Enantiodivergent synthesis of N-protected azetidine-2-carboxylic acid

Article abstract of DOI:10.1016/j.tetasy.2012.08.016

A new route to both enantiomers of N-tosyl-azetidine-2- carboxylic acid has been developed from (R)-2-cyclohexylideneglyceraldehyde which proceeded with good overall yield and excellent enantiomeric purity.

Full text of DOI:10.1016/j.tetasy.2012.08.016

Tetrahedron: Asymmetry 23 (2012) 1416–1422
Contents lists available at SciVerse ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Enantiodivergent synthesis of N-protected azetidine-2-carboxylic acid
⇑
Tanmoy Biswas, Jyoti Prasad Mukherjee, Shital K. Chattopadhyay
Department of Chemistry, University of Kalyani, Kalyani 741235, West Bengal, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 17 August 2012
Accepted 31 August 2012
A new route to both enantiomers of N-tosyl-azetidine-2- carboxylic acid has been developed from (R)-2-
cyclohexylideneglyceraldehyde which proceeded with good overall yield and excellent enantiomeric
purity.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
such as the thrombin inhibitors melagratran 5 and exenta 6,8a,b
the analgesic compound 7,8c as an ACE inhibitor,9 cell cytotoxic
Azetidine-2-carboxylic acid (aze) 1 (Fig. 1), a naturally occur-
ring1 but non-proteinogenic amino acid, has found extensive appli-
cation as; (i) a proline mimic,2 (ii) part-structure of naturally
occurring compounds3 such as mugineic acid4 and its congeners
2–4; (iii) building block in amino acid and b-lactam synthesis;5
(iv) roles in the design and synthesis of modified peptides,6 and
(v) incorporation into pharmaceutically important7 compounds
agent and radiosensitizer.10 Both enantiomers of this important
amino acid have also found application in the area of asymmetric
synthesis as chiral catalysts and/or auxiliaries in transformations
such as Diels–Alder reactions,11 Michael additions,12 cyclopropa-
nations,13
a
-aminations of ketones14 and ketone reductions15
among others. Various substituted azetidine-2-carboxylic acid
derivatives have also proven to be important in many respects.16
CO2H
CO2H
NH
CO2H
CO2H
X
N
N
H
R
1, L-azetidine-2-carboxylic acid
(L-Aze)
2, R =X= OH, mugineic acid
3
4
, R = H, X = OH 2'-deoxymugineic acid
, R = H, X = NH2
HN
Cl
N
O
(R)
N
O
O
N
HN
O
NH
R2
H2N
7
, ABT-594
OR1
5, R1 = R2= H, melagatran
1
2
6
, R = Et, R = OH, exenta
Figure 1. Selected biologically active compounds accommodating derivatives of azetidine-2-carboxylic acid 1.
⇑
Corresponding author. Fax: +91 33 25828282.
E-mail address: skchatto@yahoo.com (S.K. Chattopadhyay).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.08.016

T. Biswas et al. / Tetrahedron: Asymmetry 23 (2012) 1416–1422
1417
Thus, several elegant routes to this important amino acid either in
the racemic form17 or as the (S)-enantiomer16i,18 have been devel-
oped. However, to the best of our knowledge only one synthesis of
both enantiomers of azetidine-2-carboxylic acid has been re-
ported19 excluding several known resolution procedures. We be-
came interested in the development of a common route to both
ozonolysis and in situ reduction of the resulting aldehyde to deli-
ver the desired primary alcohol 13 in an overall yield of 73% over
three steps. Simultaneous reductive removal of the Cbz and benzyl
groups from 13 then smoothly produced amine 14. N-heterocycli-
sation of this c-amino alcohol using a tosyl chloride–KOH combi-
nation24 led to the formation of the azetidine derivative 15
possibly through an intermediate N,O-ditosylate (not isolated).
Acid mediated deprotection of the cyclohexylidene acetal moiety
in compound 15 cleanly produced diol 16 which was transformed
into a carboxyl function under Sharpless’ protocol25 using NaIO4
and a catalytic amount of RuCl3. N-Tosylazetidine-2-carboxylic
acid 17, thus produced, was esterified with methyl iodide in the
presence of caesium carbonate to obtain the corresponding methyl
enantiomers of this
a common set of reactions in continuation of our interest20 in the
synthesis of natural and non-natural -amino acids of significance.
a-amino acid from a common source and using
a
Herein, we report a new synthetic route to both enantiomers of N-
tosyl-azetidine -2-carboxylic acid.
2. Results and discussion
ester 18. The latter showed a specific rotation {[a]D = +141.9 (c 0.4,
CHCl3)} which is close in magnitude but opposite in sign to that re-
The allylation of a-chiral imines has been extensively studied as
ported26 for (S)-N-(4-methylphenyl)sulfonyl-2-azetidinecarboxylic
a route for the synthesis of homoallylic amines.21 We have recently
reported a diastereodivergent synthesis of homoallylic amines
from the allylation of an imine derived from (R)-2-cyclohexylid-
eneglyceraldehyde 8.22 We opted to study the allylation of chiral
imine 9 (Scheme 1), obtainable from 8, for the synthesis of the cor-
responding homoallylic amines 10 and 11, identified as potential
precursors of the title compounds.
acid methyl ester {[
a
]
D = ꢁ144.3 (c 1.4, CHCl3)}. The configuration
of the nitrogen-bearing stereogenic centre in each of the com-
pounds 10 and 12–18 thus followed from this specific rotation
comparison. The synthesis of compound 18 proceeded in a linear
sequence of seven steps from 11 in an overall yield of 24%.
Similarly, the anti-homoallylic amine 11 was transformed into
(S)-azetidine-2-carboxylic acid derivative 25 in an overall yield of
20.3% over seven steps through the intermediates 19–24 following
an identical sequence of reactions detailed above for the conver-
sion of 10–18. The enantiomeric purity of each of the enantiomeric
N-tosyl-azetidine-2-carboxylic acid derivatives was determined
from chiral HPLC studies on a CHIRALPAK AD-H column using
20% 2-propanol in hexane as eluent and the enenatiomeric excess
values were recorded to be 95% and 93% respectively for 17 and 24.
