Competition between non-classical single and double epimerizations in cyclitol chemistry

Article abstract of DOI:10.1002/ejoc.200300688

Two competitive regio- and stereoselective epimerization reactions were investigated in four cyclitols characterized by four contiguous OH groups with a cis-trans-trans sequence and by varied substituents (OMe, OBz, F, H) adjacent to this tetrol unit. The

Full text of DOI:10.1002/ejoc.200300688

FULL PAPER
Competition between Non-Classical Single and Double Epimerizations in
Cyclitol Chemistry[‡]
Ralf Miethchen,*[a] Katharina Neitzel,[a] Kathrin Weise,[a] Manfred Michalik,[b]
Helmut Reinke,[a] and Franziska Faltin[a]
In memory of Prof. Dr. Christian Pedersen[‡‡]
Keywords: Acetals / Inositols / Non-classical epimerization / Synthesis methods / Three-component reactions
Two competitive regio- and stereoselective epimerization re-
actions were investigated in four cyclitols characterized by
four contiguous OH groups with a cis-trans-trans sequence
and by varied substituents (OMe, OBz, F, H) adjacent to this
lower the electron-withdrawing effect of the substituents ad-
jacent to the tetrol unit, the higher the percentage of the cor-
responding doubly inverted product. However, the singly
inverted products remain the major products in all cases. X-
ray analyses are given for the starting material 1-fluoro-2-O-
tetrol unit. The starting materials were synthesized from L-
quebrachitol (compounds 5−7) and myo-inositol (compound (methyl)cyclohexane-2,3,4,5,6-pentol (5) and for the products
8). Their acetalization with the chloral/DCC reagent system
1-O-cyclohexylcarbamoyl-2,3-O-(2,2,2-trichloroethylidene)-
gave cyclic acetals with one epimerized chiral ring atom and
5-O-(methyl)cyclohexane-1,2,3,4,5-pentol (17), 3-O-acetyl-1-
also with two epimerized chiral centres. The single epimeri- O-benzoyl-6-O-cyclohexylcarbamoyl-2-O-methyl-4,5-O-
zation takes place exclusively at the middle C-atom of the
cis-trans triol unit in the tetrol sequence (products 15, 17, 19/
20 and 24−27), whereas the double epimerization occurs at
both of the "centrally located" C-atoms in the cis-trans-trans
tetrol unit (products 16, 18, 21 and 28). The product ratios of
singly to doubly inverted compounds change as follows: the
(2,2,2-trichloroethylidene)-muco-inositol (22) and 2,3-di-O-
benzoyl-1-O-cyclohexylcarbamoyl-5,6-O-(2,2,2-trichloro-
ethylidene)-(+/-)-chiro-inositol (24).
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2004)
Introduction
chloral/DCC as reagents. When these components are
heated in dichloromethane or 1,2-dichloroethane, the reac-
tion proceeds with clean inversion of the configuration at
the middle C-atom of the contiguous cis-trans triol unit.[9,10]
First studies with selected cyclitols such as quinic acid and
shikimic acid esters gave the same results in terms of regio-
and stereoselectivity.[10Ϫ13]
The biological relevance of inositols has always drawn a
lot of attention to this multifunctional family.[1Ϫ5] However,
the separation of inositol derivatives from natural sources
is limited to a few representatives and so various com-
pounds of this type are produced by chemical meth-
ods[1,2,6,7] (for the nomenclature of inositols see ref.[8]). We
focused our efforts on selective epimerizations of easily ac-
cessible cyclitol derivatives with a three-component pro-
cedure used very successfully in pyranoside chemistry (re-
view[9]). This method is based on a non-classical acetali-
zation reaction requiring a cyclic triol with contiguous
hydroxy groups in a cis-trans sequence as substrate and
A corresponding acetalization experiment with a cyclitol
derivative containing four unprotected contiguous OH
groups with a cis-trans-trans sequence gave a surprising re-
sult. -1-O-Benzyl-2-O-methyl-chiro-inositol (1), chloral
and DCC yielded cyclitol derivatives that were selectively
epimerized either at one (compounds 2 and 3) or at two
(product 4) stereogenic centres[10,11] (Scheme 1). The singly
epimerized compounds 2 and 3 had been expected in accord
with the reaction pathway described for acetalizations/epi-
merizations of cyclic cis-trans triols[9,10] (ref.[9] refers to the
review article, which describes the unconventional epimeri-
zation reaction, including the mechanism, in very detailed
fashion).
[‡]
For part 18 see ref.[10]
[a]
Department of Chemistry, University of Rostock,
Albert-Einstein-Strasse 3a, 18059 Rostock, Germany
Fax: (internat.) ϩ49-(0)381-498-6412
E-mail: ralf.miethchen@chemie.uni-rostock.de
[b]
Institute for Organic Catalysis Research at the University of
Rostock,
Buchbinderstrasse 5Ϫ6, 18055 Rostock, Germany
[‡‡] To honor an excellent Danish carbohydrate chemist and person
of high integrity
In the case of the -chiro-inositol 4 it is noteworthy that
the inversion of the configuration at two stereogenic ring
2010
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DOI: 10.1002/ejoc.200300688
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Competition between Non-Classical Single and Double Epimerizations in Cyclitol Chemistry
FULL PAPER
Scheme 1. Competing unconventional epimerizations first observed
in the acetalization of -1-O-benzyl-2-O-methyl-chiro-inositol
(1);[10,11] i ϭ chloral, DCC, CH2Cl2, reflux
atoms is accompanied by CϪN bond formation, particu-
larly as aminocyclitols are interesting species.[14]
In order to obtain preliminary information about the
scope of the two competing epimerization reactions and to
anticipate the synthetic potential of a novel double epimer-
Scheme 3. Synthesis of the 1-fluoroinositol 5 and the methylene
derivative 6; i ϭ DAST, CH2Cl2, Ϫ30 °C to room temp.; ii ϭ I2,
Ph3P, imidazole, toluene, reflux; iii ϭ Bu3SnH, AIBN, toluene; iv ϭ
80% TFA; v ϭ BzCl, pyridine, CH2Cl2, room temp.
ization reaction, the substituent pattern of the starting ma-
terial was varied as shown in Scheme 2. The starting materi-
als 5Ϫ8 all contain the required four contiguous OH groups
with cis-trans-trans sequence as well as varied substituents
adjacent to the tetrol unit. The tetrols 5 and 6 in particular
are highly comparable pairs of starting materials in terms
of the similar steric neighbouring group effects of fluorine
and hydrogen but significantly different in their electronic
natures.
Figure 1. X-ray analysis of (1S,2S,3R,4S,5S,6S)-1-fluoro-2-
methoxy-3,4,5,6-tetrahydroxycyclohexane (5)
Scheme 2. Selected starting materials for comparative studies of
single and double epimerization of cyclic cis-trans-trans tetrols
The cyclitols 6 and 7 were similarly synthesized from -
quebrachitol (9) via the common key intermediate 3,4:5,6-
di-O-cyclohexylidene-2-O-methyl-(Ϫ)-chiro-inositol
Results and Discussion
(10).[16,17] Substitution of its free OH group by iodine or
benzoylation resulted in the compounds 11 and 14, respec-
tively (Scheme 3). The iodination procedure was carried out
Synthesis of the Starting Materials
Kozikowski et al.[15] described in 1989 the fluorination analogously to that reported in ref.[18] Subsequently, the
of -quebrachitol with N,N-diethylaminosulfur trifluoride cyclohexylidene groups of 11 and 14 were cleaved by treat-
(DAST) in the absence of solvent. The crude product from ment with 80% aqueous trifluoroacetic acid (TFA;
the reaction was subsequently treated with boron tribrom- Scheme 3).
ide to obtain a stereochemically uniform product by methyl
Methylidene derivative 6 (see also ref.[19]) was synthesized
2,3:4,5-di-O-cyclohexylidene-1-iodo-6-O-(methyl)-
ether cleavage. We similarly fluorinated -quebrachitol (9) from
with DAST in a one-pot procedure, although in a dichloro- cyclohexane-2,3,4,5,6-pentol (11) in two steps. Firstly,
methane suspension. The product isolated after this pro- 1,2:3,4-di-O-cyclohexylidene-5-O-(methyl)cyclohexane-
cedure was exclusively the (1S,2S,3R,4S,5S,6S)-1-fluoro-2- 1,2,3,4,5-pentol (13) was generated by reductive deiodin-
O-(methyl)cyclohexane-2,3,4,5,6-pentol (5; Scheme 3, Fig- ation of 11 with tributylstannane/AIBN, followed by deket-
ure 1).
alization with aqueous TFA (Scheme 3).
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R. Miethchen, K. Neitzel, K. Weise, M. Michalik, H. Reinke, F. Faltin
FULL PAPER
Epimerization of the Cyclitols
When the tetrols 5 and 6 were heated at reflux with chlo-
ral/DCC in dichloromethane for 8 h and the crude products
subsequently treated with boiling methanolic triethylamine,
the product pairs 15 (18%)/16 (1.2%), and 17 (61%)/18
(19%) were obtained (Scheme 4). The small amounts of for-
mylated by-products result from a haloform cleavage of
chloral stimulated by DCC.[9] They can be deformylated to
give the corresponding major products 15 and 17, respec-
tively, by treatment with methanolic triethylamine.
Scheme 5. Synthesis and epimerization of dibenzoyl-myo-inositol
(8)
The formation of the cyclitol derivatives 15, 17, 19, 20
and 24Ϫ27 is consistent with the well investigated single
epimerizations of cyclic cis-trans-triols (pyranosides) in
carbohydrate chemistry.[9,10] Here, the middle chiral carbon
atom of an original cis-trans-triol unit is selectively inverted
(Schemes 4 and 5). In contrast, the doubly inverted prod-
ucts 16, 18, 21 and 28 are the results of a tandem mecha-
nism outlined in Scheme 6 (see also Vowinkel and Gleichen-
hagen’s isourea experiments[21]).
