Stereoselective Total Synthesis of Unnatural (+)-Anisomycin

Article abstract of DOI:10.1055/s-0035-1561365

Stereoselective total synthesis of unnatural (+)-anisomycin from d-glucose has been achieved with an overall yield of 23%. The key synthetic features are regioselective opening of an epoxide, azidation of the resulting alcohol, and finally one-pot hydroge

Full text of DOI:10.1055/s-0035-1561365

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2016, 48, 1191–1196
paper
1191
S. Ajay et al.
Paper
Synthesis
Stereoselective Total Synthesis of Unnatural (+)-Anisomycin
MeO
Sama Ajay
Puli Saidhareddy
Arun K. Shaw*
OH
OH OH
OBn
O
OH
OH
H
•HCl
N
Medicinal and Process Chemistry Division,
CSIR-Central Drug Research Institute (CSIR-CDRI),
Sector 10, Jankipuram Extension, Sitapur road,
Lucknow-226031, U. P., India
HO
N3
MeO
OH
AcO
OH
akshaw55@yahoo.com
D-glucose
(+)-anisomycin
23% overall yield
(14 steps)
Received: 14.12.2015
Accepted after revision: 18.01.2016
Published online: 10.02.2016
activities owing to apoptotic action, including on mamma-
lian cell lines RAS A, HBL 100, and MCF 7 in the nanomolar
region.2,7 It has been used in clinics successfully for the
treatment of amoebic dysentery8 and trichomoniasis, a sex-
ually transmitted disease (STD), caused by a protozoan par-
asite Trichomonas vaginitis.9 (–)-Anisomycin (1a) is used as
a valuable tool in molecular biology, as it specifically pre-
vents peptide bond formation on eukaryotic ribosomes.10
Recent studies reveal that several derivatives of anisomycin
have also exhibited potent glycosidase inhibitory activity
against α-rhamnosidase and several other glycosidases.11
These diverse biological activities and structural fea-
tures (such as the existence of a trans diol, one being acetyl-
ated) of anisomycin prompted chemists to develop several
strategies for the synthesis of (–)-anisomycin (1a) and its
analogues,12 but only a few reports are available for the
synthesis of (+)-anisomycin (1b) and its derivatives.13 How-
ever, many of them suffer from drawbacks, such as harsh
conditions, poor stereoselectivity, long reaction series re-
sulting in overall low yield, and incompetent protecting
group chemistry in the late stages. Therefore, the continued
need to search for new approaches that could give stereo-
chemically pure compound and its analogues to evaluate
their biological activities is important in the field of medici-
nal chemistry. In continuation of our ongoing project on the
synthesis of polyhydroxylated alkaloids and iminosugars,14
we herein report the stereoselective total synthesis of (+)-
anisomycin (1b) with (2S,3R,4R) absolute stereochemistry,
from the cheap and easily available carbohydrate chiral
pool starting material, D-glucose.
DOI: 10.1055/s-0035-1561365; Art ID: ss-2015-z0720-op
Abstract Stereoselective total synthesis of unnatural (+)-anisomycin
from D-glucose has been achieved with an overall yield of 23%. The key
synthetic features are regioselective opening of an epoxide, azidation of
the resulting alcohol, and finally one-pot hydrogenation leading to cy-
clization to the pyrrolidine ring in a single step.
Key words anisomycin, D-glucose, total synthesis, Grignard reaction,
chloromesyl chloride, azidation, cyclization
Anisomycin is a pyrrolidine iminosugar antibiotic that
was first isolated by Sobin and Tanner in 1954 from the fer-
mentation broths of two Streptomyces species S. griseolous
and S. roseochromogens.1 Later it was also found from two
related strains, Streptomyces sp. SA3079 and No. 638.2 A de-
cade after its preliminary isolation, the structure and rela-
tive stereochemistry of natural (–)-anisomycin (1a) were
elucidated by chemical and spectroscopic studies.3 The ab-
solute stereochemistry of 1a was confirmed as being
(2R,3S,4S)4 by X-ray crystallographic analysis (Figure 1).5
(–)-Anisomycin exhibits selective and potent activities
against pathogenic protozoa and several strains of fungi6
and has also been shown to display antitumor and antiviral
MeO
MeO
H
H
N
N
We envisaged in its retrosynthesis, that the title mole-
cule (+)-anisomycin (1b) can be synthesized by hydrogena-
tion of compound 9, which could be synthesized from com-
pound 8 by tosylation and acetylation. The compound 8
could be synthesized from 7 by performing a sequence of
(R)
(S)
(R)
(S)
(S)
(R)
AcO
AcO
OH
OH
(–)-anisomycin (1a)
(+)-anisomycin (1b)
Figure 1 Structures of (–)- and (+)-anisomycin
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 1191–1196

