Synthesis of the aminocyclitol units of (-)-hygromycin A and methoxyhygromycin from myo-inositol

Article abstract of DOI:10.1021/jo300444b

Concise and efficient syntheses of the aminocyclitol cores of hygromycin A (HMA) and methoxyhygromycin (MHM) have been achieved starting from readily available myo-inositol. Reductive cleavage of myo-inositol orthoformate to the corresponding 1,3-acetal, stereospecific introduction of the amino group via the azide, and resolution of a racemic cyclitol derivative as its diastereomeric mandelate esters are the key steps in the synthesis. Synthesis of the aminocyclitol core of hygromycin A involved chromatography in half of the total number of steps, and the aminocyclitol core of methoxyhygromycin involved only one chromatography.

Full text of DOI:10.1021/jo300444b

Note
pubs.acs.org/joc
Synthesis of the Aminocyclitol Units of (−)-Hygromycin A and
Methoxyhygromycin from myo-Inositol
Bharat P. Gurale,† Mysore S. Shashidhar,*,† and Rajesh G. Gonnade‡
‡
†Division of Organic Chemistry and Center for Materials Characterization, National Chemical Laboratory, Dr. Homibhabha Road,
Pune-411 008, India
S
* Supporting Information
ABSTRACT: Concise and efficient syntheses of the amino-
cyclitol cores of hygromycin A (HMA) and methoxyhygro-
mycin (MHM) have been achieved starting from readily
available myo-inositol. Reductive cleavage of myo-inositol
orthoformate to the corresponding 1,3-acetal, stereospecific
introduction of the amino group via the azide, and resolution
of a racemic cyclitol derivative as its diastereomeric mandelate esters are the key steps in the synthesis. Synthesis of the
aminocyclitol core of hygromycin A involved chromatography in half of the total number of steps, and the aminocyclitol core of
methoxyhygromycin involved only one chromatography.
here has been an upsurge in interest in the chemistry of
myo-inositol and its derivatives/analogues because of the
Chart 1. Structure of Hygromycin A (HMA),
Methoxyhygromycin (MHM), and Their Aminocyclitol
Units
T
involvement of phosphoinositols in cellular signal transduction
mechanisms and anchoring of certain proteins to cell
membranes.1−3 Synthetic methodologies and techniques have
been developed in the recent past for the synthesis of inositol
derivatives useful in the study of the inositol cycle, starting from
the most abundantly available isomer, myo-inositol.4 Some of
these methods have also been used for the synthesis of natural
products and their analogs.5 1,2-Acetal derivatives of myo-
inositol (acetals of vicinal hydroxyl groups) have been
frequently used as early intermediates for the synthesis of
various classes of compounds mentioned above, although the
acetalization of myo-inositol often leads to the formation of all
possible isomeric acetals, which have to be separated. In
contrast, the 1,3-bridged acetals of myo-inositol can be prepared
as single products in good yields via reductive cleavage of O-
protected orthoester derivatives of myo-inositol.6,7 1,3-Bridged
acetals provide opportunities for new selective reactions (of the
inositol hydroxyl groups) since conformation of the two six-
membered rings in these acetals can deviate from the normal
chair conformation.8−10 Hence, 1,3-acetals of myo-inositol
derivatives have the potential to emerge as useful intermediates
for the preparation of biologically relevant cyclitol derivatives
and natural products containing the cyclitol moiety. We herein
delineate the synthesis of aminocyclitol moieties of hygromycin
A (1, Chart 1), methoxyhygromycin (2), and the unnatural
enantiomer of the former aminocyclitol, from myo-inositol (5)
via its 1,3-bridged acetals.
continuous efforts in the recent past to obtain naturally
occurring aminocyclitols as well as their synthetic analogues
with enhanced or more selective biological profiles that could
be useful in the intervention of cellular processes.21,22 For
instance, certain aminocyclitol derivatives have been shown to
be potential candidates for the development of therapeutic
agents,23 as enzyme inhibitors with diverse biomedical
applications,24,25 and also as molecular tools for the
investigation of the myo-inositol cycle and related cellular
processes.26−28 Hygromycin A (1), in addition to being a
broad-spectrum antibiotic,29,30 functions as a peptidyl trans-
ferase inhibitor,31 a hemagglutination inactivator, and an
effective agent for the control of swine dysentery.32,33 A series
The aminocyclitol unit of 1 has previously been synthesized
by Trost11 and Donohoe,12,13 and a formal synthesis was
reported by Arjona.14 The aminocyclitol 4 was synthesized
from myo-inositol (5) by Chida et al.;15 biosynthesis of the
aminocyclitol (−)-3 has also been investigated.16
Aminocyclitols are a diverse class of compounds with
Received: March 1, 2012
Published: June 4, 2012
interesting biological properties.17−20 There have been
© 2012 American Chemical Society
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of synthetic modifications and structure activity relationship
studies on (−)-1 revealed that the aminocyclitol moiety in
hygromycin A is critical for the antibacterial activity, while the
fucofuranose moiety can be replaced with an allyl group or
hydrogen.16,33−35 Methoxyhygromycin (2), an analogue of
hygromycin A, has been shown to possess herbicidal
activity.16,32,36
the azides 9 and 10 was established unambiguously by single-
crystal X-ray diffraction analysis. The observed difference in
product formation in DMF and HMPA could be due to the
difference in the temperature at which the reaction takes place.
