Novel conformationally locked inositols: From aromatics to annulated cyclitols

Article abstract of DOI:10.1002/chem.200204650

A new family of ring-annulated inositols with "locked" conformations has been designed to deliver a range of these biologically important entities in "unnatural conformations" while retaining their "natural configurations". The simple "tool" of trans ring fusion has been used to "lock" the conformation of the annulated inositols. Short, simple syntheses of a range of these novel cyclitols have been achieved from readily available aromatic precursors such as tetralin and indane. Along the way, annulated C₂-symmetric cyclohexadiene-trans-diol (trans-CHD) derivatives have been prepared for the first time and serve as the pivotal building blocks for generating the oxy-functionalization pattern of inositols. The presence of chemo-differentiated hydroxyl groups in our novel inositols is expected to facilitate the installation of phosphate diversity to harness the biological potential of these entities.

Full text of DOI:10.1002/chem.200204650

FULL PAPER
Novel Conformationally Locked Inositols:
From Aromatics to Annulated Cyclitols
[a]
Goverdhan Mehta,* Ramesh S.Senaiar, and Mrinal K.Bera
Abstract: A new family of ring-annu-
lated inositols with ™locked∫ conforma-
tions has been designed to deliver a
range of these biologically important
entities in ™unnatural conformations∫
while retaining their ™natural configu-
rations∫. The simple ™tool∫ of trans ring
fusion has been used to ™lock∫ the
conformation of the annulated inositols.
Short, simple syntheses of a range of
these novel cyclitols have been achieved
from readily available aromatic precur-
sors such as tetralin and indane. Along
the way, annulated C2-symmetric cyclo-
hexadiene-trans-diol (trans-CHD) de-
rivatives have been prepared for the
first time and serve as the pivotal build-
ing blocks for generating the oxy-func-
tionalization pattern of inositols. The
presence of chemo-differentiated hy-
droxyl groups in our novel inositols is
expected to facilitate the installation of
phosphate diversity to harness the bio-
logical potential of these entities.
Keywords: annulation ¥ conforma-
tion analysis ¥ cyclitols ¥ dihydrox-
ylation ¥ signal transduction
The quest for new synthetic analogues of inositols, though
extensive,[3, 4] has largely centered on ring modification and
sidearm and phosphate variation and studies with these
structural variants continue to provide insights into struc-
ture activity relationships. Here, we introduce a new family
of ring-annulated bicyclic inositols 2 as novel entities with
several unique attributes. The trans-fused bicyclic inositols 2,
unlike 1, are rigid and can be locked in high-energy
conformations (see below) which are unattainable in 1.[5]
For example, while the most abundant myo-inositol exists in
the stable conformation 3 with five equatorial and one axial
(5e/1a) hydroxyl group, the 1,6-annulated bicyclic myo-
inositol 4 would be locked in the five axial and one equatorial
(5a/1e) conformation. Secondly, the presence of two chemo-
differentiated tertiary hydroxyl groups in 2 is expected to
facilitate the generation of functional group diversity and
phosphate variation, an essential but complicated feature of
inositol chemistry.[1] It should be noted that selective phos-
phorylation of inositols is a cumbersome, multistep protocol
which requires extensive protection deprotection maneu-
vers. Lastly, a hydrophobic appendage in the form of an
alicyclic ring in 2 could profoundly modulate the cell
membrane permeability and receptor recognition parameters
of the inositol moiety. Interestingly, the ring annulation
maneuver on inositols, which leads to 2, can be expected to
alter their reactivity and biological profile and has not been
attempted before.[3h] More importantly, the annulated inosi-
tols are destined to be locked in ™unnatural conformations∫
while retaining their ™natural configurations∫. In this paper,
we describe a simple and versatile approach to several
cyclohexa- and cyclopenta-annulated inositols 2 from readily
Introduction
Inositols 1 occupy a preeminent position among biologically
important entities known as cyclitols and constitute the only
group of cyclohexanes substituted at each carbon atom for
which all the possible (nine) diastereomers, five natural (myo,
scyllo, d-chiro, l-chiro, and neo) and four synthetic (cis, epi,
allo, and muco), are known.[1] The biological functions of
derivatives of inositol are wide-ranging and diverse and
include intercellular communication, phosphate storage and
transfer, anti-cancer and involvement in covalent anchoring of
proteins to membranes.[1a c, 2] However, it is the pivotal role of
inositol phosphate derivatives such as d-myo-inositol-1,4,5-
triphosphate [Ins(1,4,5)P3] and d-myo-inositol-1,3,4,5-tetraki-
sphosphate [Ins(1,3,4,5)P4] as second messengers in intercel-
lular signal transduction events through binding to specific
receptors and mobilizing Ca2‡ ions from intracellular stores
that has generated contemporary interest in their chemistry
and biology.[1, 2] The increased cytosolic Ca2‡ concentration
initiates a number of cell-type specific responses.[1b, 2] Thus,
intervention and selective manipulation of physiological
processes triggered by inositol polyphosphates has stimulated
the search for new and designer analogues for unraveling the
complexbiological mechanisms and development of new
pharmaceuticals.
[a] Prof. G. Mehta, R. S. Senaiar, M. K. Bera
Department of Organic Chemistry
Indian Institute Science
Bangalore 560012 (India)
Fax: ( ‡91)80-360-0936
E-mail: gm@orgchem.iisc.ernet.in
2264
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/chem.200204650
Chem. Eur. J. 2003, 9, 2264 2272

2264 2272
OAc
OH
OH
OH
OH
b, c
a
HO
HO
HO
HO
OH
OH
HO
HO
OH
OH
O
2
2
1
1
6
3
4
3
4
6
5
5
OAc
9
OH
OH
7
8
OH
OH
1
d
OH
OH
OH
OH
OH
HO
OH
HO
HO
HO
OAc
OAc
OAc
HO
HO
OH
n
e
HO
OH
OH
OH
OH
3 (5e/1a)
OAc
OAc
O
OAc
O
2 (n = 0,1)
14
13
5
(1:9)
Scheme 1. a) mCPBA, CH2Cl2, À58C, 5 min, 85%; b) 10% AcOH, RT,
2 h, 90%; c) Ac2O, BF3 ¥ Et2O, RT, 2 h, 88%; d) i) NBS, AIBN, CCl4, reflux,
4 h; ii) DBU, DMSO, RT, 52% (2 steps); e) mCPBA, CH2Cl2, 108C, 5 6 h,
73% (based on recovered starting material).
available aromatic precursors such as tetralin and indane.
While the syntheses reported here are of racemic compounds,
our overall strategy is amenable to chiral induction at several
stages along the way.
In our general approach to 2, annulated C2-symmetric
cyclohexadiene-trans-diol (trans-CHD) derivatives 5 and 6
were recognized as the pivotal building blocks and access to
them from readily available precursors was first devised.[6, 7]
For the synthesis of cyclohexa-annulated trans-CHD 5, 1,4-
dihydrotetralin (7) obtained from tetralin was subjected to
regioselective epoxidation to give 8 followed by acid-cata-
lyzed ring opening to a trans diol[8] and acetylation to furnish
the trans diacetate 9 (Scheme 1). Allylic bromination of 9 and
DBU (1,8-diazabicyclo[5.4.0]undec-7-ene)-mediated dehy-
drobromination delivered the desired C2-symmetric cyclo-
hexadiene-trans-diol diacetate 5.[9] In a similar manner, cyclo-
penta-annulated cyclohexadiene-trans-diol derivative 6 was
prepared from 1,4-dihydroindane (10) via trans-diol 11
(Scheme 2).[10] The allylic bromination-dehydrobromination
sequence, successful in the case of 9, led only to intractable
products when implemented on 11 or its diacetate derivative.
After some trials, a convenient route to the C2-symmetric
trans-CHD derivative 6 from 11 was established through
addition of bromine and acetylation to 12 and double
dehydrobromination in the presence of DBU.[9]
OH
OAc
Br
Br
a, b
c, d
OH
OAc
10
11
12
e
OAc
OAc
OAc
f
OAc
23
OAc
24
O
OAc
O
6
(1:2)
Scheme 2. a) MMPP (magnesium monoperoxyphthalate hexahydrate),
THF/H2O 1:1, 08C, 5 min, 85%; b) 10% AcOH, RT, 5 h, 90%;
c) C6H5N ¥ HBr3À, CH2Cl2, 08C, 1 h, 66 %; d) Ac2O, BF3 ¥ Et2O, RT, 1 h,
‡
89%; e) DBU, DMSO, RT, 4 h, 54%; f) mCPBA, CH2Cl2, 08C, 3 d, 60%.
the spectral data, was secured through X-ray crystallography
studies. The origin of 15 from epoxide 13 can be traced to an
intramolecular neighboring acetate-mediated opening of the
epoxide ring followed by an SN2' displacement by the distal
acetate group as shown in Scheme 4. It is this eventful
participation of both the acetate groups of 13 in the epoxide
ring opening that generates the interesting cis-1,4-diol stereo-
The C2-symmetric bicyclic trans-CHD diacetates 5 and 6
served as the key starting materials for accessing the new
family of inositols. The main theme in our approach was to
generate the network of oxygen functionalities on the diene
moiety in
a stereoselective
manner and with the minimum
number of steps. Mono-epoxi-
dation of 5 was stereoselective
and furnished a readily separa-
ble mixture of diastereomeric
epoxides 13 and 14 (9:1)
HO
AcO
AcO
OH
OH
OH
HO
HO
HO
HO
1
c
b
6
2
5
3
4
OH
OAc
OAc
HO
HO
HO
a
18
15
17
13
(Scheme 1).