1192
S. Ajay et al.
Paper
Synthesis
MeO
OH OH
(R)
MeO
H
(S)
•HCl
N
(S)
O
(R)
(R)
O
(R)
(S)
(S)
N3
(R)
N3
OBn
(R)
(R)
MeO
O
AcO
OH
BnO
8
7
1b
OH
HO
(R)
(R)
(S)
(R)
(R)
O
O
OH
OH
O
O
(R)
O
O
(R)
(S)
HO
(R)
(R)
HO
O
O
BnO
BnO
OH
D-Glucose 2
5
3
Scheme 1 Retrosynthetic analysis of (+)-anisomycin (1b)
reactions involving isopropylidene deprotection, cleavage
of the resulting diol followed by reduction of the hemiace-
tal (Scheme 1).
Compound 7 could in turn be synthesized by nucleo-
philic addition on epoxide 5 and azidation of the resulting
secondary alcohol; compound 5 could be synthesized from
D-glucose via the intermediate diol 3.
As per the discussed retrosynthetic analysis, the synthe-
sis of the title molecule (+)-anisomycin (1b) was initiated
with D-glucose. First it was converted into the diol 3 follow-
ing the reported procedure.15 The tosylation of compound 3
with p-toluenesulfonyl chloride and triethylamine in di-
chloromethane at 0 °C gave compound 4 in 79% yield.16
Treatment of the tosyl derivative 4 with K2CO3 in methanol
afforded epoxide 5 in excellent yield.13b Its regioselective
opening with freshly prepared 4-methoxyphenylmagne-
sium bromide in the presence of catalytic CuCN (10 mol%)
in anhydrous THF furnished 6 in 81% yield (Scheme 2).17
When the alcoholic group in 6 was subjected to mesyla-
tion with methanesulfonyl chloride and pyridine in CH2Cl2
followed by azidation of the mesyl intermediate with NaN3
in DMF at 90 °C, the desired azide 7 was obtained in poor
yield (45% in two steps after column purification).18 Unfor-
tunately its yield was not improved even after performing
the azidation at 120 °C. Gratifyingly, mesylation of 6 with
chloromethanesulfonyl chloride (ClMsCl) in pyridine at
OH
HO
TsO
(R)
O
O
O
O
(R)
O
OH
OH
K2CO3, MeOH
O
O
O
p-TsCl, Et3N
p-MeOC6H4MgBr, CuCN
ref. 15
(R)
HO
HO
(S)
(R)
r.t., 30 min, 96%
85% for
3 steps
THF, 0 °C to r.t., 2 h, 81%
anhyd CH2Cl2
0 °C to r.t.
HO
O
O
O
BnO
BnO
BnO
5
3
4
OH
12 h, 79%
D-glucose
2
OH OH
MeO
MeO
i) TFA/H2O/CH2Cl2 (2:1:2), 0 °C to r.t.
ii) NaIO4, THF/H2O (4:1), 0 °C
O
(S)
i) ClCH2SO2Cl, Py, r.t.,
15 min
O
(3R)
O
(R)
N3
O
HO
N3
OBn
iii) NaBH4, MeOH, 0 °C
MeO
ii) NaN3, DMF, 90 °C, 6 h
84% for 2 steps
O
O
BnO
BnO
80% for 3 steps
8
7
6
MeO
OAc OTs
i) p-TsCl, Py, CH2Cl2, 0 °C to r.t.
.
H
HCl
H2, Pd/C, HCl
MeOH, 12 h, 72%
N
ii) Ac2O, Py, 0 °C to r.t.
(S)
N3
OBn
91% for 2 steps
MeO
(R)
(R)
9
AcO
OH
anisomycin (1b)
Scheme 2 Total synthesis of (+)-anisomycin (1b)
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 1191–1196

1193
S. Ajay et al.
Paper
Synthesis
room temperature14a followed by azidation of the resulting
mesyl derivative, without purification, with NaN3 in DMF at
90 °C gave the desired azide 7 in 84% yield for two steps af-
ter column purification. Here, it is worth mentioning that
the 100% conversion of the mesyl derivative to the azide 7 is
attributed to better leaving group behavior of the chloro-
mesyl group compared to the mesyl group.
sualization of the spots was accomplished with CeSO4 and followed
by charring over a hot plate. Column chromatography was performed
by using silica gel (60–120 mesh) and silica gel (100–200 mesh). IR
spectra were recorded on Perkin–Elmer 881 and FTIR-8210 PC Shi-
madzu spectrophotometers. Optical rotations were determined using
an Autopol III polarimeter using a 1-dm cell at 21–30 °C in CHCl3 and
MeOH as the solvents; concentrations are in g/100 mL. ESI-HRMS
were recorded on a JEOL-AccuTOF, JMS-T100LC spectrometer. Mass
spectra were recorded on a JEOL JMS-600H HRMS using EI mode at 70
eV.
