The scope of the segment-coupling Prins cyclization has been investigated. The method is outlined in Scheme 1 and involves esterification of a homoallylic alcohol (1), reductive acetylation to give the alpha-acetoxy ether (3), and cyclization on treatment with a Lewis acid to produce a tetrahydropyran (4). Alkene geometries dictate the product configurations, with E-alkenes leading to equatorial substituents and Z-alkenes leading to axial substituents (Table 1). Not unexpectedly, applying the method to allylic alcohols leads to fragmentation rather than a disfavored 5-endo-trig cyclization. Dienols in which one alkene is allylic and the other alkene is homoallylic cyclize efficiently and produce the tetrahydropyrans 49-54, Table 3. Dienols with two homoallylic alkenes cyclize with modest to high regioselectively, generating tetrahydropyrans 40-45, Table 2. The relative rates for cyclization decrease in the order of vinyl > Z-alkene > E-alkene > alkyne. The configurations of the products are consistent with cyclization via a chair conformation, Figure 1. The 2-oxonia Cope rearrangement may be a factor in the regioselectivity of diene cyclizations and in the erosion of stereoselectivity with Z-alkenes. This investigation establishes the stereoselectivity and regioselectivity for a number of synthetically useful segment-coupling Prins cyclizations.
[formula: see text] The segment-coupling Prins cyclization avoids two of the problems common to other Prins cyclization protocols: side-chain exchange and partial racemization by reversible 2-oxonia Cope rearrangement. Model studies demonstrate the stereochemical fidelity of Prins cyclizations using alpha-acetoxy ethers compared with direct aldehyde-alcohol Prins reactions. Furthermore, we propose a mechanism for the racemization observed in some intermolecular Prins cyclizations. Two straightforward syntheses of optically pure (-)-centrolobine highlight the utility of Prins cyclizations.
[reaction--see text] The 2-oxonia Cope rearrangement is undetectable in typical Prins cyclization reactions. We have investigated the Cope rearrangement in a Prins cyclization reaction using a competitive reduction of the oxocarbenium ion intermediate, and a racemization reaction mediated by the rearrangement. In our unactivated substrate, the 2-oxonia Cope rearrangement was much faster than Prins cyclization. An enantioselective allyl transfer reaction also was developed using a 2-oxonia Cope rearrangement.
Tandem Prins cyclization and Friedel-Crafts reaction with an electron-rich aromatic ring were used to prepare the core structures of calyxin natural products. The proposed structure of epicalyxin F was prepared and shown to be incorrect. Several calyxin natural products, including calyxin F and L, were synthesized, and the structures were reassigned on the basis of NMR data and synthetic correlations.
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