Practical preparation of enantiopure 2-methyl-azetidine-2-carboxylic acid; a γ-turn promoter

Article abstract of DOI:10.1016/j.tetasy.2012.05.006

A robust and practical synthesis of each enantiomer of 2-methyl-azetidine- 2-carboxylic acid, based on the use of (S)-phenylglycinol as resolving agent, is described. This synthesis affords practical quantities of this quaternary amino acid suitably N- an

Full text of DOI:10.1016/j.tetasy.2012.05.006

Tetrahedron: Asymmetry 23 (2012) 690–696
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Tetrahedron: Asymmetry
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Practical preparation of enantiopure 2-methyl-azetidine-2-carboxylic acid; a
c-turn promoter
⇑
Bruno Drouillat, Karen Wright, Jérôme Marrot, François Couty
Institut Lavoisier de Versailles, UMR CNRS 8180, Université de Versailles St-Quentin en Yvelines. 45, av. des Etats-Unis, 78035 Versailles Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
A robust and practical synthesis of each enantiomer of 2-methyl-azetidine-2-carboxylic acid, based on
the use of (S)-phenylglycinol as resolving agent, is described. This synthesis affords practical quantities
of this quaternary amino acid suitably N- and C-protected for use in further peptide coupling. Synthetic
highlights include the formation of the azetidine ring by intramolecular alkylation and the facile separa-
tion of the diastereoisomeric amides derived from phenylglycinol.
Received 5 April 2012
Accepted 10 May 2012
Available online 8 June 2012
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
The search for new amino acids able to induce particular back-
bone conformations when included in peptides is an active area of
2.1. Synthesis of racemic azetidines
a
a
research.1 For example, C -methyl proline is known to enhance the
Racemic N-Bn-C -methyl azetidine-2-carboxylic acid tert-butyl
propensity of the prototype proline residue for b-turn formation,
ester 5a9 was conveniently prepared on a multigram scale, follow-
ing our recently published procedure9 in a four step sequence
starting from commercially available 2-bromo-propionyl bromide
involving esterification,10 N-alkylation with N-benzylethanol-
amine, chlorination, and cyclization. With the aim of extending
the scope of this strategy, and to allow a variation of the substitu-
ent on the azetidine ring, it was applied for the synthesis of N-Bn-
when located at the i+1 position of a peptide sequence.2 Recently,
a
C -alkyl azetidine-2-carboxylic acids were reported on by Martín-
Martínez et al.3 and demonstrated to induce
peptides, which is in sharp contrast with their higher C -methyl
proline homologues. Thus, these constrained amino acids are
emerging as new tools for conformational control of the peptide
c
-turns4 in short
a
a
backbone and would be good candidates for
c
-turn scan studies
C -phenyl azetidine-2-carboxylic acid tert-butyl ester 5b which
in higher peptides of biological interest. However, the develop-
ment of these new tools relies on an easy and scalable synthesis,
capable of providing workable quantities of each enantiomer of
these quaternary amino acids in a suitably protected form for fur-
proceeded uneventfully (Scheme 1).
2.2. Resolution via diastereoisomeric amides
a
ther peptide coupling. While this is well established for C -methyl
We next focused on a practical way to resolve compound 5a,
and after some experimentation, found that the diastereoisomeric
amides 6a and 6b derived from (S)-phenylglycinol could be conve-
niently separated by flash chromatography and isolated from 5a in
44% and 43% overall yield, respectively, on a gram scale. The abso-
lute configuration of the quaternary center in 6a was determined
by X-ray crystallography11 (Scheme 2).
Amides derived from phenylglycinol are relatively easy to
hydrolyze and this property has already been used for the purpose
of carboxylic acid resolution.12 Thus, N-Fmoc protected derivatives
(S)-8 and (R)-8 could be accessed by N-Bn hydrogenolysis, and N-
Fmoc protection followed by acidic hydrolysis of the amide moiety
with H2SO4 in a dioxane/water mixture, which occurred without
detectable cleavage of the sensitive strained quaternary azetidine.
The N-Cbz derivative 10 was prepared via the same strategy, but
showed a high discrepancy with the reported3a specific rotation
proline derivatives,5 access to enantiomerically pure
a-quaternary
a
azetidines, and more specifically to C -alkyl azetidine-2-carboxylic
acids is almost unreported in the literature.6 Thus, the most
practical route at present relies on the stereocontrolled ring clo-
sure of the N-chloroacetyl derivative of an amino ester derived
from (+)-10-(N,N-dicyclohexylsulfamoyl)-isoborneol as the chiral
auxiliary, which also needs an additional step for the chemoselec-
tive reduction of the resulting b-lactam into an azetidine.7 Based
on our previous experience in the synthesis and reactivity of
azetidinic amino acids,8 we herein report a practical access to this
particular class of unnatural azetidinic amino acids relying on ring
closure of the azetidine through intramolecular C-alkylation.
⇑
Corresponding author.
E-mail address: couty@chimie.uvsq.fr (F. Couty).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.05.006

B. Drouillat et al. / Tetrahedron: Asymmetry 23 (2012) 690–696
691
OH
BnHN
t-BuOH
O
O
pyridine
NaI (cat.), K2CO3
Br
Br
X
OtBu
Et2O
MeCN
R
R
1a: R = Me, X = Br
1b: R = Ph, X = Cl
2a: R = Me: 84%
2b: R = Ph: 64%
HO
R
CO2tBu
N
3a: R = Me: 90%
3b: R = Ph: 74%
Bn
SOCl2, DCM
Cl
tBuOK, THF 5a
or
R
CO2tBu
R
NaHMDS, THF 5b
CO2tBu
N
Bn
N
5a: R = Me: 83%
5b: R = Ph: 65%
Bn
4a: R = Me: 96%
4b: R = Ph: 63%
a
Scheme 1. Synthesis of racemic C -quaternary azetidinic amino esters.
