Intramolecular hydrogen abstraction in radicals derived from inositol 1,3-acetals: Efficient access to cyclitols

Article abstract of DOI:10.1002/ejoc.200901156

The benzylidene acetals obtained by cleavage of the orthobenzoate moiety in myoinositol 1,3,5-orthobenzoate were used to prepare mono- as well as di-deoxy inositol derivatives via their xanthates. The dideoxygenation is a result of intramolecular abstraction of the benzylidene acetal hydrogen and subsequent cleavage of the acetal ring. Such a cleavage does not take place in analogous acetals derived from, other orthoesters. The 1, 3-acetals derived from, myo- inositol 1,3,5-orthoesters were also used to prepare neo-inositol and isomeric deoxy-amino inositols. Most of the reactions in these synthetic sequences starting from myo-inositol give one product in each step. The results presented here show that myo-inositol 1,3,5-orthobenzoate offers many advantages over other orthoesters for the synthesis of cyclitol derivatives from myo-inositol.

Full text of DOI:10.1002/ejoc.200901156

FULL PAPER
DOI: 10.1002/ejoc.200901156
Intramolecular Hydrogen Abstraction in Radicals Derived from Inositol
1,3-Acetals: Efficient Access to Cyclitols
Chebrolu Murali,[a] Bharat P. Gurale,[a] and Mysore S. Shashidhar*[a]
Keywords: Radicals / Radical reactions / Deoxygenation / Cyclitols / Inositol / Inosamine / Xanthate
The benzylidene acetals obtained by cleavage of the ortho- inositol 1,3,5-orthoesters were also used to prepare neo-ino-
benzoate moiety in myo-inositol 1,3,5-orthobenzoate were
used to prepare mono- as well as di-deoxy inositol deriva-
tives via their xanthates. The dideoxygenation is a result of
sitol and isomeric deoxy-amino inositols. Most of the reac-
tions in these synthetic sequences starting from myo-inositol
give one product in each step. The results presented here
intramolecular abstraction of the benzylidene acetal hydro- show that myo-inositol 1,3,5-orthobenzoate offers many ad-
gen and subsequent cleavage of the acetal ring. Such a
cleavage does not take place in analogous acetals derived
from other orthoesters. The 1,3-acetals derived from myo-
vantages over other orthoesters for the synthesis of cyclitol
derivatives from myo-inositol.
groups is well studied.[13] In particular, myo-inositol 1,3,5-
orthoesters which can be obtained in several gram quanti-
ties as single products (Scheme 1), have been exploited for
the synthesis of phosphorylated inositol derivatives[6d,14]
but their utility for the preparation of ring-modified cyclitol
derivatives has not been exploited to the extent possible.[15]
We herein present an interesting radical initiated cleavage
of inositol-derived benzylidene acetals which led to the ef-
ficient synthesis of several cyclitol derivatives. Interestingly,
we were able to obtain deoxy and dideoxy inositols from
the same monoxanthate. It is pertinent to mention that in
most of the reactions we have obtained a single product
which circumvents the need for separation of isomeric prod-
ucts often observed in the published literature, pertaining to
synthetic sequences involving cyclitols and their derivatives.
Introduction
Cyclitols (polyhydroxy-substituted cycloalkanes), their
alkylated and aminated analogs constitute a class of natural
and synthetic compounds that are of interest to a wide cross
section of chemists due to their biological activity.[1] The
developments in chemical biology related to cyclitols, espe-
cially the phosphoinositol based signal transduction path-
ways and the associated myo-inositol cycle, in the last two
decades, snow-balled and revived the interest of chemists in
cyclitols and their derivatives.[2] Naturally occurring cycli-
tols have been used as starting materials for the synthesis
of natural products,[3] scaffolds for the construction of
metal ion complexing agents[4] and the preparation of mo-
lecular crystals that possess unusual properties.[5] Synthesis
of cyclitols and their derivatives have been accomplished
from various starting materials, such as myo-inositol,[6] que-
brachitol,[7] carbohydrates,[8] tartaric acid,[9] norbornene,[10]
benzoquinone,[11] benzene and its derivatives.[12] myo-Inosi-
tol is a convenient starting material as it is inexpensive,
Results and Discussion
myo-Inositol 1,3,5-orthobenzoate[16] (5) was prepared
abundant and methods for the manipulation of its hydroxy and subsequently converted into the benzylidene derivative
Scheme 1. Synthesis of orthoesters from myo-inositol.
6 (Scheme 2) via the tribenzyl ether (of 5) by a procedure
[a] Division of Organic Chemistry, National Chemical Laboratory,
described earlier.[17] The C5-hydroxy group was converted
Dr. Homi Bhabha road, Pune 411008, India
Fax: +91-2590-2629
into the corresponding xanthate 7 and subjected to Barton-
McCombie deoxygenation conditions when the rac-(1)3,5-
dideoxyinositol derivative 9 was obtained as the sole prod-
E-mail: ms.shashidhar@ncl.res.in
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200901156.
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C. Murali, B. P. Gurale, M. S. Shashidhar
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Scheme 2. Synthesis of (1)3,5-dideoxy-myo-inositol and neo-quercitol.
uct. The tetrol 11 was obtained by aminolysis of the benzo-
ate in 9 followed by hydrogenolysis of the benzyl ethers.
Dideoxy inositol derivatives have been used as tools to elu-
cidate the structure-activity relationship of inositol phos-
phate binding proteins.[18] De-oxygenation of only the C5-
oxygen could be achieved by first hydrolyzing the benzyl-
idene acetal in 7 to obtain the corresponding diol 12 and
subjecting it to Barton-McCombie de-oxygenation condi-
tions. The benzyl ethers in the deoxy-derivative 13 were
cleaved by hydrogenolysis to obtain neo-quercitol (14,
Scheme 2) in an overall yield of 67% (7 steps from myo-
inositol). The yield in earlier reports[19] did not exceed 27%.
Hence di-deoxygenation or mono-deoxygenation in the
xanthate 7 can be achieved by carrying out the deoxygen-
ation reaction prior to or subsequent to the hydrolysis of
the benzylidene acetal respectively.
Scheme 3. A plausible pathway for the formation of 9.
The formation of the di-deoxygenated product 9 and
conversion of the benzylidene acetal to the benzoate can
be rationalized as shown in the Scheme 3. Radical initiated
cleavage of benzylidene acetals of 1,3-diols leading to the
formation of benzoates has earlier been reported.[20] That
the cleavage of the benzylidene acetal in 15 occurred exclu-
sively due to intramolecular hydrogen abstraction was evi-
dent by the fact that deoxygenation of the xanthate 7 in the
presence of the benzylidene acetal 6 resulted in the forma-
tion of the benzoate 9 while the acetal 6 remained unaffec-
ted. Formation of the benzylidene radical via abstraction of
hydrogen by any other radical (formed in the presence of
AIBN) could be ruled out since the alcohol 6 was stable to
the reaction conditions whereas deoxygenation occurred in
the xanthate 7.
Deoxygenation of the xanthate 20 (Scheme 4), having the
neo-configuration also proceeded smoothly to afford the di-
deoxy derivative 9 (obtained from the xanthate 7 having
the myo-configuration, Scheme 2). This result indicated that
irrespective of the configuration of the starting xanthate,
the deoxygenation proceeds through the same radical inter-
mediate 16. Conformation of the myo- and neo-xanthates 7
Scheme 4. Deoxygenation of the xanthate 20 having the neo-config-
and 20 was established by single-crystal X-ray diffraction uration.
