Asymmetric synthesis of substituted azetidine type α- and β-amino acids

Article abstract of DOI:10.1055/s-2005-918421

A versatile asymmetric synthesis of 3-substituted azetidine-2-carboxylic acids and 2-substituted azetidine-3-carboxylic acids via 1,3-amino alcohols with excellent stereoselectivities (de ≥ 96%, ee ≥ 96%) is reported. The high asymmetric inductions were achieved employing the SAMP/RAMP-hydrazone methodology. A phenyl moiety was used as a synthetic equivalent of the carboxylic acid function. In addition, the amino acids prepared were tested as organocatalysts in an asymmetric aldol reaction. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-918421

3508
PAPER
Asymmetric Synthesis of Substituted Azetidine Type a- and b-Amino Acids
A
symmetric Synth
i
esis of
e
Substitute
d
t
A
zetid
e
ine
A
mino
r
A
cids Enders,* Jörg Gries
Institut für Organische Chemie, Rheinisch-Westfälische Technische Hochschule, Landoltweg 1, 52074 Aachen, Germany
Fax +49(241)8092127; E-mail: enders@rwth-aachen.de
Received 3 June 2005
have been described so far. Very recently Lubell et al. re-
Abstract: A versatile asymmetric synthesis of 3-substituted azeti-
ported the preparation of a 3-allyl substituted L-aze deriv-
ative from L-aspartic acid and the transformation of the
dine-2-carboxylic acids and 2-substituted azetidine-3-carboxylic
acids via 1,3-amino alcohols with excellent stereoselectivities (de ≥
96%, ee ≥ 96%) is reported. The high asymmetric inductions were
allyl moiety into different heteroatom containing side
achieved employing the SAMP/RAMP-hydrazone methodology. A chains.9 Hanessian et al. used Oppolzer’s sultam method-
phenyl moiety was used as a synthetic equivalent of the carboxylic
ology for the preparation of 3-substituted L-aze ana-
logues.10 Couty et al. converted 2-cyano azetidines
acid function. In addition, the amino acids prepared were tested as
organocatalysts in an asymmetric aldol reaction.
derived from ephedrine, norephedrine and phenylglycinol
Key words: amino acids, amino alcohols, azetidines, organocataly-
into the corresponding enantiopure 3-phenyl substituted
amino acids.11 Apart from these general approaches only
sis, hydrazones
some specific examples of substituted non-racemic azeti-
dine carboxylic acids have been prepared.3,12
The plant growth inhibitor (S)-azetidine-2-carboxylic acid
We now wish to describe an efficient asymmetric synthe-
[L-aze, (S)-1] was the first known example for the occur-
sis of 3-substituted azetidine-2-carboxylic acids and 2-
rence of the uncommon azetidine motif in natural prod-
substituted azetidine-3-carboxylic acids employing the
ucts.1 Since then only a few additional natural products
SAMP/RAMP-hydrazone methodology13,14 and extend-
containing this amino acid or substituted analogues have
ing our recently reported asymmetric synthesis of enan-
been isolated, such as the antifungal and antibiotic poly-
tiopure substituted azetidines.15 Our synthetic approach
oxins,2 the phytosiderophores nicotianamine and mugine-
comprises the synthesis of 1,3-amino alcohols by a-hy-
ic acid,3 medicanine,4 and substituted azetidine-2,4-
droxymethylation/1,2-addition of aldehyde SAMP/
dicarboxylic acids.5 Although quite rarely found in nature,
RAMP-hydrazones with subsequent N–N bond cleavage.
derivatives of 1 are of significant importance as active
Afterwards the 1,3-amino alcohols are cyclized to the cor-
pharmaceutical ingredients, as for example the non-opioid
responding azetidines. A phenyl substituent serves as a
analgesic agent ABT-594 [(R)-2]6 and the thrombin inhib-
synthetic equivalent of the carboxylic acid function, easily
itor melagatran (3)7 (Figure 1). Ligands derived from L-
obtained by oxidative cleavage.
aze have also been successfully employed in asymmetric
catalysis.8
The asymmetric synthesis of the azetidines 9 was carried
out as depicted in Scheme 1. First the SAMP/RAMP-
hydrazones16 4 were hydroxymethylated with excellent
diastereoselectivities (de ≥ 96%, Table 1) by a-alkylation
with (2-trimethylsilylethoxy)methyl chloride (SEMCl)
instead of benzyloxymethyl chloride as has been used in
our previous procedure.15 This alteration meant a change
of the O-protecting group from benzyl to TMS-ethyl, thus
easily enabling the selective O-deprotection in the pres-
ence of the benzylic amine moiety generated in the next
step of this synthesis.
HN
HN
O
COOH
(S)-1
NH
(R)-2
N
Cl
H2N
H
N
N
OH
N
H
O
O
O
A phenyl substituent was introduced by a nucleophilic
1,2-addition of a phenylcerium reagent to the C=N double
bond of the hydrazones 5.17 The phenylcerium reagent
was generated in situ from phenyllithium following Ima-
moto’s procedure.18 The obtained crude hydrazines 6
were directly submitted to a reductive N–N bond cleavage
to remove the chiral auxiliary.19 The corresponding O-
protected amino alcohols were subsequently refluxed
with tosyl chloride in the presence of K2CO3, yielding the
differently N,O-protected amino alcohols 7 in good yields
(58–64% over 3 steps) and excellent diastereomeric and
enantiomeric excesses (de = 94–99%, ee ≥ 96–99%,
Table 2). The de values were determined by GC or NMR
3
Figure 1 L-aze and examples of pharmaceutically important azeti-
dine derivatives
Despite these promising applications of azetidine-2-car-
boxylic acid, limited progress has been made for the prep-
aration of substituted analogues. Only a few general
routes to non-racemic substituted azetidine-2-amino acids
SYNTHESIS 2005, No. 20, pp 3508–3516
Advanced online publication: 12.10.2005
DOI: 10.1055/s-2005-918421; Art ID: Z10905SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
5

PAPER
Asymmetric Synthesis of Substituted Azetidine Amino Acids
3509
nally, the cleavage was effectively achieved by refluxing
7 together with LiBF4 in a 98:2 mixture of MeCN and wa-
ter.21 The N-protected amino alcohols 8 were not purified,
but cyclized under Mitsunobu conditions.22 The corre-
sponding N-tosylated 2-phenylazetidines 9 were obtained
in good yields (86–98% over 2 steps, Table 3) as one dia-
stereomer (de ≥ 96%) and without racemization (ee ≥ 96–
99%), as shown by HPLC on a chiral stationary phase for
(S,S)-9a and (R,R)-9a.
Table 1 a-Alkylation of Hydrazones 4 with SEMCl
Hydrazone
(R,S)-5a
(S,R)-5ab
(R,S)-5b
(R,S)-5c
(R,S)-5d
R
Yield (%)
dea (%)
≥ 96
≥ 96
≥ 96
≥ 96
≥ 96
Me
Me
Et
73
70
69
66
77
i-Pr
n-Bu
Table 3 O-Deprotection and Cyclization to the Azetidines 9
a Determined by 13C NMR spectroscopy.
b RAMP was used as chiral auxiliary.
Azetidine
(S,S)-9a
(R,R)-9a
(S,S)-9b
(S,S)-9c
(S,S)-9d
R
Yield (%)
dea (%)
≥ 96
≥ 96
≥ 96
≥ 96
≥ 96
eeb (%)
97c
Me
Me
Et
86
98
91
86
94
≥ 99c
≥ 96
≥ 96
≥ 96
spectroscopy. The ee values were measured by HPLC on
a chiral stationary phase for (S,R)-7a and (R,S)-7a, show-
ing the racemization-free course of the synthesis.
i-Pr
n-Bu
Initial attempts to remove the TMS-ethyl protecting group
employing HF·pyridine gave only moderate yields.20 Fi-
a Determined by 13C NMR spectroscopy.
b Based on the de values of the corresponding hydrazones. The
following steps are racemization-free.
Table 2 Preparation of the Protected Amino Alcohols 7 by
1,2-Addition, N–N Cleavage and N-Tosylation
c Determined by HPLC on a chiral stationary phase.
