Synthesis of protected 4-amino- and 4-azido-3-hydroxy-l-prolines from d-glucose

Article abstract of DOI:10.1055/s-0032-1316612

Differentially protected 4-azido- or 4-amino-3-hydroxy-l-prolines were synthesized in good overall yields (21-31%) from d-glucose. The synthetic strategy involved conversion of d-glucose into 3-[(benzyloxycarbonyl)amino]-3- deoxy-1,2-O-isopropylidene-α-d-glucofuranose, which was subjected to mesylation of the 5- and 6-hydroxy groups and subsequent intramolecular S _N2 displacement of the 6-O-mesyl group by the 3-(benzyloxycarbonyl) amino group to give a pyrrolidine ring. The resulting intermediate underwent intermolecular S_N2 displacement of the 5-O-mesyl group with sodium azide, hydrolysis of 1,2-acetonide group, treatment with sodium periodate, and Pinnick oxidation to give the required compounds. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0032-1316612

PAPER
▌2735
paper
Synthesis of Protected 4-Amino- and 4-Azido-3-hydroxy-L-prolines from
D-Glucose
4-Amino- and 4-Azido-3-hydroxy-L-prolines
Vijay M. Kasture, Navnath B. Kalamkar, Dilip D. Dhavale*
Department of Chemistry, Garware Research Centre, University of Pune, Pune 411007, India
Fax +91(20)25691728; E-mail: ddd@chem.unipune.ac.in
Received: 30.04.2012; Accepted after revision: 06.06.2012
Because of the varied applications of substituted amino-
prolines, a number of methods have been developed for
the synthesis of these compounds.12 For example, C3- and
C4-substituted amino or azido hydroxy L-prolines, such as
Abstract: Differentially protected 4-azido- or 4-amino-3-hydroxy-
L-prolines were synthesized in good overall yields (21–31%) from
D-glucose. The synthetic strategy involved conversion of D-glucose
into
3-[(benzyloxycarbonyl)amino]-3-deoxy-1,2-O-isopropyli-
dene-α-D-glucofuranose, which was subjected to mesylation of the the protected 4-azido-3-hydroxy-L-proline 3,13 can be pre-
5- and 6-hydroxy groups and subsequent intramolecular SN2 dis-
pared from the corresponding 3- or 4-hydroxy-L-prolines
as chiral starting materials. For example, Herdeis et al.13b
placement of the 6-O-mesyl group by the 3-(benzyloxycarbon-
yl)amino group to give
a pyrrolidine ring. The resulting
and Schofield and co-workers13a synthesized 4-azido- and
4-amino-3-hydroxy-L-prolines from 4-hydroxy-L-pro-
lines by epoxidation and subsequent regioselective cleav-
age of the oxirane ring. Gómez-Vidal and Silverman
prepared of N-tert-butoxycarbonyl-protected 4- and 3-az-
ido-L-prolines from the corresponding hydroxy-L-pro-
lines by using a Mitsunobu reaction as a key step.1 Curran
an co-workers14 adopted a similar strategy for the synthe-
sis of N-acetyl-protected 4-substituted aminoprolines. Al-
though many methods have been reported for the
synthesis of 4-amino- and 4-azido-3-hydroxy-L-prolines,
to the best of our knowledge, no synthesis has been report-
ed that starts from a carbohydrate.15 As part of our interest
in the synthesis of cyclic α-amino acids and imino sug-
ars,16 we recently reported a chiral approach to 3-
hydroxyproline16a and pipecolic acid,16b starting from D-
glucose. In the present study, we report the syntheses of
the protected 4-azido- and 4-amino-3-hydroxy-L-prolines
3–6 from D-glucose.
intermediate underwent intermolecular SN2 displacement of the 5-
O-mesyl group with sodium azide, hydrolysis of 1,2-acetonide
group, treatment with sodium periodate, and Pinnick oxidation to
give the required compounds.