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Efficient Access to Cyclitols
methods. Results of 2D-NMR spectroscopy suggested that crude product from dry methanol at low temperature (0 to
the molecular conformation in the crystal is conserved in –5 °C). Single-crystal X-ray diffraction analysis of the
the solution state as well (see Supporting Information).
ketone (good crystals were obtained by crystallization from
Deoxygenation of the racemic xanthate 24 containing the dichloromethane/light petroleum by vapor diffusion
1,3-benzylidene acetal gave a mixture of 1,3 (25) as well as method in a closed container) showed that the inositol ring
racemic 1,5-dideoxy (26) derivatives, the latter being the is slightly distorted from the chair form (see Supporting
major product (Scheme 5). The benzylidene derivative 22 Information). Swern oxidation of the C-5 hydroxy group in
could be prepared by the reaction of the trimethyl ether 6 to obtain 35 did not give consistent yields, perhaps due
of the orthoformate 3 with phenylmagnesium bromide, as to the concomitant de-protection of the acid sensitive
reported.[16a] However, our attempts to prepare the racemic benzylidene acetal. Yield of the ketone 35 on oxidation of
C3-alcohol 23 by the cleavage of the orthoformate moiety 6 with pyridinium dichromate was much lower than when
in the tribenzyl ether 30 with phenylmagnesium bromide, IBX was used. Reduction of the ketone 35 with sodium
provided the corresponding 1,3-diol (2,4,6-tri-O-benzyl-5- borohydride in a mixture of THF and methanol resulted
O-diphenylmethyl-myo-inositol) exclusively.
in the exclusive formation of the C5-alcohol 19 with neo-
The deoxygenation of the xanthates containing the form- configuration, in 94% yield (for two steps). The exclusive
aldehyde or the acetaldehyde acetals yielded the corre- formation of the alcohol 19 with neo-configuration is per-
sponding monodeoxy derivatives exclusively (Scheme 6). haps due to the bulk of the diaxial-dibenzyl ether groups
Hence monodeoxy or dideoxy myo-inositol derivatives can (at C4- and C6-positions) which prevent the attack by the
also be obtained by starting from the orthoformate or the borohydride on one face of the ketone 35. Deprotection of
orthobenzoate derivative respectively. Similar experiments the benzylidene acetal and three O-benzyl groups by cata-
with the acetaldehyde acetal 32 gave racemic viburnitol[21] lytic hydrogenolysis in the presence of Pearlmann’s catalyst
(34) in 64% yield (7 steps from myo-inositol, Scheme 6).
afforded neo-inositol 36 which was characterized as its hexa
Oxidation of the C5-hydroxy group in 6 with IBX af- acetate 37. This sequence of reactions provided neo-inositol
forded the corresponding ketone 35 (Scheme 7) in good in an overall yield of 68% starting from myo-inositol
yield and the crude product was used in the next step. The (Scheme 7). Yield of neo-inositol in the previously reported
pure ketone 35 could be obtained by crystallization of the procedures,[12d,22] did not exceed 20%. Our initial attempts
Scheme 5. Deoxygenation of the racemic xanthate 24.
Scheme 6. Deoxygenation of xanthates containing formaldehyde and acetaldehyde acetal.
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Scheme 7. Synthesis of neo-inositol.
Scheme 8. Synthesis of 5-myo-inosamine hexaacetate.
Scheme 9. Synthesis of 5-neo-inosamine hexaacetate.
for the inversion of alcohol at the C5-position in the bicyclic clean SN2 displacement reaction with sodium azide to give
derivative 6 by Mitsunobu reaction[23] failed and in most of the myo-azide 39 exclusively, while the triflate of the myo-
the experiments unreacted 6 was recovered.
alcohol 6 under similar reaction conditions gives a mixture
myo-Inosamine 40 was prepared from the protected neo- of myo- and the neo-azides. The latter result could be due
alcohol 19 (Scheme 8) via the corresponding azide 39. Re- to displacement of the triflate group (of the myo-alcohol 6)
duction of the azide as well as deprotection of the hydroxy by azide ion via SN1 mechanism or a combination of SN1
groups were achieved by hydrogenation in the presence of and SN2 mechanisms. We attempted to prepare 2-neo-inos-
Pearlmann’s catalyst. The crude 5-deoxy-5-myo-inosamine amine by Mitsunobu reaction of the myo-inositol derivative
(40) obtained was isolated and characterized as its hexaacet- 6 (with benzylamine). However, in all the attempts, the
ate (41) in a good overall yield of 60% (6 steps from myo- starting alcohol was recovered. We also attempted to pre-
inositol). The same inosamine has been synthesized from pare 2-neo-inosamine by the reductive amination of the
cis-1,2-diacetoxycyclohexa-3,5-diene in an overall yield of ketone 35, but this reaction resulted in the formation of a
1
7% (7 steps).[24]
mixture of several products as revealed by the H NMR
2-neo-Inosamine (43) present in “Hygromycin A”, an in- spectrum of the corresponding acetates.
hibitor of bacterial ribosomal peptidyltransferase produced
by Streptomyces hygroscopicus[25] was prepared from the
Conclusions
C5-alcohol 6 via the corresponding azide (Scheme 9). Reac-
tion of the triflate of the alcohol 6 with sodium azide in
The benzylidene acetals derived from myo-inositol-1,3,5-
HMPA provided the neo-azide 42 exclusively. When the orthobenzoate can be cleaved via intramolecular radical re-
same reaction was carried out in DMF (at 50 or 100 °C) a actions to obtain inositol derivatives deoxygenated at spe-
mixture of neo- and myo-azides was obtained (as revealed cific positions. Similar acetal cleavage reactions do not oc-
by 1H and 13C NMR spectra, see Supporting Information). cur in other analogous acetals. These 1,3-acetals can also
1
A comparison of the H NMR spectrum of the mixture of be used to obtain other isomeric cyclitol derivatives in high
azides with that of the bicyclic azide 39 (having the myo- yields. Thus, protection of inositol hydroxy groups as ortho-
configuration, Scheme 8), showed that 39 was present in the benzoate offers advantages over other protected derivatives
mixture of azides. The ratio of the two diastereomeric az- of myo-inositol and provides functionalized cyclohexane
ides (neo/myo) was estimated to be 2:1. It is interesting to and cyclohexanone derivatives in six to eight steps in good
see that the triflate of the bicyclic neo-alcohol 19 undergoes overall yield from abundantly available myo-inositol.
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The solvents were removed under reduced pressure and the residue
obtained was purified by column chromatography (eluent: ethyl
acetate/light petroleum).
Experimental Section
General: All the solvents were purified according to the literature
procedures[26] before use. A 60% dispersion of sodium hydride in
mineral oil was used for O-substitution reactions. Thin layer
chromatography was performed on E. Merck pre-coated 60 F254
plates and the spots were rendered visible either by shining UV
light or by charring the plates with conc H2SO4. Work up implies
the washing of organic layer successively with water, dilute aqueous
HCl (ca. 2%), water, saturated sodium hydrogen carbonate solu-
tion, water followed by brine. Column chromatographic separa-
tions were carried out on silica gel (60–120 or 230–400 mesh) with
solvent system as mentioned in experimental procedures. The com-
pounds previously reported in the literature were characterized by
rac-1-O-Benzoyl-2,4,6-tri-O-benzyl-3,5-dideoxy-myo-inositol
(9):
The xanthate 7 (3.11 g, 4.95 mmol), dry toluene (40 mL), tri-n-
butyltin hydride (5.73 g, 19.70 mmol) and AIBN (0.10 g) were used
(Procedure B) to obtain 9 as a gum (2.35 g, 91%) after column
chromatography (eluent: 10% ethyl acetate/light petroleum): IR
1
(CHCl ): ν = 1720 cm–1. H NMR (CDCl , 200 MHz): δ = 8.01–
˜
3
3
8.12 (m, 2 H, Ar H), 7.13–7.66 (m, 18 H, Ar H), 5.14 (dd, J = 9.5,
2.9 Hz, 1 H, Ins H), 4.45–4.76 (m, 6 H, 3 ϫ CH2), 3.97–4.17 (m,
2 H, Ins H), 3.71–3.95 (m, 1 H, Ins H), 2.48–2.64 (m, 1 H, CH2),
2.27–2.46 (m, 1 H, CH2), 1.48–1.71 (m, 2 H, CH2) ppm. 13C NMR
(CDCl3, 50.3 MHz): δ = 166.0 (C=O), 138.49 (Carom), 138.46
(Carom), 138.3 (Carom), 133.0 (Carom), 130.2 (Carom), 129.7 (Carom),
128.4 (Carom), 128.3 (Carom), 128.21 (Carom), 128.19 (Carom), 127.59
(Carom), 127.56 (Carom), 127.5 (Carom), 127.4 (Carom), 77.4 (Ins C),
74.3 (Ins C), 74.0 (Ins C), 72.1 (PhCH2), 71.9 (PhCH2), 71.4 (Ins
C), 70.6 (PhCH2), 36.0 (Ins CH2), 34.3 (Ins CH2) ppm. C34H34O5
(522.63): calcd. C 78.14, H 6.56; found C 78.28, H 6.54.