Acid-catalyzed
ring opening of the major ep-
oxide 13 furnished bicyclic diols
15 (3:1) and 16, which are
annulated conduritol F and
OAc
OAc
OH
e
d
4
HO
HO
OH
OH
19
B
derivatives, respectively
OH
16
(Scheme 3).[11, 12] The stereo-
structure of the acetate migra-
tion product 15, though indicat-
ed through careful scrutiny of
Scheme 3. a) 10% AcOH, THF, 508C, 16 h, 80%; b) OsO4 (cat.), NMMO, acetone/water 4:1, RT, 2 h, 88%;
c) K2CO3, MeOH, RT, 2 h, 96%; d) K2CO3, MeOH, RT, 1 h, 95%; e) OsO4 (cat.), NMMO, acetone/water 4:1, RT,
6 h, 80%.
Chem. Eur. J. 2003, 9, 2264 2272
www.chemeurj.org
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2265

G. Mehta et al.
FULL PAPER
hexaoxygenated products 20 (2:1) and 21, with the latter
arising through 1,4-acetate migration (Scheme 6). Base hy-
drolysis of both 20 and 21 furnished 3,4-cyclohexa-annulated
chiro-inositol 22.[15] The stereostructure of 22 was evident
from the C2 symmetry present and this annulated chiro-
inositol was locked in the 4a/2e conformation. It is noteworthy
that starting from the same trans-CHD diacetate 5, two
inositols (18 and 22) with the chiro-configuration and 4a/2e
conformation can be crafted by a tactic that is formally
equivalent to altering the site of annulation (2,3- and 3,4-,
respectively)[15] on chiro-inositol.
The elaboration of the cyclohexadiene-trans-diol derivative
6 to diverse cyclopenta-annulated inositols followed the
protocols successfully implemented on 5 (see above). Epox-
idation of 6 was less stereoselective (cf. 5) and furnished a
readily separable mixture (2:1) of epoxides 23 and 24
(Scheme 2). Acid-catalyzed ring opening of the major epoxide
23 furnished diols 25 and 26 in a 3:1 ratio (Scheme 7). The
stereostructures of conduritol F 25 and conduritol B 26
derivatives[11] were secured through X-ray crystal structure
determination. The major product was once again derived
through complexacetate migration analogous to that ob-
served for 13 (Scheme 4).[13] Acetate hydrolysis in 25 furnish-
ed the annulated conduritol F derivative 27, and further
catalytic OsO4-mediated dihydroxylation led stereospecifi-
cally to the 2,3-cyclopenta-annulated[15] chiro-inositol 28.
Inositol 28 was firmly locked in 4a/2e conformation. Similarly,
the minor epoxide cleavage product 26 was hydrolyzed to give
conduritol B derivative 29, and further dihydroxylation fur-
nished the cyclopenta-annulated myo-inositol 30 which was
locked in the 5a/1e ground state conformation (Scheme 7).[17]
On acid cleavage the remaining minor epoxide 24 obtained
from 6 furnished a single product 31 in which both the acetate
CH3
O
CH3
O
OH2
O
O
OAc
H3O+
15
O
O
O OH O
CH3
OAc
OH
O
CH3
13
Scheme 4. Postulated mechanism of formation of 15.
chemistry observed in 15 (Scheme 4).[13] The major product 15
from epoxide 13 was then subjected to stereospecific OsO4-
mediated dihydroxylation to furnish the inositol derivative 17
(Scheme 3). The stereochemical outcome of the dihydroxyla-
tion of 15 to give 17 was predictable and expected both on
steric considerations and Kishi×s rule[14] for the OsO4-medi-
ated dihydroxylation of allylic alcohols. Base hydrolysis of 17
led to the 2,3-cyclohexa-annulated chiro-inositol 18.[15] The
most stable conformation of chiro-inositol determined by
X-ray crystallography is 4e/2a as shown in Scheme 5.[16] In
contrast, the X-ray crystal structure of 2,3-cyclohexa-annu-
lated chiro-inositol 18 exhibited a 4a/2e conformation and is
displayed for comparison in Scheme 5.
HO
1
HO
2
6 OH
HO
5
1
6
HO
HO
HO
2
OH
5
4
3
3
4
OH
OH
HO
HO
chiro-Inositol (4e/2a)
18 (4a/2e)
Scheme 5. Stable conformations of chiro-inositol and annulated chiro-
inositol 18.
Attention was now turned to
the minor diol 16 obtained from
OH
OH
OH
OAc
OH
OH
OAc
HO
HO
HO
HO
a
b
the cleavage of epoxide 13.
Acetate hydrolysis of 16 led to
the tetrol 19, which is an annu-
lated conduritol B derivative
(Scheme 3).[11] Catalytic OsO4-
mediated dihydroxylation of 19
was smooth and stereospecific
and furnished the cyclohexa-
annulated myo-inositol 4. An
X-ray crystal structure of 4
indicated that as per our design
strategy it indeed had a 5a/1e
ground state conformation in
contrast with 5e/1a for myo-
inositol 3.[17] Once again, dihy-
droxylation of 19 occurred from
the face opposite to the secon-
dary allylic hydroxyl group.[14]
In an alternate sequence, bi-
cyclic diene diacetate 5 was
subjected to exhaustive dihy-
droxylation with catalytic OsO4
to stereospecifically furnish the
HO
AcO
OAc
OH
OAc
OH
OH
OH
OAc
5
20
21
22
(2:1)
Scheme 6. a) OsO4 (cat.), NMMO, acetone/water 4:1, 108C, 2 d, 70%; b) K2CO3, MeOH, RT, 2 h, 90%.
AcO
HO
HO
OH
OH
OH
HO
HO
b
c
OAc
OH
OH
HO
HO
HO
a
25
(3:1)
27
28
23
HO
OAc
OH
OH
OH
HO
HO
e
d
HO
HO
OAc
OH
OH
OH
29
HO
26
30
Scheme 7. a) 10% AcOH, THF, 508C, 24 h, 60%; b) K2CO3, MeOH, RT, 6 h, 81%; c) OsO4 (cat.), NMMO,
acetone/water 4:1, RT, 4 h, 84%; d) K2CO3, MeOH, RT, 4 h, 92%; e) OsO4 (cat.), NMMO, acetone/water 4:1, RT,
3 h, 86%.
2266
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2003, 9, 2264 2272

Locked Inositols
2264 2272
Experimental Section
CH3
O
OH2
CH3
O
O
AcO
AcO
O
General methods: Melting points were
recorded on a B¸chi B-540 apparatus
and are uncorrected. Infrared spectra
were recorded on JASCO FTIR 410.
Proton (1H NMR) and carbon mag-
netic resonance (13C NMR) spectra
were generally recorded on a JEOL
JNM-LA 300 spectrometer. Mass
spectra measurements were carried
out on a JEOL JMS DX 303 spec-
trometer. Elemental analyses were
carried out on a Carlo Erba Element
Analyzer 1106. Analytical thin-layer
chromatography (TLC) was per-
formed on (10 Â 5 cm) glass plates
coated (250 mm) with Acme silica
gel G or GF254 (containing 13% cal-
cium sulfate as binder). Visualization
of the spots on TLC plates was ach-
ieved either by exposure to iodine
vapor or UV light or by spraying
sulfuric acid and heating the plates at
OH
OH
OAc
a
O
O
O
OAc
24
O
O
O
O
CH3
CH3
31
b
HO
HO
OH
OH
HO
HO
c
OH
OH
HO
HO
32
33
Scheme 8. a) 10% AcOH, THF, 508C, 24 h, 74%; b) K2CO3, MeOH, RT, 3 h, 95%; c) OsO4 (cat.), NMMO,
acetone/water 4:1, RT, 3 h, 83%.
1208C. Column chromatography was performed by using Acme silica gel
(100 200 mesh) or neutral alumina. All solvents were freshly distilled over
CaH2 or Na/benzophenone as appropriate.
groups had migrated (Scheme 8). Hydrolysis of 31 led to the
conduritol E derivative 32, and further OsO4-mediated dihy-
droxylation furnished the annulated allo-inositol 33. The
stereostructure of 33 was secured through single-crystal X-ray
structure determination and had a locked 3a/3e conformation.
Lastly, the annulated trans-CHD diol 6 was subjected to
mono-dihydroxylation to stereospecifically give the diol 34
with concomitant 1,4-acetate migration (Scheme 9). The
stereostructure of 34 was again secured through X-ray crystal
structure determination. Acetate hydrolysis in 34 provided a
conduritol F derivative 35, and a second OsO4-mediated
dihydroxylation led to the 3,4-cyclopenta-annulated chiro-
inositol 36,[15] which adopts a 4a/2e conformation.
