Endocyclic path

Details of the hydrolytic process are somewhat more complicated because the acid-catalyzed hydrolysis proceeds via the initial protonation of an alkoxy oxygen followed by bond cleavage. Because the protonation can involve the exocyclic or endocyclic alkoxy group, two different sets of initial products are possible. However, in both cases the ultimate degradation products remain the same. These two possible reaction paths are shown on page 130. 

Analogously, the thermal formation of fused strained tricycles 77 can be rationalized by a mechanism which includes an exocyclic diradical intermediate 80 through an initial carbon-carbon bond formation, involving the proximal allene carbon and the internal alkene carbon atom (path C, Scheme 28). The alternative pathway leading to tricyclic 2-azetidinones 77 is proposed in path D (Scheme 28). This proposal involves an endocyclic diradical intermediate 81 arising from the initial attack of the terminal olefinic carbon onto the central allene carbon. The final ring-closure step of the diradical intermediates account for the cyclobutane formation. 

In order to ascertain the relative importance of these two reaction paths, a careful analysis of the hydrolysis products from a linear polymer based on 3,9-bis (ethylidene 2,4,8,10-tetraoxaspiro [5,5] undecane) and 1,6-hexanediol was carried out [28]. If the hydrolysis proceeds via initial protonation of the exocyclic alkoxy group, the hydrolysis proceeds to yield pentaerythritol dipropionate and the free diol. If, on the other hand, the hydrolysis proceeds via initial protonation of the endocyclic alkoxy group, then the hydrolysis proceeds to yield pentaerythritol and hexanediol propionate. 

Because a knowledge of all degradation products is important for regulatory approval, studies aimed at establishing the exact hydrolysis path were carried out [50, 51]. As already described in Sect. 4.2.3, the acid-catalyzed hydrolysis of the cyclic ortho ester bond can proceed via two paths, depending on whether cleavage occurs at the exocyclic alkoxy or endocyclic alkoxy group. 

When this 6-isomer was added to the reaction product of 1,2,6-hexanetriol and acetic acid, the 11.62 peak was enhanced. Thus, the 10.98 and 11.24 peaks in chromatogram 31a are the 1 and 2-isomers. Because the sensitivity of the gas chromatographic assay is such that as little as 0.01% of the 6-isomer can be detected, hydrolysis of this particular polymer proceeds exclusively by the exocyclic cleavage path shown in Scheme 20. This is in very good agreement with a reported hydrolysis study of the closely related model compounds 2-methoxy-l,3-dioxalane (1) and 2-phenyl, 2-methoxy-l,3-dioxalane (2) which have been reported to undergo respectively about 2.5% and less than 0.1% endocyclic cleavage [52]. 

As with the other poly (ortho esters) discussed in the previous sections, the exact hydrolysis path depends on whether initial protonation and cleavage occurs at the exocyclic or endocyclic alkoxy groups. The two possible paths are shown in Schemes 22 and 23. 

Five- and six-membered ring enolates with an endocyclic double bond also react to deliver an electrophile from the sterically less hindered face. Enolate 498 was obtained by treatment of 497 with lithium amide. Subsequent reaction with an alkyl halide led to delivery of the halide from the face opposite the alkenyl group (path a) and the trans product shown (499) was isolated in 60% yield.-. Approach via path b would have serious steric consequences, and that transition state is destabilized. Similar effects are observed with 3-alkyl-cyclohexanone derivatives. 

The hydrolysis of pyranosides is postulated to largely proceed via exocyclic cleavage to give a cyclic oxocarbe-nium ion (Path A). Yet, it has long been recognized that an alternative pathway is also possible—namely, endocyclic cleavage to give an acyclic oxocarbenium ion (Path B). 

Mechanistically, these processes involve Lewis-acid activation of the enone, subsequent 1,3-dipolar cycloaddition of the enone with azide, and ring opening of the nnstable triazoline (Scheme 7.30). In the case of exocyclic enaminone formation, antiperiplanar arrangement of the methylene gronp (path a) with the diazoninm ion facilitated ring contraction a 1,3-H shift nltimately provided product via path a. On the other hand, migration of an axially oriented R gronp led to the observed endocyclic enaminones (path b). 

The course of these radical displacements at the trivalent sulfur center of the sulfoxides is analogous to that observed for the sulfides the exocyclic displacement path obtains. Methyl (or t-butyl) o -ethylphenyl sulfoxide, the ultimate product of the alternative, endocyclic, displacement path is not observed. Our conclusion is also analogous the... 

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