1
comparison of their melting points and/or H NMR spectra with
reported data. Proton and carbon NMR spectra were recorded on
Bruker 200 or 400 or 500 MHz NMR spectrometer in solvents as
mentioned in the experimental procedures. IR spectra were re-
corded either in CHCl3 solution or as Nujol mull or as thin film
(neat) on a Shimadzu FTIR-8400 spectrophotometer. Microanalyt-
ical data were obtained using a Carlo–Erba CHNS-0 EA 1108 ele-
mental analyzer. All the melting points were recorded on a Büchi
B-540 electrothermal melting point apparatus. Yields refer to chro-
matographically and spectroscopically pure compounds. All the
asymmetrically substituted racemic myo-inositol derivatives are
shown as one of the enantiomers for convenience and clarity.
rac-2,4,6-Tri-O-benzyl-1,5-dideoxy-myo-inositol (10): A mixture of
the benzoate 9 (2.34 g, 4.48 mmol), isobutylamine (11 mL) and
methanol (20 mL) was refluxed for 12 h. Solvents were removed
under reduced pressure and the residue obtained was purified by
column chromatography (eluent: 10% ethyl acetate/light petro-
leum) to afford 10 as a colorless solid (1.74 g, 93%); m.p. 54–57 °C
General Procedure for the Preparation of Xanthates (Procedure A):
To a cooled (0 °C) solution of the required alcohol (2 to 6 mmol)
in dry THF (5 to 30 mL), sodium hydride (10 to 30 mmol) was
added and stirred at ambient temperature for 30 min. Carbon disul-
fide (30 to 80 mmol) was added to the reaction mixture and re-
fluxed for 1 h. The reaction mixture was allowed to cool to room
temperature; methyl iodide (10 to 30 mmol) was added and stirred
for 16 h. The reaction mixture was diluted with ethanol (4 to
12 mL), water (8 to 24 mL) and extracted with ethyl acetate. The
organic layer was washed with saturated ammonium chloride solu-
tion followed by brine and dried with anhydrous sodium sulfate.
The gummy residue obtained after evaporation of the solvent was
purified by column chromatography (eluent: ethyl acetate/light pe-
troleum) to obtain the xanthate.
1
(crystals from ethyl acetate). IR (CHCl ): ν = 3276–3616 cm–1. H
˜
3
NMR (CDCl3, 200 MHz): δ = 7.25–7.42 (m, 15 H, Ar H), 4.35–
4.75 (m, 6 H, 3 ϫ PhCH2), 3.88–4.02 (m, 1 H, Ins H), 3.50–3.84
(m, 3 H, Ins H), 2.44–2.69 (m, 3 H, 1 ϫ OH, 2 ϫ CH2), 1.29–1.51
(m, 2 H, Ins CH2) ppm. 13C NMR (CDCl3, 50.3 MHz): δ = 138.42
(Carom), 138.39 (Carom), 138.22 (Carom), 128.2 (Carom), 127.55
(Carom), 127.47 (Carom), 127.43 (Carom), 76.7 (Ins C), 76.1 (Ins C),
75.3 (Ins C), 71.8 (PhCH2), 71.4 (PhCH2), 70.4 (PhCH2), 35.2 (Ins
CH2), 33.7 (Ins CH2) ppm. C27H30O4 (418.52): calcd. C 77.48, H
7.23; found C 77.44, H 7.23.
rac-1,5-Dideoxy-myo-inositol (11): The tribenzyl ether 10 (0.80 g,
1.90 mmol) was hydrogenolyzed in ethanol (6 mL) in the presence
of Pd(OH)2/C at 50 psi for 4 h on a Parr hydrogenator. The catalyst
was filtered using a short bed of Celite and the catalyst was washed
with ethanol (2 ϫ 25 mL). The combined ethanol solution was
evaporated under reduced pressure to obtain an off white solid
which was dissolved in hot ethanol and allowed to cool to room
temp. Cooling the solution to 0 °C afforded the crystalline tetrol
11 (0.24 g, 84%); m.p. 154–157 °C (crystals from ethanol). IR (nu-
2,4,6-Tri-O-benzyl-1,3-O-benzylidene-5-O-[(methylthio)thiocarbonyl]-
myo-inositol (7): The alcohol 6 (2.77 g, 5.15 mmol), dry THF
(25 mL), sodium hydride (1.03 g, 25.75 mmol), carbon disulfide
(4.68 mL, 77.80 mmol), methyl iodide (1.60 mL, 25.75 mmol) were
used (Procedure A) to obtain the xanthate 7 as a colorless solid
(3.12 g, 96%) after column chromatography (eluent: 15% ethyl ace-
tate/light petroleum); m.p. 112–114 °C (crystals from dichlorometh-
jol): ν = 3090–3520 cm–1. 1H NMR (D2O, 200 MHz): δ = 3.89–
˜
ane). IR (CHCl ): ν = 1215, 1062 cm–1. 1H NMR (CDCl3,
4.16 (m, 2 H, Ins H), 3.67–3.84 (m, 1 H, Ins H), 3.41 (dd, J = 9.6,
3.3 Hz, 1 H, Ins H), 1.96–2.32 (m, 2 H, CH2), 1.24–1.60 (m, 2 H,
CH2) ppm. 13C NMR [D2O (0.6 mL) + MeOH (0.02 mL),
50.3 MHz]: δ = 75.9 (CHOH), 69.5 (CHOH), 68.2 (CHOH), 64.6
(CHOH), 41.1 (CH2), 39.1 (CH2) ppm. C6H12O4 (148.16): calcd. C
48.64, H 8.16; found C 48.78, H 7.94.
˜
3
200 MHz): δ = 7.50–7.58 (m, 2 H, Ar H), 7.16–7.48 (m, 18 H, Ar
H), 6.27 (t, J = 7.2 Hz, 1 H, Ins H), 5.81 (s, 1 H, PhCHO2), 4.73
(s, 2 H, CH2), 4.63 (ABq, J = 12.1 Hz, 4 H, 2 ϫ CH2), 4.45 (d, J
= 2.3 Hz, 2 H, Ins H), 4.13 (d, J = 7.2 Hz, 2 H, Ins H), 3.83 (t, J
= 2.3 Hz, 1 H, Ins H), 2.56 (s, 3 H, CH3) ppm. 13C NMR (CDCl3,
50.3 MHz): δ = 215.4 (C=S), 138.0 (Carom), 137.8 (Carom), 136.9
(Carom), 129.3 (Carom), 128.4 (Carom), 128.3 (Carom), 127.9 (Carom),
127.69 (Carom), 127.65 (Carom), 126.5 (Carom), 92.9 (PhCO2), 81.8
(Ins C), 79.1 (Ins C), 73.4 (Ins C), 71.5 (CH2), 70.8 (CH2), 68.1
(Ins C), 19.2 (CH3) ppm. C36H36O6S2 (628.80): calcd. C 68.76, H
5.77; found C 69.04, H 5.63.
