Stereoselective Intramolecular Oxime Olefin Cycloadditions Involving Carbohydrate Derived Precursors

Abstract

Intramolecular oxime olefin cycloaddition reactions of carbohydrate derived precursors can be used to prepare highly functionalised 3-oxa-2-azabicyclo[3.3.0]hexanes with good to excellent levels of stereocontrol.In 1970, the first example of an intramolecular oxime olefin cycloaddition (IOOC) reaction was reported by Oppolzer and Keller. 1 Further examples of IOOC reactions have been reported by the groups of Wildman, 2 Grigg, 3 Heathcock, 4 Hassner, 5 among others. 6 As part of a programme directed towards the synthesis of novel glycosidase inhibitors, we wished to determine whether IOOC reactions of carbohydrate derived precursors could be used to construct highly functionalised 3-oxa-2-azabicyclo[3.3.0]hexanes. 7 Furthermore, while some of the previous work indicated that good levels of stereocontrol can be accomplished in relatively simple IOOC reactions, it was unclear at the outset of our studies whether good, predictable levels of stereocontrol could be accomplished in more complex systems. In this letter, we describe a series of stereoselective IOOC reactions using carbohydrate derived precursors and provide some insight into the factors which control the stereochemical outcome of these reactions.Our initial studies were conducted with oxime 1, which was prepared in 6 steps from methyl α-D-glucopyranoside using a Vasella fragmentation as the key step. 7a,b To our delight, thermolysis of this oxime in refluxing toluene for 15 hours produced bicycle 2 in quantitative yield as essentially a single stereoisomer as judged by NMR spectroscopy (Scheme 1). 8,9 Similar results were obtained using either pure (E)-1 or a mixture of (E)-1 and (Z)-1. The cis ring junction and relative stereochemical relationships within bicycle 2 were established using selective nOe difference measurements. 9 To account for the observed stereochemical outcome of this reaction, we suggest that after initial 1,2-prototropic shift, the cycloaddition proceeds with the oxime and olefin components in exo orientations and the benzyl ethers orientated in pseudo equatorial positions about the forming 5-membered ring. Scheme 1To test the generality of this reaction, and to probe the remarkable stereospecificity of this cycloaddition, we have undertaken several other related reactions using other oxime precursors (see Table 1). Oximes 3-6, derived from D-glucose, D-glucal, D-mannose and D-galactose respectively, all undergo intramolecular oxime olefin cycloadditions in good yields. Benzoate protected oxime 3 yielded cycloadduct 7 as the sole product (Table 1, Entry 1). In the other cases, two stereoisomeric cycloadducts were produced in varying proportions depending on the precise structure of the oxime substrate (Table 1, Entries 2-4). With the exception of 2-deoxyglucose series (Table 1, Entry 2), the stereochemistry of the products was elucidated using nOe difference measurements.Downloaded by: University of Arizona Library. Copyrighted material. LETTERS SYNLETTFrom these results, it would appear that the stereogenic centre adjacent to the ox...

Syntheses and Biological Activities of Iminosugars as α-L-Fucosidase Inhibitors

“…14). Compound 183 [61] is a moderate inhibitor of -L-fucosidase from bovine epididymis (IC 50 = 59 μM) and its precursor compound 182 has IC 50 13.8 μM.…”

“…The synthesis of 182 and 183 [61] (Scheme 32) began with 5-deoxy-5-iodo-D-arabinofuranoside 213, obtained in three steps and 63% yield from D-arabinose, as described by Ferrier and Haines [66]. Treatment of this compound with Zn in the presence of vitamin B 12 as initiator gave the 4,5-unsaturated pentose derivative 214 in 79% yield.…”

Structure–Activity Studies of N‐Butyl‐1‐deoxynojirimycin (NB‐DNJ) Analogues: Discovery of Potent and Selective Aminocyclopentitol Inhibitors of GBA1 and GBA2

“…Treatment of aldehyde 30 with hydroxylamine hydrochloride in warm methanol in the presence of sodium bicarbonate provided the corresponding oxime 31 as a mixture of E and Z isomers. An intramolecular 1,3‐dipolar cycloaddition of the crude oxime 31 in toluene at reflux furnished cis ‐fused isoxazolidine 32 . The N − O bond was cleaved with activated zinc under acidic aqueous conditions to provide amine 33 .…”

“…[42] Treatmentofaldehyde 30 with hydroxylamine hydrochloride in warm methanol in the presence of sodiumb icarbonate provided the corresponding oxime 31 as am ixture of E and Z isomers. An intramolecular 1,3-dipolar cycloaddition [43,44] of the crude oxime 31 in toluenea tr eflux furnished cis-fused isoxazolidine 32.T he NÀO bond was cleaved with activated zinc under acidic aqueous conditions [45] to provide amine 33.T he direct reductive alkylation reaction of free amine 33 with butyraldehyde and nonyl aldehydew as low yieldinga nd the reaction products were difficult to purify. Better yields and only mono-alkylated products were obtained when the HCl salt of 33 (Et 3 Nw as used to neutralize the reaction medium) was used, providing improved yields (49!73 % and 41!70 %, respectively) of 34 a and 34 b.S ubsequently, compounds 34 c-34 d were prepared using the same protocol.…”

Imines, enamines and oximes

“…196 Highly functionalised 3-oxa-2-azabicyclo[3.3.0]hexanes are prepared in 70-100% yield with diastereomeric ratios from 1 : 0 to 6 : 1 from carbohydrate derived oxime precursors using an intramolecular oxime olefin cycloaddition. 197 3,4-Dihydro-2H-pyrroles and 2,3,4,5-tetrahydropyridines are prepared by the intramolecular cyclisation of (E)-O-methylsulfonyloximes having an active methine group at γand δ-positions respectively by treatment with DBU in 71-99% yields. 198…”