Thus, imine 9 was prepared by dehydrative condensation of
benzylamine with aldehyde 8 in the presence of powdered magne-
sium sulfate in near quantitative yield and was treated with allyl-
magnesium bromide under optimized conditions to give
a
separable mixture of the expected homoallylic amines 10 and 11
in a ratio of ꢀ5:1 in a combined yield of 81%. Similarly, when a
solution of the imine 9 was treated with allylzinc bromide (pre-
pared in situ from allyl bromide and zinc powder), the amines 10
and 11 were obtained in a comparable yield but with a reversal
of selectivity favouring the other isomer. Although the comple-
mentary mode of these addition reactions was an advantage, the
assignment of stereochemistry at the newly formed stereocentre
in each of these amines at this stage could not be made with cer-
tainty because of the fact that the nature of diastereoselection in
imine addition reactions is known to be dependent on several fac-
tors.23 However, the following synthetic work (Scheme 2) unam-
biguously established the configuration of the amines 10 and 11
to be syn- and anti-respectively.
3. Conclusion
In conclusion, we have demonstrated a concise synthesis of
both enantiomers of N-tosyl-azetidine-2-carboxylic acid starting
from a single source and using a common set of reactions. The syn-
thesis involves the use of easily available reagents and simple reac-
tion conditions. The approach involves the utilization of an initial
divergency in the allylation step of the chiral imine 9 for an ulti-
mate enantiodivergent synthesis of the title compounds, which
does not have much precedence. It may therefore complement
the existing methodologies and hence find application.
The amine 10 was protected as its Cbz derivative 12 in readi-
ness for a one-carbon degradation of the olefinic unit through
O
O
11
+
(14%)
MgBr
NHBn
BnNH2,
MgSO4
10, 67%
O
O
O
O
0oC to rt,
14 h
N
O
ZnBr
Bn
O
10
+
(11%)
O
8
9
NHBn
11, 74%
Scheme 1. Preparation of the homoallylic amines 10 and 11.

1418
T. Biswas et al. / Tetrahedron: Asymmetry 23 (2012) 1416–1422
O
O
O
O
O
O
i
OH
ii
iii
OH
10
NBn
NBn
Cbz
NH2
Cbz
14
13
12
OH
HO2C
TsN
MeO2C
TsN
iv
O
HO
vi
vii
v
O
TsN
TsN
17
18
16
15
O
O
O
O
O
O
i
OH
ii
iii
O
H
11
NBn
NBn
Cbz
NH2
21
Cbz
20
19
OH
HO2C
TsN
MeO2C
TsN
O
HO
vi
vii
v
iv
O
TsN
TsN
24
25
23
22
Scheme 2. Reagents and conditions: (i) Cbz-Cl, NaHCO3, rt, 6 h, 12 (91%), 19 (87%); (ii) O3, Me2S, and then NaBH4, 13 (81%), 20 (79%); (iii) H2, Pd(OH)2, MeOH, rt, 8 h, 14 (89%),
21 (94%); (iv) TsCl, KOH (powder), THF, reflux, 6 h, 15 (64%), 22 (61%); (v) HCl (6 M),THF, rt, 5 h, 16 (86%), 23 (85%); (vi) NaIO4, RuCl3, rt, 3 h, 17 (73%), 24 (68%); (vii) MeI,
Cs2CO3, DMF, rt, 12 h, 18 (91%), 25 (89%).
under argon from a purple solution of sodium benzophenone ketyl.
Unless stated otherwise, all reagents were purchased from com-
mercial sources and used without additional purification.
4. Experimental
4.1. General
4.1.1. (R)-N-Benzyl-1-((S)-1,4-dioxaspiro[4.5]decan-2-yl)but-3-
en-1-amine 10 and (S)-N-benzyl-1-((S)-1,4-dioxaspiro[4.5]decan-
2-yl)but-3-en-1-amine 11
Column chromatography was performed on silica gel, Merck
grade 230–400 mesh and neutral alumina. Reactions were moni-
tored by thin-layer chromatography; TLC plates were visualized
with UV, in an iodine chamber, or with vaniline solution, unless
noted otherwise. Melting points were recorded in open capillaries
and are uncorrected. Optical rotations were measured on a Ru-
dolph Autopol-IV polarimeter purchased from a DST grant. IR spec-
tra were recorded on a Perkin–Elmer Spectrum-1 instrument using
KBr disks, chloroform solution or as neat. 1H NMR and 13C NMR
spectra were recorded on a Bruker Avance 400 MHz spectrometer,
operating at 400 and 100 MHz, respectively. Chemical shifts (d) are
given from TMS (0 ppm) as internal standard for 1H NMR and
13CDCl3 (77.0 ppm) for 13C NMR. The following abbreviations were
used to denote the multiplicities: s = singlet, d = doublet, t = triplet,
q = quartet, m = multiplet, dd = double doublet, ddd = doublet of
double doublet, dt = doublet of triplet, br = broad, etc. HRMS were
performed in a JEOL-JNM mass spectrometer and obtained from a
paid source. THF, Toluene, benzene and ether were freshly distilled
A stirred solution of aldehyde 8 (0.50 g, 2.9 mmol) in dry THF
(10 mL) was cooled to 5 °C and anhydrous MgSO4 (1.5 g, excess)
followed by a solution of freshly distilled benzylamine (0.5 ml,
4.5 mmol) in THF (6 mL) were added over 10 min. The reaction
mixture was then allowed to warm to rt and stirred for 14 h. It
was filtered and the filtrate was then concentrated in vacuo to pro-
duce the crude imine derivative 9 as viscous yellowish liquid
which was used for next step without any purification. The crude
imine was then taken in dry THF (4.5 mL) and was cooled to
ꢁ30 °C before adding a solution of allylmagnesium bromide [1.0
(M) in diethyl ether, 4.6 mL] under nitrogen atmosphere. It was
stirred at 0 °C for 4 h and then at rt for 16 h. It was cooled back
to 0 °C and quenched by the slow addition of aqueous NH4Cl solu-
tion (5%, 10 mL). The reaction mixture was concentrated and then
diluted with water (25 mL) before extracting with EtOAc

T. Biswas et al. / Tetrahedron: Asymmetry 23 (2012) 1416–1422
1419
(2 ꢂ 25 mL). The combined organic layer was washed successively
with water (2 ꢂ 50 mL) and brine (50 mL), and then dried over
anhydrous Na2SO4, filtered and the filtrate was concentrated under
reduced pressure to leave a crude product which on flash column
chromatography using EtOAc in petroleum ether (1:19) provided
the diastereomeric amine derivatives, in the order 11 (0.125 g,
14%) followed by 10 (0.592 g, 67%) each as a pale yellow liquid.