2,4,6-Tri-O-benzyl-5-O-[(methylthio)thiocarbonyl]-myo-inositol (12):
A mixture of the xanthate 7 (1.26 g, 2.00 mmol), TFA (1 mL) and
THF/water mixture (10 mL + 0.5 mL) was stirred at room temp.
for 24 h. The solvents were removed under reduced pressure and
the residue was co-evaporated with dry toluene (2 ϫ 10 mL) to
afford a gummy residue which was purified by column chromatog-
raphy [eluent: ethyl acetate and light petroleum mixture (1:3)] to
General Procedure for the Deoxygenation of Xanthates (Procedure
B): To a solution of the required xanthate (1 to 5 mmol) in dry
toluene (5 to 40 mL), tri-n-butyltin hydride (5 to 20 mmol) and
AIBN (0.02 to 0.10 g) were added and heated at 100 °C for 1 h.
afford the diol 12 as a colorless gum (1.04 g, 96%): IR (CHCl ): ν
˜
3
= 3323–3580, 1211, 1059 cm–1. H NMR (CDCl3, 200 MHz): δ =
1
7.27–7.46 (m, 15 H, Ar H), 6.17 (t, J = 9.5 Hz, 1 H, Ins H), 4.82
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(s, 2 H, CH2) 4.68 (ABq, J = 11 Hz, 4 H, 2 ϫ CH2), 4.01 (t, J =
2.6 Hz, 1 H, Ins H), 3.94 (t, J = 9.6 Hz, 2 H, Ins H), 3.58–3.74 (m,
2 H, Ins H), 2.61 (s, 3 H, CH3), 3.41 (d, J = 5.5 Hz, 2 H, 2 ϫ OH)
400 MHz): δ = 7.41–7.49 (m, 2 H, Ar H), 7.28–7.38 (m, 3 H, Ar
H), 5.98 (t, J = 8.3 Hz, 1 H, Ins H), 5.95 (s, 1 H, PhCHO2), 4.61–
4.67 (m, 1 H, Ins H), 4.40–4.44 (m, 1 H, Ins H), 4.38 (t, J = 7.5 Hz,
ppm. 13C NMR (CDCl3, 50.3 MHz): δ = 215.8 (C=S), 138.4 1 H, Ins H), 4.07 (d, J = 8.3 Hz, 1 H, Ins H), 3.91 (t, J = 3.4 Hz,
(Carom), 137.8 (Carom), 128.4 (Carom), 128.2 (Carom), 127.9 (Carom), 1 H, Ins H), 3.44 (s, 3 H, OCH3), 3.41 (s, 3 H, OCH3), 3.40 (s, 3 H,
127.8 (Carom), 83.7 (Ins C), 80.0 (Ins C), 78.6 (Ins C), 75.3 (CH2),
75.0 (CH2), 72.0 (Ins C), 19.4 (CH3) ppm. C29H32O6S2 (540.69):
calcd. C 64.42, H 5.97; found C 64.58, H 5.62.
OCH3), 2.58 (s, 3 H, CH3) ppm. 13C NMR (CD2Cl2, 125.4 MHz): δ
= 216.1 (C=S), 138.6 (Carom), 129.3 (Carom), 128.5 (Carom), 126.6
(Carom), 93.5 (PhCO2), 81.1 (Ins C), 81.0 (Ins C), 74.9 (Ins C), 73.3
(Ins C), 71.8 (Ins C), 68.6 (Ins C), 59.2 (OCH3), 58.3 (OCH3), 57.3
(OCH3), 19.5 (SCH3) ppm. C18H24O6S2 (400.51): calcd. C 53.98,
H 6.04, S 16.01; found C 53.90, H 5.72, S 16.11.
1,3,5-Tri-O-benzyl-2-deoxy-neo-inositol (13): The xanthate 12
(1.00 g, 1.85 mmol), tri-n-butyltin hydride (2.15 g, 7.40 mmol),
AIBN (0.04 g) and dry toluene (15 mL) were used (Procedure B)
to obtain 13 (0.75 g, 93%) as a colorless gum after column
chromatography [eluent: ethyl acetate and light petroleum mixture,
Deoxygenation of 24: The xanthate 24 (1.00 g, 2.50 mmol), dry tol-
uene (15 mL), tri-n-butyltin hydride (3.40 mL, 12.50 mmol) and
AIBN (0.06 g) were used (Procedure B) to obtain 25 (gum, 0.12 g,
16%) and 26 (colorless solid, 0.51 g, 69%) after column chromatog-
raphy (eluent: 10% ethyl acetate/light petroleum). 25: IR (CHCl3):
(1:3)]: IR (CHCl ): ν = 3200–3650 cm–1. 1H NMR (CDCl3,
˜
3
200 MHz): δ = 7.26–7.45 (m, 15 H, Ar H), 4.84 (s, 2 H, PhCH2),
4.62 (ABq, J = 11.5 Hz, 4 H, 2 ϫ PhCH2), 4.07 (t, J = 2.4 Hz, 1
H, Ins H), 3.55–3.78 (m, 4 H, Ins H), 2.30–2.69 (m, 3 H, 1 ϫ Ins
H, 2 ϫ OH), 1.19–1.40 (m, 1 H, Ins H) ppm. 13C NMR (CDCl3,
50.3 MHz): δ = 138.7 (Carom), 138.2 (Carom), 128.4 (Carom), 128.3
(Carom), 127.7 (Carom), 127.6 (Carom), 79.3 (Ins C), 76.6 (Ins C),
75.1 (PhCH2), 74.7 (Ins C), 71.7 (PhCH2), 31.1 (Ins CH2) ppm.
C27H30O5 (434.52): calcd. C 74.63, H 6.96; found C 74.60, H 6.62.
ν = 1722 cm–1. 1H NMR (CHCl3, 400 MHz): δ = 8.06 (d, J =
˜
7.3 Hz, 2 H, Ar H), 7.56–7.59 (m, 1 H, Ar H), 7.42–7.49 (m, 2 H,
Ar H), 5.20 (t, J = 9 Hz, 1 H, Ins H), 3.68–3.74 (m, 1 H, Ins H),
3.58–3.67 (m, 2 H, Ins H), 3.37 (s, 3 H, CH3), 3.34 (s, 6 H, 2 ϫ
CH3), 2.33–2.41 (m, 2 H, Ins H), 1.46–1.55 (m, 2 H, Ins H) ppm.
13C NMR (CDCl3, 50.3 MHz): δ = 166.0 (C=O), 132.7 (Carom),
130.6 (Carom), 129.7 (Carom), 128.3 (Carom), 78.1 (Ins C), 73.6 (Ins
C), 57.7 (CH3), 56.1 (CH3), 32.9 (Ins CH2) ppm. C16H22O5
(294.34): calcd. C 65.29, H 7.53; found C 65.66, H 7.70.
2-Deoxy-neo-inositol (neo-Quercitol) (14): The tribenzyl ether 13
(0.70 g, 1.69 mmol) was hydrogenolyzed in the presence of Pd(OH)2/
C (0.03 g) in ethanol (8 mL) at 50 psi for 6 h. The catalyst was
allowed to settle and the supernatant liquid was removed using a
pipette. The catalyst was repeatedly washed with warm (50 °C)
aqueous ethanol (1:1, 3 ϫ 150 mL). Combined washings were fil-
tered through a short column of Celite. The filtrate was evaporated
under reduced pressure to obtain a colorless solid which was crys-
tallized from hot methanol to afford neo-quercitol (14) as colorless
crystals (0.245 g, 88%); m.p. 235–238 °C (lit[19d] m.p. 237–241 °C).
Data for 26: M.p. 54–55 °C (crystals from ethyl acetate). IR
(CHCl ): ν = 1710 cm–1. 1H NMR (CDCl3, 400 MHz): δ = 8.10
˜
3
(d, J = 7.3 Hz, 2 H, Ar H), 7.57 (t, J = 7.3 Hz, 1 H, Ar H), 7.46
(t, J = 7.8 Hz, 2 H, Ar H), 5.07 (dd, J1 = 3.9, J2 = 6.3 Hz, 1 H,
Ins H), 3.85–3.89 (m, 1 H, Ins H), 3.71–3.78 (m, 1 H, Ins H), 3.53–
3.61 (m, 1 H, Ins H), 3.42 (s, 3 H, OCH3), 3.39 (s, 3 H, OCH3),
3.38 (s, 3 H, OCH3), 2.44–2.52 (m, 1 H, Ins H), 2.30–2.39 (m, 1 H,
Ins H), 1.32–1.52 (m, 2 H, Ins H) ppm. 13C NMR (CDCl3,
50.3 MHz): δ = 166.0 (C=O), 132.9 (Carom), 130.1 (Carom), 129.7
(Carom), 128.2 (Carom), 76.8 (Ins C), 76.0 (Ins C), 75.6 (Ins C), 73.1
(Ins C), 58.0 (CH3), 57.1 (CH3), 56.1 (CH3), 34.6 (Ins CH2), 33.1
(Ins CH2) ppm. C16H22O5 (294.34): calcd. C 65.29, H 7.53; found
C 65.13, H 7.90.
