Non-anomeric sugar isoureas

Article abstract of DOI:10.1081/CAR-120013497

Six non-anomeric isourea derivatives of D-fructose (7, 8), D-glucose (9, 10), 6-deoxy-L-altrose (11) and L-rhamnose (12) were synthesized from the precursors 1-6 by a CuCl-catalyzed addition of a non-glycosidic OH-group to DCC and DIPC, respectively. Subs

Full text of DOI:10.1081/CAR-120013497

This article was downloaded by: [Moskow State Univ Bibliote]
On: 12 December 2013, At: 21:59
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House,
37-41 Mortimer Street, London W1T 3JH, UK
Journal of Carbohydrate Chemistry
Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/lcar20
NON-ANOMERIC SUGAR ISOUREAS
Christian Sowa a , Ralf Miethchen b & Helmut Reinke a
a Universität Rostock , Fachbereich Chemie, Albert-Einstein-Strasse 3a, Rostock, D-18051,
Germany
b Universität Rostock , Fachbereich Chemie, Albert-Einstein-Strasse 3a, Rostock, D-18051,
Germany
Published online: 16 Aug 2006.
To cite this article: Christian Sowa , Ralf Miethchen & Helmut Reinke (2002) NON-ANOMERIC SUGAR ISOUREAS, Journal of
Carbohydrate Chemistry, 21:4, 293-303, DOI: 10.1081/CAR-120013497
To link to this article: http://dx.doi.org/10.1081/CAR-120013497
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained
in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the
Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and
are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and
should be independently verified with primary sources of information. Taylor and Francis shall not be liable for
any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever
or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of
the Content.
This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any
form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://
www.tandfonline.com/page/terms-and-conditions

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2002 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
JOURNAL OF CARBOHYDRATE CHEMISTRY
Vol. 21, No. 4, pp. 293–303, 2002
NON-ANOMERIC SUGAR ISOUREAS
*
Christian Sowa, Ralf Miethchen, and Helmut Reinke
Universita¨t Rostock, Fachbereich Chemie, Albert-Einstein-Strasse 3a,
D-18051, Rostock, Germany
ABSTRACT
Six non-anomeric isourea derivatives of D-fructose (7, 8), D-glucose (9, 10),
6-deoxy-L-altrose (11) and L-rhamnose (12) were synthesized from the
precursors 1–6 by a CuCl-catalyzed addition of a non-glycosidic OH-group
to DCC and DIPC, respectively. Subsequently, the isoureido group of phenyl
2,3,4-tri-O-benzyl-6-O-(N,N’-dicyclohexylisoureido)-b-D-glucopyranoside
(10) was replaced by an azido and a thioacetyl group, respectively, yielding
the corresponding 6-deoxy-6-azido-D-glucopyranoside (13) and 6-deoxy-6-
thioacetyl-D-glucopyranoside (14) in moderate to good yields.
INTRODUCTION
Hydroxyl groups can be activated for nucleophilic substitutions via isourea
derivatives as leaving groups and various methods have been reported in the literature
for the synthesis of O-alkyl and O-acyl-isoureas.[1–5] Aliphatic isourea derivatives are
assumed to be suitable intermediates in epimerisation reactions.[6] The well known
peptide coupling procedure employing dicyclohexylcarbodiimide (DCC) runs via an O-
acylisourea[5] which is formed by addition of carboxylic acid to DCC. The acidity of
alcohols is not strong enough for addition to DCC and requires catalysis. Vowinkel and
Gleichenhagen[1] catalysed an addition of cyclohexanediols to DCC by CuCl and
described reactions of the isoureas formed with proton acidic reagents like carboxylic
acids, phenols or thiols. Mechanistic studies have shown that the nucleophilic reaction
*
Corresponding author. E-mail: ralf.miethchen@chemie.uni-rostock.de
293
DOI: 10.1081/CAR-120013497
0732-8303 (Print); 1532-2327 (Online)
www.dekker.com
Copyright D 2002 by Marcel Dekker, Inc.