CHCl3). 1H NMR (400 MHz, CDCl3): d 7.45–7.10 (m, 10H), 5.59–
5.55 (m, 1H), 5.25–5.10 (m, 2H), 5.01–4.87 (m, 2H), 4.64 (dd,
J = 16 and 29.6 Hz, 1H), 4.49 (d, J = 23.6 Hz, 1H), 4.29 (d,
J = 6.4 Hz, 1H), 4.13–3.87 (m, 2H), 3.61 (t, J = 8 Hz, 1H), 2.46–2.42
(m, 1H), 2.19–2.15 (m, 1H), 1.57–1.37 (m, 8H),1.25 (s, 2H). 13C
NMR (100 MHz, CDCl3): d 156.7 (157.2), 138.9 (138.7), 136.6,
134.4 (134.1), 128.5, 128.2 (128.3), 128.1, 127.7 (127.8), 127.4,
126.9 (127.0), 117.7, 109.5, 75.9 (76.0), 67.1 (67.4), 66.8 (67.0),
59.5, 48.4, 36.2, 34.9, 34.0 (34.4), 25.2, 24.0, 23.8. IR (neat) mmax
3065, 3032, 2935, 2861, 1698, 1450, 1413, 1250, 1229,
1100 cmꢁ1. MS (TOF MS ES+): m/z (%) = 458 (M++Na, 100). Anal.
Calcd for C27H33NO4: C, 74.45; H, 7.64; N, 3.22; Found: C, 74.58;
H, 7.71; N, 3.11.
Data for 10: Rf: 0.5 (petroleum ether/EtOAc 19/1), ½a D25
¼ ꢁ12:0
ꢃ
(c 2.4, CHCl3); 1H NMR (300 MHz, CDCl3): d 7.38–7.36 (m, 4H),
7.24–7.22 (m, 1H), 5.88–5.74 (m, 1H), 5.11 (d, J = 7.2 Hz, 1H),
5.06 (s, 1H), 4.10 (q, J = 6.7 Hz, 1H), 4.01–3.94 (m, 1H), 3.90 (s,
1H), 3.80 (d, J = 13.2 Hz, 1H), 3.71 (t, J = 7.4 Hz, 1H), 2.70 (q,
J = 6.3 Hz, 1H), 2.33–2.23 (m, 1H), 2.17–2.07 (m, 1H), 1.69–1.58
(m, 9H), 1.39 (br s, 2H). 13C NMR (100 MHz, CDCl3): d 140.6,
135.0, 128.4, 128.2, 126.9, 117.5, 109.5, 77.9, 66.4, 58.6, 51.5,
37.6, 35.1, 34.9, 25.2, 24.1, 24.0. IR (neat) mmax 3332, 2933, 2857,
1644, 1450, 1103, 926 cmꢁ1. MS (TOF MS ES+): m/z (%) = 302
(M++H, 100). Anal. Calcd for C19H27NO2: C, 75.71; H, 9.03; N,
4.65; Found: C, 75.97; H, 9.17; N, 4.52. Data for 11: Rf: 0.5 (petro-
4.1.4. Benzyl benzyl-((R)-3-hydroxy-1-((S)-1,4-
dioxaspiro[4.5]decan-2-yl)propyl) carbamate 13
Ozone was bubbled through a pre-cooled (ꢁ78 °C) solution of
12 (600 mg, 1.38 mmol) in a solvent mixture of CH2Cl2: methanol
(4:1, 25 mL) containing a pinch of NaHCO3 until the pale blue col-
our persisted. The excess ozone was flushed off with oxygen and
dimethyl sulfide (0.75 mL) was added. The reaction mixture was
warmed to 0 °C and stirred at the same temperature for 6 h. The
reaction mixture was filtered through Celite and the filter cake
was washed thoroughly with EtOAc (30 mL). Evaporation of the
solvent under reduced pressure yielded the crude aldehyde
(596 mg) which was taken in dry methanol (6 mL) and cooled to
0 °C. Sodium borohydride (79 mg, 2.07 mmol) was added in one
portion and stirring was continued for 7 h at rt. The reaction mix-
ture was quenched by the dropwise addition of saturated NH4Cl
solution (4 mL) at 0 °C and then it was concentrated, diluted with
water (25 mL) and extracted with EtOAc (2 ꢂ 25 mL). The com-
bined organic layer was washed sequentially with water
(2 ꢂ 25 mL) and brine (25 mL). The organic layer was dried over
anhydrous Na2SO4, filtered and the filtrate was concentrated under
reduced pressure to leave a crude product and column chromato-
graphic purification on silica gel using EtOAc in petroleum ether
(2:3) yielded compound 13 as a colourless liquid (491 mg, 81%).
leum ether/EtOAc 24/1). [a]
D = +18.0 (c 2.7, CHCl3); 1H NMR
(400 MHz, CDCl3): d 7.29–7.26 (m, 4H), 7.24–7.21 (m, 1H), 5.88–
5.77 (m, 1H), 5.13 (d, J = 6.8 Hz, 1H), 5.09 (s, 1H), 4.05–3.99 (m,
2H), 3.91–3.84 (m, 2H), 3.76 (d, J = 13.2 Hz, 1H), 2.80 (q,
J = 5.6 Hz, 1H), 2.32 (t, J = 6.4 Hz, 2H), 1.62–1.56 (m, 8H), 1.49 (br
s, 1H), 1.39 (br s, 2H). 13C NMR (100 MHz, CDCl3): d 140.6, 134.9,
128.4, 128.1, 126.9, 117.9, 109.3, 77.3, 66.5, 58.2, 51.8, 36.3, 35.2,
34.9, 25.2, 24.0, 23.8. IR (neat) mmax 3330, 2935, 2861, 1639,
1449, 1103, 928 cmꢁ1. MS (TOF MS ES+): m/z (%) = 302 (M++H,
100). Anal. Calcd for C19H27NO2: C, 75.71; H, 9.03; N, 4.65; Found:
C, 75.86; H, 9.26; N, 4.74.