Compound
(S,R)-7a
(R,S)-7a
(S,R)-7b
(S,R)-7c
(S,R)-7d
R
Yield (%) dea (%)
eeb (%)
97d
99 (≥ 98)c
The relative configuration of the phenyl substituent and R
was proven to be trans by NOE experiments on com-
pound (S,S)-9a (Figure 2). The absolute configuration of
the newly generated stereogenic centers was assigned ac-
cording to the previously confirmed mechanisms for a-
alkylations and 1,2-additions to SAMP-hydrazones.13,23
Me
Me
Et
64
58
61
59
58
99 (≥ 95)c
96e
≥ 99d
≥ 96
≥ 96
≥ 96
i-Pr
n-Bu
96e
99 (≥ 94)c
a Determined by GC.
H
b Based on the de values of the corresponding hydrazones. The
following steps are racemization-free.
H
TsN
H
c Before flash column chromatography.
H
CH3
d Determined by HPLC on a chiral stationary phase.
e Determined by 13C NMR spectroscopy.
Figure 2 NOE enhancements as measured on (S,S)-9a
H3CO
N
N
N
H
HN
N
N
a
b
66–77%
Si(CH3)3
Si(CH3)3
H3CO
H3CO
O
H
O
R
R
R
(S)-4
(R,S)-5
(S,R,S)-6
de ≥ 96%
58–64%
over 3 steps
R = Me, Et, i-Pr, n-Bu
c, d
Ts
Ts
Ts
N
HN
HN
f
e
Si(CH3)3
OH
O
R
86–94%
over 2 steps
R
R
(S,S)-9
de ≥ 96%, ee ≥ 96–99%
(S,R)-8
(S,R)-7
de = 94 to ≥99%, ee ≥ 96–99%
Scheme 1 Reagents and conditions: a) LDA, THF, 0 °C, then –100 °C, SEMCl; b) PhLi, CeCl3, THF, –105 °C; c) BH3·THF, THF, reflux,
then HCl; d) TsCl, K2CO3, CH2Cl2, reflux; e) LiBF4, MeCN–H2O (98:2), reflux; f) DIAD, PPh3, THF, r.t.
Synthesis 2005, No. 20, 3508–3516 © Thieme Stuttgart · New York

3510
D. Enders, J. Gries
PAPER
The preparation of the azetidines 9 was also tried without by 13C NMR (de ≥ 96%), it was assumed that racemiza-
the use of a N-protecting group by direct O-deprotection tion also did not occur (ee ≥ 96%). This assumption was
of 6 and subsequent cyclization of the hydrazines to the supported by comparison of the optical rotation of (S,S)-
corresponding N-amino azetidines. While the O-deprotec- 10c with the optical rotation reported by Hanessian et al.
tion was easily achieved with LiBF4, the cyclization of the ([a]D22 = –9.4 [c = 0.20, H2O]; Lit.10: [a]D = –9.5 [c = 0.11,
hydrazines failed under various conditions.
H2O]). However, long-term NMR experiments revealed
that the a-amino acids 10a–d contained small amounts of
an impurity (5–8%), which was identified as the acyclic b-
amino acid 11a–d, respectively.26 This side product pre-
sumably resulted from a ring-opening followed by oxida-
tion at the benzylic position.
The conversion of the 2-phenylazetidines 9 to the corre-
sponding azetidine type a-amino acids was accomplished
by catalytic oxidation with ruthenium tetraoxide in a bi-
phasic solvent system consisting of MeCN, H2O and CCl4
as introduced by Sharpless et al. (Scheme 2).24 In order to
achieve complete conversion, periodic acid had to be used As cyclic amino acids, especially proline, play a pivotal
as the stochiometric oxidant rather than sodium periodate role as efficient organocatalysts,27 we were - apart from
which is usually applied in ruthenium tetraoxide oxida- their biological activities - interested in the catalytic prop-
tions.25 N-Detosylation with sodium naphthalene gave the erties of the amino acids prepared. A screening of their
free a-amino acids 10. In order to prepare an azetidine catalytic activities, using the aldol reaction of acetone and
type b-amino acid, the same oxidation/deprotection se- p-nitrobenzaldehyde as a benchmark reaction (Scheme 3),
quence was applied for 3-phenylazetidine (R,S)-12, which showed good yields and moderate ee’s compared to pro-
was prepared as reported previously.15
line and an increased performance compared to unsubsti-
tuted L-aze [(S)-1] for 3-substituted L-aze derivatives
(Table 5).28 The b-amino acid 13 did not give an asym-
metric induction worth mentioning.
Ts
NH2
N
H
a, b
N
HO2C
+
R
51–65%
O
O
OH
HO2C
R
over 2 steps
R
O
a
+
H3C
(S,S)-9
(S,S)-10
de, ee ≥ 96%
11
(5–8%)
H3C
CH3
NO2
NO2
R = Me, Et, i-Pr, n-Bu
Ts
N
14
15
(R)-16
H
a, b
N
Scheme 3 Reagents and conditions: a) catalyst (0.2 equiv), DMSO,
n-Hex
r.t.
64%
over 2 steps
n-Hex
CO2H
Table 5 Catalytic Aldol Reaction of Acetone and p-Nitrobenzalde-
hyde
(R,S)-12
(R,S)-13
de, ee ≥ 96%
Scheme 2 Reagents and conditions: a) RuCl3, H5IO6, MeCN, CCl4,
H2O, r.t.; b) Na, naphthalene, DME, –78 °C
Entry
Catalyst
L-proline28
L-aze28
Time (h)
Yield (%) eea (%)
1
2
3
4
5
24
24
20
22
70
68
55
61
62
52
76
40
55
59
4
Table 4 Oxidation and Detosylation to the Free Acetidinic Amino
Acids
(S,S)-10c
(S,S)-10d
(R,S)-13
Amino acid
(S,S)-10a
(R,R)-10a
(S,S)-10b
(S,S)-10c
(S,S)-10d
(R,S)-13
R
Yield (%) dea (%)
eeb (%)
≥ 96
≥ 96
≥ 96
≥ 96
≥ 96
≥ 96
Me
Me
Et
57
58
51
65
54
64
≥ 96
≥ 96
≥ 96
≥ 96
≥ 96
≥ 96
a Determined by HPLC on a chiral stationary phase.
i-Pr
n-Bu
–
In conclusion we have developed an efficient asymmetric
synthesis of 3-substituted azetidine-2-carboxylic acids
and 2-substituted azetidine-3-carboxylic acids with virtu-
ally complete control of the diastereo- and enantioselec-
tivity.
a Determined by 13C NMR spectroscopy.
b Based on the ee values of 9a–d and 12, and racemization-free con-
version.
All solvents were dried and purified by conventional methods prior
to use. THF and dimethoxyethane were freshly distilled from sodi-
um/lead alloy and benzophenone under Ar. All moisture-sensitive
reactions were carried out under Ar using standard Schlenk tech-
niques. Phenyllithium solution was purchased from Fluka and n-
BuLi from Merck. Diisopropylamine was distilled from CaH2 under
Ar and stored over molecular sieves. Flash column chromatography
The Amino acids 10a–d and 13 were obtained after puri-
fication by ion exchange chromatography in 51–65%
yields (Table 4). Because no epimerization was detected
Synthesis 2005, No. 20, 3508–3516 © Thieme Stuttgart · New York

PAPER
Asymmetric Synthesis of Substituted Azetidine Amino Acids
3511
was carried out with Merck silica gel 60 (0.040–0.063 mm particle
size). Optical rotation values were measured on a Perkin-Elmer P
241 polarimeter with solvents of Merck UVASOL quality. IR spec-
tra were recorded on a Perkin-Elmer FT/IR spectrometer. NMR
spectra were measured on Varian VXR 300, Varian Gemini 300 and
Varian Inova 400 spectrometers, using TMS or HDO as internal
standard. Mass spectra were measured on Varian MAT 212 and
Finnigan SSQ 7000 instruments. Microanalyses were performed on
Heraeus, CHN-O-Rapid instrument. Melting points were measured
with a Büchi 510 apparatus and are uncorrected. Merck TLC plates
with silica gel 60 F254 were used for analytical TLC.
