1,2,4-Oxadiazolidinones as configurationally stable chiral building blocks

Article abstract of DOI:10.1002/anie.200461934

An intriguing scaffold for drug development, 1,2,4-oxadiazolidinones are obtained in enantiomerically pure form by a simple reaction and purification protocol (see scheme). These heterocycles, including the previously unknown N2-unsubstituted parent struc

Full text of DOI:10.1002/anie.200461934

Communications
Asymmetric Heterocycle Synthesis
1) methodology must be available for the convenient syn-
thesis of oxadiazolidinones in optically active form,[5] and
2) the heterocycle 3 (intermediates and end products) must be
configurationally stable. Examination of related heterocycles
casts into question the configurational stability, especially
under acidic and alkaline conditions (Scheme 1). In this
1,2,4-Oxadiazolidinones as Configurationally
Stable Chiral Building Blocks**
Tobias Ritter and Erick M. Carreira*
Heterocycles are ubiquitous in drug discovery and develop-
ment by virtue of the fact that they can serve as scaffolds
incorporating multiple points of diversification and thereby
facilitate library synthesis. Nonaromatic heterocycles can
impart added benefits in drug design, because they define out-
of-plane vectors from a central core. One of the more recent
examples of such a scaffold is the antibacterial linezolid, an
optically active oxazolidinone.[1,2] Chiral 1,2,4-oxadiazolidi-
nones 3 [Eq. (1)] constitute a structurally intriguing scaffold,
Scheme 1. Configurational stabiliy of heterocycles related to oxadiazoli-
dinones.
respect, oxazolidinone 4 racemizes upon heating in acetoni-
trile[6] and the cyclic nitrone 5 was found to undergo rapid
racemization during chromatography on silica gel through
putative ring opening to the acyl imminium ion and subse-
quent recyclization.[7] The imidazolidinone scaffold 6 was
reported to undergo degradation to the Schiff base upon
vacuum distillation (1358C, 0.05 torr).[8]
Our recent work in alkynylzinc additions to mannosyl-
and erythrosyl- (Aux1 and Aux2, respectively) derived nitro-
nes[9] led us to explore these substrates[10] in the cycloaddition
reaction for the preparation of oxadiazolidinones. The start-
ing nitrones are conveniently accessed from readily available
starting materials (mannose, hydroxylamine, aldehyde) in
three steps.[11]
Simply mixing a range of commercially available isocya-
nates 1 with mannosyl-derived nitrones 2 in CH2Cl2 led to
smooth cycloaddition at 238C to afford oxadiazolidinones 7 in
69–87% yield [Eq. (2), Table 1]. The diastereoselectivity of
the cycloaddition ranges from 4:1 to 12:1 for the products
isolated directly upon evaporation of the solvent. We were
pleased to observe that simple trituration of the products with
methanol generally furnished the desired substituted 1,2,4-
oxadiazolidinones in up to > 99:1 d.r. in analytically pure
form. Electron-deficient and -rich aromatic and heteroaro-
matic nitrones, alkenylnitrones, as well as alkylnitrones
participate in this cycloaddition, with the C-alkylnitrones
most and the electron-deficient aromatic least reactive.
Electron-deficient isocyanates react more readily than those
substituted with electron-releasing groups, consistent with
frontier orbital control. Reactions of substrates that are less
reactive can be carried out successfully in refluxing acetoni-
trile.
which bear structural similarity to oxazolidinones. However,
they have rarely been employed as biologically active agents
and then only in racemic form.[3] Their absence in the
medicinal chemistry literature likely stems from the lack of
synthetic methodology for their preparation in enantiomer-
ically pure form and, consequently, the fact that it is unclear
whether they would be configurationally stable. In this
communication we document the convenient asymmetric
synthesis of a wide range of substituted 1,2,4-oxadiazolidi-
nones by cycloaddition. Access to the enantiomerically pure
compounds allows us to ascertain for the first time the
configurational stability of this class of compounds, including
that of the unsubstituted, previously unknown parent hetero-
cycle 3.
The cycloaddition of isocyanates and nitrones was first
reported by Goldschmidt and Beckmann in 1890, but it was
not until almost 100 years later (1987) that the structure of the
cycloadducts was firmly established as 1,2,4-oxadiazolidi-
nones.[4] In order to exploit these heterocycles as potentially
useful, versatile building blocks, two key criteria must be met:
[*] T. Ritter, Prof. Dr. E. M. Carreira
Laboratorium fꢀr Organische Chemie, ETH Hꢁnggerberg
8093 Zꢀrich (Switzerland)
Fax: (+41)1-632-1328
E-mail: carreira@org.chem.ethz.ch
[**] We thank the Swiss National Science Foundation and F. Hoffmann-
LaRoche AG for support of this research, the Fonds der Chemischen
Industrie for a Kekulꢂ Fellowship (T.R.), and Prof. Andrea Vasella for
helpful discussions.
The enantiomeric oxadiazolidinones can be accessed by
using the erythrose-derived auxiliary [Eq. (3)] and removing
the auxiliary from the heterocyclic product [Eq. (4)]. In
analogy to the cycloadditions described above, concentration
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
936
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DOI: 10.1002/anie.200461934
Angew. Chem. Int. Ed. 2005, 44, 936 –938