The isopropylidene group present in azide 7 was hydro-
lyzed with TFA/CH2Cl2/H2O (2:2:1) at 0 °C to obtain the
hemiacetal, which on oxidative cleavage with sodium meta-
periodate in THF/H2O (4:1) at 0 °C furnished an aldehyde.
The resulting aldehyde was reduced by NaBH4 in methanol
at 0 °C to give the diol 8 in 80% yield (for three steps).17 At
this stage it was essential that the secondary OH group at C-
3 with R-configuration was acetylated selectively so that it
could finally be rendered to the title molecule 1b. Thus, the
C-1 OH in 8 was first tosylated using p-toluenesulfonyl
chloride and pyridine in CH2Cl2 at 0 °C followed by acetyla-
tion of C-3 OH with acetic anhydride and pyridine to give
compound 9 in 91% yield over two steps. Finally, the cleav-
age of the benzyl ether and reduction of the azide function-
ality in 9 in a single step by using Pd/C, H2 in methanol (cat-
alytic HCl) led to in situ cyclization to form the pyrrolidine
ring thus affording (+)-anisomycin (1b) in 72% yield. The 1H
and 13C NMR spectra and the specific rotation were consis-
tent with the reported data.12f,13e
(R)-2-[(3aR,5R,6S,6aR)-6-(Benzyloxy)-2,2-dimethyltetrahydrofu-
ro[2,3-d][1,3]dioxol-5-yl]-2-hydroxyethyl 4-Methylbenzenesul-
fonate (4)
To a solution of diol 3 (2.1 g, 6.77 mmol) in anhydrous CH2Cl2 (30 mL)
at 0 °C were added Et3N (1.88 mL, 13.54 mmol) and p-TsCl (1.94 g,
10.16 mmol). The mixture was allowed to stir at r.t. for 12 h. After
completion of the reaction, the mixture was extracted with CH2Cl2 (2
× 20 mL). The combined organic layers were dried (anhyd Na2SO4),
solvent was removed on a rotary evaporator, and the residue was pu-
rified by chromatography (silica gel, EtOAc/hexane 18:82) to give 4
(2.48 g, 79%) as a colorless oil; Rf = 0.47 (EtOAc/hexane, 1:2).
[α]D23 +72.4 (c 0.16 CHCl3).
IR (neat): 3550, 2959, 1693, 1591, 1432, 1252, 721 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.77–7.79 (m, 2 H), 7.30–7.37 (m, 7 H),
5.87 (d, J = 3.75 Hz, 1 H), 4.67–4.70 (m, 1 H), 4.54–4.59 (m, 2 H), 4.27
(dd, J1 = 10.19 Hz, J2 = 2.73 Hz, 1 H), 4.18–4.20 (m, 1 H), 4.10–4.11 (m,
1 H), 4.04–4.08 (m, 2 H), 2.66 (br s, 1 H), 2.44 (s, 3 H), 1.46 (s, 3 H),
1.30 (s, 3 H).
In summary, we have established a short and efficient
synthetic method for the total synthesis of unnatural (+)-
anisomycin (1b) from the inexpensive carbohydrate D-glu-
cose with an overall yield of 23%. The key features of this
approach are the regioselective opening of an epoxide, azi-
dation of the resulting alcohol, and finally hydrogenation
followed by cyclization to the pyrrolidine ring in a single
step. Here it is worth mentioning that unlike earlier reports,
our synthetic strategy to accomplish 1b does not require a
series of protection and deprotection steps in the final stag-
es.19 Thus, the present approach will find wide application
in the stereoselective synthesis of pyrrolidine iminosugars
including analogues of anisomycin to screen them against a
panel of enzymes to find selective inhibitor(s) which could
eventually be developed as drug(s) for the treatment of dis-
eases, such as cancer, diabetes, and tuberculosis, genetic
conditions, such as lysosomal storage disorders and cystic
fibrosis, and various viral infections including HIV and
HCV.20
13C NMR (100 MHz, CDCl3): δ = 145.4, 137.4, 132.9, 130.3, 129.1,
128.6, 128.4, 128.3, 112.4, 105.5, 82.5, 82.2, 79.6, 72.7, 67.7, 27.2,
26.6, 22.0.