IR (film): 2957 (s), 2875 (s), 1602 (w), 1460 (m), 1355 (m), 1248
(s), 1196 (m), 1110 (s), 969 (m), 859 (s), 838 (s), 756 (m), 694 (m)
cm–1.
1H NMR (300 MHz, CDCl3): d = 0.01 [s, 9 H, Si(CH3)3], 0.91 (t,
J = 7.9 Hz, 2 H, CH2Si), 0.92 (t, J = 7.35 Hz, 3 H, CH2CH3), 1.45
(m, 1 H, CHHCH3), 1.59 (m, 1 H, CHHCH3), 1.72–2.00 (m, 4 H,
NCH2CH2CH2), 2.39 (m, 1 H, N=CHCH), 2.74 (q, J = 8.2 Hz, 1 H,
NCHH), 3.37 (s, 3 H, OCH3), 3.30–3.61 (m, 8 H, CH2OCH2CH2Si,
NCHH, NCHCH2OCH3), 6.54 (d, J = 6.4 Hz, 1 H, N=CH).
13C NMR (75 MHz, CDCl3): d = –1.3 (SiCH3), 11.5 (CH2CH3), 18.1
(CH2Si), 22.1 (NCH2CH2), 23.4 (CH2CH3), 26.6 (NCH2CH2CH2),
44.5 (N=CHCH), 50.2 (NCH2), 59.2 (OCH3), 63.4 (NCH), 68.1
(OCH2CH2Si), 72.5 (N=CHCHCH2O), 74.7 (CH2OCH3), 140.2
(N=CH).
Alkylation of Hydrazones 4 with SEM Chloride; General Pro-
cedure (GP1)
A solution of LDA was freshly prepared by addition of n-BuLi (1.3
equiv) to a solution of diisopropylamine (1.3 equiv) in THF (1.4
mL/mmol 4) at 0 °C. After stirring for 15 min the SAMP- or
RAMP-hydrazones 4 (1 equiv) were added dropwise and the mix-
ture was stirred for 2.5 h. The reaction vessel was then cooled to
–100 °C and SEMCl (1.2 equiv) was added slowly. The mixture was
allowed to warm to r.t. within 16 h and the pH 7 buffer solution (3
mL/mmol 4) was added. After extraction with Et2O and drying over
MgSO4, the mixture was filtered through a pad of silica gel and the
solvent was evaporated. Flash column chromatography gave the
pure products 5a–d.
MS (EI, 70 eV): m/z (%) = 314 (3) [M+], 269 (100), 183 (5), 73 (26),
70 (12).
Anal. Calcd for C16H34N2O2Si (314.54): C, 61.10; H, 10.90; N, 8.91.
Found: C, 61.25; H, 10.91; N, 9.16.
(E,2R)-2-{[2-(Trimethylsilyl)ethoxy]methyl}-N-[(S)-2-(meth-
oxymethyl)pyrrolidin-1-yl]-3-methylbutan-1-imine [(R,S)-5c]
According to GP1 the alkylation of the SAMP-hydrazone (S)-4c
(1.98 g, 10 mmol) gave (R,S)-5c after chromatography (n-hexane–
EtOAc, 30:1); yield: 2.16 g (66%); colorless oil; de ≥ 96% (13C
24
NMR); [a]D –83.0 (c = 1.04, CHCl3); Rf 0.79 (n-hexane–EtOAc,
(E,2R)-3-[2-(Trimethylsilyl)ethoxy]-N-[(S)-2-(methoxymeth-
yl)pyrrolidin-1-yl]-2-methylpropan-1-imine [(R,S)-5a]
3:1).
IR (film): 2955 (s), 2873 (s), 1601 (m), 1463 (m), 1357 (m), 1249
(m), 1198 (m), 1106 (s), 969 (m), 841 (s), 759 (m), 695 (m) cm–1.
According to GP1 the alkylation of the SAMP-hydrazone (S)-4a
(2.56 g, 15 mmol) gave (R,S)-5a after chromatography (n-pentane–
Et2O, 6:1); yield: 3.31 g (73%); colorless oil; de ≥ 96% (13C NMR);
[a]D24 –86.1 (c = 1.09, CHCl3); Rf 0.34 (n-pentane–Et2O, 4:1).
1H NMR (300 MHz, CDCl3): d = 0.00 [s, 9 H, Si(CH3)3], 0.89 (d,
J = 6.7 Hz, 3 H, CHCH3), 0.90 (t, J = 8.0 Hz, 2 H, CH2Si), 0.95 (d,
J = 6.9 Hz, 3 H, CHCH3), 1.73–2.00 [m, 5 H, NCH2CH2CH2,
CH(CH3)2], 2.28 (q, J = 6.4 Hz, 1 H, N=CHCH), 2.75 (m, 1 H,
NCHH), 3.36 (s, 3 H, OCH3), 3.29–3.60 (m, 8 H, CH2OCH2CH2Si,
NCHH, NCHCH2OCH3), 6.57 (d, J = 7.2 Hz, 1 H, N=CH).
13C NMR (75 MHz, CDCl3): d = –1.3 (SiCH3), 18.1 (CH2Si), 19.4,
20.6 [CH(CH3)2], 22.1 (NCH2CH2), 26.6 (NCH2CH2CH2), 28.2
[CH(CH3)2], 44.8 (N=CHCH), 50.2 (NCH2), 59.2 (OCH3), 63.4
(NCH), 68.1 (OCH2CH2Si), 70.9 (N=CHCHCH2O), 74.8
(CH2OCH3), 139.4 (N=CH).
IR (film): 2954 (s), 2874 (s), 1602 (m), 1457 (m), 1410 (w), 1353
(m), 1248 (s), 1197 (m), 1104 (s), 967 (m), 840 (s), 757 (m), 694
(m), 609 (w), 556 (w) cm–1.
1H NMR (300 MHz, CDCl3): d = 0.01 [s, 9 H, Si(CH3)3], 0.92 (t,
J = 8.0 Hz, 2 H, CH2Si), 1.06 (d, J = 6.9 Hz, 3 H, CHCH3), 1.74–
2.00 (m, 4 H, NCH2CH2CH2), 2.62 (m, 1 H, N=CHCH), 2.71 (q, J
= 8.4 Hz, 1 H, NCHH), 3.37 (s, 3 H, OCH3), 3.29–3.61 (m, 8 H,
CH2OCH2CH2Si, NCHH, NCHCH2OCH3), 6.56 (d, J = 5.7 Hz, 1 H,
N=CH).
MS (EI, 70 eV): 328 (11) [M+], 283 (100), 197 (6), 167 (2), 142 (2),
113 (2), 84 (2), 73 (13), 70 (6).
13C NMR (75 MHz, CDCl3): d = –0.3 (SiCH3), 16.9 (CHCH3), 19.1
(CH2Si), 23.1 (NCH2CH2), 27.6 (NCH2CH2CH2), 38.5 (N=CHCH),
51.0 (NCH2), 60.1 (OCH3), 64.3 (NCH), 69.0 (OCH2CH2Si), 75.2,
75.7 (N=CHCHCH2O, CH2OCH3), 140.2 (N=CH).
Anal. Calcd for C17H36N2O2Si (328.57): C, 62.14; H, 11.04; N, 8.53.
Found: C, 61.97; H, 10.91; N, 8.82.
MS (EI, 70 eV): m/z (%) = 300 (11) [M+], 255 (100), 183 (1), 169
(E,2R)-2-{[2-(Trimethylsilyl)ethoxy]methyl}-N-[(S)-2-(meth-
oxymethyl)pyrrolidin-1-yl]hexan-1-imine [(R,S)-5d]
(6), 139 (4), 73 (23), 70 (9).
Anal. Calcd for C15H32N2O2Si (300.51): C, 59.95; H, 10.73; N, 9.32.
Found: C, 60.27; H, 10.95; N, 9.66.
