Elsevier

Tetrahedron

Volume 63, Issue 48, 26 November 2007, Pages 11984-11990
Tetrahedron

Intra-molecular nitrone–olefin cycloaddition of d-glucose derived allylic alcohol: synthesis of new aminocyclohexitols

https://doi.org/10.1016/j.tet.2007.09.011Get rights and content

Abstract

Diastereo- and regioselelective intra-molecular nitrone–olefin cycloaddition reaction of in situ generated N-benzylnitrones, obtained from d-glucose derived precursors 5a/5b furnished dihydroxy functionalized isoxazolidines. The NO bond reductive cleavage and removal of N/O-benzyl groups led to the formation of stereochemically well defined aminocyclohexitols.

Introduction

Amongst polyhydroxylated carbocycles,1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h), 1(i), 1(j), 1(k), 1(l), 1(m), 1(n), 1(o), 1(p), 1(q), 1(r), 1(s), 1(t), 1(u), 1(v), 1(w), 1(x) the amino substituted polyhydroxylated carbocycles, commonly known as aminocyclitols, constitute the key structural fragments for amino-glycoside antibiotics and are potential glycosidase inhibitors as well as antiviral agents.2, 2(a), 2(b), 2(c), 2(d) Advances in the elucidation of biological processes have proved the importance of the six membered aminocyclitols owing to their sugar-mimetic structure. For example, validamine 1 (Fig. 1), a natural aminocyclohexitol, and its unnatural derivatives are at the forefront of the bio-organic research field because of their ability to serve as potent glycosidase inhibitors. This has consequently made them valuable therapeutic agents.3, 3(a), 3(b), 3(c) These compounds, however, receive limited synthetic attention as compared to the five membered aminocyclopentitols. In general, carbohydrates have been exploited as substrates for the synthesis of the aminocyclitols utilizing ring closing metathesis, metal catalyzed reactions and free radical cyclizations1(d), 4, 4(a), 4(b), 4(c), 4(d) as the key steps. Apart from these methodologies, an intra-molecular nitrone–olefin cycloaddition (INOC) reaction, especially with the nitrones derived from sugars, has received more attention.5, 5(a), 5(b), 5(c), 5(d), 5(e), 5(f), 5(g), 5(h), 5(i), 5(j), 6, 6(a), 6(b), 6(c), 6(d), 6(e) The sugar substituted isoxazolidines thus obtained are amenable to the construction of five/six/seven membered aminocyclitols, depending on the formation of bicyclic fused/bridged isoxazolidine ring systems wherein the regio/stereo-chemical outcome of the reaction is controlled by the geometric constraints, steric and electronic factors.5(h), 7, 7(a), 7(b), 7(c), 7(d) We have recently reported the INOC reaction of an in situ generated d-glucose derived nitrone for the synthesis of aminocyclopentitol.8 As a part of our continuing interest in the area of nitrones,9, 9(a), 9(b), 9(c), 9(d) we have now investigated the INOC reaction of an in situ generated nitrone, obtained from the cleavage of the 1,2-acetonide functionality in 3,5-di-O-benzyl-6,7-dideoxy-1,2-O-isopropylidene-hept-6-ene-furanose 5 followed by treatment with N-benzylhydroxylamine hydrochloride. The reaction resulted in the formation of a fused bicyclic isoxazolidine ring skeleton, which on NO bond reductive cleavage afforded three new aminocyclohexitols 2ac. Our results in this direction are presented herein.

Section snippets

Results and discussion

As shown in Scheme 1, the Grignard reaction of vinylmagnesium bromide with 3-O-benzyl-1,2-O-isopropylidene-α-d-xylo-pentodialdose 3,10 in THF at 0 °C gave d-gluco- and l-ido-configurated allylic alcohols 4a and 4b, respectively, in the ratio of 2:3 as reported earlier by us and others.11, 11(a), 11(b), 11(c) Treatment of 4a and 4b individually with benzyl bromide and NaH in THF afforded the corresponding benzyl protected compounds 5a and 5b. Removal of the 1,2-acetonide group in 5a with TFA/H2O

General methods

Melting points were recorded with Thomas Hoover Capillary melting point apparatus and are uncorrected. IR spectra were recorded with a FTIR as a thin film or in Nujol mull or using KBr pellets and are expressed in cm−1. 1H (300 MHz) and 13C (75 MHz) NMR spectra were recorded using CDCl3 or D2O as a solvent. Chemical shifts were reported in δ units (ppm) with reference to TMS as an internal standard, and J values are given in hertz. Elemental analyses were carried out with a C, H-analyzer. Optical

Acknowledgements

We are grateful to Professor M. S. Wadia for helpful discussions. We are thankful to DST, New Delhi (SR/S1/OC-21/2005) for the financial support.

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