(4aR*,8aR*)-1,2,3,4,4a,5,8,8a-Octahydro-4a,8a-naphthalenediol (9): Ep-
oxide 8 (3 g, 0.02 mol)[8] was treated with 10% acetic acid (10 mL), and
the resulting biphasic reaction mixture was stirred vigorously at room
temperature. Upon complete consumption of the starting material
(monitored by TLC), the acid was neutralized by careful addition of solid
NaHCO3, and the resulting diol was extracted with ethyl acetate (3 Â
100 mL). The combined organic extracts were washed with saturated
aqueous NaHCO3 (2 Â 50 mL), brine (1 Â 50 mL), dried over anhydrous
Na2SO4, and concentrated under reduced pressure to furnish the trans diol
(3 g, 90%). The diol was dissolved in acetic anhydride (10 mL) and a
catalytic amount of BF3 ¥ Et2O (100 mL) was added at 08C. The resulting
dark brown solution was stirred for 2 h under N2 atmosphere. The reaction
mixture was poured into ice-cold water (10 mL) and extracted with CH2Cl2
(3 Â 100 mL). The combined organic
extracts were washed with saturated
aqueous NaHCO3 (2 Â 50 mL), brine
OH
OH
OH
OH
OH
(20 mL), dried over anhydrous Na2-
SO4, and concentrated under reduced
pressure to furnish crystalline trans
diacetate 9 (4.7 g), which was recrys-
tallized from hexane/dichloromethane
to give colorless needle-like crystals of
9 (4.54 g, 88%). M.p. 136 1378C; IR
OAc
HO
HO
a
c
b
AcO
HO
OAc
OH
OH
OH
OAc
OH
6
34
35
36
(KBr): nÄ ˆ 1727 cmÀ1
;
1H NMR
Scheme 9. a) OsO4 (cat.), NMMO, acetone/water 4:1, 08C, 2 d, 48%; b) K2CO3, MeOH, RT, 8 h, 75%; c) OsO4
(cat.), NMMO, acetone/water 4:1, RT, 6 h, 63%.
(300 MHz, CDCl3): d ˆ 5.15 (m, 2H),
3.09 (s, 1H), 3.03 (s, 1H), 2.69 (s, 1H),
2.65 (s, 1H), 2.36 (s, 1H), 2.18 (s, 1H),
2.01 (s, 6H), 1.66 1.13 (m, 6H);
13C NMR (75 MHz, CDCl3): d ˆ 169.6
(2C), 123.2 (2C), 80.8 (2C), 29.9 (2C), 28.5 (2C), 22.3 (2C), 20.8 (2C); MS
‡
Conclusion
(70 eV, EI): m/z (%): 252 [M ]; elemental analysis calcd (%) for C14H20O4
(252): C 66.64, H 7.99; found: C 66.56, H 8.03.
We have delineated short and efficient routes to ring-
annulated C2-symmetric trans-CHD diols 5 and 6 and
harnessed them to craft a range of novel bicyclic inositols.
Our design of these unusual entities employs the annulation
stratagem for generating new ™unnatural∫ conformations and
structural diversity while retaining the ™natural∫ configura-
tions of the inositols. The availability of such bicyclic inositols
with differentiated hydroxyl groups with new spatial orienta-
tions augurs well for further phosphate variations and bio-
logical evaluation.
(4aR*,8aR*)-8a-(Acetyloxy)-1,2,3,4,4a,8a-hexahydro-4-naphthalenyl ace-
tate (5): N-Bromosuccinimide (706 mg, 3.97 mmol) and a catalytic amount
of 2,2'-azabisisobutyronitrile (AIBN) (10 mg) were added to a solution of
the trans-diacetate 9 (1 g, 3.97 mmol) in dry CCl4 (10 mL), and the resulting
reaction mixture was heated at reflux for 4 h under N2. After the
completion of the reaction, floating succinimide was filtered off and the
filtrate was poured into ice-cold water (15 mL). The organic layer was
separated and aqueous layer was extracted with CH2Cl2 (3 Â 20 mL). The
combined organic extracts were successively washed with 10% HCl, (2 Â
10 mL), water (10 mL), brine (10 mL), dried over anhydrous Na2SO4, and
concentrated under reduced pressure. The residue (1.3 g) obtained was
dissolved in dry DMSO (10 mL) and DBU (0.7 mL, 4.76 mmol) was added
Chem. Eur. J. 2003, 9, 2264 2272
www.chemeurj.org
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2267

G. Mehta et al.
FULL PAPER
gradually from a syringe at 5 108C under N2 atmosphere, during which
time the reaction mixture turned from pale yellow to dark brown. The
reaction mixture was stirred at room temperature for further 2 h, before
diluting with diethyl ether (20 mL) and pouring into ice-cold water
(20 mL). The ether layer was separated and the aqueous layer was
extracted with diethyl ether (3 Â 30 mL). The combined organic extracts
were washed with 10% HCl (2 Â 10 mL), water (10 mL), brine (10 mL),
dried over anhydrous Na2SO4, and concentrated under reduced pressure to
furnish the crude product (530 mg), which on chromatography over neutral
alumina column (5% ethyl acetate/hexane) gave the crystalline trans-diene
layer was extracted with CH2Cl2 (3 Â 30 mL). The combined organic layer
was washed with saturated aqueous NaHCO3 (2 Â 10 mL), brine (10 mL),
and dried over anhydrous Na2SO4. The solvent was removed under reduced
pressure to give a solid residue, which by TLC examination was found to be
a mixture of two compounds. The residue was subjected to silica gel column
chromatography (5% ethyl acetate/hexane) to furnish epoxides 13
(295 mg, 66%) and 14 (31 mg, 7%), along with recovered starting material
5 (80 mg), in an overall yield of 73%. Compound 13: IR (thin film): nÄ ˆ
1733 cmÀ1
;
1H NMR (300 MHz, CDCl3): d ˆ 6.13 (1³2ABq, J ˆ 9.4, 3.7 Hz,
1
1H), 6.08 (d of ³2ABq, J ˆ 9.4, 3.7 Hz, 1H), 4.23 (d, J ˆ 3.7 Hz, 1H), 3.33
(brs, 1H), 2.89 (d, J ˆ 14.2 Hz, 1H), 2.41 (d, J ˆ 14.2 Hz, 1H), 2.23 2.09
(m, 1H), 2.02 (s, 3H), 2.00 (s, 3H), 1.84 1.75 (m, 1H), 1.52 1.25 (m, 4H);
5
(516 mg, 52%). M.p. 140 1418C; IR (KBr): nÄ ˆ 3052, 1731 cmÀ1
;
1H NMR (300 MHz, CDCl3): d ˆ 6.09 (m, 2H), 5.91 (m, 2H), 2.56 (s,
1H), 2.51 (s, 1H), 2.03 1.83 (m, 2H), 1.97 (s, 6H), 1.77 1.43 (m, 4H);
13C NMR (75 MHz, CDCl3): d 169.2 (2C), 130.8 (2C), 124.1 (2C), 78.8
13C NMR (75 MHz, CDCl3): d ˆ 169.3, 168.7, 134.7, 126.2, 80.7 (2C), 55.9,
‡
46.7, 28.5, 25.5, 22.0, 21.7, 20.1, 19.7; MS (EI, 70 eV): m/z (%): 207 [M
À
‡
(2C), 26.7 (2C), 21.6 (2C), 20.2 (2C); MS (EI, 70 eV): m/z: 251 [M ‡H];
OAc]; elemental analysis calcd (%) for C14H18O5 (266.2): C 63.15, H 6.81;
found: C 62.85, H 6.90.
elemental analysis calcd (%) for C14H18O4 (250): C 67.18, H 7.25; found: C,
66.90, H, 7.52.
Compound 14: IR (KBr): nÄ ˆ 1738 cmÀ1; 1H NMR (300 MHz, CDCl3): d ˆ
6.15 (d, J ˆ 9.4 Hz, 1H), 5.95 (d, J ˆ 9.4 Hz, 1H), 3.41 (d, J ˆ 3.3 Hz, 1H),
3.28 (d, J ˆ 3.3 Hz, 1H), 2.92 (d, J ˆ 13.6 Hz, 1H), 2.50 (d, J ˆ 13.6 Hz, 1H),
2.02 (s, 6H), 1.81 1.25 (m, 6H); 13C NMR (75 MHz, CDCl3): d ˆ 168.8,
168.7, 138.2, 124.4, 78.4, 77.7, 54.4, 47.6, 28.3, 27.2, 21.6, 21.2, 20.3, 20.0; MS
Compound 12: Pyridiniumbromide perbromide (8.22 g, 0.025 mmol) was
added to a solution of the known[10] trans-diol 11 (3.6 g, 0.023 mol) in dry
CH2Cl2 (50 mL), and the reaction mixture was stirred at 08C under N2
atmosphere. After consumption of the starting material (monitored by
TLC), the reaction mixture was diluted with CH2Cl2 (50 mL) and poured
into ice-cold water (100 mL). The organic layer was separated and the
aqueous layer was extracted with CH2Cl2 (3 Â 30 mL). The combined
organic extracts were washed successively with saturated aqueous Na2S2O5
solution (2 Â 20 mL), water (20 mL), brine (20 mL), and dried over
anhydrous Na2SO4. Concentration of the solvent and purification of the
resultant solid residue by silica gel chromatography afforded the dibro-
‡
(70 eV, EI): m/z (%): 267 [M ‡H]; elemental analysis calcd (%) for
C14H18O5 (266.2): C 63.15, H 6.81; found: C 62.92, H 6.95.