Scheme 4. Unconventional epimerization of the cyclitols 5, 6 and
7; i ϭ chloral, DCC, CH2Cl2, reflux; ii ϭ MeOH, Et3N, reflux;
iii ϭ acetic acid anhydride, pyridine, room temp.
In the case of 1-O-benzoyl-2-O-methyl-(Ϫ)-chiro-inositol
(7; Scheme 4) and 3,4-di-O-benzoyl-myo-inositol (8;
Scheme 5), the triethylamine procedure was not used, be-
cause in this case the deformylation was accompanied by
debenzoylation. The product mixture formed from com-
pound 7 thus contained the singly inverted major product
19 (38%), its formyl derivative 20 (2%) and the doubly in-
verted compound 21 (13%) with a (ϩ)-chiro-configuration
(Scheme 4).
Starting material 8 (prepared from 23[20]) surprisingly
gave five products after treatment with chloral/DCC; four
are singly inverted derivatives with chiro configurations
(24Ϫ27) and the fifth is the doubly inverted derivative 28
with muco configuration (Scheme 5). The range of products
is the result of a benzoyl group migration. Heating of the
product mixture 24Ϫ27 at reflux with methanolic triethyl-
Scheme 6. Tandem mechanism of the double inversion proposed
in ref.[10]
An useful side feature of the novel double epimerization
amine solution allowed simultaneous complete deformyl- reaction is a novel route to aminoinositol derivatives. The
ation and debenzoylation of the compounds, so that the ratio of single inversion products to the doubly inverted
chiro derivative 29 was obtained exclusively (Scheme 5).
products indicates that electron-withdrawing groups sup-
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Competition between Non-Classical Single and Double Epimerizations in Cyclitol Chemistry
FULL PAPER
press the tandem course with two inversions. In other
words, the lower the electron-withdrawing effect of the sub-
stituents adjacent to the tetrol unit, the higher is the per-
centage of the corresponding doubly inverted product
(Table 2).
Methods for stepwise deprotection of chloral/DCC epi-
merization products are already described in various ex-
amples in carbohydrate chemistry[9] and for the inositol de-
rivatives 2 and 4 in ref..[10] At present, we are investigating
one-pot procedures for complete deprotection of the epi-
merization products. The results will be reported in a sepa-
rate paper.
Figure 3. X-ray analysis of 3-O-acetyl-1-O-benzoyl-6-O-cyclohexyl-
carbamoyl-2-O-methyl-4,5-O-(2,2,2-trichloroethylidene)-muco-
inositol (22)
Structural Analysis of the Epimerization Products
The structures of the new products are supported by their
NMR spectroscopic data and by X-ray analyses. Thus, a
crystal of starting material 5 was investigated by X-ray dif-
1
fraction. The compound adopts a C4 chair conformation
with an equatorial arrangement of the methoxy group at C-
atom 2 (Figure 1). The length of the carbonϪfluorine bond
is 140.88 pm.
Moreover, 1-O-cyclohexylcarbamoyl-2,3-O-(2,2,2-tri-
chloroethylidene)-5-O-(methyl)cyclohexane-1,2,3,4,5-pentol
(17) crystallized from methanol to give monoclinic crystals,
which were also analysed by X-ray diffraction (Figure 2).
Furthermore, the structures of muco derivative 22 and chiro
product 24 could be confirmed in the same way (Figure 3
and 4). In the case of 24, suitable crystals were only ob-
tained by crystallization from 2-propanol, this solvent being
incorporated into the crystal lattice.
Figure 4. X-ray analysis of 2,3-di-O-benzoyl-1-O-cyclohexylcarba-
moyl-5,6-O-(2,2,2-trichloroethylidene)-(ϩ/-)-chiro-inositol
crystallized with a 2-propanol molecule
(24)
1
The assignment of signals in the H and 13C NMR spec-
tra was performed by recording of DEPT and two-dimen-
1
sional H,1H and 13C,1H correlation spectra (comparative
13C NMR spectroscopic data see ref.[22]). Key signals at-
tributable with confidence to a definite position were found
out from typical correlations (e.g., coupling of a ring proton
with fluorine, correlation of a ring proton over three bonds
to the proton signal of OMe, correlation of a ring proton to
the carbonyl function of a benzoyl group, or to the CONH
function of a carbamoyl group). On this basis the assign-
ment of signals for the other ring atoms became possible.
The atomic configurations of adjacent ring protons were
assigned with the assistance of the Karplus relationship.[23]
All spectra of the epimerized compounds show the charac-
teristic signals of a carbamoyl group and of a trichloroethy-
lidene group.
Figure 2. X-ray analysis of (1R,2R,3R,4S,5R)-1-O-cyclohexyl-
carbamoyl-2,3-O-(2,2,2-trichloroethylidene)-5-O-(methyl)cyclo-
hexane-1,2,3,4,5-pentol (17)
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R. Miethchen, K. Neitzel, K. Weise, M. Michalik, H. Reinke, F. Faltin
FULL PAPER
with Bruker AC 250 (250.13 and 62.9 MHz, respectively), ARX
300 (300.13 and 75.5 MHz, respectively), and AVANCE 500
(500.13 and 125.8 MHz, respectively) spectrometers. Calibration of
spectra was carried out with the aid of the solvent peaks (CDCl3:
1H: δ ϭ 7.25 ppm, 13C: δ ϭ 77.0 ppm. CD3OD: 1H: δ ϭ 3.30 ppm,
The latter is characterized by the singlet of the acetal pro-
ton (δ ഠ 5.38Ϫ5.94) and by the C signals of the acetal moi-
ety (δCCl3 ഠ 98.5Ϫ101.7 ppm; δCH ഠ 106.0Ϫ108.7 ppm).
For the doubly inverted compounds 16, 18, 21 and 28, the
signal for the N-substituted ring C-atom is shifted to signifi-
cantly higher field than the other ring-C-atom signals.
The puckering parameters[24] for the six-membered rings
of 5, 17, 22 and 24 are listed in Table 1. CCDC-222987
and -222989 to -222991 contain the supplementary crystal-
1
13C: δ ϭ 49.0 ppm; (CD3)2CO: H: δ ϭ 2.04 ppm, 13C: δ ϭ 29.8
ppm). 19F NMR spectra were recorded at 235.2 MHz (AC 250
spectrometer, δ19F values referenced to CFCl3). Optical rotations
were measured with a Polar Lµ P instrument (IBZ Meßtechnik).
´
Infrared spectra were recorded with a Protege Nicolet 460 IR spec-
lographic data for this paper. These data can be obtained trometer (Nujol). Column chromatography: E. Merck Silica Gel 60
(40Ϫ63 µ m); thin-layer chromatography (TLC): E. Merck Silica
Gel 60 F254 foils.
free of charge via www.ccdc.cam.ac.uk/conts/retriev-
ing.html (or from the CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK; Fax: (internat.) ϩ44 1223 336033; E-mail:
deposit@ccdc.cam.ac.uk).
For the X-ray structure determination of 17 and 22, a Bruker P4
˚
four-circle diffractometer with Mo-Kα radiation (λ ϭ 0.71073 A)
and a graphite monochromator was used. The results for 5 were
obtained on a SMART Apex with CCDC area detector and Mo-
Kα radiation, while compound 24 was investigated both with a
Bruker P4 and with a STOE IPDS, also with Mo-Kα radiation.
The structures were solved by direct methods (Bruker SHELXTL,
1990, Bruker Analytical X-ray Inst. Inc. for 5, 22, 24, SHELXS-
86[25] for 17). The refinement was carried out in all cases by the
full-matrix, least-squares method of Bruker SHELXTL, Vers.5.10,
Copyright 1997, Bruker Analytical X-ray Systems. All non-hydro-
gen atoms were refined anisotropically. For compound 5 the hydro-
gens of the OH groups were found from the difference map and
refined while allowing the groups to rotate about the CϪO bond.
For compound 24 the hydrogen of the OH group of the solvent
molecule could be found in the difference map. The refinement was
carried out as above. All other hydrogens were placed in theoretical
positions and refined by use of the riding model.
Table 1. Puckering parameters of the compounds 5, 17, 22 and 24
Compound
5
17
22
24
Puckering Amplitude 0.626(1)
0.520(8) 0.555(4)
158.1(9) 153.7(4)
0.556(2)
21.6(2)
˚
(Q)/A
Θ /°
ϕ /°
3.9(1)
193.3(14) 119(2)
177.1(10) 107.6(7)
Table 2. Yield ratio of singly to doubly epimerized products with
dependence on the starting material
Starting material
1
6
7
5
Molar ratio of the mono-to-
the-double inverted products
2.7
3.1
9.0
15.0
(1S,2S,3R,4S,5S,6S)-1-Fluoro-2-O-(methyl)cyclohexane-2,3,4,5,6-
pentol (5): A suspension of -quebrachitol (9, 2.5 g, 12.87 mmol) in
dry CH2Cl2 (25 mL) was cooled to Ϫ30 °C with stirring under an
argon atmosphere. Subsequently, DAST (5 mL, 38.15 mmol) was
added in portions, and stirring was continued for 4 h at room temp.
(TLC monitoring). After renewed cooling of the mixture to Ϫ30
°C, methanol (10Ϫ15 mL) was carefully added dropwise, and the
dark solution was heated with charcoal. After filtration through
kieselgur (diatomit, purchased from Riedel-de Hae¨n) and washing
of the filter cake with methanol, the combined organic phases were
Conclusions
(1) Cyclitols containing four contiguous hydroxy groups
with a cis/trans/trans sequence can be effectively epimerized
by an unconventional acetalization procedure with chloral/
DCC but without the need for protecting group chemistry. concentrated under reduced pressure and the residue was purified
by column chromatography (5: Rf ϭ 0.41; CHCl3/MeOH, 4:1 v/v).
