Asymmetric 1,3-Dipolar Cycloaddition Reactions of Nitrones with (S)-(-)-4-Benzyl-N-methacryloyl-2-oxazolidinone

Abstract

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.

Electronic effects in 1,3-dipolar cycloaddition reactions of N-alkyl and N-benzyl nitrones with dipolarophiles

“…This phenomenon is known to occur due to inversion at the nitrogen atom taking place on the 1 H NMR-timescale. 19 NOE analysis was inconclusive for the assignment of the signals corresponding to the two diastereomers. However, based on an analogy of chemical shifts for isoxazolidines previously obtained from diarylnitrones, 13 we could distinguish and assign 1 H NMR shifts to each of the two diastereomers.…”

Asymmetric Synthesis of Cyclopentene Compounds Containing All-Carbon Quaternary Stereocenters by (3 + 2) Cycloaddition and Its Application in the Formal Synthesis of (R)-(−)-Puraquinonic Acid

“…As observed for entry 5, α-arylated alkene 14e led to lower diastereoselectivity for adduct 15be (entry 10). The stereochemistry of the major diastereomer of 15be was confirmed by conversion into known compound 17 and comparison of the optical rotation with the literature value (Scheme ). These results demonstrate that this reaction can be used to synthesize a variety of cyclopentene compounds containing all-carbon quaternary stereocenters.…”

“…[α] 21 D −15.4 ( c 0.530, CHCl 3 ), [lit. [α] 26 D −24.0 ( c 0.8, CHCl 3 ) for 66% ee] . IR (KBr) 2977, 1731, 1694 cm –1 .…”

“…1 H NMR (500 MHz, CDCl 3 ): δ 6.44 (br s, 1H), 4.77 (m, 1H), 4.18 (q, 2H, J = 7.2 Hz), 3.13−3.04 (m, 2H), 2.48 (d, 1H, J = 16.5 Hz), 2.36 (d, 1H, J = 18.5 Hz), 1.83−1.65 (m, 4H), 1.54−1.23 (m, 6H), 1.31 (s, 3H), 1.28 (t, 3H, J = 7.2 Hz). 13 (20). The following reaction was carried out under Ar.…”