Key words: amino acids, chemoselectivity, carbohydrates, cycliza-
tion, pyrroles, stereoselective synthesis
Because of their potential therapeutic applications,1,2 the
protected 4-azido-L-proline 1 and 4-amino-L-proline 2
(Figure 1) are of interest to synthetic organic chemists and
biologists. Such compounds can be used as chiral building
blocks for the synthesis of enantiomerically pure biologi-
cally active compounds and synthetic materials, such as
peptide nucleic acids,3 cell-penetrating γ-peptides,4 pho-
toaffinity-labeling ligands,5 magnetic resonance imaging
contrast agents,6 novel helices,7 enzyme inhibitors,8 and
antifungal and herbicidal agents.9 Aminoprolines can also
be used as novel ligands in transition-metal complexes for
use in photochemical energy conversion10 and as organo-
catalysts for asymmetric synthesis.11
We hypothesized that the C2–C6 segment of D-glucofura-
nose (III) might be used to construct the carbon skeleton
of prolines in 3–6, in which the C2-carboxyl functionality
of the target molecule would be embedded as the C2 car-
bon atom of intermediate II, whereas the ring nitrogen of
the target molecule would be derived from the C3 amino
group (Scheme 1). With regard to the stereochemistry, the
C3 β-hydroxy group in 3–6 is present as the C4 ring oxy-
gen of II and the stereochemistry of the amino or azido
group at C2 and C4 in the target molecule could be intro-
duced sequentially by nucleophilic substitution with an
azide anion of a suitably protected C3- or C5-hydroxy
group in III. To achieve this, we envisioned using the 5,6
di-O-mesyl functionality of II, so that the C6-O-mesyl
group would be used in the intramolecular construction of
the pyrrolidine ring, and the C5-O-mesyl group would be
used in introducing the C4 azido or amino group by an in-
termolecular SN2 displacement to obtain the required
compound I. This strategy not only eliminates the need for
stepwise chemoselective transformations, but also affords
the key C5-azido pyrrolidine ring with a sugar framework
I, that can be converted into the target molecule.
N3
N3
OH
H2N
3
2
4
CO2Bn
CO2Me
N
CO2Me
N
N
1
Cbz
Boc
Boc
2
3
1
N3
N3
H2N
OH
OH
OH
CO2Me
CO2H
CO2H
N
N
N
Cbz
Cbz
Cbz
4
5
6
Figure 1 Protected azido- and amino-L-prolines
SYNTHESIS 2012, 44, 2735–2738
Advanced online publication: 27.07.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0032-1316612; Art ID: SS-2012-T0397-OP
© Georg Thieme Verlag Stuttgart · New York

2736
V. M. Kasture et al.
PAPER
H
N3
RO
RO
OH
H
N3/H2N
6
O
3
O
4
5
5
6 steps
O
4
1
NaH, DMF
90%
(ref. 16e)
CO2PG2
O
2
N
O
1 N
D-glucose
H
H
Cbz
60% overall
PG1
3
O
CbzHN
7 R = H
I
3–6
PG = protecting group
MsCl, Et3N
CH2Cl2
8 R = Ms (95%)
H
H
MsO
HO
O
O
5
1
2
1
5
OH
R1
H
O
4
6
O
4
3
6
3
1. TFA–H2O
2. NaIO4, acetone–H2O
3. Pinnick oxidation
MsO
R2
O
O
2
HO
O
HN
HO
OH
H
H
N
Cbz
H
65%
(3 steps)
Cbz
III (D-glucofuranose)
II
9 R1 = OMs, R2 = H
Scheme 1 Visualization of hidden symmetry in L-proline derivatives
(3–6)
NaN3, DMF
90 °C, 12 h
10 R1 = H, R2 = N3 (92%)
First, D-glucose was converted into the required N-ben-
zyloxycarbonyl-protected amino diol 7 in six steps (60%
overall yield) as previously reported by us16e and by
others17 (Scheme 2). Treatment of 7 with excess mesyl
chloride in triethylamine at 0 °C gave the dimesylated de-
rivative 8 in 95% yield. Treatment of 8 with sodium hy-
