Stereoselectivity cycloaddition orientations

It should be noted, however, that the 1,3-dipolar cycloaddition chemistry of diazo compounds has been used much less frequently for the synthesis of natural products than that of other 1,3-dipoles. On the other hand, several recent syntheses of complex molecules using diazo substrates have utilized asymmetric induction in the cycloaddition step coupled with some known diazo transformation, such as the photochemical ring contraction of A -pyrazolines into cyclopropanes. This latter process often occurs with high retention of stereochemistry. Another useful transformation involves the conversion of A -pyrazolines into 1,3-diamines by reductive ring-opening. These and other results show that the 1,3-dipolar cycloaddition chemistry of diazo compounds can be extremely useful for stereoselective target-oriented syntheses and presumably we will see more applications of this type in the near future. 

One of the most widely applied cycloaddition techniques for the preparation of thietanes is the reaction of sulfenes with enamines. The stereochemistry of these reactions has been extensively investigated by Truce and Rach. Whether the mechanism is a two-step or a concerted process, both in accordance with the stereoselective formation of the cis form in Scheme 1, is still unresolved. The special orientation of the 1,4-dipolar intermediate 64, in which the charged phenyl and dimethylamino moieties are in proximity, enforces the cis geometry of the resulting thietane dioxide. In the concerted mode of reaction, formation of the orthogonal oriented unsaturated system, 65 should also yield the cis cycloadduct. 

The stereoselectivity of monosubstituted dipolarophiles has also been studied with cyclic nitronates (Table 2.30) (84). In most cases, an exo selectivity was observed. The ratio between the endo and exo adducts can be correlated to the size of the substituents on the dipolarophile. Because of the endo preference observed with acrolein, it is believed that there is a slight electronic preference for the endo orientation in the transition state, in the absence of steric hindrance. In line with these results is the observation that, for 49, maleic anhydride reacts with complete exo selectivity, in contrast the cycloaddition with 47 (69). 

Cyano-substituted ethylenes react in a different way with aliphatic ketones. The orientation of photochemical cycloaddition (4.661 is the opposite of that found for electron-rich alkenes, and the reaction is highly stereoselective (4.69) in the early stages. These processes involve the formation and subsequent decay of an excited complex (exciplex) from the (n,n ) singlet state of the ketone and the alkene. Aryl ketones undergo intersystem crossing so efficiently that such a singlet-state reaction is rarely observed, but the reaction of a benzoate ester with an electron-rich alkene 14.70 rnay well be of this type, with the ester acting as electron-acceptor rather than electron-donor. 

The fact that molecules in L-B films keep fairly rigid relative orientations (at least within a microdomain) is potentially useful for regio- and stereoselective addition reactions (Figure 8.23). Here a derivative of cirfnamic acid forms the head-to-head dimer in the photochemical cycloaddition reaction. 

The regio and a-stereoselectivity of this low-yield cycloaddition again prove the structural stability of the intermediate diradical with a preferential anomeric semi-occupied orbital in an axial orientation. Similar observations can be made in the furanoside series [48]. 

Excellent regioselectivity and stereoselectivity has been achieved in each photocycloaddition mode [45 48], Regiochemistry and stereochemistry in the meta process is decided by the orientation of the addends in the exciplex and by stabilization of biradical intermediates having a change transfer (CT) character (6) by the substituents on the arene. Intermolecular meta cycloaddition of arenes with cycloalkenes proceeds with endo selectivity (7) (Scheme 5). In the ortho-process, selectivities can be controlled mainly by the substituents on the reactants. 

These endo-exo preferences are energetically small and are of the order of a kcal mol-1. Consequently, factors such as dipole-dipole,27 electrostatic,28 steric29 and solvent effects27,30 can also influence the stereoselectivity. Secondary orbital interactions may not provide all of the answers, but no other theory can rationalize both the preferential endo orientation of 4 + 2 and 8 + 2 cycloadditions and the exo orientation of 6 + 4 cycloadditions so efficiently. See also Exercise 12. 