Colourless crystals of 5 (1.36 g, 54%) were isolated, m.p. 176Ϫ177
°C (methanol). [α]2D4 ϭ Ϫ1.5 (c ϭ 1.10, MeOH). 1H NMR
(250 MHz, CD3OD, D2O): δ ϭ 4.47 (ddd, 2JF,1 ϭ 47.8, 3J1,2 ϭ 9.7,
One obtains two defined key products: a singly epimerized
cyclitol acetal and an aminocyclitol derivative with two epi-
merized stereogenic ring C-atoms.
(2) The results of the three-component reactions reported
in this paper allow the conclusion that electron-withdrawing
moieties adjacent to the cis/trans/trans tetrol unit suppress
the less favoured double epimerization reaction. This effect
is reflected in comparisons of the molar ratios of singly in-
verted to doubly inverted products (Table 2).
3
3
3J1,6 ϭ 2.9 Hz, 1 H, H-1), 4.21 (m, JF,6 ϭ 9.0, J5,6 ϭ 2.7 Hz, 1
3
H, H-6), 3.62Ϫ3.54 (m, J4,5 ϭ 9.9 Hz, 2 H, H-4, H-2), 3.58 (s, 3
3
4
H, OCH3), 3.44 (ddd, J5,6 ϭ 2.7, JF,5 ϭ 1.4 Hz, 1 H, H-5), 3.29
3
(m, J2,3
ϭ
3J3,4 ϭ 9.5 Hz, 1 H, H-3) ppm. 13C{1H} NMR
1
(62.9 MHz, CD3OD, D2O): δ ϭ 93.3 (d, JC,F ϭ 182.1 Hz, C-1),
82.1 (d, JC,F ϭ 17.6 Hz, C-2), 73.9 (d, 3JC,F ϭ 13.4 Hz, C-3), 73.4
2
4
2
(3) The results are not only of outstanding interest in (d, JC,F ϭ 16.9 Hz, C-4), 71.5 (d, JC,F ϭ 11.0 Hz, C-6), 71.1 (d,
3JC,F ϭ 1.9 Hz, C-5), 60.9 (s, OCH3) ppm. 19F{1H} NMR
terms of the substances isolated, but also for the assumed
tandem mechanism.
(235 MHz, CD3OD, D2O): δ ϭ Ϫ196.9 (s) ppm. X-ray structure
see Figure 1. C8H16FO5 (196.18): calcd. C 42.86, H 6.68; found C
42.61, H 6.73.
Experimental Section
(1R,2R,3S,4R,5R)-1-O-(Methyl)cyclohexane-1,2,3,4,5-pentol (6)
General Remarks: Melting points were obtained with a Leitz polar-
(1R,2S,3S,4R,5S,6S)-2,3:4,5-Di-O-cyclohexylidene-1-iodo-6-O-
(methyl)cyclohexane-2,3,4,5,6-pentol (11) and (3S,4R,5R,6R)-
izing microscope (Laborlux 12 Pol) equipped with a hot stage
(Mettler FP 90). 1H NMR and 13C NMR spectra were recorded 3,4:5,6-di-O-cyclohexylidene-2-O-(methyl)cyclohex-1-en-2,3,4,5,6-
2014
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Competition between Non-Classical Single and Double Epimerizations in Cyclitol Chemistry
FULL PAPER
pentol (12): Iodine (9.1 g, 35.8 mmol), triphenylphosphane (10 g,
38.1 mmol) and imidazole (4.0 g, 58.7 mmol) were added (under solution of cyclitol 13 (3.6 g, 10.64 mmol) in 80% aq. TFA (35 mL)
argon) to a solution of -3,4:5,6-di-O-cyclohexylidene-2-O-methyl- was stirred overnight at room temp. The workup procedure was
chiro-inositol[16,17] (7.28 g, 20.6 mmol) in dry toluene (400 mL). analogous to that used for 5. After column chromatographic separ-
(1R,2R,3S,4R,5R)-1-O-(Methyl)cyclohexane-1,2,3,4,5-pentol (6): A
After it had been heated at reflux for 3 h, the mixture was cooled
down. The excess of iodine was reduced by treatment with aq.
NaHCO3 solution and aq. Na2S2O3 solution. The organic phase
was then separated, and the aqueous phase was washed with tolu-
ene. Finally, the combined organic phases were washed with satu-
rated NaCl solution, dried over Na2SO4 and concentrated under
reduced pressure. The residue was column chromatographically
purified [eluent gradient: 1 L of heptane Ǟ heptane/EtOAc, 20:1
v/v (2 L)]. The major product (11, 7.45 g, 78%, (Rf ϭ 0.62, toluene/
EtOAc, 8:1 v/v) and the by-product (12, 695 mg, 10%, Rf ϭ 0.44
toluene/EtOAc, 8:1 v/v) were isolated. 11: M.p. 125Ϫ126 °C.
ation (CHCl3/MeOH, 10:1 v/v), the colourless crystalline product
6 (1.65 g, 87%) was isolated, m.p. 145Ϫ146 °C (MeOH). [α]2D2
ϭ
1
Ϫ67.2 (c ϭ 0.46, MeOH), Rf ϭ 0.31 (CHCl3/MeOH, 5:1 v/v). H
3
NMR (250 MHz, CD3OD, D2O): δ ϭ 4.01 (ddd, J5,6eq
ϭ
5.0 Hz,3J4,5 ϭ 3.0, J5,6eq ϭ 2.5 Hz, 1 H, H-5), 3.59 ("t", J2,3
ϭ
3
3
3J3,4 ϭ 9.3 Hz, 1 H, H-3), 3.44 (ddd, J1,2 ϭ 9.3, J1,6eq ϭ 4.4 Hz,
3
3
3
1 H, H-1), 3.42 (s, 3 H, OCH3), 3.38 (dd, J3,4 ϭ 9.3 Hz, 1 H, H-
4), 3.27 ("t", 1 H, H-2), 2.24 (m, J6ax,6eq ϭ 13.8 Hz, 1 H, H-6eq),
2
1.32 (m, 3J1,6ax ϭ 11.5, 3J5,6ax ϭ 2.5 Hz, 1 H, H-6ax) ppm. 13C{1H}
NMR (62.9 MHz, CD3OD, D2O): δ ϭ 79.5 (C-1), 77.8 (C-2), 75.3
(C-4), 74.3 (C-3), 69.5 (C-5), 57.8 (OCH3), 33.2 (C-6) ppm.
C7H14O5 (178.18): calcd. C 47.19, H 7.92; found C 47.49, H 8.29.
[α]2D3 ϭ ϩ36.6 (c ϭ 1.17, CHCl3). 12: M.p. 152Ϫ153 °C. [α]2D3
Ϫ25.25 (c ϭ 1.19, CHCl3).
ϭ
1-O-Benzoyl-2-O-methyl-(؊)-chiro-inositol (7)
Compound 11: 1H NMR (250 MHz, CDCl3): δ ϭ 4.31 ("t", 1 H,
3
3
1-O-Benzoyl-3,4:5,6-di-O-cyclohexylidene-2-O-methyl-(؊)-chiro-
inositol (14): Benzoyl chloride (4.17 mL, 36.0 mmol) was added
dropwise at 0 °C over 15 min to a stirred solution of 3,4:5,6-di-O-
cyclohexylidene-2-O-methyl-(Ϫ)-chiro-inositol (10,[16,17] 8.50 g,
24.0 mmol) in pyridine (15 mL) and CH2Cl2 (15 mL). Stirring was
continued at room temp. for 2 h (TLC monitoring). After filtration
and washing of the precipitate with CH2Cl2, the combined filtrates
were subsequently washed with water (60 mL), diluted aq. sulfuric
acid (20 mL), satd. aq. NaHCO3 solution (50 mL) and 5% aq.
NaHSO4 solution (40 mL). The solution was then dried (Na2SO4)
and concentrated under reduced pressure. The residue was purified
by column chromatography (Rf ϭ 0.44, toluene/EtOAc, 20:1 v/v)
and the colourless syrup of 14 (10.48 g, 95%) was deketalized with-
out further purification.
H-2), 4.19 (dd, J2,3 ϭ 5.0, J3,4 ϭ 9.0 Hz, 1 H, H-3), 3.97 (dd,
3J1,2 ϭ 4.8, J1,6 ϭ 9.0 Hz, 1 H, H-1), 3.76 (dd, J4,5 ϭ 10.1 Hz, 1
H, H-4), 3.72 ("t", J5,6 ϭ 9.2 Hz, 1 H, H-6), 3.60 (s, 3 H, OCH3),
3
3
3
3.20 (dd, 1 H, H-5), 1.78Ϫ1.30 (m, 20 H, cyclohexylidene CH2)
ppm. 13C{1H} NMR (62.9 MHz, CDCl3): δ ϭ 112.4, 110.1 (2 C,
cyclohexylidene Cq), 82.9 (C-6), 78.9 (C-4), 78.1 (C-5), 77.6 (C-2),
75.3 (C-3), 59.3 (OCH3), 25.3 (C-1), 38.0, 36.4, 36.3, 34.9, 24.9 (2
ϫ), 23.9, 23.7, 23.6 (2 ϫ) (10 C, cyclohexylidene CH2) ppm.
C19H29IO5 (464.34): calcd. C 49.15, H 6.30; found C 49.33, H 6.35.