1) TFA / DCM
2) HCl
O
Ph
O
Ph
3) (S)-phenylglycinol, HATU, DIPEA
4) Flash chromatography
OH
+
OH
( )
S
(
) N
H
S
( )
S
5a
N
H
(R)
87%
N
N
Bn
Bn
6a: 44%
6b: 43%
6a
Scheme 2. Synthesis and separation of diastereoisomeric amides 6a,b and ORTEP view of 6a.
(see Section 4). Alternatively, N-Boc derivative 13 was prepared by
acidic methanolysis of the amide, N-Bn to N-Boc exchange and
saponification. This procedure could not, however, be applied to
the 2-phenyl derivative since N-debenzylation of 5b led exclu-
sively to the azetidine ring opening under the hydrogenolysis con-
ditions employed. (Scheme 3).
and (S)-12 or (R)-12. After N-Boc cleavage with 1.6 M HCl in ether,
successful coupling was achieved by HATU activation, leading to
the diastereoisomeric dipeptides 14a,b in good yields, as displayed
in Scheme 4.
3. Conclusion
2.3. Peptide coupling
In conclusion, we have reported on a practical route to both
enantiomers of C -methyl azetidine-2-carboxylic acid on a multi-
gram scale, a particularly strained amino acid which is a promising
a
a
The C -quaternary amino acids may be slow to undergo N-acyl-
ation in peptide coupling reactions, due to their hindered nature.
We therefore tested the peptide coupling between Boc-L-Ala-OH
new tool for the induction of
c-turns in peptidic backbones. This
synthesis relies on a very efficient intramolecular alkylation to

692
B. Drouillat et al. / Tetrahedron: Asymmetry 23 (2012) 690–696
Ph
O
1) H2, Pd/C(cat.), EtOH
2) FmocCl, DIPEA
H2SO4
OH
OH
COOH
(S)-8
water/dioxane
N
H
6a
6b
7a
79%
N
N
66%
Fmoc
Fmoc
Ph
O
O
1) H2, Pd/C(cat.), EtOH
2) FmocCl, DIPEA
H2SO4
water/dioxane
COOH
N
H
N
59%
7b
8
(R)-
N
70%
Fmoc
Fmoc
Ph
1) H2, Pd/C(cat.), EtOH
2) CbzCl, DIPEA
H2SO4
water/dioxane
COOH
OH
N
H
6a
9
69%
N
10
78%
N
Cbz
Cbz
H2 , Pd(OH)2
Boc2O
1) NaOH
H2SO4
MeOH
CO2Me
2) HCl
COOH
6a
CO2Me
or
93%
6b
N
N
N
13
Boc
Boc
Bn
11: 71%
11: 66%
(S)-
12: 94%
12: 76%
(S)-
(R)-
(R)-
a
Scheme 3. Synthesis of suitably N-protected derivatives of C -methyl-azetidine-2-carboxylic acid.
N
N
CO2Me
1) 1.7 M HCl in Et2O
2) Boc-L-Ala-OH
HATU, DIPEA, DMF
O
O
14a: 70% from (S)-12
14b: 80% from (R)-12
(S)-12
or
NHBoc
(R)-12
CO2Me
NHBoc
Scheme 4. Dipeptide synthesis from (S)-12 and (R)-12.
build the azetidine ring and on a facile resolution step via the dia-
stereoisomeric amides derived from phenylglycinol. These amides
can be hydrolyzed using particularly mild conditions, which are
compatible with the strained four-membered ring. A generaliza-
tion of this strategy for other quaternary azetidinic amino acids
is currently under investigation.
10 (SMART iTR diamond ATR) spectrophotometer. High resolution
mass spectra (HR-MS) were obtained on a Water Micromass Q-Tof
Micro instrument.
4.2. Synthesis of azetidines
4.2.1. [Benzyl-(2-hydroxyethyl)-amino]-phenyl-acetic acid tert-
butyl ester 3b
4. Experimental
4.1. General
To a solution of N-benzylethanolamine (0.66 mL, 4.58 mmol) in
acetonitrile (20 mL) were added potassium carbonate (0.887 g,
6.42 mmol), bromophenylacetic acid tert-butyl ester (1.5 g,
5.5 mmol), and sodium iodide (0.138 g, 0.92 mmol). The reaction
mixture was heated at reflux overnight, cooled to room tempera-
ture, and concentrated under reduced pressure. The residue was
partitioned between water (70 mL) and ether (70 mL), and the
organic layer was successively washed with 5 wt-% aqueous
sodium thiosulfate (40 mL) and brine (40 mL). The organic layer
was dried over magnesium sulfate, evaporated to dryness, and
the residue was purified by chromatography (petroleum ether/
ethyl acetate 9/1). Compound 3b was obtained as a colorless oil
The 1H and 13C spectra were recorded on a Bruker Avance spec-
trometer at 200 or 300 and 75 or 50 MHz respectively; chemical
shifts are reported in ppm from TMS. Optical rotations were deter-
mined with a Perkin Elmer 141 instrument. All reactions were car-
ried out under argon. Column chromatography was performed on a
silica gel 230–400 mesh by using various mixtures of solvents.
