The [3 + 2] Nitrone–Olefin Cycloaddition Reaction

Abstract

Early researchers studying the condensation product of carbonyl compounds with N ‐substituted hydroxylamines elected to coin the term “nitrone” as a combination of the words “nitrogen” and “ketone.” This was done to emphasize the parallel between this newly discovered functionality and the already rich chemistry of the carbonyl group. For example, nitrones are capable of reacting with carbanions of various types, a consequence of the iminium species embedded in the nitrone that renders the functionality susceptible to nucleophilic attack. Thus C ‐phenyl‐ N ‐methylnitrone undergoes a Reformatsky reaction with ethyl bromoacetate in complete analogy with benzaldehyde. The intermediate zinc alkoxide cyclizes to 2‐methyl‐3‐phenylisoxazolidin‐5‐one, a type of compound that can also be prepared by the related nucleophilic addition of dialkyl malonates to nitrones. This chapter deals with a unique property of nitrones not shared by the corresponding carbonyl compounds, namely, a marked ability to undergo a [3 + 2] cycloaddition reaction in the presence of a dipolarophile. The reactions of nitrones with substituted olefins, both intermolecular and intramolecular are addressed. This process yields isoxazolidines directly, affording products related to those obtained in the Reformatsky reaction but arising by a different reaction mode. The intent of the review presented in this chapter is to provide a thorough understanding of the nitrone–olefin [3 + 2] cycloaddition reaction and to illustrate its power by describing some significant applications to complex synthetic problems. Various aspects have been reviewed. This documentation of the nitrone–olefin cycloaddition reaction begins with the preparation and stability of the nitrone component and is followed by mechanistic considerations. A presentation of the dipolarophile syntheses is beyond the scope of this chapter; however, the tabular survey provides leading references to specific examples. The important concepts of regio‐ and stereo‐selectivities are introduced next. Since the general rules of regiochemistry that apply in the intermolecular version of the reaction are often reversed in the intramolecular version, the latter are dealt with separately. Finally, important applications to the total synthesis of natural products are presented. The versatile utility of the nitrone–olefin cycloaddition reaction in the synthesis of natural products has been the major driving force in the development of this long‐neglected chemistry. An in‐depth understanding of the key transformations of the isoxazolidines afforded by the reaction will place this chemistry firmly within the arsenal of organic reactions.

Rapid, efficient, and room temperature synthesis of nitrones in excellent yields over MgO under solvent‐free conditions

“…Nitrones have proved to be very useful tools in the synthesis of structurally complex molecules, usually allowing a high degree of diastereocontrol. In this context, both the [3 + 2] cycloaddition of nitrones to alkenes [2,3] and the alkylation of nitrones by organometallic reagents [4] have been extensively studied and have become reliable synthetic procedures. One of the most common procedures for the synthesis of nitrones is the condensation of aldehydes and ketones with N-monosubstituted hydroxylamines [5,6].…”

Synthesis of Enantiopure Highly Functionalized Pyrrolizines and Indolizines from Natural α‐Amino Acids: An Ex­perimental and Theoretical Investigation

“…[1] For the past few years, we have had an interest in the synthesis of such molecules, with intramolecular nitrone cycloaddition reactions [2] being our synthetic methodology of choice. We have succeeded in the preparation of both racemic and enantiopure pyrrolizidines and indolizidines endowed with amino and hydroxy groups by using nitrones derived from 1-allylpyrrole-2-carbaldehydes 1.…”

“…On the basis of the retrosynthetic analysis of such pyrroles, natural α-amino acids were devised as building blocks for the construction of the pyrrole nucleus, allowing access to chiral non-racemic species. [ Although intramolecular nitrone cycloaddition reactions have been known for a long time and their synthetic versatility is well established, [2] the regio-and diastereoselective outcomes of these reactions are a consequence of a subtle interplay of electronic factors and geometric restraints, precluding a sound prediction in most cases. Consequently, we present our experimental work along with the results of an extensive and systematic theoretical investigation.…”

The Effects of Lewis Acid on the 1,3-Dipolar Cycloaddition Reaction of C-Arylaldonitrones with Alkenes.

“…[1][2][3] Some five-membered heterocyclic rings found in the structure of natural products has been built up directly by the reaction. 3,4) Though several dipoles other than nitrones have been used for the synthesis of natural products, nitrones have been found to have wide applications. 4) Some functional groups found in the structure of natural products have been known to be prepared all at once by ring-opening reaction of the cycloadducts.…”

“…3,4) Though several dipoles other than nitrones have been used for the synthesis of natural products, nitrones have been found to have wide applications. 4) Some functional groups found in the structure of natural products have been known to be prepared all at once by ring-opening reaction of the cycloadducts. [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21] The structure and stereochemistry of the cycloadducts depend largely on electronic nature of dipole and dipolarophile because 1,3-dipolar cycloaddition reaction is one of representative concerted reactions.…”