NMR data were in good agreement with reported
As a representative example, the synthesis of methyl
2-[(tert-pentylamino)methyl]-2,3-dibromopropanoate (13d)
is described here. To a solution of methyl 2-[(tert-pen-
tylamino)methyl]acrylate (12d) (330 mg, 1.78 mmol) in
CH2Cl2 (30 mL), a 48% aqueous solution of hydrobromic
acid (332 mg, 1.96 mmol) was added dropwise at 0°C and
the reaction mixture was stirred for 30 min. Then, a solu-
tion of Br2 (285 mg, 1.78 mmol) in CH2Cl2 (15 mL) was
added dropwise and the reaction mixture was left stirring
upon warming to room temperature for 5 h. Subsequently,
the resulting reaction mixture was neutralized by pouring
into saturated NaHCO3 solution and extracted with EtOAc
(3 9 20 mL). Drying (MgSO4), filtration, evaporation of
the solvent under reduced pressure and purification by flash
chromatography on silica gel (petroleum ether/EtOAc 9/1)
afforded dibromo ester 13d in 97% yield.
1
data (Habaue et al. 1997). H NMR (300 MHz, CDCl3): d
1.14 (9H, s, C(CH3)3), 1.31 (3H, t, J = 7.2 Hz, CH2CH3),
3.40 (2H, s, NCH2), 4.22 (2H, q, J = 7.2 Hz, CH2CH3), 5.78
(1H, dt, J = 1.3 Hz, 1.5 Hz, C=CH(H)), 6.23 (1H, s,
C=CH(H)). Anal. Calcd for C10H19NO2 (%): C, 64.83; H,
10.34; N, 7.56. Found (%): C, 64.58; H, 10.56; N, 7.41.
Ethyl 2-[(tert-pentylamino)methyl]acrylate (12b)
Colorless oil, yield 91%, Rf = 0.51 (petroleum ether/
1
EtOAc 7/3). H NMR (300 MHz, CDCl3): d 0.86 (3H, t,
J = 7.4 Hz, CCH2CH3), 1.06 (6H, s, C(CH3)2), 1.31 (3H, t,
J = 7.2 Hz, OCH2CH3), 1.44 (2H, q, J = 7.4 Hz,
CCH2CH3), 3.34 (2H, s, NCH2), 4.22 (2H, q, J = 7.2 Hz,
OCH2CH3), 5.79 (1H, dt, J = 1.4 Hz, 1.4 Hz, C=CH(H)),
6.23 (1H, d, J = 0.8 Hz, C=CH(H)). 13C NMR (75 MHz,
CDCl3): d 8.2, 14.2, 26.6, 33.1, 43.2, 52.7, 60.6, 125.4,
140.0, 166.9. IR (NaCl, cm-1) tNH = 3,328, tC=O = 1,717,
tC=C = 1,635. MS (ES, pos. mode): m/z (%): 200
(M ? H?, 100). Anal. Calcd for C11H21NO2 (%): C,
66.29; H, 10.62; N, 7.03. Found (%): C, 66.12; H, 10.37; N,
7.22.
Ethyl 2-[(tert-butylamino)methyl]-2,3-dibromopropanoate
(13a)
Colorless oil, yield 98%, Rf = 0.50 (petroleum ether/
1
EtOAc 9/1). H NMR (300 MHz, CDCl3): d 1.16 (9H, s,
C(CH3)3), 1.34 (3H, t, J = 7.2 Hz, CH2CH3), 3.24 (1H, d,
123

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A. Zukauskaite et al.
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544
J = 13.8 Hz, NCH(H)), 3.30 (1H, d, J = 13.8 Hz,
NCH(H)), 4.08 (1H, d, J = 9.9 Hz, CH(H)Br), 4.23 (1H, d,
J = 9.9 Hz, CH(H)Br), 4.22–4.39 (2H, m, CH2CH3). 13C
NMR (75 MHz, CDCl3): d 13.9, 28.5, 34.6, 46.6, 54.0,
59.8, 63.0, 168.0. IR (NaCl, cm-1): tNH = 3,327,
tC=O = 1,739. MS (ES, pos. mode): m/z (%): 344/346/348
(M ? H?, 100). Anal. Calcd for C10H19Br2NO2 (%): C,
34.81; H, 5.55; N, 4.06. Found (%): C, 34.48; H, 5.32; N,
3.84.
(1H, d, J = 13.8 Hz, NHCH(H)), 3.84 (3H, s, OCH3), 4.06
(1H, d, J = 9.6 Hz, CH(H)Br), 4.22 (1H, d, J = 9.6 Hz,
CH(H)Br). 13C NMR (75 MHz, CDCl3): d 8.4, 26.9, 27.0,
33.7, 34.5, 46.1, 52.5, 53.4, 62.6, 168.9. MS (ES, pos.
mode): m/z (%): 344/346/348 (M ? H?, 100). Anal. Calcd
for C10H19Br2NO2 (%): C, 34.81; H, 5.55; N, 4.06. Found
(%): C, 34.69; H, 5.75; N, 3.80.
Synthesis of alkyl 2-(bromomethyl)aziridine-2-
carboxylates 14a–d and alkyl 3-bromoazetidine-3-
carboxylates 15a–d
Ethyl 2-[(tert-pentylamino)methyl]-2,3-
dibromopropanoate (13b)
As a representative example, the synthesis of methyl 1-tert-
pentyl-2-(bromomethyl)aziridine-2-carboxylate (14d) and
methyl 1-tert-pentyl-3-bromoazetidine-3-carboxylate (15d)
is described here. To a solution of methyl 2-[(tert-pen-
tylamino)methyl]-2,3-dibromopropanoate (13d) (618 mg,
1.79 mmol) in CH3CN (30 mL) was added powdered
K2CO3 (371 mg, 2.69 mmol) and the reaction mixture was
stirred at 60°C for 18 h. Then the solvent was removed
under reduced pressure and Et2O (30 mL) was added. The
resulting solution was filtered and the filter cake was
washed with small portions of Et2O. Evaporation of the
solvent under reduced pressure and purification by pre-
parative TLC on silica gel (petroleum ether/Et2O 7/3)
afforded aziridine 14d in 54% yield and azetidine 15d in
26% yield.
1
Colorless oil, yield 97%, Rf = 0.71 (CH2Cl2). H NMR
(300 MHz, CDCl3): d 0.86 (3H, t, J = 7.4 Hz, CCH2CH3),
1.04 (3H, s, CCH3(CH3)), 1.05 (3H, s, CCH3(CH3)), 1.34
(3H, t, J = 7.2 Hz, OCH2CH3), 1.40 (2H, q, J = 7.3 Hz,
CCH2CH3), 3.15 (1H, d, J = 13.8 Hz, NCH(H)), 3.20 (1H,
d, J = 13.8 Hz, NCH(H)), 4.06 (1H, d, J = 9.6 Hz,
CBrH(H)), 4.22 (1H, d, J = 9.6 Hz, CBrH(H)), 4.28 (1H,
dq, J = 7.2 Hz, 10.7 Hz, OCH(H)), 4.32 (1H, dq,
J = 7.2 Hz, 10.7 Hz, OCH(H)). 13C NMR (75 MHz,
CDCl3): d 8.2, 13.9, 26.8, 27.0, 33.6, 34.4, 45.9, 52.4, 62.4,
62.7, 168.2. IR (NaCl, cm-1): tNH = 3,327 (weak),
tC=O = 1,742. MS (ES, pos. mode): m/z (%): 358/360/362
(M ? H?, 100). Anal. Calcd for C11H21Br2NO2 (%): C,
36.79; H, 5.89; N, 3.90. Found (%): C, 36.62; H, 6.12; N,
3.81.
Ethyl 1-tert-butyl-2-(bromomethyl)aziridine-2-carboxylate
(14a)
Methyl 2-[(tert-butylamino)methyl]-2,3-
dibromopropanoate (13c)
Light yellow oil, yield 50%, Rf = 0.48 (petroleum ether/
1
Yellow oil, yield 90%, Rf = 0.53 (petroleum ether/EtOAc
9/1). Spectroscopically characterized as the hydrobromide
Et2O 7/3). H NMR (300 MHz, CDCl3): d 1.08 (9H, s,
(CH3)3), 1.33 (3H, t, J = 7.2 Hz, CH2CH3), 1.83 (1H, d,
J = 1.1 Hz, NCH(H)), 2.55 (1H, dd, J = 1.1 Hz, 1.1 Hz,
NCH(H)), 3.03 (1H, d, J = 9.9 Hz, BrCH(H)), 4.05 (1H,
dd, J = 9.9 Hz, 1.1 Hz, BrCH(H)), 4.21 (1H, dq,
J = 10.7 Hz, 7.2 Hz, CH(H)CH3), 4.26 (1H, dq,
J = 11.0 Hz, 7.15 Hz, CH(H)CH3). 13C NMR (75 MHz,
CDCl3): d14.1, 28.2, 33.6, 37.0, 45.2, 55.1, 61.8, 169.6. IR
(neat, cm-1): tC=O = 1,732. MS (ES, pos. mode): m/z (%):
264/266 (M ? H?, 100). Anal. Calcd for C10H18BrNO2
(%): C, 45.47; H, 6.87; N, 5.30. Found (%): C, 45.41; H,
6.98; N, 5.19.
1
before neutralization. H NMR (300 MHz, DMSO-d6): d
1.37 (9H, s, C(CH3)3), 3.69 (2H, br s, NCH2), 3.84 (3H, s,
OCH3), 4.27 (1H, d, J = 11.0 Hz, BrCH(H)), 4.41 (1H, d,
J = 10.7 Hz, BrCH(H)), 8.58 and 8.65 (2H, 2 9 br s,
NHÁHBr). 13C NMR (75 MHz, DMSO-d6): d 24.8, 35.3,
46.2, 54.1, 55.6, 59.0, 166.7. IR (NaCl, cm-1):
tNH = 3,445, tC=O = 1,740. MS (ES, pos. mode): m/z (%):
330/332/334 (M-HBr ? H?, 100). Anal. Calcd for
C9H17Br2NO2 (%): C, 32.65; H, 5.18; N, 4.23. Found (%):
C, 32.29; H, 5.36; N, 4.07.
Methyl 2-[(tert-pentylamino)methyl]-2,3-
dibromopropanoate (13d)
Ethyl 1-tert-butyl-3-bromoazetidine-3-carboxylate (15a)
Yellow oil, yield 33%, Rf = 0.20 (petroleum ether/Et2O
7/3). 1H NMR (300 MHz, CDCl3): d 0.96 (9H, s, C(CH3)3),
1.32 (3H, t, J = 7.2 Hz, CH2CH3), 3.62 (2H, d,
J = 9.9 Hz, CH(H)NCH(H)), 3.93 (2H, d, J = 9.9 Hz,
CH(H)NCH(H)), 4.28 (2H, q, J = 7.2 Hz, CH2CH3). 13C
NMR (75 MHz, CDCl3): d 13.9, 24.1, 45.2, 52.4, 59.6,
Yellow oil, yield 97%, Rf = 0.50 (petroleum ether/EtOAc
9/1). 1H NMR (300 MHz, CDCl3): d 0.86 (3H, t,
J = 7.4 Hz, CH2CH3), 1.04 (3H, s, CH3CCH3), 1.05 (3H,
s, CH3CCH3), 1.40 (2H, q, J = 7.4 Hz, CH2CH3), 1.56
(1H, br s, NH), 3.16 (1H, d, J = 13.5 Hz, NHCH(H)), 3.20
123

Synthesis of new functionalized aziridine-2- and azetidine-3-carboxylic acid derivatives
545
62.4, 170.4. IR (neat, cm-1): tC=O = 1,739. MS (ES, pos.
mode): m/z (%): 264/266 (M ? H?, 100). Anal. Calcd for
C10H18BrNO2 (%): C, 45.47; H, 6.87; N, 5.30. Found (%):
C, 45.38; H, 7.06; N, 5.41.