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2002 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
294
SOWA, MIETHCHEN, AND REINKE
at the isourea moiety usually follows an SN2 mechanism;[2] for comparisons with the
Mitsunobu procedure see Refs. [2,3].
We are interested in sugar-isoureas in context with investigations of the reaction
sequence of a non-conventional epimerisation reaction using the chloral/DCC reagent
system.[6] Isourea moieties connected to non-anomeric positions of sugars were not
described as far as we know. However, Tsutsumi et al.[7,8] described some reactions via
1-O-isourea sugar derivatives, i.e., reactions with phenols and thiophenols to furnish
glycosides and thioglycosides, respectively. Horvat et al.[9] reported syntheses of
glycopeptides and a (1 ! 6)-disaccharide via anomeric isourea sugars as glycosyl
donors. Neither research group isolated these key intermediates.
RESULTS AND DISCUSSION
The non-glycosidic sugar isoureas 7–12 were prepared from the monosaccharides
1–6 and carbodiimides in the presence of catalytic amounts of anhydrous copper-(I)-
chloride; Scheme 1. The method of CuCl-catalyzed introduction of isourea moieties
using carbodiimide is based on a communication of Vowinkel and Gleichenhagen.[1]
The authors describe corresponding reactions with cyclohexane-1,2-diols.
The experimental procedure, described for the fructose derivative 7, is universally
applicable for isourea preparations. However, different reaction temperatures (20, 50
and 90°C, respectively) proved to be of advantage for other starting materials. Methyl
2,3-di-O-(N,N’-diisopropylisoureido)-a-L-rhamnopyranoside (12), generated from
methyl a-L-rhamnopyranoside (6) and diisopropylcarbodiimide (DIPC) was only ob-
tained in low yield, because the three unprotected OH-groups of the starting material
allowed the formation of further isourea derivatives. Compound 12 and the
monoisourea derivatives 7–11 were easily soluble in all common organic solvents.
Only the D-fructose derivative 7 and L-rhamnose derivative 12 could be crystallized.
Whereas compound 12 crystallized from heptane, compound 7 did not crystallize from
any concd soln. It became solid after removal of the solvent and showed a melting
point at 109–110°C.
The chromatographic detection and separation of the isoureas is difficult, be-
cause the basicity of this group causes tailing. The latter can be suppressed by addition
of triethylamine, however, the separation effect is reduced. Therefore, a high conver-
sion was the stated objective. Furthermore, it is noteworthy, that the isourea deriva-
tives already show lower Rf-values than the corresponding precursors with the free
OH-group.
To obtain information about the reactivity of non-glycosidic isoureido groups
model experiments were first carried out. The isoureido group of 10 was replaced by
treatment with sodium azide or thioacetic acid, yielding the azide 13 (95%) and the
thioacetic ester 14 (32%), respectively, Scheme 2. An isourea group connected to a
secondary C-atom was less reactive compared to the 6-O-isoureido sugar 10.[10a]
In connection with mechanistic studies of a non-conventional epimerisation
reaction using the chloral/DCC reagent,[6] the reactivities of 1,2-O-isopropylidene-3-O-
(N,N’-dicyclohexylisoureido)-b-D-fructopyranose and 1,2-O-isopropylidene-4-O-(N,N’-
dicyclohexylisoureido)-b-D-fructopyranose to chloral were compared.[10a] 1,2-O-Iso-
propylidene-4-O-(N,N’-dicyclohexylisoureido)-b-D-fructopyranose was prepared by

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2002 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
NON-ANOMERIC SUGAR ISOUREAS
295
OBn
O
O
O
O
O
HO
BnO
O
OPh
O
OH
OBn
OBz
O
HO
O
BzO
3
2
1
i
(50 °C)
i
i
(90 °C)
(50 °C)
O
O
O
NHC6H11
O
O
OBn
OBz
C6H11N
O
O
O
O
BnO
NHC6H11
O
C
BzO
C
OPh
O
NHC6H11
OBn
O
NC6H11
C6H11
N
8 (45 %)
9 (80 %)
7 (86 %)
OCH3
OH
O
Cl3C
H
O
CH3
HO
OCH3
O
BnO
BnO
OPh
O
H3C
O
HO
OBn
OH
4
OH
5
(50 °C)
6
i
i
i
(20 °C)
(90 °C)
OCH3
Cl3C
H
H11C6HN
O
OCH3
O
NC6H11
CH3
HO
O
H3C
O
O
O
BnO
BnO
O
OPh
O
O
NHC6H11
NC6H11
OBn
C
C
N
HN
N
NH
10 (77 %)
11 (91 %)
12 (22 %)
Scheme 1. i = DCC, DMF, CuCl, 24 h.
debenzoylation of 8 with 2% methanolic sodium methoxide (1 h, rt). The separated
crude product was dissolved in 1,2-dichloroethane and treated with anhydrous chloral
for 6 h under reflux yielding 1,2-O-isopropylidene-5-O-cyclohexylcarbamoyl-3,4-O-
trichloroethylidene-b-D-tagatopyranose (15)[11] (48%) and the cyclic carbonic acid ester
derivative 16 (20%); Scheme 3. The regioisomeric 1,2-O-isopropylidene-3-O-(N,N’-
O
N3
S
CH3
O
BnO
BnO
O
BnO
BnO
i
ii
OPh
OPh
10
OBn
32 %
95 %
OBn
13
14
Scheme 2. i = NaN3, p-TsOH, DMF, 110°C, 19 h; ii = CH3COSH, toluene, 110°C, 19 h.

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2002 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
296
SOWA, MIETHCHEN, AND REINKE
Cl3C
O
H
O
O
O
O
O
O
O
O
O
i
ii
8
+
OH
O
OH
O
N
O
HO
O
NHC6H11
O
C
NHC6H11
C6H11
O
O
16 (20 %)
15 (48 %)
Scheme 3. i = NaOMe/MeOH, rt, 1 h; ii = Cl3C–CH = O, 1,2-DCE, reflux, 6 h.
dicyclohexylisoureido)-b-D-fructopyranose, analogously treated with chloral, did not
generate any trichloroethylidene derivative.[10a,b]
The formation of 15 from 1,2-O-isopropylidene-4-O-(N,N’-dicyclohexyl-isour-
eido)-b-D-fructopyranose supports our hypothesis[6] that isoureas are intermediates in
non-conventional epimerisations with the chloral/DCC reagent. However, the different
reaction course of the two regioisomeric starting materials confirms also that the reaction
of the isourea only progresses via a cyclic imidocarbonic ester to a cyclic acetal[6] when
the isourea group is neighbour to a cis-arranged OH-group. 1,2-O-Isopropylidene-3-O-
(N,N’-dicyclohexylisoureido)-b-D-fructopyranose does not meet this prerequisite.
1
The structures of the compounds 7–14 are supported by their H and 13C NMR
spectra. The 13C NMR signal (N–C(N)–O) of an isourea moiety is found between
148 and 150 ppm. Furthermore, a strong IR-band between 1667 and 1674 cm À 1 is
characteristic for this group. The crystals of 12 were suitable for an X-ray analysis,
Figure 1. A single crystal of 12 was tested by a rotational photograph on a Bruker P4
Figure 1. X-ray structure of methyl 2,3-di-O-(N,N’-diisopropylisoureido)-a-L-rhamnopyrano-
side (12).

