4-Formylazetidin-2-ones, synthon for the synthesis of (2R,3S) and (2S,3R)-3-amino-2-hydroxydecanoic acid (AHDA)

Article abstract of DOI:10.1016/j.tet.2006.01.082

An efficient synthesis of 3-amino-2-hydroxydecanoic acid (AHDA), a nonproteinogenic amino acid, using enantiopure 3-benzyloxy-4-formylazetidin-2-one as a building block is described. Both the enantiomers of AHDA have been synthesized from the corresponding enantiomer of 3-benzyloxy-4-formylazetidin-2-one in good yield and optical purity.

Full text of DOI:10.1016/j.tet.2006.01.082

Tetrahedron 62 (2006) 4615–4621
4-Formylazetidin-2-ones, synthon for the synthesis of (2R,3S)
and (2S,3R)-3-amino-2-hydroxydecanoic acid (AHDA)
*
Nilesh M. Shirode and Abdul Rakeeb A. S. Deshmukh
Division of Organic Chemistry (Synthesis), National Chemical Laboratory, Pune 411 008, India
Received 24 October 2005; revised 3 January 2006; accepted 19 January 2006
Abstract—An efficient synthesis of 3-amino-2-hydroxydecanoic acid (AHDA), a nonproteinogenic amino acid, using enantiopure
3-benzyloxy-4-formylazetidin-2-one as a building block is described. Both the enantiomers of AHDA have been synthesized from the
corresponding enantiomer of 3-benzyloxy-4-formylazetidin-2-one in good yield and optical purity.
q 2006 Published by Elsevier Ltd.
1. Introduction
from the 4-formyl-b-lactam synthon. (2S,3R)-3-Amino-2-
hydroxydecanoic acid (1b) is an unusual novel amino acid,
which has been suggested as the N-terminal component of
the recently isolated angiotensin-converting enzyme inhibi-
tor microginin (2)11 (Figs. 1 and 2).
Apart from the antibacterial agents,1–3 azetidin-2-ones are
increasingly used as synthons for the synthesis of variety of
pharmaceutically useful products.4 This is mainly because
of the strain energy associated with the four membered
azetidinone ring, that is responsible for selective bond
cleavage, giving a variety of transformation products.
Moreover, there are many methods available to prepare
them in reasonable quantities required for synthetic purpose.
One such synthon, 4-formylazetidin-2-one, has wide
applications as a building block5,6 for the synthesis of
monobactams, isocephams, carbapenems and several other
non-b-lactam compounds like a-hydroxy aspartate and
hydroxybutanoic acids. As a part of our research program
on asymmetric synthesis of b-lactams, we have developed
an efficient method for the synthesis of enantiomerically
pure 4-formylazetidin-2-ones7a and used them as building
blocks for the synthesis of 4-aminopiperidin-2-ones,8
important intermediates for the synthesis of biologically
useful compounds.
NH2
O
OH
OH
Figure 1. (2S,3R)-3-Amino-2-hydroxydecanoic acid (1b).
Microginin is a small linear peptide isolated from the blue-
green alga Microcystis aeruginosa and its structure was
established on the basis of degradation studies, spectral data
and total synthesis.11,12 It was shown that a linear
a-hydroxy-b-aminodecanoic acid is at the N-terminal of
the peptide chain. Subsequently it was also found that
AHDA is common to other linear peptides isolated from the
same species.11b,c There are several approaches12,13 for the
synthesis of AHDA. In most cases, asymmetric functiona-
lization of alkenes13c–e via either asymmetric epoxidation or
asymmetric dihydroxylation is the common strategy. There
are few reports using ‘chiral pool’ strategies13f,g wherein a
chiral starting material is used for the synthesis. The Lewis
acid catalyzed addition of ketene acetals to chiral imines13b
is another approach for the synthesis of a-hydroxy-b-amino
acids.
2. Results and discussion
In continuation of our efforts towards the synthesis of
substituted b-lactams via the Staudinger reaction9 and their
utility as synthons7c,8,10 for the synthesis of various
biologically important compounds, we were interested in
the synthesis of 3-amino-2-hydroxydecanoic acid (AHDA)
Although b-amino acids are easily accessible by hydrolysis
of the corresponding azetidin-2-ones,4b,14 surprisingly there
is no report on the synthesis of AHDA starting from an
azetidin-2-one synthon. Therefore, we planned our
Keywords: Stereoselective synthesis; Azetidin-2-ones; Amino acids; Wittig
reaction; Staudinger reaction.
*
Corresponding author. Fax: C91 20 25893153/25893355;
e-mail: aras.deshmukh@ncl.res.in
0040–4020/$ - see front matter q 2006 Published by Elsevier Ltd.
doi:10.1016/j.tet.2006.01.082

4616
N. M. Shirode, A. R. A. S. Deshmukh / Tetrahedron 62 (2006) 4615–4621
OH
Me
O
NH2
O
H
H
N
CO2H
N
N
N
H
Me
O
O
OH
OH
Figure 2. Microginin (2).
O
H H
BnO
H H
N
H H
N
H H
BnO
BnO
BnO
H
N
O
N
O
O
PMP
O
PMP
PMP
OH
H
3
4
5
6
H H
HO
CO2H
N
NH2
O
H
AHDA (1)
7
Scheme 1.
synthesis from suitably substituted 4-formylazetidin-2-one.
