Asymmetric synthesis of hydroxy-skipped bishomo-inositols as potential glycosidase inhibitors

Article abstract of DOI:10.1016/j.tetasy.2010.07.033

Four isomeric hydroxy-skipped bishomo-inositol analogs have been synthesized from both enantiomers of 5-hydroxymethyl-2-cyclohexenone. Sharpless asymmetric dihydroxylation and substrate-directed anionic hydroxymethylation are the key reactions which have

Full text of DOI:10.1016/j.tetasy.2010.07.033

Tetrahedron: Asymmetry 21 (2010) 2199–2205
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Asymmetric synthesis of hydroxy-skipped bishomo-inositols as potential
glycosidase inhibitors
⇑
Tridib Mahapatra, Samik Nanda
Department of Chemistry, Indian Institute of Technology, Kharagpur 721302, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Four isomeric hydroxy-skipped bishomo-inositol analogs have been synthesized from both enantiomers
of 5-hydroxymethyl-2-cyclohexenone. Sharpless asymmetric dihydroxylation and substrate-directed
anionic hydroxymethylation are the key reactions which have been employed successfully for the
synthesis of new cyclitols. The synthesized cyclitols have been screened for their inhibitory effect on
Received 8 June 2010
Accepted 23 July 2010
Available online 31 August 2010
a- and b-glycosidases.
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
iminocyclitols, have also been found to inhibit glycosidases.6 This
has prompted a huge investment of research into synthesizing
and screening of several designed cyclitol libraries. Although there
exist many well-defined strategies for accessing these cyclitols in
an enantiomeric fashion,7 we are interested in developing new
asymmetric routes for making designed cyclitols where the hydro-
xy group is abolished from one carbon (hydroxy-skipped cyclitol
analog, carbasugars) and an extra methylene spacer is introduced,
that is, mono- or bis-homocyclitol analogs (Scheme 2). We would
like to adopt many enzymatic processes to generate the asymmet-
ric centers in the designed cyclitols. In the majority of the biocata-
lytic methods available for the synthesis of cyclitols, arene-
dioxygenase is one of the enzymes used in almost all the cases.
Although the reaction is very useful in terms of chemical yield
and enantioselection, it is often difficult to obtain those microbial
strains and it will always lead to the syn-1,2-diols. In terms of
developing general and appealing asymmetric processes for novel
cyclitols, we planned to carry out a unique strategy, which would
employ commercially available enzymes coupled with chemical
reagents in an efficient way.
Cyclitols are small organic molecules with a cyclic ring as their
core structural scaffold; the ring is highly substituted with hydroxy
functional groups. One of the most widely known natural cyclitols
is inositol (cyclohexanehexols), a sugar-like molecule.1 There are
nine stereoisomers of inositol, all of which may be referred to as
inositol. The most prominent naturally occurring form is myo-ino-
sitol, cis-1,2,3,5-trans-4,6-cyclohexanehexol, and it is actively in-
volved in cellular events and processes.2 Myo-inositol also plays a
significant role as the structural basis for a number of secondary
messengers in eukaryotic cells, including inositol phosphates,
phosphatidylinositol, and phosphatidylinositol phosphate lipids.
Since the discovery that myo-inositol 1,4,5-triphosphate acts as a
Ca2+-mobilizing intracellular secondary messenger, many other
inositol phosphates have been discovered, although it is only in re-
cent years that their physiological functions have started to be
understood.3 Other naturally occurring isomers include scyllo-,
chiro-, muco-, and neo-inositols (Scheme 1).
Glycosidase inhibition is an important pharmaceutical goal, as
illustrated by current treatments for various influenza (Tamiflu)
and non-insulin-dependent diabetes (Miglitol/Glyset).4 Iminocycl-
itols and other designed analogs (also often called azasugars or
iminosugars) are particularly well-studied glycosidase inhibitors
that have shown tremendous potential for the treatment of cancer,
glycosphingolipid storage disorders, and viral diseases such as HIV
infection and hepatitis B and C.5 Their efficiency has mainly been
attributed to their structural mimicry of the glycosidase ‘oxocarbe-
nium-ion-like’ transition state and special electrostatic-binding
interactions at the glycosidase active site. Interestingly, the
six-membered pyranoside isosteres, as well as the five-membered
2. Results and discussion
Both enantiomers of 5-hydroxymethyl-cyclohex-2-enone are a
scaffold which can be structurally related to hydroxy-skipped
homo inositols 1–4 by chemical analogy. The enantiomeric
5-hydroxymethyl-cyclohex-2-enone was prepared by a chemoen-
zymatic approach as depicted in the literature by our group.8 The
main highlight of our synthetic strategy is the substrate-directed
asymmetric anionic hydroxymethylation of the parent 5-hydrox-
ymethylated cyclohexenone to access 5,6-bishydroxymethylated
cyclohexenones, followed by stereoselective asymmetric dihydroxy-
lation to access the advanced intermediates for the total synthesis
of novel cyclitols.
⇑
Corresponding author.
E-mail address: snanda@chem.iitkgp.ernet.in (S. Nanda).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.07.033

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T. Mahapatra, S. Nanda / Tetrahedron: Asymmetry 21 (2010) 2199–2205
OH
OH
OH
OH
OH
OH
HO
HO
OH
OH
HO
HO
OH
OH
HO
HO
OH
OH
HO
HO
OH
OH
OH
OH
muco-inositol
scyllo-inositol
chiro-inositol
myo-inositol
Scheme 1. Naturally occurring cyclitols.
OH
HO
OH
OH
HO
2
OH
OH
O
HO
HO
HO
OH
OH
OH
OH
HO
OH
1
3
OH
HO
OH
OH
HO
4
Scheme 2. Designed hydroxy-skipped homoinositol analogs.