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2002 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
NON-ANOMERIC SUGAR ISOUREAS
297
four circle diffractometer equipped with a Mo–Ka sealed tube and a graphite
monochromator. The reduced cell was found by the automatic cell determination
routine of the Bruker SHELXTL software. The data collection was performed in
routine o-scan and the structure was solved by direct methods (Bruker SHELXTL)
and refined by the full-matrix least-squares methods of SHELXL-97 (G. M. Sheldrick,
Universita¨t Go¨ttingen, 1997). All non-hydrogen atoms were refined anisotropically
while the hydrogens were put into theoretical positions and refined according to the
riding model. There is a disorder phenomenon in both O-(N,N’-diisopropylisoureido)
moieties. Each one of the two isopropyl groups takes different positions. Of course
one can observe hydrogen bonding in the solid due to the different donating and
accepting functionalities. Beside an intramolecular hydrogen bridge O(5)–HÁÁÁN(4)
˚
with an O–N distance of 2.741 A, there are infinite chains of molecules along the
crystallographic a-axis via intermolecular H-bridges between N(2)–H and O(5) of the
˚
next molecule with an N–O distance of 3.296 A. Thus, the O(5)–H group is both a
donating and accepting site.
The puckering parameters[12] of 12 (puckering amplitude Q =0.518 A, magnitude
˚
of the distortion y= 174.5°, j-value 253°) indicate an almost undisturbed 1C4 chair
conformation of the pyranose ring.
Further details of the data collection: Diffractometer: Bruker P4; radiation:
˚
l =0.71073 A (Mo–Ka) with graphite monochromator; crystal size: 0.6 Â 0.34 Â 0.28
mm3; formula: C21H42N4O5; formula weight: 430.59; temperature 293 (2) K; crystal
˚
system: monoclinic; space group: P21; unit cell dimensions: a=9.5130 (10) A,
3
˚
˚
˚
b =14.147 (2) A, c = 9.965 (2) A; b =95.510 (10)°; volume: 1334.9 (4) A ; Z= 2;
density (calcd): 1.071 Mg/m3; absorption coefficient: 0.076 mm À 1; F(000): 472; Y
range for data collection: 2.05 to 22.00°; index ranges: À 10 ꢀ hꢀ 10, À 14 ꢀ kꢀ 14,
À 10 ꢀ l ꢀ 10; reflections collected: 3655; independent reflections: 3269 [R(int) =
0.0212], 2754 reflections with I > 2s(I), completeness to Y = 22.00°, 100%; data/re-
straints/parameters: 3269/1/320; goodness-of-fit on F2: 1.044; final R indices [I > 2s(I)]:
R1 =0.0498, wR2 = 0.1284; R indices (all data): R1 =0.0606, wR2 =0.1391; absolute
structure parameter: À 0.1 (17); largest diff. peak/ hole: 0.113/ À 0.137 e.A À 3. The
˚
weighting scheme was calculated according to wÀ 1 =s2 (Fo ) +(0.0716P)2 + 0.0601P
2
with P =(Fo2 +2Fc )/3.
2
Full crystallographic details, excluding structure factors, have been deposited with
the Cambridge Crystallographic Data Centre as supplementary publication no. CCDC-
175568 These data may be obtained, on request, from the CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK. Tel.: + 44-1223-336408, fax: + 44-1223-336033, E-mail:
deposit@ccdc.cam.ac.uk.
CONCLUSION
In this paper, we have shown that isourea groups can be easily introduced into
any one non-glycosidic position of carbohydrates with carbodiimides catalysed by
CuCl. The isourea moieties are potential leaving groups.
Moreover, it could be confirmed that isoureas are intermediates in non-con-
ventional acetalation/epimerisation reactions with the chloral/carbodiimide reagent as
reported in Ref. [6]; Scheme 4. Whereas 1,2-O-isopropylidene-4-O-(N,N’-dicyclohex-

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2002 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
298
SOWA, MIETHCHEN, AND REINKE
CCl3
CH
OH
CCl3
CH
O
H
O
O
O
Chloral
DCC
HO
OH
OH
NR
OH
NHR
O
O
RNH
RNH
-
(
RNH2 )
CCl3
CH
O
CCl3
CH
OH
O
O
O
H
Cl3C
O
O
O
O
NHR
O
O
N
O
N
R
H
R
Scheme 4. Mechanism of the non-conventional epimerisation of carbohydrates and inositols
reported in Ref. [6].
ylisoureido)-b-D-fructopyranose yielded 5-O-cyclohexylcarbamoyl-1,2-O-isopropyli-
dene-3,4-O-trichloroethylidene-b-D-tagatopyranose (15)[11] on heating with chloral
(Scheme 3), the regioisomeric 1,2-O-isopropylidene-3-O-(N,N’-dicyclohexylisoureido)-
b-D-fructopyranose did not form a chloral acetal. It follows from this also that one of
the OH-groups neighboured to the isoureido moiety has to be cis-arranged allowing the
subsequent formation of the cyclic imidocarbonic ester intermediate as postulated in
previous papers, e.g. Ref. [6,13].
EXPERIMENTAL
General procedures. Melting points were obtained on a polarizing microscope
Leitz (Laborlux 12 Pol) equipped with a hot stage (Mettler FP 90). 1H NMR and 13C NMR
spectra were recorded on a Bruker AC-250 spectrometer (300.13 and 75.5 MHz,
respectively). Calibration of spectra was carried out by means of solvent peaks. (CDCl3:
1
1
d H =7.25; d 13C= 77.0; CD3OD: d H =3.30; d 13C =49.0). Optical rotations were
measured on a Polar LmP (IBZ Mebtechnik). Infrared spectra were recorded on a Protege´
Nicolet 460 IR-spectrometer (Nujol). Column chromatography: E. Merck Silica Gel 60
(40–63 mm); thin-layer chromatography (TLC): E. Merck Silica Gel 60 F254 foils.
3-O-(N, N’ -Dicyclohexylisoureido)-1,2:4,5-di-O-isopropylidene-b-D-fructopy-
ranose (7). To a soln of 1,2:4,5-di-O-isopropylidene-b-D-fructopyranose (1)[14] (4.97 g,
19.1 mmol) and DCC (5.47 g, 26.5 mmol) in anhydrous DMF (10 mL) copper-(I)-
chloride (10 mg, 0.1 mmol) was added under stirring at 25°C (argon atmosphere). After
roughly ten minutes the colour of the suspension turned to green. Now the mixture was
warmed to 90°C and stirring was continued for 24 h. Then, the suspension was cooled
down and filtered from precipitated dicyclohexylurea. Ethyl acetate (40 mL) was added
to the filtrate before the soln was subsequently washed with sat. Na2–EDTA-soln (twice
5 mL), water (10 mL) and brine (10 mL) and was dried (Na2SO4). After filtration and