Compounds 15 and 16: A solution of epoxide 13 (250 mg, 0.94 mmol) in
THF (5 mL) was treated with 10% AcOH (2 mL), and the resulting
mixture was stirred at 508C for 16 h. Upon completion of the reaction
(monitored by TLC), the mixture was cooled and neutralized by the
addition of solid NaHCO3, followed by extraction with ethyl acetate (3 Â
30 mL). The combined organic extracts were washed with saturated
aqueous NaHCO3 (2 Â 10 mL), brine (10 mL), dried over anhydrous
modiol (4.7 g, 66%). m.p. 1068C; IR (thin film): nÄ ˆ 3531, 3457 cmÀ1
;
1H NMR (300 MHz, CDCl3): d ˆ 4.89 (s, 2H), 2.87 (d, J ˆ 16Hz, 2H), 2.47
(s, 2H), 2.28 (d, J ˆ 15.6 Hz, 2H), 1.86 1.80 (m, 4H), 1.62 (br s, 2H);
13C NMR (75 MHz, CDCl3): d ˆ 80.0 (2C), 50.1 (2C), 35.8 (2C), 33.3 (2C),
Na2SO4, and concentrated under reduced pressure to give
a solid.
Purification of the residue by column chromatography over silica gel
(30% ethyl acetate/hexane) gave 15 (160 mg, 60%) and 16 (53 mg, 20%) as
colorless crystalline solids in 80% overall yield. Compound 15: m.p. 198
‡
18.9 (2C); MS (70 eV, EI): m/z (%): 314 [M ]. The dibromodiol was
dissolved in acetic anhydride (10 mL) and BF3 ¥ Et2O (100 mL) was added at
08C and stirred at the same temperature for 1 h under N2. On complete
consumption of the starting material (monitored by TLC), the reaction
mixture was quenched by the careful addition of ice-cold water (50 mL)
and diluted with CH2Cl2 (30 mL). The aqueous layer was extracted with
CH2Cl2 (3 Â 30 mL) and the combined organic extracts were washed
carefully with saturated aqueous NaHCO3 (2 Â 20 mL), brine (20 mL), and
dried over anhydrous Na2SO4. The residue obtained after concentration at
reduced pressure was purified by silica gel chromatography to furnish the
dibromodiacetate 12 (5.3 g, 89%) as a colorless crystalline solid. M.p.
1998C; IR (KBr): nÄ ˆ 3478, 1735 cmÀ1
;
1H NMR (300 MHz, CDCl3): d ˆ
5.98 (ddd, J ˆ 10.2, 4.6, 2.2 Hz, 1H), 5.55 (dd, J ˆ 10.3, 1.3 Hz, 1H), 5.42 (d,
J ˆ 1.3 Hz, 1H), 4.68 (dd, J ˆ 11.1, 4.6 Hz, 1H), 3.14 (d, J ˆ 11.1 Hz, 1H),
2.72 (d, J ˆ 14.7 Hz, 1H), 2.45 (s, 1H), 2.26 2.05 (m, 1H), 2.16 (s, 3H), 2.04
(s, 3H), 1.67 1.56 (m, 4H); 13C NMR (75 MHz, CDCl3): d ˆ 170.1, 169.3,
129.2, 124.6, 83.1 (2C), 73.6, 72.9, 64.8, 31.7, 24.5, 22.2, 21.0, 20.3; MS (70 eV,
‡
EI): m/z (%): 285 [M ‡H]; elemental analysis calcd (%) for C14H20O6
(284): C 59.14, H 7.09; found: C 59.08, H 7.04.
Compound 16: m.p. 162 1638C; IR (KBr): nÄ ˆ 3402, 1737, 1723 cmÀ1
;
127.38C; IR (thin film): nÄ ˆ 1742 cmÀ1
;
1H NMR (300 MHz, CDCl3): d ˆ
1H NMR (300 MHz, CDCl3): d ˆ 6.21 (d, J ˆ 10 Hz, 1H), 5.91 (dd, J ˆ 10,
3.3 Hz, 1H), 5.54 (d, J ˆ 8.4 Hz, 1H), 4.29 (brs, 1H), 3.04 (d, J ˆ 9.6 Hz,
1H), 2.61 (d, J ˆ 11.1 Hz, 1H), 2.21 2.09 (m, 2H), 2.04 (s, 3H), 2.00 (s,
3H), 1.87 1.78 (m, 2H), 1.66 1.22 (m, 4H); 13C NMR (75 MHz, CDCl3):
d ˆ 169.8, 167.7, 130.1, 129.7, 80.5, 79.9, 73.5, 70.5, 27.7, 24.5, 22.2, 21.8, 20.2,
4.76 (s, 2H), 3.20 (brs, 1H), 3.14 (brs, 1H), 2.69 (d, J ˆ 3.9 Hz, 1H), 2.64 (d,
J ˆ 3.9 Hz, 1H), 2.57 2.53 (m, 2H), 2.01 (s, 6H), 1.8 1.6 (m, 4H);
13C NMR (75 MHz, CDCl3): d ˆ 170.1 (2C), 86.7 (2C), 48.2 (2C), 30.7
‡
(2C), 27.4 (2C), 23.3 (2C), 18.4; MS (70 eV, EI): m/z (%): 317 [M À BrÀ
‡
H], 319 [M À Br‡H].
‡
19.8; MS (70 eV, EI): m/z (%): 242 [M À Ac‡H]; elemental analysis calcd
(3aR*,7aR*)-2,3,3a,7a-Tetrahydro-1H-3a,7a-indenediol (6): Dibromodia-
cetate 12 (1 g, 2.51 mmol) was dissolved in dry DMSO (5 mL) and DBU
(0.75 mL, 5.02 mmol) was added dropwise at 5 108C from a syringe under
N2 atmosphere, during which time the reaction turned dark brown. The
reaction mixture was stirred at room temperature for further 2 h, before
diluting with diethyl ether (30 mL) and pouring into ice-cold water
(10 mL). The organic layer was separated and the aqueous layer was
extracted with diethyl ether (3 Â 50 mL). The combined organic extracts
were washed with 10% HCl (2 Â 20 mL), water (20 mL), brine (15 mL),
dried over anhydrous Na2SO4, and concentrated under reduced pressure.
The resultant solid residue was purified by chromatography over neutral
alumina (5% ethyl acetate/hexane) to furnish crystalline trans-diene 6
(%) for C14H20O6 (284.3): C 59.14, H 7.09; found: C 58.91, H 7.07.
Crystal data for compound 15: Structure was solved by direct methods
(SIR92). Refinement was by full-matrixleast-squares procedures on F2 by
using SHELXL-97. Crystal system: rhombohedral-hexagonal, space group:
R3c, cell parameters: a ˆ 27.761(2), b ˆ 27.761(2), c ˆ 9.956(10) ä, g ˆ
120(6)8, Vˆ 6645.19 ä3, Z ˆ 18, 1calcd ˆ 1.279 gcmÀ3, F(000) ˆ 2736, m ˆ
0.10mmÀ1, l ˆ 0.71 ä. R1 ˆ 0.0491 for Fo > 2s(Fo) and 0.0499 for all
2111 data. wR2 ˆ 0.1392, GOF ˆ 1.097. There are four independent mole-
cules in the asymmetric unit. An ORTEP drawing of compound 15 with
50% ellipsoidal probability level is shown in Figure 1.
Compound 17: OsO4 (2 mg, 1 mol%) and 50% aqueous N-methylmorpho-
line N-oxide (NMMO) (130 mL, 0.56 mmol) were added to a solution of
diol 15 (155 mg, 0.545 mmol) in acetone/water (4:1, 5 mL) at 08C, and the
resulting pale yellow reaction mixture was stirred at room temperature for
2 h, before quenching with solid NaHSO3. The resulting mixture was
diluted with ethyl acetate (10 mL), filtered through Celite, and the filtrate
was concentrated under reduced pressure. The residue was subjected to
column chromatography over silica gel (80% ethyl acetate/hexane) to
afford the tetrol 17 (152 mg, 88%). IR (KBr): nÄ ˆ 3391, 1727 cmÀ1; 1H NMR
(300 MHz, D2O): d ˆ 5.19 (d, J ˆ 10.2 Hz, 1H), 5.56 (d, J ˆ 2.5 Hz, 1H),
4.10 (dd, J ˆ 10.2, 4 Hz, 1H), 4.04 (dd, J ˆ 4, 2.5 Hz, 1H), 2.28 (d, J ˆ
(319 mg, 54%). M.p. 139.58C; IR (KBr): nÄ ˆ 1724 cmÀ1
;
1H NMR
(300 MHz, CDCl3): d ˆ 6.43 (d, J ˆ 10.2 Hz, 2H), 5.90 (d, J ˆ 10.2 Hz,
2H), 2.41 2.35 (m, 2H), 2.09 1.99 (m, 2H), 1.94 1.84 (m, 2H), 1.94 (s,
6H); 13C NMR (75 MHz, CDCl3): d ˆ 169.6 (2C), 128.9 (2C), 125.6 (2C),
‡
87.2 (2C), 28.4 (2C), 21.7 (2C), 21.2; MS (70 eV, EI): m/z (%): 152 [M
2Ac‡2].