dride in N,N-dimethylformamide at 0 °C gave the known
pyrrolidine derivative 9 in 90% yield by cyclization be-
tween the N-(benzyloxycarbonyl)amino group at C3 and
the primary mesyl group at C6.18 Pyrrolidine 9 was previ-
ously synthesized by Nishimura and co-workers18a by
catalytic hydrogenation of 3-azido-3-deoxy-1,2-O-iso-
propylidene-5,6-di-O-mesyl-α-D-glucofuranose, whereas
Yamada et al.18b synthesized it by treatment of 3-amino-3-
deoxy-1,2,5,6-di-O-isopropylidine-α-D-glucofuranose with
lithium aluminum hydride with subsequent mesylation at
the C-5 hydroxy group. Intermolecular SN2 displacement
of the secondary C5 O-mesyl group in 9 by sodium azide
in N,N-dimethylformamide gave the protected azide 10 as
a white solid in 92% yield. Cleavage of the isopropylidene
N3
OH
H2N
H
OH
H2, Pd/C
H
H
H
MeOH, 8 h
CO2R
CO2H
N
N
(70%)
H
Cbz
H
Cbz
6 R = H
5
BnBr, K2CO3
DMF (90%)
CH2N2, Et2O
(95%)
3 R = Bn
4 R = Me
Scheme 2 Synthesis of protected 4-amino- and 4-azido-3-hydroxy-L-
prolines
5, 22%; 6, 31%), compared with the 7% yield of 3 starting
from 4-hydroxyproline.3a The synthetic strategy is simple
and cost-effective, and all the steps are high yielding
(>90%) and can be performed in a stereoselective manner
to provide single diastereomers that can be readily puri-
fied by column chromatography.
moiety in 10 with aqueous trifluoroacetic acid gave a Melting points were recorded with a Thomas Hoover capillary melt-
ing point apparatus and are uncorrected. IR spectra were recorded
hemiacetal that was directly subjected to oxidative cleav-
age with aqueous sodium periodate to give the corre-
sponding aldehyde. Pinnick oxidation of the aldehyde
on a Shimadzu FTIR-8400 spectrometer as thin films or by using
1
KBr pellets. H (300-MHz) and 13C (75-MHz) NMR spectra were
recorded with a Varian Mercury instrument using CDCl3, D2O, or
with sodium chlorite, sodium dihydrogen phosphate, and
hydrogen peroxide gave the acid 6 in 65% overall yield
for the three steps. Acid 6 was converted to its known ben-
zyl ester 3 by treatment with benzyl bromide and potassi-
um carbonate. The specific rotation and spectral data of
ester 3 were found to match those reported by Schofield et
DMSO-d6 as a solvent. Chemical shifts are reported in δ (ppm) with
reference to TMS as internal standard. Elemental analyses were car-
ried out with a FlashEA 1112 analyzer (Thermo-Electron Corp.) at
the Department of Chemistry of the University of Pune. TLC was
performed on precoated plates (0.25 mm, silica gel 60 F254). Visu-
alization was performed by UV irradiation or by thermal develop-
ment after spraying with 3.5% soln of 2,4-dinitrophenylhydrazine
in EtOH, with H2SO4, or with basic aq KMnO4. Column chromatog-
raphy was carried out with silica gel (100–200 mesh). Unless other-
wise mentioned, reactions were carried out in oven-dried glassware
under dry N2. Acetone, CH2Cl2, THF, MeCN, and MeOH were pu-
rified and dried before use. Distilled hexane, EtOAc, MeOH, and
CHCl3 were used for column chromatography.
25
25
al.{[α]D +5.12 (c 3.0 in CHCl3); Lit.13a [α]D +4.98 }.
Alternatively, acid 6 was converted into its monomethyl
ester 4 in almost quantitative yield by treatment with di-
azomethane. Chemoselective reduction of the C4-azido
group in acid 6 by controlled hydrogenation gave the N-
protected γ-amino acid 5 in 70% yield. This product can
be used in peptide-coupling reactions.