4.1.2. (S)-N-Benzyl-1-((S)-1,4-dioxaspiro[4.5]decan-2-yl)but-3-
en-1-amine 11 and (R)-N-benzyl-1-((S)-1,4-dioxaspiro[4.5]decan-
2-yl)but-3-en-1-amine 10
The crude imine derivative 9 (2.16 g, 8.34 mmol) was taken in
dry THF (9 mL) and was added dropwise to a stirred solution of
allylzinc bromide [excess, prepared in situ from allyl bromide
(2.34 mL) and Zn dust (1.89 g) in dry THF (22 mL)] under a nitrogen
atmosphere at 0 °C and stirred for 16 hours at room temperature. It
was again cooled to 0 °C and quenched with aqueous NH4Cl solu-
tion (5%, 20 mL). The reaction mixture was concentrated, diluted
with water (25 mL) and then extracted with EtOAc (2 ꢂ 25 mL).
The combined organic layer was washed successively with water
(2 ꢂ 50 mL) and brine (50 mL), and then dried over anhydrous
Na2SO4. It was filtered and the filtrate was concentrated under re-
duced pressure to leave a crude product which on column chroma-
tography on flash silica gel using EtOAc in petroleum ether (1:19)
as eluent provided the diastereomeric amine derivatives, in the or-
der 11 (1.97 g, 74%) followed by the minor isomer 10 (0.29 g, 11%).
Compounds 10 and 11 displayed nearly identical spectroscopic
data as recorded before.
Rf: 0.4 (petroleum ether/EtOAc: 7/3), ½a D25
¼ þ20:0 (c 1.00, CHCl3).
ꢃ
1H NMR (400 MHz, CDCl3): d 7.36–7.25 (m, 10H), 5.25–5.14 (m,
2H), 4.57 (dd, J = 18.2, 15.6 Hz, 2H), 4.28 (t, J = 6.8 Hz, 1H), 4.19
(d, J = 6.4 Hz, 1H), 4.01 (t, J = 6.8 Hz, 1H), 3.67 (t, J = 7.2 Hz, 1H),
3.43 (s, 1H), 3.35–3.20 (m, 1H), 2.57 (br s, 1H), 1.75 (s, 2H), 1.59–
1.45 (m, 8H), 1.38 (s, 2H). 13C NMR (100 MHz, CDCl3): d 157.6,
138.6, 136.3, 128.5, 128.1, 128.0, 127.9, 127.7, 127.3, 110.0, 75.5,
67.6, 67.2, 58.3, 56.8, 36.3, 35.0, 32.0, 25.1, 23.9, 23.8. IR (neat) mmax
3454, 2936, 2862, 1692, 1450, 1417, 1331, 1221, 1109 cmꢁ1. MS
(TOF MS ES+): m/z (%) = 462 (M++Na, 100). Anal. Calcd for
C26H33NO5: C, 71.05; H, 7.57; N, 3.19; Found: C, 71.24; H, 7.81;
N, 3.05.
4.1.5. (R)-3-Amino-3-((S)-1,4-dioxaspiro[4.5]decan-2-yl)propan-
1-ol 14
4.1.3. Benzyl-(R)-1-((S)-1,4-dioxaspiro[4.5]decan-2-yl)but-3-
enyl(benzyl)carbamate 12
Palladium hydroxide on carbon (Pearlman’s catalyst, 25 mg)
was added to a solution of compound 13 (0.48 g, 1.09 mmol) in
EtOAc (10 mL) at rt and the heterogeneous mixture was stirred un-
der hydrogen atmosphere for 8 h. It was then filtered through Cel-
ite and the filter cake was thoroughly washed with EtOAc (30 mL).
The combined filtrate was concentrated in vacuo to leave a crude
mass which was purified by chromatography over neutral alumina
using 80% EtOAc in petroleum ether as eluent to furnish the prod-
uct 14 as a colourless liquid (0.21 g, 89%). Rf: 0.4 (petroleum ether/
At first, NaHCO3 (0.75 g), water (0.15 mL) and benzyl chlorofor-
mate (0.41 mL, 1.99 mmol) were sequentially added to a stirred
solution of the compound 10 (0.50 g, 1.66 mmol) in EtOAc
(12 mL) and the resulting mixture was stirred at rt for 6 h. It was
then diluted with water (25 mL) and further extracted with EtOAc
(2 ꢂ 25 mL). The combined organic layer was washed with water
(2 ꢂ 50 mL) followed by brine (50 mL). The organic extract was
then dried over anhydrous Na2SO4, filtered and the filtrate was
concentrated in vacuo to leave a crude product which on column
chromatography on silica gel using EtOAc in petroleum ether
(1:49) provided the product 12 as a colourless liquid (0.66 g,
EtOAc/methanol: 5/4/1), ½a D25
ꢃ
¼ ꢁ6:95 (c 0.75, CHCl3); 1H NMR
(400 MHz, CDCl3): d 4.03 (t, J = 7.5 Hz, 1H), 3.93 (q, J = 6.4 Hz,
1H), 3.84 (t, J = 5.2 Hz, 2H), 3.64 (t, J = 7.2 Hz, 1H), 2.93–2.88 (m,
1H), 2.82 (br s, 3H), 1.59–1.49 (m, 10H), 1.48–1.25 (m, 2H). 13C
NMR (100 MHz, CDCl3): d 109.9, 79.7, 66.3, 62.3, 55.2, 36.3, 34.7,
91%). Rf: 0.5 (petroleum ether/EtOAc: 97/3), ½a D25
¼ þ4:3 (c 1.00,
ꢃ

1420
T. Biswas et al. / Tetrahedron: Asymmetry 23 (2012) 1416–1422
34.5, 25.1, 24.0, 23.8. IR (neat) mmax 3371, 2936, 2862, 1696, 1367,
1164 cmꢁ1. HRMS (TOF MS ES+): obsd 216.1594 (M+H); calcd
216.1599.