2.1. Synthesis of cyclitols 1 and 2
assuming a half chair-like (envelope) conformation for the parent
cyclohexenone 12, in which the bottom face is shielded by the
bulky TBDPS group; hence dihydroxylation occurs exclusively from
the top face (Scheme 3). It is worth noting that protection at the 5-
and 6-positions (in the parent cycloalkenones 5, by bulky TBDPS
group) acts as a diastereomeric handle for the dihydroxylation
reaction. In the cycloalkenone 7, the 5-hydroxymethyl group is
protected as its TBDPS ether and it directs the addition of OsO4
through the olefinic double bond from the bottom face to yield
the diol 8. Conversely in cycloalkenone 12, the 6-hydroxymethylat-
ed group is protected as its TBDPS ether and directs the addition
from the more accessible top face to afford diol 13.
The synthesis started from (S)-5-hydroxymethyl-2-cyclohexe-
none 5. The free hydroxy group was protected as its TBDPS ether
to afford compound 6 in 88% yield. Base-induced anionic hydrox-
ymethylation with benzotriazol-1-yl-methanol (as the formalde-
hyde source)9 on 6 afforded hydroxymethylated compound 7 in
80% yield as a single diastereomer. Asymmetric dihydroxylation
on 7 with AD-mix-a
yielded diol 8 in 76% yield.10 The stereoselec-
tivity in the dihydroxylation step can be explained by assuming a
half chair-like (envelope) conformation for the parent cyclohexe-
none 7, in which the top face is shielded by the bulky TBDPS group;
hence the dihydroxylation exclusively occurs from the bottom face
(Scheme 3). The keto group in 8 was reduced stereoselectively by
NaBH4 to afford the corresponding tetrol as a single diastereomer
in 90% yield, followed by deprotection of the TBDPS group with
TBAF to afford compound 1 in 72% yield. For the synthesis of
compound 2, the free hydroxy group in compound 5 was protected
as its PMB-ether by treatment with PMB-Bundle11 to afford
2.2. Synthesis of cyclitols 3 and 4
Enantiomeric (R)-5-hydroxymethyl-2-cyclohexenone 14 was
used for the synthesis of the remaining two cyclitols. The strategy
employed was same as outlined in Scheme 3 for compounds 1 and
2. The key reactions were again the substrate-directed anionic
hydroxymethylation reaction, which installs a hydroxymethyl
group at the 6-position in the parent compound 14. Selective
protection/deprotection was subsequently used to make use of
the protected hydroxymethyl group either at the 5- or the
6-position as a diastereomeric handle for the stereoselective
dihydroxylation reaction. Finally NaBH4-mediated 1,2-anti reduc-
tion furnished the hydroxy-skipped bishomo-inositol analogs 3
and 4 (Scheme 4).
compound
9 in 92% yield. Hydroxymethylation on 9 with
benzotriazol-1-yl-methanol (as formaldehyde source) afforded
compound 10 in 68% yield. The free hydroxy group was protected
as its TBDPS ether to afford compound 11 in 92% yield. Deprotec-
tion of the PMB group with DDQ12 afforded compound 12 in 85%
yield. Asymmetric dihydroxylation with AD-mix-b on compound
12 afforded diol 13 as the single diastereomer in 78% yield. The ste-
reoselectivity in the dihydroxylation step can be explained by

T. Mahapatra, S. Nanda / Tetrahedron: Asymmetry 21 (2010) 2199–2205
2201
O
O
O
a
e
OTBDPS
OH
OPMB
6
9
5
b
f
10, R = PMB, R' = H
g
O
11, R = PMB, R' = TBDPS
O
h
12, R = H, R' = TBDPS
OH
OR'
OR
OTBDPS
7
12
OTBDPS
OH
O
O
c
i
OH
half chair (envelope)
OTBDPS
half chair (envelope)
O
O
HO
HO
OH
HO
OTBDPS
OTBDPS
OH
8
HO
13
d
d
OH
OH
HO
HO
HO
HO
OH
OH
OH
OH
1
2
Scheme 3. Reagents and conditions: (a) TBDPS-Cl, imidazole, 88%; (b) LTMP, benzotriazol-1-yl-methanol, ꢀ78 °C, 80%; (c) AD-Mix-
a
, MeSO2NH2, tBuOH/H2O (1:1), 76%; (d)
(i) NaBH4, MeOH, 90%, (ii) TBAF–THF, 72%; (e) PMB-O(C@NH)CCl3, cyclohexane/DCM (2:1), CSA, 92%; (f) LTMP, benzotriazol-1-yl-methanol, ꢀ78 °C, 68%; (g) TBDPS-Cl,
imidazole, 92%; (h) DDQ, DCM/H2O (19:1), 85%; (i) AD-Mix-b, MeSO2NH2, tBuOH/H2O (1:1), 78%.
2.3. Glycosidase inhibition study
Glycosidase ( -glycosidase and b-glycosidase) inhibition exper-
moderate inhibition rates were obtained. Future studies directed
toward synthesis of
underway.
a novel class of cyclitols are currently
a
iments were performed by using the corresponding para-nitro-
phenyl glycosides as the substrate in the presence of all the
synthesized cyclitols 1–4. The results are summarized in Table 1.
Cyclitol 4 seems to exhibit the best inhibitory activity toward
4. Experimental
4.1. General
both
59 1.6% for 10
the synthesized cyclitols showed good inhibitory activity toward
glycosidases ( and b), their activities were substantially lower
when compared to commercially available anti-diabetic drugs such
as migitol (IC50 = 1.3 M), voglibose (IC50 = 0.11 M), and acarbose
(IC50 = 0.35 -glycosidase inhibitors.
M),13 all of which are potent
a- and b-glycosidases and inhibition rates were 53 2% and
lM concentration of the compounds. Although
Unless otherwise stated, materials were obtained from com-
mercial suppliers and used without further purification. THF and
diethylether were distilled from sodiumbenzophenone ketyl.