Methyl 1-tert-butyl-3-bromoazetidine-3-carboxylate (15c)
Yellow oil, yield 25%, Rf = 0.16 (petroleum ether/Et2O
7/3). 1H NMR (300 MHz, CDCl3): d 0.96 (9H, s, C(CH3)3),
3.60–3.64 (2H, m, CH(H)NCH(H)), 3.83 (3H, s, OCH3),
3.91–3.95 (2H, m, CH(H)NCH(H)). 13C NMR (75 MHz,
CDCl3): d 24.1, 44.9, 52.4, 53.5, 59.7, 170.9. IR (neat,
cm-1): tC=O = 1,736. MS (ES, pos. mode): m/z (%):
250/252 (M ? H?, 100). Anal. Calcd for C9H16BrNO2
(%): C, 43.22; H, 6.45; N, 5.60. Found (%): C, 42.83; H,
6.61; N, 5.41.
Ethyl 1-tert-pentyl-2-(bromomethyl)aziridine-2-
carboxylate (14b)
Light yellow oil, yield 54%, Rf = 0.48 (petroleum ether/Et2O
7/3). 1H NMR (300 MHz, CDCl3): d 0.90 (3H, t, J = 7.4 Hz,
CCH2CH3), 0.95 (3H, s, CCH3(CH3)), 0.97 (3H, s,
CCH3(CH3)), 1.33 (3H, t, J = 7.2 Hz, OCH2CH3), 1.45 (1H,
qd, J = 7.3 Hz, 13.5 Hz, CCH(H)CH3), 1.49 (1H, qd,
J = 7.6 Hz, 13.6 Hz, CH(H)CH3), 1.84 (1H, d, J = 1.1 Hz,
NCH(H)), 2.59 (1H, dd, J = 1.2 Hz, 1.2 Hz, NCH(H)), 3.03
(1H, d, J = 9.9 Hz, BrCH(H)), 4.07 (1H, dd, J = 1.2 Hz,
10.0 Hz, BrCH(H)), 4.21 (1H, dq, J = 7.0 Hz, 10.7 Hz,
Methyl 1-tert-pentyl-2-(bromomethyl)aziridine-2-
carboxylate (14d)
Light yellow oil, yield 54%, Rf = 0.48 (petroleum ether/
1
Et2O 7/3). H NMR (300 MHz, CDCl3): d 0.90 (3H, t,
OCH(H)), 4.26 (1H, dq, J = 7.1 Hz, 10.6 Hz, OCH(H)). 13
C
J = 7.6 Hz, CH2CH3), 0.94 (3H, s, CH3CCH3), 0.96 (3H,
s, CH3CCH3), 1.36–1.58 (2H, m, CH2CH3), 1.85 (1H, s,
NCH(H)), 2.59 (1H, s, NCH(H)), 3.05 (1H, d, J = 9.9 Hz,
BrCH(H)), 3.77 (3H, s, OCH3), 4.07 (1H, d, J = 10.2 Hz,
BrCH(H)). 13C NMR (75 MHz, CDCl3): d 8.8, 24.1, 24.4,
33.9, 36.5, 36.9, 44.3, 52.7, 57.4, 170.4. IR (neat, cm-1):
tC=O = 1,732. MS (ES, pos. mode): m/z (%): 264/266
(M ? H?, 100). Anal. Calcd for C10H18BrNO2 (%): C,
45.47; H, 6.87; N, 5.30. Found (%): C, 45.38; H, 6.98; N,
5.02.
NMR (75 MHz, CDCl3): d 8.7, 14.0, 24.0, 24.4, 33.7, 36.4,
37.0, 44.4, 57.4, 61.6, 169.7. IR (neat, cm-1): tC=O = 1,736.
MS (ES, pos. mode): m/z (%): 278/280 (M ? H?, 100). Anal.
Calcd for C11H20BrNO2 (%): C, 47.49; H, 7.25; N, 5.04.
Found (%): C, 47.24; H, 7.41; N, 4.82.
Ethyl 1-tert-pentyl-3-bromoazetidine-3-carboxylate (15b)
Yellow oil, yield 24%, Rf = 0.48 (petroleum ether/EtOAc
9/1). 1H NMR (300 MHz, CDCl3): d 0.83 (3H, t,
J = 7.6 Hz, CCH2CH3), 0.88 (6H, s, C(CH3)2), 1.24 (2H,
q, J = 7.4 Hz, CCH2CH3), 1.32 (3H, t, J = 7.0 Hz,
OCH2CH3), 3.60 (2H, d, J = 9.6 Hz, CH(H)NCH(H)),
3.90 (2H, d, J = 9.6 Hz, CH(H)NCH(H)), 4.28 (2H, q,
J = 7.1 Hz, OCH2). 13C NMR (75 MHz, CDCl3): d 8.5,
13.9, 20.1, 31.5, 45.5, 54.7, 59.3, 62.2, 170.4. IR (neat,
cm-1): tC=O = 1,739. MS (ES, pos. mode): m/z (%):
278/280 (M ? H?, 90). Anal. Calcd for C11H20BrNO2
(%): C, 47.49; H, 7.25; N, 5.04. Found (%): C, 47.41; H,
7.36; N, 4.84.
Methyl 1-tert-pentyl-3-bromoazetidine-3-carboxylate (15d)
Yellow oil, yield 26%, Rf = 0.31 (petroleum ether/Et2O
7/3). 1H NMR (300 MHz, CDCl3): d 0.83 (3H, t,
J = 7.4 Hz, CH2CH3), 0.88 (6H, s, C(CH3)2), 1.24 (2H, q,
J = 7.4 Hz, CH2CH3), 3.59–3.62 (2H, m, CH(H)NCH(H)),
3.83 (3H, s, OCH3), 3.89–3.92 (2H, m, CH(H)NCH(H)).
13C NMR (75 MHz, CDCl3): d 8.6, 20.1, 31.6, 45.3, 53.4,
54.8, 59.5, 171.0. IR (neat, cm-1): tC=O = 1,742. MS (ES,
pos. mode): m/z (%): 264/266 (M ? H?, 100). Anal. Calcd
for C10H18BrNO2 (%): C, 45.47; H, 6.87; N, 5.30. Found
(%): C, 45.12; H, 7.08; N, 5.42.
Methyl 1-tert-butyl-2-(bromomethyl)aziridine-2-
carboxylate (14c)
Isomerisation of alkyl 2-(bromomethyl)aziridines
14a–d to alkyl 3-bromoazetidines 15a–d
Light yellow oil, yield 44%, Rf = 0.45 (petroleum ether/
1
Et2O 7/3). H NMR (300 MHz, CDCl3): d 1.07 (9H, s,
As a representative example, the synthesis of methyl 1-tert-
pentyl-3-bromoazetidine-3-carboxylate (15d) is described
here. Methyl 1-tert-pentyl-2-(bromomethyl)aziridine-2-
carboxylate (14d) (100 mg, 0.38 mmol) was dissolved in
DMSO (2 mL) and heated at 70°C for 5 h. After cooling,
the reaction mixture was poured into water (2 mL) and
extracted with EtOAc (3 9 15 mL). The combined organic
extracts were washed with brine (2 9 15 mL) and water
(15 mL). Drying (MgSO4), filtration, evaporation of the
(CH3)3), 1.84 (1H, d, J = 1.1 Hz, NCH(H)), 2.55 (1H, dd,
J = 1.1 Hz, 1.0 Hz, NCH(H)), 3.06 (1H, d, J = 9.9 Hz,
BrCH(H)), 3.78 (3H, s, OCH3), 4.05 (1H, dd, J = 10.2 Hz,
1.1 Hz, BrCH(H)). 13C NMR (75 MHz, CDCl3): d 28.2,
33.6, 36.7, 45.0, 52.7, 55.1, 170.2. IR (neat, cm-1):
tC=O = 1,732. MS (ES, pos. mode): m/z (%): 250/252
(M ? H?, 100). Anal. Calcd for C9H16BrNO2 (%): C,
43.22; H, 6.45; N, 5.60. Found (%): C, 43.06; H, 6.69; N,
5.34.
123

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A. Zukauskaite et al.
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546
solvent under reduced pressure and purification by pre-
parative TLC on silica gel (hexane/EtOAc 9/1) afforded
azetidine 15d in 50% yield.
tC=O = 1,734. MS (ES, pos. mode): m/z (%): 225
(M ? H?, 100). Anal. Calcd for C12H20N2O2 (%): C,
64.26; H, 8.99; N, 12.49. Found (%): C, 64.01; H, 8.84; N,
12.61.
Synthesis of alkyl 2-(cyanomethyl)aziridine-2-
carboxylates 16a–c
Methyl 1-tert-butyl-2-(cyanomethyl)aziridine-2-
carboxylate (16c)
As a representative example, the synthesis of methyl
1-tert-butyl-2-(cyanomethyl)aziridine-2-carboxylate (16c)
is described here. A solution of methyl 1-tert-butyl-
2-(bromomethyl)aziridine-2-carboxylate (14c) (118 mg,
0.47 mmol) and potassium cyanide (31 mg, 0.47 mmol) in
DMSO (2 mL) was heated at 60°C for 4 h. After cooling,
the reaction mixture was poured into water (15 mL) and
extracted with Et2O (3 9 15 mL). The combined organic
extracts were washed with brine (2 9 15 mL) and water
(15 mL). Drying (MgSO4), filtration, evaporation of the
solvent under reduced pressure and purification by pre-
parative TLC on silica gel (petroleum ether/EtOAc 8/2)
afforded 2-(cyanomethyl)aziridine 16c in 57% yield.
Yellow oil, yield 57%, Rf = 0.24 (petroleum ether/EtOAc
1
7/3). H NMR (300 MHz, CDCl3): d 1.11 (9H, s, (CH3)3),
1.96 (1H, d, J = 1.4 Hz, NCH(H)), 2.60 (1H, d,
J = 1.4 Hz, NCH(H)), 2.67 (1H, d, J = 16.8 Hz,
CH(H)CN), 2.81 (1H, d, J = 17.1 Hz, CH(H)CN), 3.79
(3H, s, OCH3). 13C NMR (75 MHz, CDCl3): d 25.2, 28.4,
33.7, 39.7, 53.0, 54.8, 117.2, 170.2. IR (neat, cm-1):
tCN = 2,253 (weak), tC=O = 1,728. MS (ES, pos. mode):
m/z (%): 197 (M ? H?, 100). Anal. Calcd for C10H16N2O2
(%): C, 61.20; H, 8.22; N, 14.27. Found (%): C, 61.14; H,
8.43; N, 14.25.