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2002 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
NON-ANOMERIC SUGAR ISOUREAS
299
evaporation of the solvents the residue was purified by column chromatography
(heptane/EtOAc 5:1) yielding 7.71 g (86%) of 7, which crystallized overnight after
several hours under fine vacuum; mp 109–110°C, [a]D24 = À 123 (c 1.2, CHCl3).
1H NMR (250 MHz, CDCl3): d= 5.47 (br, 1 H, JW/2 =9 Hz, H-3), 4.24 (dd, 1H,
J3,4 = 8.5 Hz, H-4), 4.13 (dd, 1H, J4,5 =5.2 Hz, H-5), 4.06 (dd, 1H, J5,6b = 2.4 Hz, H-6b),
3.98 (d, 1H, J6a,6b =13.3 Hz, H-6a), 3.97 (d, 1H, H-1b), 3.82 (d, 1H, J1a,1b =9.2 Hz, H-
1a), 3.39 (br, 2H, cyclohexyl-CH, NH), 2.73, (br, 1H, cyclohexyl-CH), 1.29, 1.33, 1.42,
1.51 (4 s, 12H, CH3), 0.97–1.70 (m, 20H, cyclohexyl-CH2). 13C NMR (62 MHz,
CDCl3): d =150.1 (imino-C), 109.2, 111.2 (C(CH3)2), 104.9, (C-2), 60.3, (C-6), 68.8,
71.7, 74.0, 75.6 (C-1, C-3, C-4, C-5), 50.7, 53.8 (cyclohexyl-CH), 34.4 (cyclohexyl-
CH2), 25.0–27.8 (CH3, cyclohexyl-CH2). IR (KBr): 1672 cm À 1 ðC NÞ:
Anal. Calcd for C25H42N2O6 (466.6): C, 64.35; H, 9.07; N, 6.00. Found: C,
64.61; H, 9.13; N, 5.97.
3,5-Di-O-benzoyl-4-O-(N,N’ -dicyclohexylisoureido)-1,2-O-isopropylidene-b-D-
fructopyranose (8). From 1,2-O-isopropylidene-3,5-di-O-benzoyl-b-D-fructopyranose
(2) (200 mg, 0.46 mmol),[10a,c] DCC (150 mg, 0.73 mmol) and CuCl (10 mg, 0.1
mmol) in anhydrous DMF for 1.5 h at 50°C. The work up procedure is analogous to
that for 7. Column chromatographic separation (Rf 0.38, toluene/EtOAc 9:1). Yield of
8: 132 mg (45%) yellowish syrup, [a]D24 = À 168 (c 1.4, CHCl3).
1H NMR (250 MHz, CDCl3): d =8.12 (m, 2H, Ph-H), 7.85 (m, 2H, Ph-H), 7.12–
7.62 (m, 6H, Ph-H), 6.26 (d, 1H, H-3), 5.71 (dd, 1H, J4,5 =3.4 Hz, J3,4 =10.8 Hz, H-4),
5.65 (m, 1H, H-5), 4.26 (d, 1H, H-6a), 4.23 (d, 1H, H-1a), 4.02 (d, 1H, J1 gem. =9.0 Hz,
H-1b), 3.99 (dd, 1H, J5,6a =1.8 Hz, J6a,6b =13.3 Hz, H-6b), 3.30 (br, 1H, cyclohexyl-
CH), 2.83 (br, 1H, cyclohexyl-CH), 1.54 (s, 3H, CH3), 1.44 (s, 3H, CH3), 1.18–1.90
(m, 20H, cyclohexyl-CH2). 13C NMR (62 MHz, CDCl3): d=165.7, 166.0 ðBz
C
OÞ,
150.1 (imino-C), 133.0, 133.2 (ipso-Ar–C), 128.1, 128.2, 128.4, 129.1, 129.8, 130.0
(Ar–C), 111.7 (ketal-C), 105.8 (C-2), 71.7 (C-1), 66.2, 70.6, 70.9 (C-3, C-4, C-5), 62.3
(C-6), 50.1, 53.5 (cyclohexyl-CH), 34.2, 34.5 (cyclohexyl-CH2) 26.3, 26.7 (CH3), 24.5,
24.8, 24.9, 25.5 (cyclohexyl-CH2). IR (KBr): 1669 cm À 1 ðC NÞ, 1728 cm À 1 ðC OÞ,
3405 cmÀ 1 (NH).
Anal. Calcd for C36H46N2O8 (634.8): C, 68.12 H, 7.30; N, 4.41. Found: C, 68.05;
H, 7.46; N, 4.12.
Phenyl 2,3,6-tri-O-benzyl-4-O-(N,N’ -dicyclohexylisoureido)-b-D-glucopyrano-
side (9). From phenyl 2,3,6-tri-O-benzyl-b-D-glucopyranoside (3) (300 mg, 0.57
mmol), DCC (210 mg, 1.0 mmol) and CuCl (10 mg, 0.1 mmol) in anhydrous DMF for
24 h at 50°C. The work up procedure is analogous to that for 7. Column chroma-
tographic separation (Rf 0.13, toluene/EtOAc/EtOH 4:2:1 v/v/v). Yield of 9: 343 mg
(80%) syrup, [a]D24 = À 8 (c 0.99, CHCl3).
1H NMR (250 MHz, CDCl3): d =5.06 (d, 1H, J1,2 = 6.4 Hz, H-1), 5.05 (d, 1H,
Jgem., Bn–CH =10.99 Hz, Bn–CH2), 4.87 (d, 1H, Jgem., Bn–CH =10.99 Hz, Bn–CH2),
4.81 (d, 1H, Jgem., Bn–CH =10.99 Hz, Bn–CH2), 4.68 (d, 1H, Jgem., Bn–CH =10.99 Hz,
2
2
2
2
Bn–CH2), 4.59 (d, 1H, Jgem., Bn–CH =11.75 Hz, Bn–CH2), 4.49 (d, 1H, Jgem., Bn–CH
=
2
2
11.75 Hz, Bn–CH2), 3.72–3.85 (m, 4H, H-2, H-3, H-5, H-6), 3.65 (d, 1H, J6a,6b =10.2
Hz , H-6a), 3.46 (m, 1H, cyclohexyl-CH), 3.30 (m, 1H, cyclohexyl-CH), 1.45–1.79 (m,
10H, cyclohexyl-CH2), 1.01–1.34 (m, 10H, cyclohexyl-CH2). 13C NMR (62 MHz,