TLCs were run on Merck Kieselgel 60F254 plates. Melting points
are uncorrected. Infrared spectra were recorded on a Nicolet iS

B. Drouillat et al. / Tetrahedron: Asymmetry 23 (2012) 690–696
693
(1.16 g, 74%). Rf: 0.17 (petroleum ether/ethyl acetate 90/10), 1H
NMR (300 MHz, CDCl3): d = 1.51 (s, 9H, tBu), 2,65 (s, 1H, OH),
2.79–2.85 (m, 1H, NCHHCH2OH), 2.94–3.01 (m, 1H, NCHHCH2OH),
3.39–3.49 (m, 1H, CHHOH), 3.50–3.63 (m, 1H, CHHOH), 3.83 (s, 2H,
pressure, and the residue was coevaporated with toluene to re-
move trace amounts of trifluoroacetic acid. This residue was taken
up in toluene (10 mL) and a 2 M HCl aqueous solution (10 mL) was
added. The mixture was concentrated under reduced pressure. To a
solution of the resulting hydrochloride salt in THF (120 mL) were
added (S)-phenylglycinol (2.14 g, 16.3 mmol), DIPEA (8.4 mL,
50.4 mmol) and HATU (5.93 g, 16.3 mmol). The reaction mixture
was stirred overnight at 25 °C and concentrated under reduced
pressure. The residue was taken up in DCM (400 mL) and the or-
ganic layer was successively washed with a saturated aqueous
solution of NH4Cl (100 mL), a saturated aqueous solution of NaCl
(100 mL) and a saturated aqueous solution of NaHCO3 (100 mL).
The organic phase was dried over magnesium sulfate, the solvent
was evaporated to dryness, and the residue was purified by chro-
matography (200 g of silica for 5 g of crude residue) using gradient
elution (petroleum ether/EtOAc/15% aqueous NH3: 40/60/0.38 to
20/80/0.38, Rf: 0.4). Compound 6a was first eluted as a white solid
(1.94 g, 44% overall) and compound 6b was obtained as a white so-
lid (1.89 g, 43% overall). 6a: Rf: 0.40 (DCM/MeOH: 8/2), Mp: 88–
NCH2Ph), 4,52 (s, 1H, CH
a
), 7.28–7.41 (m, 10H, Ar) ppm. 13C NMR
),
(75 MHz, CDCl3): d = 28.0 (tBu), 52.2, 55.4, 59.6 (CH2), 67.5 (C
a
81.7 (CqtBu), 127.3, 127.9, 128.4, 128.5, 128.7, 128.9 (CHAr),
136.6, 139.2 (Cq Ar), 171.7 (CO) ppm. IR (ATR) mmax 3505, 3448,
3084, 3027, 2974, 2933, 2843, 1722, 1698, 1495, 1450, 1366,
1139, 1057, 735, 694 cmꢀ1; ESIHRMS (positive mode) m/z calcd
for C21H28NO3 [M+H]+: 342.2069, found 342.2078.
4.2.2. [Benzyl-(2-chloroethyl)-amino]-phenyl-acetic acid tert-
butyl ester 4b
To a solution of 3b (1.16 g, 3.40 mmol) in DCM (20 mL) was
added thionyl chloride (0.5 mL, 6.8 mmol). The reaction mixture
was heated at reflux for 2 h, cooled to 0 °C, and neutralized by
the careful addition of a saturated aqueous solution of sodium
hydrogen carbonate (35 mL). The aqueous layer was extracted with
DCM (2 ꢁ 20 mL) and the organic layer was washed with brine
(20 mL), dried over magnesium sulfate, and evaporated to dryness.
Compound 4b was obtained as a white solid (0.70 g, 63%). Rf: 0.80
(petroleum ether/ethyl acetate 90/10), Mp: 58 °C, 1H NMR
(300 MHz, CDCl3): d = 1.43 (s, 9H, tBu), 2.92–2.99 (m, 2H,
NCH2CH2Cl), 3.11–3.22 (m, 2H, NCH2CH2Cl), 3.71 (d, part of a AB
90 °C, ½a 2D0
ꢂ
¼ ꢀ37:9 (c 1.1, CH2Cl2), 1H NMR (300 MHz, CDCl3):
d = 1.61 (s, 3H, Me), 1.88–1.96 (m, 1H, H-3), 2.18–2.27 (m, 1H, H-
30), 3.06–3.15 (m, 2H, OH, H-4), 3.28–3.34 (m, 1H, H-40), 3.48 (d,
part of AB syst., J = 12.9 Hz, 1H, NCHHPh), 3.71 (ad, J = 5.6 Hz, 2H,
CH2OH), 3.76 (d, part of a AB syst., J = 12.9 Hz, 1H, NCHHPh),
4.89–4.95 (m, 1H, H
1H, NH) ppm. 13C NMR (75 MHz, CDCl3) d = 14.8 (CH3), 30.3, 48.9,
55.2 (CH2), 56.2, (CH ), 67.2 (CH2), 67.8 (Cq), 126.6, 127.2, 127.8,
a), 7.26–7.39 (m, 10H, Ar), 8.46 (d, J = 6.5 Hz,
syst., J = 13.9 Hz, 1H, NCHHPh), 3.81 (d, part of
J = 13.9 Hz, 1H, NCHHPh), 4,43 (s, 1H, CH ), 7.16–7.28 (m, 10H,
Ar) ppm. 13C NMR (75 MHz, CDCl3): d = 28.2 (tBu), 42.6, 46.8,
56.5 (CH2), 68.4 (C ), 81.7 (CqtBu), 127.3, 127.6, 127.9, 128.4,
a AB syst.,
a
a
128.5, 128.7, 128.8 (CHAr), 137.9, 139.1 (CqAr), 176.2 (CO) ppm.
