Unexpected formation of a D-chiro inositol from a L-chiro precursor

Article abstract of DOI:10.1016/S0040-4039(01)01899-8

In a one-step procedure, L-1-O-benzyl-2-O-methyl-chiro-inositol (1) was acetalized to the L-muco-inositol derivatives 2, 3 and D-2-O-benzyl-3-O-cyclohexylcarbamoyl-4-(N,N′-dicyclohexylureido)-4- deoxy-1-O-methyl-5,6-O-trichloroethylidene-chiro-inositol (4

Full text of DOI:10.1016/S0040-4039(01)01899-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 8637–8639
Unexpected formation of a
D
-chiro inositol from a
L
-chiro precursor
Ralf Miethchen,a,* Christian Sowaa and Manfred Michalikb
aUniversity of Rostock, Department of Organic Chemistry, Albert-Einstein-Strasse 3A, 18051 Rostock, Germany
bInstitute for Organic Catalysis Research at the University of Rostock, Buchbinderstrasse 5/6, D-18055 Rostock, Germany
Received 9 July 2001; revised 8 October 2001; accepted 9 October 2001
Abstract—In a one-step procedure,
3 and -2-O-benzyl-3-O-cyclohexylcarbamoyl-4-(N,N%-dicyclohexylureido)-4-deoxy-1-O-methyl-5,6-O-trichloroethylidene-chiro-
inositol (4). -1-O-Benzyl-6-O-cyclohexylcarbamoyl-3-O-formyl-2-O-methyl-4,5-O-trichloroethylidene-muco-inositol (3) was
quantitatively deformylated to -1-O-benzyl-6-O-cyclohexylcarbamoyl-2-O-methyl-4,5-O-trichloroethylidene-muco-inositol (2) by
boiling methanolic triethylamine. © 2001 Elsevier Science Ltd. All rights reserved.
L-1-O-benzyl-2-O-methyl-chiro-inositol (1) was acetalized to the L-muco-inositol derivatives 2,
D
L
L
The separation of inositol derivatives from natural
sources is limited to a few representatives, so that
various compounds of this type were prepared by
chemical methods.1–4 Some of the nine stereoisomeric
inositols are only available in limited amounts, e.g.
myo-inositol) failed; however, the tetrahydroxy deriva-
tive (1S,2S,3S,4R,5R)-1-O-methylcyclohexane-1,2,3,4,
5-pentol could be epimerized.6
Surprising results were just found starting with L-1-O-
L
-muco and
D
-chiro inositols. In 1994, a new epimeriza-
benzyl-2-O-methyl-chiro-inositol (1).7–10 Refluxing of 1
in 1,2-dichloroethane with chloral/DCC for about 8 h
tion method was reported for carbohydrates which used
the reagent combination of chloral/DCC.5 First
attempts to apply this method to inositols containing
yielded three products, the crystalline
derivatives 2 (25%) and 3 (16%) and
derivative 4 (15%); Scheme 1. The latter is easily soluble
L
-muco-inositol
D-chiro-inositol
five or six unprotected OH-groups (
L
-quebrachitol or
Scheme 1.
* Corresponding author. Fax: +49 381 498 6412; e-mail: ralf.miethchen@chemie.uni-rostock.de
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01899-8