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2002 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
300
SOWA, MIETHCHEN, AND REINKE
CDCl3): d=157.4 (ipso-Ph), 149.1 (imino-C), 138.4 (3 quat. Bn–C), 127.6–129.6 (Ar–
C), 116.8 (p-Ph), 101.5 (C-1), 70.5, 73.7, 75.0, 81.6, 82.7 (C-2, C-3, C-4, C-5, C-6),
54.2 (cyclohexyl-CH), 50.3 (cyclohexyl-CH), 34.4 (cyclohexyl-CH2), 24.8–25.6
(cyclohexyl-CH2). IR (KBr): 1669 cm À 1 ðC NÞ:
Anal. Calcd for C46H56N2O6 (733.0): C, 75.38 H, 7.70; N, 3.82. Found: C, 75.17;
H, 7.58; N, 3.73.
Phenyl 2,3,4-tri-O-benzyl-6-O-(N, N’ -dicyclohexylisoureido)-b-D-glucopyrano-
side (10). From phenyl 2,3,4-tri-O-benzyl-b-D-glucopyranoside (4) (240 mg, 0.45
mmol), DCC (200 mg, 0.9 mmol) and CuCl (10 mg, 0.1 mmol) in anhydrous DMF for
24 h at rt. The work up procedure is analogous to that for 7. Column chromatographic
separation (Rf 0.21, toluene/EtOAc/EtOH 4:2:1 v/v/v). Yield of 10: 254 mg (77%)
colourless syrup, [a]D23 = À 10 (c 1.0, CHCl3).
1H NMR (250 MHz, CDCl3): d =7.28–7.42 (m, 20H, Ph-H), 5.10 (d, 1H,
Jgem.,
Jgem., Bn–CH = 11.0 Hz, Bn–CH2), 4.93 (d, 2H, Jgem., Bn–CH =11.0 Hz, Bn–CH2), 4.88
= 10.8 Hz, Bn–CH2), 5.07 (d, 1H, J1,2 =6.6 Hz, H-1), 5.01 (d, 1H,
Bn–CH2
2
2
(d, 1H, Jgem., Bn–CH =11.4 Hz, Bn–CH2), 4.70 (d, 1H, Jgem., Bn–CH =10.6 Hz, Bn–
2
2
CH2), 4.63 (d, 1H, J6a,6b = 11.9 Hz, H-6a), 4.29 (dd, 1H, J5,6 =5.3 Hz, H-6b), 3.60–3.82
(m, 4H, H-2, H-3, H-4, H-5), 3.49 (m, 1H, cyclohexyl-CH), 3.30 (m, 1H, cyclohexyl-
CH), 1.08–2.03 (m, 20H, cyclohexyl-CH2). 13C NMR (62 MHz, CDCl3): d= 157.4
(ipso-Ph), 148.5 (imino-C), 138.5, 138.3, 137.9 (3 quat. Bn–C), 127.6–129.6 (Ar–C),
116.7 ( p-Ph), 101.6 (C-1), 74.0, 77.4, 82.1, 84.5 (C-2, C-3, C-4, C-5), 54.2
(cyclohexyl-CH), 64.5 (C-6), 55.8, 49.0 (cyclohexyl-CH), 34.9, 34.3, 34.0, 34.0
(cyclohexyl-CH2), 24.8–25.6 (cyclohexyl-CH2. IR (KBr): 1667 cm À 1 ðC NÞ:
Anal. Calcd for C46H56N2O6 (733.0): C, 75.38 H, 7.70; N, 3.82. Found: C, 75.21;
H, 7.56; N, 4.09.
Methyl 2-O-(N,N’ -dicyclohexylisoureido)-3,4-O-trichloroethylidene-6-deoxy-a-
L-altropyranoside (11). From methyl 3,4-O-trichloroethylidene-6-deoxy-a-L-altropyr-
anoside (5)[15] (1.0 g, 3.2 mmol), DCC (1.0 g, 4.8 mmol) and CuCl (10 mg, 0.1 mmol)
in anhydrous DMF for 18 h at 50°C. The work up procedure is analogous to that for 7.
Column chromatographic separation (Rf 0.19, toluene/EtOAc 3:1 v/v). Yield of 11:
1.52 g (91%) colourless syrup, [a]D23 = À 46 (c 1.15, CHCl3).
1H NMR (250 MHz, CDCl3): d= 5.45 (s, 1H, acetal-H), 5.27 (br, 1H, H-1), 4.72
(br, 1H, JW/2 = 3.0 Hz, H-2), 4.67 (dd, 1H, J2,3 =3.1 Hz, H-3), 4.17 (dd, 1H, J3,4 =5.7
Hz, H-4), 3.82 (dd, 1H, J4,5 = 9.2 Hz, H-5), 3.38 (s, 3H, OMe), 3.38 (br, 2H,
cyclohexyl-CH, NH), 2.83 (br, 1H, cyclohexyl-CH), 0.96–1.99 (m, 20H, cyclohexyl-
CH2), 1.37 (d, 3H, J5,6 = 6.3 Hz, H-6). 13C NMR (62 MHz, CDCl3): d= 148.4 (imino-
C), 106.6 (acetal-C), 99.7 (C-1), 98.8 (CCl3), 61.9, 67.9, 76.8, 78.3 (C-2, C-3, C-4, C-5),
55.7 (OMe), 50.6, 53.8 (cyclohexyl-CH), 34.1 (cyclohexyl-CH2), 24.5–26.0 (cyclo-
hexyl-CH2), 18.7 (C-6). IR (KBr): 1674 cm À 1 ðC NÞ:
Anal. Calcd for C22H37Cl3N2O6 (531.9): C, 49.68 H, 7.01; N, 5.27. Found: C,
49.97; H, 6.78; N, 5.14.
Methyl 2,3-di-O-(N,N’ -diisopropylisoureido)-a-L-rhamnopyranoside (12).
From methyl a-L-rhamnopyranoside (6)[16] (1.0 g, 5.6 mmol), DIPC (1.4 g, 11.2
mmol) and CuCl (10 mg, 0.1 mmol) in anhydrous DMF (10 mL) for 8 h at 90°C. The