À
Compounds 13 and 14: mCPBA (70%, 493 mg, 2 mmol) was added at 08C
to a solution of 5 (500 mg, 2 mmol) in dry CH2Cl2 (10 mL), and the reaction
mixture was stirred at room temperature for 5 h before quenching with
10% Na2SO3 (5 mL). The organic layer was separated and the aqueous
2268
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2003, 9, 2264 2272

Locked Inositols
2264 2272
Annulated myo-inositol 4: The annulated inositol 4 (18 mg, 80%) was
obtained from the olefin 19 (20 mg, 0.1 mmol) by dihydroxylation following
the procedure described above for the conversion of 15 to 17 but using
OsO4 (1 mg, 5 mol%) and NMMO (30 mL, 0.128 mmol) in acetone/water
(4:1, 1 mL) and purification by silica gel column chromatography (10%
methanol/ethyl acetate). M.p. 196 1978C; IR (KBr): nÄ ˆ 3308 cmÀ1
;
1H NMR (300 MHz, D2O): d ˆ 3.98 (brs, 1H), 3.94 (m, 1H), 3.74 (m,
1H), 3.42 (brs, 1H), 2.08 2.00 (m, 1H), 1.65 (brd, J ˆ 9.3 Hz, 1H), 1.51
1.28 (m, 5H), 1.24 (d, J ˆ 14 Hz, 1H); 13C NMR (75 MHz, D2O): d 77.3,
76.2, 75.6, 74.8, 74.1, 68.4, 30.5, 30.1, 20.1, 19.6; MS (ES): m/z (%): 257
‡
[M ‡Na].
Crystal data for the compound 4: Structure was solved by direct methods
(SIR92). Refinement was by full-matrixleast-squares procedures on F2 by
≈
Figure 1. ORTEP drawing for 15.
using SHELXL-97. Crystal system: triclinic, space group: P1, cell param-
eters: a ˆ 6.113(1), b ˆ 7.612(1), c ˆ 11.667(2) ä, a ˆ 102.326(4), b ˆ
97.912(4), g ˆ 91.817(4)8, Vˆ 524.39 ä3, Z ˆ 2, 1calcd ˆ 1.484 gcmÀ3
,
F(000) ˆ 252.0, m ˆ 0.12mmÀ1, l ˆ 0.71 ä. R1 ˆ 0.0498 for 892 Fo > 4s(Fo)
and 0.0788 for all 1273 data wR2 ˆ 0.0963, GOF ˆ 1.100, restrained GOF ˆ
1.100 for all data. An ORTEP drawing of compound 4 with 50% ellipsoidal
probability level is shown in Figure 3.
14.7 Hz, 1H), 2.06 (s, 3H), 1.95 (s, 3H), 1.92 1.86 (m, 1H), 1.55 1.21 (m,
6H); 13C NMR (75 MHz, D2O): d ˆ 175.5, 174.5, 83.7, 77.5, 76.1, 74.3, 71.2,
‡
67.4, 30.1, 25.6, 22.9, 21.6, 20.1 (2C); MS (70 eV, EI): m/z (%): 319 [M ‡H];
elemental analysis calcd (%) for C14H22O8 (318.3): C 52.82, H 6.97; found: C
52.63, H 7.07.
Annulated chiro-inositol 18: Solid K2CO3 (78 mg, 0.566 mmol) was added
to a solution of tetrol 17 (90 mg, 0.283 mmol) in methanol (3 mL), and the
reaction mixture was stirred at room temperature for 2 h, before removal of
methanol under reduced pressure. The residue obtained was dissolved in
deionized water (2 mL) and the solution was passed though a Dowex
‡
50WÂ 8 (H form) ion exchange resin column and eluted with water. The
eluent was concentrated under reduced pressure to give the annulated
Figure 3. ORTEP drawing for 4.
chiro-inositol 18 (63 mg, 96%). M.p. 209 2108C; IR (KBr): nÄ ˆ 3353 cmÀ1
;
1H NMR (300 MHz, D2O): d ˆ 4.00 (dd, J ˆ 3.6, 3.3 Hz, 1H), 3.89 (dd, J ˆ
9.9, 3.6 Hz, 1H), 3.61 (d, J ˆ 9.9 Hz, 1H), 3.55 (d, J ˆ 3.3 Hz, 1H), 2.05
1.95 (m, 1H), 1.66 (d, J ˆ 13.2 Hz, 1H), 1.54 1.43 (m, 5H), 1.29 (d, J ˆ
13.2 Hz, 1H); 13C NMR (75 MHz, D2O): d ˆ 80.5, 78.8, 77.4, 77.1, 75.1, 72.3,
Compounds 20 and 21: A solution of the diene 5 (100 mg, 0.4 mmol) in
acetone/water (4:1, 5 mL) was treated with OsO4 (1 mg, 1 mol%) and
NMMO (190 mL, 0.8 mmol), and the resulting solution was stirred at 108C
for 2 d. The reaction was quenched by the addition of solid NaHSO3. After
dilution with ethyl acetate (20 mL), the reaction mixture was filtered
through a Celite pad, and the filtrate was concentrated under reduced
pressure to give a solid residue, which was indicated to be a mixture of two
compounds by TLC. The isomers 20 and 21 were separated by chromatog-
raphy over a silica gel (40% ethyl acetate/hexane) to furnish 20 (53 mg,
47%) and 21 (26 mg, 23%).
‡
33.0, 32.1, 22.5, 22.1; MS (ES): m/z (%): 257 [M ‡Na].
Crystal data for the compound 18: Structure was solved by direct methods
(SIR92). Refinement was by full-matrixleast-squares procedures on F2 by
≈
using SHELXL-97. Crystal system: triclinic, space group: P1, cell param-
eters: a ˆ 12.558(3), b ˆ 12.915(4), c ˆ 13.859(4) ä, a ˆ 87.959(6), b ˆ
87.627(6), g ˆ 70.606(6)8, Vˆ 2118.20 ä3, Z ˆ 8, 1calcd ˆ 1.285 gcmÀ3
,
F(000) ˆ 882, m ˆ 0.11mmÀ1, l ˆ 0.71 ä. R1 ˆ 0.0512 for 4439 Fo > 4s(Fo)
and 0.0923 for all 7191 data, wR2 ˆ 0.1563, GOF ˆ 0.883, restrained
GOF ˆ 0.883 for all data. There are four independent molecules in the
asymmetric unit. An ORTEP drawing of compound 18 with 50%
ellipsoidal probability level is shown in Figure 2.
Compound 20: m.p. 210 2118C; IR (KBr): nÄ ˆ 3419, 1731 cmÀ1; 1H NMR
(300 MHz, D2O): d ˆ 4.50 (s, 2H), 3.78 (s, 2H), 2.38 (s, 1H), 2.34 (s, 1H),
2.01 1.97 (m, 2H), 1.96 (s, 6H), 1.5 1.4 (m, 2H), 1.13 1.06 (m, 2H);
13C NMR (75 MHz, D2O): d ˆ 172.5 (2C), 86.0 (2C), 71.4 (2C), 67.4 (2C),
‡
24.8 (2C), 22.2 (2C), 19.5 (2C); MS (70 eV, EI): m/z (%): 223 [M
À
2H2O À OAc]; elemental analysis calcd (%) for C14H22O8 (318.3): C
52.82, H 6.97; found: C 52.96, H 7.27.
Compound 21: m.p. 215 2168C; IR (thin film): 3419 cmÀ1 1H NMR
;
(300 MHz, D2O): d ˆ 5.12 (dd, J ˆ 10.6, 3 Hz, 1H), 4.89 (brs, 1H), 4.28
4.20 (m, 2H), 2.79 (brs, 1H), 2.60 2.55 (m, 2H), 2.16 (s, 3H), 2.14 (s, 3H),
1.85 1.30 (m, 5H); 13C NMR (75 MHz, D2O): d ˆ 170.9, 168.4, 85.0, 78.4,
74.1, 71.7, 71.6, 66.8, 30.3, 24.6, 22.2, 21.1, 19.9, 19.1; MS (70 eV, EI): m/z
‡
(%): 283 [M À 2H2O‡H].
Annulated chiro-inositol 22: By following a procedure similar to that used
for the conversion of 17 to 18, tetrols 20 (45 mg, 0.158 mmol) and 21 (25 mg,
0.088 mmol) were separately hydrolyzed using K2CO3 (43 mg, 0.316 mmol
for 20, 24 mg, 0.176 mmol for 21) in methanol to afford the annulated
Figure 2. ORTEP drawing for 18.
inositol 22 (34 mg, 18 mg, respectively, 90%). IR (thin film): 3364 cmÀ1
;
Compound 19: The tetrol 19 (35 mg, 95%) was obtained from diacetate 16
(53 mg, 0.187 mmol) by following a procedure similar to that described for
the conversion of 17 to 18 but using K2CO3 (51 mg, 0.374 mmol) in
methanol (2 mL) and purification over a silica gel (50% ethyl acetate/
1H NMR (300 MHz, D2O): d ˆ 3.95 (s, 2H), 3.51 (s, 2H), 2.00 1.91 (m,
2H), 1.52 1.38 (m, 4H), 1.18 (s, 1H), 1.14 (s, 1H); 13C NMR (75 MHz,
D2O): d ˆ 78.8 (2C), 74.5 (2C), 69.2 (2C), 30.6 (2C), 19.8 (2C); MS (EI,
‡
70 eV): m/z (%): 217 [M À H2O‡H].
hexane). M.p. 202 2038C; IR (thin film): nÄ ˆ 3273 cmÀ1
;
1H NMR
1
(300 MHz, D2O): d ˆ 5.71 (d ³2ABq, J ˆ 10, 3.8 Hz, 1H), 5.61 (1³2ABq,
Compound 23 and 24: Mono-epoxidation of 6 was carried out by following
a procedure similar to that described for 5 by treating the diene (1.2 g,
5.08 mmol) with mCPBA (70%, 1.25 g, 5.08 mmol) in dry CH2Cl2 (10 mL)
at 08C, followed by chromatography over silica gel (elution with 10% ethyl
acetate/hexane) to furnish mono-epoxides 23 (537 mg, 42%) and 24
(230 mg, 18%).
