Nitrones frontier orbitals

Frontier-orbital Interactions for 1,3-Dipolar Cycloaddition Reactions of Nitrones... 

Two dipoles especially important in organic synthesis are nitrile oxides and nitrones. The frontier orbital picture for a simple nitrile oxide is shown in Fig. 6.37, where we can see that the easy reactions ought to be decisively dipole-LU-controlled, and fast with C- and X-substituted alkenes. This matches well with the reactions of benzonitrile oxide with styrene, terminal alkenes, enol ethers and enamines which all give only the 5-substituted isoxazolines 6.235. 

The frontier orbital picture for a simple nitrone is shown in Fig. 6.38, where we can see that the easy reactions will be dipole-LU-controlled with X-substituted alkenes and dipole-HO-controlled with Z-substituted alkenes. In practice, phenyl, alkoxy, and methoxycarbonyl substituents speed up the cycloadditions. Any substituent on the carbon atom of the dipole introduces a steric element in favour of the formation of the 5-substituted isoxazolidines 6.238. The selectivity with monosubstituted alkenes is in favour of this regioisomer, decisively so with C- and X-substituents, but delicately balanced with Z-substituents, since the HOMO of the dipole is not strongly polarised. With methyl crotonate, both adducts have the methyl group on the 5-position and the ester group on the 4-position. 

In agreement with frontier orbital considerations, crotonic esters add to nitrones to produce p-o o esters regioselectively. This reaction provides the basis for a synthesis of the Senecio alkaloid supinidine (7). Reaction of 1 with methyl 4-hydroxycrotonate yields the isoxazolidinone 5, which is easily converted to the... 

The relative frontier molecular orbital (FMO) energies of the reagents are very important for the catalytic control of 1,3-dipolar cycloadditions. In order to control the stereochemical outcome of a reaction with a substoichiometric amount of a ligand-metal catalyst, it is desirable that a large rate acceleration is obtained in order to assure that the reaction only takes place in the sphere of the metal and the chiral ligand. The FMO considerations will be outlined in the following using nitrones as an example. 

Exceptions do exist, however, and one must be particularly alert to substituent-induced changes in the direction of polarization, as well as to their affect upon the energy of the frontier molecular orbitals. For example, nitrone cycloaddition regiochemistry is generally LU controlled, leading to the production of C-S substituted isoxazolines in excellent yield. However, as the ionization potential of the nitrone decreases or the electron affinity of the dipolarophile increases, there exists an increased propensity for formation of the C-4 regioisomer. Eventually, a switch from LU to HO control occurs and substantial amounts of the C-4 isomer are produced (equation 14). 

The extent and the sense of diastereoselection largely depends on the steric and electronic nature of the cycl oaddends, and is commonly rationalized in terms of frontier molecular orbital (FMO) theory and steric considerations1-2,6-26 34. Although endo transition states generally seem favored in intermolecular reactions, stereoselection is often unpredictable. In some cases, isomerization of the commonly obtained Z-nitrone to the more reactive -form is invoked to explain anomalous results. However, as in the case of cyclic nitrones where isomerization... 

Nature of the Activation Effect One of the principal questions that may be interpreted with the help of theoretical methods is the reasons for the activation of nitriles toward DCA upon their coordination to a metal center. Traditionally, the reactivity of dipoles and dipolarophiles in the DCA reactions is explained in terms of the frontier molecular orbital (FMO) theory and depends on the predominant type of the FMO interaction. The coupling of nitrones with nitriles is usually controlled by the interaction of the highest occupied molecular orbital (HOMO) of nitrone and the lowest unoccupied molecular orbital (LUMO) of nitrile centered on the C N bond (so-called normal electron demand reactions). For such processes, the coordination of N CR to a Lewis acid (e.g., to a metal) decreases the LUMOncr energy, providing a smaller HOMOjii -one - LUMOncr and, hence, facilitates the DCA reaction (Fig. 13.1a). 

Figure 13.1 Frontier molecular orbitals of nitrone and free or coordinated nitrile (a) and transition state of the concerted as5mchronous mechanism of the nitrone-to-nitrile cycloaddition (b).

Figure 13.2 Energies of frontier molecular orbitals of nitrone CH2=N(Me)0 and free and coordinated acetonitrile.

Based on these affirmations and using the Frontier Moleeular Orbital (FMO) theory, justify the regio- and stereochemistry of compound 6, obtained in the reaction between nitronate 4 and methyl propenoate 5 (Scheme 22.2). 

---