solid (0.96 g, 73%). Rf: 0.4 (petroleum ether/EtOAc 3/7), Mp: 135–
137 °C, ½a 2D5
ꢃ
¼ þ148:3 (c 0.59, CHCl3), lit.26b
[
a
]
D = ꢁ154.7 (c 1,
CHCl3), for (S)-enantiomer; 1H NMR (400 MHz, CDCl3): d 7.70 (d,
J = 8.0 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 7.12 (br s, 1H), 4.46 (t,
J = 8.0 Hz, 1H), 3.66 (t, J = 8.0 Hz, 2H), 2.40 (s, 3H), 2.46–2.36 (m,
1H), 2.28–2.23 (m, 1H). 13C NMR (100 MHz, CDCl3): d 172.7,
145.1, 131.2, 130.1, 128.4, 60.6, 47.7, 21.7, 19.8. IR (KBr) mmax
3413, 2923, 1722, 1707, 1348, 1161, 1094 cmꢁ1. HRMS (TOF MS
ES+): obsd 278.0465 (M++Na); calcd 278.0463.
4.1.6. (R)-2-((S)-1,4-Dioxaspiro[4.5]decan-2-yl)-1-tosylazetidine
15
p-Toluenesulfonyl chloride (1.30 g, 6.84 mmol) and anhydrous
KOH dust (0.37 g, 6.84 mmol) were added sequentially into a solu-
tion of the amino alcohol 14 (0.49 g, 2.28 mmol) in dry THF (25 mL)
under a nitrogen atmosphere. The resulting mixture was heated at
reflux for 6 h, and then allowed to come to rt. It was diluted with
water (25 mL) before being extracted with EtOAc (2 ꢂ 25 mL).
The combined organic layer was washed sequentially with HCl
(1 N, 50 mL), aqueous NaHCO3 solution (10%, 50 mL), water
(2 ꢂ 50 mL) and brine (50 mL). It was then dried over anhydrous
Na2SO4, filtered and the filtrate was concentrated under reduced
pressure to leave a crude product which was purified by column
chromatography on silica gel using EtOAc in petroleum (1:9) as
eluent to provide the compound 15 as a colourless gummy liquid.
4.1.9. (R)-Methyl 1-tosylazetidine-2-carboxylate 18
Methyl iodide (0.06 mL, 0.94 mmol) was added dropwise to a
stirred solution of 17 (0.06 g, 0.23 mmol) in dry DMF (3 mL) at
0 °C under a nitrogen atmosphere and then anhydrous Cs2CO3
(0.15 g, 0.47 mmol) was added to the reaction mixture in one por-
tion. Stirring was continued for 12 h at rt and then diluted with
water (25 mL) and extracted with EtOAc (2 ꢂ 25 mL). The com-
bined organic layer was washed successively with water
(2 ꢂ 25 mL) and brine (25 mL). The organic extract was then dried
over anhydrous Na2SO4, filtered and the filtrate was concentrated
in vacuo to leave a crude product which was purified by column
chromatography on silica gel using EtOAc in petroleum ether
(1:9) solvent to provide compound 18 as a colourless solid
(0.058 g, 91%). Rf: 0.6 (petroleum ether/EtOAc: 4/1), Mp: 99–
(0.51 g, 64%). Rf: 0.5 (petroleum ether/EtOAc: 9/1), ½a D25
¼ þ91:5 (c
ꢃ
0.79, CH3OH). 1H NMR (300 MHz, CDCl3): d 7.74 (d, J = 7.5 Hz, 2H),
7.37 (d, J = 7.5 Hz, 2H), 4.39 (s, 1H), 4.25–4.20 (m, 1H), 4.10 (t,
J = 7.3 Hz, 2H), 3.72–3.68 (m, 1H), 3.56 (q, J = 8.2 Hz, 1H), 2.46 (s,
3H), 2.19–2.13 (m, 1H), 1.93–1.86 (m, 1H), 1.57 (s, 8H), 1.39 (br
s, 2H). 13C NMR (100 MHz, CDCl3): d 144.1, 131.7, 129.7, 128.4,
110.1, 75.3, 64.3, 62.9, 48.0, 36.2, 34.2, 25.1, 24.0, 23.7, 21.6,
100 °C,
½
a 2D5
ꢃ
¼ þ141:9 (c 0.37, CHCl3), lit.26a
[
a
]
D = ꢁ144.3 (c
1.435, CHCl3), for the (S)-enantiomer; 1H NMR (400 MHz, CDCl3):
d 7.77 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 4.60 (t, J = 8.6 Hz,
1H), 3.87 (q, J = 8.4 Hz, 1H), 3.76- 3.73 (m, 1H), 3.72 (s, 3H), 2.45
(s, 3H), 2.41–2.34 (m, 1H), 2.32–2.04 (m, 1H). 13C NMR
(100 MHz, CDCl3): d 169.9, 143.7, 132.8, 129.2, 127.8, 60.1, 52.0,
47.3, 21.1, 19.0. IR (KBr) mmax 2925, 2854, 1739, 1348, 1159,
17.0. IR (neat) mmax 2932, 2860, 1339, 1156, 1098, 1037 cmꢁ1
.
HRMS (TOF MS ES+): obsd 374.1403 (M++Na); calcd 374.1402.