Angewandte
Chemie
auxiliaries is removed in the aqueous workup, leading to the
isolation of the N2-unsubstituted heterocycles in > 99% ee as
determined by HPLC.
The results in Table 2 make apparent that the optically
active oxadiazolidinones are stable towards acid, even when
Table 1: Diastereoselective nitrone cycloaddition [Eq. (2)].[a]
R1 R2
d.r. d.r.
(crude prod.) (isolated prod.)
Table 2: Cleavage of the chiral auxiliary [Eq. (4)].
Yield [%][b]
R1
R2
Yield [%]
ee [%]
from Aux1
p-C6H4OMe
p-C6H4OMs
p-C6H4OMs
Ph
p-C6H4NO2 p-C6H4NO2 11:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
19:1
84
87
85
83
81
84
80
Bn
88
87
87
81
65
65
35
>99
>99
>99
>99
>99
>99
>99
p-C6H4Br
p-C6H4CF3
Ph
10:1
10:1
8:1
p-C6H4F
p-C6H4F[a]
p-C6H4F
p-C6H4F
p-C6H4NO2
H[b]
p-C6H4CF3
p-C6H4F
p-C6H4OMe
p-C6H4OMs
3-Py
12:1
8:1
8:1
3-Py
Me
1-Naph
p-C6H4F
2-C4H3S
2-furyl
8:1
7:1
79[c]
82[c]
76
from Aux2
p-C6H4OMe
p-C6H4OMs
Ph
13:1
Bn
p-C6H4F
86
91
>99
>99
E-styryl
p-C6H4NO2 Bz
10:1
5:1
>99:1
24:1
71
79
[a] Reaction conditions: MeOH/aq HCl conc. 5:1, 15 h, 238C. [b] Reac-
tion conditions: 408C, 6 h.
1-Naph
10:1
7:1
10:1
4:1
>99:1
>99:1
>99:1
>99:1
19:1
p-C6H4Br
p-C6H4OMe
Me
Bn
74[d]
76[c]
69
p-C6H4NO2
conc. aq. HCl in MeOH is used.[12] Additionally, the hetero-
cycles have also been shown to be stable under alkaline
conditions. Thus, as exemplified for 10, cleavage of the N-
benzoyl group with K2CO3 in aq. MeOH leads to monosub-
stituted oxadiazolidinone 11 in > 99% ee after auxiliary
removal (Scheme 2).
Cy
5:1
84
70
70
tBu
p-C6H4OMe 6:1
2,6-Cl2C6H3 6:1
>99:1
>99:1
[a] Reaction conditions: CH2Cl2, 238C. Abbreviations used: Cy=cyclo-
hexyl, Ms=methanesulfonyl, Naph=naphthyl, Py=pyridyl. [b] Yield of
the isolated, analytically pure material. [c] Reaction conducted at reflux.
[d] Reaction conducted in acetonitrile at reflux.
Scheme 2. Synthesis of oxadiazolidinone 11.
of the reaction mixture and simple trituration of the resulting
solids (MeOH) generally affords the desired heterocycles in
analytically pure form (> 99:1 d.r.).
Auxiliary removal is readily accomplished under acidic
conditions (0.5m toluenesulfonic acid (TsOH), aq. MeOH)
[Eq. (4)]. We found that in the course of this reaction the
isopropylidene protecting groups on the auxiliary first
undergo hydrolysis followed by release of the heterocycle.
Consequently, the water-soluble carbohydrate remnant of the
Trichloroacetyl isocyanate (13) participates in rapid cyclo-
addition (6 min) with the least reactive nitrone investigated
(12). An added advantage is that product 14 is produced
directly, since the trichloroacetyl group is cleaved during
workup. Subsequent acid treatment affords 11. These obser-
vations collectively underscore the fact that the oxadiazoli-
dinones are inherently configurationally stable, even in their
least substituted form.
Angew. Chem. Int. Ed. 2005, 44, 936 –938
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ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
937

