The [3+2]-nitrone-mediated cycloaddition reaction of (S)-(-)-4-benzyl-N-methacryloyl-2-oxazolidinone has been applied to the synthesis of highly substituted isoxazolidines with controlled stereochemistry. The absolute configuration of the major diastereoisomer derived from the reaction between N-(p-nitrobenzylidene)methylamine N-oxide and (S)-(-)-4-benzyl-Nmethacryloyl-2-oxazolidinone has been deduced from the corresponding X-ray structure.Asymmetric 1,3-dipolar cycloaddition reactions between nitrones and chiral acrylamide derived dipolarophiles have attracted considerable interest in recent times. 1 This is part due to the enhanced p-diastereoselectivity associated with chiral auxiliary based dipolarophiles 2 coupled with the ease with which the chemistry may then be transferred onto a solid support media 3 by immobilising either the dipole or the dipolarophile onto a polymer-derived support. Some recent examples of immobilisation have been revealed using a chiral sultam, 4 a sugar 5 or a chiral oxazolidinone. 6In conjunction with clinical collaborators we were keen to establish methods for accessing g-lactams for biological evaluation, in particular, a range of examples containing a C-3 tertiary hydroxyl group. Previous studies 7 from our laboratories revealed that lactams such as 2 may be readily accessed via a TiCl 3 -mediated cleavage of the comparatively weak N-O of an isoxazolidine such as 1 (Scheme 1).That being the case we reasoned that suitable candidates for screening would be readily available from a nitronemediated cycloaddition reaction using a methacryloylbased amide dipolarophile such as 3.The corresponding lactam 5 might then be produced directly in one step from isoxazolidine 4 using TiCl 3 or by a two-step process involving an initial hydrolysis of the auxiliary followed by an N-O bond cleavage reaction (Scheme 2).From our survey of the chemical literature we found relatively few examples 8 of methacryloyl-based amides as partners in nitrone cycloaddition reactions. However 3-hydroxy-b-lactams and related compounds have been synthesised via nitrone cycloaddition reactions with 3-methylene b-lactams. 9As a general observation the regioselectivity of reactions involving nitrones and 1,1-disubstituted dipolarophiles, such as 3, are completely unambiguous in affording the corresponding 5,5-disubstituted isoxazolidine. It is an outcome which is largely influenced by the substituent effects of the dipolarophile rather than electronic influences. 10 Our preliminary investigation focussed upon a comparatively simple model that involved the cyclisation reaction between the dipolarophile 7 and the dipoles 6a,b (Scheme 3). Scheme 3Scheme 2 Scheme 1Downloaded by: Queen's University. Copyrighted material.
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