Dichloromethane (DCM), dimethylformamide (DMF), and dimeth-
ylsulfoxide (DMSO) were distilled from calciumhydride.
dase (yeast), b-glycosidase (sweet almonds), PNP- -glycoside, and
a
l
l
a-Glycosi-
l
a
a
The inhibitory activities for the synthesized cyclitols are attributed
mainly to their mimicking nature with the structure of a ‘strained
activated complex’14 (transition state analog) involved in the case
of glycosidic hydrolysis.
PNP-b-glycoside were obtained from SRL (Sisco Research Laborato-
ries), India. Reactions were monitored by thin-layer chromatogra-
phy (TLC) and carried out on 0.25 mm silica gel plates (Merck) with
UV light, ethanolic anisaldehyde, and phosphomolybdic acid/heat
as developing agents. Silica gel 100–200 mesh was used for column
chromatography. Concentrations were performed on a Buchi rotary
evaporator at a temperature below 40 °C. Yields refer to chromato-
graphically and spectroscopically homogeneous materials unless
otherwise stated. NMR spectra were recorded on Bruker 400 MHz
spectrometers at 25 °C in CDCl3 using TMS as the internal standard.
Chemical shifts are shown in d. 13C NMR spectra were recorded
with a complete proton decoupling environment. The chemical
shift value is listed as dH and dC for 1H and 13C, respectively. For
NMR spectra in deuterated solvents, the solvent peak was used
as reference (CDCl3: d = 7.26 for 1H, 76.93 for 13C; MeOH-d4:
3. Conclusion
In conclusion, four isomeric (two sets of enantiomers) hydroxy-
skipped bishomo-inositol analogs have been synthesized starting
from enantiomers of 5-hydroxymethyl-2-cyclohexenone. The key
reactions involved are the substrate-directed hydroxymethylation
reaction and the stereoselective dihydroxylation reaction directed
by the presence of bulky protecting group at the 5- and 6-positions
in the parent cycloalkenone. A glycosidase inhibition experiment
was carried out with the newly synthesized cyclitols and good to

2202
T. Mahapatra, S. Nanda / Tetrahedron: Asymmetry 21 (2010) 2199–2205
O
O
O
a
e
OTBDPS
OH
OPMB
15
18
14
b
f
19, R = PMB, R' = H
g
O
20, R = PMB, R' = TBDPS
O
h
21, R = H, R' = TBDPS
OH
OR'
OR
OTBDPS
16
HO
21
OTBDPS
H
H
O
c
i
O
OTBDPS
half chair (envelope)
OH
O
O
half chair (envelope)
HO
HO
OH
HO
OTBDPS
OH
OTBDPS
17
HO
22
d
d
OH
OH
HO
HO
HO
HO
OH
OH
OH
OH
3
4
Scheme 4. Reagents and conditions: (a) TBDPS-Cl, imidazole; (b) LTMP, benzotriazol-1-yl-methanol, ꢀ78 °C, 72%; (c) AD-Mix-
a
, MeSO2NH2, tBuOH/H2O (1:1), 78%; (d) (i)
NaBH4, MeOH, 90%, (ii) TBAF–THF, 75%; (e) PMB-O(C@NH)CCl3, cyclohexane/DCM (2:1), CSA, 88%; (f) LTMP, benzotriazol-1-yl-methanol, ꢀ78 °C, 70%; (g) TBDPS-Cl,
imidazole, 89%; (h) DDQ, DCM/H2O (19:1), 88%; (i) AD-Mix-b, MeSO2NH2, tBuOH/H2O (1:1), 75%.
Table 1
Inhibition of glycosidases by cyclitols 1–4
-glycosidasea
Inhibition (%) b-glycosidaseb
IC50
(l
M)
a-glycosidase
IC50 (lM) b-glycosidase
c
c
Cyclitol
Parent pyranose
Inhibition (%)
11 3.8
a
1
2
3
4
22 1.5
9.5 2.5
NI
16 1.5
18.5 2.2
nd
17.2 2.0
21.2 1.8
nd
L
-Mannose
-Gulose
17
8
2
L
0.5
D
-Mannose
-Gulose
53 2d
59 1.6
6.5 1.1
8.0 0.6
D
NI: no inhibition; nd: not determined.
a
a
-Glycosidase from yeast.
b
c
b-Glycosidase from sweet almonds.
Concentration required for 50% inhibition of the enzyme activity under the assay conditions.
Four experiments were performed for all compounds and in triplicate in each experiment.
d
d = 3.31 for 1H, and 49.00 for 13C). Where necessary, NMR data
were assigned using HH- and CH-correlated spectra. Elemental
analysis was performed in the Departmental Research Facility,
IIT-Kharagpur, with a Perkin–Elmer 2400 series CHN analyzer.
Optical rotations were measured on a JASCO P-1020 digital polar-
imeter. Mass spectral analysis was performed at Central Research
Facility (CRF, IIT-Kharagpur).
trometrically (Shimadzu UV–vis spectrophotometer) in the pres-
ence of the synthesized compounds. A typical enzymatic assay
(final volume 3 ml) contained 0.03–0.06 units mlꢀ1 of the enzyme
(1 unit = 1 enzyme unit liberating 1 lmol of p-nitrophenol per
minute from p-nitrophenyl glycoside). Each assay was performed
with the p-nitrophenyl glycoside derivatives of the appropriate su-
gar as the substrate in a potassium phosphate buffer (67 mM, pH
6.8). The assays were performed with four different concentrations
of the substrates (1, 2, 3, and 4 mM in the aq buffer solution). The
enzyme and inhibitor (10 mM) were preincubated for 1–2 min at
37 °C dependent on the enzyme; the reaction was started by the
addition of the substrate. The p-nitrophenolate formed was mea-
sured by UV spectroscopy at 400 nm after every 30 s interval. A
suitable blank assay was performed in each case without adding
the inhibitors.