Our synthesis is based on the application of well-defined
stereochemistry at both the stereocentres of cis-3-benzy-
loxy-4-formylazetidin-2-one ring, which is required for the
synthesis of natural AHDA. The synthesis involves Wittig
olefination of cis-3-benzyloxy-4-formylazetidin-2-one,
followed by hydrogenation and careful hydrolysis of the
azetidinone ring to get the desired AHDA (Scheme 1). The
Scheme is simple and it can be applied for the synthesis of
both the enantiomers of AHDA, since both the enantiomers
of starting cis-4-formylazetidin-2-one can be prepared in
reasonable yields and good optical purities. Also by
following the synthetic protocol, one can easily prepare
other analogues of AHDA.
(3b) was also synthesized (Scheme 3) from L-glyceralde-
hyde acetonide, which was easily prepared from
L-ascorbic acid in three steps.16
Having both the enantiomers in hand, we initially started our
work with (3R,4R)-3-benzyloxy-4-formylazetidin-2-one (3a)
since it can be easily prepared in large quantities from
L-diethyl tartrate.7a The aldehyde 3a, on Wittig olefination
reaction with the Wittig reagent derived from triphenyl-
phosphine and n-1-bromohexane, gaveolefin 4ain goodyield.
The olefin 4a on catalytic hydrogenation with Pd/C (10%)
gave 4-heptanyl-b-lactam 5a, in very good yield (90%).
A small amountof debenzylatedcompound18a (6%)was also
obtained along with 5a, which was separated by flash column
chromatography. The oxidative removal of the p-methoxy-
phenyl (PMP) group from 5a was achieved by cerric
ammonium nitrate (CAN)17 to get (3R,4S)-3-benzyloxy-4-
heptanyl-azetidin-2-one (6a) in 85% yield. The benzyl group
was removed bytransfer hydrogenation18 using Pd/C (10%) to
afford 3-hydroxy-b-lactam 7a in quantitative yield. Hydroly-
sisof7awasachievedbyheatingwith3 MHClat60 8Cfor6 h
andtheproductwaspurifiedbyion-exchangechromatography
(Dowex 50 W!2-400) using 5% NH4OH as the eluent to
afford pure (2R,3S)-AHDA (1a) in 70% yield (Scheme 4).
Enantiomerically pure (3R,4R)-3-benzyloxy-4-formylaze-
tidin-2-one (3a) was prepared from L-diethyl tartrate using
a synthetic method developed by our group.7a C2-
Symmetry of natural tartaric acid has been exploited to
achieve the synthesis of 2 mol of cis-4-formylazetidin-2-
ones from 1 mol of diethyl tartrate acetonide (Scheme 2).
Alternatively enantiopure 3a can also be prepared from
D-mannitol diacetonide in four steps.15 The other
enantiomer (3S,4S)-3-benzyloxy-4-formylazetidin-2-one
BnO
H
O
PMP
H H
BnO
CHO
PMP
H
O
N
N
CO2Et
CO2Et
N
N
O
O
O
O
PMP
PMP
(a)
(b)
(c)
N
O
H
O
PMP
H
BnO
3a
8
9
O
10
Reagents and conditions: (a) DIBAL-H, PMP-NH2, toluene, -78°C to rt, 15 h (b) BnOCH2COCl, Et3N, CH2Cl2,
–23°C to rt, 14 h (c) i) 2.5 M HClO4, THF, rt, 4-8 h; ii) NaIO4, acetone-H2O, rt, 4-12 h
Scheme 2.

N. M. Shirode, A. R. A. S. Deshmukh / Tetrahedron 62 (2006) 4615–4621
4617
O
OH
OH
OH
O
O
H
O
OH
O
O
O
a)
c)
b)
H
O
O
O
d)
O
OH
OH
HO
HO
HO
OH
11
13
14
12
OH
H
O
O
O
H H
H H
H H
H
O
H
BnO
BnO
OH
BnO
O
g)
f)
e)
H
N
N
N
N
O
O
O
PMP
PMP
PMP
PMP
15
16
17
3b
PMP = 4-Methoxyphenyl; Bn = Benzyl
Reagents and conditions: a) H2, Pd/C (10%), 50 Psi, 50 ˚C, H2O, 95% b) 2-Methoxypropene, DMF, PTSA, 24 h,
rt, 70% c) NaIO4, H2O, 0 ˚C to rt, 2h d) PMP-NH2, CH2Cl2, 2 h, rt e) BnOCH2COCl, Et3N, CH2Cl2, 0 ˚C to rt, 12h,
50% f) PTSA, THF/H2O, reflux, 18h, 98% g) NaIO4, Acetone/H2O, 85%.
Scheme 3.
O
H H
H H
N
H H
N
H H
BnO
HO
BnO
BnO
a)
b)
H
+
N
N
O
O
O
O
PMP
PMP
PMP
OH
PMP
3a
4a
5a
18a
Major
Minor
H H
H H
BnO
HO
O
c)
d)
e)
CO2H
5a
N
NH2
N
O
H
H
6a
7a
(2R,3S)-AHDA (1a)
Reagents and conditions: a) CH3(CH2)5PPh3+ Br-, n-BuLi, 0 ˚C, 6h, dry THF, 75% b) H2, Pd/C (10%), 50 psi, 6h, EtOAc, 90%
c) CAN, CH3CN/H2O, 0 ˚C, 25 min, 85% d) HCOONH4, Pd/C (10%), MeOH, reflux, 6h, 95% e) 3M HCl, 60 ˚C, 6h, Ion-exchange
resin, Dowex 50W x 2-400, 5% NH4OH, 70%.
Scheme 4.