Compound 12: 1H NMR (250 MHz, CDCl3): δ ϭ 4.88 (ddd, 3J5,6 ϭ
3
4
7.0, J1,6 ϭ 3.5, J ϭ 1.0 Hz, 1 H, H-6), 4.63 (dd, J1,3 ϭ 2.0 Hz, 1
H, H-1), 4.32 (dd, 3J4,5 ϭ 9.8 Hz, 1 H, H-5), 4.09 (ddd, 3J3,4 ϭ 9.0,
J ϭ 1.0 Hz, 1 H, H-3), 3.62 ("t", 1 H, H-4), 3.65 (s, 3 H, OCH3),
1.75Ϫ1.28 (m, 20 H, cyclohexylidene CH2) ppm. 13C{1H} NMR
(62.9 MHz, CDCl3): δ ϭ 156.2 (C-2), 114.2, 111.0 (2 C, cyclohexyl-
idene Cq), 90.4 (C-1), 80.6 (C-4), 74.6 (C-5), 74.4 (C-6), 72.9 (C-3),
55.4 (OCH3) 37.5, 36.4, 35.9, 34.5, 25.1, 24.9, 23.9, 23.6, 23.5, 23.4
(10 C, cyclohexylidene CH2) ppm. C19H28O5 (336.42): calcd. C
67.83, H 8.39; found C 67.77, H 8.61.
1-O-Benzoyl-2-O-methyl-(؊)-chiro-inositol (7): A solution of com-
pound 14 (13.6 g, 29.7 mmol) in 80% aq. TFA (90 mL) was stirred
overnight at room temp. The workup procedure was analogous to
that used for 5. After column chromatographic separation of 7
(Rf ϭ 0.28, CHCl3/MeOH, 6:1 v/v), the crystalline product 7
(6.66 g, 75%) was isolated, m.p. 143Ϫ144 °C (EtOAc), Rf ϭ 0.31,
CHCl3/MeOH, 5:1 v/v, [α]2D4 ϭ ϩ50.1 (c ϭ 1.01, MeOH). 1H
NMR (300 MHz, CD3OD): δ ϭ 7.99 (m, 2 H, o-Ph), 7.61 (m, 1 H,
(1R,2R,3R,4S,5R)-1,2:3,4-Di-O-cyclohexylidene-5-O-(methyl)cyclo-
hexane-1,2,3,4,5-pentol (13): A solution of 11 (3.69 g, 10.94 mmol),
Bu3SnH (3.5 mL, 13.12 mmol) and AIBN (179.6 mg, 1.094 mmol)
in dry toluene (70 mL) was heated at reflux for about 3 h under
argon. After completion of the reaction (TLC monitoring, toluene/
EtOAc, 8:1 v/v), the mixture was cooled down, satd. aq. KF solu-
tion was added, and the mixture was vigorously stirred for 30 min.
The precipitate (Bu3SnF) was removed by filtration and washed
with toluene. The organic phase was separated, and washed with
water (twice, 10 mL) and satd. aq. NaCl solution (10 mL). After
concentration of the dried (Na2SO4) solution under reduced press-
3
3
p-Ph), 7.48 (m, 2 H, m-Ph), 5.64 (dd, J1,2 ϭ 3.1, J1,6 ϭ 4.1 Hz, 1
H, H-1), 4.01 (dd, 3J1,6 ϭ 4.1, 3J5,6 ϭ 2.4 Hz, 1 H, H-6), 3.75Ϫ3.63
3
3
(m, 3 H, H-3, H-4, H-5), 3.56 (dd, J1,2 ϭ 3.1, J2,3 ϭ 10.0 Hz, 1
H, H-2), 3.43 (s, 3 H, OMe) ppm. 13C{1H} NMR (75.5 MHz,
CD3OD): δ ϭ 166.7 (COC6H5), 134.5 (p-Ph), 131.1 (i-Ph), 130.6
(o-Ph), 129.7 (m-Ph), 80.9 (C-2), 74.5, 74.3, 72.8 (C-3, C-4, C-5),
71.0 (C-1), 70.9 (C-6), 58.3 (OCH3) ppm. C14H18O7 (298.28): calcd.
C 56.37, H 6.08; found C 56.23, H 6.10.
ure and flash chromatographic purification (Rf ϭ 0.36 (toluene/ 3,4-Di-O-benzoyl-myo-inositol (8): A solution of 3,4-di-O-benzoyl-
EtOAc, 8:1 v/v), compound 13 (3.63 g, 98%) was isolated as a
1,2:5,6-di-O-isopropylidene-myo-inositol (23,[20] 1.0 g, 2.1 mmol) in
80% aq. TFA (20 mL) was stirred at room temp. overnight. The
colourless syrup; [α]2D3 ϭ Ϫ45.2 (c ϭ 0.92, CHCl3). 1H NMR
(250 MHz, CDCl3): δ ϭ 4.38 (ddd, 1 H, H-1), 4.18 (dd, 3J1,2 ϭ 5.8, workup procedure was analogous to that used for 5. After column
3
3J2,3 ϭ 8.5 Hz, 1 H, H-2), 3.64 (ddd, 1 H, H-5), 3.54 (dd, J2,3
ϭ
chromatographic separation (toluene/EtOAc/EtOH, 5:2:1 v/v/v) the
3
8.5 Hz, 1 H, H-3), 3.45 (s, 3 H, OCH3), 3.33 (dd, J3,4 ϭ 10.1, colourless crystalline product 8 (0.60 g, 72%) was isolated, m.p.
3J4,5 ϭ 8.8 Hz, 1 H, H-4), 2.40 (ddd, 2J6eq,6ax ϭ 15.2, 3J5,6eq ϭ 6.0,
101Ϫ103 °C (iPrOH), Rf ϭ 0.33 (toluene/EtOAc/EtOH, 4:2:1 v/v/
v); for the 1H NMR spectroscopic data see also ref..[26] The crystals
of inositol 8 obtained by crystallization from iPrOH contain one
equivalent of the solvent. 1H NMR (300 MHz, CD3OD): δ ϭ
3J1,6eq ϭ 4.0 Hz, 1 H, H-6eq), 1.68 (ddd, J5,6ax ϭ 7.8, J1,6ax
ϭ
3
3
5.2 Hz, 1 H, H-6ax) 1.65Ϫ1.30 (m, 20 H, cyclohexylidene CH2)
ppm. 13C{1H} NMR (62.9 MHz, CDCl3): δ ϭ 112.0, 110.0 (2 C,
cyclohexylidene Cq), 79.4 (C-3), 79.4 (C-4), 76.9 (C-2), 76.6 (C-5), 7.96Ϫ7.91 (m, 4 H, o-Ph), 7.53Ϫ7.46 (m, 2 H, p-Ph), 7.39Ϫ7.32
3
73.6 (C-1), 57.3 (OCH3), 32.2 (C-6) 38.0, 36.5, 36.4, 34.8, 25.0 (2
ϫ), 23.9, 23.7, 23.6, 23.5 (10 C, cyclohexylidene CH2) ppm.
(m, 4 H, m-Ph), 5.82 (dd, J4,5 ϭ 9.5 Hz, 1 H, H-4), 5.19 (dd,
3J3,4 ϭ 10.4, 3J2,3 ϭ 2.4 Hz, 1 H, H-3), 4.29 (dd, 3J1,2 ϭ 2.8, 3J2,3 ϭ
C19H30O5 (338.44): calcd. C 67.43, H 8.93; found C 66.92, H 8.63. 2.4 Hz, 1 H, H-2), 3.92 (sept, 1 H, CH-iPrOH), 3.85 (dd, J1,6
3
ϭ
Eur. J. Org. Chem. 2004, 2010Ϫ2018
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2015

R. Miethchen, K. Neitzel, K. Weise, M. Michalik, H. Reinke, F. Faltin
FULL PAPER
9.8, 3J5,6 ϭ 9.5 Hz, 1 H, H-6), 3.67 (d, 3J ϭ 9.5 Hz, 1 H, H-5), 3.61 Compound 16: 1H NMR (250 MHz, CDCl3): δ ϭ 5.55 (br. dd,
3
3
(dd, J1,2 ϭ 2.8, J1,6 ϭ 9.8 Hz, 1 H, H-1), 1.15 (d, J ϭ 6.1 Hz, 6
3JF,2 ϭ 22.5, 3J2,3 ϭ 7.0 Hz, 1 H, H-2), 5.38 (s, 1 H, CHCCl3), 5.21
H, CH3-iPrOH) ppm. 13C{1H} NMR (75.5 MHz, CD3OD): δ ϭ (br., 1 H, H-4), 5.09 (br. d, JF,1 ϭ 49.0 Hz, 1 H, H-1), 4.78 (br., 1
167.8 (COC6H5), 167.4 (COC6H5), 134.4 (p-Ph), 134.2 (p-Ph),
131.4 (i-Ph), 130.9 (i-Ph), 130.8 (o-Ph), 130.6 (o-Ph), 129.4 (2 ϫ) 7.5 Hz, 1 H, NH), 3.87 (br. m, 1 H, H-6), 3.67Ϫ3.56 (br. m, 2 H,
(2C, m-Ph), 74.7 (C-3), 74.5 (C-4), 74.4 (C-6), 74.3 (C-1), 73.0 (C- H-3, cyclohexyl CHNH), 3.52 (s, 3 H, OCH3), 3.47 (m, 1 H, cyclo-
2
H, H-5), 4.55 (d, 3JNH,CH ϭ 7.5 Hz, 1 H, NH), 4.22 (d, 3JNH,CH ϭ
5), 71.7 (C-2), 64.8 (CH-iPrOH), 25.3 (CH3-iPrOH) ppm. hexyl CHNH), 3.14 (m, 1 H, cyclohexyl CHN), 2.00Ϫ1.00 (m, 30
C23H28O9 (448.46): calcd. C 61.60, H 6.29; found C 61.44, H 6.30.