According to GP1 the alkylation of the SAMP-hydrazone (S)-4d
(3.19 g, 15 mmol) gave (R,S)-5d after chromatography (n-pentane–
Et2O, 15:1 → 13:1); yield: 3.95 g (77%); colorless oil; de ≥ 96%
(E,2S)-3-[2-(Trimethylsilyl)ethoxy[-N-[(R)-2-(methoxymeth-
yl)pyrrolidin-1-yl]-2-methylpropan-1-imine [(S,R)-5a]
According to GP1 the alkylation of the RAMP-hydrazone (R)-4a
(1.70 g, 10 mmol) gave (S,R)-5a after chromatography (n-pentane–
Et2O, 6:1); yield: 2.10 g (70%); colorless oil; de ≥ 96% (13C NMR);
[a]D22 +83.6 (c = 1.28, CHCl3).
22
(13C NMR); [a]D –82.2 (c = 1.39, CHCl3); Rf 0.53 (n-pentane–
Et2O, 4:1).
IR (film): 2953 (s), 2857 (s), 1602 (m), 1461 (m), 1406 (w), 1353
(m), 1303 (w), 1248 (s), 1197 (m), 1108 (s), 1022 (w), 972 (m), 839
(s), 756 (m), 695 (m), 666 (w), 613 (w), 535 (w) cm–1.
1H NMR (400 MHz, CDCl3): d = 0.01 [s, 9 H, Si(CH3)3], 0.89 (t,
J = 6.6 Hz, 3 H, CH2CH3), 0.92 (t, J = 8.1 Hz, 2 H, CH2Si), 1.24–
1.47 (m, 5 H, CHHCH2CH2CH3), 1.53 (m, 1 H, CHHCH2CH2CH3),
1.76–1.99 (m, 4 H, NCH2CH2CH2), 2.47 (m, 1 H, N=CHCH), 2.73
(q, J = 8.2 Hz, 1 H, NCHH), 3.37 (s, 3 H, OCH3), 3.30–3.60 (m, 8
H, CH2OCH2CH2Si, NCHH, NCHCH2OCH3), 6.51 (d, J = 6.6 Hz,
1 H, N=CH).
The other analytical data corresponded to those of (R,S)-5a.
(E,2R)-2-{[2-(Trimethylsilyl)ethoxy]methyl}-N-[(S)-2-(meth-
oxymethyl)pyrrolidin-1-yl]butan-1-imine [(R,S)-5b]
According to GP1 the alkylation of the SAMP-hydrazone (S)-4b
(3.69 g, 20 mmol) gave (R,S)-5b after chromatography (n-pentane–
Et2O, 7:1); yield: 4.36 g (69%); colorless oil; de ≥ 96% (13C NMR);
[a]D24 –88.2 (c = 1.86, CHCl3); Rf 0.36 (n-pentane–Et2O, 4:1).
13C NMR (100 MHz, CDCl3): –0.3 (SiCH3), 15.1 (CH2CH3), 19.1
(CH2Si), 23.1 (NCH2CH2), 23.4 (CH2CH3), 27.5 (NCH2CH2CH2),
Synthesis 2005, No. 20, 3508–3516 © Thieme Stuttgart · New York

3512
D. Enders, J. Gries
PAPER
30.2 (CH2CH2CH2CH3), 31.2 (CH2CH2CH2CH3), 43.9 (N=CHCH),
51.1 (NCH2), 60.1 (OCH3), 64.3 (NCH), 69.0 (OCH2CH2Si), 73.8
(N=CHCHCH2O), 75.6 (CH2OCH3), 141.3 (N=CH).
Anal. Calcd for C22H33NO3SSi (419.65): C, 62.97; H, 7.93; N, 3.34.
Found: C, 63.32; H, 7.59; N, 3.45.
(1R,2S)-3-[2-(Trimethylsilyl)ethoxy]-2-methyl-1-phenyl-N-to-
sylpropan-1-amine [(R,S)-7a]
MS (EI, 70 eV): m/z (%) = 342 (8) [M+], 297 (100), 211 (7), 181 (3),
123 (3), 73 (23), 70 (9).
According to GP2 the hydrazone (S,R)-5a (1.40 g, 4.7 mmol) was
converted into (R,S)-7a and purified by column chromatography (n-
pentane–Et2O, 5:1 → 4:1); yield: 992 mg (58% over 3 steps); color-
less solid; de ≥ 95% (GC, CP-Sil-8, 160-10-100, ≥ 99% after chro-
matography); ee ≥ 99% (HPLC, Daicel AS, n-heptane–i-PrOH,
9:1); [a]D22 +57.2 (c = 1.01, CHCl3).
Anal. Calcd for C18H38N2O2Si (342.59): C, 63.10; H, 11.18; N, 8.18.
Found: C, 63.32; H, 11.59; N, 8.47.
Synthesis of the N,O-Protected 1,3-Amino Alcohols 7; General
Procedure (GP2)
CeCl3·7H2O (4.0 equiv) was dehydrated for 2.5 h at 140 °C under
reduced pressure (0.1 torr) and suspended in anhyd THF (17 mL/
mmol 5) by sonification for 15 min and additional stirring for 12 h.
The suspension was cooled to –78 °C and phenyllithium (4.0 equiv)
was added. After 2 h the mixture was cooled to –105 °C and a solu-
tion of the hydrazones 5 (1 equiv) in THF (1.5 mL/mmol) was slow-
ly added to the cerium reagent along the wall of the cooled reaction
vessel. After warming to ca. –50 °C within 2.5 h the reaction mix-
ture was hydrolyzed with sat. aq NaHCO3 solution and additional
water, extracted with CH2Cl2 (3 ×), dried over Na2SO4 and filtered
through a pad of silica gel. After removal of the solvent in vacuo,
the crude hydrazines 6 were obtained.
All other analytical data corresponded to those of (S,R)-7a.
(1S,2R)-2-{[2-(Trimethylsilyl)ethoxy]methyl}-1-phenyl-N-to-
sylbutan-1-amine [(S,R)-7b]
According to GP2 the hydrazone (R,S)-5b (0.56 g, 1.78 mmol) was
converted into (S,R)-7b and purified by column chromatography (n-
pentane–Et2O, 10:1 → 4:1); yield: 0.47 g (61% over 3 steps); color-
less solid; de ≥ 96% (1H NMR); mp 71 °C; [a]D24 –49.2 (c = 1.17,
CHCl3); Rf 0.76 (n-pentane–Et2O, 1:1).
IR (KBr): 3284 (m), 3063 (w), 3031 (w), 2956 (s), 2877 (m), 1600
(m), 1493 (m), 1456 (m), 1420 (m), 1329 (s), 1249 (m), 1161 (s),
1096 (s), 1026 (m), 936 (m), 915 (m), 839 (s), 763 (m), 702 (s), 669
(s), 552 (s) cm–1.
1H NMR (400 MHz, CDCl3): d = 0.05 [s, 9 H, Si(CH3)3], 0.81 (t,
J = 7.4 Hz, 3 H, CH2CH3), 0.91–1.07 (m, 2 H, CH2Si), 1.34 (m, 2
H, CH2CH3), 1.60 (m, 1 H, NCHCH), 2.33 (s, 3 H, CqCH3), 3.22
(dd, J = 4.7, 9.6 Hz, 1 H, CHCHHO), 3.31 (dd, J = 2.5, 9.6 Hz, 1 H,
CHCHHO), 3.43 (m, 2 H, OCH2CH2Si), 4.46 (t, J = 6.1 Hz, 1 H,
PhCHNH), 6.63 (d, J = 6.1 Hz, 1 H, NH), 7.07–7.19 (m, 7 H,
CHarom.), 7.51 (d, J = 8.2 Hz, 2 H, SO2CCHarom.).
N–N Cleavage was then performed by dissolving 6 in THF (1.5 mL/
mmol) and addition of a 1 M solution of BH3 in THF (10 equiv).
The mixture was refluxed for 4 h, cooled to –5 °C and hydrolyzed
by addition of an aq 2 M HCl solution (10 mL/mmol). After heating
at reflux for 2 min the solvent was removed under reduced pressure
and the aqueous residue was neutralized with a sat. NaHCO3 solu-
tion. The aqueous phase was extracted with CH2Cl2 (3 ×). Drying of
the organic phase over Na2SO4 and removal of the solvent gave the
crude amines, which were tosylated without further purification.