HRMS (ESI): m/z [M + Na]+ calcd for C23H28NaO8S: 487.1397; found:
487.1402.
(3aR,5R,6S,6aR)-6-(Benzyloxy)-2,2-dimethyl-5-[(R)-oxiran-2-
yl]tetrahydrofuro[2,3-d][1,3]dioxole (5)
To a solution of tosylate 4 (1.2 g, 2.59 mmol) in MeOH (15 mL) at r.t.
was added K2CO3 (540 mg, 3.89 mmol) portionwise. The mixture was
stirred for 30 min at this temperature. Upon completion of the reac-
tion, the mixture was filtered through a short pad of silica, and the
filtrate was evaporated under reduced pressure to give a semisolid
that was extracted with EtOAc (2 × 50 mL). The combined organic ex-
tracts were dried (Na2SO4) and concentrated in vacuo. The residue
was purified by chromatography (silica gel, EtOAc/hexane, 6:94) to
furnish 5 (0.73 g, 96%) as an oily liquid; Rf = 0.52 (EtOAc/hexane, 1:9).
[α]D24 –9.0 (c 0.42, CHCl3).
IR (neat): 3532, 2963, 1632, 1527, 1342, 1221, 779 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.30–7.36 (m, 5 H), 5.95 (d, J = 3.66 Hz,
1 H), 4.67–4.74 (m, 2 H), 4.63–4.64 (m, 1 H), 4.08 (d, J = 3.21 Hz, 1 H),
3.76 (dd, J1 = 7.11 Hz, J2 = 3.16 Hz, 1 H), 3.29–3.32 (m, 1 H), 2.92 (dd,
J1 = 5.12 Hz, J2 = 3.88 Hz, 1 H), 2.78 (dd, J1 = 5.12 Hz, J2 = 2.60 Hz, 1 H),
1.45 (s, 3 H), 1.31 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 137.7, 128.9, 128.3, 127.9, 112.3,
105.7, 83.1, 82.4, 82.1, 72.7, 48.6, 47.3, 27.2, 26.6.
Organic solvents were dried using standard procedures. All the prod-
ucts were characterized by 1H NMR, 13C NMR, heteronuclear single
quantum coherence (HSQC), ESI-HRMS, and IR. NMR spectra were re-
corded on Bruker Avance 400 MHz spectrometer at 400 MHz (1H) and
100 MHz (13C) in CDCl3 and CD3OD at 25 °C referenced to TMS at δ =
0.00 for 1H and 13C; CDCl3 appeared at δ = 77.40 and CD3OD appeared
at δ = 48.70 for 13C NMR. Analytical TLC was performed using 2.5 × 5
cm plates coated with a 0.25-mm thickness of silica gel (60F-254), vi-
HRMS (ESI): m/z [M + Na]+ calcd for C16H20NaO5: 315.1203; found:
315.1207.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 1191–1196

1194
S. Ajay et al.
Paper
Synthesis
(R)-1-[(3aR,5R,6S,6aR)-6-(Benzyloxy)-2,2-dimethyltetrahydrofu-
ro[2,3-d][1,3]dioxol-5-yl]-2-(4-methoxyphenyl)ethanol (6)
1H NMR (400 MHz, CDCl3): δ = 7.35–7.38 (m, 5 H), 7.02–7.04 (m, 2 H),
6.80–6.81 (m, 2 H), 5.99 (d, J = 3.76 Hz, 1 H), 4.73–4.76 (m, 1 H), 4.70
(d, J = 4.01 Hz, 1 H), 4.43–4.46 (m, 1 H), 4.11–4.14 (m, 1 H), 3.95–3.96
(m, 1 H), 3.88–3.93 (m, 1 H), 3.79 (s, 3 H), 2.62–2.66 (m, 1 H), 2.40–
2.46 (m, 1 H), 1.50 (s, 3 H), 1.34 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 158.9, 137.2, 130.6, 129.7, 129.0,
128.7, 128.5, 114.3, 112.3, 105.2, 83.0, 82.2, 82.1, 72.2, 63.6, 55.6,
36.5, 27.2, 26.7.
A portion of 4-bromoanisole (approx. 50 mg) dissolved in anhydrous
THF (15 mL) and Mg turnings (414 mg, 17.24 mmol) were taken in a
50-mL flame-dried, two-necked round bottom flask, fitted with a re-
flux condenser and a rubber septum. A catalytic amount of I2 was
added and the mixture was refluxed with vigorous stirring followed
by dropwise addition of the remaining solution of 4-bromoanisole
(1.3 mL, 9.03 mmol) in THF (10 mL). After completion of the addition,
reflux was continued for a further 2 h and the solution was cooled to
r.t.