Synthesis of alkyl 2-(thiocyanomethyl)aziridine-2-
Ethyl 1-tert-butyl-2-(cyanomethyl)aziridine-2-carboxylate
(16a)
carboxylates 17a–b
As a representative example, the synthesis of ethyl 1-tert-
butyl-2-(thiocyanomethyl)aziridine-2-carboxylate (17a) is
described here. A solution of ethyl 1-tert-butyl-2-(bromo-
methyl)aziridine-2-carboxylate (14a) (132 mg, 0.5 mmol)
and potassium thiocyanate (97 mg, 1 mmol) in DMF
(2 mL) was heated at 70°C for 2 h. After cooling, the
reaction mixture was poured into water (15 mL) and
extracted with EtOAc (3 9 15 mL). The combined organic
extracts were washed with brine (2 9 15 mL) and water
(15 mL). Drying (MgSO4), filtration, evaporation of the
solvent under reduced pressure and purification by pre-
parative TLC on silica gel (petroleum ether/Et2O 7/3)
afforded 2-(thiocyanomethyl)aziridine 17a in 48% yield.
Pink oil, yield 47%, Rf = 0.26 (petroleum ether/Et2O 7/3).
1H NMR (300 MHz, CDCl3): d 1.12 (9H, s, C(CH3)3),
1.34 (3H, t, J = 7.2 Hz, CH2CH3), 1.95 (1H, d,
J = 1.4 Hz, NCH(H)), 2.60 (1H, d, J = 1.1 Hz, NCH(H)),
2.65 (1H, d, J = 17.1 Hz, CH(H)CN), 2.81 (1H, d,
J = 16.8 Hz, CH(H)CN), 4.21 (1H, dq, J = 11.0 Hz,
7.2 Hz, CH(H)CH3), 4.87 (1H, dq, J = 10.9 Hz, 7.2 Hz,
CH(H)CH3). 13C NMR (75 MHz, CDCl3): d 14.0, 25.4,
28.4, 33.6, 39.9, 54.9, 62.2, 117.3, 169.7. IR (neat, cm-1):
tCN = 2,253 (weak), tC=O = 1,733. MS (ES, pos. mode):
m/z (%): 211 (M ? H?, 100). Anal. Calcd for
C11H18N2O2 (%): C, 62.83; H, 8.63; N, 13.32. Found (%):
C, 62.95; H, 8.78; N, 13.17.
Ethyl 1-tert-butyl-2-(thiocyanomethyl)aziridine-2-
carboxylate (17a)
Ethyl 1-tert-pentyl-2-(cyanomethyl)aziridine-2-carboxylate
(16b)
Yellow oil, yield 48%, Rf = 0.31 (petroleum ether/Et2O
1
Pink oil, yield 54%, Rf = 0.29 (petroleum ether/Et2O 7/3).
1H NMR (300 MHz, CDCl3): d 0.92 (3H, t, J = 7.4 Hz,
CCH2CH3)), 1.00 (3H, s, CCH3), 1.01 (3H, s, CCH3), 1.33
(3H, t, J = 7.2 Hz, OCH2CH3), 1.39–1.56 (2H, m,
CCH2CH3)), 1.97 (1H, d, J = 1.7 Hz, NCH(H)), 2.63 (1H,
d, J = 1.4 Hz, NCH(H)), 2.66 (1H, d, J = 16.8 Hz,
CH(H)CN), 2.84 (1H, d, J = 16.8 Hz, CH(H)CN), 4.21
(1H, dq, J = 10.7 Hz, 7.2 Hz, OCH(H)CH3), 4.26 (1H, dq,
J = 10.7 Hz, 7.2 Hz, OCH(H)CH3). 13C NMR (75 MHz,
CDCl3): d 8.8, 14.0, 23.9, 24.6, 25.3, 33.8, 37.0, 39.2, 57.2,
62.2, 117.3, 169.9. IR (neat, cm-1): tCN = 2,253 (weak),
7/3). H NMR (300 MHz, CDCl3): d 1.10 (9H, s, (CH3)3),
1.33 (3H, t, J = 7.2 Hz, CH2CH3), 2.05 (1H, d, J = 1.2 Hz,
NCH(H)), 2.64 (1H, s, NCH(H)), 3.28 (1H, d, J = 12.9 Hz,
CH(H)SCN), 3.39 (1H, d, J = 12.9 Hz, CH(H)SCN), 4.20
(1H, dq, J = 11.0 Hz, 7.2 Hz, CH(H)CH3), 4.28 (1H, dq,
J = 10.7 Hz, 7.2 Hz, CH(H)CH3). 13C NMR (75 MHz,
CDCl3): d 14.0, 28.3, 33.4, 40.2, 42.7, 54.9, 62.2, 113.1,
169.7. IR (neat, cm-1): tSCN = 2,154, tC=O = 1,735. MS
(ES, pos. mode): m/z (%): 243 (M ? H?, 100). Anal. Calcd
for C11H18N2O2S (%): C, 54.52; H, 7.49; N, 11.56. Found
(%): C, 54.69; H, 7.61; N, 11.37.
123

Synthesis of new functionalized aziridine-2- and azetidine-3-carboxylic acid derivatives
547
Ethyl 1-tert-pentyl-2-(thiocyanomethyl)aziridine-2-
carboxylate (17b)
Ethyl 1-tert-pentyl-2-(azidomethyl)aziridine-2-carboxylate
(18b)
Yellow oil, yield 44%, Rf = 0.30 (petroleum ether/EtOAc
9/1). 1H NMR (300 MHz, CDCl3): d 0.91 (3H, t,
J = 7.7 Hz, CCH2CH3), 0.98 (3H, s, CCH3), 1.01 (3H, s,
CCH3), 1.33 (3H, t, J = 7.2 Hz, OCH2CH3), 1.37-1.58 (2H,
m, CCH2CH3), 2.07 (1H, s, NCH(H)), 2.66 (1H, s, NCH(H)),
3.32 (1H, d, J = 12.9 Hz, CH(H)SCN), 3.43 (1H, d,
J = 13.2 Hz, CH(H)SCN), 4.19 (1H, dq, J = 10.7 Hz,
7.2 Hz, OCH(H)CH3), 4.27 (1H, dq, J = 11.0 Hz, 7.2 Hz,
OCH(H)CH3). 13C NMR (75 MHz, CDCl3): d 8.8, 14.0,
23.9, 24.7, 33.4, 36.8, 40.3, 42.0, 57.3, 62.2, 113.1, 169.9. IR
(neat, cm-1): tSCN = 2,155, tC=O = 1,735. MS (ES, pos.
mode): m/z (%): 257 (M ? H?, 100). Anal. Calcd for
C12H20N2O2S (%): C, 56.22; H, 7.86; N, 10.93. Found (%):
C, 55.98; H, 8.02; N, 10.68.
Yellow oil, yield 93%, Rf = 0.50 (petroleum ether/EtOAc
9/1). 1H NMR (300 MHz, CDCl3): d 0.91 (3H, t,
J = 7.4 Hz, CCH2CH3), 0.97 (3H, s, CCH3), 0.99 (3H, s,
CCH3), 1.32 (3H, t, J = 7.2 Hz, OCH2CH3), 1.46 (1H, dq,
J = 13.8 Hz, 7.3 Hz, CCH(H)CH3), 1.51 (1H, dq, J =
13.6 Hz, 7.5 Hz, CCH(H)CH3), 1.90 (1H, d, J = 1.1 Hz,
NCH(H)), 2.50-2.51 (1H, m, NCH(H)), 3.26 (1H, d,
J = 12.7 Hz, CH(H)N3), 3.70 (1H, d, J = 12.7 Hz,
CH(H)N3), 4.19 (1H, dq, J = 11.0 Hz, 7.2 Hz, OCH
(H)CH3), 4.25 (1H, dq, J = 10.7 Hz, 7.2 Hz, OCH
(H)CH3). 13C NMR (75 MHz, CDCl3): d 8.8, 14.0, 24.0,
24.6, 32.1, 36.6, 42.5, 55.7, 57.0, 61.7, 170.7. IR (neat,
cm-1): tN3 = 2,101, tC=O = 1,734. MS (ES, pos. mode):
m/z (%): 241 (M ? H?, 100). Anal. Calcd for C11H20N4O2
(%): C, 54.98; H, 8.39; N, 23.32. Found (%): C, 54.61; H,
8.53; N, 23.14.
Synthesis of alkyl 2-(azidomethyl)aziridine-2-
carboxylates 18a–d
Methyl 1-tert-butyl-2-(azidomethyl)aziridine-2-carboxylate
(18c)
As a representative example, the synthesis of methyl
1-tert-butyl-2-(azidomethyl)aziridine-2-carboxylate (18c)
is described here. Methyl 1-tert-butyl-2-(bromomethyl)azi-
ridine-2-carboxylate (14c) (250 mg, 1 mmol) and sodium
azide (130 mg, 2 mmol) were heated in DMSO (5 mL) at
60°C for 3 h. After cooling, the reaction mixture was poured
into water (15 mL) and extracted with Et2O (3 9 25 mL).
The combined organic extracts were washed with brine
(2 9 15 mL) and water (15 mL). Drying with MgSO4, fil-
tration of the drying agent, evaporation of the solvent under
reduced pressure and purification by flash chromatography
on silica gel (Hexane/Et2O 9/1–7/3) afforded 2-(azido-
methyl)aziridine 18c in 91% yield.
Light yellow oil, yield 91%, Rf = 0.53 (hexane/Et2O 7/3).
1H NMR (300 MHz, CDCl3): d 1.09 (9H, s, C(CH3)3), 1.90
(1H, d, J = 1.1 Hz, NCH(H)), 2.47 (1H, s, NCH(H)), 3.29
(1H, d, J = 12.7 Hz, CH(H)N3), 3.67 (1H, d, J = 12.7 Hz,
CH(H)N3), 3.77 (3H, s, OCH3). 13C NMR (75 MHz,
CDCl3): d 28.2, 32.0, 42.9, 52.7, 54.6, 55.6, 61.8, 171.0. IR
(neat, cm-1): tN3 = 2,105, tC=O = 1,740. MS (ES, pos.
mode): m/z (%): 213 (M ? H?, 100). Anal. Calcd for
C9H16N4O2 (%): C, 50.93; H, 7.60; N, 26.40. Found (%):
C, 50.64; H, 7.47; N, 26.51.
Methyl 1-tert-pentyl-2-(azidomethyl)aziridine-2-
carboxylate (18d)
Ethyl 1-tert-butyl-2-(azidomethyl)aziridine-2-carboxylate
(18a)
Yellow oil, yield 64%, Rf = 0.25 (petroleum ether/Et2O 9/1).