The other enantiomer, (2S,3R)-AHDA (1b) was also
synthesized (Scheme 5) from (3S,4S)-3-benzyloxy-4-formyl-
azetidin-2-one (3b) by following a similar synthetic protocol
as shown in Scheme 4. The spectral data and the specific
rotations are comparable with that of the reported in the
literature.12ab,13a
(AHDA), from corresponding enantiomer of 4-formyl-3-
benzyloxyazetidin-2-one. (2S,3R)-AHDA is a nonproteino-
genic amino acid, an important constituent of natural
product microginin (2).
4. Experimental
4.1. General
3. Conclusion
In conclusion, we have accomplished the synthesis of both
the enantiomers of 3-amino-2-hydroxydecanoic acid
1H and 13C NMR spectra were recorded in CDCl3 solutions
on Bru¨ker AC 200, AV 400 spectrometers, and chemical
shifts are reported in ppm downfield from tetramethylsilane
OH
CO2H
O
H H
1
for H NMR. Infrared spectra were recorded on Perkin-
BnO
H
Elmer Infrared Spectrophotometer, Model 599-B or
Shimadzu FTIR-8400 using sodium chloride optics. Melting
points were determined on a Thermonik Campbell melting
point apparatus and are uncorrected. The microanalyses
were performed on a Carlo-Erba, CHNS-O EA 1108
N
NH2
O
PMP
(2S,3R)-1b
3b
Scheme 5.

4618
N. M. Shirode, A. R. A. S. Deshmukh / Tetrahedron 62 (2006) 4615–4621
elemental analyzer. Optical rotations were recorded on ADP
220 polarimeter BellinghamCStanley Ltd. under standard
conditions. Mass spectra were recorded on API QSTAR
PULSAR using electron spray ionization (ESI) method.
The compound 18a (0.035 g, 6%) was obtained as a white
crystallinesolid;mp105–107 8C;[FoundC, 70.20;H, 8.70; N,
4.93. C17H25NO3 requires C, 70.06, H, 8.66; N, 4.81%]; Rf
(40% EtOAc/pet ether) 0.27; [a]3D0 C107.50 (c 0.4, CHCl3);
nmax (CHCl3) 1724, 3365 cmK1; dH (400 MHz, CDCl3) 0.89
(t, JZ6.8 Hz, 3H, (CH2)6CH3), 1.28–1.50 (m, 10H, CH2
(CH2)5CH3), 1.80–2.00 (m, 2H, CH2(CH2)5CH3), 2.88 (br s,
1H, OH), 3.81 (s, 3H, Ar-OCH3), 4.14–4.20 (m, 1H, C4H),
5.05 (d, JZ5.2 Hz, 1H, C3H), 6.85 (d, JZ9.0 Hz, 2H, Ar),
7.32 (d, JZ9.0 Hz, 2H, Ar); dC (50.32 MHz) 13.9, 22.5, 25.7,
27.1, 29.1, 29.6, 31.7, 55.4, 59.1, 75.1, 114.4, 119.0, 130.5,
156.5, 167.2; MS (m/z): 292 (MCC1).
4.1.1. (3R,4S)-3-Benzyloxy-4-hept-1-enyl-1-(4-methoxy-
phenyl)-azetidin-2-one (4a). To a solution of a n-hexyl-
triphenylphosphonium bromide (1.538 g, 3.6 mmol) in
anhydrous THF at 0 8C was added n-butyl lithium
(2.20 mL, 3.3 mmol, 1.5 M, colour change from yellow to
orange red was observed). Reaction mixture was stirred at
this temperature for 45 min. A solution of azetidin-2-one 3a
(0.934 g, 3 mmol) in anhydrous THF (20 mL) was added
drop-wise at 0 8C to the reaction mixture and then allowed
to warm up to room temperature. After 6 h, the reaction
mixture was quenched with saturated solution of NH4Cl
(5 mL). The solvent was removed under reduced pressure
and the residue was dissolved in EtOAc (20 mL), washed
with water (10 mL) and then with saturated brine solution
(5 mL) to afford the crude 4a, which was then purified by
flash column on silica gel (EtOAc/pet ether 1:9 as eluent), to
get E/Z isomeric mixture of 4a (0.853 g, 75%) as a viscous
oil. The geometrical isomers were difficult to separate by
flash column chromatography and used as such for further
reaction. [Found C, 75.65; H, 7.52; N, 3.80. C24H29NO3
requires C, 75.95; H, 7.72; N, 3.69%]; nmax (CHCl3)
1747 cmK1; dH (200 MHz, CDCl3) 0.94 (m, 3H),
CH3(CH2)6), 1.28–1.51 (m, 6 H, ]CH–CH2 (CH2)3–
CH3), 2.08–2.40 (m, 2H, CH]CH–CH2), 3.79 (s, 3H, Ar-
OCH3), 4.54–4.95 (m, 4H, C3H, C4H, OCH2Ph), 5.56–5.68
(m, 1H, CH]CH–CH2–(CH2)3–CH3), 5.83–6.06 (m, 1H,
CH]CH–CH2–(CH2)3–CH3), 6.85 (d, JZ9.1 Hz, 2H, Ar),
7.28–7.43 (m, 7H, Ar); dC (75.48 MHz) 14.0, 22.5, 27.9,
28.5, 29.1, 31.2, 31.6, 32.4, 55.4, 55.5, 60.9, 72.6, 72.7,
82.2, 82.4, 114.4, 118.6, 118.7, 124.0, 124.3, 128.0, 128.4,
131.1, 137.0, 137.5, 138.8, 156.4, 163.5; MS (m/z): 380
(MCC1).
