Secondary orbital effects

Another possible route to thienamycin (487) has utilized the dipolar cycloaddition of 1-pyrroline 1-oxide (482) with methyl crotonate (79TL4359). The reaction is highly stereoselective due to the operation of secondary orbital effects. The isoxazolidine (483), produced in 90% yield, was subjected to hydrogenolysis, and the resulting amino alcohol (484) was selectively blocked with hexamethyldisilazane to give (485). Treatment with ethylmagnesium bromide then gave /3-lactam (486 Scheme 107). 

Duncan, J. A. Calkins, D. E. G. Chavarha, M. Secondary orbital effect in the elec-trocyclic ring closure of 7-azahepta-l,2,4,6-tetraene - a CASSCF molecular orbital study, 7. Am. Chem. Soc. 2008,130, 6740-6748. 

Grieco has used his aqueous imnicmium Diels-Alder procedure to effect a number of intramolecular reactions. In one case, diene aldehyde (83) was treated with ammonium chloride to afford a 2.2 1 mixture of isomeric Diels-Alder adducts (87) and (85) (Scheme 10). Since intermediate immonium ions (84)/(86) cannot participate in secondary orbital effects as is the case with A-acyl imines (c/. 80), these results are probably due to steric factors. It was suggested that adduct (85) derives from conformation (84) and adduct (87) comes from (86). Conformer (84) is favored since there is a severe eclipsing of Ha b in (86). A more detailed account of the stereochemical aspects of intramolecular Diels-Alder reactions can be found in Chapter 4.4. 

The formation of adduct 20 can be rationalized if one considers the (Z)-sulfinyl carbamate reacting via parallel conformer 19A (Scheme 1-VI). If this dienophile conformer is attacked by the diene from the more exposed face in an endo transition state, adduct 20 will result. Another possibility is for conformer 19B of the E dienophile to react via an exo transition state to give 20. Although the second possibility would seem less likely than the first, it has not been established that secondary orbital effects are important in cycloaddition reactions of JV-sulfinyl carbamates and thus the exo case should not be summarily dismissed at this time. 

There are probably several factors which contribute to determining the endo exo ratio in any specific case. These include steric effects, dipole-dipole interactions, and London dispersion forces. MO interpretations emphasize secondary orbital interactions between the It orbitals on the dienophile substituent(s) and the developing 7t bond between C-2 and C-3 of the diene. There are quite a few exceptions to the Alder rule, and in most cases the preference for the endo isomer is relatively modest. For example, whereas cyclopentadiene reacts with methyl acrylate in decalin solution to give mainly the endo adduct (75%), the ratio is solvent-sensitive and ranges up to 90% endo in methanol. When a methyl substituent is added to the dienophile (methyl methacrylate), the exo product predominates. ... 

The complexation with Lewis acids or the protonation influences both the energy and the coefficients of carbon atoms of the LUMO orbital of the dienophile. The coefficient of the carbonyl carbon orbital increases (Scheme 1.16) consequently, the stabilizing effect of the secondary orbital interaction is greatly increased and the endo addition is more favored. 

Keywords it-Facial selectivity, a/ir Interaction, CH/ir Interaction, Ciplak effect, Diels-AIder reaction, Electrostatic interaction, Orbital mixing rule. Orbital phase environment, Secondary orbital interaction, Steric repulsion, Torsional control... 

In the case of the reverse-electron-demand Diels-Alder reactions, the secondary orbital interaction between the Jt-HOMO of dienophile and the LUMO of 114 or the effect of the orbital phase enviromnents (Chapter Orbital Phase Enviromnents and Stereoselectivities by Ohwada in this volume) cannot be ruled out as the factor controlling the selectivity (Scheme 55). 

The authors (162) attempted to explain the stereochemical outcome of the reactions (Schemes 3.169 and 3.170) in the terms used earlier (337), that is, by steric factors, which destabilize the endo approach of a dipolarophile, and the electronic effect (secondary orbital interactions), which is most typical for electron-rich dipolarophiles and can slightly stabilize the endo approach of these olefins. 

There has been, however, an ongoing debate about other factors which may control endo selectivity. Endo selectivity has been observed when no secondary orbital interactions are possible and have been ascribed to steric effects in these cases58,59. Recently, the... 

For instance, steric effects are frequently suggested to be important in determining the selectivity, especially in the reactions of a-substituted dienophiles and in reactions forming the unexpected exo-product with high selectivity (Scheme 5)71,72. London dispersion interactions have also been considered, and it has been argued that these interactions can sometimes override secondary orbital interactions73-75. 

Apart from the aqueous rate accelerations, the aqueous medium has also a favorable effect on the endo-exo selectivity. Substantially higher preferences for the endo isomer were found. This effect can be explained taking the more efficient secondary orbital interactions into considerations as well as additional... 

JCS(P1)1113]. The formation of the trans adduct involves a boatlike endo transition state (110 versus 111), which is enhanced in aqueous solution by some extra charge separation resulting from both secondary orbital interaction and by a hydrophobic packing effect of the substrate (94JOC1358, 94TL595). 

The effectiveness of the secondary orbital interactions on the selectivity of the cyclopropanation reactions was demonstrated by the formation of a single cyclopropane isomer in the reaction of la with ( )—Mc2NC0CH=CHC02Me (Scheme 8.17). Simple Hilckel calculations show that the highest coefficient of the HOMO of the aUcene is located at the amido group, and thus despite the smaller steric demand of the ester group, the amido substiment lies syn with respect to the phosphino group. 

An alternative two-step mechanism involving a spin-paired diradical intermediate has also been considered for 1,3-cycloadditions.18,68,69 However, ab initio calculations70-72 on a wide variety of 1,3-dipoles and dipolarophiles are found to coincide essentially with a synchronous 1,3-cycloaddition mechanism.15,17 On the other hand, a two-step mechanism passing through two transition states separated by an intermediate has been derived using the MINDO/3 method, and found to be compatible with substituent and solvent effects as well as stereospecificity observed in 1,3-cycloadditions.73 However, several factors beyond FMO interactions, such as closed shell repulsions, geometrical distortions, polarization, and secondary orbital interactions, all influence mechanisms, rates, and regioselectivities in cycloaddition reactions.74... 

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