8638
R. Miethchen et al. / Tetrahedron Letters 42 (2001) 8637–8639
Scheme 2.
1
compared to the other ring-C-atom signals. In the H
spectrum of 4 recorded at room temperature some
signals were displayed as broad signals which were
sharpened at higher temperature indicating a dynamic
process due to the flexibility of the molecule.15
in light petroleum and numerous other organic sol-
vents; however, it did not crystallize.11
Compound 3 is the 3-O-formyl derivative of L-muco-
inositol derivative 2. Boiling methanolic triethylamine
allows a selective removal of formyl groups. By this
procedure, compound 3 was quantitatively converted
into 2 within 15 min (Scheme 1). The formation of 2
and 3 from 1 is in conformity with the mechanism of
epimerizations described for cis–trans triol units of
pyranoses.5,6,12 That means, species A shown in Scheme
2 is the key intermediate; the configuration at the
middle carbon atom (C-5) of the cis–trans triol unit
(C-4/5/6) of 1 is inverted. As a consequence of imi-
docarbonate opening, the carbamoyl group must be
located in the 6-position of the muco-derivatives 2 and
3.
Acknowledgements
The authors are very grateful to Professor Stephen J.
Angyal (Sydney) for interesting suggestions and discus-
sions and for a gift of
L-quebrachitol and to Dr.
Michael Frank for important experimental pre-investi-
gations. The Deutsche Forschungsgemeinschaft and the
Fonds der Chemischen Industrie promoted our research
by financial support.
The formation of the inositol derivative 4 came as a
surprise. Related to 1 the configuration at two C-atoms
(C-4 and C-5) was inverted. We assume that compound
4 results from a reaction sequence via the key interme-
diate B which is formed from A (addition of 4-OH to
DCC after hemiacetal displacement to 3-OH). Interme-
diate B allows a Tandem-sequence as marked by arrows
in Scheme 2; the postulated CꢀN-bond formation is
supported by results of Vowinkel and Gleichenhagen.13
References
1. Posternak, T. Les Cyclitols; Hermann: Paris, 1962;
English ed.; Holden-Day: San Francisco, 1965.
2. Hudlicky, T.; Cebulak, M. Cyclitols and Their Deriva-
tives. A Handbook of Physical, Spectral and Synthetic
Data; VCH Weinheim: New York, Cambridge, 1993.
3. Angyal, S. J.; Odier, L. Carbohydr. Res. 1980, 80, 203–
206.
4. Takahashi, Y.; Nakayama, H.; Katagiri, K.; Ichikawa,
K.; Ito, N.; Takita, T.; Takeuchi, T.; Miyake, T. Tetra-
hedron Lett. 2001, 42, 1053–1056.
The configuration of 4 corresponds to a D-chiro-inositol
derivative (compare formulas of 4 in Scheme 1). There-
fore, the numbering of 4 was adapted corresponding to
the rules.14
5. Miethchen, R.; Rentsch, D. Liebigs Ann. Chem. 1994,
1191–1197.
6. Frank, M.; Miethchen, R.; Reinke, H. Eur. J. Org. Chem.
The structures of the compounds 2–4 are supported by
NMR measurements; selected data of 2 and 4 see Ref.
1999, 1259–1263 and references cited therein.
1
15. The assignment of signals in the H and 13C NMR
7. Compound
MeOH) was synthesized from
3,4:5,6-di-O-cyclohexylidene-2-O-methyl-chiro-inositol
1
(mp 153–154°C; [h]2D4=−54.2 (c=1.0,
spectra was performed by recording DEPT and two-
dimensional 1H, 1H and 13C, 1H correlation spectra.
Thus, the signals for C-1 and C-2 could be confirmed
by the correlation over three bonds to the proton
signals OBn and OMe, respectively. On this basis the
assignment of signals for the other ring atoms became
possible. All spectra show the characteristic signals of a
carbamoyl group and a trichloroethylidene group. The
latter is characterized by the singlet of the acetal proton
(2: l=5.39, 3: l=5.46, 4: l=5.45) and by the C signals
(lCCl398.9–99.7; lCH105.9–107.2) of the acetal moiety.
The formyl group of 3 is characterized by the 1H
doublet l=8.14, J=1.0 Hz and the 13C-signal l=
160.2. For compound 4, the signal for C-4 is signifi-
cantly shifted to higher field due to the N-substituent
L
-quebrachitol via L-
and
L-1-O-benzyl-3,4:5,6-di-O-cyclohexylidene-2-O-
methyl-chiro-inositol using well-known procedures.8,9
Deacetalization was carried out with aqueous trifl-
uoroacetic acid analogously to Ref. 10.
8. Angyal, S. J.; Irving, G. C.; Rutherford, D.; Tate, M. E.
J. Chem. Soc. 1965, 6662–6664.
9. Gero, S. D. Tetrahedron Lett. 1966, 6, 591–595.
10. Bath, S.; Billington, D. C.; Gero, S. D.; Quiclet-Sire, B.;
Samadi, M. J. Chem. Soc., Chem. Commun. 1994, 12,
1495–1496.
11. A mixture of 1 (10 mmol), DCC (25 mmol) and chloral
(35 mmol) in 1,2-dichloroethane (100 ml) was refluxed for
8 h. After addition of CH2Cl2 (150 ml) and 10% aq.

