6-Enolendo cyclization

The Hajos-Parrish-Eder-Sauer-Wiechert synthesis (Scheme 5) was the first example of an intramolecular proline-catalyzed asymmetric aldol reaction. Systematically, this reaction can be described as a 6-enolendo cyclization. In 2003, List et al. described the first example of an intramolecular enolexo aldolization 85). This approach was then used by Pearson and Mans for the synthesis of (-i-)-cocaine 92, starting from the weso-dialdehyde 90 on treatment with (S)-12 86). This desymmetrization process gave 91 as a mixture of epimers with good enantio-selectivity. The tropane skeleton 91 could be further transformed into +)-92 by conventional means (Scheme 21). 

Note that the 5-(enolendo)-exo-tet cyclization shown below is a disfavored ringclosing alkylation. 

The aluminum-mediated Petasis-Ferrier rearrangement is a stepwise [1,3]-sigmatropic process. The first step is the coordination of the Lewis-acid to the 0-atom of the enol. Coordination to the ether O-atom is reversible and nonproductive. Cleavage of the adjacent C-O-bond, assisted by the antiperiplanar lone pair of the etheral O-atom, stereospecifically gives rise to an oxocarbenium enolate species, which cyclizes to the desired oxacycle. The rate difference in the rearrangement for the five- versus six-membered series can be explained by the more facile 6-(enolendo)-endo-trig cyclization. The last step is the intramolecular equatorial hydride delivery. 

Two competing intramolecular cyclizations (see the aldol condensation-sec. 9.4.A.ii) are illustrated for triketone 205.jn this case, only the favored 6-enolendo-exo-trig product (206) was obtained and not the disfavored 5-enol-endo-exo-trig products (207 and 208). Enolates generally tend to undergo 5-exo-tet reactions at oxygen, whereas 6-enolendo-exo-tet reactions prefer carbon. In order to form a five-membered... 

In general, organocatalytic cyclization processes conform to Baldwin s Rules of ring closure and all fall into one of the four following classes [1]. The most common modes of cyclization, are the enolexo-exo-trig (Fig. 1.2a) and the enolendo-exo-trig... 

Aldol Reactions.— Baldwin has extended the nomenclature for classifying ring-closures to include intramolecular aldol reactions. Observations of the modes of cyclization of polyketonic substrates have shown that, for example, 6-(enolendo)-exo-trig cyclizations are indeed favoured whereas the five-membered version is disfavoured (Scheme 50). Such generalizations may prove powerful aids to recognition of likely pathways that cyclizations may follow when a multitude of cyclization modes are formally possible, and to the evaluation of the likelihood of success in aldol reactions by which complex cyclic targets are prepared. 

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