3-[(Benzyloxycarbonyl)amino]-3-deoxy-1,2-O-isopropylidene-
5,6-di-O-mesyl-α-D-glucofuranose (8)
In conclusion, we efficiently exploited D-glucose as an in-
expensive chiral starting material for the synthesis of the
optically pure protected 4-amino- and 4-azido-3-hydroxy-
L-prolines 3–6 in good overall yields (3, 28%; 4, 29%;
A soln of MsCl (2.19 mL, 28.3 mmol) in CH2Cl2 (10 mL) was added
dropwise over 10 min to a stirred soln of diol 7 (5.00 g, 14.2 mmol)
in dry CH2Cl2 (50 mL) containing Et3N (5.5 mL, 42.5 mmol) at 0
°C, and the mixture was stirred at the 0 °C for 3 h. The reaction was
then quenched with H2O (20 mL). The organic layer was washed
Synthesis 2012, 44, 2735–2738
© Georg Thieme Verlag Stuttgart · New York

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4-Amino- and 4-Azido-3-hydroxy-L-prolines
2737
with H2O (2 × 20 mL) and brine (20 mL), dried (Na2SO4), and con-
centrated under reduced pressure in a rotary evaporator. The residue
was purified by column chromatography [silica gel, hexane–EtOAc
(80:20)] to give a colorless solid; yield: 6.84 g (95%); mp 152–154
°C. Rf = 0.4 (hexane–EtOAc, 70:30); [α]D22 –0.75 (c 0.75, CH2Cl2).
mmol) and the mixture was stirred for 1 h at 25 °C. The solvent was
evaporated in a rotary evaporator and the residue was extracted with
CHCl3 (3 ×10 mL). The organic layers were combined, washed with
H2O (3 × 10 mL) and brine (20 mL), dried (Na2SO4), and concen-
trated under reduced pressure in a rotary evaporator to give the
crude aminal as a thick liquid; yield: 0.82 g (95%).
IR (KBr): 3390, 2933, 1692, 1543, 1348, 1170 cm–1.
A stirred soln of the crude aminal (0.750 g, 2.6 mmol) in MeCN (8
mL) was added a soln of NaH2PO4 (0.062 g, 0.5 mmol) in H2O (3
mL) containing 30% H2O2 (0.20 mL, 2.8 mmol). The mixture was
stirred and cooled to –10 °C and then a soln of NaClO2 (0.26 g, 2.8
mmol) in H2O (4 mL) was added dropwise over 30 min. The mix-
ture was stirred at 15 °C while the reaction was monitored by ob-
serving the evolution of O2 through a bubbler connected to the
apparatus. After 2 h, the mixture was treated with a small amount of
Na2SO3 (0.1 g) and acidified with 10% aq HC1 (5 mL). The organic
layer was separated and the aqueous layer was extracted with EtO-
Ac (4 × 10 mL). The organic layers were combined and concentrat-
ed to give a residue that was dissolved in 10% aq NaHCO3 (25 mL).
The bicarbonate layer was washed with EtOAc (3 ×5 mL), acidified
to pH 2, and extracted again with EtOAc (3 × 10 mL). The organic
layers were combined, washed with H2O (2 × 10 mL) and brine (20
mL), dried (Na2SO4), and concentrated under reduced pressure in a
rotary evaporator to give the required product as a thick liquid;
yield: 0.66 g (65%, three steps); Rf = 0.4 (CHCl3–MeOH , 7:3);
[α]D22 –9.8 (c 0.45, CH2Cl2).
1H NMR (300 MHz, CDCl3 + one drop of D2O): δ = 1.30 (s, 3 H),
1.51 (s, 3 H), 3.08 (s, 6 H), 4.30–4.50 (m, 3 H), 4.56–4.71 (m, 2 H),
4.93–5.05 (br s, 1 H), 5.11 (s, 2 H), 5.86 (s, 1 H), 7.26–7.22 (m, 5
H, Ar).
13C NMR (75 MHz, CDCl3): δ = 26.0, 26.5, 37.5, 38.6, 56.6, 67.4,
68.3, 73.6, 75.2, 84.4, 104.4, 112.6, 128.2, 128.3, 128.5, 135.8,
155.6.
Anal. Calcd for C19H27NO11S2: C, 44.79; H, 5.34. Found: C, 44.98;
H, 5.27.