The crude product was dissolved in CH2Cl2 (10 mL/mol), and
K2CO3 (10 equiv) and tosyl chloride (1.5 equiv) were added. The
suspension was refluxed for 2 h and stirred for 12 h at r.t. The reac-
tion mixture was then rinsed through a pad of silica gel with Et2O.
The pure tosylated amino alcohols 7 were obtained upon flash col-
umn chromatography.
13C NMR (100 MHz, CDCl3): d = 1.1 (SiCH3), 12.6 (CH2CH3), 19.4
(CH2Si), 22.5 (CqCH3), 23.2 (CH2CH3), 47.2 (NCHCH), 61.9
(NCH), 69.9 (OCH2CH2Si), 71.0 (CHCH2O), 127.7, 127.8, 128.8,
128.9, 129.9 (ArCH), 141.9, 139.2 (ArCqSO2, ArCqCH), 143.3
(ArCqCH3).
MS (EI, 70 eV): m/z (%) = 433 (1) [M+], 332 (24), 278 (12), 260
(100), 228 (13), 155 (16), 106 (8), 91 (19), 73 (10).
(1S,2R)-3-[2-(Trimethylsilyl)ethoxy]-2-methyl-1-phenyl-N-to-
sylpropan-1-amine [(S,R)-7a]
Anal. Calcd for C23H35NO3SSi (433.68): C, 63.70; H, 8.13; N, 3.23.
Found: C, 63.99; H, 8.38; N, 3.10.
According to GP2 the hydrazone (R,S)-5a (1.50 g, 5.0 mmol) was
converted into (S,R)-7a and purified by column chromatography (n-
pentane–Et2O, 5:1 → 4:1); yield: 1.35 g (64% over 3 steps); color-
less solid; de ≥ 98% (GC, CP-Sil-8, 160-10-100, ≥ 99% after chro-
matography); ee ≥ 97% (HPLC, Daicel AS, n-heptane–i-PrOH,
9:1); mp 79 °C; [a]D23 –55.8 (c = 0.96, CHCl3); Rf 0.42 (n-pentane–
Et2O, 2:1).
(1S,2R)-2-{[2-(Trimethylsilyl)ethoxy]methyl}-3-methyl-1-phe-
nyl-N-tosylbutan-1-amine [(S,R)-7c]
According to GP2 the hydrazone (R,S)-5c (1.28 g, 3.9 mmol) was
converted into (S,R)-7c and purified by column chromatography (n-
pentane–Et2O, 10:1); yield: 1.02 g (59% over 3 steps); colorless oil;
de ≥ 96% (1H NMR); [a]D –53.1 (c = 1.02, CHCl3); Rf 0.28 (n-
24
IR (KBr): 3274 (s), 3062 (w), 3031 (m), 2952 (s), 2893 (s), 2859 (s),
1601 (m), 1498 (m), 1442 (m), 1319 (s), 1250 (m), 1161 (s), 1097
(s), 1040 (m), 992 (w), 962 (m), 920 (m), 836 (s), 763 (m), 708 (s),
676 (s), 592 (s), 569 (s), 543 (m), 487 (w) cm–1.
1H NMR (400 MHz, CDCl3): d = 0.05 [s, 9 H, Si(CH3)3], 0.76 (d,
J = 7.2 Hz, 3 H, CHCH3), 1.01 (m, 2 H, CH2Si), 1.96 (m, 1 H,
NCHCH), 2.33 (s, 3 H, CqCH3), 3.19 (dd, J = 6.3, 9.6 Hz, 1 H,
CHCHHO), 3.33 (dd, J = 3.0, 9.6 Hz, 1 H, CHCHHO), 3.45 (t, J =
8.4 Hz, 2 H, OCH2CH2Si), 4.46 (dd, J = 5.2, 7.1 Hz, 1 H, PhCHNH),
6.64 (d, J = 5.2 Hz, 1 H, NH), 7.06–7.18 (m, 7 H, CHarom.), 7.49 (d,
J = 8.2 Hz, 2 H, SO2CCHarom.).
13C NMR (100 MHz, CDCl3): d = –0.3 (SiCH3), 16.2 (CH3), 19.3
(CH2Si), 22.5 (CqCH3), 40.1 (NCHCH), 64.2 (NCH), 69.8
(OCH2CH2Si), 74.5 (CHCH2O), 127.9, 127.9, 128.1, 128.9, 129.9
(ArCH), 138.9, 141.5 (ArCqSO2, ArCqCH), 143.3 (ArCqCH3).
MS (EI, 70 eV): m/z (%) = 419 (1) [M+], 332 (22), 260 (100), 228
(13), 155 (14), 131 (5), 106 (6), 91 (13), 73 (8).
pentane–Et2O, 6:1).
IR (film): 3293 (m), 3062 (w), 3030 (m), 2956 (s), 2876 (s), 1600
(m), 1494 (m), 1455 (m), 1419 (m), 1329 (s), 1249 (m), 1161 (s),
1095 (s), 1028 (m), 939 (m), 917 (m), 839 (s), 755 (s), 700 (s), 664
(s), 549 (s) cm–1.
1H NMR (300 MHz, CDCl3): d = 0.06 [s, 9 H, Si(CH3)3], 0.84 (d,
J = 7.1 Hz, 3 H, CHCH3), 0.88 (d, J = 6.9 Hz, 3 H, CHCH3), 0.94–
1.08 (m, 2 H, CH2Si), 1.36 (m, 1 H, CHCH3), 1.72 (m, 1 H,
NCHCH), 2.34 (s, 3 H, CqCH3), 3.30 (m, 2 H, OCH2CH2Si), 3.44
(m, 2 H, CHCH2O), 4.64 (t, J = 5.8 Hz, 1 H, PhCHNH), 6.81 (d,
J = 5.8 Hz, 1 H, NH), 7.04–7.18 (m, 7 H, CHarom.), 7.48 (d, J = 8.5
Hz, 2 H, SO2CCHarom.).
13C NMR (75 MHz, CDCl3): d = –1.4 (SiCH3), 18.3 (CH2Si), 19.0,
21.2 [CH(CH3)2], 21.4 (CqCH3), 25.7 [CH(CH3)2], 51.0 (NCHCH),
59.7 (NCH), 68.1, 68.8 (OCH2CH2Si, CHCH2O), 126.7, 126.9,
127.0, 128.0, 129.0 (ArCH), 138.5, 141.2 (ArCqSO2, ArCqCH),
142.3 (ArCqCH3).
Synthesis 2005, No. 20, 3508–3516 © Thieme Stuttgart · New York

PAPER
Asymmetric Synthesis of Substituted Azetidine Amino Acids
3513
MS (EI, 70 eV): m/z (%) = 332 (19), 292 (5), 260 (100), 244 (2), 228
H, NCHH), 3.91 (t, J = 7.6 Hz, 1 H, NCHH), 4.34 (d, J = 7.4 Hz, 1
(9), 155 (14), 106 (10), 91 (18), 73 (10).
H, NCH), 7.24–7.39 (m, 7 H, CHarom.), 7.68 (d, J = 8.2 Hz, 2 H,
CHaromCSO2).
Anal. Calcd for C24H37NO3SSi (447.71): C, 64.39; H, 8.33; N, 3.13.
Found: C, 64.40; H, 8.64; N, 3.48.
13C NMR (100 MHz, CDCl3): d = 17.6 (CHCH3), 21.5 (CqCH3),
35.0 (NCHCH), 54.5 (NCH2), 73.1 (NCH), 125.9, 127.8, 128.2,
128.3, 129.4 (ArCH), 131.9 (ArCqSO2), 139.7 (ArCqCH), 143.7
(ArCqCH3).