1H NMR (300 MHz, CDCl3): d 0.91 (3H, t, J = 7.6 Hz,
CCH2CH3), 0.96(3H, s, CCH3), 0.98(3H, s, CCH3), 1.45(1H,
dq, J = 13.6 Hz, 7.3 Hz, CCH(H)CH3), 1.50 (1H, dq,
J = 13.6 Hz, 7.7 Hz, CCH(H)CH3), 1.92(1H,d,J = 1.4 Hz,
NCH(H)), 2.50–2.51 (1H, m, NCH(H)), 3.28 (1H, d,
J = 12.7 Hz, CH(H)N3), 3.69 (1H, d, J = 12.7 Hz,
CH(H)N3), 3.77 (3H, s, OCH3). 13C NMR (75 MHz, CDCl3):
d 8.8, 23.9, 24.5, 32.1, 36.6, 42.2, 52.6, 55.6, 56.9, 171.3. IR
(neat, cm-1): tN3 = 2,100, tC=O = 1,732. MS (ES, pos.
mode): m/z (%): 227 (M ? H?, 100). Anal. Calcd for
C10H18N4O2 (%): C, 53.08; H, 8.02; N, 24.76. Found (%): C,
52.85; H, 8.24; N, 24.59.
Yellow oil, yield 58%, Rf = 0.47 (petroleum ether/EtOAc
8/2). 1H NMR (300 MHz, CDCl3): d 1.09 (9H, s, C(CH3)3),
1.33 (3H, t, J = 7.2 Hz, CH2CH3), 1.88 (1H, d, J = 1.7 Hz,
NCH(H)), 2.47–2.48 (1H, m, NCH(H)), 3.26 (1H, d,
J = 12.7 Hz, CH(H)N3), 3.68 (1H, d, J = 12.7 Hz,
CH(H)N3), 4.19 (1H, dq, J = 10.7 Hz, 7.2 Hz, OCH
(H)CH3), 4.26 (1H, dq, J = 10.7 Hz, 7.2 Hz, OCH(H)CH3).
13C NMR (75 MHz, CDCl3): d 14.0, 28.3, 32.0, 43.1, 54.6,
55.8, 61.8, 170.4. IR (neat, cm-1): tN3 = 2,101, tC=O
=
1,734. MS (ES, pos. mode): m/z (%): 227 (M ? H?, 100).
Anal. Calcd for C10H18N4O2 (%): C, 53.08; H, 8.02; N,
24.76. Found (%): C, 52.77; H, 8.17; N, 24.45.
123

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A. Zukauskaite et al.
_
548
(M ? H?, 100). Anal. Calcd for C17H25NO3 (%): C, 70.07;
Synthesis of alkyl 2-(phenoxymethyl)aziridine-2-
carboxylates 19a–b
H, 8.65; N, 4.81. Found (%): C, 69.91; H, 8.83; N, 4.54.
As a representative example, the synthesis of ethyl 1-tert-
butyl-2-(phenoxymethyl)aziridine-2-carboxylate (19a) is
described here. Ethyl 1-tert-butyl-2-(bromomethyl)aziri-
dine-2-carboxylate (14a) (80 mg, 0.3 mmol) was added to
a mixture of phenol (57 mg, 0.6 mmol) and K2CO3
(168 mg, 1.2 mmol) in DMSO (4 mL) and the reaction
mixture was heated at 60°C for 8 h. After cooling, the
reaction mixture was poured into water (15 mL) and
extracted with Et2O (3 9 15 mL). The combined organic
extracts were washed with brine (2 9 15 mL), saturated
NaOH (aq.) solution (2 9 10 mL) and water (15 mL).
Drying (MgSO4), filtration, evaporation of the solvent
under reduced pressure and purification by preparative
TLC on silica gel (petroleum ether/EtOAc 9/1) afforded
2-(phenoxymethyl)aziridine 19a in 60% yield.
Synthesis of ethyl 1-tert-butyl-3-cyanoazetidine-3-
carboxylate (21a)
A solution of ethyl 1-tert-butyl-3-bromoazetidine-3-car-
boxylate (15a) (132 mg, 0.5 mmol) and potassium cyanide
(65 mg, 1 mmol) in DMSO (2 mL) was heated at 60°C for
4 h. After cooling, the reaction mixture was poured into
water (20 mL) and extracted with Et2O (3 9 15 mL). The
combined organic extracts were washed with brine
(2 9 15 mL) and water (15 mL). Drying (MgSO4), filtra-
tion, evaporation of the solvent under reduced pressure and
purification by preparative TLC on silica gel (petroleum
ether/EtOAc 8/2) afforded 3-cyanoazetidine 21a in 79%
yield. Yellow oil, Rf = 0.43 (petroleum ether/EtOAc 7/3).
1H NMR (300 MHz, CDCl3): d 0.96 (9H, s, C(CH3)3), 1.34
(3H, t, J = 7.2 Hz, CH2CH3), 3.62 (2H, d, J = 7.2 Hz,
CH(H)NCH(H)), 3.72 (2H, d, J = 7.4 Hz, CH(H)NCH(H)),
4.30 (2H, q, J = 7.2 Hz, CH2CH3). 13C NMR (75 MHz,
CDCl3): d 14.0, 23.8, 34.6, 52.2, 54.3, 63.2, 119.0, 167.0. IR
(neat, cm-1): tCN = 2,246 (weak), tC=O = 1,742. MS (ES,
pos. mode): m/z (%): 211 (M ? H?, 100). Anal. Calcd for
C11H18N2O2 (%): C, 62.83; H, 8.63; N, 13.32. Found (%): C,
62.91; H, 8.79; N, 13.01.
Ethyl 1-tert-butyl-2-(phenoxymethyl)aziridine-2-
carboxylate (19a)
Yellow oil, yield 60%, Rf = 0.33 (petroleum ether/EtOAc
1
9/1). H NMR (300 MHz, CDCl3): d 1.11 (9H, s, (CH3)3),
1.25 (3H, t, J = 7.2 Hz, CH2CH3), 1.92 (1H, d,
J = 1.1 Hz, NCH(H)), 2.49 (1H, s, NCH(H)), 3.72 (1H, d,
J = 9.4 Hz, CCH(H)O), 4.18 (1H, dq, J = 10.7 Hz,
7.2 Hz, OCH(H)CH3), 4.22 (1H, dq, J = 10.7 Hz, 7.2 Hz,
OCH(H)CH3), 4.60 (1H, d, J = 9.6 Hz, CCH(H)O),
6.86–6.97 (3H, m, 3 9 CHarom), 7.23–7.30 (2H, m,
2 9 CHarom). 13C NMR (75 MHz, CDCl3): d 14.1, 28.2,
31.7, 43.6, 54.6, 61.5, 72.1, 114.9, 121.1, 129.5, 158.7,
170.4. IR (neat, cm-1): tC=O = 1,730. MS (ES, pos.
mode): m/z (%): 278 (M ? H?, 100). Anal. Calcd for
C16H23NO3 (%): C, 69.29; H, 8.36; N, 5.05. Found (%): C,
69.43; H, 8.61; N, 4.76.
Synthesis of alkyl 3-thiocyanoazetidine-3-carboxylates
22a–b
As a representative example, the synthesis of ethyl
1-tert-butyl-3-thiocyanoazetidine-3-carboxylate (22a) is
described here. A solution of ethyl 1-tert-butyl-3-bromoa-
zetidine-3-carboxylate (15a) (94 mg, 0.36 mmol) and
potassium thiocyanate (52 mg, 0.53 mmol) in DMSO
(2 mL) was heated at 60°C for 3 h. After cooling, the
reaction mixture was poured into water (15 mL) and
extracted with Et2O (3 9 20 mL). The combined organic
extracts were washed with brine (2 9 15 mL) and water
(15 mL). Drying (MgSO4), filtration, evaporation of the
solvent under reduced pressure and purification by pre-
parative TLC on silica gel (petroleum ether/Et2O 7/3)
afforded 3-thiocyanoazetidine 22a in 59% yield.
Ethyl 1-tert-pentyl-2-(phenoxymethyl)aziridine-2-
carboxylate (19b)
Yellow oil, yield 67%, Rf = 0.19 (petroleum ether/EtOAc
9/1). 1H NMR (300 MHz, CDCl3): d 0.94 (3H, t,
J = 7.4 Hz, CCH2CH3), 0.97 (3H, s, CCH3), 1.00 (3H, s,
CCH3), 1.25 (3H, t, J = 7.2 Hz, OCH2CH3), 1.45–1.59 (2H,
m, CCH2CH3), 1.93 (1H, d, J = 1.4 Hz, NCH(H)), 2.53
(1H, s, NCH(H)), 3.70 (1H, d, J = 9.4 Hz, CCH(H)O), 4.18
(1H, dq, J = 10.7 Hz, 7.2 Hz, OCH(H)CH3), 4.21 (1H, dq,
J = 11.0 Hz, 7.2 Hz, OCH(H)CH3), 4.61 (1H, dd,
J = 9.4 Hz, 0.8 Hz, CCH(H)O), 6.85–6.97 (3H, m,
3 9 CHarom), 7.23-7.30 (2H, m, 2 9 CHarom). 13C NMR
(75 MHz, CDCl3): d 8.8, 14.1, 24.0, 24.5, 31.9, 36.4, 42.8,
56.9, 61.4, 72.1, 114.9, 121.1, 129.5, 158.8, 170.7. IR (neat,
cm-1): tC=O = 1,730. MS (ES, pos. mode): m/z (%): 292
Ethyl 1-tert-butyl-3-thiocyanoazetidine-3-carboxylate
(22a)
Yellow oil, yield 59%, Rf = 0.17 (petroleum ether/Et2O
7/3). 1H NMR (300 MHz, CDCl3): d 0.98 (9H, s, C(CH3)3),
1.35 (3H, t, J = 7.2 Hz, OCH2CH3), 3.44 (2H, d,
J = 8.8 Hz, CH(H)NCH(H)), 3.83 (2H, d, J = 8.8 Hz,
CH(H)NCH(H)), 4.32 (2H, q, J = 7.2 Hz, OCH2CH3). 13
NMR (75 MHz, CDCl3): d 14.1, 24.0, 47.4, 52.4, 55.7,
C
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Synthesis of new functionalized aziridine-2- and azetidine-3-carboxylic acid derivatives
549
63.0, 109.9, 169.2. IR (neat, cm-1): tSCN = 2,157,
tC=O = 1,736. MS (ES, pos. mode) m/z (%): 243 (M ? H?,
100). Anal. Calcd for C11H18N2O2S (%): C, 54.52; H, 7.49; N,
11.56. Found (%): C, 54.27; H, 7.64; N, 11.64.
J = 7.4 Hz, CCH2CH3), 1.34 (3H, t, J = 7.2 Hz,
OCH2CH3), 3.30 (2H, dd, J = 7.2 Hz, 1.4 Hz, CH(H)
NCH(H)), 3.70 (2H, dd, J = 7.3 Hz, 1.4 Hz, CH(H)NCH(H)),
4.28 (2H, q, J = 7.2 Hz, OCH2CH3). 13C NMR (75 MHz,
CDCl3): d 8.6, 14.2, 20.0, 31.5, 54.3, 54.6, 59.7, 62.3, 170.0.
IR (neat, cm-1): tN3 = 2,108, tC=O = 1,738. MS (ES, pos.
mode): m/z (%): 241 (M ? H?, 100). Anal. Calcd for
C11H20N4O2 (%): C, 54.98; H, 8.39; N, 23.32. Found (%): C,
54.59; H, 8.53; N, 23.64.
Ethyl 1-tert-pentyl-3-thiocyanoazetidine-3-carboxylate
(22b)
Yellow oil, yield 83%, Rf = 0.21 (petroleum ether/Et2O 7/3).