4.2. Enzymatic assay
Inhibitory activities of the synthesized compounds were deter-
mined by conducting a spectrophotometric assay of glycosidase by
using PNP-glucosides (a or b) in the presence of the synthesized
cyclitols 1–4. The residual hydrolytic activities of glycosidases of
the corresponding p-nitrophenyl glycosides were measured spec-

T. Mahapatra, S. Nanda / Tetrahedron: Asymmetry 21 (2010) 2199–2205
2203
4.3. (S)-5-(tert-Butyl-diphenyl-silanyloxymethyl)-cyclohex-2-
enone 6
The tetrol that was prepared as above (30 mg, 0.09 mmol) was
taken in a dry flask. Next, THF (2 ml) and TBAF (1 M in THF,
0.1 ml, 0.09 mmol) were added to it, and the reaction mixture
was stirred for 3 h at room temperature. After that time, the THF
was evaporated, and the content of the flask was directly loaded
into a silica gel column and purified by flash chromatography
(1:1; CHCl3/MeOH) to afford cyclitol 1 as a gummy solid in 72%
yield. dH (CD3OD, 400 MHz): 4.2 (br s, 1H), 4.01 (br s, 1H), 3.8–
3.72 (m, 3H), 3.62 (m, 1H), 3.54 (m, 1H), 2.17 (m, 1H), 1.92 (m,
1H), 1.64 (m, 2H). dC (CD3OD, 100 MHz): 75.4, 71.4, 71.1, 65.3,
63.4, 42.9, 34.6, 29.6. Elemental Anal. Calcd for C8H16O5: C,
The compound has been prepared from the parent hydroxy
compound (S)-5 as outlined in the literature.8a
4.4. (5S,6S)-5-(tert-Butyl-diphenyl-silanyloxymethyl)-6-
hydroxymethyl-cyclohex-2-enone 7
To a stirred solution of n-butyllithium (3.5 ml, 1.6 M in hexane,
5.7 mmol) in anhydrous THF (15 mL) was added dropwise 2,2,6,6-
tetramethylpiperidine (1 mL, 5.7 mmol) at ꢀ10 °C. The solution
was allowed to stir at 0 °C for 30 min and then cooled to ꢀ78 °C.
Compound 6 (500 mg, 1.9 mmol) in anhydrous THF (5 mL) was
added dropwise and stirred for an additional 1 h. Benzotriazol-1-
yl-methanol (566 mg, 3.8 mmol) in anhydrous THF (4 mL) was
added dropwise over 10 min and the solution was kept for 2 h at
this temperature. The reaction was quenched with water (5 mL),
extracted with diethyl ether (50 mL), then washed successively
with 4 M NaOH (15 mL) and brine (15 mL). The organic layer was
dried over Na2SO4, filtered, and concentrated in vacuo. The product
was purified by flash chromatography (1:5; hexane/EtOAc) to af-
ford compound 7 as a colorless liquid in 80% yield. dH (CDCl3,
400 MHz): 7.65–7.46 (m, 4H), 7.44–7.38 (m, 6H), 7.0–6.97 (m,
1H), 6.02 (dd, J = 10.4, 2.0 Hz, 1H), 4.05–4.03 (m, 1H), 3.7–3.66
(m, 3H), 2.77 (br s, 1H), 2.63–2.59 (m, 2H), 2.4–2.2 (m, 2H), 1.07
(s, 9H). dC (CDCl3, 100 MHz): 202.2, 150.0, 135.5, 133.1, 129.8,
49.99; H, 8.39. Found: C, 49.95; H, 8.45. ½a D28
¼ þ66:8 (c 1.0,
ꢁ
MeOH).
4.7. (S)-5-(4-Methoxy-benzyloxymethyl)-cyclohex-2-enone 9
A solution of 4-methoxybenzyl alcohol (200 mg, 1.5 mmol) in
5 mL of ether was added to a suspension of 65% NaH (8 mg,
0.2 mmol) in 2 mL of ether at room temperature. The resulting
mixture was stirred at room temperature for 30 min and then
cooled to 0 °C. Trichloroacetonitrile (TCA, 0.15 ml, 1.5 mmol) was
added to it and the reaction mixture was allowed to warm slowly
to room temperature for 6 h. The solution was evaporated to an or-
ange syrup, which was dissolved in anhydrous hexane (40 mL)
containing a few drops of MeOH. This suspension was shaken vig-
orously and filtered through Celite, and the filtrate was concen-
trated to afford the crude imidate. The crude imidate (3.68 g,
13 mmol) was taken in cyclohexane (20 mL) and a solution of alco-
hol 5 (70 mg, 0.55 mmol) in 10 ml of DCM was added. The resulting
solution was cooled to 0 °C after which CSA (catalytic) was added.
The reaction mixture was stirred overnight at room temperature,
while a white precipitate of trichloroacetamide slowly formed.
The solution was filtered off and washed with DCM. The filtrate
was washed with NaHCO3 solution, water, and brine. Purification
by means of silica gel chromatography (9:1 and hexane/EtOAc)
yielded compound 9 as a colorless liquid in 92% yield. dH (CDCl3,
400 MHz): 7.25 (d, J = 8.8 Hz, 2H), 6.98–6.90 (m, 1H), 6.88 (d,
J = 8.8 Hz, 2H), 6.01–5.97 (m, 1H), 4.42 (s, 2H), 3.8 (s, 3H), 3.38
(d, J = 6.4 Hz, 2H), 2.54–2.14 (m, 5H). dC (CDCl3, 100 MHz): 199.4,
159.2, 149.6, 130.2, 129.7, 129.2, 113.8, 72.9, 72.82, 55.3, 41.1,
129.2, 127.7, 64.6, 59.3, 50.2, 38.4, 29.0, 26.9, 19.3. ½a D28
¼ þ17:0
ꢁ
(c 1.0, MeOH). ESI MS for (M++Na) = 417.1211.