4.1.7. (S)-1-((R)-1-Tosylazetidin-2-yl) ethane-1,2-diol 16
At first, HCl (6 M, 6 mL) was added dropwise to a solution of 15
(0.45 g, 1.28 mmol) in THF (6 mL), and the resulting reaction mix-
ture was stirred at rt for 5 h. It was then diluted with water (25 mL)
and extracted with EtOAc (2 ꢂ 25 mL). The combined organic layer
was washed successively with aqueous NaHCO3 solution (10%,
50 mL), water (2 ꢂ 50 mL) and brine (50 mL). The EtOAc extract
was then dried over anhydrous Na2SO4, filtered and the filtrate
was concentrated in vacuo to leave a crude product which on col-
umn chromatography over silica gel using EtOAc in petroleum
ether (2:3) as eluent provided compound 16 as a colourless gum-
my solid (0.30 g, 86%). Rf: 0.5 (petroleum ether/EtOAc: 4/6),
1091 cmꢁ1
.
4.1.10. Benzyl (S)-1-((S)-1,4-dioxaspiro[4.5]decan-2-yl)but-3-
enyl (benzyl) carbamate 19
Compound 19 was prepared from 11 by following the proce-
dure described for 12. Yield: 87%. Rf: 0.5 (petroleum ether/EtOAc
49/1). ½a 2D5
ꢃ
¼ þ22:95 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3): d
7.37–7.19 (m, 10H), 5.73–5.59 (m, 1H), 5.23–5.14 (m, 2H), 5.04–
4.94 (m, 2H), 4.56 (d, J = 16 Hz, 1H), 4.35 (d, J = 16 Hz, 1H), 4.14
(br s, 1H), 3.98 (br s, 1H), 3.71 (br t, 1H), 3.55–3.45 (m, 1H), 2.52
-2.42 (m, 2H), 1.56–1.53 (m, 8H), 1.44–1.35 (m, 2H).13C NMR
(100 MHz, CDCl3): d 156.8, 138.7, 136.5, 135.0, 128.4, 128.1,
127.9, 127.6, 127.4, 127.2, 117.3 (117.2), 110.2, 76.8, 67.6, 67.3
(67.2), 59.5, 48.4, 36.4 (36.3), 34.8, 33.1, 25.1, 24.0, 23.7. IR (neat)
mmax 3032, 2935, 2860, 1699, 1450, 1421, 1225, 1100, 1040,
926 cmꢁ1. MS (TOF MS ES+): m/z (%) = 458 (M++Na, 100), 474
(M++K, 10). Anal. Calcd for C27H33NO4: C, 74.45; H, 7.64; N, 3.22;
Found: C, 74.57; H, 7.77; N, 3.37.
½
a 2D5
ꢃ
¼ þ102:5 (c 0.86, CH3OH); 1H NMR (300 MHz, CDCl3): d 7.74
(d, J = 7.5 Hz, 2H), 7.41 (d, J = 7.5 Hz, 2H), 4.01 (q, J = 7.5 Hz, 1H),
3.88 (s, 2H), 3.73 (d, J = 9.3 Hz, 2H), 3.54 (q, J = 8.4 Hz, 2H), 2.48
(s, 3H), 2.33 (s, 1H), 2.09–1.98 (m, 1H), 1.93 (d, J = 7.8 Hz, 1H).
13C NMR (100 MHz, CDCl3): d 144.7, 130.4, 130.0, 128.6, 74.6,
65.8, 61.9, 48.1, 21.6, 18.3. IR (neat) mmax 3412, 2925, 2888, 1598,
1355, 1160, 1092 cmꢁ1. HRMS (TOF MS ES+): obsd 294.0775
(M++Na); calcd 294.0776.
4.1.8. (R)-1-Tosylazetidine-2-carboxylic acid 17
4.1.11. Benzyl benzyl((S)-3-hydroxy-1-((S)-1,4-dioxaspiro[4.5]-
decan-2-yl) propyl) carbamate 20
Sodium metaperiodate (0.44 g, 2.07 mmol) was added to a solu-
tion of diol 16 (0.14 g, 0.52 mmol) in a mixture of CCl4 (2.6 mL),
CH3CN (2.6 mL) and water (4 mL). The reaction mixture was vigor-
ously stirred at rt for 5 min and then ruthenium trichloride (4 mg,
2.5 mol %) was added to it. Stirring was continued for 3 h. It was
then diluted with CH2Cl2 (15 mL) and extracted with aqueous NaH-
CO3 solution (1 M, 20 mL). This aqueous layer was washed with
ether and carefully acidified with saturated aqueous KHSO4 solu-
tion. The acidified solution was then extracted with EtOAc
(2 ꢂ 25 mL) and the combined organic layer was washed sequen-
tially with water (2 ꢂ 25 mL) and brine (25 mL). The organic layer
was then dried over anhydrous Na2SO4, filtered and the filtrate was
concentrated under reduced pressure to leave a crude product
which on column chromatography on silica gel using EtOAc in
petroleum ether (3:2) yielded the carboxylic acid 17 as a colourless
Compound 20 was prepared from 19 by following the proce-
dure described for 13. Yield: 79%. Rf: 0.5 (petroleum ether/EtOAc:
7/3), ½a 2D5
ꢃ
¼ þ2:9 (c 0.80, CHCl3). 1H NMR (400 MHz, CDCl3): d
7.22–7.28 (m, 10H), 5.21–5.16 (m, 2H), 4.59 (d, J = 15.6 Hz, 1H),
4.42 (d, J = 15.6 Hz, 1H), 4.24 (br s, 1H), 3.77 (t, J = 7.2 Hz, 1H),
3.59–3.51 (m, 2H), 3.45–3.38 (m, 1H), 2.10–1.92 (m, 1H), 1.82–
1.71 (m, 1H), 1.57 (br s, 6H), 1.45–1.43 (m, 4H), 1.36 (br s, 2H).
13C NMR (100 MHz, CDCl3): d 157.6, 138.4, 136.1, 128.5, 128.4,
128.2, 128.1, 127.6, 127.3, 110.5, 67.9, 67.2, 58.8, 56.1, 42.0, 36.1,
34.6, 30.9, 27.0, 25.1, 24.0, 23.7. IR (neat) mmax 3482, 2936, 1698,
1450, 1416, 1163, 1102, 1039, 929, 771, 699 cmꢁ1. MS (TOF MS
ES+): m/z (%) = 462 (M++Na, 100), 478 (M++K,10). Anal. Calcd for
C26H33NO5: C, 71.05; H, 7.57; N, 3.19; Found: C, 71.22; H, 7.69;
N, 3.02.