IR (ATR) mmax 3373, 3314, 2950, 2865, 1647, 1508, 1494, 1455,
1334, 1247, 1082, 941, 738, 695 cmꢀ1; ESIHRMS (positive mode)
m/z calcd for C20H25N2O2 [M+H]+: 325.1913, found 325.1916. 6b:
a
128.5, 128.8, 128.9 (CHAr), 137.2, 139.5 (Cq Ar), 171.5 (CO) ppm.
IR (ATR) mmax 3084, 3061, 3025, 2978, 2938, 2863, 1717, 1491,
1452, 1366, 1117, 743, 694 cmꢀ1; ESIHRMS (positive mode) m/z
calcd for C21H27NO2Cl [M+H]+: 360.1730, found 360.1731.
Rf: 0.38 (DCM/MeOH: 8/2), Mp: 103 °C, ½a D20
¼ þ36:5 (c 1.9,
ꢂ
CH2Cl2), 1H NMR (300 MHz, CDCl3): d = 1.49 (s, 3H, Me), 1.89–
1.96 (m, 1H, H-3), 2.24–2.34 (m, 1H, H-30), 3.02–3.10 (m, 1H, H-
4), 3.28–3.34 (m, 2H, OH, H-40), 3.39 (d, part of AB syst.,
J = 12.9 Hz, 1H, NCHHPh), 3.59 (d, part of a AB syst., J = 12.9 Hz,
1H, NCHHPh), 3.81 (ad, J = 5.4 Hz, 2H, CH2OH), 4.83–4.89 (m, 1H,
4.2.3. 1-Benzyl-2-phenyl-azetidine-2-carboxylic acid tert-butyl
ester 5b
Compound 4b (0.70 g, 2.14 mmol) was dissolved in dry THF
(32 mL) at ꢀ78 °C after which a 2 M solution of sodium bis(tri-
methylsilyl)amide in THF (1.4 mL, 2.8 mmol) was added dropwise.
The reaction mixture was warmed up to room temperature over
2 h and hydrolyzed by the addition of a saturated aqueous solution
of ammonium chloride (30 mL). The aqueous layer was extracted
with ethyl acetate (2 ꢁ 20 mL) and the organic layer was washed
with brine (20 mL), dried over magnesium sulfate, and evaporated
to dryness. The residue was purified by flash chromatography
(petroleum ether/diethyl ether 95/5). Compound 5b was obtained
as a pale yellow oil (0.447 g, 65%). Rf: 0.63 (petroleum ether/ethyl
acetate 95/5), 1H NMR (300 MHz, CDCl3): d = 1.54 (s, 9H, tBu),
2.29–2.38 (m, 1H, H-3), 2.92–2.99 (m, 1H, H-30), 3.23–3.35 (m,
2H, H-4, H-40), 3.61 (d, part of AB syst., J = 13.0 Hz, 1H, NCHHPh),
4.03 (d, part of AB syst., J = 13.0 Hz, 1H, NCHHPh), 7.28–7.49 (m,
10H, Ar) ppm. 13C NMR (75 MHz, CDCl3): d = 28.3 (tBu), 30.1,
50.1, 57.6 (CH2), 81.8 (CqtBu), 125.3, 127.0, 127.3, 128.2, 128.4,
128.6 (CHAr), 138.5, 143.2 (Cq Ar), 171.8 (CO) ppm. IR (ATR) mmax
3060, 3026, 2974, 2928, 2832, 1715, 1600, 1493, 1446,
1391, 1366, 1251, 1163, 1136, 1102, 844, 696 cmꢀ1; ESIHRMS
(positive mode) m/z calcd for C21H26NO3 [M+H]+: 324.1964, found
324.1967.
Ha
), 7.07–7.30 (m, 10H, Ar), 8.47 (d, J = 6.7 Hz, 1H, NH) ppm. 13C
NMR (75 MHz, CDCl3): d = 14.6 (CH3), 30.7, 49.0, 55.4 (CH2), 56.3,
(CH ), 67.8 (CH2), 67.9 (Cq), 126.6, 127.2, 127.9, 128.5, 128.6,
a
128.9 (CHAr), 137.7, 138.8 (CqAr), 176.6 (CO) ppm. IR (ATR) mmax
3449, 3364, 2911, 2860, 1648, 1505, 1455, 1434, 1374, 1195,
1091, 938, 760, 702 cmꢀ1; ESIHRMS (positive mode) m/z calcd for
C
20H25N2O2 [M+H]+: 325.1913, found 325.1916.