J ˆ 10, 3.8 Hz, 1H), 3.97 (d, J ˆ 3.8 Hz, 1H), 3.53 (s, 1H), 2.09 2.00 (m,
1H), 1.65 1.29 (m, 7H); 13C NMR (75 MHz, D2O): d ˆ 134.6, 127.9, 77.7,
‡
71.4, 70.9, 70.6, 32.7, 30.3, 20.4, 19.9; MS (70 eV, EI): m/z (%): 164 [M
À
2H2O]; elemental analysis calcd (%) for C10H16O4 (200.2): C 59.98, H 8.05;
found: C 59.79, H 7.89.
Chem. Eur. J. 2003, 9, 2264 2272
www.chemeurj.org
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2269

G. Mehta et al.
FULL PAPER
Compound 23: m.p. 1678C; IR (KBr): nÄ ˆ 1730 cmÀ1; 1H NMR (300 MHz,
CDCl3): d ˆ 6.44 (d, J ˆ 9.3 Hz, 1H), 6.06 (dd, J ˆ 9.8 Hz, 3.9 Hz, 1H), 4.31
(d, J ˆ 4.2 Hz, 1H), 3.31 3.29 (m, 1H), 2.68 2.61 (m, 1H), 2.34 2.24 (m,
2H), 1.97 1.79 (m, 9H); 13C NMR (75 MHz, CDCl3): d ˆ 169.5, 169.1,
133.1, 127.4, 89.1, 86.1, 51.8, 47.5, 30.1, 27.4, 22.0, 21.9, 20.7; MS (70 eV, EI):
‡
m/z (%): 209 [M À Ac]; elemental analysis calcd (%) for C13H16O5 (252.2):
C 61.09, H 6.39; found: C 61.47, H 6.36.
Copmound 24: m.p. 1708C; IR (thin film): nÄ ˆ 1731 cmÀ1
;
1H NMR
(300 MHz, CDCl3): d ˆ 6.47 (d, J ˆ 9.9 Hz, 1H), 5.95 (d, J ˆ 9.9 Hz, 1H),
3.68 (d, J ˆ 3.6 Hz, 1H), 3.29 (s, 1H), 2.75 2.66 (m, 1H), 2.43 2.35 (m,
1H), 2.17 1.75 (m, 4H), 1.97 (s, 6H); 13C NMR (75 MHz, CDCl3): d ˆ
169.1, 168.9, 134.8, 125.3, 86.4, 85.5, 52.7, 48.0, 30.5, 29.3, 21.7, 21.2, 19.2;
‡
MS(70 eV, EI): m/z (%): 167 [M À 2Ac‡H].
Compounds 25 and 26: Epoxide 23 (500 mg, 1.98 mmol) was transformed
into diols 25 (246 mg, 46%) and 26 (75 mg, 14%) by following a procedure
similar to that used for the conversion of the epoxide 13 into diols 15 and 16
but using 10% AcOH (3 mL) and separation of the isomers by chroma-
tography over silica gel (40% ethyl acetate/hexane).
Figure 5. ORTEP drawing for 26.
Compound 25: m.p. 99.68C; IR (KBr): nÄ ˆ 3437, 1744, 1731 cmÀ1; 1H NMR
(300 MHz, CDCl3): d ˆ 6.02 5.96 (m, 1H), 5.62 5.57 (m, 2H), 4.80 (dd,
J ˆ 10.8, 4.8 Hz, 1H), 2.64 2.53 (m, 3H), 2.15 (s, 3H), 1.96 (s, 3H), 1.96
1.90 (m, 1H), 1.80 1.70 (m, 2H); 13C NMR (75 MHz, CDCl3): d ˆ 170.0,
169.4, 130.6, 125.5, 90.5, 81.4, 73.6, 64.5, 34.7, 26.6, 22.2, 21.1, 18.8; MS
restrained GOF ˆ 1.227 for all data. An ORTEP drawing of compound 26
with 50% ellipsoidal probability is shown in Figure 5.
Compound 27: Diol 25 (230 mg, 0.85 mmol) was hydrolyzed with K2CO3
(234 mg, 1.7 mmol) in methanol (3 mL) at room temperature for 6 h.
Removal of the solvent under reduced pressure gave a solid residue which
was purified by chromatography over silica gel (70% ethyl acetate/hexane)
to furnish the tetrol 27 (128 mg, 81%). IR (KBr): nÄ ˆ 3399 cmÀ1; 1H NMR
(300 MHz, D2O): d ˆ 5.86 5.81 (m, 1H), 5.65 (d, J ˆ 9.9 Hz, 1H), 4.23 (s,
1H), 3.92 (s, 1H), 2.29 2.24 (m, 1H), 1.78 (brs, 4H), 1.58 1.52 (m, 1H);
13C NMR (75 MHz, D2O): d ˆ 131.9, 128.8, 82.5, 81.9, 71.4, 69.7, 33.9, 31.6,
‡
(70 eV, EI): m/z (%): 210 [M À Ac À H2O‡H]; elemental analysis calcd
(%) for C13H18O6 (270.2): C 57.77, H 6.71; found: C 57.61, H 6.70.
Compound 26: m.p. 150.38C; IR (KBr): nÄ ˆ 3467, 1730, 1711 cmÀ1; 1H NMR
(300 MHz, CDCl3): d ˆ 6.42 (d, J ˆ 9.6 Hz, 1H), 5.88 (dd, J ˆ 10.1, 3 Hz,
1H), 4.55 (brs, 1H), 4.40 (brs, 1H), 2.59 2.28 (m, 3H), 2.11 1.95 (m, 1H),
1.99 (s, 3H), 1.95 (s, 3H), 2.11 1.95 (m, 1H), 1.89 1.85 (m, 1H); 13C NMR
(75 MHz, CDCl3): d ˆ 169.9, 168.1, 131.9, 127.8, 89.6, 88.6, 73.2, 72.9, 30.02,
‡
18.9; MS (70 eV, EI): m/z (%): 150 [M À 2H2O]; elemental analysis calcd
(%) for C9H14O4 (186.2): C 58.05, H 7.58; found: C 58.14, H 7.71.
‡
25.9, 22.3, 21.7, 19.8; MS (70 eV, EI): m/z (%): 228 [M À Ac‡H].
Annulated chiro-inositol 28: The tetrol 27 (128 mg, 0.688 mmol) was
dihydroxylated by following a procedure similar to that described for 17 but
using OsO4 (2 mg, 1 mol%) and NMMO (175 mL, 0.75 mmol) in acetone/
water (4:1, 3 mL), followed by chromatography over silica gel (10%
methanol/ethyl acetate) to afford the annulated chiro-inositol 28 (127 mg,
Crystal data for the compound 25: Structure was solved by direct methods
(SIR92). Refinement was by full-matrixleast-squares procedures on F2 by
using SHELXL-97. Crystal system: monoclinic, space group: P121/m1, cell
parameters: a ˆ 10.4616(4), b ˆ 10.476(4), c ˆ 12.454(5) ä, b ˆ 101.117(8)8,
84%). IR (KBr): nÄ ˆ 3364 cmÀ1
;
1H NMR (300 MHz, D2O): d ˆ 4.02 (s,
Vˆ 1339.40 ä3, Z ˆ 4, 1calcd ˆ 1.34 gcmÀ3, F(000) ˆ 576.0, m ˆ 0.11mmÀ1
,
1H), 3.96 3.81 (m, 3H), 2.22 2.11 (m, 1H), 1.89 1.77 (m, 3H), 1.64 1.61
l ˆ 0.71073 ä. Total number of l.s. parameters ˆ 433. R1 ˆ 0.1012 for
1953 Fo > 4s(Fo) and 0.2277 for all 3949 data. wR2 ˆ 0.2523, GOF ˆ 1.252,
restrained GOF ˆ 1.252 for all data. An ORTEP drawing of compound 25
with 50% ellipsoidal probability is shown in Figure 4. There are two
independent molecules in the asymmetric unit.
(m, 1H), 1.51 1.45 (m, 1H); 13C NMR (75 MHz, D2O): d ˆ 86.9, 83.7, 75.8,
‡
72.6, 72.4, 70.7, 33.2, 31.3, 19.7; MS (70 eV, EI): m/z (%): 184 [M À 2H2O];
elemental analysis calcd (%) for C9H16O6 (220.2): C, 49.09, H 7.32; found: C
48.69, H 7.29.