1H NMR (300 MHz, CDCl3): d 0.85 (3H, t, J = 7.4 Hz,
CCH2CH3), 0.90 (6H, s, C(CH3)2), 1.25 (2H, q, J = 7.7 Hz,
CCH2CH3), 1.35 (3H, t, J = 7.2 Hz, OCH2CH3), 3.43 (2H, d,
J = 8.8 Hz, CH(H)NCH(H)), 3.82 (2H, d, J = 9.4 Hz,
CH(H)NCH(H)), 4.31 (2H, q, J = 7.2 Hz, OCH2CH3). 13C
NMR (75 MHz, CDCl3): d 8.5, 14.1, 20.2, 31.4, 47.9, 54.8,
55.6, 63.0, 110.0, 169.3. IR (neat, cm-1): tSCN = 2,157,
tC=O = 1,736. MS (ES, pos. mode) m/z (%): 257 (M ? H?,
100). Anal. Calcd for C12H20N2O2S (%): C, 56.22; H, 7.86; N,
10.93. Found (%): C, 56.09; H, 8.01; N, 10.64.
Methyl 1-tert-butyl-3-azidoazetidine-3-carboxylate (23c)
Yellow oil, yield 79%, Rf = 0.22 (petroleum ether/EtOAc
7/3). 1H NMR (300 MHz, CDCl3): d 0.99 (9H, s, C(CH3)3),
3.33 (2H, d, J = 7.4 Hz, CH(H)NCH(H)), 3.70 (2H, d,
J = 7.4 Hz, CH(H)NCH(H)), 3.84 (3H, s, OCH3). 13C
NMR (75 MHz, CDCl3): d 24.0, 52.2, 53.2, 54.5, 59.4,
170.5. IR (neat, cm-1): tN3 = 2,109, tC=O = 1,740. MS
(ES, pos. mode): m/z (%): 213 (M ? H?, 100). Anal. Calcd
for C9H16N4O2 (%): C, 50.93; H, 7.60; N, 26.40. Found
(%): C, 50.79; H, 7.69; N, 26.21.
Synthesis of alkyl 3-azidoazetidine-3-carboxylates
23a–c
Synthesis of alkyl 3-phenoxyazetidine-3-carboxylates
As a representative example, the synthesis of ethyl 1-tert-
pentyl-3-azidoazetidine-3-carboxylate (23b) is described
here. A solution of ethyl 1-tert-pentyl-3-bromoazetidine-3-
carboxylate (15b) (111 mg, 0.4 mmol) and sodium azide
(52 mg, 0.8 mmol) in DMSO (2 mL) was heated at 60°C for
3 h. After cooling, the reaction mixture was poured into water
(15 mL) and extracted with Et2O (3 9 15 mL). The com-
bined organic extracts were washed with brine (2 9 15 mL)
and water (10 mL). Drying (MgSO4), filtration, evaporation
of the solvent under reduced pressure and purification by
preparative TLC on silica gel (petroleum ether/Et2O 8/2)
afforded 3-azidoazetidine 23b in 98% yield.
20a–b
As a representative example, the synthesis of ethyl 1-tert-
pentyl-3-phenoxyazetidine-3-carboxylate (20b) is described
here. Ethyl 1-tert-pentyl-3-bromoazetidine-3-carboxylate
(15b) (83 mg, 0.3 mmol) was added to a mixture of phenol
(70 mg, 0.75 mmol) and K2CO3 (206 mg, 1.5 mmol) in
DMSO (2 mL) and the reaction mixture was heated at 60°C
for 8 h. After cooling, the reaction mixture was poured into
water (15 mL) and extracted with Et2O (3 9 15 mL). The
combined organic extracts were washed with brine
(2 9 15 mL), saturated NaOH (aq.) solution (2 9 10 mL)
and water (15 mL). Drying (MgSO4), filtration, evaporation
of the solvent under reduced pressure and purification by
preparative TLC on silica gel (petroleum ether/Et2O 7/3)
afforded 3-phenoxyazetidine 20b in 81% yield.
Ethyl 1-tert-butyl-3-azidoazetidine-3-carboxylate (23a)
Yellow oil, yield 86%, Rf = 0.18 (petroleum ether/Et2O7/3).1H
NMR (300 MHz, CDCl3): d 0.99 (9H, s, C(CH3)3), 1.34 (3H, t,
J = 7.2 Hz, CH2CH3), 3.32 (2H, d, J = 7.4 Hz,
CH(H)NCH(H)), 3.70 (2H, d, J = 7.4 Hz, CH(H)NCH(H)),
4.29 (2H, q, J = 7.2 Hz, OCH2CH3). 13C NMR (75 MHz,
CDCl3): d 14.2, 24.0, 52.2, 54.4, 59.3, 62.4, 170.0. IR (neat,
cm-1): tN3 = 2,109, tC=O = 1,737. MS (ES, pos. mode): m/
z(%): 227 (M ? H?, 100). Anal. Calcd for C10H18N4O2 (%): C,
53.08; H, 8.02; N, 24.76. Found (%): C, 52.74; H, 8.31; N, 24.90.
Ethyl 1-tert-butyl-3-phenoxyazetidine-3-carboxylate (20a)
Yellow oil, yield 36%, Rf = 0.25 (petroleum ether/Et2O 1/1).
1H NMR (300 MHz, CDCl3): d 1.00 (9H, s, C(CH3)3), 1.15
(3H, t, J = 7.2 Hz, CH2CH3), 3.51 (2H, d, J = 9.1 Hz,
CH(H)NCH(H)), 3.88 (2H, d, J = 9.1 Hz, CH(H)NCH(H)),
4.21 (2H, q, J = 7.2 Hz, OCH2CH3), 6.65-6.69 (2H, m,
2 9 CHarom), 6.93–6.98 (1H, m, CHarom), 7.20–7.27 (2H, m,
2 9 CHarom). 13C NMR (75 MHz, CDCl3): d 14.1, 24.1, 52.2,
55.0, 61.9, 73.8, 115.2, 121.5, 129.6, 155.4, 171.4. IR (neat,
cm-1): tC=O = 1,736. MS (ES, pos. mode): m/z (%): 278
(M ? H?, 100). Anal.CalcdforC16H23NO3 (%):C, 69.29;H,
8.36; N, 5.05. Found (%): C, 69.02; H, 8.59; N, 4.83.
Ethyl 1-tert-pentyl-3-azidoazetidine-3-carboxylate (23b)
Yellow oil, yield 98%, Rf = 0.24 (petroleum ether/Et2O
1
8/2). H NMR (300 MHz, CDCl3): d 0.85 (3H, t, J = 7.4
Hz, CCH2CH3), 0.91 (6H, s, C(CH3)2), 1.27 (2H, q,
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Ethyl 1-tert-pentyl-3-phenoxyazetidine-3-carboxylate (20b)
1-tert-butyl-2-(azidomethyl)aziridine-2-carboxylate (18c)
(65 mg, 0.31 mmol) in degassed CH3CN (8 mL), Pd
(6.5 mg, 10 wt% on carbon) and di-tert-butyl dicarbonate
(334 mg, 1.53 mmol) were added and the reaction mixture
was stirred under H2 atmosphere (10 bar) at room tem-
perature for 3 h. Subsequently, the reaction mixture was
filtered over CeliteÒ and the filter cake was washed with
small portions of CH3CN. Evaporation of the solvent under
reduced pressure and purification by flash chromatography
on silica gel (hexane/EtOAc 9/1) afforded aziridine 25c in
76% yield.
Yellow oil, yield 81%, Rf = 0.27 (petroleum ether/Et2O
7/3). 1H NMR (300 MHz, CDCl3): d 0.85 (3H, t,
J = 7.4 Hz, CCH2CH3), 0.92 (6H, s, C(CH3)2), 1.15 (3H, t,
J = 7.2 Hz, OCH2CH3), 1.30 (2H, q, J = 7.4 Hz,
CCH2CH3), 3.51 (2H, d, J = 8.0 Hz, CH(H)NCH(H)),
3.86 (2H, d, J = 8.0 Hz, CH(H)NCH(H)), 4.21 (2H, q,
J = 7.2 Hz, OCH2CH3), 6.66–6.69 (2H, m, 2 9 CHarom),
6.93-6.98 (1H, m, CHarom), 7.21–7.26 (2H, m,
2 9 CHarom). 13C NMR (75 MHz, CDCl3): d 8.7, 14.1,
20.0, 31.5, 54.7, 54.8, 61.8, 74.1, 115.2, 121.5, 129.6,
155.5, 171.4. IR (neat, cm-1): tC=O = 1,736. MS (ES, pos.
mode): m/z (%): 292 (M ? H?, 100). Anal. Calcd for
C17H25NO3 (%): C, 70.07; H, 8.65; N, 4.81. Found (%): C,
70.34; H, 8.40; N, 4.60.
Ethyl 1-tert-pentyl-2-(tert-butoxycarbonylaminomethyl)-
aziridine-2-carboxylate (25b)
Light yellow oil, yield 62%, Rf = 0.13 (hexane/EtOAc 9/1).
1H NMR (300 MHz, CDCl3): d 0.91 (3H, t, J = 7.7 Hz,
CCH2CH3), 0.96 (3H, s, NCCH3), 0.97 (3H, s, CCH3), 1.29
(3H, t, J = 7.2 Hz, OCH2CH3), 1.40–1.50 (2H, m,
CCH2CH3), 1.43 (9H, s, NCCH3), 1.86 (1H, d, J = 1.1 Hz,
NCH(H)), 2.39 (1H, s, NCH(H)), 3.30 (1H, dd, J = 13.8 Hz,
4.4 Hz, CH(H)NH), 3.60 (1H, d, J = 13.8 Hz, 7.7 Hz,
Synthesis of ethyl 1-tert-pentyl-2-
(aminomethyl)aziridine-2-carboxylate (24b)
To a solution of ethyl 1-tert-pentyl-2-(azidomethyl)aziri-
dine-2-carboxylate (18b) (70 mg, 0.29 mmol) in EtOH
(7 mL), Pd (7 mg, 10 wt% on carbon) was added and the
reaction mixture was stirred under H2 atmosphere (4 bar) at
room temperature for 3 h. Subsequently, the reaction
mixture was filtered over CeliteÒ and the filter cake was
washed with small portions of EtOH. Evaporation of the
solvent under reduced pressure and purification by pre-
parative TLC on silica gel (CH2Cl2/MeOH 100/5) afforded
2-(aminomethyl)aziridine 24b. Yellow oil, yield 68%,
Rf = 0.27 (CH2Cl2/MeOH 9/1). 1H NMR (300 MHz,
CDCl3): d 0.92 (3H, t, J = 7.6 Hz, CCH2CH3), 0.94 (3H, s,
CCH3), 0.98 (3H, s, CCH3), 1.30 (3H, t, J = 7.2 Hz,
OCH2CH3), 1.48 (1H, dq, J = 13.6 Hz, 7.4 Hz, CCH
(H)CH3), 1.51 (1H, dq, J = 13.4 Hz, 7.4 Hz, CCH
(H)CH3), 1.78 (1H, d, J = 1.1 Hz, CH(H)N), 1.86 (2H, br
s, NH2), 2.41 (1H, d, J = 1.4 Hz, CH(H)N), 2.87 (1H, d,
J = 13.8 Hz, CH(H)NH2), 2.89 (1H, d, J = 13.8 Hz,
CH(H)NH2), 4.16 (1H, dq, J = 10.7 Hz, 7.2 Hz, OCH(H)
CH3), 4.22 (1H, dq, J = 10.7 Hz, 7.2 Hz, OCH(H)CH3).