Better facility of the nucleophilic substitution reaction in
HMPA (dielectric constant = 30) as compared to DMF
(dielectric constant = 38) due to solvation of the cation by
HMPA is well precedented in the literature.38 However, further
experimental and perhaps theoretical investigations are
necessary to understand the effect of the solvent on the
selectivity of this nucleophilic substitution reaction in this
conformationally flexible bicyclic derivative 8.10
A comparison of the structure of the aminocyclitol (−)3 and
myo-inositol (5) reveals that the relative orientation of all the
substituents on the carbocylic ring, except the C5-substituent, is
the same in both molecules. To convert 5 to (−)-3, (a) the C5-
hydroxyl group must be converted to an amino group with
inversion of configuration at the C5-carbon, (b) the C2 and
C3-hydroxyl groups must be converted to the corresponding
methylidene acetal, and (c) the myo-inositol derivative must be
resolved or desymmetrized to obtain one enantiomer of the
aminocyclitol unit of HMA. Key reactions in our synthetic
approach to achieve these changes in myo-inositol were (i) one-
pot conversion of myo-inositol to 4,6-di-O-benzyl orthoformate
6, (ii) regioselective cleavage of the orthoformate in 7, (iii)
stereospecific introduction of the azido group at C5, and (iv)
the resolution of the racemic-alcohol 13 as its mandelate esters.
Our synthesis began with a one-pot conversion of the
commercially available myo-inositol (5) to the dibenzyl ether 6
(Scheme 1).37 The C-2 hydroxyl group in 6 was protected as
Our initial attempts to cleave the PMB ether in 9 with DDQ
resulted in the concomitant cleavage of one of the benzyl ethers
as well (Scheme 2).39 However, we could achieve the exclusive
Scheme 2. PMB Ether Cleavage in 9 and the Attempted
Isomerization of the 1,3-Acetal to the Corresponding 1,2-
Acetal
Scheme 1. Synthesis of the Azido Cyclitol 9
cleavage of the PMB ether by carrying out the reaction of 9
with DDQ under controlled conditions. The structures of the
benzyl ethers 11 and ( )-12 were established by single-crystal
X-ray diffraction analysis.
Our attempts to isomerize the 1,3-methylidene acetal in 9
and 11 in the presence of Lewis acids (TiCl4, ZnCl2, MgBr2,
BF3·OEt2)6,40−42 to the corresponding 1,2-methylidene acetal
( )-13, failed.43 This isomerization initially appeared feasible
since the inositol ring in the acetals 9 and 11 is locked in a
relatively less stable “axial rich” conformation compared to the
acetal ( )-13, which exists in the relatively stable “equatorial
rich” conformation. In addition, the 1,3-acetal 14 on treatment
with a stoichiometric quantity of titanium tetrachloride is
known to give the 1,2-acetal ( )-16 (Scheme 2).6,44 The
conversion of 14 to ( )-16 appears to require the chelation of
titanium with three axially oriented oxygen atoms of the
cyclitol. Perhaps the isomerization of 9 or 11 to the
corresponding acetal did not proceed because of the absence
of a suitably oriented oxygen atom at the C5-position of the
inositol ring in 9 and 11 to aid the chelation of the Lewis acid
(see 15).
the PMB ether 7, and the crude 7 was subjected to
regioselective cleavage6,7 by DIBAL-H to obtain the alcohol
8. The high preference observed for the cleavage of the C5−O
bond is due to the preferential complexation of the C5-oxygen
atom of 7 with aluminum (in DIBAL-H). The steric bulk of the
reducing agent precludes complexation of aluminum with C1
and C3 oxygen atoms of 7. The free hydroxyl group in 8 was
converted to the corresponding triflate by treatment with triflic
anhydride in dichloromethane/pyridine at −10 °C. Nucleo-
philic displacement of the triflate by the azide8 in HMPA gave
the desired azide 9 in 94% yield (over four steps, 6−9); the
azide 9 was isolated by crystallization. We initially used DMF as
a solvent for the substitution of the triflate (of 8) by the azide
ion.8 This reaction did not proceed at ambient temperature; the
reaction did proceed at 100 °C but gave a mixture of isomeric
azides 9 and 10, separable by chromatography. Configuration of
The PMB group and the 4,6-methylidene acetal in 9 were
cleaved with concd HCl to obtain the triol 17 (Scheme 3).
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Scheme 3. Synthesis of the Aminocyclitol Unit of HMA and Its Enantiomer from 9
Treatment of the triol 17 with TMSOTf/lutidine in dimethoxy-
methane gave the methoxymethyl ether of ( )-13; the
methoxymethyl ether could be cleaved in refluxing methanol
in the presence of catalytic amount of TsOH without disturbing
the cis-acetal to obtain the racemic alcohol 13 exclusively.11,45 In
our initial attempts, we observed that 17 could be converted to
the desired 1,2-methylidene acetal ( )-13 by using POCl3 and
DMSO,46 but the yield obtained was very low (20%). Hence,
we opted for the conversion of 17 to ( )-13 via the MOM
ether.
Scheme 4. Synthesis of the Aminocyclitol Unit of MHM
was established by single-crystal X-ray diffraction analysis. This
synthetic sequence involved 10 steps, in four pots, and the
overall yield of 20 was 56%.
To synthesize the enantiomeric aminocyclitol of HMA, the
racemic-alcohol 13 was O-acylated with (R)-(−)-O-acetylman-
delic acid in the presence of DCC. The diasteriomeric esters 18
(48%) and 19 (47%) were separated by flash column
chromatography. The structure and the relative configuration
of 18 were confirmed by single-crystal X-ray diffraction analysis.