HRMS (ESI): m/z [M + Na]+ calcd for C23H27N3NaO5: 448.1843; found:
448.1835.
To another 50-mL two-necked, oven-dried round bottom flask
equipped with a magnetic stir bar, a rubber septum, and a N2 inlet,
were added CuCN (73.5 mg, 0.821 mmol) and compound 5 (2.4 g, 8.21
mmol) in anhydrous THF (40 mL). The mixture was cooled to 0 °C and
the Grignard reagent prepared above was added dropwise using a
long needle. After completion of the addition, stirring was continued
for 30 min at 0 °C and an additional 2 h at r.t. After completion of the
reaction, sat. NH4Cl solution was added and stirring was continued
until a blue aqueous layer was obtained. The two layers were separat-
ed and the aqueous layer was extracted with EtOAc (3 × 20 mL). The
combined organic layers were dried (Na2SO4) and evaporated in vac-
uo. The organic solvent was evaporated under reduced pressure to
give a black residue that was purified by column chromatography
(EtOAc/hexane 15:85) to obtain 6 (2.66 g, 81%) as a syrup; Rf = 0.45
(EtOAc/hexane, 1:4).
(2R,3R,4S)-4-Azido-2-(benzyloxy)-5-(4-methoxyphenyl)pentane-
1,3-diol (8)
To a solution of 7 (821 mg, 1.93 mmol) in CH2Cl2/H2O (2:1, 6 mL) at
0 °C, TFA (4 mL) was added and the mixture was stirred for 4 h at r.t.
After completion of the reaction (approx. 4 h), it was cooled to 0 °C
and sat. aq NaHCO3 solution was added to neutralize excess TFA. The
aqueous phase was extracted with CH2Cl2 (2 × 10 mL). The combined
organic phases were dried (Na2SO4) and concentrated under reduced
pressure to obtain a residue that was then dissolved in THF/H2O (4:1,
10 mL). To the mixture, in an ice bath, was added NaIO4 (620 mg, 2.9
mmol) in one portion. Stirring was continued at 0 °C for 1 h and after
completion of the reaction, it was quenched with Na2S2O3 and ex-
tracted with EtOAc (2 × 15 mL). The combined organic layers were
dried (Na2SO4). After evaporating the organic solvent, the resulting
crude aldehyde was dissolved in MeOH and kept at 0 °C. After 5 min,
NaBH4 (80 mg, 2.12 mmol) was added to the mixture and stirring was
continued until the starting material was completely consumed (ap-
prox. 1 h, monitored by TLC). After completion of the reaction, it was
filtered through a short pad of Celite. The resulting filtrate was evapo-
rated under reduced pressure to give a residue that was subjected to
column chromatography (EtOAc/hexane, 30:70) to afford 8 (550 mg,
80%) as an oil; Rf = 0.42 (EtOAc/hexane, 1:1.5).
[α]D23 –37.0 (c 0.29, CHCl3).
IR (neat): 3637, 3021, 2926, 2171, 1439, 1277, 971, 785, 699 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.28–7.35 (m, 5 H), 7.15–7.17 (m, 2 H),
6.82–6.85 (m, 2 H), 5.98 (d, J = 3.78 Hz, 1 H), 4.69–4.72 (m, 1 H), 4.63
(d, J = 3.85 Hz, 1 H), 4.49–4.52 (m, 1 H), 4.10–4.16 (m, 1 H), 4.05–4.06
(m, 1 H), 3.95–3.98 (m, 1 H), 3.77 (s, 3 H), 2.97 (dd, J1 = 14.05 Hz, J2 =
3.68 Hz, 1 H), 2.72 (dd, J1 = 14.05 Hz, J2 = 7.88 Hz, 1 H), 2.00 (d, J = 5.78
Hz, 1 H), 1.45 (s, 3 H), 1.32 (s, 3 H).
[α]D28 –17.9 (c 0.21, CHCl3).
IR (neat): 3636, 3321, 2979, 2653, 2133, 1631, 1358, 1218, 768 cm–1
.
13C NMR (100 MHz, CDCl3): δ = 158.7, 137.5, 131.1, 131.0, 129.0,
128.6, 128.4, 114.2, 112.1, 105.5, 82.6, 82.1, 81.9, 72.4, 69.9, 55.6,
40.0, 27.1, 26.7.
HRMS (ESI): m/z [M + Na]+ calcd for C23H28NaO6: 423.1778; found:
423.1790.