13C NMR (75 MHz, CDCl3): d 8.9, 14.1, 23.8, 24.5, 31.4,
36.7, 46.9, 56.5, 61.3, 172.1. IR (neat, cm-1):
tNH2 = 3,381 (weak), tC=O = 1,724. MS (ES, pos. mode):
m/z (%): 215 (M ? H?, 100). Anal. Calcd for C11H22N2O2
(%): C, 61.65; H, 10.35; N, 13.07. Found (%): C, 61.27; H,
10.62; N, 12.91.
CH(H)NH), 4.18(2H, m, OCH2CH3), 4.90(1H, br s, NH). 13
C
NMR (75 MHz, CDCl3): d 8.8, 14.0, 24.2, 24.6, 28.5, 31.0,
36.7, 42.3, 43.5, 56.6, 61,4, 79.3, 155.9, 171.6. IR (neat,
cm-1): tNH = 3,382, tC=O = 1,717. MS (ES, pos. mode):
m/z (%): 315 (M ? H?, 100). Anal. Calcd for C16H30N2O4
(%): C, 61.12; H, 9.62; N, 8.91. Found (%): C, 61.39; H, 9.51;
N, 8.86.
Methyl 1-tert-butyl-2-(tert-butoxycarbonylaminomethyl)-
aziridine-2-carboxylate (25c)
Light yellow oil, yield 76%, Rf = 0.07 (hexane/EtOAc 9/1).
1H NMR (300 MHz, CDCl3): d 1.07 (9H, s, NC(CH3)3), 1.44
(9H, s, OC(CH3)3), 1.87 (1H, d, J = 1.1 Hz, NCH(H)), 2.34
(1H, s, NCH(H)), 3.33 (1H, dd, J = 13.8 Hz, 4.4 Hz,
CH(H)NH), 3.57 (1H, dd, J = 13.8 Hz, 7.2 Hz, CH(H)NH),
3.72 (3H, s, OCH3), 4.93 (1H, br s, NH). 13C NMR (75 MHz,
CDCl3): d 28.4, 28.5, 31.0, 42.9, 43.6, 52.4, 54.3, 79.3, 155.9,
172.0. IR (neat, cm-1): tNH = 3,382, tC=O = 1,718. MS (ES,
pos. mode): m/z (%): 287 (M ? H?, 100). Anal. Calcd for
C14H26N2O4 (%): C, 58.72; H, 9.15; N, 9.78. Found (%): C,
58.59; H, 9.38; N, 9.59.
Synthesis of ethyl 1-tert-butyl-3-aminoazetidine-3-
carboxylate (26a)
Synthesis of alkyl 2-(tert-butoxycarbonylaminomethyl)-
aziridine-2-carboxylates 25b–c
To a solution of ethyl 1-tert-butyl-3-azidoazetidine-3-car-
boxylate (23a) (52 mg, 0.23 mmol) in EtOH (5 mL), Pd
(5.2 mg, 10 wt% on carbon) was added and the reaction
mixture was stirred under H2 atmosphere (4 bar) at room
temperature for 3 h. Subsequently, the reaction mixture was
As a representative example, the synthesis of methyl 1-tert-
butyl-2-(tert-butoxycarbonylaminomethyl)aziridine-2-car-
boxylate (25c) is described here. To a solution of methyl
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Synthesis of new functionalized aziridine-2- and azetidine-3-carboxylic acid derivatives
551
filtered over CeliteÒ and the filter cake was washed with small
portions of EtOH. Evaporation of the solvent under reduced
pressure and purification by preparative TLC on silica gel
(petroleum ether/EtOAc 1/1) afforded 3-aminoazetidine 26a
in 78% yield. Yellow oil, Rf = 0.10 (petroleum ether/EtOAc
1/1). 1H NMR (300 MHz, CDCl3): d 0.99 (9H, s, C(CH3)3),
1.31 (3H, t, J = 7.2 Hz, CH2CH3), 2.37 (2H, br s, NH2), 3.10
(2H, d, J = 8.3 Hz, NCH(H)), 3.72 (2H, d, J = 8.3 Hz,
NCH(H)), 4.22 (2H, q, J = 7.2 Hz, OCH2CH3). 13C NMR
(75 MHz, CDCl3): d 14.3, 24.0, 52.2, 53.1, 57.7, 61.5, 173.9.
IR (neat, cm-1): tNH2 = 3,376 (weak), tC=O = 1,730. MS
(ES, pos. mode): m/z (%): 201 (M ? H?, 100). Anal. Calcd
forC10H20N2O2 (%):C, 59.97;H, 10.07;N, 13.99.Found(%):
C, 59.61; H, 10.17; N, 13.64.
q, J = 7.7 Hz, CCH2CH3), 4.07 (2H, d, J = 11.0 Hz,
CH(H)NCH(H)), 4.54 (2H, d, J = 11.6 Hz, CH(H)
NCH(H)). 13C NMR (75 MHz, CD3OD): d 8.6, 20.0, 31.5,
54.3, 54.6, 59.7, 170.0. IR (neat, cm-1): tOH = 3,417,
tN3 = 2,102, tC=O = 1,604. MS (ES, pos. mode): m/z (%):
213 (M ? H?, 100). Anal. Calcd for C9H16N4O2 (%): C,
50.93; H, 7.60; N, 26.40. Found (%): C, 50.74; H, 7.78; N,
26.29.
Synthesis of alkyl 3-aminoazetidine-3-carboxylic acids
28a–b
As a representative example, the synthesis of 1-tert-pentyl-
3-aminoazetidine-3-carboxylic acid (28b) is described
here. To a solution of 1-tert-pentyl-3-azidoazetidine-3-
carboxylic acid (27b) (60 mg, 0.3 mmol) in MeOH
(12 mL), Pd (6 mg, 10 wt% on carbon) was added and
the reaction mixture was stirred under H2 atmosphere
(3 bar) at room temperature for 3 h. Subsequently, the
reaction mixture was filtered over CeliteÒ and the
filter cake was washed with small portions of MeOH.
The solvent was evaporated under reduced pressure. The
residue was dissolved in H2O and purified by means
of ion-exchange chromatography on Dowex H? (50 9
8–100) by sequential elution with H2O and 1 N NH4OH
aq. solution. The eluted aqueous solution of the ammo-
nium salt was neutralized with 2 N HCl aq. solution and
the solvent was evaporated under reduced pressure. The
residue was taken up in CH2Cl2, filtered and evaporated
under reduced pressure to afford amino acid 28b in 80%
yield.
Synthesis of alkyl 3-azidoazetidine-3-carboxylic acids
27a–b
As a representative example, the synthesis of 1-tert-butyl-
3-azidoazetidine-3-carboxylic acid (27a) is described here.
To a solution of ethyl 1-tert-butyl-3-azidoazetidine-3-car-
boxylate (23a) (96 mg, 0.42 mmol) in MeOH (3 mL), 2 N
NaOH (aq.) solution (3 mL) was added dropwise at 0°C
and the reaction mixture was stirred at room temperature
for 3 h. The reaction mixture was acidified with 1 N HCl
aq. solution till pH = 7 and the solvents were evaporated
under reduced pressure. The residue was dissolved in H2O
and purified by means of ion-exchange chromatography on
Dowex H? (50 9 8–100) by sequential elution with H2O
and 1 N NH4OH aq. solution. The eluted aqueous solution
of the ammonium salt was neutralized with 2 N HCl aq.
solution and the solvent was evaporated under reduced
pressure. The residue was taken up in CH2Cl2, filtered and
evaporated under reduced pressure to afford carboxylic
acid 27a in 90% yield.
1-tert-Butyl-3-aminoazetidine-3-carboxylic acid (28a)
Brown viscous oil, yield 76%, Rf = 0.02 (CH2Cl2/MeOH
9/1). 1H NMR (300 MHz, CD3OD): d 1.21 (9H, s,
C(CH3)3), 3.75 (2H, d, J = 10.5 Hz, CH(H)NCH(H)), 4.25
(2H, d, J = 10.5 Hz, CH(H)NCH(H)). 13C NMR (75 MHz,
CD3OD): d 23.5, 54.2, 59.1, 59.3, 176.4. IR (neat, cm-1):
tOH,NH2 = 3,379, tC=O = 1,650. MS (ES, pos. mode):
m/z (%): 173 (M ? H?, 100). Anal. Calcd for C8H16N2O2
(%): C, 55.79; H, 9.36; N, 16.27. Found (%): C, 55.51; H,
9.52; N, 16.39.
1-tert-Butyl-3-azidoazetidine-3-carboxylic acid (27a)
Yellow viscous oil, yield 90%, Rf = 0.15 (CH2Cl2/MeOH
9/1). 1H NMR (300 MHz, CD3OD): d 1.34 (9H, s, C(CH3)3),
4.05 (2H, d, J = 11.0 Hz, CH(H)NCH(H)), 4.51 (2H, d,
J = 11.6 Hz, CH(H)NCH(H)). 13C NMR (75 MHz,
CD3OD): d 24.2, 53.5, 55.6, 62.2, 176.5. IR (neat, cm-1):
tOH = 3,425, tN3 = 2,121, tC=O = 1,623. MS (ES, pos.
mode): m/z (%): 199 (M ? H?, 100). Anal. Calcd for
C8H14N4O2 (%): C, 48.47; H, 7.12; N, 28.26. Found (%): C,
48.09; H, 6.98; N, 28.07.
1-tert-Pentyl-3-aminoazetidine-3-carboxylic acid (28b)
Brown viscous oil, yield 80%, Rf = 0.03 (CH2Cl2/MeOH
9/1). 1H NMR (300 MHz, CD3OD): d 0.96 (3H, t,
J = 7.4 Hz, CCH2CH3), 1.21 (6H, s, C(CH3)2), 1.56 (2H,
q, J = 7.4 Hz, CCH2CH3), 3.72 (2H, d, J = 10.5 Hz,
CH(H)NCH(H)), 4.24 (2H, d, J = 9.9 Hz, CH(H)
NCH(H)). 13C NMR (75 MHz, CD3OD): d 8.6, 20.0, 30.8,
54.8, 59.3, 61.5, 176.8. IR (neat, cm-1): tOH,NH2 = 3,338,
1-tert-Pentyl-3-azidoazetidine-3-carboxylic acid (27b)
Yellow viscous oil, yield 76%, Rf = 0.21 (CH2Cl2/MeOH
9/1). 1H NMR (300 MHz, CD3OD): d 0.98 (3H, t,
J = 7.7 Hz, CCH2CH3), 1.30 (6H, s, C(CH3)2), 1.27 (2H,
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552
tC=O = 1,625. MS (ES, pos. mode): m/z (%): 187
(M ? H?, 100). Anal. Calcd for C9H18N2O2 (%): C, 58.04;
H, 9.74; N, 15.04. Found (%): C, 57.85; H, 9.87; N, 14.83.