4.4. Hydrolysis and protection
4.4.1. (1S,2S)-(9H-Fluoren-9-yl)methyl 2-(2-hydroxy-1-phenyl-
ethylcarbamoyl)-2-methylazetidine-1-carboxylate 7a
To a solution of 6a (0.825 g, 2.54 mmol) in 95% ethanol (44 mL)
and 2 M HCl aqueous solution (2.55 mL) was added 10% wt Pd on
carbon (0.4 g). The reaction mixture was hydrogenated overnight
at atmospheric pressure at 25 °C. After filtration of the catalyst, so-
dium carbonate (0.54 g, 5.08 mmol) was added to the filtrate and
the solvent was evaporated to dryness. To a solution of the result-
ing residue in acetonitrile (25 mL) cooled to 0 °C were added DIPEA
(0.89 mL, 5.08 mmol) and FmocCl (0.92 g, 3.55 mmol). The reaction
mixture was stirred overnight at 25 °C and concentrated under re-
duced pressure. The residue was taken up in ethyl acetate (20 mL)
and a saturated aqueous solution of NaCl (20 mL) was added. The
aqueous layer was extracted with ethyl acetate (2 ꢁ 20 mL), the or-
ganic layer was dried over magnesium sulfate, and the solvent was
evaporated to dryness to give a residue, which was purified by
chromatography (petroleum ether/EtOAc 1/1). Compound 7a was
obtained as a white foam (0.683 g, 79% overall). Rf: 0.18 (petroleum
4.3. Resolution via amides
4.3.1. (1S,2S)- and (1S,2R)-1-Benzyl-N-(2-hydroxy-1-phenyl-
ethyl)-2-methylazetidine-2-carboxamide 6a and 6b
To a solution of 5a (3.57 g, 13.6 mmol) in DCM (25 mL) cooled
to 0 °C was added trifluoroacetic acid (25 mL). The reaction mix-
ture was stirred overnight at 25 °C, concentrated under reduced
ether/EtOAc: 1/1), Mp: 61 °C, ½a D20
ꢂ
¼ ꢀ86 (c 1.4, CH2Cl2), 1H NMR

694
B. Drouillat et al. / Tetrahedron: Asymmetry 23 (2012) 690–696
(300 MHz, CDCl3): d = 1.64 (s, 3H, CH3), 1.89–1.97 (m, 1H, H-3),
2.59–2.65 (m, 1H, H-30), 3.65–3.81 (m, 4H, CH2OH, H-4, H-40),
4.11 (t, J = 6.1 Hz, 1H, NCOOCH2CH), 4.30 (d, J = 6.1 Hz, 2H,
at atmospheric pressure at 25 °C. After filtration of the catalyst, so-
dium carbonate (85 mg, 0.80 mmol) was added to the filtrate and
the solvent was evaporated to dryness. To a solution of the result-
ing residue in acetonitrile (6 mL) cooled to 0 °C were added DIPEA
NCOOCH2CH), 4.97–4.99 (m, 1H, Ha), 7.12–7.23 (m, 7H, Ar),
7.28–7.33 (m, 2H, Ar), 7.43–7.48 (m, 2H, Ar), 7.66–7.68 (m, 2H,
(0.170 mL, 0.80 mmol) and CbzCl (80 lL, 0.56 mmol). The reaction
Ar), 8.23 (d, J = 7.3 Hz, 1H, NH) ppm. 13C NMR (75 MHz, CDCl3):
mixture was stirred overnight at 25 °C and concentrated under re-
duced pressure. The residue was taken up in ethyl acetate (10 mL)
and a saturated aqueous solution of NaCl (10 mL) was added. The
aqueous layer was extracted with ethyl acetate (2 ꢁ 10 mL). The
organic layer was dried over magnesium sulfate. The solvent was
evaporated to dryness and the residue was purified by chromatog-
raphy (petroleum ether/EtOAc 25/75). Compound 9 was obtained
as a white solid (0.115 g, 78% overall). Rf: 0.5 (EtOAc), Mp: 84 °C,
d = 22.7 (CH3), 25.5, 44.5 (CH2), 47.1 (CH), 55.9 (CHa), 66.9, 67.2
(CH2), 70.4 (Cq), 120.1, 124.9, 126.7, 127.1, 127.8, 128.8 (CHAr),
138.7, 141.3, 143.5, 143.6 (CqAr), 156.3, 174.7 (CO) ppm. IR
(ATR) mmax 3404, 3306, 3065, 2966, 2928, 1674, 1526, 1450,
1411, 1342, 1167, 1078, 738, 698 cmꢀ1; ESIHRMS (positive mode)
m/z calcd for C28H28N2O4Na [M+Na]+: 479.1947, found 479.1947.
4.4.2. (1S,2R)-(9H-fluoren-9-yl)methyl 2-(2-hydroxy-1-phenyl-
ethylcarbamoyl)-2-methylazetidine-1-carboxylate 7b
½
a 2D0
ꢂ
¼ þ95:5 (c 0.62, CHCl3), 1H NMR (300 MHz, CDCl3): Two rota-
mers (9:1 ratio), d = 1.61 (minor rotamer) and 1.68 (major rotamer)
(s, 3H, Me), 1.91–2.01 (m, 1H, H-3), 2.57–2.66 (m, 1H, H-30), 2.94
(br s, 1H, OH), 3.54–3.98 (m, 4H, H-4, H-40, CH2OH), 4.83–5.12
(m, 3H, CHPh, PhCH2O), 7.06–7.25 (m, 5H, Ar), 8.31 (d, J = 6.0 Hz,
1H, NH) ppm. 13C NMR (75 MHz, CDCl3): Major rotamer d = 22.8
Following the above procedure for 7a, and starting with 6b
(0.800 g, 2.46 mmol), compound 7b was obtained as a white solid
(0.557 g, 59% overall). Rf: 0.18 (petroleum ether/EtOAc: 1/1), Mp:
68 °C, ½a 2D0
ꢂ
¼ þ29 (c 1.1, CH2Cl2); 1H NMR (300 MHz, CDCl3):
d = 1.66 (s, 3H, Me), 2.00–2.09 (m, 1H, H-3), 2.50 (s, 1H, OH),
2.77–2.86 (m, 1H, H-30), 3.75–3.94 (m, 4H, CH2OH, H-4, H-40),
4.25 (t, J = 6.7 Hz, 1H, NCOOCH2CH), 4.37–4.49 (m, 2H,
(CH3), 27.6, 44.5 (CH2), 55.9, (CHa), 66.9, 67.0 (CH2), 70.5 (Cq),
126.8, 127.7, 128.0, 128.3, 128.6, 128.8 (CHAr), 136.1, 139.0 (CqAr),
156.4, 174.8 (CO) ppm; ESIHRMS (positive mode) m/z calcd for
NCOOCH2CH), 5.04–5.10 (m, 1H, H
a
), 7.27–7.36 (m, 7H, Ar),
C
21H24N2O4Na (M+Na)+: 391.1634, found 391.1641.