Compound 29: Diol diacetate 26 (75 mg, 0.278 mmol) was hydrolyzed with
K2CO3 (76 mg, 0.556 mmol) in methanol (2 mL) by following a procedure
similar to that used for the conversion of 16 to 19. Purification of the
resultant residue over silica gel (70% ethyl acetate/hexane) furnished 29
(47 mg, 92%). M.p. 124.68C; IR (thin film): nÄ ˆ 3338 cmÀ1
;
1H NMR
(300 MHz, D2O): d ˆ 5.99 (d, J ˆ 10.2, 1H), 5.76 (d, J ˆ 7.2 Hz, 1H), 4.15 (s,
1H), 3.83 (s, 1H), 2.17 2.06 (m, 1H), 1.81 1.77 (m, 3H), 1.63 1.48 (m,
2H); 13C NMR (75 MHz, D2O): d ˆ 131.0, 130.6, 80.3, 79.9, 75.8, 72.6, 33.4,
‡
29.94, 19.8; MS (70 eV, EI): m/z (%): 167 [M À H2O À H].
Annulated myo-inositol 30: Tetrol 29 (45 mg, 0.242 mmol) was dihydroxy-
lated with OsO4 (1 mg, 2 mol%) and NMMO (70 mL, 0.29 mmol) in
acetone/water (4:1, 2 mL) following a procedure described above for the
conversion of 19 to 4. Chromatography of the resultant residue over silica
gel (10% methanol/ethyl acetate) afforded annulated myo-inositol 30
(45 mg, 86%). IR (KBr): nÄ ˆ 3386 cmÀ1
;
1H NMR (300 MHz, D2O): d ˆ
4.06 (s, 1H), 3.96 (s, 2H), 3.79 (s, 1H), 2.20 2.13 (m, 1H), 1.80 1.61 (m,
4H), 1.47 1.42 (m, 1H); 13C NMR (75 MHz, D2O): d ˆ 85.8, 84.7, 76.5,
Figure 4. ORTEP drawing for 25.
‡
74.6, 73.7, 68.50, 33.6, 31.6, 18.7; MS (70 eV, EI): m/z (%): 166 [M
À
3H2O].
Crystal data for the compound 26: Structure was solved by direct methods
(SIR92). Refinement was by full-matrixleast-squares procedures on F2 by
using SHELXL-97. Crystal system: monoclinic, space group: P21/c, cell
parameters: a ˆ 7.949(3), b ˆ 22.668(11), c ˆ 7.970(3) ä, b ˆ 112.605(8)8,
Compound 31: Epoxide 24 (225 mg, 0.893 mmol) was converted to the diol
31 (178 mg, 74%) by following a procedure similar to that used for the
major epoxide 23 but with 10% AcOH (3 mL) and purification over silica
gel (40% ethyl acetate/hexane). M.p. 124.58C; IR (KBr): nÄ ˆ 3452,
Vˆ 1325.81 ä3, Z ˆ 4, 1calcd ˆ 1.354 gcmÀ3, F(000) ˆ 576.0, m ˆ 0.11mmÀ1
,
1716 cmÀ1
;
1H NMR (300 MHz, CDCl3): d ˆ 5.69 (s, 2H), 5.67(s, 2H),
l ˆ 0.71073 ä. Total number of l.s. parameters ˆ 244. R1 ˆ 0.0832 for
2250 Fo > 4s(Fo) and 0.1002 for all 2680 data. wR2 ˆ 0.1882, GOF ˆ 1.227,
2.14 (s, 6H), 2.21 2.05 (m, 2H), 1.96 1.83 (m, 2H), 1.75 1.67 (m, 2H);
13C NMR (75 MHz, CDCl3): d ˆ 170.0 (2C), 128.0 (2C), 83.3 (2C), 73.8
2270
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2003, 9, 2264 2272

Locked Inositols
2264 2272
‡
(2C), 34.7 (2C), 21.1 (2C), 19.4; MS (70 eV, EI): m/z (%): 210 [M
AcO À H2O‡H].
À
Compound 32: The diol diacetate 31 (175 mg, 0.648 mmol) was hydrolyzed
with K2CO3 (178 mg, 1.296 mmol) in methanol (3 mL) by following a
procedure similar to that used for the conversion of 16 to 19 to afford the
tetrol 32 (114 mg, 95%). M.p. 1148C; IR (KBr): nÄ ˆ 3400 cmÀ1
;
1H NMR
(300 MHz, D2O): d ˆ 5.49 (s, 2H), 4.21 (s, 2H), 1.91 1.71 (m, 6H);
13C NMR (75 MHz, D2O): d ˆ 131.0 (2C), 85.2 (2C), 71.2 (2C), 33.9 (2C),
‡
19.5; MS (70 eV, EI): m/z (%): 150 [M À 2H2O].
Annulated allo-inositol 33: Tetrol 32 (100 mg, 0.537 mmol) was dihydroxy-
lated by using OsO4 (1 mg, 1 mol%) and NMMO (150 mL, 0.644 mmol) by
following a procedure similar to that used for the conversion of 19 to 4.
Purification by chromatography over silica gel (10% methanol/ethyl
Figure 7. ORTEP drawing for 34.
acetate) led to 33. M.p. 2378C; IR (KBr): nÄ ˆ 3382 cmÀ1
;
1H NMR
(300 MHz, D2O): d ˆ 3.96 (s, 1H), 3.78 3.68 (m, 3H), 1.87 1.59 (m, 6H);
‡
(%): 167 [M À H2O À H]; elemental analysis calcd (%) for C9H14O4
13C NMR (75 MHz, D2O): d ˆ 87.7, 85.1, 75.7, 72.6, 72.2, 68.8, 33.2, 32.9, 19.7.
(186.2): C 58.05, H 7.58; found: C 58.35, H 7.76.
Crystal data for compound 33: Structure was solved by direct methods
(SIR92). Refinement was by full-matrixleast-squares procedures on F2 by
using SHELXL-97. Crystal system: monoclinic, space group: P 121 1, cell
Compound 36: Tetrol 35 (45 mg, 0.242 mmol) was subjected to a procedure
similar to that detailed for the conversion of 19 to 4 but with OsO4 (2 mg,
2 mol%) and NMMO (60 mL, 0.25 mmol) in acetone/water (4:1, 2 mL),
followed by purification by chromatography over silica gel (10% methanol/
ethyl acetate) to afford 36 (33 mg, 0.152 mmol). M.p. 188.68C; IR (KBr):
parameters:
a ˆ 7.221(17),
b ˆ 11.507(27),
c ˆ 7.291(17) ä,
b ˆ
103.692(31)8, Vˆ 588.63 ä3, Z ˆ 2, 1calcd ˆ 1.242 gcmÀ3
,
F(000) ˆ 236.0,
m ˆ 0.10mmÀ1, l ˆ 0.71073 ä. Total number of l.s. parameters ˆ 200. R1 ˆ
0.0349 for 1436 Fo > 4s(Fo) and 0.0406 for all 1589 data. wR2 ˆ 0.0815,
GOF ˆ 1.08, restrained GOF ˆ 1.08 for all data. An ORTEP drawing of
compound 33 with 50% ellipsoidal probability is shown in Figure 6.
nÄ ˆ 3316 cmÀ1
;
1H NMR (300 MHz, D2O): d ˆ 4.00 (s, 2H), 3.89 (s, 2H),
2.17 2.06 (m, 2H), 1.87 1.77 (m, 2H), 1.42 1.34 (m, 2H); 13C NMR
(75 MHz, D2O): d ˆ 83.2 (2C), 74.5 (2C), 69.9 (2C), 31.1 (2C), 19.8; MS
‡
(70 eV, EI): m/z (%): 166 [M À 3H2O].
CCDC 196758 (15), -196759 (18), -196760 (4), -196755 (25), -196756 (26), -
196757 (33), -196754 (34) contain the supplementary crystallographic data
and can be obtained free of charge via www.ccdc.cam.ac.uk/conts/
retrieving.html (or from the Cambridge Crystallographic Data Centre,
12 Union Road, Cambridge CB2 1EZ, UK; fax: (‡44)1223-336-033; or
deposit@ccdc.cam.uk).
Figure 6. ORTEP drawing for 33.
Acknowledgements
Compound 34: A solution of diene 6 (200 mg, 0.847 mmol) in acetone/
water (4:1, 5 mL) was treated with OsO4 (2 mg, 1 mol%) and NMMO
(200 mL, 0.847 mmol), and the resulting mixture was stirred at 08C for 2 d.
The reaction was quenched by the addition of solid NaHSO3. After dilution
with ethyl acetate (25 mL), the reaction mixture was filtered through a
Celite pad and the filtrate was concentrated under reduced pressure to
yield a solid residue. Column chromatography over silica gel (elution with
50% ethyl acetate/hexane) furnished the diol diacetate 34 (109 mg, 48%).
M.p. 122.78C; IR (KBr): nÄ ˆ 3373, 1739 cmÀ1; 1H NMR (300 MHz, CDCl3):
d ˆ 6.12 (d, J ˆ 10.2 Hz, 1H), 5.56 (d, J ˆ 10.2 Hz, 1H), 5.29 (brs, 1H), 5.24
(brs, 1H), 2.41 (m, 2H), 2.14 (s, 3H), 1.98 (s, 3H), 2.04 1.66 (m, 4H);
R.S.S. and M.K.B. would like to thank CSIR (India) and UGC (India),
respectively, for the award of a research fellowship. We thank the CCD
facility at IISc for help with the X-ray crystal structure determination.