Benzyl (3aR,4aS,5S,7aS,7bR)-2,2-Dimethyl-5-(mesyloxy)hexa-
hydro-7H-[1,3]dioxolo[4,5]furo[3,2-b]pyrrole-7-carboxylate (9)
A soln of dimesylate 8 (5.00 g, 9.8 mmol) in DMF (20 mL) was add-
ed over 10 min to an ice-cooled suspension of NaH (0.589 g, 14.8
mmol) in dry DMF (40 mL) under N2, and the mixture was then
stirred at r.t. for 3 h. The reaction was quenched with sat. aq NH4Cl
(10 mL) and the mixture was extracted with EtOAc (3 × 100 mL).
The combined organic layer was washed with H2O (3 × 100 mL)
and brine (200 mL), dried (Na2SO4), and concentrated under re-
duced pressure in a rotary evaporator. The residue was purified by
column chromatography [silica gel, hexane–EtOAc (70:30] to give
a crystalline solid; yield: 3.66 g (90%); mp 126–128 °C (Lit.18 125–
126 °C); [α]D25 –24.3 (c 1.0, CHCl3) (Lit.18 –26.0).
IR (neat): 3371, 2922, 2115, 1689, 1427, 1357, 1134, 769, 698 cm–1.
1H NMR (300 MHz, CDCl3 + 1 drop of D2O): δ = 3.35–3.45 (dd,
J = 11.5, 4.7 Hz) and 3.47–3.56 (br d, J = 8.8 Hz) (both integrating
for 1 H, H-5a), 3.84 (dd, J = 11.4, 6.1 Hz, 1 H, H-5b), 3.92–4.1 (br
m, 1 H, H-4), 4.32–4.42 (m, 1 H, H-3), 4.50 (br d, J = 6.0 Hz, 1 H,
H-1), 5.0–5.20 (ABq, J = 12.6 Hz, 2 H, H-6a,b), 7.15–7.42 (m, 5 H,
5Ar-H).
Anal. Calcd for C18H23NO8S: C, 52.29; H, 5.61. Found: C, 52.52; H,
5.74.
13C NMR (75 MHz, CDCl3): δ (two conformational isomers) = 48.6
and 49.1, 62.6, 63.6 and 63.8, 67.8 and 68.0, 74.5 and 75.4, 127.6
and 127.9, 128.1 and 128.3, 128.5 and 128.5, 135.6 and 135.8,
154.9 and 155.5, 172.5 and 172.9.
Benzyl (3aR,4aS,5R,7aS,7bR)-5-Azido-2,2-dimethylhexahydro-
7H-[1,3]dioxolo[4,5]furo[3,2-b]pyrrole-7-carboxylate (10)
A mixture of mesylate 9 (5.00 g, 12.1 mmol) and NaN3 (0.943 g,
14.5 mmol) in DMF (40 mL) was stirred at 90 °C for 24 h. The mix-
ture was then diluted with EtOAc (100 mL) and the organic phase
was washed with H2O (3 × 100 mL) and brine (100 mL), dried
(Na2SO4), and concentrated. The residue was purified by column
chromatography [silica gel, hexane–EtOAc (80:20] to give a color-
less solid; yield: 3.21 g (92%); mp 86–88 °C; Rf = 0.5 (hexane–
EtOAc, 70:30); [α]D22 –40.17 (c 1.1, CH2Cl2).
Anal. Calcd for C13H14N4O5: C, 50.98; H, 4.61. Found: C, 51.26; H,
4.92.
(3R,4S)-4-Amino-1-(benzyloxycarbonyl)-3-hydroxy-L-proline
(5)
A mixture of 6 (0.25 g, 0.8 mmol) and 10% Pd/C (0.030 g) in MeOH
(10 mL) was hydrogenated at balloon pressure for 8 h at 25 °C. The
catalyst was filtered off on Celite, and the soln was concentrated and
purified by column chromatography [silica gel, CHCl3–
MeOH (6:4)] to give a colorless liquid: yield: 0.160 g (70%);
Rf = 0.4 (CHCl3–MeOH, 5:5); [α]D22 +2.2 (c 2.3, H2O).
IR (KBr): 2106, 1695, 1415, 1359, 1211, 1014, 732 cm–1.