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2002 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
NON-ANOMERIC SUGAR ISOUREAS
301
work up procedure is analogous to that for 7. Column chromatographic separation (Rf
0.11, heptane/EtOAc/Et3N 12:4:1 v/v/v). Yield of 12: 550 mg (22%) colourless
crystals, mp 160–161°C (heptane), [a]D24 = À 122 (c 1.4, CHCl3).
1H NMR (250 MHz, CDCl3): d =5.35 (dd, 1H, H-2), 4.77 (dd, 1H, J2,3 =3.5 Hz,
J3,4 = 9.1 Hz, H-3), 4.74 (d, 1H, J1,2 =1.8 Hz, H-1), 3.64–3.91 (br, 4H, NH), 3.58 (m,
2H, H-4, H-5), 3.39 (br, 1H, CH), 3.36 (s, 3H, OMe), 3.11 (br, 1H, CH), 1.35 (d, 3H,
J5,6 = 5.9 Hz, H-6), 0.97–1.18 (m, 24H, 8 CH3). 13C NMR (62 MHz, CDCl3): d =148.2,
152.9 (2 imino-C), 96.7 (C-1), 67.4, 68.2, 68.6, 71.1 (C-2, C-3, C-4, C-5), 52.8 (OMe),
41.7, 42.1, 43.9, 44.2 (4 CH(CH3)2) 22.0 (4 CH(CH3)2), 16.5 (C-6). IR (KBr): 1652
cm À 1, 1668 cmÀ 1 ðC NÞ:
Anal. Calcd for C21H42N4O5 (430.6): C, 58.58 H, 9.83; N, 13.01. Found: C,
58.62; H, 9.94; N, 13.00.
Phenyl 6-azido-6-deoxy-2,3,4-tri-O-benzyl-b-D-glucopyranoside (13). A soln
of 10 (250 mg, 0.38 mmol), p-toluenesulfonic acid monohydrate (10 mg) and sodium
azide (65 mg, 1.0 mmol) in dry DMF was heated with stirring at 110°C for 19 h.
Then DMF was removed under reduced pressure and the residue was treated with
acetone (10 mL) without heating. After filtration to remove the precipitated
dicyclohexylurea, the filtrate was concd and the residue was purified by flash
chromatography (Rf 0.19; heptane/EtOAc 8:1 v/v). The cryst compd 13 (199 mg,
95%) was isolated; colourless crystals mp 74–76°C (heptane/EtOAc); [a]D24 = À 26 (c
1.0, CHCl3).
1H NMR (250 MHz, acetone-d6): d= 7.19–7.40 (m, 1H, Ph-H), 5.24 (d, 1H,
J1,2 = 7.6 Hz, H-1), 5.09 (d, 1H, JBn–CH =11.3 Hz, Bn–CH2), 5.00 (d, 1H, JBn–CH
11.1 Hz, Bn–CH2), 4.93 (d, 1H, JBn–CH = 11.4 Hz, Bn–CH2), 4.87 (d, 1H, JBn–CH
11.3 Hz, Bn–CH2), 4.84 (d, 1H, JBn–CH = 11.3 Hz, Bn–CH2), 4.68 (d, 1H, JBn–CH
=
=
=
2
2
2
2
2
2
11.1 Hz, Bn–CH2), 3.55–3.88 (m, 5H, H-2, H-3, H-4, H-5, H-6b), 3.48 (dd, 1H,
J6a,6b = 13.3 Hz, J6a,5 = 6.4 Hz, H-6a). 13C NMR (62 MHz, acetone-d6): d= 158.6 (quat.
Ar–C; Ph), 139.6, 139.9, 140.1 (quat. Ar–C; Bn), 128.3, 128.5, 128.6, 128.8, 128.8,
129.0, 129.1, 129.2, 129.3, 129.4, 129.9, 130.6 (Ar–C), 123.6 ( p-Ph), 117.7 (o-Ph),
102.2 (C-1), 75.3, 79.5, 83.1, 85.3 (C-2, C-3, C-4, C-5), 75.6, 75.7, 76.3 (3 Bn–CH2),
52.6 (C-6). IR (KBr): 2100 cm À 1 (azide).
Anal. Calcd for C33H33N3O5 (551.6): C, 71.85 H, 6.03; N, 7.62. Found: C, 71.80;
H, 6.24; N, 7.39.
Phenyl 2,3,4-tri-O-benzyl-6-deoxy-6-thioacetyl-b-D-glucopyranoside (14). A
soln of 10 (240 mg, 0.3 mmol) and thioacetic acid (0.5 mL) in dry toluene (5 mL)
was refluxed for 14 h. Then the mixture was concd under reduced pressure and the
residue was purified by flash chromatography (Rf 0.14; heptane/EtOAc 8:1 v/v). 14 (60
mg, 32%) was isolated as colourless cryst substance from a heptane–toluene mixture;
mp 126–127°C (toluene/EtOAc); [a]D24 = À 10 (c 1.02, CHCl3).
1H NMR (250 MHz, CDCl3): d= 7.28–7.42 (m, 17H, Ar–H), 7.04–7.12 (m, 3H,
Ar–H), 5.06 (d, 1H, Jgem., Bn–CH =11.3 Hz, Bn–CH2), 4.97 (d, 1H, Jgem., Bn–CH =10.9
Hz, Bn–CH2), 4.97 (d, 1H, J1,2 =7.7 Hz, H-1), 4.93 (d, 1H, Jgem., Bn–CH = 10.9 Hz,
2
2
2
Bn–CH2), 4.83 (d, 2H, Jgem., Bn–CH = 10.9 Hz, 2 Bn–CH2), 4.69 (d, 1H, Jgem., Bn–CH
11.3 Hz, Bn–CH2), 3.43–3.62 (m, 5H, H-2, H-3, H-4, H-5, H-6), 2.35 (s, 3H, Me), 3.00
=
2
2
(dd, 1H, J5,6a =8.6 Hz, J6a,6b =14.4, H-6). 13C NMR (62 MHz, CDCl3): d =194.7