[1] For leading reviews dealing with the chemistry and biology of
inositols, see: a) M. J. Berridge, R. F. Irvine, Nature 1984, 312, 315;
b) M. J. Berridge, R. F. Irvine, Nature 1989, 341, 197; c) B. V. L. Potter,
Nat. Prod. Rep. 1990, 1; d) B. V. L. Potter, D. Lampe, Angew. Chem.
1995, 107, 1933; Angew. Chem. Int. Ed. Engl. 1995, 34, 1933; e) K.
Hinterding, D. A. DÌaz, H. Waldmann, Angew. Chem. 1998, 110, 716;
Angew. Chem. Int. Ed. Engl. 1998, 37, 688; f) Y-T. Chang, G. R.
Rosania, S-K. Chung, Exp. Opin. Ther. Patents 2001, 11, 1.
13C NMR (75 MHz, CDCl3): d ˆ 170.1, 169.7, 131.9, 123.8, 89.3, 78.2, 70.5,
‡
67.6, 32.6, 26.2, 22.0, 21.1, 18.8; MS (70 eV, EI): m/z (%): 186 [M
À
2Ac‡2]; elemental analysis calcd (%) for C13H18O6 (270.3): C 57.77, H
6.71; found: C 57.86, H 6.75.
[2] M. J. Berridge, Nature 1993, 361, 315.
[3] For selected references on inositol analogues, see: a) A. M. Riley,
B. V. L. Potter, J. Org. Chem. 1995, 60, 4970; b) C. Liu, B. V. L. Potter,
J. Org. Chem. 1997, 62, 8335; c) A. M. Riley, B. V. L. Potter,
Tetrahedron Lett. 1999, 40, 2213; d) H. Sun, G. B. Reddy, C. George,
E. J. Meuillet, M. Berggren, G. Powis, A. P. Kozikowski, Tetrahedron
Lett. 2002, 43, 2835; e) D. J. Jenkins, A. M. Riley, B. V. L. Potter, J.
Org. Chem. 1996, 61, 7719; f) A. P. Kozikowski, A. H. Fauq, G. Powis,
D. C. Melder, J. Am. Chem. Soc. 1990, 112, 4528; g) A. B. Cheikh,
L. E. Craine, J. Zemlicka, M. H. Heeg, Carbohydr. Res. 1990, 199, 19;
h) A. Schnaars, C. Schultz, Tetrahderon 2001, 57, 519.
Crystal data for the compound 34: Structure was solved by direct methods
(SIR92). Refinement was by full-matrixleast-squares procedures on F2 by
using SHELXL-97. Crystal system: monoclinic, space group: P21/n, cell
parameters: a ˆ 7.027(1), b ˆ 8.318(1), c ˆ 23.002(3) ä, b ˆ 92.490(3)8, Vˆ
1343.26 ä3, Z ˆ 4, 1calcd ˆ 1.336 gcmÀ3, F(000) ˆ 576.0, m ˆ 0.11mmÀ1, l ˆ
0.71073 ä. Total number of l.s. parameters ˆ 244. R1 ˆ 0.0458 for
1449 Fo > 4s(Fo) and 0.1048 for all 2815 data. wR2 ˆ 0.0994, GOF ˆ 0.820,
restrained GOF ˆ 0.820 for all data. An ORTEP drawing of compound 34
with 50% ellipsoidal probability is shown in Figure 7.
Compound 35: Diol diacetate 34 (100 mg, 0.370 mmol) was hydrolyzed
with K2CO3 (102 mg, 0.74 mmol) in methanol (2 mL) followed by
purification by chromatography over silica gel (10% methanol/ethyl
acetate eluent) to give tetrol 35 (51 mg, 75%). M.p. 146.78C; IR (KBr):
[4] For recent synthetic studies on inositols, see: a) Y. U. Kwon, C. Lee,
S. K. Chung, J. Org. Chem. 2002, 67, 3327; b) H. Takahashi, H. Kittaka,
S. Ikegami, J. Org. Chem. 2001, 66, 2705; c) K. S. Kim, J. I. Park, H. K.
Moon, H. Yi, Chem. Commun. 1998, 1945; d) Y. Landias, Chimia 1998,
52, 104; e) A. M. Riley, D. J. Jenkins, B. V. L. Potter, Carbohydr. Res.
1998, 314, 277; f) W. Motherwell, A. S. Williams, Angew. Chem. 1995,
107, 2207; Angew. Chem. Int. Ed. Engl. 1995, 34, 2031; g) T. Hudlicky,
M. Mandel, J. Rouden, R. S. Lee, B. Bachmann, T. Dudding, K. J.
nÄ ˆ 3364 cmÀ1
;
1H NMR (300 MHz, D2O): d ˆ 5.88 (d, J ˆ 10.2 Hz, 1H),
5.54 (d, J ˆ 10.2 Hz, 1H), 4.38 (m, 1H), 4.02 (d, J ˆ 4.8 Hz, 1H), 2.17 2.07
(m, 1H), 1.69 1.67 (m, 3H), 1.53 1.43 (m, 2H); 13C NMR (75 MHz, D2O):
d ˆ 130.6, 129.9, 81.3, 80.0, 72.3, 68.5, 33.1, 31.2 19.0; MS (70 eV, EI): m/z
Chem. Eur. J. 2003, 9, 2264 2272
www.chemeurj.org
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2271

G. Mehta et al.
FULL PAPER
Yost, J. S. Merola, J. Chem. Soc. Perkin Trans. 1 1994, 1553; h) C.
Jaramillo, M. M. Lomas, Tetrahedron Lett. 1991, 32, 2501.
[5] a) C. J. Volkmann, G. M Chateauneuf, J. Pradhan, A. T. Baumann,
R. E. Brown, P. P. N. Murthy, Tetrahedron Lett. 2002, 43, 4853; b) L. G.
Barrientos, P. P. N. Murthy, Carbohydr. Res. 1996, 296, 39; c) C. Liang,
C. S. Ewig, T. R. Stouch, A. T. Hagler, J. Am. Chem. Soc. 1994, 116,
3904; d) I. Lee, J. H. Sohn, S. C. Kim, Y. K. Jeon, J. Korean Chem. Soc.
1979, 3, 271.
reminiscent of the use of cis-cyclohexadiene diols derived from
benzene derivatives. See: T. Hudlicky, D. Gonzalez, D. T. Gibson,
Aldrichimia Acta 1999, 32, 35.
[10] E. Giovannini, H. Wegm¸ller, Helv. Chim. Acta 1958, 41, 933.
[11] Conduritols in their own right are important biologically active
natural products of current interest (see ref. [12]) and our synthetic
efforts described here also provide access to a range of novel ring-
annulated bicyclic conduritols.
[6] Cyclohexadiene-trans-diols (trans-CHD), unlike their cis counter-
parts, are not easily accessible and synthetic access to them is generally
tedious (ref. [7a d]). However, a preparative route to trans-CHD by
using recombinant E. coli cells has been reported (ref. [7e]). Annu-
lated trans-CHD and its derivatives to the best of our knowledge
remain unknown.
[7] a) B. M. Trost, L. S. Chupak, T. L¸bbers, J. Am. Chem. Soc. 1998, 120,
1732; b) B. P. McKibben, G. S. Barnosky, T. Hudlicky, Synlett 1995,
806; c) D. K. Boyd, N. D. Sharma, H. Dalton, D. A. Clarke, Chem.
Commun. 1996, 45; d) H. B. Mereyala, M. Pannala, J. Chem. Soc.
Perkin Trans. 1 1997, 1755; e) D. Franke, G. A. Sprenger, M. M¸ller,
Angew. Chem. 2001, 113, 578; Angew. Chem. Int. Ed. Engl. 2001, 40,
555.
[12] a) M. Balci, Pure Appl. Chem. 1997, 69, 97; b) D. C. Billington, F. P.
Sierra, S. Beaubras, J. Duhault, J. Episnal, S. Challal, in Carbohydrate
Mimics-Concepts and Methods (Ed.: Y. Chapleur), Wiley-VCH,
Weinheim, 1998, p. 433.
[13] a) S. J. Angyal, G. J. H. Melrose, J. Chem. Soc. 1965, 6494; b) H.
Paulsen, Adv. Carbohydr. Chem. Biochem. 1971, 26, 127; c) V. I.
Shvets, Russ. Chem. Rev. 1974, 43, 488.
[14] a) J. K. Cha, W. J. Christ, Y. Kishi, Tetrahedron Lett. 1983, 24, 3943;
b) T. J. Donohoe, Synlett 2002, 1233.
[15] The site of annulation on the inositol moiety has been identified by
following the corresponding parent inositol numbering. For inositol
numbering see, IUPAC-IUB 1973 recommendation for cyclitols: Pure
Appl. Chem. 1974, 37, 283 and refs. [1b] and [4b].
[8] a) M. G. Banwell, J. H. Ryan, D. A. Winkler, Aust. J. Chem. 1991, 44,
593; b) W. H¸ckel, U. Wˆrffel, Chem. Ber. 1956, 89, 2098.
[9] We regard the annulated cyclohexadiene trans-diols 5 and 6 as
extremely versatile new building blocks which can be employed to
[16] G. A. Jeffrey, Y. Yeon, Carbohydr. Res. 1987, 159, 211.
[17] I. N. Rabinowitz, J. Kraut, Acta Crystallogr. 1964, 17, 159.
generate
a
variety of natural product analogues in
a
manner
Received: December 6, 2002 [F4650]
2272
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2003, 9, 2264 2272