Communications
In conclusion, we report the first general synthesis of
enantiomerically pure oxadiazolidinones including the pre-
viously unknown optically active N2-unsubstituted parent
structures. The salient features of this process include the
convenient experimental protocol (simple dissolution of the
two reactants in CH2Cl2) and the isolation of analytically pure
products upon trituration with methanol in up to > 99:1 d.r.
Of additional importance, we document that this class of
optically active heterocycles is configurationally stable. These
compounds should find application as building blocks for
pharmaceutical and other biologically relevant substances in
industry and academia.
Received: September 9, 2004
Published online: December 28, 2004
Keywords: asymmetric synthesis · cycloaddition · heterocycles ·
.
isocyanates · nitrones
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2010.
[2] A related chiral heterocyclic core can be found in HIV protease
inhibitors, see G. V. De Lucca, P. Y. S. Lam, Drugs Future 1998,
23, 987.
[3] For application as microbiocides, see: Merck Patent Gesellschaft
mit beschrꢀnkter Haftung (DE), US 6455529 B1, 2002; b) For
application as adhesion receptor antagonists see: Du Pont Merck
Pharma (US), US 5610294, 1997; c) For application as retroviral
protease inhibitors, see: Syngenta Crop Protection, US2004/
0063937, 2004.
[4] a) H. Goldschmidt, Ber. Dtsch. Chem. Ges. 1890, 23, 2746; b) E.
Beckmann, Ber. Dtsch. Chem. Ges. 1890, 23, 3319; c) A. M. T.
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Taylor, I. C. Whittaker, M. J. Begley, J. Chem. Soc. Perkin Trans.
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[5] In a study of asymmetric cycloaddition involving nitrones and
olefins, brief mention of the cycloaddition reaction with phenyl-
isocyanate is described. At best a 2:1 ratio of diastereomers was
obtained, and attempts to remove the phenethyl auxiliary led to
destruction of the heterocycle, see: C. Belzecki, I. Panfil, J.
Chem. Soc. Chem. Commun. 1977, 303.
[6] D. Blaser, D. Seebach, Liebigs Ann. Chem. 1991, 1067.
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[8] R. Fitzi, D. Seebach, Tetrahedron 1988, 44, 5277.
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Chem. 2002, 114, 3180; Angew. Chem. Int. Ed. 2002, 41, 3054.
[10] For the development of the chiral mannose-derived nitrones,
see: A. Vasella, Helv. Chim. Acta 1977, 60, 1273.
[11] A. Basha, R. Henry, M. A. McLaughlin, J. D. Ratajczyk, S. J.
Wittenberger, J. Org. Chem. 1994, 59, 6103.
[12] The configurational stability of these heterocycles may be
related to the low basicity of the N2 nitrogen. Preliminary
investigations with the oxadiazolidinone derived from p-fluo-
rophenyl isocyanate and p-mesyloxyphenyl-derived nitrone
provide an estimate of the pKa as ꢀ 2 for the corresponding
conjugate acid.
938
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
Angew. Chem. Int. Ed. 2005, 44, 936 –938