Insofar as one of the fundamental objectives of organic synthesis is the construction of complex molecules from simpler ones, the importance of synthetic efficiency becomes immediately apparent and has been well-recognized.1 The increase in molecular complexity2 that necessarily accompanies the course of a synthesis provides a guide (and a measure) of synthetic efficiency. As a goal, one would like to optimally match the change in molecular complexity at each step with reactions of comparable synthetic complexity. Thus, the creation of many bonds, rings, and stereocenters in a single transformation is a necessary (though not sufficient) condition for high synthetic efficiency. The ultimate, perfect match would constitute single-step syntheses. More realistically, especially in view of the desire for general synthetic methods, the combination of mulScott E. Denmark was born in New York in 1953. He obtained an S.B. degree from MIT in 1975 and carried out research with Daniel Kemp and Richard Holm. His graduate studies at the ETH-Zurich with Albert Eschenmoser culminated with the D. Sc. Tech. degree in 1980. That same year he joined the faculty of the University of Illinois at UrbanasChampaign and was promoted to full professor in 1987. In 1991 he was named the Reynold C. Fuson Professor of Chemistry. His research interests are primarily in the invention of new synthetic reactions, structure and reactivity of organoelement reagents, and the origin of stereocontrol in fundamental carbon−carbon bond forming reactions.

Tandem [4+2]/[3+2] Cycloadditions of Nitroalkenes.

Imines 1a and 1b react with dihydrofuran (DHF) under Lewis acid catalysis via Diels–Alder-type addition to form the tetrahydroquinoline derivatives 3a, b and 4a, b. Besides these compounds, the methanol adduct 2 of 1a, or 1a in the presence of methanol, gives the methanol-containing tetrahydrofuran derivative 7a and the hexahydrofuro[3,2-b]furan derivatives 5 and 6. In the presence of methanol, 1b gives 3b and 4b, and also 7b and 8. The products 3a, b, 5, 6 and 7a, b originate from approach of the Si(or Re) face of 1a, b onto the Si(or Re) face of DHF; 4a, b and 8 derive from interaction of the Si(or Re) face of 1a, b with the Re(or Si) face of DHF. The dependence of the product distribution on the polarity of the solvent suggests that a concerted mechanism predominates in the former mode and a zwitterionic one in the latter. In the addition of 1a or 2 the mechanistic preference may be exclusive.

Acid-catalysed addition of N-aryl imines to dihydrofuran. Postulated dependence of the reaction mechanism on the relative face of approach of reactants

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.


Keywords:

cycloaddition reactions;
[3 + 2] reaction;
nitrone;
olefins;
nitrone stability;
mechanism;
regioselectivity;
intermolecular reaction;
intramolecular reaction;
C-alkenylnitrones;
N-alkenylnitrones;
natural products;
alkaloids;
biotin;
aldehyde-derived nitrones;
ketone-derived nitrones;
endocyclic nitrones;
exocyclic nitrones;
amino glycosides;
adaline;
nitrogen-free systems;
experimental procedures

The [3 + 2] Nitrone–Olefin Cycloaddition Reaction

The bis(pentaammineruthenium(II)) complex of dicyanonorbornadiene has been prepared and characterized. Its photochemical conversion into a dicyanoquadricyclane complex by irradiation in methanol has been followed by UV−visible spectroscopy, IR spectroscopy, 1H NMR spectroscopy, and cyclic voltammetry. The dicyanonorbornadiene complex exhibits an intervalence transition in the 1000−1600 nm range when oxidized to the ruthenium(II)−ruthenium(III) state. This allows the determination of the effective coupling Vab through the dicyanonorbornadiene ligand, which is found as 0.023 eV. No such band is observed in the case of the dicyanoquadricyclane complex. These results show the possibility to modulate an intramolecular electron transfer process by using a photoisomerizable bridging ligand.

Electron Transfer through Norbornadiene and Quadricyclane Moieties as a Model for Molecular Switching

1,3-Dipolar cycloaddition of nitrile oxides with unsymmetrically substituted norbornenes

The 1,3-dipolar cycloadditions of phenylglyoxylonitrile oxide, benzonitrile-N-phenylimine, or N-phenyl-C-p-nitrophenylnitrone to norbornadiene, 2,3-dicyanonorbornadiene, and 2,3-bis(methoxycarbonyl...

1,3-Dipolar Cycloadditions to Bicyclic Olefins. I. 1,3-Dipolar Cycloadditions to Norbornadienes

The exo/endo product ratios for three types of 1,3-dipolar cycloadditions of phenylglyoxylonitrile oxide(1) to 2,3-bis(methoxycarbonyl)norbornadiene(2a), norbornadiene, and 2,3-dicyanonorbornadiene decrease with increasing ET value of the non-aromatic polar solvent used. The exo/endo ratio in the reaction of 1 with 2a is larger than unity, but the value of ΔHexo\eweq−ΔHendo\eweq is nevertheless positive. This phenomenon is attributed to the relatively large positive value of ΔSexo\eweq−ΔSendo\eweq, that is, ΔGexo\eweq−ΔGendo\eweq<0 at ordinary temperatures. On the basis of these results, the conditions, under which the exo/endo ratio in the reaction of 1 with 2a is smaller than unity, were determined. The results can be reasonably explained by the assumption that the dipole moment of the endo-form in the transition state is greater than that of the exo-form.

1,3-Dipolar Cycloadditions to Bicyclic Olefins. II. The Effects of Non-aromatic Polar Solvents on the exo/endo Product Ratios in 1,3-Dipolar Cycloadditions to Norbornadienes

1,3-Dipolar cycloadditions of phenylglyoxylonitrile oxide, benzonitrile-N-phenylimine, or N-phenyl-C-p-nitrophenylnitrone to norbornadiene and 2,3-disubstituted norbornadienes gave the endo-adducts together with the exo-adducts. These observations show that 1,3-dipolar cycloadditions to norbornadienes do not follow the “exo rule” of Alder and Stein.

Yoshihiro Yoshida

Papers

1,3-Dipolar Cycloadditions to Bicyclic Olefins. I. 1,3-Dipolar Cycloadditions to Norbornadienes

1,3-Dipolar Cycloadditions to Bicyclic Olefins. II. The Effects of Non-aromatic Polar Solvents on the exo/endo Product Ratios in 1,3-Dipolar Cycloadditions to Norbornadienes

Inapplicability of the “exo rule” to the 1,3-dipolar cycloadditions to norbornadienes

Inapplicability of the ′exo rule′ to the 1,3-dipolar cycloadditions to norbornadienes