4.1.3. (3R,4S)-3-Benzyloxy-4-heptylazetidin-2-one (6a).
A solution of 5a (0.572 g, 1.5 mmol) in acetonitrile (15 mL)
was cooled to 0 8C and treated with a solution of CAN
(2.469 g, 4.51 mmol) in water (20 mL) over 3 min. The
reaction mixture was stirred at K5 to 0 8C for 25 min and
diluted with water (110 mL). The mixture was extracted
with EtOAc (3!25 mL). The organic extracts were washed
with 5% NaHCO3 (2!25 mL) and the aqueous extracts
back washed with EtOAc (10 mL). The combined organic
layer was washed with 10% sodium sulfite (until the
aqueous layer remained colourless), 5% NaHCO3 (10 mL)
and brine (10 mL). The organic layer was then dried over
anhydrous Na2SO4, evaporated under reduced pressure to
yield the crude product 6a, which was then purified by flash
column chromatography on silica gel (EtOAc/pet ether 3:7
as eluent) to get pure 6a (0.351 g, 85%) as a white solid; mp
53–55 8C; [Found C, 74.13; H, 8.93; N, 4.95. C17H25NO2
requires C, 74.13; H, 9.17; N, 5.08%]; Rf (40% EtOAc/pet
ether) 0.18; [a]D30 C40.57 (c 0.30, CHCl3); nmax (CHCl3)
1757 cmK1; dH (200 MHz, CDCl3) 0.89 (t, JZ6.4 Hz, 3H,
CH3(CH2)6), 1.05–1.45 (m, 10 H, CH2(CH2)5CH3), 1.50–
1.75 (m, 2H, CH2(CH2)5CH3), 3.67–3.77 (m, 1H, C4H),
4.66–4.72 (m, 2H, C3H, CHaHbPh,), 4.87 (d, JZ11.9 Hz,
1H, CHaHbPh), 6.21 (br s, 1H, N–H), 7.25–7.45 (m, 5H,
Ar); dC (50.32 MHz) 13.8, 22.3, 25.7, 28.9, 29.2, 29.4, 29.7,
31.5, 55.0, 72.5, 82.2, 127.4, 127.6, 128.1, 137.1, 169.4; MS
(m/z): 276 (MCC1).
4.1.2. (3R,4S)-3-Benzyloxy-4-heptyl-1-(4-methoxy-
phenyl)azetidine-2-one (5a) and (3R,4S)-4-heptyl-3-
hydroxy-1-(4-methoxyphenyl)-azetidine-2-one (18a).
Compound 4a (0.760 g, 2 mmol) was dissolved in EtOAc
(20 mL) and Pd/C (10%) (70 mg) was added. The mixture
was hydrogenated at 50 psi of H2 in a Parr hydrogenator for
6 h at room temperature. The catalyst was removed by
filtration through Celite and washed with EtOAc. The
solvent was distilled off under reduced pressure and the
crude product was purified by flash column chromatography
on silica gel (EtOAc/pet ether 15:85 as eluent) to afford
compound 5a; (0.688 g, 90%) as viscous oil. [Found C,
75.47; H, 8.35; N, 3.61. C24H31NO3 requires C, 75.57; H,
8.21; N, 3.67%]; Rf (40% EtOAc/pet ether) 0.56; [a]D30
C112.38 (c 1.05, CHCl3); nmax (CHCl3) 1742 cmK1; dH
(200 MHz, CDCl3) 0.89 (t, JZ6.5 Hz, 3H, (CH2)6CH3),
1.2–1.5 (m, 10H, CH2(CH2)5CH3), 1.83–1.94 (m, 2H,
CH2(CH2)5CH3), 3.80 (m, 3H, Ar-OCH3), 4.11–4.19 (m,
1H, C4H), 4.74–4.80 (m, 2H, C3H, CHaHbPh), 4.98 (d, JZ
11.9 Hz, 1H, CHaHbPh), 6.89 (d, JZ9.1 Hz, 2H, Ar), 7.28–
7.43 (m, 7H, Ar); dC (50.32 MHz) 13.7, 22.2, 25.3, 27.0,
28.7, 29.3, 31.3, 54.9, 57.5, 72.7, 80.7, 114.1, 118.3, 127.3,
127.4, 128.0, 130.5, 137.1, 156.0, 164.4; MS (m/z): 382
(MCC1).
4.1.4. (3R,4S)-4-Heptyl-3-hydroxyazetidin-2-one (7a).
To a solution of 6a (0.275 g, 1 mmol) in methanol
(10 mL), 10% Pd/C (30 mg) was added followed by
ammonium formate (0.315 g, 5 mmol) and the reaction
mixture was heated at reflux under argon for 6 h. After
completion of the reaction (TLC), the reaction mixture was
allowed to cool to room temperature and filtered through
Celite. The solvent was distilled off under reduced pressure
and the residue was dissolved in CH2Cl2 (20 mL), washed
with water (5 mL), brine (5 mL) and dried over anhydrous
Na2SO4. Evaporation of the solvent under reduced pressure
gave crude product, which was then purified by flash
column chromatography on silica gel (EtOAc/pet ether 6:4
as eluent) to get pure 7a (0.176 g, 95%) as a white solid, mp
112–113 8C; [Found C, 64.91; H, 10.40; N, 7.77.