4.5. (2S,3S,5S,6S)-3-(tert-Butyl-diphenyl-silanyloxymethyl)-5,6-
dihydroxy-2-hydroxymethyl-cyclohexanone 8
At first, tBuOH (3 ml), H2O (3 ml), and AD-mix-a (545 mg) were
mixed and the mixture was stirred for 15 min. Methanesulfonam-
ide (43 mg, 0.44 mmol) was then added and the stirring was con-
tinued for a further 15 min. Compound 7 (110 mg, 0.374 mmol)
was then added in one portion. The slurry was stirred vigorously
at 20 °C for 24 h. After that time, sodium sulfite (15 g) was added
and the stirring was continued for further 1 h. The reaction mixture
was extracted with EtOAc (4 ꢂ 100 ml). The organic layer was
dried (Na2SO4) and evaporated in vacuo. The diol was purified by
flash chromatography (1:1; hexane/EtOAc) to afford the diol 8 as
a colorless liquid in 76% yield. dH (CDCl3, 400 MHz): 7.64–7.60
(m, 4H), 7.45–7.38 (m, 6H), 4.42 (m, 1H), 4.2 (br s, 1H), 4.0–3.62
(m, 5H), 2.75 (br s, 1H), 2.5–2.31 (m, 3H), 2.24–2.04 (m, 2H),
1.07 (s, 9H). dC (CDCl3, 100 MHz): 212.8, 135.6, 133.1, 129.9,
127.8, 77.2, 71.8, 64.2, 58.5, 51.1, 36.9, 31.7, 26.9, 19.4.
35.6, 29.0. ½a 2D8
¼ þ7:25 (c 1.0, MeOH). Elemental Anal. Calcd for
ꢁ
C
15H18O3: C, 73.15; H, 7.37. Found: C, 73.18; H, 7.44.
4.8. (5S,6S)-6-Hydroxymethyl-5-(4-methoxy-benzyloxymethyl)-
cyclohex-2-enone 10
The hydroxymethylation reaction was performed as described
in Section 4.4 to afford compound 10 as a colorless liquid in 68%
yield. dH (CDCl3, 400 MHz): 7.28 (d, J = 8.8 Hz, 2H), 7.0–6.91 (m,
1H), 6.89 (d, J = 8.8 Hz, 2H), 6.01 (d, J = 10.2 Hz, 1H), 4.46 (s, 2H),
4.12–4.04 (m, 1H), 3.76 (s, 3H), 3.72–3.69 (m, 1H), 3.57–3.42 (m,
2H), 2.86–2.82 (m, 1H), 2.6–2.44 (m, 3H). dC (CDCl3, 100 MHz):
202.0, 159.3, 149.9, 131.1, 130.0, 129.3, 113.8, 73.0, 70.88, 59.3,
½
a 2D8
ꢁ
¼ þ27:3 (c 1.0, MeOH). ESI MS for (M++Na) = 451.0750.
4.6. (1S,2S,3S,4S,5S)-4,5-Bis-hydroxymethyl-cyclohexane-1,2,3-
triol 1
Compound 8 (65 mg, 0.2 mmol) was taken in anhydrous MeOH.
Next, NaBH4 (8 mg, 0.2 mmol) was added to the reaction mixture.
After completion of the reaction as indicated by TLC analysis, the
content of the flask was evaporated and the residue was taken in
DCM, and then washed with water and brine. The organic layer
was dried (MgSO4) and evaporated. The crude tetrol was further
purified by silica gel chromatography (1:1; hexane/EtOAc) to af-
ford the tetrol as a gummy solid 90% yield. dH (CDCl3, 400 MHz):
7.63–7.61 (m, 4H), 7.44–7.36 (m, 6H), 4.25 (br s, 1H), 4.09 (br s,
1H), 3.84–3.74 (m, 3H), 3.65–3.63 (m, 1H), 3.44 (m, 1H), 2.2–2.16
(m, 1H), 1.92–1.89 (m, 1H), 1.64–1.61 (m, 2H), 1.08 (s, 9H). dC
(CDCl3, 100 MHz): 135.52, 133.12, 129.79, 127.73, 75.46, 71.42,
71.12, 65.32, 63.45, 42.91, 34.62, 29.63, 26.85, 19.24.
55.3, 50.8, 36.7, 29.6. ½a D28
¼ þ14:5 (c 1.0, MeOH). Elemental Anal.
ꢁ
Calcd for C16H20O4: C, 69.55; H, 7.30. Found: C, 69.53; H, 7.34. ESI
MS for (M++Na) = 299.0317.
4.9. (5S,6S)-6-(tert-Butyl-diphenyl-silanyloxymethyl)-5-(4-
methoxy-benzyloxymethyl)-cyclohex-2-enone 11
Compound 10 (40 mg, 0.14 mmol) was taken in anhydrous DCM
(4 ml) and cooled to 0 °C. Imidazole (15 mg, 0.21 mmol) was added
to the reaction mixture followed by the addition of TBDPS-Cl
(56 ll, 0.21 mmol). The reaction was allowed to warm to room
temperature for 6 h. After that water was added to it and the or-
ganic layer was washed with brine and dried (MgSO4). Evaporation

2204
T. Mahapatra, S. Nanda / Tetrahedron: Asymmetry 21 (2010) 2199–2205
and purification yielded the mono-TBDPS-protected compound 11
as a colorless liquid in 92% yield. dH (CDCl3, 400 MHz): 7.7–7.63
(m, 4H), 7.42–7.37 (m, 6H), 7.20–7.14 (m, 2H), 6.95–6.81 (m,
3H), 6.08–6.01 (m, 1H), 4.4–4.24 (m, 3H), 3.78 (s, 3H), 3.66–3.62
(m, 1H), 3.45–3.38 (m, 2H), 2.71–2.62 (m, 1H), 2.5–2.38 (m, 3H),
1.01 (s, 9H). dC (CDCl3, 100 MHz): 198.8, 159.2, 148.9, 135.8,
135.7, 133.6, 133.2, 129.6, 129.1, 127.6, 113.8, 72.8, 71.0, 60.2,
3.64 (m, 2H), 2.79–2.77 (m, 1H), 2.38–2.35 (m, 1H), 2.18–2.14
(m, 1H), 2.04–1.99 (m, 1H), 1.05 (s, 9H). dC (CDCl3, 100 MHz):
211.1, 132.9, 132.5, 130.0, 129.9, 76.7, 71.8, 64.2, 58.6, 51.0, 36.9,
31.8, 28.7, 19.6. ESI MS for (M++Na) = 451.0750.
