Regioselectivity intramolecular cycloadditions

A systematic exploration of the intramolecular [4+2]/[3+2] cycloaddition cascade of 1,3,4-oxadiazoles was described. The studies permit the use of unsymmetrical dienophiles, dipolarophiles, and oxadiazoles as well as to control the cycloaddition regioselectivity and diastereoselectivity. The scope and utility of the reaction were defined <2006JA10589>. The tandem intramolecular [4+2]/[3+2] cycloaddition cascade reaction of 1,3,4-oxadiazole was applied to the syntheses of a series of natural products including a total synthesis of (-)- and ent-(+)-vindoline <2006JA10596>. 

Three novel stereo- and regioselective schemes for the total synthesis of (+ )-brefeldin A 440 have been accomplished. Each of them exploit intermolec-ular nitrile oxide cycloaddition for constructing the open chain and introducing substituents, but differ in subsequent stages. The first (480) and the second (481) use intramolecular cycloaddition for the macrocycle closure. However, in the second scheme INOC is followed by C=C bond cis-trans-isomerization. In the third scheme (481) intermolecular cycloaddition is followed by ring closing metathesis as the key step. 

While the perfluorinated acetates do prefer insertion, they are still capable of forming 1,3-dipoles and have demonstrated interesting effects on the regioselectivity of intramolecular cycloaddition reactions, presumably through Lewis acid-mediated effects on the dipolarophile [83]. Other chemoselectivity effects have been noted in the intramolecular cycloaddition reactions and may or may not be partially induced by conformation and sterics [84]. It was further demonstrated thaL when possible, O-H insertion is the predominant outcome over other types of insertion for rhodium]II)-car-benes, independently of the catalyst. However, cycloaddition reactions have been demonstrated to be hgand-dependent [85]. 

Titanium ylides are generated from imine esters with titanium isopropoxide chlorides and amines or by transmetalation of the N-lithiated ylides (90,91). The regioselectivity of their reactions with methyl acrylate is opposite to that normally observed (90). A transition state is proposed in Scheme 11.13 to explain this alternative regioselectivity. Intramolecular cycloadditions of the titanium ylides offer a synthetic application of this regioselectivity. 

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