H, cyclohexyl CH2) ppm. 13C{1H} NMR (62.9 MHz, CDCl3): δ ϭ
156.4 (NHCON), 154.1 (NHCOO), 105.9 (CHCCl3), 99.6 (CCl3),
89.4 (d, 1JC,F ϭ 182 Hz, C-1), 79.8 (2 C, C-4, C-5), 76.8 (d, 2JC,F ϭ
(1R,2S,3R,4R,5S,6S)-2-O-Cyclohexylcarbamoyl-1-fluoro-6-O-
methyl-3,4-O-(2,2,2-trichloroethylidene)cyclohexane-2,3,4,5,6-pentol
(15) and (1R,2S,3R,4R,5S,6S)-2-O-Cyclohexylcarbamoyl-3-(N,NЈ-
dicyclohexylureido)-1-fluoro-6-O-methyl-4,5-O-(2,2,2-trichlorethyl-
idene)cyclohexane-2,4,5,6-tetrol (16): A suspension of the fluorocy-
clitol 5 (2.0 g, 10.20 mmol) and chloral (3.46 mL, 35.68 mmol) in
CH2Cl2 (80 mL) was stirred for 1Ϫ2 h at room temp. A solution
of DCC (6.31 g, 30.58 mmol) in CH2Cl2 (10 mL) was then added
and the mixture was heated at reflux for 8 h (under argon). After
the reaction mixture had been cooled to room temp. and sub-
sequent addition of CH2Cl2 (100 mL) and 10% aqueous AcOH
(150 mL), it was shaken for about 30 min to destroy excess DCC.
The precipitated N,NЈ-dicyclohexylurea was removed by filtration,
the organic phase was separated, and the aqueous phase was
washed with CHCl3 (3 ϫ 50 mL). The combined extracts were
washed with satd. aq. NaHCO3 solution (50 mL) and water (2 ϫ
40 mL), dried (Na2SO4) and concentrated under reduced pressure.
The crude product was treated with cold acetone (50 mL) to dis-
solve the cyclitol products; further crystalline N,NЈ-dicyclohexylu-
rea remains undissolved. The filtrate was concentrated and the resi-
due was dissolved in dry MeOH (15 mL) and triethylamine (1 mL).
The formylated by-products were selectively deformylated by heat-
ing of this solution at reflux for 15 min. After concentration of the
methanolic solution under reduced pressure and a second treat-
ment of the residue with cold acetone, a solution of the crude prod-
uct almost free of N,NЈ-dicyclohexylurea was obtained. Finally, the
products 15 and 16 were separated by column chromatography
(heptane/EtOAc, 3:1 v/v).
2
29.5 Hz, C-6), 69.6 (d, JC,F ϭ 16.3 Hz, C-2), 58.9 (OCH3), 57.5
3
(cyclohexyl CHN), 54.0 (d, JC,F ϭ 6.5 Hz, C-3), 49.9, 49.1 (2 C,
cyclohexyl CHNH), 33.9, 33.8, 33.4, 33.1, 32.3 (2 ϫ), 26.3 (2 ϫ),
25.7 (2 ϫ), 25.4, 25.0 (2 ϫ), 24.7 (2 ϫ) (15 C, cyclohexyl CH2)
ppm. 19F{1H} NMR (235 MHz, CDCl3): δ ϭ Ϫ206.6 (s) ppm. IR:
ν˜ ϭ 1722 cmϪ1 (CϭO, carbamoyl), 1645 cmϪ1 (CϭO, urea) 3326
and 3462 cmϪ1 (NϪH). C29H45Cl3FN3O6 (657.05): calcd. C 53.01,
H 6.90, N 6.40; found C 52.71, H 6.91, N 6.37.
(1R,2R,3R,4S,5R)-1-O-Cyclohexylcarbamoyl-2,3-O-(2,2,2-tri-
chloroethylidene)-5-O-(methyl)cyclohexane-1,2,3,4,5-pentol (17) and
(1R,2R,3R,4S,5R)-1-O-Cyclohexylcarbamoyl-2-(N,NЈ-dicyclo-
hexylureido)-5-O-methyl-3,4-O-(2,2,2-trichloroethylidene)cyclo-
hexane-1,2,4,5-tetrol (18): Compound 6 (1.1 g, 6.17 mmol), chloral
(2.1 mL, 21.61 mmol) and DCC (3.81 g, 18.51 mmol) were reacted
in CH2Cl2 (40 mL); the procedure is analogous to that used for 5.
After column chromatographic separation (eluent gradient: hep-
tane/EtOAc, 6:1 v/v, 2.0 L to 3:1 v/v, 1.0 L), of compound 17
(1.62 g, 61%) was isolated and crystallized from cyclohexane (yel-
lowish needles). After recrystallization from MeOH, m.p. 176Ϫ177
°C, Rf ϭ 0.36 (heptane/EtOAc, 1:1 v/v), [α]2D4 ϭ ϩ20.6 (CHCl3, c ϭ
1.06). The crystalline product 18 (750 mg, 19%) was also obtained,
m.p. 126Ϫ128 °C (cyclohexane), Rf ϭ 0.48 (heptane/EtOAc, 1:1 v/
v), [α]2D3 ϭ ϩ5.1 (CHCl3, c ϭ 0.67).
Compound 17: 1H NMR (500 MHz, CDCl3): δ ϭ 5.42 (s, 1 H,
3
CHCCl3), 5.29 (br. m, 1 H, H-1), 4.60 (d, JNH,CH ϭ 7.5 Hz, 1 H,
3
3
NH), 4.56Ϫ4.46 (m, 2 H, H-2, H-3), 3.60 (dd, J4,5 ϭ 9.0, J3,4
ϭ
6.4 Hz, 1 H, H-4), 3.46 (br. m, 1 H, cyclohexyl CH), 3.40 (s, 3 H,
Compound 15: Yield (826 mg, 18%), colourless needles m.p.
145Ϫ146 °C (cyclohexane), Rf ϭ 0.11 (heptane/EtOAc, 2:1 v/v).
[α]2D2 ϭ ϩ7.1 (c ϭ 0.53, CHCl3).
3
3
3
OCH3), 3.30 (ddd, J5,6ax ϭ 10.8, J4,5 ϭ 9.0, J5,6eq ϭ 3.8 Hz, 1
2
H, H-5), 2.91 (br., 1 H, OH), 2.19 (d"t", J6ax,6eq ϭ 14.2 Hz, 1 H,
H-6eq), 1.92 (br. m, 2 H, cyclohexyl CH2), 1.74Ϫ1.55 (m, 4 H, H-
6ax, cyclohexyl CH2), 1.39Ϫ1.04 (m, 5 H, cyclohexyl CH2) ppm
13C{1H} NMR (125.8 MHz, CDCl3): δ ϭ 153.8 (NHCOO), 106.3
(CHCCl3), 99.1 (CCl3), 82.0, 77.3 (C-2, C-3), 76.7 (C-5), 73.7 (C-
4) 67.9 (C-1), 57.1 (OCH3), 50.1 (cyclohexyl CH), 28.2 (C-6), 33.3
(2 ϫ), 25.4, 24.7 (2 ϫ) (5 C, cyclohexyl CH2) ppm. X-ray structure
see Figure 2. C16H24Cl3NO6 (432.73): calcd. C 44.41, H 5.59, N
3.24; found C 44.70, H 5.78, N 3.21.
Compound 16: Yield (80 mg (1.2%), foam-like solidified substance;
m.p. 236 °C, Rf ϭ 0.21 (heptane/EtOAc, 2:1 v/v), [α]2D3 ϭ ϩ1.9 (c ϭ
0.93, CHCl3).
Compound 15: 1H NMR (500 MHz, CDCl3): δ ϭ 5.39 (s, 1 H,
3
3
3
CHCCl3), 5.17 (ddd, JF,2 ϭ 21.8, J2,3 ϭ 6.0, J1,2 ϭ 2.8 Hz, 1 H,
2
3
3
H-2), 4.76 (ddd, JF,1 ϭ 48.2, J1,6 ϭ 5.0, J1,2 ϭ 2.8 Hz, 1 H, H-
1), 4.68 (m, 2 H, H-3, NH), 4.56 (ddd, J4,5 ϭ 8.5, J3,4 ϭ 6.6, Compound 18: 1H NMR (500 MHz, CDCl3): δ ϭ 5.40 (s, 1 H,
5JF,4 ϭ 1.3 Hz, 1 H, H-4), 3.67 ("t", 3J5,6 ϭ 8.5 Hz, 1 H, H-5), 3.48 CHCCl3), 5.27 (br., 1 H, H-1), 5.10 (br., 1 H, H-3), 4.61 (dd, J ϭ
(s, 3 H, OCH3), 3.40 (ddd, 2JF,6 ϭ 15.7, 3J5,6 ϭ 8.5, 3J1,6 ϭ 5.0 Hz, 5.5, J ϭ 4.0 Hz, 1 H, H-4), 4.52 (br., 1 H, NH), 4.34 (d, 3JNH,CH ϭ
3
3
1 H, H-6) 3.40 (m, 1 H, cyclohexyl CH), 2.78 (br., 1 H, OH), 1.88
(m, 2 H, cyclohexyl CH2), 1.64 (m, 2 H, cyclohexyl CH2), 1.53 (m,
1 H, cyclohexyl CH2), 1.27 (m, 2 H, cyclohexyl CH2), 1.09 (m, 3
6.0 Hz, 1 H, NH), 3.78 (br. m, 1 H, H-5), 3.63 (m, 1 H, cyclohexyl
CHNH), 3.48Ϫ3.39 (m, 2 H, cyclohexyl CHNH, H-2), 3.43 (s, 3
H, OCH3), 3.15 (m, 1 H, cyclohexyl CHN), 2.28 (m, 1 H, H-6),
H, cyclohexyl CH2) ppm. 13C{1H} NMR (75.5 MHz, CDCl3): δ ϭ 1.66 (m, 1 H, H-6), 1.85Ϫ0.96 (m, 30 H, cyclohexyl CH2) ppm.