4.15. (1R,2R,3R,4R,5R)-4,5-Bis-hydroxymethyl-cyclohexane-
1,2,3-triol 3
55.2, 50.4, 35.6, 28.3, 26.8, 19.3. ½a D28
¼ þ33:3 (c 1.0, MeOH). ESI
ꢁ
MS for (M++Na) = 537.0786.
The NaBH4 reduction and TBDPS deprotection were performed
as described in Section 4.6 to afford cyclitol 3 as a gummy solid.
dH (CDCl3, 400 MHz): 4.27–3.45 (m, 7H), 2.85–2.33 (br s, 5H, -OH),
1.89–1.86 (m, 1H), 1.66–1.6 (m, 2H), 1.32–1.28 (m, 1H). dC (CDCl3,
100 MHz): 76.6, 71.6, 71.1, 65.7, 64.2, 43.2, 34.7, 28.0. Elemental
Anal. Calcd for C8H16O5: C, 49.99; H, 8.39. Found: C, 49.91; H,
4.10. (5S,6S)-6-(tert-Butyl-diphenyl-silanyloxymethyl)-5-
hydroxymethyl-cyclohex-2-enone 12
Compound 11 (260 mg, 0.5 mmol) was taken in 15 mL of DCM/
H2O (19:1). Next, DDQ (172 mg, 0.75 mmol) was added to it in one
portion. The reaction mixture was stirred at room temperature for
1 h. The reaction mixture was filtered off, and the filtrate was
washed with 5% NaHCO3 solution, water, and brine. The organic
layer was dried (MgSO4) and evaporated. Purification by silica gel
chromatography (3:1, hexane/EtOAc) afforded the pure compound
12 as a colorless liquid in 85% yield. dH (CDCl3, 400 MHz): 7.69–
7.64 (m, 4H), 7.45–7.36 (m, 6H), 76.94–6.91 (m, 1H), 6.0 (d,
J = 10.4 Hz, 1H), 4.14–4.02 (m, 2H), 3.82–3.78 (m, 1H), 3.66–3.63
(m, 1H), 2.54–2.41 (m, 4H), 2.37 (br s, 1H), 1.05 (s, 9H). dC (CDCl3,
400 MHz): 198.9, 149.2, 135.8, 133.1, 130.0, 129.5, 127.9, 64.5,
8.46. ½a 2D8
¼ ꢀ66:2 (c 1.0, MeOH).
ꢁ
4.16. (5R,6R)-6-Hydroxymethyl-5-(4-methoxy-benzyloxy-
methyl)-cyclohex-2-enone 19
The compound was prepared as described in Section 4.4. dH
(CDCl3, 400 MHz): 7.25 (d, J = 8.8 Hz, 2H), 6.91–6.88 (m, 1H), 6.84
(d, J = 8.8 Hz, 2H), 5.90 (d, J = 10.0 Hz, 1H), 4.34 (s, 2H), 4.04–3.97
(m, 1H), 3.70 (s, 3H), 3.65–3.63 (m, 1H), 3.48–3.33 (m, 2H), 2.79
(br s, 1H, –OH), 2.46–2.21 (m, 4H). dC (CDCl3, 100 MHz): 202.0,
159.3, 149.9, 130.0, 129.3, 113.8, 73.0, 70.8, 59.3, 55.2, 50.8, 36.7,
29.5, 26.4. ESI MS for (M++Na) = 299.0317.
61.8, 51.1, 40.2, 28.8, 27.0, 19.3. ½a D28
¼ þ11:25 (c 1.0, MeOH). ESI
ꢁ
MS for (M++Na) = 417.1211.
4.17. (5R,6R)-6-(tert-Butyl-diphenyl-silanyloxymethyl)-5-(4-
4.11. (2S,3S,5R,6R)-2-(tert-Butyl-diphenyl-silanyloxymethyl)-
methoxy-benzyloxymethyl)-cyclohex-2-enone 20
5,6-dihydroxy-3-hydroxymethyl-cyclohexanone 13
The compound was prepared as described in Section 4.10. dH
(CDCl3, 400 MHz): 7.71–7.63 (m, 4H), 7.41–7.32 (m, 6H), 7.19 (d,
J = 8.8 Hz, 2H), 6.93–6.81 (m, 3H), 4.39–4.25 (m, 3H), 3.75 (s, 3H),
3.70–3.63 (m, 1H), 3.45–3.41 (m, 2H), 2.7–2.64 (m, 1H), 2.48–
2.37 (m, 3H), 1.04 (s, 9H). dC (CDCl3, 100 MHz): 198.8, 159.2,
149.1, 135.8, 133.7, 133.3, 130.4, 129.7, 129.2, 127.7, 113.8, 72.8,
71.1, 60.2, 55.3, 50.5, 35.7, 28.4, 26.9, 19.4. ESI MS for
(M++Na) = 537.0786.
Asymmetric dihydroxylation of compound 12 was performed as
described in Section 4.5 with AD-mix-b to afford the triol 13 as a
colorless liquid in 78% yield. dH (CDCl3, 400 MHz): 7.69–7.59 (m,
4H), 7.46–7.36 (m, 6H), 4.39 (br s, 1H), 4.14–4.1 (m, 2H), 3.93–
3.89 (m, 2H), 3.65–3.62 (m, 1H), 2.63–2.59 (m, 1H), 2.39–2.35
(m, 1H), 2.10–2.02 (m, 2H), 1.05 (s, 9H). dC (CDCl3, 400 MHz):
209.2, 135.8, 132.7, 130.0, 127.7, 76.7, 71.6, 64.2, 60.9, 51.8, 39.7,
32.1, 26.8, 19.1.