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2002 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
302
SOWA, MIETHCHEN, AND REINKE
ðC OÞ, 128.6, 129.6, 157.2 (quat. Ph–C), 127,8, 127.8, 127.9, 128.0, 128.3, 128.5 (Ar–
C), 122.8 (p-Ph–C), 116.9 (o-Ph–C), 101.6 (C-1), 75.1, 75.3, 75.8 (Bn–CH2), 74.5,
80.3, 82.0, 84.4 (C-2, C-3, C-4, C-5), 30.9 (C-6), 30.5 (Me). IR (KBr): 1691 cm À 1
ðC OÞ:
Anal. Calcd for C35H36O6S (584.7): C, 71.89 H, 6.21; S, 5.48. Found: C, 71.72;
H, 6.38; S, 5.46.
(R)-5-O-Cyclohexylcarbamoyl-1,2-O-isopropylidene-3,4-O-trichloroethyli-
dene-b-D-tagatopyranose (15) and 4,5-O-carbonyl-1,2-O-isopropylidene-b-D-fructo-
pyranose (16). To a soln of 8 (130 mg, 0.2 mmol) in anhyd methanol (10 mL)
sodium (about 70 mg) was added with stirring at rt. After the sodium had disappeared,
stirring was continued for 1 h. Then the soln was immediately neutralized with the
acidic ion exchange resin Amberlite IR 120 (about 7.0 g), filtered and concd under
reduced pressure at a temperature below 40°C. The syrupy residue of 4-O-(N,N’-
dicyclohexylisoureido)-1,2-O-isopropylidene-b-D-fructopyranose was dissolved in 1,2-
dichloroethane (10 mL). After addition of chloral (0.5 mL), the mixture was refluxed
for 6 h, cooled down and subsequently washed with sat. Na2–EDTA-soln (twice 5 mL),
water (10 mL) and brine (10 mL). The TLC (toluene/EtOAc 6:1 v/v) showed two main
spots (15: Rf 0.57; 16: Rf 0.15). After drying (Na2SO4), filtration and evaporation of
the solvents, the residue was purified by column chromatography (toluene/EtOAc 10:1
1
v/v) yielding 46 mg (48%) of 15, mp 198–200°C (Lit.: 198.5–201°C[11]; H and 13C
NMR data are identical with those of Ref. [11]), and 10 mg (20%) of 16, mp 112–
113°C (toluene/EtOAc/EtOH).
1
16: H NMR (250 MHz, CDCl3): d =4.81 (dd, 1H, J3,4 =5.1 Hz, J4,5 =7.4 Hz, H-
4), 4.77 (dd, 1H, J5,6 = 2.0 Hz, H-5), 4.17 (dd, 1H. J6 gem. =14.1 Hz, H-6a), 4.14 (d, 1H,
J1 gem. =9.3 Hz, H-1a), 4.06 (d, 1H, H-6b), 3.99 (d, 1H, H-1b), 3.89 (d, 1H, H-3), 3.00
(br, 1H, OH), 1.50 (s, 3H, CH3), 1.44 (s, 3H, CH3). 13C NMR (62 MHz, CDCl3):
d= 154.3 ðC OÞ, 112.5 (C(CH3)2), 103.3 (C-2), 76.8, 74.9, 72.6, 68.7 (C-1, C-3, C-4,
C-5), 60.1 (C-6), 26.3, 25.9 (C(CH3)2). IR (KBr): 1829 cm À 1 ðC OÞ:
Anal. Calcd for C10H14O7 (246.2): C, 48.78 H, 5.73. Found: C, 48.92; H, 5.81.
ACKNOWLEDGMENTS
C.S. is grateful for a grant by the Studienstiftung des deutschen Volkes. The
Deutsche Forschungsgemeinschaft and the Fonds der Chemischen Industrie promoted
our research by financial support.
REFERENCES
1. Vowinkel, E.; Gleichenhagen, P. Untersuchungen zur Oxazolidinbildung aus 1,2-
Diolen und Dicyclohexylcarbodiimid. Tetrahedron Lett. 1974, 2, 139–142.
2. Jaeger, R. Inversion of configuration of alcohols with O-alkyl-N,N’-dicyclohex-
ylureas. Synthesis 1991, 465–469.
3. Kaulen, J. Inversion of the alcohol configuration via in-situ synthesized isourea
ether. Angew. Chem., Int. Ed. 1987, 26, 773–775.