The mandelate ester in 18 was hydrolyzed with methanolic
KOH at room temperature to obtain (−)13. Finally, cleavage of
the two benzyl ethers and reduction of the azide to the
corresponding amine was carried out by catalytic hydro-
genolysis in the presence of Pd/C in methanol−acetic acid to
afford the amino cyclitol (−)-3. Similarly, we also converted 19
to the unnatural isomer (+)-3. The 11-step synthetic sequence
starting from myo-inositol described so far, provided the
aminocyclitol (−)-3 as well as its enantiomer, in 31% overall
yield (see the Supporting Information for comparison with
previous literature reports). It is pertinent to note that none of
the synthetic steps during the conversion of 5 to 9 involved
chromatography, and the latter six steps (except the separation
of 18 and 19) resulted in the formation of a single product,
which was isolated by chromatography. We also prepared the
racemic amino cyclitol unit of HMA by reduction of the azide
and cleavage of the benzyl ethers in racemic 13. This was done
in order to optimize the reaction conditions before the
resolution of racemic 13 and preparation of the optically pure
aminocyclitol (−)-3.
To conclude, new syntheses from myo-inositol of the key
aminocyclitol portion of hygromycin A as well as methoxyhy-
gromycin are reported. During the synthesis of the former, only
five column chromatographic purifications were necessary (out
of a total of 11 steps), while the synthesis of the latter required
only one column chromatographic purification and all the
intermediates were purified by crystallization. These syntheses
represent the highest yielding routes reported for the
aminocyclitols (−)-3 and 4 and illustrate the advantages of
using inositol-1,3-acetals as early intermediates in syntheses
starting from myo-inositol.
EXPERIMENTAL SECTION
■
General Experimental Methods. All of the solvents were
purified according to the literature procedures47 before use. A 60%
dispersion of sodium hydride in mineral oil was used for O-alkylation
reactions. Workup implies washing of the organic layer successively
with water, dilute HCl (∼2%), water, saturated sodium bicarbonate
solution, water, followed by brine. Column chromatographic
separations were carried out on silica gel (60−120 mesh or 230−
400 mesh) or neutral alumina with a solvent system as mentioned in
individual procedures. The compounds previously reported in the
literature were characterized by comparison of their melting points
and/or 1H NMR spectra with reported data. All the racemic
derivatives of myo-inositol (numbered with the prefix ( )) are
represented in schemes by one of the enantiomers without numbering
of the inositol ring carbon atoms.
4,6-Di-O-benzyl-myo-inositol 1,3,5-Orthoformate (6). myo-
Inositol (5, 11.36 g, 63.10 mmol), triethyl orthoformate (16.00 mL,
96.78 mmol), and p-toluenesulfonic acid (1.08 g, 6.31 mmol) in dry
DMF (100 mL) were heated at 110 °C for 4 h. The clear solution
obtained was allowed to cool to room temperature, and dry
triethylamine (1.2 mL) was added. The reaction mixture was
concentrated under reduced pressure to afford a gummy solid which
The synthesis of the aminocyclitol unit of methoxyhygro-
mycin began with the methylation of the C2-hydroxyl group of
the alcohol 11 (Scheme 4). Deprotection of all the hydroxyl
groups as well as reduction of the azide to the amine was
accomplished in a single step, and the aminocyclitol unit of
MHM was isolated as its pentaacetate 20. The structure of 20
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was dissolved in dry DMF (500 mL) and stirred after the addition of
lithium hydride (2.00 g, 252.4 mmol) at ambient temperature for 1 h.
To the thick slurry formed was added benzyl bromide (16.5 mL,
138.82 mmol) and the mixture stirred for 12 h. Ice was added to the
reaction mixture, which was stirred for 2 h; solvents were removed
under reduced pressure, and the residue was worked up with ethyl
acetate and dried over anhyd sodium sulfate. The solvent was removed
under reduced pressure, and the crude product was crystallized from
hot 30% ethyl acetate in light petroleum to afford the crystalline
dibenzyl ether 6 (19.63 g, 84%): mp 123−124 °C (lit.48 mp 124−125
°C).
2-O-(4-Methoxybenzyl)-4,6-di-O-benzyl-myo-inositol 1,3,5-
Orthoformate (7). To a solution of the dibenzyl ether 6 (14.81 g,
40.00 mmol) in dry DMF (100 mL) was added sodium hydride (1.92
g, 48.00 mmol) and the mixture stirred for 10 min. p-Methoxybenzyl
chloride (6.00 mL, 44.00 mmol) was then added dropwise, and the
reaction mixture was stirred for 3 h. Excess sodium hydride was
quenched by the addition of ice-cold water. The solvent was
evaporated under reduced pressure, and the residue was worked up
with ethyl acetate and dried over anhyd sodium sulfate. The solvent
was removed under reduced pressure to afford the 7 (19.60 g) as a
gum, which was used for the next reaction without purification.
A small quantity of the crude 7 was purified by column
chromatography (eluent: 15% ethyl acetate in light petroleum) to
afford 7 as a gummy liquid: TLC Rf = 0.3 in 15% ethyl acetate/light
petroleum; 1H NMR (CDCl3, 200 MHz) δ 7.15−7.32 (m, 12H),
6.80−6.85 (m, 2H), 5.52 (d, J = 1.2 Hz, 1H), 4.59 (s, 2H), 4.54 (q, J =
11.4 Hz, 4H), 4.40−4.42 (m, 1H), 4.29−4.37 (m, 2H), 4.22−4.28 (m,
2H), 4.01−4.06 (m, 1H), 3.76 (s, 3H) ppm; 13C NMR (CDCl3, 50.3
MHz) δ 159.2, 137.5, 129.7, 128.3, 127.7, 127.4, 113.7, 103.1, 73.9,
71.4, 71.1, 70.5, 68.0, 66.5, 55.1. Anal. Calcd for C29H30O7 (490.54):
C, 71.00; H, 6.16. Found: C, 71.26; H, 6.10.