2,4,6-Tri-O-benzyl-1,3-O-benzylidene-5-O-[(methylthio)thiocarbonyl]-
neo-inositol (20): The alcohol 19 (1.50 g, 2.80 mmol), dry THF
(20 mL), sodium hydride (0.56 g, 14.0 mmol), carbon disulfide
(2.5 mL, 41.70 mmol), methyl iodide (0.90 mL, 14.46 mmol) were
used (Procedure A) to obtain the xanthate 20 as a colorless solid
(1.68 g, 96%) after column chromatography (eluent: 10% ethyl ace-
tate/light petroleum); m.p. 100–102 °C (crystallized from 15% hot
2,4,6-Tri-O-benzyl-1,3-O-methylidene-5-O-[(methylthio)thiocarbonyl]-
myo-inositol (28): The alcohol 27 (2.31 g, 5.0 mmol), dry THF
(30 mL), sodium hydride (1.0 g, 25 mmol), carbon disulfide
(4.5 mL, 75.0 mmol) and methyl iodide (1.50 mL, 24.19 mmol)
were used (Procedure A) to obtain the xanthate 28 as a colorless
solid (2.71 g, 98%) after column chromatography (eluent: 5% ethyl
acetate/light petroleum); m.p. 86–87 °C (crystallized from 10% hot
1
ethyl acetate/light petroleum). IR (CHCl ): ν = 1377 cm–1. H
˜
3
NMR (CDCl3, 200 MHz): δ = 7.50–7.60 (m, 2 H, Ar H), 7.27–7.47
(m, 18 H, Ar H), 6.49 (t, J = 4.4 Hz, 1 H, Ins H), 5.93 (s, 1 H,
PhCHO2), 4.66 (ABq, J = 12.1 Hz, 4 H, PhCH2), 4.65 (s, 2 H,
CH2), 4.30–4.40 (m, 4 H, Ins H), 4.27 (t, J = 2.1 Hz, 1 H, Ins H),
2.58 (s, 3 H, CH3) ppm. 13C NMR (CDCl3, 50.3 MHz): δ = 215.8
(C=S), 139.5 (Carom), 137.7 (Carom), 129.3 (Carom), 128.3 (Carom),
127.8 (Carom), 126.6 (Carom), 95.4 (PhCO2), 77.8 (Ins C), 76.2 (Ins
C), 73.9 (Ins C), 71.8 (CH2), 70.6 (CH2), 65.7 (Ins C), 19.3 (CH3)
ppm. C36H36O6S2 (628.80): calcd. C 68.76, H 5.77, S 10.20; found
C 68.65, H 5.57, S 9.95.
1
ethyl acetate/light petroleum). IR (CHCl ): ν = 1377 cm–1. H
˜
3
NMR (CDCl3, 200 MHz): δ = 7.27–7.45 (m, 15 H, Ar H), 6.07 (s,
1 H, Ins H), 5.55 (d, J = 4.5 Hz, 1 H, HCHO2), 4.80 (d, J = 12 Hz,
2 H, CH2), 4.6–4.71 (m, 5 H, HCHO2 and PhCH2O), 4.32–4.4 (m,
3 H, Ins H), 4.0 (q, J = 1.7 Hz, 2 H, Ins H), 2.52 (s, 3 H, CH3)
ppm. 13C NMR (CDCl3, 50.3 MHz): δ = 214.1 (C=S), 137.5
(Carom), 128.4 (Carom), 128.3 (Carom), 127.8 (Carom), 127.7 (Carom),
127.6 (Carom), 85.3 (H2CO2), 78.7 (Ins C), 76.4 (Ins C), 72.1 (CH2),
70.8 (Ins C), 70.6 (CH2), 70.0 (Ins C), 18.3 (CH3) ppm. C30H32O6S2
(552.70): calcd. C 65.19, H 5.84; found C 64.79, H 5.74.
rac-2,4,6-Tri-O-benzyl-1-O-benzoyl-3,5-dideoxy-myo-inositol (9):
The xanthate 20 (1.25 g, 2.00 mmol), dry toluene (15 mL), tri-n-
butyltin hydride (2.0 mL, 7.43 mmol) and AIBN (0.04 g) were used
(Procedure B) to obtain 9 as a gum (0.95 g, 91%) after column
chromatography (eluent: 10% ethyl acetate/light petroleum).
(1)3,5-O-Benzylidene-2,4,6-tri-O-methyl-1(3)-O-[(methylthio)thio-
carbonyl]-myo-inositol (24): The alcohol 22 (1.15 g, 3.7 mmol), dry
THF (20 mL), sodium hydride (0.74 g, 18.50 mmol), carbon disul-
2,4,6-Tri-O-benzyl-5-deoxy-1,3-O-methylidene-myo-inositol (29):
The xanthate 28 (1.66 g, 3.0 mmol), dry toluene (20 mL), tri-n-
butyltin hydride (3.0 mL, 11.13 mmol) and AIBN (0.08 g) were
fide (3.5 mL, 58.33 mmol) and methyl iodide (1.1 mL, 17.67 mmol) used (Procedure B) to obtain deoxy inositol derivative 29 as a
were used (Procedure A) to obtain the xanthate 24 as a gum (1.42 g,
colorless solid (1.26 g, 94%) after column chromatography (eluent:
96%) after column chromatography (eluent: 7% ethyl acetate/light
10% ethyl acetate/light petroleum); m.p. 60–62 °C (crystalized from
1
petroleum): IR (CHCl ): ν = 1062, 1213 cm–1. H NMR (CD Cl ,
20% hot ethyl acetate/light petroleum). IR (CHCl ): ν = 1454 cm–1.
˜
˜
3
2
2
3
760
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Eur. J. Org. Chem. 2010, 755–764

Efficient Access to Cyclitols
1H NMR (CDCl3, 200 MHz): δ = 7.2–7.4 (m, 15 H, Ar H), 5.6 (d,
with anhydrous sodium sulfate. The crude product (0.90 g) ob-
J = 4.3 Hz, 1 H, HCO2), 4.55–4.71 (m, 5 H, HCHO2 and 2 ϫ tained after evaporation of the solvent was used in the next step.
CH2), 4.32–4.51 (m, 5 H), 3.90 (br. s, 2 H, Ins H), 2.16–2.32 (m, 1
The crude tribenzyl ether (0.90 g) was debenzylated in the presence
H, CH2), 1.95–2.1 (m, 1 H, CH2) ppm. 13C NMR (CDCl3,
of Pearlmann’s catalyst [20% Pd(OH)2/C, 0.03 g] in ethanol by hy-
50.3 MHz): δ = 138.4 (Carom), 137.8 (Carom), 128.2 (Carom), 128.1
drogenolysis (60 psi) at room temp. for 12 h. The catalyst was al-
(Carom), 127.7 (Carom), 127.5 (Carom), 127.3 (Carom), 85.4 (H2CO2),
lowed to settle and the supernatant liquid was removed using a
77.4 (Ins C), 71.3, (Ins C), 71.0 (CH2), 70.2 (CH2), 70.1 (Ins C),
pipette. The catalyst was repeatedly washed with warm (50 °C)
23.2 (CH2) ppm. C28H30O5 (446.53): calcd. C 75.31, H 6.77; found
aqueous methanol (1:1, 3ϫ150 mL). Combined washings were fil-
C 75.32, H 6.82.
tered through a short column of Celite. The filtrate was evaporated
2,4,6-Tri-O-benzyl-(1)3,5-O-ethylidene-myo-inositol (31): To a
cooled (0 °C) solution of 30 (2.76 g, 6.0 mmol) in dry benzene
(30 mL) was added methylmagnesium iodide (1  solution in diethyl
ether, 12.0 mL, 12 mmol) and stirred for 15 h at room temperature.