1H NMR (300 MHz, CDCl3): δ (two conformational isomers in a
1:1 ratio) = 1.30 (s, 3 H), 1.45 (s, 3 H), 3.52 and 3.54 (2 × d, J = 12.4
Hz, 1 H, H-6a), 3.76 and 3.86 (2 × d, J = 12.4 Hz, 1 H, H-6b), 4.06
(d, J = 4.1 Hz, 1 H, H-3), 4.38 and 4.42 (2 × d, J = 4.1 Hz, 1 H, H-
4), 4.68 and 4.87 (2 × d, J = 3.5 Hz, 1 H, H-2), 4.72 (br s, 1 H, H-
5), 5.15 (s) and 5.22 (ABq, J = 12.6 Hz) (both integrating for 2 H,
OCH2Ph), 5.79 (t, J = 3.9 Hz, 1 H, H-1), 7.20 (m, 5 H, Ar).
13C NMR (75 MHz, CDCl3): δ = 26.3 and 26.4, 27.5, 50.1 and 50.3,
61.6 and 62.1, 65.6 and 66.0, 67.3 and 67.3, 82.8 and 83.8, 84.2 and
85.1, 105.9, 112.5, 127.7 and 127.9, 128.1 and 128.1, 128.4, 136.0
and 136.2, 154.2 and 154.4.
IR (neat): 3365, 1678, 1595, 1429, 1359, 1138, 976 cm–1.
1H NMR (300 MHz, D2O): δ = 3.24–3.55 (m, 2 H, H-4 and H-5a),
3.78–3.90 (m, 1 H, H-5b), 4.22–4.32 (m, 1 H, H-3), 4.35 (d, J = 7.0
Hz) and 4.43 (d, J = 7.0 Hz) (both doublets integrating for 1 H, H-
2), 5.10–5.28 (m, 2 H, OCH2Ph), 7.26–7.60 (m, 5 H, ArH).
13C NMR (75 MHz, D2O): δ (two conformational isomers) = 50.0,
54.5 and 55.1, 64.6, 67.3 and 67.4, 75.3 and 75.8, 127.3 and 127.9,
128.1 and 128.4, 128.6 and 128.7, 136.3, 156.2 and 156.4, 175.6
and 175.8.
Anal. Calcd for C17H20N4O5: C, 56.66; H, 5.59. Found: C, 56.93; H,
5.75.
Anal. Calcd for C13H16N2O5: C, 55.71; H, 5.75. Found: C, 55.82; H,
5.89.
(3S,4S)-4-Azido-1-[(benzyloxy)carbonyl]-3-hydroxy-L-proline
(6)
A soln of azide 10 (1.2 g, 3.3 mmol) in 2:3 TFA–H2O (15 mL) was
stirred for 15 min at 0 °C, warmed to 25 °C, and stirred for a further
3 h. The TFA was co-evaporated with toluene in a rotary evaporator
under high vacuum to give the hemiacetal as a thick liquid; crude
yield: 1.05 g (98%).
Dibenzyl (2S,3S,4S)-4-Azido-3-hydroxypyrrolidine-1,2-dicar-
boxylate (3)
A soln of azide 6 (0.100 g, 0.3 mmol) in DMF (5 mL) under N2 was
treated with anhyd K2CO3 (0.096 g, 0.7 mmol), NaI (0.058 g, 0.4
mmol), and BnBr (0.12 mL, 1.0 mmol), and the mixture was stirred
overnight. The mixture was then diluted with H2O and extracted
with EtOAc (3 × 5 mL). The organic solvent was evaporated under
An ice-cooled soln of the crude hemiacetal (0.950 g, 3.0 mmol) in
5:1 acetone–H2O (10 mL) was treated with NaIO4 (0.952 g, 4.5
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2735–2738

2738
V. M. Kasture et al.
PAPER
vacuum, and the residue was purified by column chromatography
[silica gel, hexane–EtOAc (6:4)] to give a colourless oil; yield:
(4) Farrera-Sinfreu, J.; Giralt, E.; Castel, S.; Albericio, F.; Royo,
M. J. Am. Chem. Soc. 2005, 127, 9459.
(5) Fisher, A.; Mann, A.; Verma, V.; Thomas, N.; Mishra, R. K.;
Johnson, R. L. J. Med. Chem. 2006, 49, 307.
