Synthesis of a new class of aminocyclitol analogues with the conduramine D-2 configuration

Article abstract of DOI:10.3762/bjoc.6.15

A new class of aminocyclitol derivatives with the bicyclo[4.2.0]octane skeleton was synthesized starting from cyclooctatetraene. Photooxygenation of trans-7,8-diacetoxy- and cis-7,8-dichlorobicyclo[4.2.0]octa-2,4-diene afforded the bicyclic endoperoxides. Reduction of the latter with thiourea followed by a Pd(0) catalyzed ionization/cyclization reaction gave the corresponding oxazolidinone derivatives. Oxidation of the double bond with KMnO₄ or OsO₄ followed by acetylation gave the acetate derivatives, the exact configuration of which was determined by spectroscopic methods. Hydrolysis of the oxazolidinone rings and removal of the acetate groups furnished the desired aminocyclitols.

Full text of DOI:10.3762/bjoc.6.15

Synthesis of a new class of aminocyclitol analogues
with the conduramine D-2 configuration
Latif Kelebekli, Yunus Kara* and Murat Celik*
Full Research Paper
Open Access
Address:
Beilstein Journal of Organic Chemistry 2010, 6, No. 15.
Atatürk University, Faculty of Science, Department of Chemistry,
TR-25240, Erzurum, Turkey
doi:10.3762/bjoc.6.15
Received: 28 September 2009
Accepted: 07 February 2010
Published: 15 February 2010
Email:
Yunus Kara* - yukara@atauni.edu.tr; Murat Celik* -
mcelik@atauni.edu.tr
Associate Editor: J. N. Johnston
* Corresponding author
© 2010 Kelebekli et al; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
aminocyclitol; cyclitols; endoperoxide; oxidation; X-ray analysis
Abstract
A new class of aminocyclitol derivatives with the bicyclo[4.2.0]octane skeleton was synthesized starting from cyclooctatetraene.
Photooxygenation of trans-7,8-diacetoxy- and cis-7,8-dichlorobicyclo[4.2.0]octa-2,4-diene afforded the bicyclic endoperoxides.
Reduction of the latter with thiourea followed by a Pd(0) catalyzed ionization/cyclization reaction gave the corresponding
oxazolidinone derivatives. Oxidation of the double bond with KMnO4 or OsO4 followed by acetylation gave the acetate derivatives,
the exact configuration of which was determined by spectroscopic methods. Hydrolysis of the oxazolidinone rings and removal of
the acetate groups furnished the desired aminocyclitols.
Introduction
Among the myriad of naturally occurring compounds are the the design of carbohydrate mimetics, which can be potent in-
aminocyclitol-containing natural products, which represent a hibitors of glycosidase (1–4) [11-16], we have developed a
large family of sugar derived microbial secondary metabolites method for rapid entry to these compounds.
and include the clinically active aminoglycoside inhibitors
[1-11], many of which are widely used for the treatment of
diseases in humans, animals and plants [1-15].
Glycosidase and related enzymes are involved in the biosyn-
thesis of the oligosaccharide chains [1-15]. Carba analogues of
oligosaccharides (carbasugars), generated by replacing the
endocyclic O-atom in a monosaccharide [1-11], are thought to
be better drug candidates than natural sugars, since they are
hydrolytically stable. Spurred on by the heightened interest in
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Beilstein Journal of Organic Chemistry 2010, 6, No. 15.