1H NMR (400 MHz, CDCl3): δ = 7.32–7.35 (m, 5 H), 7.12–7.14 (m, 2 H),
6.84–6.86 (m, 2 H), 4.74 (d, J = 11.66 Hz, 1 H), 4.61 (d, J = 11.66 Hz, 1
H), 4.54 (m, 1 H), 4.13–4.19 (m, 2 H), 4.04 (dd, J1 = 5.37 Hz, J2 = 2.68
Hz, 1 H), 3.96–4.00 (m, 1 H), 3.78 (s, 3 H), 3.16 (dd, J1 = 13.66 Hz, J2 =
5.58 Hz, 1 H), 2.73–2.78 (m, 1 H).
(3aR,5R,6S,6aR)-5-[(S)-1-Azido-2-(4-methoxyphenyl)ethyl]-6-
(benzyloxy)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole (7)
13C NMR (100 MHz, CDCl3): δ = 158.9, 137.7, 131.1, 129.0, 128.5,
128.3, 114.6, 86.3, 74.5, 72.9, 72.3, 62.7, 55.6, 35.9.
HRMS (ESI): m/z [M + H]+ calcd for C19H24N3O4: 358.1761; found:
358.1760.
To a solution of compound 6 (1.4 g, 3.5 mmol) in pyridine (5 mL) at r.t.
was added dropwise chloromesyl chloride (0.35 mL, 3.85 mmol). The
mixture was stirred at this temperature for 15 min. After completion
of the reaction, water was added and the resulting solution was ex-
tracted with EtOAc (2 × 15 mL). The combined organic extracts were
dried (Na2SO4) and concentrated under reduced pressure; excess pyri-
dine was co-evaporated with toluene. The residue was used directly
in the next step without purification. To the crude mesyl derivative
dissolved in anhydrous DMF (10 mL) was added NaN3 (680 mg, 10.5
mmol). The mixture was heated at 90 °C for 6 h. After completion of
the reaction, the mixture was diluted Et2O and extracted with Et2O (2
× 20 mL). The combined organic layers were dried (Na2SO4) and con-
centrated under reduced pressure to give a residue that was purified
by column chromatography (silica gel, EtOAc/hexane 7:93) to obtain 7
(1.25 g, 84%) as a colorless oil; Rf = 0.48 (EtOAc/hexane, 1:9).
(2S,3R,4R)-2-Azido-4-(benzyloxy)-1-(4-methoxyphenyl)-5-(tosyl-
oxy)pentan-3-yl Acetate (9)
To a stirred solution of 8 (550 mg, 1.55 mmol) in anhydrous CH2Cl2 (8
mL) were added pyridine (0.25 mL, 3.1 mmol) and p-TsCl (439 mg, 2.3
mmol) at 0 °C. The mixture was stirred at 0 °C for 30 min and at r.t. for
4 h. After completion of the reaction, water was added to the mixture
and it was extracted with CH2Cl2 (2 × 10 mL). The organic solvent was
removed under vacuum and the crude residue was dissolved in pyri-
dine (5 mL) and the solution was cooled to 0 °C. The Ac2O (0.22 mL,
2.3 mmol) was added and the mixture was stirred at r.t. for 4 h. After
complete disappearance of the starting material (TLC), water was
added, and the solution was extracted with EtOAc (2 × 10 mL). The
combined organic extracts were dried (Na2SO4) and the solvent re-
[α]D24–10.0 (c 0.43, CHCl3).
IR (neat): 3621, 2984, 2121, 1596, 1387, 1139, 765 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 1191–1196

1195
S. Ajay et al.
Paper
Synthesis
moved under reduced pressure to give a residue that was purified by
column chromatography (silica gel, EtOAc/hexane, 4:96) to give 9 (78
mg, 91%) as a pale yellow liquid; Rf = 0.6 (EtOAc/hexane, 1:9).
[α]D28 –1.9 (c 0.34, CHCl3).
References
(1) Sobin, B. A.; Tanner, F. W. J. Am. Chem. Soc. 1954, 76, 4053.
(2) (a) Ishida, S.; Yamada, O.; Futatsuya, F.; Ito, K.; Yamamoto, H.;
Munakata, K. Proceedings of the First Intersectional Congress of
IAMS; Vol. 3; Hasegawa, T., Ed.; Science Council of Japan: Tokyo,
1975, 641. (b) Hosoya, Y.; Kameyama, T.; Naganawa, H.; Okami,
Y.; Takeuchi, T. J. Antibiot. 1993, 46, 1300.
(3) Beereboom, J. J.; Butler, K.; Pennington, F. C.; Solomons, I. A.
J. Org. Chem. 1965, 30, 2334.
(4) Wong, C. M. Can. J. Chem. 1968, 46, 1101.