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2002 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
NON-ANOMERIC SUGAR ISOUREAS
303
4. Mathias, L.J. Esterification and alkylation reactions employing isoureas. Synthesis
1979, 561–576.
5. Griehl, C.; Kolbe, A.; Merkel, S. Quantitative description of epimerization path-
ways using the carbodiimide method in the synthesis of peptides. J. Chem. Soc.,
Perkin Trans. 2 1996, 2, 2525–2529.
6. Frank, M.; Miethchen, R.; Reinke, H. Non-classical epimerisation of (1S,2S,
3S,4R,5R)-1-O-methylcyclohexane-1,2,3,4,5-pentol. Eur. J. Org. Chem. 1999,
1259–1263 and papers cited therein.
7. Tsutsumi, H.; Ishido, Y. Synthesis of phenyl D-glucopyranoses; nucleophilic subs-
titution of O-(2,3,4,6-tetra-O-benzyl-D-glucopyranosyl)-pseudoureas by phenols.
Carbohydr. Res. 1981, 88, 61–75.
8. Tsutsumi, H.; Ishido, Y. Syntheses of 1-O-acylaldose derivatives via the cor-
responding O-glycosylpseudoureas. Carbohydr. Res. 1982, 111, 75–84.
9. Horvat, S.; Varga, L.; Horvat, J. A new utility of O-glycosylpseudoureas for
synthesis of glucopeptides and (1 !6)-disaccharides. Synth. Commun. 1986,
209–211.
10a. Sowa, Chr. Carbodiimid Assistierte Reaktionen an Kohlenhydraten. Dissertation;
Universita¨t Rostock, 2001.
10b. Prepared by Deisopropylidenation of 1,2:4,5-Di-O-isopropylidene-3-O-(N,N’-dicy-
clohexylisoureido)-b-D-fructopyranose.
10c. Compd 2 was contaminated with its 4,5-di-O-benzoyl isomer (ratio about 2:1).
11. Frank, M.; Miethchen, R.; Degenring, D. D-Tagatose derivatives from D-fructose by
a facile epimerisation procedure. Carbohydr. Res. 1999, 318, 167–170.
12a. Cremer, D.; Pople, J.A. A general definition of ring puckering coordinates. J. Am.
Chem. Soc. 1975, 97, 1354–1358.
12b. Cremer, D.; Pople, J.A. Molecular orbital theory of the electronic structure of
organic compounds. XXIII. Pseudorotation in saturated five-membered ring
compounds. J. Am. Chem. Soc. 1975, 97, 1358–1367.
13. Zur, C.; Miller, A.O.; Miethchen, R. Perfluoroalkylidene sugars by non-classical
acetalation of pyranoses. J. Fluorine Chem. 1998, 90, 67–76.
14. Brady, R.F., Jr. Cyclic acetals of ketoses. Re-inversion of the synthesis of the iso-
meric di-O-isopropylidene-b-D-fructopyranoses. Carbohydr. Res. 1970, 15, 35–40.
15. Miethchen, R.; Rentsch, D. Von manno-Pyranosiden zu 3,4-O-(2,2,2-Trichlorethy-
liden)altropyranosylfluoriden in nur zwei Reaktionsschritten. Synthesis 1994,
827–831.
16. Jary´, J.; Capek, K.; Kova´r, J. Synthese von Derivaten der 3,6-Didesoxy-3-amino-L-
idose. Collect. Czech. Chem. Commun. 1963, 28, 2171–2181.
Received February 22, 2002
Accepted April 2, 2002