Cyclization oxacycle preparation

Scheme 1. Radical cyclization reactions for oxacycle preparation...

An interesting variant involves the use of an allylic alcohol as the alkene component. In this process, re-oxidation of the catalyst is unnecessary since the cyclization occurs with /Uoxygen elimination of the incipient cr-Pd species to effect an SN2 type of ring closure. Both five- and six-membered oxacycles have been prepared in this fashion using enol, hemiacetal, and aliphatic alcohol nucleophiles.439,440 With a chiral allylic alcohol substrate, the initial 7r-complexation may be directed by the hydroxyl group,441 as demonstrated by the diastereoselective cyclization used in the synthesis of (—)-laulimalide (Equation (120)).442 Note that the oxypalladation takes place with syn-selectivity, in analogy with the cyclization of phenol nucleophiles (1vide supra). 

Type III Reactions and Other Reactions of Acetals. Treatment of symmetric acetals with alkenols or al-kynols in the presence of TiCU results in transacetalization to give mixed acetals such as (285) which react further via cation (286) to give cyclic products such as (287) in 50-99% yield. In this one-pot procedure the alkenic acetal need not be isolated. Acetoxyalkoxyacetic esters, such as (288), prepared in two steps from methyl glyoxylate and unsaturated alcohols, cyclize under the influence of SnCU in CH2CI2 to give oxacyclic carboxylic esters such as (290). These reactions proceed through the intermediacy of methoxycarbonylcarbonium ion (289). 

A number of oxacyclic natural products were synthesized via carbocycle-forming radical reaction of oxacyclic intermediates. An early example is the synthesis of (-)-dihydroagarofuran (170) by Biichi [109] (Scheme 58). The bridgehead chloride 168 obtained from the corresponding hydroxy ketone was amenable to radical cycliza-tion, and the tricyclic ether 169 was duly obtained. The aplysin synthesis [110] provides another example, and (—)-karahana ether (173) was synthesized via radical cyclization of the substrate 171 [111] (Scheme 59). Lactonic natural products (-1-)-eremantholide A [112], alliacolide [113], and (-)-anastrephin [114] were prepared via a variety of carbocycle-forming radical cyclization reactions. In the total synthesis of spongian-16-one (176) [115] (Scheme 60), the butenolide moiety in the substrate 174 served as the final radical acceptor for three consecutive 6-endo-. rig cyclizations. 

By this cyclization tetrahydroftiran derivatives have also been prepared. Compare the Lewis-acid induced tandem oxacyclization with oxepane formation in ref [9]. 

A group of polycyclic polyether natural products are of special interest owing to their fascinating structure and biological activities. One of the proposed biosynthetic origins of these molecules features an epoxide-opening cascade pathway. Shi asymmetric epoxidation of un-activated alkenes has been frequently employed in the preparation of polyepoxide intermediates. McDonald and co-workers studied a series of tandem e 7o-selective and stereospecific oxacyclization of polyepoxides mediated by Lewis acid. Polyepoxides, such as 64, can be obtained from the epoxidation of triene 63 with ketone 2. Furthermore, a cascade cyclization, initiated by a Lewis acid-promoted epoxide opening of 64, furnished the desired polyether 65. 

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