7.40–7.45 (m, 2H, Ar), 7.58–7.61 (m, 2H, Ar), 7.77–7.80 (m, 2H,
Ar), 8.37 (d, J = 7.3 Hz, 1H, NH) ppm. 13C NMR (75 MHz, CDCl3):
d = 22.5 (CH3), 27.5, 44.5 (CH2), 47.1 (CH), 55.9 (CHa), 66.9, 67.2
4.4.5. (S)-2-Methyl-azetidine-1,2-dicarboxylic acid 1-benzyl
ester 103a
(CH2), 70.3 (Cq), 120.0, 125.0, 125.1, 126.6, 127.1, 127.8, 128.8
(CHAr), 138.8, 141.3, 143.6, 143.6 (CqAr), 156.4, 174.5 (CO) ppm.
IR (ATR) mmax 3400, 3307, 2926, 1674, 1526, 1450, 1411, 1342,
1167, 1078, 738, 698 cmꢀ1; ESIHRMS (positive mode) m/z calcd
for C28H28N2O4Na [M+Na]+: 479.1947, found 479.1947.
A solution of 9 (0.103 g, 0.279 mmol) in dioxane (6 mL) and
aqueous 3 N H2SO4 (6 mL) was refluxed for 1 h, then cooled to rt,
diluted with water (15 mL) and extracted with EtOAc
(3 ꢁ 15 mL). The organic layer was washed with water (20 mL),
brine (20 mL) and dried over MgSO4. Concentration under reduced
pressure gave 10 as a clear oil (48 mg, 69%). Rf: 0.3 (EtOAc/EtOH:
4.4.3. (S)- and (R)-2-Methyl-azetidine-1,2-dicarboxylic acid 1-
(9H-fluoren-9-ylmethyl) ester 8
95/5), ½a 2D0
ꢂ
¼ ꢀ88 (c 1.2, CHCl3), Lit3a: ½a D20
¼ ꢀ7:6 (c 0.09, CHCl3);
ꢂ
1H NMR (300 MHz, CDCl3): Two rotamers (7:3 ratio), d = 1.67 (min-
or rotamer) and 1.74 (major rotamer) (s, 3H, Me), 1.98–2.09 (m,
1H, H-3), 2.30–2.42 (m, 1H, H-30 minor rotamer), 2.55–2.68 (br s,
1H, H-30 minor rotamer), 3.58–3.98 (m, 2H, H-4, H-40), 5.06 (br s,
2H, PhCH2O), 7.09–7.28 (m, 5H, Ar), 8.41 (br s, 1H, COOH) ppm;
13C NMR (75 MHz, CDCl3): Major rotamer d = 22.2 (CH3), 28.3,
44.8, 67.4, (CH2), 70.5 (Cq), 128.1, 128.4, 128.6, 128.8 (CHAr),
135.8 (CqAr), 156.7, 175.3 (CO) ppm; ESIHRMS (positive mode)
m/z calcd for C13H15NO4Na (M+Na)+: 272.0899, found 272.0912.
A solution of 7a (0.658 g, 1.44 mmol) in dioxane (40 mL) and
3 M H2SO4 aqueous solution (40 mL) was stirred at reflux for 1 h.
After cooling, the aqueous layer was extracted with ethyl acetate
(2 ꢁ 70 mL). The organic layer was washed with water
(3 ꢁ 70 mL) and dried over magnesium sulfate. The solvent was
evaporated to dryness and the residue was purified by chromatog-
raphy (dichloromethane/methanol 98/2). Compound (S)-8 was ob-
tained as a white solid (0.320 g, 66%). Rf: 0.30 (dichloromethane/
methanol 90/10), Mp: 126 °C, ½a D20
ꢂ
¼ ꢀ82 (c 1.0, CH2Cl2), 1H NMR
(300 MHz, CDCl3): Two rotamers (75:25 ratio), d = 1.43 (minor rot-
amer) and 1.73 (major rotamer) (s, 3H, Me), 2.12–2.21 (m, 1H, H-
3), 2.29–2.46 (minor rotamer) and 2.71–2.74 (major rotamer) (m,
1H, H-30), 3.89–3.97 (m, 2H, H-4, H-40), 4.17–4.27 (m, 1H, OCH2CH),
4.40–4.52 (m, 2H, OCH2), 7.30–7.36 (m, 4H, Ar), 7.40–7.45 (m, 2H,
Ar), 7.56–7.58 (m, 2H, Ar) ppm. 13C NMR (75 MHz, CDCl3): Major
rotamer d = 22.2 (CH3), 28.3, 28.9, 44.6, 45.0 (CH2), 47.1 (CH),
66.9, 67.6 (CH2), 68.0, 68.7 (Cq), 120.0, 125.0, 127.1, 127.6, 127.9
(CHAr), 141.3, 143.4, 143.5, 143.8 (CqAr), 155.8, 156.5 (NCOO),
175.5, 177.6 (COOH) ppm. IR (ATR) mmax 3065, 2964, 2887, 1743,
1705, 1661, 1448, 1417, 1345, 1156, 1078, 757, 738 cmꢀ1; ESI-
4.4.6. (S)- and (R)-1-Benzyl-2-methyl-azetidine-2-carboxylic
acid methyl ester 11
A solution of 6b (3.065 g, 9.46 mmol) in MeOH (50 mL) and
H2SO4 (9.7 mL) was stirred under reflux for 2 days. After cooling
to 0 °C, the reaction mixture was poured into a saturated aqueous