sulfate. The solvent was removed under reduced pressure to obtain the
crude product, which was purified by crystallization (hot 10% ethyl
acetate in light petroleum) to afford the azide 9 (11.67 g, 94% for four
steps) as a colorless solid: TLC Rf = 0.5 in 30% ethyl acetate/light
petroleum; mp 81−82 °C; IR (Nujol) ν 2110 cm−1; 1H NMR (CDCl3,
̅
200 MHz) δ 7.28−7.37 (m, 10H), 7.13−7.20 (m, 2H), 6.72−6.82 (m,
2H), 5.46 (d, J = 4.6 Hz, 1H), 4.67 (q, J = 11.9 Hz, 4H), 4.52 (brs,
1H), 4.41 (s, 2H), 4.37−4.39 (m, 1H), 4.21−4.26 (m, 2H), 4.05 (t, J =
4.2 Hz, 2H), 3.74 (s, 3H), 3.69−3.73 (m, 1H) ppm; 13C NMR
(CDCl3, 50.3 MHz) δ 159.2, 137.7, 129.5, 129.4, 128.3, 127.7, 127.6,
113.8, 85.4, 80.2, 73.4, 70.4, 70.2, 68.8, 55.1, 53.7 ppm. Anal. Calcd for
C29H31N3O6 (517.57): C, 67.30; H, 6.04; N, 8.12. Found: C, 67.07; H,
6.36; N, 8.32%.
Reaction of the Triflate of 8 with Sodium Azide in DMF. A
mixture of the crude triflate (0.62 g, ∼1.0 mmol; prepared from
alcohol 8), sodium azide (0.33 g, 2.14 mmol), and DMF (10 mL) was
stirred at 100 °C for 1 h in an atmosphere of argon. The solvent was
evaporated under reduced pressure, and the residue worked up with
ethyl acetate and dried over anhydrous sodium sulfate. The solvent
was removed under reduced pressure, and the products were separated
by column chromatography to obtain 9 (0.238 g, 46%; eluent: 10%
ethyl acetate in light petroleum) and 10 (0.243 g, 47%; eluent: 15%
ethyl acetate in light petroleum) as colorless solids.
Data for 10: TLC Rf = 0.4 in 30% ethyl acetate/light petroleum;
mp 61−62 °C (crystals from hot 10% ethyl acetate in light
1
petroleum); IR (neat) ν 2104 cm−1; H NMR (CDCl3, 200 MHz)
̅
δ 7.28−7.45 (m, 12H), 6.82−6.90 (m, 2H), 5.23 (d, J = 5.2 Hz, 1H),
4.74 (d, J = 5.1 Hz, 1H), 4.60−4.71 (m, 4H), 4.58 (s, 2H), 4.25 (brs,
2H), 3.87 (t, J = 1.8 Hz, 1H), 3.78−3.83 (m, 2H), 3.79 (s, 3H), 3.56
(t, J = 7.0 Hz, 1H) ppm; 13C NMR (CDCl3, 50.3 MHz) δ 159.4,
137.1, 129.5, 128.4, 127.9, 113.9, 85.5, 81.1, 71.9, 71.7, 70.6, 69.6, 63.5,
55.2 ppm. Anal. Calcd for C29H31N3O6 (517.57): C, 67.30; H, 6.04; N,
8.12. Found: C, 67.25; H, 6.01; N, 8.02.
1,3-O-Methylidene-2-O-(4-methoxybenzyl)-4,6-di-O-benzyl-
myo-inositol (8). A 1 M solution of DIBAL-H in toluene (100.0 mL,
100.00 mmol) was added dropwise over a period of 15 min to a
solution of the crude 7 (19.58 g) in dry dichloromethane (250 mL) at
0 °C and then stirred at room temperature for 3 h. The reaction
mixture was poured into a stirred solution of sodium potassium
tartarate (240 g in 400 mL water) and saturated solution of
ammonium chloride (400 mL) and stirred for 12 h. The mixture
was extracted with dichloromethane (2 × 400 mL), washed with brine,
and dried over anhyd sodium sulfate. The solvent was removed under
reduced pressure to obtain the alcohol 8 (19.73 g) as a gummy liquid
which was used for next reaction without purification. A small quantity
of the crude 8 was purified by column chromatography (eluent: 15%
ethyl acetate in light petroleum): TLC Rf = 0.3 in 15% ethyl acetate/
1,3-Di-O-benzyl-2-azido-2-deoxy-4,6-O-methylidene-neo-in-
ositol (11). To a solution of 9 (3.10 g, 6.00 mmol) in
dichloromethane (40 mL) and water (2 mL) was added DDQ (3.40
g, 15.00 mmol) and the mixture stirred for 2.5 h at room temperature.
The reaction mixture was diluted with dichloromethane (100 mL) and
washed with satd NaHCO3 solution and water followed by brine and
dried over anhyd sodium sulfate. The solvent was evaporated under
reduced pressure to obtain a gum which was purified by column
chromatography (eluent: 20% ethyl acetate in light petroleum) to
afford 11 (2.10 g, 88%) as a colorless solid: TLC Rf = 0.3 in 20% ethyl
acetate/light petroleum; mp 55.5−57 °C (crystals from hot 20% ethyl
1
acetate in light petroleum); IR (Nujol) ν 3200−3650, 2108 cm−1; H
̅
NMR (CDCl3, 200 MHz) δ 7.27−7.43 (m, 10H), 5.48 (d, J = 4.6 Hz,
1H), 4.83 (d, J = 11.8 Hz, 2H), 4.56−4.69 (m, 4H), 4.14−4.21 (m,
2H), 4.07 (t, J = 4.2 Hz, 2H), 3.76 (t, J = Ins H, 3.9 Hz, 1H), 2.07 (s,
1H) ppm; 13C NMR (CDCl3, 50.3 MHz) δ 137.6, 128.3, 127.8, 127.7,
85.2, 79.9, 73.5, 72.6, 62.7, 53.7 ppm. Anal. Calcd for C21H23N3O5
(397.42): C, 63.46; H, 5.83; N, 10.57. Found: C, 63.80; H, 5.45; N,
10.96.
