Atropisomeric carbohydrate imidazolidines: A novel class of nonbiaryl atropisomers

Article abstract of DOI:10.1016/S0957-4166(99)00428-0

Stable axially chiral atropisomers have been prepared by reaction of 2- aminosugars with o,o'-disubstituted aryl isocyanates and isothiocyanates; these rotationally restricted heterobiaryls constitute a novel class of atropisomers for use in atroposelecti

Full text of DOI:10.1016/S0957-4166(99)00428-0

Pergamon
Tetrahedron: Asymmetry 10 (1999) 4071–4074
Atropisomeric carbohydrate imidazolidines: a novel class of
nonbiaryl atropisomers
Martín Avalos,a Reyes Babiano,a,∗ Pedro Cintas,a Francisco J. Higes,b José L. Jiménez,a
Juan C. Palacios a and Guadalupe Silvero a
aDepartamento de Química Orgánica, Facultad de Ciencias, Universidad de Extremadura, E-06071 Badajoz, Spain
bDepartamento de Química Inorgánica, Facultad de Ciencias, Universidad de Extremadura, E-06071 Badajoz, Spain
Received 15 September 1999; accepted 27 September 1999
Abstract
Stable axially chiral atropisomers have been prepared by reaction of 2-aminosugars with o,o0-disubstituted aryl
isocyanates and isothiocyanates; these rotationally restricted heterobiaryls constitute a novel class of atropisomers
for use in atroposelective reactions. © 1999 Elsevier Science Ltd. All rights reserved.
Recent observations have suggested that nonbiaryl atropisomers may be useful conveyors of chirality
for asymmetric induction.1 However, unlike classical biaryl derivatives which remain among the most
useful auxiliaries and catalysts,2 atroposelective reactions involving nonbiaryl atropisomerically pure
ligands are rare.1,3 An additional interest in the dynamics and control of rotational motion about single
bonds include the design of molecular brakes,4 ratchets,5 gears,6,7 propellers,6 and turnstiles,8 which
could eventually culminate in the development of a molecular machine.9 Likewise, it is worthy to mention
that the biological activity of individual rotamers has just been evaluated in the case of 1,7-naphthyridine-
6-carboxamides,10 indicating a conformational requirement for receptor binding.
We have now studied a different type of molecule as a potential atropisomerically pure auxiliary,
readily available from D-glucosamine in a few steps sequence. In previous studies we have shown
that unprotected aminosugars can be converted into bicyclic imidazolidinones and imidazolidinethiones
by simple reaction with isocyanates and isothiocyanates under acid catalysis.11 This synthesis can be
adapted to induce atropisomerism as a result of hindered rotation about the C–N single bond, if one
introduces a large aromatic substituent in the heterocyclic ring. Variable-temperature NMR studies show
that some signals of bicyclic systems bearing either a naphthyl group or an o-monosubstituted phenyl
ring are split into two at 273 K or below, but only a few imidazolidinethiones exhibit atropisomerism at
room temperature. Moreover, the barriers to rotation of these bicyclic systems were also estimated from
molecular mechanics calculations.12
∗
Corresponding author. E-mail: reyes@unex.es
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00428-0

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Fig. 1 displays the transition structures for the interconversion of M and P13 rotamers. For o-
monosubstituted compounds, the lower energy barrier corresponds to a transition structure in which
the o-hydrogen atom can pass over the 2-amido (X=O) or thioamido (X=S) group without appreciable
crowding, whereas an enhanced barrier occurs when the o-substituent passes over the 2-position of the
heterocyclic ring. Anyway, the barriers to rotation are too low to make it possible to isolate rotational
isomers at room temperature, because such barriers must be 23.5 kcal mol−1 or more.14 However, o,o0-
disubstituted derivatives will always exhibit an important steric interaction between a substituent and the
C_X group for both transition structures.
Figure 1.
Realizing that isolation is possible when the internal rotation about the pivotal bond is frozen, and
deducing that di-ortho substituted nonbiaryls could be resolvable only if the substituents are large
enough, we incorporated this structural feature into imidazolidine-2-ones and -2-thiones. Nevertheless,
aryl isocyanates di-ortho substituted with large groups failed to react with aminosugars in an aqueous
medium owing to steric hindrance. Under such circumstances, hydrolysis of the isocyanate occurs leading
to the unwanted N,N0-diarylurea. Conversely, it is possible to accomplish successfully the synthesis of
di-ortho substituted derivatives starting from O-protected aminosugars (e.g. 1), thereby permitting the
condensation with aryl isocyanates in an aprotic solvent (Scheme 1, method A). Subsequent deprotection
followed by acid-catalyzed cyclization afforded 3.
Scheme 1.
The formation of the atropisomeric imidazolidinethiones 4 (Scheme 1, method B) can advantageously
be conducted in the presence of water arising from the condensation with the inexpensive D-glucosamine
2, since the competing hydrolysis of aryl isothiocyanates proceeds slowly. Compounds 3 and 4 together
with their O-acetylated counterparts 5 and 6 were a mixture of two atropisomers as revealed by NMR
analyses (see Table 1), and duplicated signals did not coalesce even at 373 K. The spectra implied that the
rotational isomers should be isolable at room temperature. Indeed, M and P rotamers of 5a were isolated
by preparative chromatography.

M. Avalos et al. / Tetrahedron: Asymmetry 10 (1999) 4071–4074
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Table 1
The slower-moving spot was identified as a rotamer possessing an axial chirality determined as P by
X-ray crystallography (Fig. 2).14 M and P atropisomers of 6 (and 4) should also show a much higher
barrier to rotation by virtue of the longer C_S bond length and the larger size of the sulfur atom, and in
fact rotational isomers of 6a were also separable.
Figure 2.
These amide rotamers share a number of important features. Such substances combine axial chirality of
defined configuration along with the inherent chirality provided by several stereocenters. In this context,
these diastereomerically pure rotamers could be converted into enantiomeric atropisomers by oxidative
degradation of the polyhydroxyalkyl sugar fragment. Likewise, these aromatic amides and thioamides
contain lone pairs whose chelation potential could be harnessed for use in the development of nonracemic
ligands.
In conclusion, we have found the first examples of nonbiaryl rotamers derived from carbohydrates that
can be resolved at room temperature. Further application of these systems in atroposelective reactions as
well as exploration of their use as molecular devices are well underway in our laboratories.
Acknowledgements
Financial support by grants from the Ministry of Education and Culture (DGICYT, PB95-0259) and
the Junta de Extremadura-Fondo Social Europeo (IPR98-C040) is gratefully acknowledged. We also
thank Dr. I. López for his valuable assistance with NMR experiments.

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14. Crystal data for (P)-5a: C20H23ClN2O8, Mr=454.9, crystal dimensions 0.42×0.36×0.28 mm, Siemens P4 diffractometer,
MoKα radiation (λ=0.71073 Å), highly oriented graphite crystal monochromator, ω/2θ scan mode, 2.0<2θ<57.0°, scan
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Crystallographic data have been deposited with the Cambridge Crystallographic Data Centre: CCDC-104131.