(24–33%) were obtained via separation by preparative TLC
up to 1 g scale (Table 2, entries 2–5).
It was envisioned that aziridines 14 are the kinetic
cyclization products, while azetidines 15 result from a
thermodynamical equilibration. The isomerization of
2-(halomethyl)aziridines to 3-haloazetidines, although only
in some cases observable for 2-(chloromethyl)aziridines
which lack a second substituent at the 2-position, was
explained via the intermediacy of a bicyclic azo-
nia[1.1.0]bicyclobutane I and eventually the corresponding
carbenium ion II, followed by recombination with the
initially expelled halide to give 3-haloazetidines or
2-(halomethyl)aziridines (Gaertner 1970; Higgins and Kidd
1998). In order to experimentally prove this isomerization
of aziridine 14 to azetidine 15, alkyl 2-(bromomethyl)azi-
ridine-2-carboxylates 14 were heated under several condi-
tions similar to the reaction conditions used in the
preparation of azetidines 15 from acyclic dibromo amino
esters 13 (Table 3).
Results and discussion
The synthesis of N-substituted alkyl 2-(aminomethyl)acry-
lates 12 via substitution reactions of alkyl 2-(bromo-
methyl)acrylates 11 with primary amines was performed
under optimized conditions in analogy with literature proce-
dures (Baraki et al. 1999; Habaue et al. 1997). Addition of
alkyl 2-(bromomethyl)acrylates 11 to a solution of primary
amine and triethylamine in dichloromethane at 0°C afforded
ethyl and methyl 2-[(alkylamino)methyl]acrylates 12 in
excellent yields (Table 1). Subsequently, following a typical
procedure for the bromination of functionalized allylamines
(De Smaele et al. 2001), the amino group of alkyl 2-[(alkyl-
amino)methyl]acrylates 12 was protected by treatment with
aqueous hydrobromic acid in dichloromethane to the corre-
sponding hydrobromide salts. Subsequent bromination fol-
lowed by neutralization of the reaction mixture with an
aqueous NaHCO3 solution afforded the desired dibromopro-
panoates 13 in excellent yields (Table 1).
Heating ofaziridine14a in acetonitrile at60°C for 3 h gave
noreaction(entry1), whileprolongedheatinginacetonitrileat
60°CinthepresenceofKBr, whichisformedinsituduringthe
cyclization of 13, resulted in decomposition to unidentified
compounds after 24 h (entry 3). Nevertheless, a satisfactory
isomerization of aziridine 14a to azetidine 15a was observed
upon heating in DMSO, giving a mixture of 14a and 15a in a
2:1 ratio (1H NMR analysis) at 55°C after 24 h. The latter
mixture further isomerized to 14a and 15a in a 1:2.8 ratio after
additional heating at 65°C for 6 h. After raising the temper-
ature to 70°C, full isomerization of aziridines 14a–d to az-
etidines 15a–d was obtained within 45 h with 45–50% yield
(Table 3, entries 6–9). Attempts to improve the outcome of
the isomerization reaction by adding KBr resulted in a lower
yield of 26% of azetidine 15a, while addition of water to the
reaction (Table 3, entries 11–12) slowed down the isomeri-
zation and eventually led to total decomposition.
With the targeted dibromo amino esters 13 in hand, their
ring closure upon treatment under basic conditions to the
desired aziridines 14 and/or azetidines 15 was investigated.
After extensive screening of different bases, solvents,
reaction temperatures and reaction times, it was found that
a clean conversion of dibromo amines 13 to the aziridines
14 as major products together with the azetidines 15 as
minor compounds could be achieved by using K2CO3 in
acetonitrile at 60°C. However, the yields of the isolated
aziridines 14 and azetidines 15 were low after purification
by flash chromatography on silicagel as, apparently, these
azaheterocycles partly decompose on column (Table 2,
entry 1). To our satisfaction, good overall yields of the
targeted isolated aziridines 14 (44–54%) and azetidines 15
Introduction of new functional groups in alkyl aziridine-
2-carboxylates 14 and alkyl azetidine-3-carboxylates 15 in
Table 1 Synthesis and bromination of alkyl 2-(aminomethyl)acrylates 12
1) 1.1 equiv HBr
R2
R2
1.02 equiv R2NH2
1.04 equiv Et3N
CH2Cl2/H2O
0 oC, 30 min
Br
NH
NH
Br
CH2Cl2, 0 oC, 30 min
2) 1 equiv Br2
CH2Cl2, r.t., 5 - 14 h
3) NaHCO3, EtOAc
Br
COOR1
COOR1
COOR1
11
12 (91-98%)
13 (90-98%)
Entry
Substrate
R1
R2
12 (%)
13 (%)a
1
2
3
4
a
11a
11a
11b
11b
Et
t-Bu
12a (97)
12b (91)
12c (94)
12d (98)
13a (98)
13b (97)
13c (90)
13d (97)
Et
t-Pentyl
t-Bu
Me
Me
t-Pentyl
Values between parentheses indicate yields of isolated products
123

Synthesis of new functionalized aziridine-2- and azetidine-3-carboxylic acid derivatives
553
Table 2 Synthesis of alkyl aziridine-2-carboxylates 14 and alkyl azetidine-3-carboxylates 15
R2
N
R2
R2
1.5 equiv K2CO3
NH
Br
COOR1
N
+
Br
CH3CN, 60 oC, 8 - 19 h
Br
COOR1
Br
15 (24-33%)
COOR1
13a (R1 = Et, R2 = t-Bu)
13b (R1 = Et, R2 = t-Pentyl)
13c (R1 = Me, R2 = t-Bu)
13d (R1 = Me, R2 = t-Pentyl)
14 (44-54%)
Entry
Substrate
Reaction time (h)
Result (%)a,b
1
2
3
4
5
a
13a
13a
13b
13c
13d
19
19
12
8
14a (19)a ? 15a (13)a
14a (50)b ? 15a (33)b
14b (54)b ? 15b (24)b
14c (44)b ? 15c (25)b
14d (54)b ? 15d (26)b
18
Values between parentheses indicate yields of isolated products after purification by flash chromatography
Values between parentheses indicate yields of isolated products after purification by preparative TLC
b
Table 3 Isomerization of 2-(bromomethyl)aziridines 14 to 3-bromoazetidines 15
R2
R2
N
R2
N
R2
N
N
Br
(see table)
COOR1
COOR1
Br
COOR1
15 (45-50%)
COOR1
14a (R1 = Et, R2 = t-Bu)
14b (R1 = Et, R2 = t-Pentyl)
14c (R1 = Me, R2 = t-Bu)
14d (R1 = Me, R2 = t-Pentyl)
I
II
Entry
Substrate
Reaction conditions
Result
1
14a
14a
14a
14a
14a
14a
14b
14c
14d
14a
14a
14a
CH3CN, 60°C, 3 h
CH3CN, D, 15 h
No reaction
2
Decomposition
Decomposition
14a:15a = 2:1a
14a:15a = 1:2.8a
15a (45%)b
15b (45%)b
15c (45%)b
3
1 equiv KBr, CH3CN, 60°C, 24 h
DMSO, 55°C, 24 h
DMSO, 55°C, 24 h ? 65°C, 6 h
DMSO, 70°C, 18 h
DMSO, 70°C, 45 h
DMSO, 70°C, 5 h
DMSO, 70°C, 5 h
1 equiv KBr, DMSO, 70°C, 18 h
DMSO/H2O 1/1, 70°C, 48 h
4
5
6
7
8
9
15d (50%)b
15a (26%)b
10
11
12
a
Decomposition
Decomposition
1 equiv KBr, DMSO/H2O 1/1, 70°C, 48 h
1
Ratio determined by H NMR analysis
b
Values between parentheses indicate yields of isolated products
particular, would highly enrich the chemistry of these
important classes of a- and b-amino acid derivatives.
Therefore, the potential of the synthesized alkyl 2-(bromo-
methyl)aziridine-2-carboxylates 14 and alkyl 3-bromoaze-
tidine-3-carboxylates 15 for further functionalization via
substitution reactions with C-, S-, N- and O-nucleophiles was
investigated (Tables 4, 5). Treatment of alkyl 2-(bromo-
methyl)aziridine-2-carboxylates 14a–c with potassium
cyanide in DMSO at 60°C for 3–4 h uneventfully afforded
the corresponding alkyl 2-(cyanomethyl)aziridine-2-car-
boxylates 16a–c in 47–57% yield (Table 4, entries 1–3). Few
2-(cyanomethyl)aziridines can be found in the literature
123

ˇ
_
A. Zukauskaite et al.
554
Table 4 Reactions of alkyl 2-(bromomethyl)aziridines 14 with different nucleophiles
R2
N
R2
N
R2
N
+
Br
COOR1
Nu
COOR1
(see table)
Nu COOR1
14a (R1 = Et, R2 = t-Bu)
14b (R1 = Et, R2 = t-Pentyl)
14c (R1 = Me, R2 = t-Bu)
14d (R1 = Me, R2 = t-Pentyl)
16 (Nu = CN)
17 (Nu = SCN)
18 (Nu = N3)
20 (Nu = OPh)
19 (Nu = OPh)
Entry
Substrate
Reaction conditions
Result (%)a
1
2
14a
14b
14c
14a
14b
14a
14b
14c
14d
14a
1 equiv KCN, DMSO, 60°C, 3 h
1 equiv KCN, DMSO, 60°C, 4 h
1 equiv KCN, DMSO, 60°C, 4 h
2 equiv KSCN, DMF, 70°C, 2 h
2 equiv KSCN, DMF, 70°C, 6 h
2 equiv NaN3, DMSO, 60°C, 1.5 h
2 equiv NaN3, DMSO, 60°C, 2 h
2 equiv NaN3, DMSO, 60°C, 3 h
2 equiv NaN3, DMSO, 60°C, 3 h
2.2 equiv PhOH, 5 equiv K2CO3
acetone/DMF 1/1, D, 125 h
2.2 equiv PhOH, 5 equiv K2CO3
acetone/DMF 1/1, D, 160 h
2 equiv PhOH, 4 equiv K2CO3
DMSO, 60°C, 8 h
16a (47)
16b (54)
16c (57)
17a (48)
17b (44)
18a (58)
18b (93)
18c (91)
18d (64)
19a (10)
3
4
5
6
7
8
9
10
11
12
13
14
a
14b
14a
14b
14b
–
19a (60) ? 20a (5)
19b (34) ? 20b (4)
19b (67)
2 equiv PhOH, 4 equiv K2CO3
DMSO, 60°C, 5 h
3 equiv PhOH, 6 equiv K2CO3
DMSO, 60°C, 16 h
Values between parentheses indicate yields of isolated products
(Gaertner 1970; Subbaraj et al. 1989; Antunes et al. 2007;
Vedejs et al. 2003; Krasnova et al. 2005), and some have
been used recently for the synthesis of biologically relevant
N-(2-cyanocyclopropyl)benzimidates (D’hooghe et al. 2006a),
2-aminocyclopropanecarbonitriles (Mangelinckx et al.