light petroleum; IR (neat) ν 3510−3570 cm−1; 1H NMR (CDCl3, 200
̅
MHz) δ 7.15−7.35 (m, 12H), 6.7−6.85 (m, 2H), 5.55 (d, J = 4.9 Hz,
1H), 4.69 (d, J = 4.9 Hz, 1H), 4.50−4.66 (m, 6H), 4.39−4.46 (m,
2H), 4.27−4.32 (m, 1H), 3.90−4.07 (m, 3H), 3.77 (s, 3H), 3.00 (d, J
= 9.9 Hz, 1H) ppm; 13C NMR (CDCl3, 50.3 MHz) δ 159.2, 137.8,
129.5, 128.2, 127.5, 127.3, 113.7, 85.5, 81.0, 72.5, 71.9, 70.1, 69.4, 69.3,
55.1 ppm. Anal. Calcd for C29H32O7 (492.56): C, 70.71; H, 6.55.
Found: C, 70.32; H, 6.65.
rac-1-O-Benzyl-2-azido-2-deoxy-4,6-O-methylidene-neo-in-
ositol [( )-12]. To a solution of 9 (1.03 g, 2.00 mmol) in
dichloromethane (30 mL) and water (1.5 mL) was added DDQ
(1.1 g, 5.00 mmol), and the mixture was stirred for 12 h at room
temperature. The reaction mixture was diluted with dichloromethane
(50 mL), washed with satd NaHCO3 solution and water followed by
brine, and dried over anhyd sodium sulfate. The solvent was
evaporated under reduced pressure to obtain a gum which was
purified by column chromatography to afford 11 (0.32 g, 40%; eluent:
15% ethyl acetate in light petroleum) and ( )-12 (0.41 g, 52%; eluent:
30% ethyl acetate in light petroleum) as colorless solids. Data for
( )-12: TLC Rf = 0.3 in 30% ethyl acetate/light petroleum; mp 107−
1,3-Di-O-benzyl-2-azido-2-deoxy-4,6-O-methylidene-5-O-(4-
methoxybenzyl)-neo-inositol (9). To a cooled (−10 °C) solution
of crude 8 (12.40 g, ∼25.0 mmol) in dry pyridine (15 mL) and dry
dichloromethane (50 mL) was added triflic anhydride (3.26 mL, 30.00
mmol) dropwise over a period of 15 min. The temperature of the
reaction mixture was then allowed to rise to room temperature, and
stirring was continued for 1 h. The solvents were removed under
reduced pressure, and the residue was worked up with dichloro-
methane and dried over anhyd sodium sulfate. The solvent was
removed under reduced pressure to afford the crude triflate (15.7 g) as
a gum which was used in the next step.
To a solution of the crude triflate (15.0 g) in HMPA (30 mL) was
added sodium azide (3.90 g, 60.00 mmol) and the reaction mixture
stirred for 12 h at room temperature. The reaction mixture was poured
into cold water and extracted with diethyl ether (3 × 100 mL). The
ether extract was washed with brine and dried over anhyd sodium
108 °C (crystals from hot 50% ethyl acetate in light petroleum); IR
1
(Nujol) ν 3200−3500, 2109 cm−1; H NMR (CDCl3, 200 MHz) δ
̅
7.27−7.45 (m, 5H), 5.57 (d, J = 4.6 Hz, 1H), 4.79 (d, J = 11.5 Hz,
1H), 4.51−4.68 (m, 3H), 4.16−4.33 (m, 4H), 4.04−4.12 (m, 1H),
2.89 (d, J = 6.6 Hz, 1H), 2.39 (d, J = 4.2 Hz, 1H) ppm; 13C NMR
(CDCl3+CD3OD, 50.3 MHz) δ 136.8, 128.3, 127.9, 85.0, 79.4, 74.7,
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73.8, 72.3, 72.2, 60.9, 54.7 ppm. Anal. Calcd for C14H17N3O5 (307.30):
C, 54.72; H, 5.58; N, 13.67. Found: C, 54.84; H, 5.59; N, 13.30.
1,3-Di-O-benzyl-2-azido-2-deoxy-neo-inositol (17). A mixture
of 9 (9.31 g, 18.00 mmol), THF−methanol (25 mL + 75 mL), and
concd HCl (10 mL) was refluxed for 2 h. The solvents were removed
under reduced pressure to obtain a solid which was purified by column
chromatography (eluent: 50% ethyl acetate in light petroleum) to
afford 17 (6.80 g, 98%) as a colorless solid: TLC Rf = 0.3 in 50% ethyl
(dd, J1 = 4.9 Hz, J2 = 7.4 Hz, 1H), 4.05 (t, J = 4.6 Hz, 1H), 3.85 (t, J =
3.0 Hz, 1H), 3.76 (dd, J1 = 3.1 Hz, J2 = 9.4 Hz, 1H), 3.3 (dd, J1 = 2.9
Hz, J2 = 7.5 Hz, 1H), 2.19 (s, 3H) ppm; 13C NMR (CDCl3, 50.3
MHz) δ 170.1, 168.0, 137.4, 133.2, 129.1, 128.6, 128.5, 128.4, 128.0,
127.9, 127.86, 127.7, 127.4, 94.8, 75.2, 74.9, 74.4, 74.2, 72.9, 71.9, 71.3,
61.8, 20.6 ppm. Anal. Calcd for C31H31N3O8 (573.59): C, 64.91; H,
5.45; N, 7.33. Found: C, 65.01; H, 5.68; N, 7.00.