½
a 2D8
ꢁ
¼ þ6:1 (c 1.0, MeOH).ESI MS for
(M++Na) = 451.0750.
4.18. (5R,6R)-6-(tert-Butyl-diphenyl-silanyloxymethyl)-5-
hydroxymethyl-cyclohex-2-enone 21
4.12. (1R,2R,3R,4S,5S)-4,5-Bis-hydroxymethyl-cyclohexane-
1,2,3-triol 2
The compound was prepared as described in Section 4.11. dH
(CDCl3, 400 MHz): 7.72–7.64 (m, 4H), 7.41–7.4 (m, 6H), 6.93–
6.87 (m, 1H), 5.99 (d, J = 10.2 Hz, 1H), 4.13–4.07 (m, 2H), 3.8–3.6
(m, 2H), 2.79 (br s, 1H, –OH), 2.49–2.45 (m, 4H), 1.06 (s, 9H). dC
(CDCl3, 100 MHz): 199.0, 149.3, 135.7, 132.3, 129.9, 129.3, 127.8,
64.1, 61.52, 50.8, 39.6, 28.4, 26.9, 19.2. ESI MS for
(M++Na) = 417.1211.
The NaBH4 reduction and TBDPS deprotection were performed
as described in Section 4.6 to afford cyclitol 2 as a gummy solid.
dH (CDCl3, 400 MHz): 4.12–4.05 (m, 2H), 3.94–3.91 (m, 1H), 3.83–
3.79 (m, 1H), 3.68–3.64 (m, 1H), 3.52–3.48 (m, 1H), 3.46–3.44
(m, 1H), 3.0–2.7 (br s, 5H, -OH), 2.0 (m, 2H), 1.57 (m, 2H). dC (CDCl3,
100 MHz): 74.7, 71.5, 71.1, 66.0, 64.4, 43.8, 34.7, 29.8. Elemental
Anal. Calcd for C8H16O5: C, 49.99; H, 8.39. Found: C, 49.92; H,
4.19. (2R,3R,5S,6S)-2-(tert-Butyl-diphenyl-silanyloxymethyl)-
5,6-dihydroxy-3-hydroxymethyl-cyclohexanone 22
8.40. ½a 2D8
ꢁ
¼ þ97:1 (c 1.0, MeOH).
4.13. (5R,6R)-5-(tert-Butyl-diphenyl-silanyloxymethyl)-6-
The asymmetric dihydroxylation reaction was performed with
hydroxymethyl-cyclohex-2-enone 16
AD mix-a as described in Section 4.5 to afford triol 22. dH (CDCl3,
400 MHz): 7.69–7.63 (m, 4H), 7.44–7.38 (m, 6H), 4.39 (m, 1H),
4.14–4.08 (m, 2H), 3.93–3.89 (m, 2H), 3.65–3.62 (m, 1H), 2.63–
2.61 (m, 1H), 2.38–2.36 (m, 1H), 2.05–2.03 (m, 2H), 1.05 (s, 9H). dC
(CDCl3, 100 MHz): 209.1, 135.7, 132.7, 130.0, 127.8, 76.7, 71.5,
64.2, 61.0, 51.8, 39.8, 32.0, 26.8, 19.1. ESI MS for (M++Na) = 451.0750.
The compound was prepared as described in Section 4.4 and has
similar characteristic spectroscopic values to those of enantiomer 7.
4.14. (2R,3R,5R,6R)-3-(tert-Butyl-diphenyl-silanyloxymethyl)-
5,6-dihydroxy-2-hydroxymethyl-cyclohexanone 17
4.20. (1S,2S,3S,4R,5R)-4,5-Bis-hydroxymethyl-cyclohexane-
The asymmetric dihydroxylation reaction was performed with
AD-mix-b as described in Section 4.5 to afford triol 17. dH (CDCl3,
400 MHz): 7.65–7.62 (m, 4H), 7.45–7.38 (m, 6H), 4.42 (m, 1H),
4.21–4.2 (m, 1H), 3.92–3.89 (m, 1H), 3.88–3.78 (m, 1H), 3.67–
1,2,3-triol 4
NaBH4 reduction and TBDPS deprotection were performed as
described in Section 4.6 to afford cyclitol 4 as a gummy solid. dH

T. Mahapatra, S. Nanda / Tetrahedron: Asymmetry 21 (2010) 2199–2205
2205
Hermann-Rinke, C. Diabetes Metab. Rev. 1998, 14, S31–S38; (g) Mehta, A.;
Zitzmann, N.; Rudd, P. M.; Block, T. M.; Dwek, R. A. FEBS Lett. 1998, 430, 17–22;
(h) Von Itzstein, M. Nat. Rev. Drug Disc. 2007, 6, 967–974; (i) Zhang, J.; Xu, W.
Mini-Rev. Med. Chem. 2006, 6, 428–448.
(CDCl3, 400 MHz): 4.14–4.12 (m, 1H), 4.07–3.99 (m, 1H), 3.94–3.9
(m, 1H), 3.86–3.81 (m, 1H), 3.75–3.72 (m, 1H), 3.65–3.59 (m, 1H),
3.51–3.39 (m, 1H), 2.08–2.0 (m, 2H), 1.59–1.53 (m, 2H). dC (CDCl3,
100 MHz): 75.1, 71.5, 71.1, 66.1, 64.3, 43.5, 34.8, 29.7.
6. (a) Lillelund, V. H.; Jensen, H. H.; Liang, X.; Bols, M. Chem. Rev. 2002, 102, 515–
553; (b)Iminosugars as Glycosidase Inhibitors. Nojirimycin and Beyond; Stutz, A.
E., Ed.; Wliey-VCH: Weinheim, 1999; (c) Asano, N.; Nash, R. J.; Molyneux, R. J.;
Fleet, G. W. J. Tetrahedron: Asymmetry 2000, 11, 1645–1680; (d) Heightman, T.
