Prins-Type Cyclizations

Prins cyclization and its many variants are convenient methods to assemble tetrahydropyran rings that are common moieties in many natural products. Early 

Li et al. reported an early use of the mild InC to promote the tandem carbonyl allylation and Prins cyclization reaction to give symmetrical tetrahydropyran rings [199]. Ally lie tin compounds were used for the allylation of aldehydes, and the resulting allylic alcohols proceeded to react with excess aldehydes to form either 

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In the case of terminal alkynes having oxygenated functions in the linear chain (Scheme 10, route D), Martin, Padron, and coworkers found that homopropargylic alcohols reacted properly, yielding 2-substituted dihydropyrans as sole products, probably via a Prins-type cyclization. This cyclization provides a new approach toward 2-alkyM-halo-5,6-dihydro-2//-pyrans through a concomitant C-C and C-O bond formation (Scheme 21) [35]. 

Scheme 21 Plausible mechanism for Prins-type cyclization promoted by iron(III) halides...

Scheme 28 Halide exchange with halogenated solvents during the acetylenic Prins-type cyclization...

Whereas the Prins-type cyclizations reported in this and the preceeding chapter were performed using stoichiometric amounts of Fe salts as Lewis acids, a breakthrough in the field of catalysis was reported in 2009 when the first iron-catalyzed Prins- and aza-Prins cyclization was reported. The catalytic system, which is obtained by combining catalytic amounts of an iron salt with trimethylsilyl halides as a halide source, is widely applicable and promotes the construction of substituted six-membered oxa- and aza-cycles (Scheme 33) [44]. 

A fourfold anionic sequence which is not initiated by a Michael but an aldol reaction has been reported by the group of Suginome and Ito (Scheme 2.129) [295]. In this approach, the borylallylsilane 2-573 reacts selectively in the presence of TiCl4 with two different aldehydes which are added sequentially to the reaction mixture. First, a Lewis acid-mediated allylation of the aldehyde with 2-573 takes place to form a homoallylic alcohol which reacts with the second aldehyde under formation of the oxenium ion 2-574. The sequence is terminated by a Prins-type cyclization of 2-574 and an intramolecular Friedel-Crafts alkylation of the intermediate 2-575 with formation of the fraws-1,2-be rizoxadeca lines 2-576 as single diastereomers. 

Tetrahydropyrans hydroxylated at the 4-position have good synthetic value [113]. Although many synthetic methods have been reported [17-23,114,115], the search for potential alternate approaches and the development of eco-friendly and high-yielding reactions resulted in the development of a method that poses less problems for the environment. Synthesis of tetrahydropyranol derivatives can be achieved through the Prins-type cyclization reaction of homoallylic alcohols with aldehydes using bismuth triflate as catalyst in [bmim]PF6 solvent system [108] (Fig. 22). 

An intramolecular Prins-type cyclization of a-acetoxy acetals 239 is catalyzed by (7-PrO)2Ti(NTf)2 and provides a stereoselective route to 2,6- A-substituted 3,6-dihydropyrans 240 (Equation 107, Table 5) <2004BKC1625>. 

An iron(m)-catalyzed Prins-type cyclization between a homopropargylic alcohol and an aliphatic aldehyde provides 2-alkyl-3-halo-3,6-dihydropyrans in excellent yield (Equation 113). The solvent and the catalyst equally contribute to the halogen observed in the product therefore, a straightforward choice of catalyst and solvent provides a route to either monochlorinated 252 or monobrominated 3,6-dihydropyrans 253 (Equation 113). Indium compounds have also shown potential as catalysts for this process, with high yields also obtained <20030L1979>. 

An acid-mediated Prins type cyclization of enol ether 328 followed by basic hydrolysis of the intermediate trifluoro-acetate provides a key step during synthetic studies toward leucascandrolide A (Equation 139) <20010L755>. The acid-promoted Prins cyclization of enol ethers attracts much attention <20030L1499, 2004HCA2750, 2005OL2683>. 

Yang, J., Viswanathan, G. S., Li, C.-J. Highly effective synthesis of 4-halotetrahydropyrans via a highly diastereoselective in situ Prins-type cyclization reaction. Tetrahedron Lett. 1999,40,1627-1630. 

Lopez, F., Castedo, L. and Mascarenas, J.L. (2002) Atom-efficient assembly of 1,5-oxygen-bridged medium-sized carbocycles by sequential combination of a Ru-catalyzed alkyne-alkene coupling and a Prins-type cyclization. Journal of the American Chemical Society, 124, 4218-4219 Lopez, F., Castedo, L. and Mascarenas, J.L. (2005) Practical asymmetric approach to medium-sized carbocycles based on the combination of two Ru-catalyzed transformations and a Lewis add-induced cydization. Organic Letters, 7, 287—290. 

Formaldehyde can be coupled to an alkene in the presence of an acid to give a diol (152) or a 1,3-dioxane derivative (154) in what is known as the Prins reaction. l Allylic alcohols such as 153 can also be produced in this reaction. Camphene (155) reacted with formaldehyde and acid to give a 1 1 mixture of allylic alcohol 156 and the acetate 157, in 94% yield. Scandium tiiflate has been used to prepare tetrahydropyran-4-ol derivatives from aldehydes and homoallylic alcohols via a Prins-type cyclization. 3... 

In a separate investigation by Porco, Jr. and coworkers, the isatin derivative 134 (R = H) was converted to spirooxindole pyran 141 in 13 1 dr and 99% ee by means of a Prins-type cyclization involving homoaUyhc alcohol 140 [79]. The diastereos-electivity of the transformation has been proposed to arise from a preferred chairlike transition state with the benzenoid ring of oxindole in a pseudoequatorial orientation. Spirooxindole oxepenes also were prepared via diastereoselective spiro-annulation of isatins with bis-homoallyhc alcohols. 

Prins-type cyclization reactions in natural product synthesis 12COC1277, 13EJ01193. 

Cyclizations. In addition to the use of SEM-Cl as a means of one-carbon homologation, it has also been employed in the generation of acetals capable of undergoing a variety of cy-clization events. Alkylation of allylic alcohols with SEM-Cl permits haloacetalization to afford di- and trisubstituted 1,2-dioxanes (eq 28). Alternatively, homoallylic alcohols permit Prins-type cyclizations (eq 29) to furnish 2,4,5-trisubstituted tetrahydro-pyrans. Transition metals can also be employed to promote the formation of substituted benzofurans (eq 30). ... 

This formal [2h-2h-2] alkyne/alkene/carbonyl cycloaddition proceeds through the opening of the cyclopropyl carbene intermediate 1-4 by the carbonyl group to form oxonium cation 1-5, which undergoes nucleophilic attack by the vinylgold intermediates in a Prins-type cyclization to give tetrahydropyranyl cation 1-6. 

Barluenga J, Fernandez A, Di6guez A, Rodriguez F, Fananas FJ (2009) Gold- or platinum-catalyzed cascade processes of alkynol derivatives involving hydroalkoxylation reactions followed by Prins-type cyclizations. Chem-Eur J 15 11660-11667. doi 10.1002/ chem.200900856... 

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