Data for 19: TLC Rf = 0.45 in 25% ethyl acetate/light petroleum;
[α]D25 +30 (c = 1.0, CHCl3); IR (CHCl3) ν 2106, 1751, 1744 cm−1; 1H
acetate/light petroleum; mp 106−107.5 °C; IR (Nujol) ν 3350−3430,
̅
̅
2099 cm−1; 1H NMR (CDCl3, 200 MHz) δ 7.30−7.45 (m, 10H), 4.63
(q, J = 11.6 Hz, 4H), 4.14 (t, J = 2.9 Hz, 1H), 4.00 (t, J = 3.0 Hz, 1H),
3.84 (dd, J1 = 3.0 Hz, J2 = 9.7 Hz, 2H), 3.67 (dd, J1 = 3.2 Hz, J2 = 9.6
Hz, 2H), 2.56 (brs, 3H) ppm; 13C NMR (CD3OD, 50.3 MHz) δ
139.6, 129.4, 129.1, 128.8, 78.5, 73.7, 73.4, 71.0, 62.4 ppm. Anal. Calcd
for C20H23N3O5 (385.41): C, 62.33; H, 6.01; N, 10.90. Found: C,
62.22; H, 6.42; N, 11.18.
NMR (CDCl3, 200 MHz) δ 7.26−7.55 (m, 13H), 6.97−7.07 (m, 2H),
6.03 (s, 1H), 5.46 (dd, J1 = 4.1 Hz, J2 = 9.8 Hz, 1H), 5.06 (s, 1H), 4.97
(s, 1H), 4.62 (q, J = 12.2 Hz, 2H), 4.35 (dd, J1 = 5.0 Hz, J2 = 12.4 Hz,
1H), 4.24 (t, J = 4.5 Hz, 1H), 4.02 (q, J = 12.3 Hz, 2H), 3.70 (t, J = 3.1
Hz, 1H), 3.62 (dd, J1 = 3.0 Hz, J2 = 10.2 Hz, 1H), 3.30 (dd, J1 = 2.9
Hz, J2 = 8.5 Hz, 1H), 2.19 (s, 3H) ppm; 13C NMR (CDCl3, 50.3
MHz) δ 170.2, 168.0, 137.3, 137.2, 133.3, 129.3, 128.7, 128.5, 128.4,
128.0, 127.8, 127.7, 127.6, 127.5, 94.9, 77.0, 75.2, 74.6, 74.4, 74.2, 72.7,
71.8, 71.5, 61.9, 20.6 ppm; HRMS (ES+) calcd for C31H31N3O8Na [M
+ Na]+ 596.2009, found 596.2047.
rac-1,3-Di-O-benzyl-2-azido-2-deoxy-4,5-O-methylidene-
neo-inositol [( )-13]. To a cooled (0 °C) solution of 17 (1.93 g,
5.00 mmol) in dimethoxymethane (20 mL) were added 2,6-lutidine
(1.40 mL, 12.00 mmol) and trimethylsilyl trifluoromethanesulfonate
(TMSOTf, 3.60 mL, 20.00 mmol). The reaction mixture was allowed
to warm to ambient temperature, and stirring was continued for 1 h.
The reaction mixture was quenched by solid sodium bicarbonate, and
the solvents were removed under reduced pressure. The crude reaction
mixture was dissolved in ethyl acetate, washed successively with water
and saturated sodium bicarbonate solution followed by brine, and
dried over anhyd sodium sulfate. The solvent was removed under
reduced pressure to afford a gum (2.20 g; TLC Rf = 0.3 in 15% ethyl
acetate/light petroleum) which was used in the next step without
purification.
1L-1,3-Di-O-benzyl-2-azido-2-deoxy-4,5-O-methylidene-
neo-inositol [(−)-13]. To a solution of the ester 18 (0.57 g, 1.00
mmol) in methanol (10 mL) was added KOH (0.28 g, 5.00 mmol)
and the mixture stirred for 3 h at room temperature. The solvents were
removed under reduced pressure, and the residue was dissolved in
ethyl acetate, washed with water and brine, and dried over anhyd
sodium sulfate. Solvent was removed under reduced pressure to obtain
the crude alcohol which was purified by column chromatography
(eluent: 40% ethyl acetate/light petroleum) to obtain (−)-13 as a gum
(0.39 g, 98%): TLC Rf = 0.3 in 40% ethyl acetate/light petroleum;
[α]2D5 −32 (c = 1.0 in CHCl3); IR (neat) ν 3320−3600, 2103 cm−1; 1H
̅
NMR (CDCl3, 200 MHz) δ 7.27−7.45 (m, 10H), 5.09 (s, 1H), 4.96
(s, 1H), 4.60−4.79 (m, 4H), 4.32−4.8 (dd, J1 = 5.2 Hz, J2 = 7.6 Hz,
1H) 4.13−4.26 (m, 2H), 3.95 (t, J1 = 3.0 Hz, 1H), 3.59−3.365 (dd, J1
= 2.7 Hz, J2 = 9.0 Hz, 1H), 3.37−3.42 (dd, J1 = 3.0 Hz, J2 = 7.7 Hz,
1H), 2.57 (brs, 1H) ppm; 13C NMR (CDCl3, 50.3 MHz) δ 137.5,
137.3, 128.6, 128.4, 128.1, 127.9, 127.8, 127.76, 127.6, 94.8, 77.7, 77.2,
76.5, 76.0, 72.7, 72.0, 68.1, 61.1 ppm; HRMS (ES+) calcd for
C21H24N3O5 [M + H]+ 398.1716, found 398.1715.