Antibiotics containing an aminocyclitol unit have stimulated the catalyzed reaction of diol 11 and TsNCO [32]. Thus treatment
development of synthetic methodologies [16] in the search for of the cis-diol 11 in THF with 2 equiv of p-toluenesulfonyl
analogues with enhanced pharmacological profiles [6]. Balci isocyanate gave the corresponding bis-carbamate 12 which was
and Kara [20-22] have synthesized the polyhydroxylated subsequently added to a solution of 5 mol % of the catalyst,
bicyclic molecule 5 having the bicyclo[4.2.0]octane skeleton prepared by stirring a mixture of ligand (triisopropylphosphite)
bis-homoinositol. Furthermore, Trost et al. [23,24] have and tris(dibenzylideneacetone)–dipalladium-chloroform
reported a regio- and stereoselective Pd(0) catalyzed reaction of complex in THF. Subsequent purification by column chroma-
diols in the presence of p-toluenesulfonyl isocyanate for the tography gave oxazolidinone 13 in 48% yield (Scheme 1). The
introduction of the amino alcohol functionality.
structure of 13 was assigned by 1H and 13C NMR and later by
X-ray analysis of product 15.
We are currently interested in the synthesis of cyclitols and their
derivatives [25]. As a part of our program directed towards the The observed regio- and stereoselectivity was remarkable since
synthesis of potential glycosidase inhibitors we used a the leaving groups are diastereotopic.
bicyclo[4.2.0]octane framework for OH, chlorine and NH2
groups as an intriguing carbohydrate alternative [26-30].
The metal–olefin complexation is a likely source of the
stereoselectivity. Mechanistically, only palladium–olefin
Herein, we report the synthesis of the new aminocyclitol complexation anti to the leaving group will lead to the product
analogues 6 and 7 from cyclooctatetraene.
13 [33,34], which is inconsistent with a steric preference for the
metal approaching the double bond in 12 from the side of the
four-membered ring to form complex 14 (Scheme 2).
Since the double bond is not symmetrically disubstituted, palla-
dium can theoretically form two complexes 15 and 16 after
ionization. We assume that the formation of complex 15 is
hindered due to the presence of an acetate group in the endo
position.
Results and Discussion
Diacetoxydiene 9 was synthesized in 99% yield from
cyclooctatetraene (8) by the addition of mercury(II) acetate cis-Dihydroxylation of 13 with KMnO4 at −15 °C gave a single
[31]. Tetraphenylporphyrin sensitized photooxygenation of diol 17, which was converted into the tetraacetate by treatment
diacetoxydiene 9 with singlet oxygen gave the expected endo- with acetic anhydride/CH3COONa [35] (Scheme 3). Careful
peroxide 10. Reduction of the peroxide bond in 10 was examination of the reaction mixture did not reveal the forma-
performed with thiourea under very mild conditions to give the tion of the other isomer. The stereochemical course of the
cis-diol 11 in 99% yield. The introduction of the amino alcohol hydroxylation may be syn or anti with respect to the
functionality was achieved by a regio- and stereoselective Pd(0) oxazolidinone and cyclobutane rings. NMR spectroscopic
Scheme 1: Synthesis of bis-carbamate 12 and oxazolidinone 13.
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Beilstein Journal of Organic Chemistry 2010, 6, No. 15.
Scheme 2: Mechanism of the palladium-catalyzed ionization/cyclization reaction.
Scheme 3: Synthesis of aminocyclitol analogue 6.
studies did not allow the assignment of the exact orientation of resembles the configuration of conduramine D-2 [36-38].
the hydroxyl groups. X-ray analysis of 18 (Figure 1) revealed Hydrolysis of the acetate groups with H2SO4 proceeded
the exact configuration of the compound. This also confirms the smoothly to deliver aminocyclitol 6 in 84% yield.
configurations of endoperoxide 10, oxazolidinone 13 and cis-
hydroxylation product 17.
For the synthesis of dichloro derivative, we replaced the
acetoxy groups in 9 with cis- configured chlorine atoms. This
The all cis-configuration of the four acetate and amino groups provides a route for the synthesis of other haloaminocyclitol de-
in aminocyclitol 18 [25] attached to the six-membered ring rivatives.