solution of sodium hydrogen carbonate (500 mL). The aqueous
layer was extracted with ethyl acetate (2 ꢁ 250 mL). The organic
layer was dried over magnesium sulfate, the solvent was evapo-
rated to dryness and the residue was purified by chromatography
(pentane/ethyl acetate 75/25). Compound (R)-11 was obtained as
a colorless oil (1.36 g, 66%). Rf: 0.70 (pentane/ethyl acetate 25/
HRMS (positive mode) m/z calcd for
C
20H19NO4Na [M+Na]+:
75),
½
a 2D0
ꢂ
¼ þ47 (c 1.1, CH2Cl2), 1H NMR (300 MHz, CDCl3):
360.1212, found 360.1203. Following the same procedure, and
d = 1.41 (s, 3H, Me), 1.80–1.88 (m, 1H, H-3), 2.46–2.55 (m, 1H, H-
30), 2.98–3.05 (m, 1H, H-4), 3.13–3.20 (m, 1H, H-40), 3.49 (d, part
of AB syst., J = 12.7 Hz, 1H, NCHHPh), 3.66 (s, 3H, MeO), 3.68 (d,
part of a AB syst., J = 12.7 Hz, 1H, NCHHPh), 7.11–7.24 (m, 5H, Ar)
ppm. 13C NMR (75 MHz, CDCl3): d = 18.7 (CH3), 28.6, 49.1 (CH2),
51.7, (CH3), 55.7 (CH2), 67.7 (Cq), 126.9, 128.2, 128.7 (CHAr),
138.2 (CqAr), 175.2 (CO) ppm. IR (ATR) mmax 3448, 3364, 2959,
2912, 2860, 1723, 1649, 1495, 1456, 1373, 1270, 1175, 1107,
1091, 1027, 832, 697 cmꢀ1; ESIHRMS (positive mode) m/z calcd
for C13H18NO2 [M+H]+: 220.1338, found 220.1336. Following the
same procedure, and starting from 6a (1.487 g, 4.59 mmol),
starting from 7b (0.591 g, 1.29 mmol), (R)-8 was obtained as a
white solid (0.305 g, 70%): Mp: 122 °C, ½a D20
¼ þ76 (c 1.1, CH2Cl2);
ꢂ
ESIHRMS (positive mode) m/z calcd for C20H19NO4 [M]+: 337.1314
found 337.1306.
4.4.4. (1S,2S)-2-(2-Hydroxy-1-phenyl-ethylcarbamoyl)-2-methyl-
azetidine-1-carboxylic acid benzyl ester 9
To a solution of 6a (0.130 g, 0.401 mmol) in 95% ethanol (7 mL)
and 2 M HCl aqueous solution (0.4 mL) was added 10%wt Pd on
carbon (63 mg). The reaction mixture was hydrogenated overnight

B. Drouillat et al. / Tetrahedron: Asymmetry 23 (2012) 690–696
695
compound (S)-11 was obtained as an oil (0.718 g, 71%): ½a D20
ꢂ
¼ ꢀ42
(0.576 g, 70%). Rf: 0.38 (pentane/ethyl acetate 50/50), ½a D20
ꢂ
¼ ꢀ64
(c 2.0, CH2Cl2); ESIHRMS (positive mode) m/z calcd for C13H18NO2
(c 1.55, CH2Cl2), 1H NMR (300 MHz, CDCl3): d = 1.18 (d, J = 6.8 Hz,
3H, CH3), 1.31 (1s, 9H, tBu), 2.06–2.20 (m, 1H, H-3), 2.25–2.40
[M+H]+: 220.1338, found 220.1337.
(m, 1H, H-30), 3.64 (s, 3H, MeO), 3.99–4.21 (m, 3H, H
a
, H-4, H-
40), 5.27 (d, J = 8.07 Hz, 1 H, NH) ppm. 13C NMR (75 MHz, CDCl3):
d = 17.8 (CH3: C
), 21.8 (CH3: Cꢀ2), 28.2 (tBu), 28.3 (C-3), 45.8
(C ), 46.5 (C-4), 52.4 (CO2CH3), 67.4 (Cq), 79.3 (Cq), 154.9,
4.4.7. (S)- and (R)-2-Methyl-azetidine-1,2-dicarboxylic acid 1-
tert-butyl ester 2-methyl ester 12
a
To a solution of (R)-11 (1.36 g, 6.21 mmol) in 95% EtOH (50 mL)
were added Pd(OH)2 on carbon, 50% wt in water (150 mg) and
Boc2O (2.71 g, 12.42 mmol). The reaction mixture was stirred un-
der a hydrogen pressure of 8 bars for 16 h. After filtration over Cel-
ite, the solvent was evaporated to dryness and the residue was
purified by chromatography (pentane/ethyl acetate 90/10). Com-
pound (R)-12 was obtained as a colorless oil (1.085 g, 76%). Rf:
a
171.66, 172.2 (CO) ppm. IR (ATR) mmax 3321, 2978, 2933, 2888,
1739, 1708, 1649, 1507, 1452, 1427, 1365, 1287, 1247, 1158,
1131, 1060 cmꢀ1
C
;
ESIHRMS (positive mode) m/z calcd for
12H24N2O5Na [M+Na]+: 323.1583, found 323.1575.