T. Biswas et al. / Tetrahedron: Asymmetry 23 (2012) 1416–1422
1421
4.1.12. (S)-3-Amino-3-((S)-1,4-dioxaspiro[4.5]decan-2-yl)pro-
pan-1-ol 21
1347, 1161, 1092, 680 cmꢁ1. MS (TOF MS ES+): m/z (%) = 292
(M++Na, 100), 270 (M++H, 40).
Compound 21 was prepared from 20 by following the proce-
dure described for 14. Yield: 94%. Rf: 0.5 (petroleum ether/EtOAc/
Acknowledgements
methanol: 5/4/1), ½a D25
ꢃ
¼ þ6:4 (c 0.78, CHCl3); 1H NMR (400 MHz,
CDCl3): d 4.02 (t, J = 7.6 Hz, 1H), 3.97 (q, J = 6.4 Hz, 1H), 3.84 (dd,
J = 4.4 and 6.4 Hz, 2H), 3.75 (dd, J = 6.0 and 7.6 Hz, 1H) 3.02–3.07
(m, 1H), 2.26 (br s, 3H), 1.71 (qd, J = 4.0 and 14.4 Hz, 1H), 1.62–
1.52 (m, 8H), 1.53–1.43 (m, 1H), 1.42–1.36 (m, 2H). 13C NMR
(100 MHz, CDCl3): d 109.8, 79.2, 65.0, 62.4, 54.0, 36.1, 34.5, 34.3,
25.1, 24.0, 23.7. IR (neat) mmax 3788, 3351, 2934, 2860, 1600,
We are thankful to DST, New Delhi, for funds (Grant No. SR/S1/
OC-51/2005), and CSIR, New Delhi, for fellowships.
References
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1449, 1366, 1163, 1103, 929 cmꢁ1
(%) = 216 (M++H, 100), 238 (M++Na, 10).
. MS (TOF MS ES+): m/z
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4.1.13. (S)-2-((S)-1,4-Dioxaspiro[4.5]decan-2-yl)-1-tosylazeti-
dine 22
Compound 22 was prepared from 21 by following the proce-
dure described for 15. Yield: 61%. Rf: 0.6 (petroleum ether/EtOAc:
9/1), ½a 2D5
ꢃ
¼ ꢁ77:0 (c 0.82, CHCl3); 1H NMR (400 MHz, CDCl3): d
7.73 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.4 Hz, 2H), 4.33 (q, J = 6.4 Hz,
1H), 4.07 (dd, J = 6.0 and 8.4 Hz, 1H), 3.88 (q, J = 7.6 Hz, 1H), 3.80
(dd, J = 6.0 and 8.8 Hz, 1H), 3.75 (dt, J = 4.4 and 8.0 Hz, 1H), 3.61
(q, J = 8.0 Hz, 1H), 2.46 (s, 3H), 2.27–2.20 (m, 1H), 1.99–1.95 (m,
1H), 1.57–1.52 (m, 8H), 1.43–1.36 (m, 2H). 13C NMR (100 MHz,
CDCl3): d 144.1, 132.1, 129.8, 128.3, 110.0, 77.2, 66.4, 63.9, 48.1,
36.2, 34.7, 25.1, 24.0, 23.7, 21.6, 18.2. IR (neat) mmax 2934, 2859,
1335, 1163, 1100, 1039, 927, 815, 676 cmꢁ1. MS (TOF MS ES+):
m/z (%) = 374 (M++Na, 100). Anal. Calcd for C18H25NO4S: C, 61.51;
H, 7.17; N, 3.99; Found: C, 61.66; H, 7.33; N, 3.82.
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Zwanenburg, B. Tetrahedron 1998, 54, 4991.
4.1.14. (S)-1-((S)-1-Tosylazetidin-2-yl)ethane-1,2-diol 23
Compound 23 was prepared from 22 by following the proce-
dure described for 16. Yield: 85%. Rf: 0.5 (petroleum ether/EtOAc:
12. Yamaguchi, M.; Shiraishi, T.; Hirama, M. J. Org. Chem. 1996, 61, 3520.
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2250; (f) Burtoloso, A. C. B.; Correia, C. R. D. Tetrahedron 2008, 64, 9928; (g)
Enders, D.; Gries, J. Synthesis 2005, 3508; (h) Sajjadi, Z.; Lubell, W. D. J. Pept. Res.
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P.; Moya, J. F.; Unthank, M. G.; McGarrigle, E. M.; Aggarwal, V. K. Synthesis 2012,
44, 1584; (d) Wasserman, H. H.; Lipshutz, B. H.; Tremper, A. W.; Wu, J. S. J. Org.
Chem. 1981, 46, 2991; (e) De Nicola, A.; Einhorn, C.; Einhorn, J.; Luche, J. L.
Chem. Commun. 1994, 879; (f) Yamada, Y.; Emori, T.; Kinoshita, S.; Okada, H.
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Zwanenburg, B. Tetrahedron: Asymmetry 1998, 9, 429; (i) Wu, W. L.; Caplen, M.
A.; Domalski, M. S.; Zhang, H.; Fawzi, A.; Burnett, D. A. Bioorg. Med. Chem. Lett.
2002, 12, 3157; (j) De Nicola, A.; Einhorm, C.; Einhorn, J.; Luche, J. L. J. Chem.
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(Sumimoto Chemical Company), EP 974 670, 2000; Chem. Abstr. 2000, 132, 107
041.
18. (a) Miyoshi, M.; Sugano, H.; Fujii, T.; Ishihara, T.; Yoneda, N. Chem. Lett. 1973, 5;
(b) Kondo, T.; Ueyama, N. PCT US Appl. US 0 171 849 A1, 2003.; (c) Baldwin, J.
E.; North, M.; Flinn, A. Tetrahedron 1988, 44, 637; (d) Ciapetti, P.; Mann, A.;
Shoenfelder, A.; Taddei, M. Tetrahedron Lett. 1998, 39, 3843; (e) Bouazaoui, M.;
Martinez, J.; Cavelier, F. Eur. J. Org. Chem. 2009, 2729; (f) Nagashima, N.