IR (neat): 3607, 2821, 2133, 1729, 1635, 1358, 1212, 817, 741 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.67–7.69 (m, 2 H), 7.23–7.24 (m, 5 H),
7.10–7.12 (m, 2 H), 6.96–6.98 (m, 2 H), 6.75–6.77 (m, 2 H), 4.98 (m, 1
H), 4.49–4.52 (m, 1 H), 4.33–4.36 (m, 1 H), 4.18 (dd, J1 = 11.03 Hz, J2 =
3.40 Hz, 1 H), 4.08–4.12 (m, 1 H), 3.78–3.81 (m, 1 H), 3.72 (s, 3 H),
3.54–3.58 (m, 1 H), 2.65–2.66 (m, 2 H), 2.36 (s, 3 H), 2.00 (s, 3 H).
(5) Schaefer, J. P.; Wheatley, P. J. J. Org. Chem. 1968, 33, 166.
(6) (a) Jimenez, A.; Vazquez, D. In Antibiotics; Hahn, F. E., Ed.;
Springer: Berlin, 1979, 1–19. (b) Grollman, A. P. J. Biol. Chem.
1967, 242, 3226.
(7) Schwartdt, O.; Veith, U.; Gaspard, C.; Jager, V. Synthesis 1999,
1473.
13C NMR (100 MHz, CDCl3): δ = 171.2, 159.1, 145.4, 137.5, 133.1,
130.5, 130.3, 128.9, 128.6, 128.4, 128.4, 128.3, 114.6, 76.3, 73.6, 72.9,
69.4, 61.6, 55.6, 36.4, 22.0, 21.0.
HRMS (ESI): m/z [M + NH4]+ calcd for C28H35N4O7S: 571.2221; found:
571.2218.
(8) Santander, V. M.; Cue, A. B.; Diaz, J. G. H.; Balmis, F. J.; Miranda,
G.; Urbina, E.; Portilla, J.; Plata, A. A.; Zapata, H. B.; Munoz, V. A.;
Abreu, L. M. Rev. Invest. Biol. Univ. Guadalajara 1961, 1, 94.
(9) (a) Frye, W. W.; Mule, J. G.; Swartzwelder, C. Antibiot. Annu.
1955, 820. (b) Armstrong, T.; Santa Maria, O. Antibiot. Annu.
1955, 824.
(10) Korzybski, T.; Kowszyk-Gindifer, Z.; Kurytowicz, W. Antibiotics;
Vol. 1; American Society of Microbiology: Washington DC,
1978, 343–346.
(11) (a) Kim, J. H.; Curtis-Long, M. J.; Woo, D. S.; Jin, H. L.; Byong, W.
L.; Yong, J. Y.; Kyu, Y. K.; Park, K. H. Bioorg. Med. Chem. Lett.
2005, 15, 4282. (b) Chapman, T. M.; Courtney, S.; Hay, P.; Davis,
B. G. Chem.Eur. J. 2003, 9, 3397.
(2S,3R,4R)-4-Hydroxy-2-(4-methoxybenzyl)pyrrolidin-3-yl Ace-
tate Hydrochloride [(+)-Anisomycin 1b)]
To a solution of compound 9 (56 mg, 0.10 mmol) in MeOH (2 mL) was
added HCl (1 drop) and catalytic amount of Pd/C (10% on carbon) and
the mixture stirred under a positive pressure of H2 (balloon) at r.t. for
12 h. After completion of the reaction, Pd/C was filtered off through a
short pad of Celite and the filtrate was concentrated under reduced
pressure to give a residue that was purified by flash column chroma-
tography (MeOH/CHCl3, 5:95) to afford 1b (19 mg, 72%) as a white
solid; Rf = 0.54 (MeOH/CHCl3, 1:9); mp 109–111 °C.
[α]D –3.8 (c 0.24, MeOH) {Lit.13e [α]D –3.6; Lit.12f [α]D +4.0 (c 0.28,
26
25
MeOH) for (–)-anisomycin}.
(12) For recent literature: (a) Zeng, J.; Zhang, Q.; Zhang, H. K.; Chen,
A. RSC Adv. 2013, 3, 20298. (b) Li, J.; Feng, Y. H.; Li, X. B.; Han,
W.; Liu, H. Q.; Shao, G. G. Chin. Chem. Lett. 2012, 23, 647.