D.; Vasella, A. T. Angew. Chem., Int. Ed. 1999, 38, 750–770; (e) Watson, A. A.;
Fleet, G. W. J.; Asano, N.; Molyneux, R. J.; Nash, R. J. Phytochemistry 2001, 56,
265–295; (f) Asano, N. Glycobiology 2003, 13, 93R–104R.
½
a 2D8
ꢁ
¼ ꢀ113:0 (c 1.0, MeOH). Elemental Anal. Calcd for C8H16O5:
C, 49.99; H, 8.39. Found: C, 49.93; H, 8.44.
Acknowledgments
7. (a) Baran, A.; Balci, M. J. Org. Chem. 2009, 74, 88–95; (b) Azab, A. N.; He, Q.; Ju,
S.; Li, G.; Greenberg, M. L. Mol. Microbiol. 2007, 63, 1248–1258; (c) Moris, M.-A.;
Caron, A. Z.; Guillemette, G.; Rognan, D.; Schmitt, M.; Schlewer, G. J. Med. Chem.
2005, 48, 1251–1255; (d) Freeman, S.; Hudlicky, T. Bioorg. Med. Chem. Lett.
2004, 14, 1209–1212; (e) Podeschwa, M.; Plettenburg, O.; vom Brocke, J.; Block,
O.; Adelt, S.; Altenbach, H.-J. Eur. J. Org. Chem. 2003, 1958–1972; (f) Mills, S. J.;
Riley, A. M.; Liu, C.; Mahon, M. F.; Potter, B. V. L. Chem. Eur. J. 2003, 9, 6207–
6214; (g) Cid, M. B.; Bonilla, J. B.; Alfonso, F.; Martin-Lomas, M. Eur. J. Org. Chem.
2003, 3505–3514; (h) Dinkel, C.; Schultz, C. Tetrahedron Lett. 2003, 44, 1157–
1159; (i) Praveen, T.; Shashidhar, M. S. Carbohyd. Res. 2001, 330, 409–411; (j)
Chung, S.-K.; Kwon, Y.-U.; Chang, Y.-T.; Sohn, K.-H.; Shin, J.-H.; Park, K.-H.;
Hong, B.-J.; Chung, I.-H. Bioorg. Med. Chem. 1999, 7, 2577–2589; (k) Riley, A. M.;
Jenkins, D. J.; Potter, B. V. L. Carbohydr. Res. 1998, 314, 277–281; (l) Brammer, L.
E., Jr.; Hudlicky, T. Tetrahedron: Asymmetry 1998, 9, 2011–2014.
We are thankful to DST-SERC (New Delhi, India) for providing
financial support. We are also thankful to DST (New Delhi) for pro-
viding the departmental NMR facility under the DST-IRPHA pro-
gramme. One of the authors, T.M., is thankful to CSIR (New Delhi,
India) for a research fellowship.
References
1. Michell, R. H. Nat. Rev. Mol. Cell Biol. 2008, 9, 151–161; Inositol Phosphates and
Derivatives: Synthesis, Biochemistry and Therapeutic Potential; Reitz, A. B., Ed.;
American Chemical Society: Washington, DC, 1991.
8. (a) Mahapatra, T.; Nanda, S. Tetrahedron: Asymmetry 2009, 20, 610–615; (b)
Mahapatra, T.; Bhunya, R.; Nanda, S. Tetrahedron Lett. 2009, 50, 5392–5394.
9. Deguest, G.; Bischoff, L.; Fruit, C.; Marsais, F. Org. Lett. 2007, 9, 1165–1167.
10. Tietze, L. F.; Eicher, T.; Diederichsen, U.; Speicher, A. Reactions and Syntheses;
Wiley-VCH: Weinheim, 2007. p 211.
11. Iversen, T.; Bundle, K. R. J. Chem Soc., Chem. Commun. 1981, 1240–1241.
12. Horita, K.; Yoshioka, T.; Tanaka, Y.; Oikawa, Y.; Yonemitsu, O. Tetrahedron 1986,
42, 3021.
13. Kuriyama, C.; Kamiyama, O.; Ikeda, K.; Sanae, F.; Kato, A.; Adachi, I.; Imahori,
T.; Takahata, H.; Okamoto, T.; Asano, N. Biorg. Med. Chem. 2008, 16, 7330–7336.
14. (a) Pauling, L. Chem. Eng. News 1946, 24, 1375; (b) Pauling, L. Nature 1948, 161,
707.
2. Berridge, M. J.; Irvine, R. F. Nature 1984, 312, 315–321.
3. (a) Berridge, M. J. Nature 1993, 361, 315–325; (b) Irvine, R. F.; Schell, M. J. Nat.
Rev. Mol. Cell Biol. 2001, 2, 327–338.
4. Gloster, T. M.; Davies, G. J. Org. Biomol. Chem. 2010, 8, 305–320.
5. (a) Suzuki, Y.; Ichinomiya, S.; Kurosawa, M.; Ohkubo, M.; Watanabe, H.;
Iwasaki, H.; Matsuda, J.; Noguchi, Y.; Takimoto, K.; Itoh, M.; Tabe, M.; Lida, M.;
Kubo, T.; Ogawa, S.; Nanbe, E.; Higaki, K.; Ohno, K.; Brady, R. O. Ann. Neurol.
2007, 62, 671–675; (b) Sawkar, A. R.; Cheng, W. C.; Beutler, C. H.; Wong, W. E.
Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 15428–15433; (c) Yam, G. H. F.; Bosshard,
N.; Zuber, C.; Steinmann, B.; Roth, J. Am. J. Physiol: Cell Physiol. 2006, 290,
C1076–C1082; (d) Fan, J. Q.; Ishii, S.; Asano, N.; Suzuki, Y. Nat. Med. 1999, 5,
112–115; (e) Krentz, A. J.; Bailey, C. J. Drugs 2005, 65, 386–411; (f) Goke, B.;