(KanekaCorporation), WO 2001055104, 2003; Chem. Abstr. 2001, 135, 137391;
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WO 9 847 867, 1998; Chem. Abstr. 1998, 129, 316132; (i) Wasserman, H. H.;
Lipshutz, B. H.; Temper, A. W.; Wu, J. S. J. Org. Chem. 1981, 46, 2991.
19. Couty, F.; Evano, G.; Vargas-Sanchez, M.; Bouzas, G. J. Org. Chem. 2005, 70,
9028.
20. (a) Kundu, I.; Maitra, R.; Jana, M.; Chattopadhyay, S. K. Synthesis 2012, 304; (b)
Chattopadhyay, S. K.; Roy, S. P.; Saha, T. Synthesis 2011, 2664; (c) Sarkar, K.;
Singha, S.; Chattopadhyay, S. K. Tetrahedron: Asymmetry 2009, 20, 1719; (d)
Bandyopadhyay, A.; Pahari, A.; Chattopadhyay, S. K. Tetrahedron Lett. 2009, 50,
6036; (e) Bandyopadhyay, A.; Pal, B. K.; Chattopadhyay, S. K. Tetrahedron:
Asymmetry 1875, 2008, 19; (f) Chattopadhyay, S. K.; Sarkar, K.; Thander, L.; Roy,
1/1), ½a 2D5
ꢃ
¼ ꢁ45:6 (c 0.60, CHCl3); 1H NMR (400 MHz, CDCl3): d
7.73 (d, J = 8.0 Hz, 2H), 7.40 (d, J = 8.4 Hz, 2H), 4.05 (dt, J = 4.0 and
8.0 Hz, 1H), 3.94–3.88 (m, 1H), 3.78–3.68 (m, 3H), 3.54 (q,
J = 8.4 Hz, 1H), 2.80 (d, J = 5.2 Hz, 1H), 2.48 (s, 3H), 2.32–2.25 (m,
1H), 2.14–2.11 (m, 1H), 1.92–1.83 (m, 1H). 13C NMR (100 MHz,
CDCl3): d 144.5, 131.1, 130.0, 128.5, 72.4, 65.2, 62.6, 48.3, 21.6,
17.2. IR (neat) mmax 3509, 3408, 2970, 2919, 2878, 1598, 1332,
1154, 1098 cmꢁ1. MS (TOF MS ES+): m/z (%) = 294 (M++Na, 100),
272 (M++H, 10). Anal. Calcd for C12H17NO4S: C, 53.12; H, 6.32; N,
5.16; Found: C, 53.19; H, 6.40; N, 5.03.
4.1.15. (S)-1-Tosylazetidine-2-carboxylic acid 24
Compound 24 was prepared from 23 by following the proce-
dure described for 17. Yield: 68%. Rf: 0.4 (petroleum ether/EtOAc
3/7), Mp: 133–136 °C,
½
a 2D5
ꢃ
¼ ꢁ149:2 (c 0.62, CHCl3), lit.26b
[
a]
D = ꢁ154.7° (c 1, CHCl3); 1H NMR (400 MHz, CDCl3): d 7.77 (d,
J = 8.0 Hz, 2H), 7.42 (d, J = 7.6 Hz, 2H), 4.50 (t, J = 8.4 Hz, 1H),
3.76–3.66 (m, 2H), 2.48 (s, 3H), 2.53–2.43 (m, 1H), 2.33–2.25 (m,
1H). 13C NMR (100 MHz, CDCl3): d 172.4, 145.1, 130.9, 130.1,
128.5, 60.7, 47.7, 21.7, 19.8. IR (neat) mmax 2923, 2853, 1705,
1435, 1340, 1163, 1094, 7734, 683 cmꢁ1. MS (TOF MS ES+): m/z
(%) = 278 (M++Na, 100), 256 (M++H, 15).
4.1.16. (S)-methyl 1-tosylazetidine-2-carboxylate 25
Compound 25 was prepared from 24 by following the proce-
dure described for 18. Yield: 89%. Rf: 0.6 (petroleum ether/EtOAc:
4/1), Mp: 97–99 °C,
½
a 2D5
ꢃ
¼ ꢁ146:5 (c 0.51, CHCl3), lit.26a
[
a]
D = ꢁ144.3° (c 1.435 in CHCl3); 1H NMR (400 MHz, CDCl3): d
7.77 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 4.60 (t, J = 8.8 Hz,
1H), 3.87 (q, J = 8.4 Hz, 1H), 3.76–3.73 (m, 1H), 3.72 (s, 3H), 2.45
(s, 3H), 2.42–2.35 (m, 1H), 2.32–2.26 (m, 1H). 13C NMR
(100 MHz, CDCl3): d 170.4, 144.2, 133.3, 129.7, 128.2, 60.6, 52.4,
47.8, 21.6, 19.5. IR (neat) mmax 3437, 2924, 2853, 1742, 1438,

1422
T. Biswas et al. / Tetrahedron: Asymmetry 23 (2012) 1416–1422
S. P. Tetrahedron Lett 2007, 48, 6113; (g) Chattopadhyay, S. K.; Sarkar, K.;
Karmakar, S. Synlett 2005, 2083.
21. For reviews, see: (a) Yamamoto, Y.; Asano, N. Chem. Rev. 1993, 93, 2207; (b)
Enders, D.; Reinhold, U. Tetrahedron: Asymmetry 1895, 1997, 8; (c) Thomas, E. J.
Chem. Commun. 1997, 411; (d) Block, R. Chem. Rev. 1998, 98, 1407; (e)
Kobayashi, S.; Ishitani, H. Chem. Rev. 1999, 1069, 99.
24. (a) Thander, L.; Sarkar, K.; Chattopadhyay, S. K. Tetrahedron: Asymmetry 2009,
20, 1213; (b) Ghorai, M. K.; Das, K.; Kumar, A. Tetrahedron Lett. 2007, 48, 2471;
(c) Cernerud, M.; Adolfsson, H.; Moberg, C. Tetrahedron: Asymmetry 1997, 8,
2655.
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