(1S,2R)-2-{[2-(Trimethylsilyl)ethoxy]methyl}-1-phenyl-N-to-
sylhexan-1-amine [(S,R)-7d]
According to GP2 the hydrazone (R,S)-5d (2.06 g, 6.0 mmol) was
converted into (S,R)-7d and purified by column chromatography (n-
pentane–Et2O, 13:1 → 10:1); yield: 1.62 g (58% over 3 steps); col-
orless oil; de ≥ 94% (GC, CP-Sil-8, 120-10-100, ≥ 99% after chro-
MS (EI, 70 eV): m/z (%) = 301 (8) [M+], 300 (9), 260 (5), 195 (4),
155 (71), 146 (100), 118 (52), 104 (16), 91 (61), 77 (6), 65 (7).
Anal. Calcd for C17H19NO2S (301.40): C, 67.74; H, 6.35; N, 4.65.
Found: C, 67.71; H, 6.58; N, 4.65.
23
matography); [a]D –66.1 (c = 0.80, CHCl3); Rf 0.43 (n-pentane–
Et2O, 4:1).
(2R,3R)-3-Methyl-2-phenyl-1-tosylazetidine [(R,R)-9a]
According to GP3 the azetidine (R,R)-9a was prepared from (R,S)-
7a (0.94 g, 2.2 mmol) and purified by column chromatography (n-
pentane–Et2O, 6:1); yield: 661 mg (98% over 2 steps); colorless sol-
id; de ≥ 96% (1H NMR); ee ≥ 99% (HPLC, Daicel OD, n-heptane–
i-PrOH, 4:1); [a]D22 +238.5 (c = 1.02, CHCl3).
IR (film): 3292 (s), 3062 (m), 3031 (m), 2953 (s), 2867 (s), 1807
(w), 1600 (m), 1494 (m), 1455 (m), 1455 (m), 1420 (m), 1331 (s),
1249 (s), 1161 (s), 1094 (s), 940 (m), 911 (m), 839 (s), 756 (m), 701
(s), 671 (s), 551 (s) cm–1.
1H NMR (400 MHz, CDCl3): d = 0.05 [s, 9 H, Si(CH3)3], 0.79 (t,
J = 7.0 Hz,
3 H, CH2CH3), 0.91–1.32 (m, 8 H, CH2Si,
All other analytical data corresponded to those of (S,S)-9a.
CH2CH2CH2CH3), 1.65 (m, 1 H, NCHCH), 2.34 (s, 3 H, CqCH3),
3.19 (dd, J = 4.4, 9.6 Hz, 1 H, CHCHHO), 3.28 (dd, J = 2.5, 9.6 Hz,
1 H, CHCHHO), 3.43 (m, 2 H, OCH2CH2Si), 4.46 (t, J = 5.4 Hz, 1
H, PhCHNH), 6.65 (d, J = 5.4 Hz, 1 H, NH), 7.10–7.20 (m, 7 H,
CHarom.), 7.54 (d, J = 8.3 Hz, 2 H, SO2CCHarom.).
13C NMR (100 MHz, CDCl3): d = –1.4 (SiCH3), 13.8 (CH3), 18.3
(CH2Si), 21.3 (CqCH3), 22.6, 28.9 (CH2CH2CH3), 29.3
(NCHCHCH2), 44.5 (NCHCH), 60.9 (NCH), 68.8 (OCH2CH2Si),
70.1 (CHCH2O), 126.6, 126.6, 126.8, 127.8, 128.9 (ArCH), 138.1,
141.0 (ArCqSO2, ArCqCH), 142.3 (ArCqCH3).
(2S,3S)-3-Ethyl-2-phenyl-1-tosylazetidine [(S,S)-9b]
According to GP3 the azetidine (S,S)-9b was prepared from (S,R)-
7b (0.30 g, 0.69 mmol) and purified by column chromatography (n-
pentane–Et2O, 5:1); yield: 196 mg (91% over 2 steps); colorless sol-
id; de ≥ 96% (1H NMR); mp 81 °C; [a]D26 –215.0 (c = 1.03, CHCl3);
Rf 0.31 (n-pentane–Et2O, 4:1).
IR (KBr): 3087 (w), 3059 (w), 3033 (m), 2969 (m), 2945 (m), 2927
(m), 2861 (m), 1810 (w), 1597 (m), 1494 (m), 1459 (s), 1387 (w),
1340 (s), 1302 (m), 1160 (s), 1093 (s), 1042 (m), 991 (m), 946 (m),
915 (m), 813 (m), 790 (m), 746 (m), 599 (m), 667 (s), 601 (s), 549
(s), 503 (m) cm–1.
1H NMR (400 MHz, CDCl3): d = 0.70 (t, J = 7.4 Hz, 3 H, CH2CH3),
1.27 (m, 1 H, CHCHHCH3), 1.38 (m, 1 H, CHCHHCH3), 2.34 (m,
1 H, NCHCH), 2.43 (s, 3 H, CqCH3), 3.36 (t, J = 7.7 Hz, 1 H,
NCHH), 3.89 (t, J = 7.7 Hz, 1 H, NCHH), 4.43 (d, J = 7.1 Hz, 1 H,
NCH), 7.24–7.34 (m, 5 H, CHarom.), 7.39 (d, J = 8.2 Hz, 2 H,
CHarom.CCH3), 7.67 (d, J = 8.2 Hz, 2 H, CHaromCSO2).
MS (EI, 70 eV): m/z (%) = 461 (0.4) [M+], 434 (2), 332 (21), 306
(11), 260 (100), 244 (4), 228 (10), 155 (16), 117 (2), 106 (6), 91
(14), 73 (10).
Anal. Calcd for C25H39NO3SSi (461.73): C, 65.03; H, 8.51; N, 3.03.
Found: C, 65.10; H, 8.64; N, 3.33.
O-Deprotection of 7 and Cyclization to the Phenyl Azetidines 9;
General Procedure (GP3)
The amino alcohols 7 (1 equiv) were dissolved in a MeCN–H2O
mixture (98:2, 20 mL/mmol) and LiBF4 (5 equiv) was added. The
mixture was heated at reflux until complete conversion of the start-
ing material was observed by TLC (22–72 h). The reaction mixture
was worked up (pH 7 buffer, CH2Cl2, Na2SO4) and the solvent was
evaporated, yielding the crude deprotected amino alcohols 8 as col-
orless solids.
13C NMR (100 MHz, CDCl3): d = 10.7 (CH2CH3), 21.5 (CqCH3),
26.0 (CH2CH3), 41.3 (NCHCH), 52.9 (NCH2), 71.5 (NCH), 126.2,
127.7, 128.2, 128.3, 129.4 (ArCH), 132.2 (ArCqSO2), 140.0
(ArCqCH), 143.7 (ArCqCH3).
MS (EI, 70 eV): m/z (%) = 315 (9) [M+], 314 (8), 260 (17), 160
(100), 155 (62), 132 (12), 117 (21), 104 (15), 91 (56), 77 (4), 65 (6).
Anal. Calcd for C18H21NO2S (315.13): C, 68.54; H, 6.71; N, 4.44.
Found: C, 68.32; H, 6.52; N, 4.21.
Compound 8 and PPh3 (1.5 equiv) were then dissolved in anhyd
THF (25 mL/mmol 8). Diisopropyl azodicarboxylate (DIAD, 1.5
equiv) was slowly added and the mixture was stirred for up to 24 h.
After complete conversion of the starting material the reaction mix-
ture was rinsed through a pad of silica gel with Et2O, evaporated and
finally purified by flash column chromatography.
(2S,3S)-3-Isopropyl-2-phenyl-1-tosylazetidine [(S,S)-9c]
According to GP3 the azetidine (S,S)-9c was prepared from (S,R)-
7c (0.97 g, 2.2 mmol) and purified by column chromatography (n-
pentane–Et2O, 6:1); yield: 616 mg (86% over 2 steps); colorless sol-
id; de ≥ 96% (1H NMR); mp 78 °C; [a]D24 –209.2 (c = 0.78, CHCl3);
Rf 0.27 (n-pentane–Et2O, 4:1).