2009), 4-amino-2-butenenitriles (D’hooghe et al. 2007a, b),
3,4-diaminobutanenitriles (D’hooghe et al. 2007a), and
2-aminopentanedinitriles (D’hooghe et al. 2008). Ethyl
2-(thiocyanomethyl)aziridine-2-carboxylates 17a–b were syn-
thesized in moderate yield (44–48%) utilizing potassium
thiocyanate in DMF at 70°C due to the formation of some
unidentified reaction products which were present in the crude
reaction mixture (Table 4, entries 4–5). Only one report on the
synthesis of 2-(thiocyanomethyl)aziridines, which were used
for an intramolecular cyclisation to 2-iminothiazolidines, has
been made (D’hooghe et al. 2005b).
literature (Jamookeeah et al. 2008; Han et al. 2008;
D’hooghe et al. 2005a). Methyl (2R,3R)-1-benzyl-3-(azi-
domethyl)-2-aziridinecarboxylate has been used in routes
towards the synthesis of aziridinomitosenes as antitumor
antibiotics (Shaw et al. 1985). Upon reaction of ethyl
2-(bromomethyl)aziridine-2-carboxylates 14a–b with phe-
nol and K2CO3 in a mixture of acetone and DMF (1/1)
under reflux, no satisfactory results were obtained even
after prolonged reaction time (Table 4, entries 10–11).
However, treating ethyl 2-(bromomethyl)aziridine-2-car-
boxylates 14a–b with phenol and K2CO3 in DMSO at
60°C for 5–16 h afforded ethyl 1-tert-butyl-2-(phenoxy-
methyl)aziridine-2-carboxylate19a and ethyl 1-tert-pentyl-2-
(phenoxymethyl)aziridine-2-carboxylate 19b in 60–67%
yield (Table 4, entries 12–14). Noteworthy, besides the azir-
idines19 asmajorcompounds, the rearrangedcompounds, i.e.
ethyl 1-tert-butyl-3-phenoxyazetidine-3-carboxylate 20a and
ethyl 1-tert-pentyl-3-phenoxyazetidine-3-carboxylate 20b,
were isolated in small amounts (4–5%) from this reac-
tion. 2-(Aryloxymethyl)aziridines have recently been used
Alkyl 2-(azidomethyl)aziridine-2-carboxylates 18a–
d were prepared in good to excellent yield by reaction with
sodium azide in DMSO at 60°C (Table 4, entries 6–9).
2-(Azidomethyl)aziridines are also scarcely reported in the
123

Synthesis of new functionalized aziridine-2- and azetidine-3-carboxylic acid derivatives
555
Table 5 Reactions of alkyl 3-bromoazetidines 15 with different nucleophiles
R2
R2
N
N
(see table)
Nu COOR1
Br
COOR1
15a (R1 = Et, R2 = t-Bu)
15b (R1 = Et, R2 = t-Pentyl)
15c (R1 = Me, R2 = t-Bu)
20 (Nu = OPh)
21 (Nu = CN)
22 (Nu = SCN)
23 (Nu = N3)
Entry
Substrate
Reaction conditions
Result (%)
1
2
3
4
5
6
7
8
15a
15a
15b
15a
15b
15c
15a
15b
2 equiv KCN, DMSO, 60°C, 4 h
21a (79)
22a (59)
22b (83)
23a (86)
23b (98)
23c (79)
20a (36)
20b (81)
1.5 equiv KSCN, DMSO, 60°C, 3 h
1.5 equiv KSCN, DMSO, 60°C, 3 h
2 equiv NaN3, DMSO, 60°C, 3 h
2 equiv NaN3, DMSO, 60°C, 3 h
2 equiv NaN3, DMSO, 60°C, 3 h
3 equiv PhOH, 6 equiv K2CO3, DMSO, 60°C, 3 h
2.5 equiv PhOH, 5 equiv K2CO3, DMSO, 60°C, 4 h
for the synthesis of biologically relevant 2-amino-1-aryloxy-
3-methoxypropanes (D’hooghe et al. 2006b), and for the
synthesis of 1H-tetrazole-1-alkanenitriles as potent orally
2-(aminomethyl)aziridine-2-carboxylate 24b and 3-aminoa-
zetidine-3-carboxylate 26a (Scheme 1, 2).
Noteworthy, the ring opening of 2-(aminomethyl)aziri-
dine templates with thioacid peptides has recently been
developed as a method for chemoselective peptidomimetic
ligation (Assem et al. 2010). Furthermore, 2-(azido-
methyl)aziridines 18 could be directly transformed into the
corresponding N-Boc-protected 2-(aminomethyl)aziridines
25 by hydrogenation in the presence of di-tert-butyl
dicarbonate (Scheme 1). All efforts to saponify 2-(azido-
methyl)aziridine-2-carboxylic esters via basic hydrolysis
(aq. Na2CO3 or aq. LiOH) failed, resulting in either no
reaction or formation of complex reaction mixtures.
However, simple hydrolysis of ethyl 3-azidoazetidine-3-
carboxylates 23a, b to the corresponding 3-azidoazetidine-
3-carboxylic acids 27 was achieved upon reaction with 2 N
aqueous NaOH solution in methanol at room temperature
for 3 h (Scheme 2). Further hydrogenolysis of 3-azidoa-
zetidine-3-carboxylic acids 27 afforded 3-aminoazetidine-
3-carboxylic acids 28. Besides their potential use as
foldameric building blocks, the elaborated 3-aminoazeti-
dine-3-carboxylates 26–28 can be important for the syn-
thesis of series of active compounds used in SAR, as
exemplified for EGF receptor tyrosine kinase inhibitors
´
bioavailable growth hormone secretagogues (Hernandez
et al. 2008).
In analogy with the reactions of aziridines 14, treatment
of the 3-bromoazetidines 15 with potassium cyanide, potas-
sium thiocyanate, sodium azide and potassium phenoxide in
DMSO at60°Cfor 3–4 haffordedthe corresponding3-cyano-
, 3-thiocyano-, 3-azido- and 3-phenoxyazetidine-3-carboxylic
esters 20–23 in 36–98% yield (Table 5). 3-Substituted
azetidines are frequently used in structure–activity rela-
tionship (SAR) studies for the preparation of libraries of
bioactive compounds, e.g., bronchodilating and anti-
inflammatory drugs (Provins et al. 2007), antibacterial
agents (Murphy et al. 2007), and antidepressant agents
(Melloni et al. 1979).
In order to extend the potential applicability of the syn-
thesizedconstrainedaminoacidderivativesasbuildingblocks
for the synthesis of foldamers, the deprotection of several
amino acid derivatives was studied as well. Using simple
hydrogenolysis, ethyl 1-tert-pentyl-2-(azidomethyl)aziridine-
2-carboxylate 18b and 1-tert-butyl-3-azidoazetidine-3-car-
boxylate 23a were converted into the corresponding ethyl
Scheme 1 Synthesis of alkyl
t-Pentyl
Pd/C, H2 (5-10 bar)
5 equiv Boc2O
R2
N
R2
N
2-(aminomethyl)aziridine-2-
carboxylates
Pd/C, H2 (4 bar)
EtOH, 3 h, r.t.
N
NH2
N3
COOR1
NHBoc
COOR1
CH3CN, 3-5 h, r.t.
COOEt
24b (68%)
18
25b (R1 = Et, R2 = t-Pentyl, 62%)
25c (R1 = Me, R2 = t-Bu, 76%)
123

ˇ
A. Zukauskaite et al.
_
556
R2
N
Scheme 2 Synthesis of
3-aminoazetidine-3-carboxylic
acid derivatives
t-Bu
Pd/C, H2 (4 bar)
N
EtOH, 3 h, r.t.
R2 = t-Bu
N3 COOEt
H2N COOEt
23
26a (78%)
R1
N
R1
N
1) Pd/C, H2 (3 bar)
MeOH, r.t., 3 h
1) 2N NaOH (aq), MeOH, r.t., 3 h
2) 1N HCl (aq)
3) Dowex
2) Dowex
H2N COOH
N3 COOH
28a (R1 = t-Bu, 76%)
28b (R1 = t-Pentyl, 80%)
27a (R1 = t-Bu, 90%)
27b (R1 = t-Pentyl, 76%)
Baraki H, Habaue S, Okamoto Y (1999) Stereospecific anionic
polymerization and novel hydrogen-transfer polymerization of
a-(aminomethyl)acrylates having unprotected amino group.
Polym J 31:1260–1266
(Hennequin et al. 2006), CB1 receptor antagonists (Brandt
et al. 2009), and modulators of the NMDA receptor com-
plex (Kozikowski and Fauq 1991).
In conclusion, a short synthesis of alkyl 2-(bromo-
methyl)aziridine-2-carboxylates and alkyl 3-bromoazetidine-3-
carboxylates was developed involving amination, bromination,
and base-induced cyclization of alkyl 2-(bromomethyl)acry-
lates. The aziridines are the kinetically favored cyclization
products and could be transformed into 3-bromoazetidine-3-
carboxylic acid derivatives via thermal isomerization. The
new small ring azaheterocyclic a- and b-amino acid deriva-
tives proved to be excellent building blocks for the synthesis
of different substituted aziridines and azetidines through
nucleophilic substitution of the bromide by different carbon,
sulfur, oxygen, and nitrogen nucleophiles in good to
high yields. Elaboration of the amino and carboxyl group
madenew conformationallyconstrainedfunctionalizeda- and
b-amino acids synthetically accessible for potential applica-
tion in foldamer research.
Brandt TA, Caron S, Damon DB, DiBrino J, Ghosh A, Griffith DA,
Kedia S, Ragan JA, Rose PR, Vanderplas BC, Wei L (2009)
Development of two synthetic routes to CE-178, 253, a CB1
antagonist for the treatment of obesity. Tetrahedron 65:3292–
3304
Cardillo G, Gentilucci L, Tolomelli A (2003) Aziridines and
oxazolines: valuable intermediates in the synthesis of unusual
amino acids. Aldrichim Acta 36:39–50
Cardillo G, Gentilucci L, Tolomelli A (2006) Unusual amino acids:
synthesis and introduction into naturally occurring peptides and
biologically active analogues. Mini-Rev Med Chem 6:293–304
´
Cativiela C, Ordon˜ez M (2009) Recent progress on the stereoselective
synthesis of cyclic quaternary a-amino acids. Tetrahedron
Asymm 20:1–63
Cheng RP, Gellman SH, DeGrado WF (2001) b-Peptides: from
structure to function. Chem Rev 101:3219–3232
Cowell SM, Lee YS, Cain JP, Hruby VJ (2004) Exploring
Ramachandran and Chi space: conformationally constrained
amino acids and peptides in the design of bioactive polypeptide
ligands. Curr Med Chem 11:2785–2798
D’hooghe M, Rottiers M, Kerkaert I, De Kimpe N (2005a) Ring
opening of 2-(bromomethyl)-1-sulfonylaziridines towards 1,
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Acknowledgments The authors are indebted to the Research
Foundation—Flanders (FWO—Flanders) and Ghent University
(BOF) for financial support.
D’hooghe M, Waterinckx A, De Kimpe N (2005b) A novel entry
toward 2-imino-1,3-thiazolidines and 2-imino-1,3-thiazolines by
ring transformation of 2-(thiocyanomethyl)aziridines. J Org
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