Tetrahydropyrans annulation

Loh and coworkers used a combination of a carbonyl-ene and an oxenium-ene reaction for the synthesis of annulated tetrahydropyrans 1-61, using methylenecyclo-hexane 1-60 as substrates (Scheme 1.16) [15]. The most appropriate catalyst for this reaction with the aldehydes 1-59 turned out to be In(OTf)3, which furnished the desired products in good to excellent yields and high stereoselectivity [16]. 

Rychnovsky and coworkers very recently described a so-far unknown domino Michael addition/2 -oxonia Cope/aldol-type reaction to give tetrahydropyran rings [475]. The transformation has as its origin an annulation process (see Section 2.1) which was discovered by the same group. 

Ketoacetals are available from the Lewis acid catalysed Michael addition of hemiacetal vinylogues to 3,4-dihydropyrans. The products are a source of hydroxy- and amino- acetals and hence give access to annulated tetrahydropyrans (95JCS(P 1)2103). 

Keck, G. E., Covel, J. A., Schiff, T., Yu, T. Pyran Annulation Asymmetric Synthesis of 2,6-Disubstituted-4-methylene Tetrahydropyrans. 

Subsequently, aryl amidines 63, instead of 5-aminopyrazoles, reacted with aromatic aldehydes 69 and tetrahydrothiopyran-4-one (or tetrahydropyran-4-one) 79b, respectively, to give the annulated pyrimidine derivatives 84 (Scheme 12.31) [52]. 

Panek s synthesis is highUghted by the efficient construction of a cis-and trans-2,6-disubstituted tetrahydropyran ring. As described in Sect. 2.4, Panek s annulation between aldehydes and chiral allylsilanes can be regarded as a Hosomi-Sakurai-Prins reaction, in which the stereochemistry of cis-... 

Sames et al. reported a Sc(OTf)3-catalyzed intramolecular hydroalkylation of isolated electron-deficient olefins (Scheme 43) [95]. Tetrahydropyrans or tetrahy-drofurans carrying C(2)-Iinked a, P-unsaturated malonate side chain 109 and 111 were employed as substrate to furnish the spiroether product 110 and 112 in excellent yields. Notably, germinal substitution along the olefin tether was not required for efficient annulation for the reason that benzylidene malonate activated by Sc(OTf)3 were reactive enough, thus higher conformational rigidity to increase the reactivity of hydride acceptor was not indispensable [96]. 

In 2005, Panek and co-workers reported a total synthesis of leucascandrolide A, the highlights of which are based on the two consecutive [4 -I- 2] annulation reactions between aldehydes and chiral aUylsilane and crotylsilane for the construction of bis-tetrahydropyran in leucascandrolide A. The macrocyclization of the synthesis relies upon the spontaneous macrolactolization that Kozimin utilized previously. With the key [4 + 2] annulations reactions in mind, the synthesis... 

A common strategy for the synthesis of tetrahydropyran rings is C2-C3 disconnection (Scheme 30). The natural order of reactivity typically generates an oxocarbenium ion at C2 while C3 acts as the nucleophile. This strategy is manifested in three general classes of reactions Prins cyclizatiOTis (Eq. 1), Petasis-Ferrier union/rearrangements (Eq. 2), and Panek annulation (Eq. 3). 

---