C10H19NO2 requires C, 64.81; H, 10.36; N, 7.56%]; Rf
(60% EtOAc/pet ether) 0.22; [a]3D0 C40 (c 0.25, CHCl3);
nmax (CHCl3) 1751 cmK1; dH (200 MHz, CDCl3) 0.88
(t, JZ6.3 Hz, 3H, CH3(CH2)6), 1.15–1.65 (m, 12H,
(CH2)6CH3), 3.65–3.85 (m, 1H, C4H), 4.55–4.85 (m, 1H,
C3H), 4.91 (br s, 1H, OH), 6.80 (br s, 1H, N–H); dC

N. M. Shirode, A. R. A. S. Deshmukh / Tetrahedron 62 (2006) 4615–4621
4619
(50.32 MHz) 14.1, 22.6, 25.9, 29.2, 29.5, 29.7, 31.7, 56.7,
76.5, 172.0; MS (m/z): 186 (MCC1).
16 (3.83 g, 10 mmol) and PTSA (0.570 g, 3 mmol) in THF
(40 mL) and water (15 mL) was refluxed for 24 h. After
completion of reaction (TLC), the reaction mixture was
neutralized with NaHCO3 and the solvent was removed under
reduced pressure. The residue was dissolved in EtOAc
(25 mL) and the organic layer was washed with saturated
brine solution (10 mL) and dried over anhydrous Na2SO4. The
solvent was removed under reduced pressure to afford diol 17,
which was then dissolved in acetone (50 mL) and water
(25 mL) and cooled to 0 8C. To the cooled diol solution,
NaIO4 (2.60 g, 12 mmol) was added in portions. After
completion of addition, the reaction mixture was stirred at
room temperature for 1 h. After completion of reaction
(TLC), the solid was filtered off and washed with acetone.
The solvent was removed and the residue was dissolved in
CH2Cl2 (30 mL), washed with water (2!10 mL), saturated
NaHCO3 (2!10 mL), brine solution (15 mL) and dried over
anhydrous Na2SO4. The solvent was evaporated under
reduced pressure to afford 3b (2.65 g, 85%) as a white
solid, mp 157–158 8C; [Found C, 69.33; H, 5.58; N, 4.63.
C18H17NO4 requires C, 69.43; H, 5.51; N, 4.50%]; Rf (30%
EtOAc/pet ether) 0.28; [a]3D0ZK176.19 (c 0.42, CHCl3);
nmax (CHCl3) 1753 cmK1; dH (200 MHz, CDCl3) 3.79 (s, 3H,
Ar-OCH3), 4.51 (dd, JZ5.3, 3.7 Hz, 1H, C4H), 4.71 (d,
JZ11.3 Hz, 1H, OCHaHbPh), 4.84 (d, JZ11.3 Hz, 1H,
OCHaHbPh), 5.05 (d, JZ5.3 Hz, 1H, C3H), 6.88
(d, JZ9.1 Hz, 2H, Ar), 7.26 (d, JZ9.1 Hz, 2H, Ar), 7.30–
7.50 (m, 5H, Ar), 9.72 (d, JZ3.7 Hz, 1H, CHO); dC
(50.32 MHz) 55.5, 63.2, 73.5, 82.6, 114.6, 118.1, 128.3,
128.5, 128.6, 130.5, 135.8, 156.9, 162.9, 198.9; MS (m/z):
312 (MCC1).
4.1.5. (2R,3S)-3-Amino-2-hydroxydecanoic acid (1a).
A solution of 7a (93 mg, 0.5 mmol) in 3 M HCl (5 mL) was
heated at 60 8C for 6 h. After completion of the reaction
(TLC), the solution was cooled to room temperature and
extracted with CH2Cl2 (3 mL). The aqueous layer was
evaporated to dryness under reduced pressure and the residue
was further subjected to ion exchange chromatography
(Dowex 50 W!2-400) using 5% NH4OH as the eluent to
afford 1a (71 mg, 70%) as a white solid, mp 220–223 8C
(dec), lit. mp 152–156 8C (dec);12a [Found C, 59.28; H, 10.53;
N, 7.10. C10H21NO3 requires C, 59.07; H, 10.43; N, 6.89%];
[a]3D0 K6.2 (c 0.40, 1 M HCl); dH (200 MHz, D2O) 0.84 (t,
JZ6.7 Hz, 3H, CH3(CH2)6), 1.19–1.45 (m, 10H, CH2(CH2)5-
CH3), 1.50–1.83 (m, 2H, CH2(CH2)5CH3), 3.38–3.50 (m, 1H,
C3H), 4.08 (d, JZ3.8 Hz, 1H, C2H); dC (50.32 MHz, DMSO-
d6) 14.0, 22.1, 24.7, 28.4, 28.7, 29.1, 31.2, 52.7, 69.3, 172.9;
MS (m/z): 204 (MC1).