25
0.116 g (90%); Rf = 0.5 (hexane–EtOAc, 6:4); [α]D +5.12 (c 3.0,
CHCl3) (Lit.3a +4.98).
(6) Williams, M. A.; Rapoport, H. J. Org. Chem. 1994, 59,
3616.
(7) (a) Babu, I. R.; Ganesh, K. N. J. Am. Chem. Soc. 2001, 123,
2079. (b) Sonar, M. V.; Ganesh, K. N. Org. Lett. 2010, 12,
5390.
(8) Tripathy, R.; Gu, Z.; Dunn, D.; Senadhi, S. E.; Ator, M. A.;
Chatterjee, S. Bioorg. Med. Chem. Lett. 1998, 8, 2647.
(9) Klein, L. L.; Li, L.; Chen, H.-J.; Curty, C. B.; DeGoey, D.
A.; Grampovnik, D. J.; Leone, C. L.; Thomas, S. A.; Yeung,
C. M.; Funk, K. W.; Kishore, V.; Lundell, E. O.; Wodka, D.;
Meulbroek, J. A.; Alder, J. D.; Nilius, A. M.; Lartey, P. A.;
Plattner, J. J. Bioorg. Med. Chem. 2000, 8, 1677.
(10) (a) McCafferty, D. G.; Friesen, D. A.; Danielson, E.; Wall,
C. G.; Saderholm, M. J.; Erickson, B. W.; Meyer, T. J. Proc.
Natl. Acad. Sci. U.S.A. 1996, 93, 8200. (b) Serron, S. A.;
Aldridge, W. S. III; Danell, R. M.; Meyer, T. J. Tetrahedron
Lett. 2000, 41, 4039.
1-Benzyl 2-Methyl (2S,3S,4S)-4-Azido-3-hydroxypyrrolidine-
1,2-dicarboxylate (4)
A stirred soln of acid 6 (0.100 g, 0.3 mmol) in THF (5 mL) at
–10 °C was treated with a ~2.5 M soln of diazomethane in Et2O (10
mL), and the mixture was stirred for 1 h at –10 °C. After the com-
pletion of the reaction, the reaction mixture was vigorously stirred
at r.t. (25 °C) for 1 h inside the fume hood cupboard and work up
was done in the fume hood. The organic layer was concentrated, and
the residue was purified by column chromatography [silica gel,
hexane–EtOAc (7:3) to give a colorless sticky liquid; yield: 0.10 g
22
(95%); Rf = 0.5 [hexane–EtOAc (6:4)]; [α]D +24.05 (c 2.65,
CH2Cl2).
IR (neat): 3367, 2953, 2110, 1740, 1690 cm–1.
1H NMR (300 MHz, CDCl3): δ = 2.18 (br s, 1 H, OH, exchangeable
with D2O), 3.4 (ddd, J = 12.1, 5.5 Hz, 1 H, H-5a), 3.60 (s) and 3.77
(s) (both singlets integrating for 3 H, CH3), 3.86–3.99 (m, 1 H, H-
5b), 4.08 (quin, J = 12.1, 6.1 Hz, 1 H, H-4), 4.38 (br t, J = 5.5 Hz,
1 H, H-3), 4.48 (d, J = 7.0 Hz) and 4.52 (d, J = 7.0 Hz) (both dou-
blets integrating for 1 H, H-2), 4.97–5.24 (m, 2 H, OCH2Ph), 7.21–
7.43 (m, 5 H, Ar).
13C NMR (75 MHz, CDCl3): (two rotational isomers) δ = 48.3 and
48.5, 52.4 and 52.4, 62.3, 63.4 and 63.9, 67.6 and 67.7, 74.5 and
75.3, 127.8 and 127.9, 128.2 and 128.3, 128.5 and 128.5, 135.9 and
135.9, 154.3 and 154.8, 170.1.