1L-2-Amino-2-deoxy-4,5-O-methylidene-neo-inositol
[(−)-3]. The azide (−)13 (0.36 g, 0.91 mmol) was hydrogenolyzed in
a mixture of methanol (6 mL) and acetic acid (0.1 mL) in the presence
of 20% Pd/C (0.09 g) at 400 psi at rt for 40 h in a Parr reactor. The
catalyst was filtered using a short bed of Celite, and the catalyst was
washed with methanol (2 × 25 mL) and distilled water (2 × 10 mL)
successively. The combined filtrate was evaporated under reduced
pressure and the residue coevaporated with triethylamine (2 × 5 mL)
to obtain the crude amine which was purified by column
chromatography [neutral alumina; eluent: MeOH/CHCl3/NH4OH
(10:10:0.1)] to isolate (−)3 as a colorless amorphous solid (0.163 g,
94%): [α]2D5 −29 (c = 1.1, H2O) [lit.49 [α]D22 −33 (c = 1.97, H2O)]; mp
150−157 °C (lit.50 mp 151−156 °C).
1D-2-Amino-2-deoxy-4,5-O-methylidene-neo-inositol [(+)-3].
To a solution of the ester 19 (0.57 g, 1.00 mmol) in methanol (10
mL) was added KOH (0.28 g, 5.00 mmol) and the mixture stirred for
3 h at room temperature. The solvents were removed under reduced
pressure, and the residue was dissolved in ethyl acetate, washed with
water and brine, and dried over anhyd sodium sulfate. Solvent was
removed under reduced pressure to obtain the crude alcohol (0.40 g)
as a gummy liquid which was used in the next reaction without
purification.
The crude product (0.40 g) was hydrogenolyzed in a mixture of
methanol (6 mL) and acetic acid (0.1 mL) in the presence of 20% Pd/
C (0.10 g) at 400 psi at rt for 40 h in a Parr reactor. The catalyst was
filtered using a short bed of Celite, and the catalyst was washed with
methanol (2 × 25 mL) and distilled water (2 × 10 mL) successively.
The combined filtrate was evaporated under reduced pressure and the
residue coevaporated with triethylamine (2 × 5 mL) to obtain the
crude amine which was purified by column chromatography [neutral
alumina; eluent: MeOH/CHCl3/NH4OH (10:10:0.1)] to obtain
(+)-3 as a colorless amorphous solid (0.176 g, 92%): [α]2D5 +30 (c =
To a solution of the crude gum (2.20 g) in dichloromethane (15
mL) were added methanol (25 mL), water (2 mL), and p-
toluenesulfonic acid (0.10 g, 0.53 mmol), and the mixture refluxed
for 12 h. After neutralization with solid Na2CO3 and filtration, the
residue was concentrated under reduced pressure. Purification of the
residue by column chromatography (eluent: 40% ethyl acetate in light
petroleum) gave ( )-13 (1.89 g, 95%, two steps) as a gum: TLC Rf =
0.3 in 40% ethyl acetate/light petroleum; IR (neat) ν 3300−3600,
̅
2102 cm−1; 1H NMR (CDCl3, 200 MHz) δ 7.27−7.45 (m, 10H), 5.09
(s, 1H), 4.96 (s, 1H), 4.60−4.79 (m, 4H), 4.35 (dd, J1 = 5.2 Hz, J2 =
7.6 Hz, 1H), 4.12−4.26 (m, 2H), 3.95 (t, J1 = 3.0 Hz, 1H), 3.62 (dd, J1
= 2.7 Hz, J2 = 9.0 Hz, 1H), 3.40 (dd, J1 = 3.0 Hz, J2 = 7.7 Hz, 1H), 2.57
(brs, 1H) ppm; 13C NMR (CDCl3, 50.3 MHz) δ 137.5, 137.3, 128.6,
128.4, 128.1, 127.9, 127.8, 127.76, 127.6, 94.8, 77.7, 77.2, 76.5, 76.0,
72.7, 72.0, 68.1, 61.1 ppm. Anal. Calcd for C21H23N3O5 (397.42): C,
63.46; H, 5.83; N, 10.57. Found: C, 63.26; H, 5.88; N, 10.38.
Reaction of the Triol 17 with POCl3 in DMSO.46 To a solution
of 17 (0.50 g, 1.3 mmol) in dry DMSO (7 mL) was added POCl3 (0.2
mL, 2.2 mmol) and the mixture stirred at 65 °C for 3 h. The reaction
mixture was then diluted with water and extracted with dichloro-
methane (3 × 100 mL). After the usual workup, the crude 13 was
purified by column chromatography (eluent: 40% ethyl acetate in light
petroleum) to obtain ( )-13 (0.10 g, 20%) as a gum.