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Beilstein Journal of Organic Chemistry 2010, 6, No. 15.
the diene unit exclusively from the less crowded side of the
molecule in accord with previous reports [20,21]. Reduction of
the peroxide bond in 20 with thiourea under very mild condi-
tions gave the cis-diol 21 in 95% yield. Diol 21 in THF was
treated with 2 equiv of p-toluenesulfonyl isocyanate to give the
intermediate bis-carbamate 22 which was then treated as
described above for 12 with the same Pd(0) catalyst to afford,
after chromatography on a silica gel with hexane/ethyl acetate
(3:1) as eluant, the oxazolidinone 23 in 61% yield.
The structure of 23 was assigned by 1H NMR and 13C NMR
spectroscopy. The double bond in 22 is symmetrically disubsti-
tuted, and therefore palladium can form only one complex 25
after ionization (Scheme 5).
Figure 1: The thermal ellipsoid plot of the single crystal X-ray crystallo-
graphic structure of 18.
Hydrolysis of oxazolidinone 23 with K2CO3 gave alcohol 26,
which was subsequently converted into acetate 27 by treatment
cis-Dichlorobicyclooctadiene 19 was synthesized from with Ac2O/NaOAc [35] (Scheme 6).
cyclooctatetraene 8 by the addition of chlorine following the lit-
erature procedure [39]. Photooxygenation of cis-dichlorobicylo- cis-Hydroxylation of 27 with OsO4 at 0°C gave the correspond-
octadiene 19 with singlet oxygen gave the expected endoper- ing diol 28, which was further converted into triacetate 7 with
oxide 20 [19-21] (Scheme 4). Since the dichlorobicycloocta- Ac2O/NaOAc (Scheme 6). The exact configuration of triacetate
diene 19 has no plane of symmetry, singlet oxygen approaches 7 was confirmed by differential 1H NMR NOE measurements
Scheme 4: Synthesis of oxazolidone 23.
Scheme 5: Mechanism of the palladium-catalyzed ionization/cyclization reaction in dichloro biscarbamate 22.
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Beilstein Journal of Organic Chemistry 2010, 6, No. 15.
Scheme 6: Synthesis of dichloroaminocyclitol 7.
(Figure 2). Irradiation of H3 (H3–CNHTs) at δ 3.85 caused 7 based on the bicyclo[4.2.0]octane frame work, with stereo-
signal enhancements of H1, H2, and H4 at δ = 5.45, 5.28 and control during the formation of all the stereogenic centres.
5.15, respectively. This result is consistent with a cis-relation-
ship between H1, H2, H3 and H4 protons.
Experimental
Melting points were determined on a Büchi 539 capillary
We assume that the stereochemical course of the hydroxylation melting apparatus and are uncorrected. Infrared spectra were
of 27 proceeds through syn addition as previously observed in obtained from KBr or film on a Mattson 1000 FT-IR spectro-
the hydroxylation of 13, a quite similar structure to 27.
photometer. The 1H and 13C NMR spectra were recorded on
200 (50) and 400 (100) MHz Varian spectrometer and are
The all cis-configuration of the acetate and amino groups at- reported in δ units with SiMe4 as internal standard. Thin layer
tached to the six-membered ring resembles the configuration of chromatography (TLC) was performed on E. Merck Silica Gel
conduramine D-2 [31,40,41]. The cyclic polyhdroxylated 60 F254 plate (0.2 mm). All column chromatography was
amines, also known as aminocyclitols, possess a wide variety of performed on silica gel (60 mesh, Merck). Elemental analyses
biological activities [42-45]. In conclusion, we have outlined were carried out on a Carlo Erba 1108 model CHNS-O
the synthesis of a new family of aminocyclitols analogues 6 and analyzer.
Figure 2: 1H NMR NOE spectrum of compound 7.
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Beilstein Journal of Organic Chemistry 2010, 6, No. 15.
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Supporting Information
19.El Ashry, E. S. H.; Rashed, N.; Shobier, A. H. S. Pharmazie 2000, 55,
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Supporting Information File 1
Experimental Section
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The experimental section describes the synthesis,
purification and characterization data of all substances
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Acknowledgements
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The authors are indebted to the Department of Chemistry
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(DPT) for purchasing a NMR, GS-MS and The Scientific and
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105T162).
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