(11) Tsogoeva, S. B.; Jagtap, S. B.; Ardemasova, Z. A.
Tetrahedron: Asymmetry 2006, 17, 989.
(12) (a) Pandey, S. K. Tetrahedron: Asymmetry 2012, 22, 1817.
(b) Mauger, A. B. J. Nat. Prod. 1996, 59, 1205. (c) Valle, J.
R. D.; Goodman, M. J. Org. Chem. 2003, 68, 3923.
(d) Mauger, A. B.; Witkop, B. Chem. Rev. 1966, 66, 47.
(13) (a) Robinson, J. K.; Lee, V.; Claridge, T. D. W.; Baldwin, J.
E.; Schofield, C. J. Tetrahedron 1998, 54, 981. (b) Herdeis,
C.; Aschenbrenner, A.; Kerfel, A.; Schwabenlander, F.
Tetrahedron: Asymmetry 1997, 14, 2421.
Anal. Calcd for C14H16N4O5: C, 52.50; H, 5.03. Found: C, 52.85; H,
5.35.
(14) Curran, T. P.; Marquesa, K. A.; Bilimoria, S. I. Lett. Org.
Chem. 2005, 2, 15.
(15) (a) Austin, G. N.; Baird, P. D.; Fleet, G. W. J.; Feach, J. M.;
Smith, P. W.; Watkin, D. J. Tetrahedron 1987, 43, 3095.
(b) Mazzini, C.; Sambri, L.; Regeling, H.; Zwanenburg, B.;
Chittenden, G. J. F. J. Chem. Soc., Perkin Trans. 1 1997,
3351.
(16) For cyclic α-amino acids, see: (a) Kalamkar, N. B.; Kasture,
V. M.; Dhavale, D. D. Tetrahedron Lett. 2010, 51, 6745.
(b) Kalamkar, N. B.; Kasture, V. M.; Dhavale, D. D. J. Org.
Chem. 2008, 73, 3619. For imino sugars, see: (c) Jabgunde,
A. M.; Kalamkar, N. B.; Chavan, S. T.; Sabharwal, S. G.;
Dhavale, D. D. Bioorg. Med. Chem. 2011, 19, 6720.
(d) Kalamkar, N. B.; Kasture, V. M.; Chavan, S. T.;
Sabharwal, S. G.; Dhavale, D. D. Tetrahedron 2010, 66,
8522. (e) Vyavahare, V. P.; Chattopadhyay, S.; Puranik, V.
G.; Dhavale, D. D. Synlett 2007, 559. (f) Chaudhari, V. D.;
Ajish Kumar, K. S.; Dhavale, D. D. Tetrahedron Lett. 2004,
45, 8363.
Acknowledgment
We are grateful to Prof M. S. Wadia for helpful discussions. We
thank the Department of Science and Technology, New Delhi, for
financial support (Project File No. SR/S1/OC-20/2010). V.M.K.
and N.B.K. are grateful to CSIR, New Delhi, for fellowships.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
nnfomartit
References
(1) Gómez-Vidal, J. A.; Silverman, R. B. Org. Lett. 2001, 3,
2481.
(2) Torino, D.; Mollica, A.; Pinnen, F.; Feliciani, F.; Spisani, S.;
Lucente, G. Bioorg. Med. Chem. 2009, 17, 251.
(3) (a) Püschl, A.; Tedeschi, T.; Nielsen, P. E. Org. Lett. 2000,
2, 4161. (b) Gangamani, B. P.; Kumar, V. A.; Ganesh, K. N.
Tetrahedron. 1999, 55, 177. (c) Gangamani, B. P.; Kumar,
V. A.; Ganesh, K. N. Tetrahedron 1999, 52, 15017.
(17) Chen, H.; Guo, Z.; Liu, H-W. J. Am. Chem. Soc. 1998, 120,
9951.
(18) (a) Nishimura, Y.; Kondo, S.; Umezawa, H. J. Org. Chem.
1985, 50, 5210. (b) Yamada, M.; Tachibana, K.; Kuroda, T.
Carbohydr. Res. 1983, 112, 189.
Synthesis 2012, 44, 2735–2738
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