4.1.6. (3S,4R)-3-Benzyloxy-4-(2,2-dimethyl-1,3-dioxolan-
4-yl)-1-(4-methoxyphenyl)azetidine-2-one (16). To a
stirred solution of 5,6-O-isopropylidene-L-gulono-1,4-lactone
13 (10.90 g, 50 mmol) in water (150 mL), NaIO4 (21.37 g,
100 mmol) was added portion-wise at 0 8C, over 30 min, at
pH 5.5 (adjusted by addition of 2 M NaOH). The suspension
was further stirred at room temperature for 2 h, and filtered
through filter paper to get a crude aqueous solution of L-(S)-
glyceraldehyde acetonide (14), which was then cooled to
10 8C under argon and vigorously stirred with a solution of
p-anisidine (5.72 g, 46.5 mmol) in CH2Cl2 (150 mL) for
30 min. The organic layer was separated and the aqueous
layer was further extracted with CH2Cl2 (2!50 mL). The
combined organic layers dried over anhydrous Na2SO4
under argon. The organic layers were collected and reduced
in volume to 30 mL. To this solution dry triethylamine
(6.22 g, 61.5 mmol) was added and the reaction mixture was
then cooled to 0 8C. A solution of benzyloxyacetyl chloride
(8.59 g, 46.5 mmol) in dry CH2Cl2 (100 mL) was added
drop-wise to the above reaction mixture. The reaction
mixture was further stirred for 12 h at room temperature and
then washed with water (3!15 mL), 1 N hydrochloric acid
(10 mL), saturated NaHCO3 (25 mL), water (25 mL) and
brine solution (20 mL). The organic phase dried over
anhydrous Na2SO4, filtered and evaporated under reduced
pressure. The crude product was purified by flash column
chromatography (EtOAc/pet ether 15:85 as eluent) to get a
pure product 16 (8.90 g, 50%) as a white solid, mp 117 8C;
[Found C, 68.98; H, 6.73; N, 3.61. C22H25NO5 requires C,
68.90; H, 6.58; N, 3.65%]; Rf (30% EtOAc/pet ether) 0.57;
4.1.8. (3R,4S)-3-Benzyloxy-4-hept-1-enyl-1-(4-methoxy-
phenyl)azetidin-2-one (4b). Following the similar pro-
cedure described for 4a, an inseparable mixture of E and Z
isomers of 4b was obtained from 3b as a viscous oil.
4.1.9. (3S,4R)-3-Benzyloxy-4-heptyl-1-(4-methoxy-
phenyl)azetidine-2-one (5b) and (3S,4R)-4-heptyl-3-
hydroxy-1-(4-methoxyphenyl)azetidine-2-one (18b).
Following the similar procedure described for 5a and 18a,
compound 5b and 18b were prepared from 4b.
Compound 5b was obtained as viscous oil, [Found C, 75.57;
H, 8.35; N, 3.61. C24H31NO3 requires C, 75.57; H, 8.21; N,
3.67%]; [a]3D0 K113.42 (c 0.80, CHCl3); MS (m/z): 382
(MCC1); spectral data same as for 5a.
Compound 18b was obtained as white crystals, mp 106–
107 8C; [Found C, 70.33; H, 8.79; N, 4.95. C17H25NO3
requires C, 70.06, H, 8.66; N, 4.81%]; [a]3D0 K110.30
(c 0.52, CHCl3); MS (m/z): 292 (MCC1); spectral data
same as for 18a.
[a]3D0ZK113.4 (c 0.70, CHCl3); nmax (CHCl3) 1735 cmK1
;
dH (200 MHz, CDCl3) 1.35 (s, 3H, CH3), 1.54 (s, 3H, CH3),
3.73–3.89 (m, 1H, OCHCH2), 3.75 (s, 3H, Ar-OCH3), 4.10–
4.50 (m, 3H, C4H, OCH2CHO), 4.70–4.80 (m, 2H, C3H,
OCHaHbPh), 5.00 (d, JZ11.8 Hz, 1H, OCHaHbPh), 6.85 (d,
JZ9.2 Hz, 2H, Ar), 7.30–7.45 (m, 5H, Ar), 7.70 (d, JZ
9.2 Hz, 2H, Ar); dC (50.32 MHz) 24.8, 26.5, 55.3, 61.6,
66.9, 73.1, 79.6, 109.6, 113.8, 119.4, 127.8, 128.1, 128.4,
131.1, 136.6, 156.3, 164.8; MS (m/z): 383 (MCC1).
4.1.10. (3S,4R)-3-Benzyloxy-4-heptylazetidin-2-one (6b).
Following the similar procedure described for 6a, com-
pound 6b was prepared from 5b. It was obtained as a white
solid, mp 55–56 8C; [Found C, 74.18; H, 9.09; N, 4.96.
C17H25NO2 requires C, 74.13; H, 9.17; N, 5.08%]; [a]D30
K38.57 (c 0.7, CHCl3); MS (m/z): 276 (MCC1); spectral
data same as for 6a.
4.1.7. (3S,4S)-3-Benzyloxy-1-(4-methoxyphenyl)-4-oxo-
azetidin-2-carbaldehyde (3b). A mixture of azetidin-2-one

4620
N. M. Shirode, A. R. A. S. Deshmukh / Tetrahedron 62 (2006) 4615–4621
Arrieta, A.; Cossio, F. P.; Aizpurua, J. M.; Mielgo, A.;
Aurrekoetxea, N. Tetrahedron Lett. 1990, 31, 6429–6432.
(e) Palomo, C.; Cabre, F.; Ontoria, J. M. Tetrahedron Lett.
1992, 33, 4819–4822. (f) Annunziata, R.; Benaglia, M.;
Cinquini, M.; Cozzi, F.; Ponzini, F. J. Org. Chem. 1993, 58,
4746–4748.
4.1.11. (3S,4R)-4-Heptyl-3-hydroxyazetidin-2-one (7b).
Following the similar procedure described for 7a, com-
pound 7b was prepared from 6b. It was obtained as a white
crystalline solid, mp 111–113 8C; [Found C, 64.97; H,
10.33; N, 7.73. C10H19NO2 requires C, 64.81; H, 10.36; N,
7.56%]; [a]3D0 K40.5 (c 0.25, CHCl3); (m/z): 186 (MCC1);
spectral data same as for 7a.