Fig. 15.41. Orientation-selective and stereoselective 1,3-dipolar cycloaddition of diazomethane. The trans-configured 2-methyl-2-butenoic acid is converted to the trans-configured cycloadduct with a diastereoselectivity of better than 99.997 0.003.

Therefore, some conclusions have been generally accepted and have been summarized as follows the cycloaddition reaction is a stepwise reaction rather than a concerted one the reaction is initiated by nucleophihc attack of an imine to a ketene, giving rise to a zwitterionic intermediate a conrotatory eleclrocyclic ring-closure of the zwitterionic intermediate produces the final 2-azetidone product [85], As the stereochemistry of the structure of the P-lactams strongly affects their biological activity, the stereoselectivity of the process must be carefully considered. Uncatalysed as well as catalysed processes have been reported organometallic and organic catalysts have been utilized in procedures oriented to the syntheses of enantiopure P-lactams [90-92],... 

As seen in 61 and 63, various 1,3-diene functionalities can now be readily incorporated into the bieyclolactone. Summarized in Table 3 are the results of the cycloaddition of 63 with various dienophiles <02TL5591>. Notably, cycloaddition proceeded in a highly regio- and stereoselective fashion to provide, in all cases, virtually a single diastereomer out of four possible isomers <01OL2949>. Interestingly, the reaetion of nor-Br-bicyclic diene 66 with N-ethylmaleimide afforded a mixture of two diasteromers 6 7-endo and 67-exo in a ratio of 62 38 (Scheme 18, representations in an alternative orientation for clarity). 

Although it was stated that allyltrialkylsilanes were unsuccessful in the Lewis acid mediated addition to acryloylFp complexes, a stereoselective procedure has been developed for [3 + 2] cycloadditions of allylsilanes to enones10. The reaction occurs in the presence of titanium(IV) chloride (TiCl4) as Lewis acid and the single cycloaddition product formed is the m-fused eyclopentane with the trimethylsilyl group in the endo orientation. The reaction appears to follow a similar pathway to the previous process although, as yet, yields and experimental procedures have not been documented. 

It has been reported that substituents on tethers also play an important role in the stereoselectivity of the reaction. Giguere and co-workers have reported an example of a highly diastereoselective 4+3 cycloaddition of trienol 54 upon treatment with triflic anhydride at low temperature (Scheme 16). The product 56 was formed in 82% yield in a ratio of 92 5 3 0 (only the major isomer shown). The dramatic stereochemical outcome could be explained using a preferred transition state 55. The methyl group on the tether occupies a pseudo-equatorial orientation on the puckered, incipient five-membered ring with the diene oriented so as to minimize gauche interactions. 

The Trost group has devised a strategy for stereoselective spirocyclic ring installation across 3-alkylidene oxindoles via palladium-catalyzed [3-1-2] cycloaddition with cyano-substituted trimethylenemethane (Scheme 33) [74, 75]. As illustrated, the opposite sense of diastereoselectivity was observed depending on the choice of chiral ligand 125 or 126. Preferential orientation of the benzenoid portion of the oxindole as dictated by the varied steric environments of the naphthyl ring systems on the catalysts has been put forth as a rationale for the observed difference in stereochemical outcomes. Spirooxindoles 127 and 128 were obtained in 92% ee and 99% ee, respectively. A variation of this methodology has been applied in the racemic synthesis of marcfortine B [75]. 

The factors that determine the steric course of these cycloaddition reactions are still not completely clear. It appears that a number of forces operate in the transition state and the precise composition of the product depends on the balance among these. The preference for the endo adduct, in which the dienophile substituents are oriented over the residual unsaturation of the diene in the transition state, has been rationalized by Woodward and Hoffmann in terms of secondary orbital interactions. In this explanation, the atomic orbital at C-2 (and/or C-3) in the HOMO of the diene interacts with the atomic orbital of the activating group in the LUMO of the dienophile. However, there is no evidence for this secondary orbital interaction and the stereoselectivities in the Diels-Alder reaction can be explained in terms of steric interactions, solvent effects, hydrogen-bonding, electrostatic and other forces (3.70). ... 

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