1
153.8 (NHCOO), 107.3 (CHCCl3), 99.3 (CCl3), 90.6 (d, JC,F
ϭ
13C{1H} NMR (125.8 MHz, CDCl3): δ ϭ 156.8 (NHCON), 154.6
2
199.0 Hz, C-1), 81.0 (d, JC,F ϭ 23.0 Hz, C-6), 80.5 (C-4), 76.7 (d, (NHCOO), 106.4 (CHCCl3), 99.5 (CCl3), 79.6 (C-4), 79.2 (C-3),
3JC,F ϭ 7.0 Hz, C-3), 72.0 (d, 3JC,F ϭ 7.0 Hz, C-5), 69.8 (d, 2JC,F ϭ
75.0 (C-5), 68.4 (br., C-1), 58.4 (OCH3), 56.9 (cyclohexyl CHN),
18.0 Hz, C-2), 59.4 (OCH3), 50.3 (cyclohexyl CH), 33.2 (2 ϫ), 25.4, 56.7 (br., C-2), 49.7, 49.3 (2C, cyclohexyl CHNH), 30.3 (C-6),
24.7 (2 ϫ) (5 C, cyclohexyl CH2) ppm. 19F{1H} NMR (235 MHz,
CDCl3): δ ϭ Ϫ202.7 (s) ppm. IR: ν˜ ϭ 1721 cmϪ1 (CϭO, carba-
33.91, 33.87, 33.5, 33.3, 32.5, 32.4, 26.5 (2 ϫ), 25.8, 25.6, 25.4,
25.0 (2 ϫ), 24.8, 24.7 (15C, cyclohexyl CH2) ppm. C29H46Cl3N3O6
moyl), 3390 cmϪ1 (NϪH). C16H23Cl3FNO6 (450.71): calcd. C (639.06): calcd. C 54.50, H 7.26, N 6.58; found C 54.71, H 6.91,
42.64, H 5.14, N 3.11; found C 42.83, H 5.23, N 3.10.
N 6.37.
2016
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 2010Ϫ2018

Competition between Non-Classical Single and Double Epimerizations in Cyclitol Chemistry
FULL PAPER
3
1-O-Benzoyl-6-O-cyclohexylcarbamoyl-2-O-methyl-4,5-O-(2,2,2-
trichloroethylidene)-muco-inositol (19), 1-O-Benzoyl-6-O-cyclo-
6.27 (d, JNH,CH ϭ 8.2 Hz, 1 H, NH), 5.60Ϫ5.53 (m, 2 H, H-3, H-
3
3
6), 5.59 (s, 1 H, CHCCl3), 5.42 (dd, J1,2 ϭ 2.5, J1,6 ϭ 8.4 Hz, 1
3
hexylcarbamoyl-3-O-formyl-2-O-methyl-4,5-O-(2,2,2-trichloro- H, H-1), 4.80Ϫ4.71 (m, 2 H, H-4, H-5), 3.84 (dd, J1,2 ϭ 2.5,
ethylidene)-muco-inositol (20) and 2-O-Benzoyl-3-O-cyclohexyl-
carbamoyl-4-(N,NЈ-bis(cyclohexylureido)-4-deoxy-1-O-methyl-5,6-
O-(2,2,2-trichloroethylidene)-(؉)-chiro-inositol (21): Compound 7
3J2,3 ϭ 6.0 Hz, 1 H, H-2), 3.46 (s, 3 H, OCH3), 3.34 (br., 1 H,
cyclohexyl CH), 2.12 (s, 3 H, COCH3), 1.85Ϫ1.46 (m, 5 H, cyclo-
hexyl CH2), 1.38Ϫ0.90 (m, 5 H, cyclohexyl CH2) ppm. 13C{1H}
(2.26 g, 7.6 mmol), chloral (2.58 mL, 26.5 mmol) and DCC (3.91 g, NMR [75.5 MHz, (CD3)2CO]:
δ ϭ 169.5 (COMe), 165.6
18.9 mmol) were reacted in (CH2Cl)2 (80 mL); the procedure was (COC6H5), 154.7 (NHCOO), 134.0 (p-Ph), 130.3 (i-Ph), 130.2 (o-
analogous to that used for 5. After column chromatographic sepa-
ration (heptane/EtOAc, 2:1 v/v), the first fraction (Rf ϭ 0.33), be-
Ph), 129.1 (m-Ph), 106.6 (CHCCl3), 99.7 (CCl3), 79.6, 79.3 (C-4,
C-5), 77.8 (C-2), 70.3 (C-1), 68.2, 68.1 (C-3, C-6), 58.7 (OCH3),
sides formyl compound 20 (0.08 g, 2%), also contained small 50.7 (cyclohexyl CH), 33.3, 33.2, 25.8, 25.3, 25.2 (5C, cyclohexyl
amounts of the corresponding 3-O-acetyl derivative 22, and so for-
myl derivative 20 could not be obtained analytically pure. When
the syrupy fraction of 21 (Rf ϭ 0.23, 0.75 g, 13%) was allowed to
stand, an amorphous solid deposited. This was washed with pen-
CH2), 20.5 (COCH3) ppm. MS (70 eV): m/z ϭ 595 [M], 476 [M Ϫ
CCl3]. MS (FAB): m/z ϭ 618 [M ϩ Na]; X-ray structure see Fig-
ure 3. C25H30Cl3NO9 (594.87): calcd. C 50.48, H 5.08, N 2.35;
found C 50.80, H 5.11, N 2.21.
tane and recrystallized from EtOAc, m.p. 110Ϫ112 °C, [α]2D5
ϭ
2,3-Di-O-benzoyl-1-O-cyclohexylcarbamoyl-5,6-O-(2,2,2-trichloro-
ethylidene)-(؉/-)-chiro-inositol (24), 3,4-Di-O-benzoyl-1-O-cyclo-
hexylcarbamoyl-4-O-formyl-5,6-O-(2,2,2-trichloroethylidene)-(؉/-)-
chiro-inositol (25), 2,3-Di-O-benzoyl-1-O-cyclohexylcarbamoyl-5,6-
O-(2,2,2-trichloroethylidene)-(؉/-)-chiro-inositol (26), 3,4-Di-O-
benzoyl-1-O-cyclohexylcarbamoyl-2-O-formyl-5,6-O-(2,2,2-tri-
chloroethylidene)-(؉/-)-chiro-inositol (27) and 2,3-Di-O-benzoyl-1-
O-cyclohexylcarbamoyl-6-N,NЈ-bis(cyclohexylureido)-6-deoxy-5,6-
O-(2,2,2-trichloroethylidene)-muco-inositol (28): DCC (9.96 g,
48.1 mmol) was added with stirring to a suspension of 3,4-di-O-
benzoyl-myo-inositol (8, 7.49 g, 19.3 mmol) and chloral (6.59 mL,
67.7 mmol) in 1,2-dichloroethane (225 mL), and the mixture was
heated at reflux for 8 h (under argon ). The workup procedure was
analogous to that used for 15/16, except for the Et3N/MeOH treat-
ment for deformylation. Four UV-active spots were detected in the
primary crude product mixture. Column chromatographic sepa-
ration (heptane/EtOAc, 2:1 v/v) gave the two regioisomeric major
products 24 (2.88 g, 23%), m.p. 196 °C (iPrOH), Rf ϭ 0.31 and 25
(2.79 g, 23%), m.p. 175Ϫ176 °C (MeNO2), Rf ϭ 0.25 as well as a
mixture of the regioisomers 26 and 27 (1.08 g, 8%), Rf ϭ 0.38. The
pure crystalline component 26 (mp, 210Ϫ215 °C) was obtained by
fractional crystallization from iPrOH. The fourth spot (Rf ϭ 0.43)
corresponds to the doubly inverted cyclitol 28 (0.93 g, 6%), m.p.
146Ϫ148 °C (diethyl ether/petroleum ether).
ϩ42.8 (CHCl3, c ϭ 1.11). Compound 19 (Rf ϭ 0.17, 4.36 g, 38%)
was isolated as a foam-like amorphous solid, melting range 60Ϫ74
°C, [α]2D4 ϭ ϩ8.5 (CHCl3, c ϭ 1.04). The compound was quantitat-
ively converted into its 3-O-acetyl derivative 22 by treatment with
acetic acid anhydride/pyridine, giving crystals suitable for an X-ray
analysis; analytical data see below. A further by-product (0.64 g,
Rf ϭ 0.11) could not be identified.
Compound 19: 1H NMR [300 MHz, (CD3)2CO]: δ ϭ 8.07Ϫ8.03 (m,
2 H, o-Ph), 7.69Ϫ7.62 (m, 1 H, p-Ph), 7.55Ϫ7.48 (m, 2 H, m-Ph),
6.25 (d, 3JNH,CH ϭ 8.2 Hz, 1 H, NH), 5.57 (dd, 3J1,6 ϭ 8.5, 3J5,6
ϭ
3
2.8 Hz, 1 H, H-6), 5.56 (s, 1 H, CHCCl3), 5.46 (dd, J1,6 ϭ 8.5,
3J1,2 ϭ 2.8 Hz, 1 H, H-1), 4.93 (d, J ϭ 4.5 Hz, 1 H, OH), 4.73Ϫ4.68
(m, 2 H, H-4, H-5), 4.42 (m, 1 H, H-3), 3.76 (dd, 3J1,2 ϭ 2.8, 3J2,3 ϭ
5.2 Hz, 1 H, H-2), 3.45 (s, 3 H, OCH3), 3.31 (br., 1 H, cyclohexyl
CH), 1.82Ϫ1.46 (m, 5 H, cyclohexyl CH2), 1.40Ϫ0.90 (m, 5 H,
cyclohexyl CH2) ppm. 13C{1H} NMR [75.5 MHz, (CD3)2CO]: δ ϭ
166.0 (COC6H5), 155.3 (NHCOO), 134.1 (p-Ph), 130.8 (i-Ph), 130.5
(o-Ph), 129.4 (m-Ph), 106.9 (CHCCl3), 100.4 (CCl3), 82.1 (C-4),
80.9 (C-2), 80.2 (C-5), 70.8 (C-1), 69.2 (C-6), 67.5 (C-3), 59.0
(OCH3), 50.9 (cyclohexyl CH), 33.5 (2 ϫ), 26.2, 25.6 (2 ϫ) (5 C,
cyclohexyl CH2) ppm. C23H28Cl3NO8 (552.83): calcd. C 49.97, H
5.11, N 2.53; found C 50.50, H 5.57, N 2.58.