(2S,3S)-3-Methyl-2-phenyl-1-tosylazetidine [(S,S)-9a]
According to GP3 the azetidine (S,S)-9a was prepared from (S,R)-
7a (1.22 g, 2.9 mmol) and purified by column chromatography (n-
pentane–Et2O, 6:1); yield: 753 mg (86% over 2 steps); colorless sol-
id; de ≥ 96% (1H NMR); ee = 97% (HPLC, Daicel OD, n-heptane–
i-PrOH, 4:1); mp 112 °C; [a]D24 –228.5 (c = 1.02, CHCl3); Rf 0.53
(n-pentane–Et2O, 2:1).
IR (KBr): 3062 (m), 3034 (m), 2952 (m), 2871 (m), 1942 (w), 1807
(w), 1598 (m), 1494 (m), 1464 (m), 1392 (w), 1343 (s), 1300 (m),
1246 (w), 1164 (s), 1094 (m), 1049 (m), 1019 (m), 988 (m), 914
(m), 824 (m), 806 (m), 786 (m), 736 (m), 696 (m), 665 (s), 601 (s),
552 (s), 508 (m) cm–1.
1H NMR (300 MHz, CDCl3): d = 0.69 [d, J = 6.7 Hz, 6 H,
CH(CH3)2], 1.45 [m, 1 H, CH(CH3)2], 2.17 (m, 1 H, NCHCH), 2.43
(s, 3 H, CqCH3), 3.41 (t, J = 7.8 Hz, 1 H, NCHH), 3.86 (t, J = 7.8
Hz, 1 H, NCHH), 4.49 (d, J = 7.2 Hz, 1 H, NCH), 7.24–7.35 (m, 5
H, CHarom.), 7.41 (d, J = 7.9 Hz, 2 H, CHaromCCH3), 7.67 (d, J = 7.9
Hz, 2 H, CHaromCSO2).
IR (KBr): 3037 (m), 2968 (m), 2927 (m), 2861 (m), 1595 (m), 1494
(m), 1456 (m), 1339 (s), 1302 (s), 1158 (s), 1091 (m), 1056 (m),
1024 (s), 931 (m), 912 (m), 810 (s), 742 (m), 702 (m), 664 (s), 595
(s), 547 (s), 494 (m) cm–1.
1H NMR (400 MHz, CDCl3): d = 0.96 (d, J = 6.6 Hz, 3 H, CHCH3),
2.43 (s, 3 H, CqCH3), 2.47 (m, 1 H, NCHCH), 3.33 (t, J = 7.6 Hz, 1
Synthesis 2005, No. 20, 3508–3516 © Thieme Stuttgart · New York

3514
D. Enders, J. Gries
PAPER
(2S,3S)-3-Methylazetidine-2-carboxylic Acid [(S,S)-10a]29
According to GP4 the phenylazetidine (S,S)-9a (142 mg, 0.47
mmol) was converted into amino acid (S,S)-10a; yield: 31 mg (57%
over 2 steps); colorless solid; de ≥ 96% (13C NMR); mp 187–192
°C (decomp.); [a]D22 –4.2 (c = 0.24, H2O).
13C NMR (75 MHz, CDCl3): d = 19.2, 19.4 [CH(CH3)2], 21.6
(CqCH3), 32.1 [CH(CH3)2], 46.7 (NCHCH), 51.6 (NCH2), 70.7
(NCH), 126.9, 128.0, 128.3, 128.4, 129.5 (ArCH), 132.6
(ArCqSO2), 140.4 (ArCqCH), 143.8 (ArCqCH3).
MS (EI, 70 eV): m/z (%) = 329 (7) [M+], 260 (29), 195 (3), 174
(100), 155 (70), 131 (25), 118 (8), 104 (12), 91 (52), 77 (3), 65 (5).
IR (KBr): 2969 (m), 1624 (s), 1458 (m), 1412 (m), 1385 (m), 1309
(m), 1123 (m), 1020 (m), 639 (m), 538 (m) cm–1.
1H NMR (300 MHz, D2O): d = 1.11 (d, J = 6.9 Hz, 3 H, CH3), 2.75
(m, 1 H, NCHCH), 3.47 (dd, J = 8.2, 10.4 Hz, 1 H, NCHH), 3.75
(dd, J = 8.8, 10.4 Hz, 1 H, NCHH), 4.16 (d, J = 8.2 Hz, 1 H, NCH).
13C NMR (75 MHz, D2O): d = 17.0 (CH3), 32.3 (NCHCH), 48.4
(NCH2), 65.0 (NCH), 173.0 (COOH).
MS (EI, 70 eV): m/z (%) = 116 (20) [M + 1+], 115 (20) [M+], 87
(20), 74 (12), 70 (100), 56 (12).
HRMS (EI): m/z [M+] calcd for C5H9NO2: 115.0633; found:
115.0634.
Anal. Calcd for C19H23NO2S (329.46): C, 69.27; H, 7.04; N, 4.25.
Found: C, 69.06; H, 7.08; N, 4.04.
(2S,3S)-3-Butyl-2-phenyl-1-tosylazetidine [(S,S)-9d]
According to GP3the azetidine (S,S)-9d was prepared from (S,R)-
7d (1.39 g, 3.0 mmol) and purified by column chromatography (n-
pentane–Et2O, 10:1 → 8:1); yield: 974 mg (94% over 2 steps); col-
orless oil; de ≥ 96% (1H NMR); [a]D22 –185.8 (c = 1.21, CHCl3); Rf
0.36 (n-pentane–Et2O, 6:1).
IR (film): 3032 (m), 2955 (s), 2928 (s), 2866 (m), 1671 (w), 1598
(m), 1495 (m), 1457 (m), 1347 (s), 1163 (s), 1092 (m), 1028 (m),
917 (m), 815 (m), 747 (m), 700 (m), 670 (s), 605 (m), 552 (m), 506
(w) cm–1.
1H NMR (300 MHz, CDCl3): d = 0.76 (t, J = 7.1 Hz, 3 H, CH2CH3),
0.94–1.43 (m, 6 H, CH2CH2CH2CH3), 2.38 (m, 1 H, NCHCH), 2.42
(s, 3 H, CqCH3), 3.36 (t, J = 7.7 Hz, 1 H, NCHH), 3.89 (t, J = 7.7
Hz, 1 H, NCHH), 4.43 (d, J = 7.2 Hz, 1 H, NCH), 7.24–7.41 (m, 7
H, CHarom.), 7.67 (d, J = 8.2 Hz, 2 H, CHaromCSO2).
(2R,3R)-3-Methylazetidine-2-carboxylic Acid [(R,R)-10a]
According to GP4 the phenylazetidine (R,R)-9a (302 mg, 1.0 mmol)
was converted into amino acid (R,R)-10a; yield: 67 mg (58% over
2 steps); colorless solid; de ≥ 96% (13C NMR); [a]D23 +5.0 (c = 0.24,
H2O).
All other analytical data corresponded to those of (S,S)-10a.
13C NMR (75 MHz, CDCl3): d = 13.8 (CH2CH3), 21.6 (CqCH3),
22.4, 28.6, 32.7 (CH2CH2CH2CH3), 39.9 (NCHCH), 53.3 (NCH2),
71.8 (NCH), 126.4, 127.9, 128.4, 128.4, 129.5 (ArCH), 132.4
(ArCqSO2), 140.2 (ArCqCH), 143.9 (ArCqCH3).
MS (EI, 70 eV): m/z (%) = 343 (3) [M+], 260 (12), 195 (9), 188 (57),
155 (45), 117 (24), 104 (29), 91 (100), 77 (11), 65 (20), 55 (11).
(2S,3S)-3-Ethylazetidine-2-carboxylic Acid [(S,S)-10b]29
According to GP4 the phenylazetidine (S,S)-9b (281 mg, 0.89
mmol) was converted into amino acid (S,S)-10b; yield: 59 mg (51%
over 2 steps); colorless solid; de ≥ 96% (13C NMR); mp 187 °C
(dec.); [a]D22 –1.8 (c = 0.23, H2O).
IR (KBr): 2963 (m), 2874 (m), 1624 (s), 1463 (m), 1406 (m), 1300
(m), 1270 (m), 755 (m), 476 (m) cm–1.