6. Alcaide, B.; Almendros, P. Chem. Soc. Rev. 2001, 30,
226–240.
7. (a) Jayaraman, M.; Deshmukh, A. R. A. S.; Bhawal, B. M.
J. Org. Chem. 1994, 59, 932–934. (b) Jayaraman, M.;
Nandi, M.; Sathe, K. M.; Deshmukh, A. R. A. S.; Bhawal,
B. M. Tetrahedron: Asymmetry 1993, 4, 609–612. (c)
Jayaraman, M. J.; Deshmukh, A. R. A. S.; Bhawal, B. M.
Tetrahedron 1996, 52, 8989–9004.
4.1.12. (2S,3R)-3-Amino-2-hydroxydecanoic acid (1b).
Following the similar procedure described for 1a, com-
pound 1b was prepared from 7b. It was obtained as a white
solid, mp 219–220 8C (dec), lit. mp 218.4–219.7 8C (dec);9a
[Found C, 59.33; H, 10.48; N, 6.95. C10H21NO3 requires C,
59.07; H, 10.43; N, 6.89%]; [a]3D0 C6.5 (c 0.47, 1 N HCl),
lit. [a]2D2 C7.3 (c 0.34, 1 N HCl),13a [a]2D5 C5.4 (c 0.59, 1 M
HCl);12b MS (m/z): 204 (MCC1); spectral data same as
for 1a.
8. Krishnaswamy, D.; Govande, V. V.; Deshmukh, A. R. A. S.
Synthesis 2003, 12, 1903–1908.
9. (a) Govande, V. V.; Arun, M.; Deshmukh, A. R. A. S.;
Bhawal, B. M. Synth. Commun. 2000, 30, 4177–4182. (b)
Joshi, S. N.; Deshmukh, A. R. A. S.; Bhawal, B. M.
Tetrahedron: Asymmetry 2000, 11, 1477–1485. (c)
Krishnaswamy, D.; Bhawal, B. M.; Deshmukh,
A. R. A. S. Tetrahedron Lett. 2000, 41, 417–419. (d)
Thiagarajan, K.; Puranik, V. G.; Deshmukh, A. R. A. S.;
Bhawal, B. M. Tetrahedron 2000, 56, 7811–7816. (e)
Karupaiyan, K.; Puranik, V. G.; Deshmukh, A. R. A. S.;
Bhawal, B. M. Tetrahedron 2000, 56, 8555–8560. (f)
Bhawal, B. M.; Joshi, S. N.; Krishnaswamy, D.; Deshmukh,
A. R. A. S. J. Indian Inst. Sci. 2001, 81, 265–276. (g)
Joshi, S. N.; Puranik, V. G.; Deshmukh, A. R. A. S.;
Bhawal, B. M. Tetrahedron: Asymmetry 2001, 12,
3073–3076. (h) Arun, M.; Govande, V. V.; Deshmukh,
A. R. A. S.; Bhawal, B. M. Indian J. Chem. 2002, 41B,
856–857. (i) Krishnaswamy, D.; Govande, V. V.; Gumaste,
V. K.; Bhawal, B. M.; Deshmukh, A. R. A. S. Tetrahedron
2002, 58, 2215–2225. (j) Patil, R. T.; Parveen, G.;
Gumaste, V. K.; Bhawal, B. M.; Deshmukh, A. R. A. S.
Synlett 2002, 1455–1458. (k) Joshi, S. N.; Phalgune, U. D.;
Bhawal, B. M.; Deshmukh, A. R. A. S. Tetrahedron Lett.
2003, 44, 1827–1830. (l) Arun, M.; Joshi, S. N.; Puranik,
V. G.; Bhawal, B. M.; Deshmukh, A. R. A. S. Tetrahedron
2003, 59, 2309–2316. (m) Shinkre, B. A.; Puranik, V. G.;
Bhawal, B. M.; Deshmukh, A. R. A. S. Tetrahedron:
Asymmetry 2003, 14, 453–459. (n) Jayanthi, A.; Gumaste,
V. K.; Deshmukh, A. R. A. S. Synlett 2004, 979–982. (o)
Shaikh, A. L.; Puranik, V. G.; Deshmukh, A. R. A. S.
Tetrahedron 2005, 61, 2441–2451.
Acknowledgements
Authors thank D.S.T., New Delhi, for financial support and
N.M.S. thanks UGC, New Delhi, for research fellowship.
References and notes
1. For reviews on b-lactam antibiotics, see: (a) Du¨rkheimer, W.;
Blumbach, J.; Lattrell, R.; Scheunemann, K. H. Angew.
Chem., Int. Ed. Engl. 1985, 24, 180–202. (b) Morin, R. B.,
Gorman, M., Eds.; Chemistry and Biology of b-Lactam
Antibiotics; Academic: New York, 1982; Vols. 1–3.
(c) Coulton, S.; Hunt, E. In Lukacs, G., Ed.; Recent Progress in
the Chemical Synthesis of Antibiotics and Related Microbial
Products; Springer: Berlin, 1993; Vol. 2, p 621. (d) Southgate, R.
Contemp. Org. Synth. 1994, 1, 417–431.
2. The Chemistry of b-lactams; Page, M. I., Ed.; Chapman and
Hall: London, 1992.
3. For comprehensive general reviews, see: (a) Koppel, G. A. In
Hasner, A., Ed.; Small Ring Heterocycles; Wiley: New York,
1983; Vol. 42, p 219. (b) Backes, J. In Houben-Weyl,
Methoden der Organischem Chemie; Muller, E., Bayer, O.,
Eds.; Thieme: Stuttgart, 1991; p 31; Band E16B. (c) de Kimpe,
N. In Katritzky, A. R., Rees, C. W., Scriven, E. F. V.,
Padwa, A., Eds.; Comprehensive Heterocyclic Chemistry II;
Pergamon: Oxford, 1996; Vol. 1B, p 507.