R. Miethchen et al. / Tetrahedron Letters 42 (2001) 8637–8639
8639
AcOH (200 ml), the mixture was shaken to destroy excess
DCC. Precipitated urea was removed, the organic phase
was concentrated and the crude product was treated with
50 ml of acetone (further urea remains). After concentra-
tion of the filtrate 2 (Rf=0.11), 3 (Rf=0.40) and 4
(Rf=0.28) were isolated by column chromatography
(heptane/EtOAc 2:1 v/v). The syrupy product 2 (25%)
crystallized from heptane; mp 124–124.5°C, [h]2D9=−13
CH
6
-CCl3), 4.79 and 4.59 (d, J~12.0 Hz, CH2
6
-Ph), 4.67 (d,
1H, JNH,CH~8.0 Hz, NH), 4.58 (dd, 1H, H-5), 4.54 (dd,
1H, J3,4~J4,5~6.3 Hz, H-4), 4.16 (dd, 1H, J2,3~9.8 Hz,
J3,4~6.3 Hz, H-3), 3.93 (ddd, 1H, J1,6~3.7 Hz, J1,2~2.6 Hz,
4J1,5~1.0 Hz, H-1), 3.30 (s, 3H, OMe), 3.22 (dd, 1H,
J2,3~9.8 Hz, J1,2~2.6 Hz, H-2), 2.88 (br, 1H, OH), 2.00–
1.05 (m, 10H, cyclohexyl-CH2); 13C NMR (75.5 MHz,
CDCl3): l=153.5 (C(O)NH), 105.9 (C
(CCl3), 81.7 (C-4), 78.9 (C-2), 77.8 (C-5), 72.4 (C-1), 71.8
6 H-CCl3), 99.2
(c=1.34, CHCl3);
3 (16%) crystallized from light
petroleum/diethyl ether (2:1 v/v) mp 142–143°C, [h]2D9=
−8 (c=1.37, CHCl3) and the syrupy product 4 (15%) gave
only an amorphous solid after concentration of its light
petroleum solution under reduced pressure (melting range
85–90°C), [h]2D2= +7 (c=1.07, CHCl3).
(C6 H2-Ph), 68.6 (C-3), 67.0 (C-6), 57.5 (OMe).
Compound 4 1H NMR (300.13 MHz, CDCl3, 55°C)
l=5.30 (dd, 1H, J3,4~8.2 Hz, J2,3~3.5 Hz, H-3), 5.45 (s,
1H, CH
H-5), 4.80 and 4.71 (d, J~12.0 Hz, CH
1H, J1,6~5.5 Hz, J5,6~6.7 Hz, H-6), (d, 1H, J~12.0 Hz,
CH2-Ph), 4.89 (br, 1H, H-4), 4.54 (d, 1H, J~7.5 Hz, NH),
6
-CCl3), 5.14 (dd, 1H, J5,6~6.7 Hz, J4,5~9.8 Hz,
6
2-Ph), 4.79 (dd,
12. Miethchen, R.; Rentsch, D.; Frank, M. J. Carbohydr.
Chem. 1996, 15, 15–31.
13. Vowinkel, E.; Gleichenhagen, P. Tetrahedron Lett. 1974,
139–142.
6
4.41 (d, 1H, J~7.5 Hz, NH), 3.79 (dd, 1H, J2,3~3.5 Hz,
J1,2~2.0 Hz, H-2), 3.70 (dd, 1H, J1,6~5.5 Hz, J1,2~2.0 Hz,
H-1), 3.44 (s, 3H, OMe); 13C NMR (75.5 MHz, CDCl3)
14. Angyal, S. J.; Anderson, L.; Cahn, R. S.; Dawson, R. M.
C.; Hoffmann-Ostenhof, O.; Klyne, W.; Posternak, T.,
Nomenclature of Cyclitols, Recommendations 1973, Pure
Appl. Chem. 37, 1974, 285–297.
l=156.7 (NHC(O)N), 154.4 (NHC(O)O), 107.2 (C6 H-
CCl3), 99.7 (CCl3), 80.3 (C-6), 78.8 (C-1), 77.6 (C-2), 76.9
(C-5), 72.1 (CH2-Ph), 70.7 (C-3), 58.0 (OMe), 56.3 (C-4);
IR (Nujol): 1631 cm−1 (CꢁO, urea moiety), 1722 cm−1
(CꢁO, carbamoyl moiety), 3330 cm−1, 3381 cm−1 (NH).
15. Compound 2: 1H NMR (300.13 MHz, CDCl3): l=5.52
(dd, 1H, J1,6~3.7 Hz, J5,6~2.0 Hz, H-6), 5.39 (s, 1H,