(c) Chouthaiwale, P. V.; Kotkar, S. P.; Sudalai, A. ARKIVOC 2009,
(ii), 88. (d) Joo, J.-E.; Lee, K.-Y.; Pham, V.-T.; Tian, Y-S.; Ham, W.-
H. Org. Lett. 2007, 9, 3627. (e) Kim, J. H.; Curtis-Long, M. J.; Seo,
W. D.; Ryu, Y. B.; Yang, M. S.; Park, K. H. J. Org. Chem. 2005, 70,
4082; and references cited therein. (f) Hulme, A. N.; Rosser, E.
M. Org. Lett. 2002, 4, 265; and references cited therein.
(13) (a) Detz, R. J.; Abiri, Z.; Griel, R. L.; Hiemstra, H.; Maarseveen, J.
H. V. Chem. Eur. J. 2011, 17, 5921. (b) Reddy, K. S.; Rao, B. V. Tet-
rahedron: Asymmetry 2011, 22, 190. (c) Reddy, J. S.; Kumar, A.
R.; Rao, B. V. Tetrahedron: Asymmetry 2005, 16, 3154.
(d) Meyers, A. I.; Dupre, B. Heterocycles 1987, 113. (e) Wong, C.
M.; Buccini, J.; Chang, I.; Te Raa, J.; Schwenk, R. Can. J. Chem.
1969, 47, 2421. (f) Wong, C. M.; Buccini, J.; Te Raa, J. Can. J. Chem.
1968, 46, 3091.
IR (neat): 3386, 3284, 3232, 1782, 1621, 1529, 1214, 714 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.24–7.26 (m, 2 H), 6.90–6.93 (m, 2 H),
5.06 (d, J = 2.92 Hz, 1 H), 4.16–4.20 (m, 1 H), 3.79 (s, 3 H), 3.63 (dd, J1 =
12.83 Hz, J2 = 4.48 Hz, 1 H), 3.21–3.24 (m, 1 H), 3.03–3.11 (m, 1 H),
2.97–3.00 (m, 1 H), 2.19 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 170.8, 160.5, 130.9, 129.8, 128.9,
115.5, 78.2, 73.4, 63.6, 55.7, 52.6, 32.1, 20.6.
HRMS (ESI): m/z [M + H]+ or [M – Cl]+ calcd for C14H20NO4: 266.1387;
found: 266.1379.
Acknowledgment
S.A. and P.S. thanks the CSIR, New Delhi for awarding Senior Research
Fellowship and also we are thankful to Mr A. K. Pandey for technical
assistance and SAIF, CDRI, for providing spectral data. The financial
grant from DST (SB/S1/OC-28/2014) is gratefully acknowledged. CDRI
Communication No. 9174.
(14) (a) Arora, I.; Kashyap, V. K.; Singh, A. K.; Dasgupta, A.; Kumar, B.;
Shaw, A. K. Org. Biomol. Chem. 2014, 12, 6855. (b) Das, P.;
Kundooru, S.; Pandole, R.; Sharma, S. K.; Singh, B. N.; Shaw, A. K.
Tetrahedron: Asymmetry 2016, 27, 101.
(15) Morillo, M.; Lequart, V.; Grand, E.; Goethals, G.; Usubillaga, A.;
Villa, P.; Martin, P. Carbohydr. Res. 2001, 334, 281.
Supporting Information
(16) Meurillon, M.; Marton, Z.; Hospital, A.; Jordheim, L. P.; Béjaud,
J.; Lionne, C.; Dumontet, C.; Périgaud, C.; Chaloin, L.; Peyrottes,
S. Eur. J. Med. Chem. 2014, 77, 18.
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1561365.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
(17) Mereyala, H. B.; Gadikota, R. R. Tetrahedron: Asymmetry 1998, 9,
827.
(18) Kundooru, S.; Das, P.; Meena, S.; Kumar, V.; Siddiqi, M. I.; Datta,
D.; Shaw, A. K. Org. Biomol. Chem. 2015, 13, 8241.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 1191–1196

1196
S. Ajay et al.
Paper
Synthesis
(19) (a) Kaden, S.; Brockmann, M.; Reissig, H.-U. Helv. Chim. Acta
2005, 88, 1826. (b) Kang, S. H.; Choi, H.-W. Chem. Commun.
1996, 1521.
Fleet, G. W. J. Future Med. Chem. 2011, 3, 1513. (d) Compain, P.;
Martin, O. R. Iminosugars: From Synthesis to Therapeutics Appli-
cations; John Wiley: Chichester, 2007.
(20) (a) Horne, G.; Wilson, F. X.; Tinsley, J.; Williams, D. H.; Storer, R.
Drug Discovery Today 2011, 16, 107. (b) Horne, G.; Wilson, F. X.
Prog. Med. Chem. 2011, 50, 135. (c) Nash, R. J.; Kato, A.; Yu, C. Y.;
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 1191–1196