Compound 21: 1H NMR [500 MHz, (CD3)2CO]: δ ϭ 8.06 (m, 2 H,
o-Ph), 7.64 (m, 1 H, p-Ph), 7.51 (m, 2 H, m-Ph), 6.03 (br., 1 H, H-
Compound 24: 1H NMR [500 MHz, (CD3)2CO]: δ ϭ 7.97 (m, 2 H,
o-Ph), 7.89 (m, 2 H, o-Ph), 7.55 (m, 2 H, p-Ph), 7.45Ϫ7.38 (m, 4
3
3), 5.93 (d, 1 H, JNH,CH ϭ 7.8 Hz, NH), 5.68 (s, 1 H, CHCCl3),
3
3
5.66 (m, 1 H, H-5), 5.31 (dd, J1,2 ϭ 2.8, J2,3 ϭ 8.2 Hz, 1 H, H-
3
H, m-Ph), 6.74 (d, JNH,CH ϭ 7.8 Hz, 1 H, NH), 5.82 (s, 1 H,
3
3
2), 5.25 (d, JNH,CH ϭ 7.8 Hz, 1 H, NH), 4.76 (dd, J1,6 ϭ 3.8,
3J5,6 ϭ 5.5 Hz, 1 H, H-6), 4.09 (dd, 1 H, H-1), 3.58 (m, 1 H, cyclo-
hexyl CH), 3.49 (s, 3 H, OCH3), 3.49 (m, 1 H, cyclohexyl CH),
3.47 (m, 1 H, H-4), 3.28 (m, 1 H, cyclohexyl CH), 1.98Ϫ0.91 (m,
30 H, cyclohexyl CH2) ppm. 13C{1H} NMR [125.8 MHz,
3
CHCCl3), 5.71 ("t", J1,2
ϭ
3J1,6 ϭ 3.3 Hz, 1 H, H-1), 5.66 ("t",
3J2,3
ϭ ϭ
3J3,4 ϭ 9.7 Hz, 1 H, H-3), 5.54 (dd, J2,3 ϭ 9.7, J1,2
3
3
3.3 Hz, 1 H, H-2), 5.43 (d, JOH,H-4 ϭ 5.0 Hz, 1 H, OH), 4.75Ϫ4.72
(m, 2 H, H-5, H-6), 4.30 (m, 1 H, H-4), 3.88 (sept, 1 H, CH-
iPrOH), 3.27 (br., 1 H, cyclohexyl CH), 2.89 (br., 1 H, OH-iPrOH),
1.85Ϫ1.51 (m, 5 H, cyclohexyl CH2), 1.31Ϫ1.11 (m, 5 H, cyclo-
hexyl CH2), 1.09 (d, JCH,CH3 ϭ 6.0 Hz, 6 H, CH3-iPrOH) ppm.
13C{1H} NMR [75.5 MHz, (CD3)2CO]: δ ϭ 166.2 (COC6H5), 165.8
(COC6H5), 154.8 (NHCOO), 134.2 (p-Ph), 134.0 (p-Ph), 130.9 (i-
Ph), 130.3 (o-Ph, 4C), 130.3 (i-Ph), 129.2 (m-Ph, 4 C), 107.0
(CHCCl3), 100.2 (CCl3), 83.4 (C-5), 77.7 (C-6), 72.3 (C-3), 72.0 (C-
4), 71.0 (C-2), 68.0 (C-1), 63.7 (CH-iPrOH), 51.1 (cyclohexyl CH),
33.7, 33.5, 26.2 (3 C, cyclohexyl CH2), 25.7 (CH3-iPrOH), 25.6,
25.5 (2 C, cyclohexyl CH2) ppm. X-ray structure see Figure 4. 24
(crystallized with one equivalent of iPrOH) 24ϩ iPrOH:
C32H38Cl3NO10 (703.01): calcd. C 54.67, H 5.45, N 1.99; found C
55.09, H 5.85, N 1.72.
(CD3)2CO]:
δ ϭ 166.1 (COC6H5), 157.3 (NHCON), 155.2
(NHCOO), 134.1 (p-Ph), 130.9 (i-Ph), 130.6 (o-Ph), 129.4 (m-Ph),
107.1 (CHCCl3), 100.6 (CCl3), 79.2, 79.1 (C-5, C-6), 77.9 (C-1),
74.0 (C-2), 68.7 (C-3), 59.7 (OCH3), 58.3 (C-4), 57.0, 50.6, 50.1 (3
ϫ) (5 C, cyclohexyl CH), 34.3, 34.2, 33.8, 33.5, 33.4, 33.2, 27.2,
26.9, 26.6, 26.2 (3 ϫ), 26.1, 25.6 (2 ϫ) (15 C, cyclohexyl CH2) ppm.
C36H50Cl3N3O8 (759.16): calcd. C 56.96, H 6.64, N 5.54; found C
56.57, H 6.64, N 5.06.
3-O-Acetyl-1-O-benzoyl-6-O-cyclohexylcarbamoyl-2-O-methyl-4,5-
O-(2,2,2-trichloroethylidene)-muco-inositol (22): Colourless crystals,
m.p. 205Ϫ207 °C (iPrOH), [α]2D5 ϭ ϩ8.1 (CHCl3, c ϭ 1.10); yield
of 22 (95%) by acetylation of 19 with acetic acid anhydride/pyridine
at room temp.
Compound 25: 1H NMR [300 MHz, (CD3)2CO]: δ ϭ 7.97 (m, 4 H,
Compound 22: 1H NMR [300 MHz, (CD3)2CO]: δ ϭ 8.06Ϫ7.02 (m, o-Ph), 7.59 (m, 2 H, p-Ph), 7.45 (m, 4 H, m-Ph), 6.57 (d, 3JNH,CH ϭ
3
2 H, o-Ph), 7.69Ϫ7.62 (m, 1 H, p-Ph), 7.55Ϫ7.49 (m, 2 H, m-Ph),
8.0 Hz, 1 H, NH), 5.81 (s, 1 H, CHCCl3), 5.71 (dd, J4,5 ϭ 8.1,
Eur. J. Org. Chem. 2004, 2010Ϫ2018
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2017

R. Miethchen, K. Neitzel, K. Weise, M. Michalik, H. Reinke, F. Faltin
3J3,4 ϭ 9.0 Hz, 1 H, H-4), 5.56 (dd, J2,3 ϭ 7.7, J3,4 ϭ 9.0 Hz, 1 5, C-6), 75.6, 74.5, 73.3, 72.6 (C-1, C-2, C-3, C-4), 52.3 (cyclohexyl
FULL PAPER
3
3
3
3
H, H-3) 5.43 (dd, J1,2 ϭ 3.0, J1,6 ϭ 4.1 Hz, 1 H, H-1), 5.08 (dd, CH), 34.9 (2 ϫ), 27.5, 27.0 (2 ϫ) (5 C, cyclohexyl CH2) ppm.
3
3J5,6 ϭ 5.5, J4,5 ϭ 8.1 Hz, 1 H, H-5), 4.97 (d, J ϭ 6.0 Hz, 1 H,
C15H22Cl3NO7 (434.70): calcd. C 41.45, H 5.10, N 3.22; found C
41.26, H 5.10, N 3.10.
3
3
OH), 4.85 (dd, J1,6 ϭ 4.1, J5,6 ϭ 5.5 Hz, 1 H, H-6), 4.38 (m, 1
H, H-2), 3.41 (br., 1 H, cyclohexyl CH), 1.96Ϫ1.10 (m, 10 H, cyclo-
hexyl CH2) ppm. 13C{1H} NMR [75.5 MHz, (CD3)2CO]: δ ϭ 166.2
(COC6H5), 166.0 (COC6H5), 155.3 (NHCOO), 134.3 (p-Ph), 134.1
(p-Ph), 130.7 (i-Ph), 130.4 (o-Ph), 130.3 (o-Ph), 130.3 (i-Ph), 129.4
(m-Ph), 129.3 (m-Ph), 107.5 (CHCCl3), 100.1 (CCl3), 80.3 (C-5),
78.4 (C-6), 73.7 (C-3), 73.3 (C-4), 71.8 (C-1), 69.3 (C-2), 51.0
(cyclohexyl CH), 33.7 (2 ϫ), 26.2, 25.7 (2 ϫ) (5 C, cyclohexyl CH2)
ppm. MS (70 eV): m/z ϭ 643 [M]. C29H30Cl3NO9 (642.92): calcd.
C 54.18, H 4.70, N 2.18; found C 53.88, H 4.76, N 2.43.
[1]
T. Posternak, Les Cyclitols, Hermann, Paris, 1962; Engl. Ed.
Holden-Day, San Francisco, 1965.
[2]
T. Hudlicky, M. Cebulak, Cyclitols and Their Derivatives. A
Handbook of Physical, Spectral, and Synthetic Data, Wiley-
VCH Weinheim, New York, Cambridge, 1993.
Y. Takahashi, H. Nakayama, K. Katagiri, K. Ichikawa, N. Ito,
[3]
T. Takita, T. Takeuchi, T. Miyake, Tetrahedron Lett. 2001, 42,
1053Ϫ1056 and papers cited therein.