4.5.2. (1S,2R)-1-(2-tert-Butoxycarbonylamino-propionyl)-2-
methyl-azetidine-2-carboxylic acid methyl ester 14b
0.70 (pentane/ethyl acetate 25/75), ½a D20
ꢂ
¼ þ36 (c 3.3, CH2Cl2), 1H
NMR (300 MHz, CDCl3): d = 1.39 (s, 9H, tBu), 1.60 (s, 3H, Me),
2.06–2.15 (m, 1H, H-3), 2.26 (m, 1H, H-30), 3.76 (s, 3H, MeO),
3.77–3.82 (m, 1H, H-4), 3.93–3.99 (m, 1H, H-40) ppm. 13C NMR
(75 MHz, CDCl3): d = 22.8 (CH3), 28.2 (CH2), 28.3 (tBu), 44.6
(CH2), 52.2, (CH3), 67.9, 79.6 (Cq), 155.2, 173.4 (CO) ppm. IR
(ATR) mmax 2975, 2933, 2895, 1740, 1701, 1451, 1382, 1364,
1285, 1252, 1194, 1145, 1128, 1070, 876, 859, 778, 542 cmꢀ1; ESI-
HRMS m/z calcd for C11H19NO4Na [M+Na]+: 252.1212, found
252.1211. Following the same procedure, and starting from (S)-
11 (637 mg, 2.9 mmol), compound (S)-12 was obtained as an oil
Following the above procedure for 14a, and starting from (R)-12
(1.36 g, 6.21 mmol), compound 14b was obtained as a colorless oil
(1.143 g, 80%). Rf: 0.70 (pentane/ethyl acetate 25/75), ½a D20
¼ þ27
ꢂ
(c 1.59, CH2Cl2), 1H NMR (300 MHz, CDCl3): Two rotamers (85:15
ratio), d = 1.26–30 (m, 3H, CH3), 1.70 (minor rotamer), 1.74 (major
rotamer) (s, 9H, tBu), 2.14–2.23 (m, 1H, H-3), 2.39–2.48 (major rot-
amer) and 2.51–2.57 (minor rotamer) (m, 1H, H-30), 3.76 (major
rotamer) and 3.79 (minor rotamer) (s, 3H, MeO), 3.83–4.11 (m,
1H, H-4), 4.14–4.25 (m, 1H, Ha
), 4.28–4.37 (m, 1H, H-40), 5.08 (d,
J = 9.6 Hz, NH minor rotamer), 5.33 (d, J = 7.7 Hz, NH major rot-
(627 mg, 94%): ½a D20
¼ ꢀ41 (c 2.4, CH2Cl2); ESIHRMS (positive
ꢂ
amer) ppm. 13C NMR (75 MHz, CDCl3): Major rotamer d = 18.6
mode) m/z calcd for C11H19NO4Na [M+Na]+: 252.1212, found
(CH3Ca), 21.8 (CH3C-2), 28.3 (tBu and C-3), 45.9 (Ca), 46.8 (C-4),
252.1210.
52.6 (CO2CH3), 67.5 (C-2), 79.5 (Cq), 155.0, 172.1, 172.3 (CO)
ppm. IR (ATR) mmax 3301, 2975, 2933, 2888, 1739, 1709, 1648,
4.4.8. (S)-2-Methyl-azetidine-1,2-dicarboxylic acid 1-tert-butyl
ester 13
1451, 1426, 1365, 1364, 1288, 1247, 1159, 1131, 1061, 733 cmꢀ1
;
ESIHRMS (positive mode) m/z calcd for C14H24N2O5Na [M+Na]+:
To a solution of (S)-12 (0.250 g, 1.09 mmol) in THF (13 mL) and
methanol (7 mL) was added a solution of sodium hydroxide
(0.087 g, 2.17 mmol) in water (1.3 mL). After stirring at 60 °C for
1 h, water (50 mL) was added to the reaction mixture and the or-
ganic solvents were evaporated. The aqueous layer was washed
with ether (4 ꢁ 10 mL) and acidified to pH 1 with a 0.5 M HCl
aqueous solution (5 mL). The aqueous layer was extracted with
ether (4 ꢁ 25 mL). The organic layer was dried over magnesium
sulfate and evaporated to dryness. Compound 13 was obtained as
a white solid (0.209 g, 93%). Rf: 0.40 (DCM/methanol 90/10), Mp:
323.1583, found 323.1582.
Acknowledgments
CNRS and the University of Versailles St-Quentin-en-Yvelines
are acknowledged for financial support.
References
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99 °C, ½a 2D0
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¼ ꢀ126 (c 0.5, CH2Cl2), 1H NMR (300 MHz, CDCl3):
d = 1.48 (s, 9H, tBu), 1.72 (s, 3H, CH3), 2.02–2.11 (m, 1H, H-3),
2.71–2.80 (m, 1H, H-30), 3.75–3.90 (m, 2H, H-4, H-40), 8.51–10.56
(s, 1H, COOH) ppm. 13C NMR (75 MHz, CDCl3): d = 22.2 (CH3),
27.6 (Cꢀ3), 28.3 (tBu), 44.5 (C-4), 69.1 (C-2), 82.6 (Cq), 157.3,
174.8 (CO) ppm. IR (ATR) mmax 2973, 2931, 2896, 2653, 2552,
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azetidine-2-carboxylic acid methyl ester 14a
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c = 15.8021(9) Å, c
= 90°. Volume: 1775.76(17) Å3, Z, Calculated density: 4,
1.213 Mg/m3. F(000)696. Data have been deposited at the Cambridge
Crystallographic Data Centre and allocated the deposition number CCDC
866018.
11. Crystal system: space group: Orthorhombic, P2(1)2(1)2(1). Unit cell
12. Helmchen, G.; Nill, D.; Flockerzi, D.; Youssef, M. S. K. Angew. Chem., Int. Ed.
1979, 18, 63–65.
dimensions:
a = 10.6000(6) Å,
a
= 90°,
b = 10.6014(6) Å,
b = 90°,