1L-1,3-Di-O-benzyl-2-azido-2-deoxy-4,5-O-methylidene-6-
[(R)-(−)-O-(acetylmandeloyl)]-neo-inositol (18) and 1D-1,3-Di-
O-benzyl-2-azido-2-deoxy-4,5-O-methylidene-6-[(R)-(−)-O-
(acetylmandeloyl)]-neo-inositol (19). To a solution of ( )-13
(0.84 g, 2.12 mmol) in dry dichloromethane (15 mL) were added (R)-
(−)-O-acetylmandelic acid (0.62 g, 3.18 mmol), DCC (0.52 g, 2.52
mmol), and DMAP (0.02 g, 0.21 mmol), and the mixture was stirred
at room temperature for 12 h. The solvent was removed under
reduced pressure to obtain a gum which was purified by flash column
chromatography to afford 18 (0.58 g, 48%; eluent: 10 to 15% ethyl
acetate in light petroleum) as a solid and 19 (0.57 g, 47%; eluent: 15
to 20% ethyl acetate in light petroleum) as a gummy liquid. Data for
18: TLC Rf = 0.5 in 25% ethyl acetate/light petroleum; mp 106−107.5
°C (crystals from hot 10% chloroform in n-hexane); [α]2D5 −36 (c =
1.0, CHCl3); IR (CHCl3) ν 2106, 1755, 1748 cm−1; 1H NMR (CDCl3,
̅
200 MHz) δ 7.27−7.50 (m, 15H), 5.98 (s, 1H), 5.49 (dd, J1 = 4.3 Hz,
J2 = 9.4 Hz, 1H), 4.88 (s, 1H), 4.75 (s, 1H), 4.48−4.70 (m, 4H), 4.30
5805
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The Journal of Organic Chemistry
Note
1.2, H2O); mp 153−159 °C; 1H NMR (D2O, 500 MHz; with acetone
as internal reference at δ 2.08 ppm): 5.07 (s, 1H), 4.83 (s, 1H), 4.17
(dd, J1 = 4.9 Hz, J2 = 7.7 Hz, 1H), 4.06 (t, J = 4.6, 1H), 4.01 (dd, J1 =
4.2 Hz, J2 = 9.7 Hz, 1H), 3.73 (dd, J1 = 3.7 Hz, J2 = 9.8 Hz, 1H), 3.60
(dd, J1 = 3.1 Hz, J2 = 7.7 Hz, 1H), 3.26 (t, J = 3.1 Hz, 1H) ppm; 13C
NMR (D2O, 125.76 MHz) δ 95.5, 76.8, 76.2, 70.5, 67.74, 67.70, 50.9
ppm; HRMS (ES+) calcd for C7H14NO5 [M + H]+ 192.0872, found
192.0881.
1,3,4,6-Tetra-O-acetyl-2-acetylamino-2-deoxy-5-O-methyl-
neo-inositol (20). To a solution of the alcohol 11 (0.40 g, 1.01
mmol) in dry DMF (5 mL) was added sodium hydride (0.05 g, 1.25
mmol) and the mixture stirred for 10 min. Methyl iodide (0.1 mL, 1.6
mmol) was then added dropwise, and the reaction mixture was stirred
for 3 h. Excess sodium hydride was quenched by the addition of ice-
cold water. The solvent was evaporated under reduced pressure, and
the residue was worked up with ethyl acetate and dried over anhyd
sodium sulfate. The solvent was removed under reduced pressure to
obtain the corresponding methyl ether (0.405 g) as a gum, which was
used for the next reaction without purification.
One-pot deprotection of benzyl groups, 1,3-O-methylidene acetal,
and reduction of the azide was carried out by hydrogenation in a
mixture of methanol (7 mL) and concd HCl (1 mL) in the presence of
20% Pd/C (0.10 g) at 400 psi at 55 °C for 12 h in a Parr reactor. The
catalyst was filtered using a short bed of Celite, and the catalyst was
washed with methanol (2 × 25 mL) and distilled water (2 × 10 mL)
successively. The combined filtrate was evaporated under reduced
pressure and the residue coevaporated with triethyl amine (2 × 5 mL)
to obtain the crude amine (0.095 g) as a dirty white solid. The crude
amine was acetylated with acetic anhydride (2.0 mL) and DMAP (0.01
g) in dry pyridine (5 mL) at 60 °C for 12 h. The solvents were
removed under reduced pressure, and the residue obtained was
worked up with dichloromethane and dried over anhyd sodium sulfate.
The solvent was evaporated, and the crude acetate was purified by
crystallization from a mixture of hot ethyl acetate/light petroleum
(4:1) to obtain colorless crystals of 20 (0.33 g, 81% for three steps):
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TLC Rf = 0.3 in ethyl acetate; mp 159−162 °C; IR (CHCI3) ν 3379,
̅
1
1747, 1720, 1684 cm−1; H NMR (CDCI3, 400 MHz) δ 6.47 (d, J =
9.8 Hz, 1H), 5.44 (dd, J1 = 5.5 Hz, J2 = 11.0 Hz, 2H), 5.17 (dd, J1 = 2.5
Hz, J2 = 11.0 Hz, 2H), 4.95−5.04 (m, 1H), 3.93 (t, J = 2.6 Hz, 1H),
3.52 (s, 3H), 2.12 (s, 6H), 2.06 (s, 3H), 2.01 (s, 6H) ppm; 13C NMR
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ASSOCIATED CONTENT
■
(24) Chang, Y.; Choi, G.; Bae, Y.; Burdett, M.; Moon, H.; Lee, J.;
Gray, N.; Schultz, P.; Meijer, L.; Chung, S.; Choi, K.; Suh, P.; Ryu, S.
ChemBioChem 2002, 3, 897−901.
S
* Supporting Information
1
[Crystallographic data for 9−12, 18, and 20 and copies of H
and 13C NMR spectra for all new compounds appearing in the
schemes. This material is available free of charge via the
Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*E-mail: ms.shashidhar@ncl.res.in.
■
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Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
B.P.G. is a recipient of a Senior Research Fellowship from the
Council of Scientific and Industrial Research, New Delhi.
Financial assistance for this work was provided by the
Department of Science and Technology, New Delhi. Technical
help by Dr. Shobhana Krishnaswamy in solving the crystal
structures is appreciated.
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