D. C. Billington, Chem. Soc. Rev. 1989, 18, 83Ϫ122.
D. C. Billington, The Inositol PhosphatesϪChemical Synthesis
[4]
1
Compound 26: H NMR [300 MHz, (CD3)2CO]: δ ϭ 8.30 (s, 1 H,
CHO), 7.95Ϫ7.88 (m, 4 H, o-Ph), 7.62Ϫ7.54 (m, 2 H, p-Ph),
7.48Ϫ7.38 (m, 4 H, m-Ph), 6.76 (d, JNH,CH ϭ 7.8 Hz, 1 H, NH),
[5]
3
and Biological Significance, Wiley-VCH Weinheim, 1993.
Y. Takahashi, H. Nakayama, K. Katagiri, K. Ichikawa, N. Ito,
[6]
5.94 (s, 1 H, CHCCl3), 5.86Ϫ5.62 (m, 4 H, H-1, H-2, H-3, H-4),
5.01, 4.85 (2 ϫ m, 2 H, H-5, H-6), 3.28 (br., 1 H, cyclohexyl CH),
1.90Ϫ1.50 (m, 5 H, cyclohexyl CH2), 1.34Ϫ1.13 (m, 5 H, cyclo-
hexyl CH2) ppm. 13C{1H} NMR [75.5 MHz, (CD3)2CO]: δ ϭ 165.8
(COC6H5), 165.6 (COC6H5), 161.0 (CHO), 154.6 (NHCOO), 134.4
(p-Ph), 134.3 (p-Ph), 130.4 (o-Ph), 130.4 (o-Ph), 130.1 (i-Ph), 130.0
(i-Ph), 129.4 (m-Ph), 129.3 (m-Ph), 107.3 (CHCCl3), 99.7 (CCl3),
80.4, 77.9 (C-5, C-6), 72.1, 70.9, 69.8, 67.8 (C-1, C-2, C-3, C-4),
51.1 (cyclohexyl CH), 33.7, 33.5, 26.2, 25.6, 25.5 (5 C, cyclohexyl
CH2) ppm. C30H30Cl3NO10 (670.93): calcd. C 53.71, H 4.51, N
2.09; found C 54.25, H 4.95, N 1.89.
T. Takita, T. Takeuchi, T. Miyake, Tetrahedron Lett. 2001, 42,
1053Ϫ1056 and papers cited therein.
[7]
S. J. Angyal, L. Odier, Carbohydr. Res. 1980, 80, 203Ϫ206.
[8a] IUPAC-IUB Commun. on Biochem. Nomencl., in Tentative
[8]
rules for cyclitol nomenclature, Biol. Chem. 1968, 243,
[8b]
5809Ϫ5819.
Nomenclature of Cyclitols, Recommendations
1973: S. J. Angyal, L. Anderson, R. S. Cahn, R. M. C. Dawson,
O. Hoffmann-Ostenhof, W. Klyne, T. Posternak, Pure Appl.
Chem. 1974, 37, 285Ϫ297.
[9]
R. Miethchen, J. Carbohydr. Chem. 2003, 22, 801Ϫ825 (re-
view).
[10]
[11]
Part 18: R. Miethchen, Chr. Sowa, M. Frank, M. Michalik, H.
Reinke, Carbohydr. Res. 2002, 337, 1Ϫ9.
R. Miethchen, C. Sowa, M. Michalik, Tetrahedron Lett. 2001,
42, 8637Ϫ8639.
1
Compound 28: H NMR (300 MHz, CDCl3): δ ϭ 8.06 (m, 2 H, o-
Ph), 7.91 (m, 2 H, o-Ph), 7.47 (m, 2 H, p-Ph), 7.40Ϫ7.28 (m, 4 H,
3
3
m-Ph), 5.99 (dd, J2,3 ϭ 9.0, J1,2 ϭ 3.5 Hz, 1 H, H-2), 5.82 (dd,
[12]
[13]
M. Frank, R. Miethchen, Carbohydr. Res. 1998, 313, 49Ϫ53.
M. Frank, R. Miethchen, H. Reinke, Eur. J. Org. Chem. 1999,
1259Ϫ1263.
3J2,3 ϭ 9.0, 3J3,4 ϭ 6.4 Hz, 1 H, H-3), 5.57 ("t", 3J1,6 ϭ 3.8, 3J1,2
ϭ
3
3.5 Hz, 1 H, H-1), 5.53 (s, 1 H, CHCCl3), 5.21 ("t", J3,4 ϭ 6.4,
3J4,5 ϭ 6.0 Hz, 1 H, H-4), 5.02 (dd, J4,5 ϭ 6.0, J5,6 ϭ 2.5 Hz, 1
[14] [14a]
3
3
G. I. Drummond, L. Anderson, J. Am. Chem. Soc. 1956,
H, H-5), 4.71 (d, 3JNH,CH ϭ 8.0 Hz, 1 H, NH), 4.28 (d, JNH,CH ϭ
3
[14b]
78, 1750Ϫ1753.
T. Naito, J. Antibiotics, Series B 1962, 15,
373Ϫ379. [14c] T. Suami, T. Machinami, Bull. Chem. Soc., Japan
8.0 Hz, 1 H, NH), 3.84 (br., 1 H, H-6), 3.63 (br. m, 1 H, cyclohexyl
CHNH), 3.30 (br. m, 1 H, cyclohexyl CHNH), 3.19 (br. m, 1 H,
cyclohexyl CHN), 2.14Ϫ0.90 (m, 30 H, cyclohexyl CH2) ppm.
13C{1H} NMR (75.5 MHz, CDCl3): δ ϭ 165.8 (COC6H5), 165.1
(COC6H5), 156.5 (NHCON), 154.2 (NHCOO), 133.1 (p-Ph), 132.9
(p-Ph), 130.0 (o-Ph), 129.7 (i-Ph), 129.6 (o-Ph), 129.5 (i-Ph), 128.3
(m-Ph), 128.2 (m-Ph), 106.0 (CHCCl3), 99.7 (CCl3), 82.3 (C-5), 80.4
(C-4), 72.2 (C-1), 70.9 (C-2), 69.3 (C-3), 57.8 (cyclohexyl CH), 55.5
(C-6), 49.9, 49.5 (2 C, cyclohexyl CH), 33.9, 33.8, 33.2 (2 ϫ), 32.0,
31.8, 26.2, 26.1, 25.7, 25.4, 25.2, 25.1, 25.0, 24.7, 24.6 (15 C, cyclo-
hexyl CH2) ppm. C42H52Cl3N3O9 (849.25): calcd. C 59.40, H 6.17,
N 4.95; found C 59.16, H 6.21, N 4.61.
[14d]
1970, 43, 2953Ϫ2956.
Biochem. Pharmacology 1979, 28, 1301Ϫ1306.
J. M. Heal, P. Fox, P. S. Schein,
[14e]
B. J. Paul,
J. Willis, T. A. Martinot, I. Ghiviriga, K. A. Abboud, T. Hud-
licky, J. Am. Chem. Soc. 2002, 124, 10416Ϫ10426.
A. P. Kozikowski, A. H. Fauq, J. M. Rusnak, Tetrahedron Lett.
1989, 30, 3365Ϫ3368.
S. J. Angyal, G. C. Irving, D. Rutherford, M. E. Tate, J. Chem.
Soc. 1965, 6662Ϫ6664.
S. D Gero, Tetrahedron Lett. 1966, 6, 591Ϫ595.
P. J. Garegg, B. Samuelsson, J. Chem. Soc., Perkin I 1980,
2866Ϫ2869.
S. C. Johnson, J. Dahl, T. L. Shih, D. J. A. Schedler, L. Ander-
son, T. L. Benjamin, D. C. Baker, J. Med. Chem. 1993, 36,
3628Ϫ3635.
[15]
[16]
[17]
[18]
[19]
1-O-Cyclohexylcarbamoyl-5,6-O-(2,2,2-trichloroethylidene)-(؉/-)-
chiro-inositol (29): Heating of compounds 24Ϫ27 (0.15 mmol) at
reflux in methanol (10 mL) and Et3N (1.0 mL, 7.2 mmol) for 30
min exclusively gave the same compound 29. The syrupy crude
product crystallized from CHCl3 (yield 90%), m.p. 186Ϫ188 °C. 1H
NMR (250 MHz, CD3OD): δ ϭ 5.53 (s, 1 H, CHCCl3), 5.20 ("t",
[20]
[21]
S. M. Khersonsky, Y.-T. Chang, Carbohydr. Res. 2002, 337,
75Ϫ78.
E. Vowinkel, P. Gleichenhagen, Tetrahedron Lett. 1974,
139Ϫ142.
S. J. Angyal, L. Odier, Carbohydr. Res. 1982, 100, 43Ϫ54.
M. Karplus, J. Chem. Phys. 1959, 30, 11Ϫ15.
D. Cremer, J. A. Pople, J. Am. Chem. Soc. 1975, 97,
1354Ϫ1358.
[22]
[23]
[24]
3J1,2
ϭ
3J1,6 ϭ 2.8 Hz, 1 H, H-1), 4.60 (dd, 1 H, H-4), 4.49 (dd,
3J2,3 ϭ 7.0, 3J3,4 ϭ 6.2 Hz, 1 H, H-3), 3.76 (dd, 3J1,2 ϭ 2.8, 3J2,3
ϭ
7.0 Hz, 1 H, H-2), 3.64Ϫ3.52 (m, 2 H, H-5, H-6), 3.36 (br., 1 H,
cyclohexyl CH), 1.91Ϫ1.60 (m, 5 H, cyclohexyl CH2), 1.41Ϫ1.14
(m, 5 H, cyclohexyl CH2) ppm. 13C NMR (62.9 MHz, CD3OD):
δ ϭ 157.8 (NHCOO), 108.7 (CHCCl3), 101.7 (CCl3), 84.3, 79.4 (C-
[25]
[26]
G. M. Sheldrick, University of Göttingen, 1986.
S. K. Chung, Y. T. Chang, J. Chem. Soc., Chem. Commun.
1995, 11Ϫ13.
Received October 30, 2003
2018
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2004, 2010Ϫ2018