1H NMR (300 MHz, D2O): d = 0.78 (t, J = 7.4 Hz, 3 H, CH3), 1.59
(m, 2 H, CH2CH3), 2.41 (m, 1 H, NCHCH), 3.60 (dd, J = 7.9, 10.4
Hz, 1 H, NCHH), 3.87 (dd, J = 8.9, 10.4 Hz, 1 H, NCHH), 4.26 (d,
J = 7.7 Hz, 1 H, NCH).
Anal. Calcd for C20H25NO2S (343.48): C, 69.93; H, 7.34; N, 4.08.
Found: C, 69.91; H, 7.64; N, 4.17.
Synthesis of Azetidine Carboxylic Acids; General Procedure
(GP4)
The tosylazetidines 9 and 12 (1 equiv) were dissolved in a mixture
consisting of CCl4 (2 mL/mmol), MeCN (2 mL/mmol) and water (3
mL/mmol). H5IO6 (15 equiv) and RuCl3·hydrate (0.05 equiv) were
added to the vigorously stirred mixture and the reaction vessel was
left open to the atmosphere. Whenever the orange color of the solu-
tion turned to black, additional small portions of H5IO6 were added
until complete conversion of the starting material was detected by
TLC (24–72 h). The reaction mixture was diluted with Et2O and
stirred for an additional 30 min. Water was added and the mixture
was extracted with Et2O (3 ×), dried over MgSO4, filtered and con-
centrated in vacuo. The resulting crude tosylazetidine carboxylic
acids were dried under high vacuum and detosylated without further
purification.
13C NMR (75 MHz, D2O): d = 9.8 (CH3), 25.9 (CH2CH3), 39.0
(NCHCH), 47.8 (NCH2), 64.3 (NCH), 173.7 (COOH).
MS (EI, 70 eV): m/z (%) = 129 (12) [M+], 114 (6), 101 (16), 100
(15), 84 (100), 82 (7), 74 (17), 70 (6), 69 (6), 68 (7), 56 (23), 55 (22).
HRMS (EI): m/z [M+] calcd for C6H11NO2: 129.0790; found:
129.0790.
(2S,3S)-3-Isopropylazetidine-2-carboxylic Acid [(S,S)-10c]
According to GP4 the phenylazetidine (S,S)-9c (503 mg, 1.5 mmol)
was converted into amino acid (S,S)-10c; yield: 141 mg (65% over
2 steps); colorless solid; de ≥ 96% (13C NMR); mp 187 °C (de-
comp.); [a]D22 –9.4 (c = 0.29, H2O) {Lit.10 mp 188–191 °C; [a]D
–9.5 (c = 0.11, H2O)}.
Sodium metal (6 equiv) and naphthalene (6 equiv) were dissolved
in DME (20 mL/mmol azetidine) and stirred at 0 °C for 1 h and af-
terwards at r.t. for 1.5 h. A solution of the azetidine dissolved in a
small amount of DME was then slowly added at –78 °C and the
mixture was stirred for 30 min at this temperature. The reaction was
stopped by addition of aq 2 M HCl solution. The aqueous phase was
separated and the organic phase was extracted with 2 M HCl (3 ×).
The combined aqueous phases were concentrated to a small volume
at temperatures below 45 °C under high vacuum. The acidic solu-
tion of the amino acids was then submitted to ion exchange chroma-
tography with Dowex 50X2-200 resin. The amino acids were
isolated as colorless solids, which turned slightly yellow on storing
at r.t.
IR (KBr): 2959 (m), 2874 (m), 1630 (s), 1469 (m), 1392 (s), 1310
(m), 1242 (m), 759 (m), 706 (w), 668 (w), 639 (w), 610 (w) cm–1.
1H NMR (300 MHz, D2O): d = 0.73 (d, J = 6.7 Hz, 3 H, CH3), 0.81
(d, J = 6.7 Hz, 3 H, CH3), 1.77 [m, 1 H, CH(CH3)2], 2.41 (m, 1 H,
NCHCH), 3.64 (dd, J = 7.9, 10.6 Hz, 1 H, NCHH), 3.85 (dd, J = 8.9,
10.6 Hz, 1 H, NCHH), 4.31 (d, J = 7.4 Hz, 1 H, NCH).
13C NMR (75 MHz, D2O): d = 17.8, 18.3 [C(CH3)2], 31.2
[CH(CH3)2], 44.1 (NCHCH), 46.7 (NCH2), 63.5 (NCH), 173.7
(COOH).
MS (EI, 70 eV): m/z (%) = 143 (9) [M+], 128 (6), 115 (7), 113 (4),
106 (4), 100 (19), 98 (100), 87 (6), 82 (11), 74 (7), 69 (15), 55 (30).
HRMS (EI): m/z [M+] calcd for C7H13NO2: 143.0946; found:
143.0946.
Synthesis 2005, No. 20, 3508–3516 © Thieme Stuttgart · New York

PAPER
Asymmetric Synthesis of Substituted Azetidine Amino Acids
3515
(2S,3S)-3-Butylazetidine-2-carboxylic Acid [(S,S)-10d]
Acknowledgment
According to GP4 the phenylazetidine (S,S)-9d (384 mg, 1.1 mmol)
was converted into amino acid (S,S)-10d; yield: 112 mg (54% over
2 steps); colorless solid; de ≥ 96% (13C NMR); mp 178–181 °C (de-
comp.); [a]D22 +14.0 (c = 0.16, H2O).
This work was supported by the Deutsche Forschungsgemeinschaft
(Graduiertenkolleg 440, Sonderforschungsbereich 380) and the
Fonds der Chemischen Industrie. We would like to thank Degussa
AG, BASF AG, Bayer AG and Wacker Chemie for the donation of
chemicals.
IR (KBr): 2957 (m), 2929 (m), 2854 (m), 1625 (s), 1462 (m), 1402
(m), 1303 (m), 1272 (w), 1127 (w), 1019 (w), 874 (w), 725 (w), 470
(m) cm–1.
1H NMR (300 MHz, D2O): d = 0.68 (t, J = 6.6 Hz, 3 H, CH3), 1.10
(m, 4 H, CH2CH2CH2CH3), 1.52 (m, 2 H, CH2CH2CH2CH3), 2.64
(m, 1 H, NCHCH), 3.52 (dd, J = 8.2, 10.4 Hz, 1 H, NCHH), 3.79
(dd, J = 8.8, 10.4 Hz, 1 H, NCHH), 4.20 (d, J = 7.7 Hz, 1 H, NCH).
13C NMR (75 MHz, D2O): d = 12.5 (CH3), 21.0, 27.1, 31.9
(CH2CH2CH2CH3), 36.9 (NCHCH), 47.5 (NCH2), 64.0 (NCH),
173.1 (COOH).
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(2R,3S)-2-Hexylazetidine-3-carboxylic Acid [(R,S)-13]
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IR (KBr): 2960 (s), 2927 (s), 2856 (s), 1633 (m), 1567 (s), 1523 (m),
1465 (m), 1389 (s), 1282 (m), 1124 (m), 1031 (w), 839 (m), 775 (w),
720 (m), 664 (m), 525 (m), 496 (m) cm–1.
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1.20 (m, 8 H, CH2CH2CH2CH2CH3), 1.74 (m, 2 H, NCHCH2), 3.14
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NCHH), 3.92 (dd, J = 9.1, 10.4 Hz, 1 H, NCHH), 4.30 (dt, J = 7.7,
8.8 Hz, 1 H, NCH).
13C NMR (75 MHz, D2O): d = 12.8 (CH3), 21.3, 23.2, 27.2, 30.2,
32.2 (CH2CH2CH2CH2CH2CH3), 43.2 (NCHCH), 45.0 (NCH2),
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100 (99), 82 (52), 73 (20), 70 (17), 68 (15), 56 (52), 55 (51).
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185.1415.
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7.56 (d, J = 8.7 Hz, 2 H, CHarom.), 8.19 (d, J = 8.7 Hz, 2 H, CHarom.).
The analytical data corresponded to those reported previously.28
Synthesis 2005, No. 20, 3508–3516 © Thieme Stuttgart · New York

3516
D. Enders, J. Gries
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Synthesis 2005, No. 20, 3508–3516 © Thieme Stuttgart · New York