10. (a) Jayaraman, M.; Puranik, V. G.; Bhawal, B. M. Tetrahedron
1996, 52, 9005–9016. (b) Srirajan, V.; Deshmukh, A. R. A. S.;
Puranik, V. G.; Bhawal, B. M. Tetrahedron: Asymmetry 1996,
7, 2733–2738. (c) Deshmukh, A. R. A. S.; Bhawal, B. M.;
Krishnaswamy, D.; Govande, V. V.; Shinkre, B. A.;
Jayanthi, A. Curr. Med. Chem. 2004, 11, 1889–1920.
(d) Shirode, N. M.; Kulkarni, K. C.; Gumaste, V. K.;
Deshmukh, A. R. A. S. ARKIVOC (i) 2005, 53–64.
4. (a) Ojima, I. In The Chemistry of b-Lactams; Georg, G. I., Ed.;
VCH: New York, 1993; p 197; and references cited therein. (b)
Palomo, C.; Aizpurua, J.; Ganboa, I. In Enantioselective
Synthesis of Beta-Amino Acids; Juaristi, E., Ed.; Wiley-VCH:
New York, 1997; pp 279–357; and references cited therein.
(c) For a review on this subject see: Ojima, I.; Delaloge, F. Chem.
Soc. Rev. 1997, 26, 377–386. (d) Alcaide, B.; Almendros, P.
Chem. Soc. Rev. 2001, 30, 226–240. (e) Alcaide, B.; Almendros,
P. Synlett 2002, 381–393.
11. (a) Okino, T.; Matsuda, H.; Murakami, M.; Yamaguchi, K.
Tetrahedron Lett. 1993, 34, 501–504. (b) Ishida, K.; Kato, T.;
Murakami, M.; Watanabe, M.; Watanabe, M. F. Tetrahedron
2000, 56, 8643–8656. (c) Ishida, K.; Matsuda, H.; Murakami, M.
Tetrahedron 1998, 54, 13475–13484.
5. (a) Nagahara, T.; Kametani, T. Heterocycles 1987, 25,
729–806. (b) Thomas, R. C. In Recent Progress in the
Chemical Synthesis of Antibiotics; Lukacs, G., Ohno, M., Eds.;
Springer: Berlin, 1990; p 553. (c) Palomo, C. In Recent
Progress in the Chemical Synthesis of Antibiotics; Lukacs, G.,
Ohno, M., Eds.; Springer: Berlin, 1990; p 565. (d) Palomo, C.;
12. (a) Matsuura, F.; Hamada, Y.; Shioiri, T. Tetrahedron
1994, 50, 11303–11314. (b) Bunnage, M. E.; Burke, A. J.;
Davies, S. G.; Goodwin, C. J. Tetrahedron: Asymmetry
1995, 6, 165–176.

N. M. Shirode, A. R. A. S. Deshmukh / Tetrahedron 62 (2006) 4615–4621
4621
13. (a) Wee, A. G. H.; McLeod, D. D. J. Org. Chem. 2003, 68,
6268–6273. (b) Ha, H. J.; Ahn, Y.-G.; Woo, J.-S.; Lee, G. S.;
Lee, W. K. Bull. Chem. Soc. Jpn. 2001, 74, 1667–1672. (c)
Bergmeier, S. C.; Stanchina, D. M. J. Org. Chem. 1999, 64,
2852–2859. (d) Sugimura, H.; Miura, M.; Yamada, N.
Tetrahedron: Asymmetry 1997, 8, 4089–4099. (e) Righi, G.;
Chionne, A.; D’Achille, R.; Bonini, C. Tetrahedron:
Asymmetry 1997, 8, 903–907. (f) Jefford, C. W.; Mcnulty, J.;
Lu, Z. H.; Wang, J. B. Helv. Chim. Acta1996, 79, 1203–1216. (g)
Tuch, A.; Saniere, M.; Merrer, Y. L.; Depezay, J. Tetrahedron:
Asymmetry 1996, 7, 2901–2909. (h) Bunnage, M. E.;
Burke, A. J.; Davies, S. G.; Goodwin, C. J. Tetrahedron:
Asymmetry 1994, 5, 203–206.
14. Palomo, C.; Aizpurua, J.; Ganboa, I.; Oiarbide, M. Synlett
2001, 1813–1826.
15. (a) Banik, B. K.; Manhas, M. S.; Kaluza, Z.; Barakat, K. J.;
Bose, A. K. Tetrahedron Lett. 1992, 33, 3603–3606.
(b) Wagle, D. R.; Garai, C.; Chiang, J.; Monteleone, M. G.;
Kurys, B. E.; Strohmeyer, T. M.; Hegde, V. R.; Manhas, M. S.;
Bose, A. K. J. Org. Chem. 1988, 53, 4227–4236.
16. (a) Andrews, G. C.; Crawford, T. C.; Bacon, B. E. J. Org.
Chem. 1981, 46, 2977–2979. (b) Hubschwerlen, C. Synthesis
1986, 962–964.
17. Kronenthal, D. R.; Han, C. Y.; Taylor, M. K. J. Org. Chem.
1982, 47, 2765–2768.
18. Bieg, T.; Szeja, W. Synthesis 1985, 76–77.