The reaction mixture was then diluted with diethyl ether (100 mL)
and washed with saturated solution of NH4Cl. The organic layer
was washed with brine and dried with anhydrous sodium sulfate.
The gummy residue obtained after evaporation of the solvent was
purified by column chromatography (eluent: 10 % ethyl acetate/
light petroleum) to obtain the alcohol 31[17a] as a syrupy liquid
(2.40 g, 84%).
under reduced pressure to obtain a colorless solid which was crys-
tallized from hot methanol to afford colorless crystals (0.29 g, 88%)
of racemic 34; m.p. 158–160 °C (ref.[21] m.p. 163 °C). IR (nujol): ν
˜
1
= 3540, 1445 cm–1. H NMR (D2O, 200 MHz): δ = 4.0–4.07 (m, 1
H), 3.66–3.82 (m, 1 H), 3.42–3.6 (m, 2 H), 3.17–3.32 (m, 1 H), 2.0–
2.14 (m, 1 H), 1.46–1.60 (m, 1 H) ppm. 13C NMR (D2O,
50.3 MHz): δ = 73.2, 73.5, 72.5, 68.2, 68.2, 34.9 (CH2) ppm.
C6H12O5 (164.16): calcd. C 43.90, H 7.37; found C 44.22, H 7.24.
2,4,6-Tri-O-benzyl-1,3-O-benzylidene-5-myo-inosose (35): To a solu-
tion of the alcohol 6 (2.69 g, 5.00 mmol) in ethyl acetate (25 mL)
was added 2-iodoxybenzoic acid (2.80 g, 10 mmol) and refluxed for
2,4,6-Tri-O-benzyl-3(1),5-O-ethylidene-1(3)-O-[(methylthio)thiocarb- 3 h. The reaction mixture was filtered through sintered glass funnel,
onyl]-myo-inositol (32): The alcohol 31 (1.43 g, 3.0 mmol), dry THF and the residue washed with ethyl acetate (2ϫ15 mL). The com-
(20 mL), sodium hydride (0.60 g, 15 mmol), carbon disulfide
(2.70 mL, 45.0 mmol) and methyl iodide (0.93 mL, 15.0 mmol)
were used (Procedure A) to obtain the xanthate 32 (1.66 g, 98%)
as a thick oil after column chromatography (eluent: 10% ethyl ace-
bined filtrate and washings was evaporated under reduced pressure
to get the ketone 35 (2.71 g) as a colorless solid. Crystals of the
pure ketone 35 could be obtained by crystallization from methanol
or from dichloromethane/light petroleum mixture at low tempera-
tate/light petroleum): IR (CHCl ): ν = 1359 cm–1 1H NMR ture (–5 °C); m.p. 106–108 °C. IR (CHCl ): ν = 1717 cm–1. 1H
.
˜
3
˜
3
(CDCl3, 200 MHz): δ = 7.2–7.4 (m, 15 H, Ar H), 6.27 (t, J =
NMR (CDCl3, 200 MHz): δ = 7.40–7.52 (m, 2 H, Ar H), 7.17–7.39
8.2 Hz, 1 H, Ins H), 5.20 (q, J = 4.8 Hz, 1 H, CO2), 4.5–4.8 (m, 6 (m, 18 H, Ar H), 5.67 (s, 1 H, PhCHO2), 4.65–4.80 (m, 4 H,
H), 4.16–4.46 (m, 4 H, Ins H), 3.98 (t, J = 3.8 Hz, 1 H, Ins H),
2ϫCH2), 4.45–4.62 (m, 4 H), 4.25 (t, J = 2.1 Hz, 1 H, Ins H), 4.17
2.51 (s, 3 H, SCH3), 1.22 (d, J = 4.8 Hz, 3 H, CH3) ppm. 13C NMR (d, J = 4 Hz, 2 H, Ins H) ppm. 13C NMR (CDCl3, 50.3 MHz): δ
(CDCl3, 50.3 MHz): δ = 215.3 (C=S), 137.7 (Carom), 137.4 (Carom), = 200.9 (C=O), 137.8 (Carom), 137.7 (Carom), 136.5 (Carom), 129.4
128.4 (Carom), 128.3 (Carom), 128.1 (Carom), 128 (Carom), 127.9
(Carom), 127.8 (Carom), 127.64 (Carom), 127.59 (Carom) 90.7 (HCO2), 127.8 (Carom), 127.6 (Carom), 126.2 (Carom), 93.8 (PhCHO2), 79.2
80.6 (Ins C), 77.8 (Ins C), 73.3 (Ins C), 72.9 (CH2), 71.5 (CH2), (Ins C), 73.6 (Ins C), 71.8 (CH2), 70.9 (CH2), 66.4 (Ins C) ppm.
(Carom), 128.4 (Carom), 128.3 (Carom), 128.2 (Carom), 128.0 (Carom),
71.4 (CH2), 69.1 (Ins C), 68.1 (Ins C), 20.7 (CH3), 19.0 (CH3) ppm. C34H32O6 (536.61): calcd. C 76.10, H 6.01; found C 76.34, H 5.96.
C31H34O6S2 (566.73): calcd. C 65.70, H 6.05; found C 65.42, H
2,4,6-Tri-O-benzyl-1,3-O-benzylidene-neo-inositol (19): The crude
5.97.
ketone 35 (2.71 g) was dissolved in a mixture of THF (5 mL) and
2,4,6-Tri-O-benzyl-(1)3,5-O-ethylidene-1(3)-deoxy-myo-inositol
(33): The xanthate 32 (1.50 g, 2.65 mmol), dry toluene (20 mL), tri-
methanol (20 mL) and cooled to 0 °C. To this solution, sodium
borohydride (0.57 g, 15.07 mmol) was added in one lot and stirred
n-butyltin hydride (3.50 mL, 13.01 mmol) and AIBN (0.07 g) were for 1 h at ambient temperature. TLC analysis of the reaction mix-
used (Procedure B) to obtain the deoxy inositol derivative 33 as a
ture showed the absence of the starting material. The solvents were
removed under reduced pressure and the gummy residue obtained
gum (1.12 g, 92%) after column chromatography (eluent: 10% ethyl
acetate/light petroleum): IR (CHCl ): ν = 1514 cm–1. 1H NMR was worked up with dichloromethane. The product was purified
˜
3
(CDCl3, 400 MHz): δ = 7.2–7.4 (m, 15 H, Ar H), 5.44 (q, J = by column chromatography [eluent: ethyl acetate/dichloromethane/
4.8 Hz, 1 H, HCO2), 4.64 (d, J = 11.8 Hz, 1 H, CH2), 4.61 (t, J =
4.1 Hz, 1 H, Ins H) 4.55–4.58 (m, 3 H), 4.47–4.52 (m, 2 H, Ins H),
4.42 (d, J = 11.8 Hz, 1 H, CH2), 4.35 (br. s, 1 H, Ins H), 4.09–4.13
light petroleum (1:1:8)] to afford the alcohol 19 as a colorless solid
(2.52 g, 94%); m.p. 98–102 °C (crystals from dichloromethane). IR
1
(CHCl ): ν = 3332–3593 cm–1. H NMR (CDCl , 200 MHz): δ =
˜
3
3
(dd, J1 = 11.2, J2 = 4.3 Hz, 1 H, Ins H), 3.75–3.82 (m, 1 H, Ins 7.47–7.59 (m, 2 H, Ar H), 7.16–7.44 (m, 18 H, Ar H), 5.81 (s, 1 H,
H), 2.24–2.42 (m, 1 H, Ins H), 2.05–2.17 (m, 1 H, Ins H), 1.25 (d, PhCHO2), 4.55–4.76 (m, 6 H, 3ϫCH2), 4.27–4.49 (m, 3 H, Ins H),
J = 4.8 Hz, 3 H, CH3) ppm. 13C NMR (CDCl3, 50.3 MHz): δ = 4.04–4.13 (m, 3 H, Ins H), 3.22 (d, J = 11.0 Hz, 1 H, OH) ppm.
138.6 (Carom), 138.5 (Carom), 137.6 (Carom), 128.2 (Carom), 127.6 (Ca-
rom), 127.4 (Carom), 127.3 (Carom), 89.6 (HCO2), 77.3 (Ins C), 71.7
(Ins C), 71.4 (CH2), 71.2 (Ins C), 71.2 (CH2), 70.9 (CH2), 69.3 (Ins
C), 67.3 (Ins C), 26.8 (CH2), 21.4 (CH3) ppm. C29H32O5 (460.56):
calcd. C 75.63, H 7.00; found C 75.52, H 7.24.
13C NMR (CDCl3, 50.3 MHz): δ = 139.5 (Carom), 138.2 (Carom),
137.7 (Carom), 129.3 (Carom), 128.4 (Carom), 128.3 (Carom), 127.82
(Carom), 127.79 (Carom), 127.6 (Carom), 127.5 (Carom), 126.9 (Carom),
126.5 (Carom), 95.4 (PhCHO2), 78.7 (Ins C), 73.9 (CH2), 71.0 (Ins
C), 70.4 (CH2), 67.7 (Ins C), 65.4 (Ins C) ppm. C34H34O6 (538.63):
calcd. C 75.82, H 6.36; found C 75.84, H 6.49. The alcohol 19
formed crystals with the inclusion of dichloromethane in its crystal
lattice (see Supporting Information).
Racemic vibo-Quercitol (Viburnitol) (34): A mixture of 33 (0.92 g,
2.00 mmol), THF/water mixture (10 mL + 0.5 mL), and concd.
HCl (1 mL) was refluxed for 2 h. The solvents were removed under
reduced pressure to obtain a gummy residue which was dissolved
in ethyl acetate (100 mL). The solution was washed with saturated
sodium hydrogen carbonate solution followed by brine and dried
neo-Inositol (36): The neo-alcohol 19 (2.3 g, 4.27 mmol) was hydro-
genolyzed (50 psi) in ethanol (15 mL) in the presence of Pd(OH)2/
C (20%, 0.16 g) for 36 h at room temp. The catalyst was allowed
Eur. J. Org. Chem. 2010, 755–764
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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761

C. Murali, B. P. Gurale, M. S. Shashidhar
FULL PAPER
to settle and the supernatant liquid was removed using a pipette.
The catalyst was repeatedly washed with warm (50 °C) distilled
water (6ϫ100 mL). The combined washings were filtered through
a short column of Celite. The filtrate was evaporated under reduced
pressure to get an off white solid which was washed with hot ethyl
acetate to afford neo-inositol (36) as a colorless solid (0.64 g, 83%);
m.p. 305–310 °C (ref.[27] m.p. 315 °C).
(d, J = 9.3 Hz, 2 H, Ins H), 3.53–3.62 (m, 2 H, Ins H) ppm. 13C
NMR (CDCl3, 50.3 MHz): δ = 137.6 (Carom), 136.7 (Carom), 129.4
(Carom), 128.5 (Carom), 128.4 (Carom), 128.1 (Carom), 127.8 (Carom),
127.7 (Carom), 126.4 (Carom), 92.7 (PhCHO2), 80.2 (Ins C), 73.0
(Ins C), 71.7 (CH2), 70.8 (CH2), 68.1 (Ins C), 65.0 (Ins C) ppm.
C34H33N3O5 (563.64): calcd. C 72.45, H 5.90, N 7.46; found C
72.30, H 5.77, N 7.35.
neo-Inositol Hexaacetate (37): neo-Inositol 36 (0.05 g, 0.28 mmol)
was suspended in dry pyridine (6 mL) and cooled to 0 °C. Acetic
anhydride (0.47 mL, 4.98 mmol) was added drop wise and stirring
continued at ambient temperature until the reaction mixture turned
to a clear solution (≈ 40 h). The solvents were removed under re-
duced pressure and the residue obtained was worked up with
dichloromethane followed by drying over anhydrous sodium sul-
fate. The solvent was removed under reduced pressure and the
crude product was purified by column chromatography (eluent: 5%
ethyl acetate/dichloromethane) to afford the hexaacetate 37 as a
colorless solid (0.115 g, 96%); m.p. 255–258 °C (ref.[28] m.p. 257–
259 °C).
1,2,3,4,6-Penta-O-acetyl-5-deoxy-5-acetylamino-myo-inositol (41):
The azide 39 (0.64 g, 1.10 mmol) was hydrogenolyzed (50 psi) in
the presence of Pd(OH)2/C (20%, 0.04 g) in ethanol (4 mL) and
acetic acid (2 mL) at room temp. for 44 h. The catalyst was filtered
by using a short bed of Celite and the catalyst was washed with
water (2ϫ10 mL). The combined filtrate and washings was evapo-
rated under reduced pressure and the residue co-evaporated with
dry toluene (2ϫ5 mL) to get the crude product (0.26 g) as an off
white solid. The crude product was dissolved in dry pyridine
(5 mL), cooled with ice and acetic anhydride (2.0 mL) was added
dropwise. The resulting mixture was stirred for 40 h and the sol-
vents were removed under reduced pressure. The residue obtained
was worked up with dichloromethane by washing with water, satu-
rated sodium hydrogen carbonate solution and brine followed by
drying over anhydrous sodium sulfate. The solvent was evaporated
under reduced pressure and the crude product was purified by col-
umn chromatography (eluent: 1:1 dichloromethane/ethyl acetate) to
afford the hexa-acetate 41 as a colorless solid (0.41 g, 83% for two
steps); m.p. 264–270 °C (crystals from dichloromethane). IR
neo-Inositol Hexabenzoate (38): neo-Inositol 36 (0.03 g, 0.17 mmol)
was suspended in dry pyridine (2 mL) and cooled to 0 °C. Benzoyl
chloride (0.6 mL, 5.17 mmol) was added dropwise and stirring con-
tinued at ambient temperature for 56 h. Excess of benzoyl chloride
was quenched with ice cold water and the solvent removed under
reduced pressure. The gummy residue was worked up with dichlo-
romethane followed by drying over anhydrous sodium sulfate. The
crude product was purified by column chromatography (eluent: 7%
ethyl acetate/dichloromethane) to afford neo-inositol hexabenzoate
(38) as a colorless solid (0.125 g, 93%); m.p. 287–290 °C (crystals
(CHCl ): ν = 3385, 1751, 1690, 1686 cm–1. 1H NMR (CDCl3,
˜
3
200 MHz): δ = 5.63 (t, J = 2.8 Hz, 1 H, Ins H), 5.55 (d, J = 9.8 Hz,
1 H, NH), 5.07–5.36 (m, 4 H, Ins H), 4.23–4.44 [m, 1 H,
from methanol). IR (CHCl ): ν = 1732 cm–1. 1H NMR (CDCl3, (CHNHAc)], 2.19 (s, 3 H, CH3), 2.04 (s, 6 H, CH3), 2.00 (s, 6 H,
˜
3
200 MHz): δ = 8.07–8.20 (m, 4 H, Ar H), 7.78–7.92 (m, 8 H, Ar
CH3), 1.91 (s, 3 H, CH3) ppm. 13C NMR (CDCl3, 50.3 MHz): δ =
H), 7.39–7.74 (m, 10 H, Ar H), 7.20–7.35 (m, 8 H, Ar H), 6.44 (s, 170.9 (C=O), 170.1 (C=O), 169.5 (C=O), 169.2 (C=O), 69.6 (Ins
2 H, Ins H), 6.20 (s, 4 H, Ins H) ppm. 13C NMR (CDCl3, C), 68.8 (Ins C), 68.3 (Ins C), 51.7 (Ins CH-NH), 22.9 (CH3), 20.6
100.6 MHz): δ = 165.35 (C=O), 165.33 (C=O), 133.7 (Carom), 133.4
(CH3), 20.5 (CH3), 20.4 (CH3) ppm. C18H25NO11 (431.39): calcd.
(Carom), 129.9 (Carom), 129.7 (Carom), 129.0 (Carom), 128.8 (Carom), C 50.12, H 5.84, N 3.25; found C 49.9, H 6.0, N 3.2.
128.7 (Carom), 128.3 (Carom), 69.1 (Ins C), 68.7 (Ins C) ppm.
5-Azido-2,4,6-tri-O-benzyl-1,3-O-benzylidine-5-deoxy-neo-inositol
(42): To a cooled (–42 °C) solution of the alcohol 6 (2.15 g,
4.00 mmol) in a mixture of dry pyridine (8 mL) and dry dichloro-
methane (8 mL), triflic anhydride (1.00 mL, 5.94 mmol) was added
dropwise over 10 min with stirring. The cooling bath was removed
and stirring was continued at ambient temperature for 2 h. The
solvents were removed under reduced pressure and the residue was
dissolved in dichloromethane, washed successively with water, satu-
rated sodium hydrogen carbonate solution followed by brine and
dried with anhydrous sodium sulfate. The solvent was removed un-
der reduced pressure and the crude product was dissolved in
HMPA (10 mL), sodium azide (1.62 g, 25 mmol) was added and
stirred for 12 h under argon atmosphere. The reaction mixture was
diluted with diethyl ether and washed successively with water and
brine and dried with anhydrous sodium sulfate. The solvent was
removed under reduced pressure and the crude product was puri-
fied by column chromatography (eluent: 10% ethyl acetate/light pe-
troleum) to afford the neo-azide 42 (2.07 g, 92%) as a colorless
solid; m.p. 87–89 °C (crystals from 15% hot ethyl acetate/light pe-
C48H36O12 (804.79): calcd. C 71.64, H 4.51; found C 71.44, H 4.86.
5-Azido-2,4,6-tri-O-benzyl-1,3-O-benzylidene-5-deoxy-myo-inositol
(39): To a cooled (–42 °C) solution of the neo-alcohol 19 (1.35 g,
2.50 mmol) in dry pyridine (5 mL) and dry dichloromethane
(5 mL), triflic anhydride (1.06 g, 3.75 mmol) was added dropwise
over a period of 15 min. The temperature of the reaction mixture
was allowed to rise to room temperature and stirring was continued
for 2 h. The solvents were removed under reduced pressure and the
crude reaction mixture was dissolved in dichloromethane, washed
successively with water, saturated sodium hydrogen carbonate solu-
tion followed by brine and dried with anhydrous sodium sulfate.
The solvent was removed under reduced pressure to afford the trifl-
ate as a gum (1.53 g), which was used in the next step.
A mixture of the crude triflate (1.53 g), sodium azide (0.97 g,
15.00 mmol) and dry DMF (8 mL) was stirred at room temperature
for 12 h under argon atmosphere. The solvent was removed under
reduced pressure and the residue obtained was dissolved in ethyl
acetate and washed with water and brine followed by drying over
anhydrous sodium sulfate. The solvent was removed and the crude
troleum). IR (CHCl3):
ν =
˜
2109 cm–1. 1H NMR (CDCl3,
product was purified by column chromatography (eluent: 10% 200 MHz): δ = 7.44–7.52 (m, 2 H, Ar H), 7.22–7.41 (m, 18 H, Ar
ethyl acetate/light petroleum) to afford the myo-azide 39 (1.24 g,
88%) as a colorless solid; m.p. 90–93 °C (crystals from dichloro-
H), 5.78 (s, 1 H, PhCHO2), 4.70 (ABq, J = 12 Hz, 4 H, 2ϫPhCH2),
4.53 (s, 2 H, PhCH2), 4.18–4.32 (m, 5 H, Ins H), 3.66 (t, J = 5 Hz,
1 H, Ins H) ppm. 13C NMR (CDCl3, 50.3 MHz): δ = 139.7 (Carom),
138.0 (Carom), 137.2 (Carom), 129.2 (Carom), 128.4 (Carom), 128.2
methane). IR (CHCl ): ν = 2106 cm–1. 1H NMR (CDCl3,
˜
3
200 MHz): δ = 7.47–7.56 (m, 2 H, Ar H), 7.26–7.46 (m, 18 H, Ar
H), 5.59 (s, 1 H, PhCHO2), 4.72 (s, 2 H, PhCH2), 4.67 (ABq, J = (Carom), 128.0 (Carom), 127.7 (Carom), 127.6 (Carom), 126.4 (Carom),
11.4 Hz, 4 H, 2ϫPhCH2), 4.40 (d, J = 2.4 Hz, 2 H, Ins H), 3.93 94.8 (PhCHO2), 79.2 (Ins C), 73.6 (CH2), 70.8 (Ins C), 70.5 (CH2),
762
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Eur. J. Org. Chem. 2010, 755–764

Efficient Access to Cyclitols
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65.8 (Ins C), 57.46 (Ins C) ppm. C34H33N3O5 (563.64): calcd. C
72.45, H 5.90, N 7.46; found C 72.10, H 6.19, N 7.42.
1,2,3,4,6-Penta-O-acetyl-5-acetylamino-5-deoxy-neo-inositol (44):
The azide 42 (0.96 g, 1.65 mmol) was hydrogenolyzed (at 50 psi) in
the presence of Pd(OH)2/C (20%, 0.07 g) in ethanol (6 mL) and
trifluoroacetic acid (3 mL) at room temp. for 32 h. The catalyst was
filtered by using a short bed of Celite and the catalyst was washed
with water (2ϫ15 mL). The combined filtrate and washings was
evaporated under reduced pressure and the residue co-evaporated
with dry toluene (2ϫ7 mL) to get the crude product (0.39 g) as an
off white solid. The crude product was dissolved in dry pyridine
(7 mL), cooled with ice and acetic anhydride (3.0 mL) was added
dropwise. The resulting mixture was stirred for 45 h and the sol-
vents were removed under reduced pressure. The residue obtained
was taken in dichloromethane, washed with water, saturated so-
dium hydrogen carbonate solution followed by brine and dried with
anhydrous sodium sulfate. The solvent was evaporated and the
crude product was purified by column chromatography (eluent: 1:1
dichloromethane/ethyl acetate) to afford the hexaacetate 44 as a
colorless solid (0.63 g, 86% for two steps); m.p. 276–278 °C (re-
[3]
[4]
[5]
[6]
f.[25a,25b] m.p. 278–279 °C). IR (CHCl ): ν = 3385, 1751, 1690, 1686
˜
3
cm–1. H NMR (CDCl3, 200 MHz): δ = 6.24–6.44 (m, 1 H, NH),
1
δ = 5.61 (t, J = 2.6 Hz, 1 H, Ins H), 5.21–5.43 (m, 4 H, Ins H),
4.96–5.1 [m, 1 H, (CHNHAc)], 2.18 (s, 3 H, CH3), 2.06 (s, 3 H,
CH3), 2.04 (s, 6 H, CH3), 2.03 (s, 6 H, CH3) ppm. 13C NMR
(CDCl3, 50.3 MHz): δ = 171.3 (C=O), 170.5 (C=O), 170.0 (C=O),
169.6 (C=O), 169.3 (C=O), 67.6 (Ins C), 66.9 (Ins C), 46.8 (Ins
CH-NH), 22.8 (CH3), 20.8 (CH3), 20.6 (CH3), 20.5 (CH3) ppm.
C18H25NO11 (431.39): calcd. C 50.12, H 5.84, N 3.25; found C
49.80, H 6.12, N 3.06.
Supporting Information (see also the footnote on the first page of
this article): Experimental procedures for compounds 14, 35, 1H,
13C NMR spectra of all new compounds, NOESY spectrum of
xanthate 7, 20 and 24, crystallographic data for compounds 7, 19,
20, 28, 29, 35, 39 and 42.
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Acknowledgments
C. M. and B. P. G. thank Council of Scientific and Industrial Re-
search (CSIR), New Delhi, for the award of research fellowships.
Funding for this work by the Department of Science and Technol-
ogy (DST), New Delhi is gratefully acknowledged. We thank Dr.
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Received: October 14, 2009
Published Online: December 8, 2009
764
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