Abstract
Functionalized tetrahydropyran (THP) rings are important building blocks and ubiquitous scaffolds in many natural products and active pharmaceutical ingredients (API). Among various established methods, the Prins reaction has emerged as a powerful technique in the stereoselective synthesis of the tetrahydropyran skeleton with various substituents, and the strategy has further been successfully applied in the total synthesis of bioactive macrocycles and related natural products. In this context, hundreds of valuable contributions have already been made in this area, and the present review is intended to provide the systematic assortment of diverse Prins cyclization strategies, covering the literature reports of the last twenty years (from 2000 to 2019), with an aim to give an overview on exciting advancements in this area and designing new strategies for the total synthesis of related natural products.
Highlights
Ring-closing metathesis (RCM) [16], halo etherification [17], reductive etherification [18,19], and metal-mediated cyclization [20,21], etc. are the most frequent strategies utilized for THP ring construction (Scheme 1)
The Kriewitz reaction was an ene reaction, the mechanism of the reaction was described to proceed via an oxocarbenium ion intermediate captured by a π-nucleophile, followed by the addition of an external nucleophile, leading to the formation of products
Alder and co-workers explained the formation of all-cis-2,4,6-trisubstituted THPs with the help of density functional theory (DFT) and stated that in the presence of an external nucleophile, the stabilization of the carbocation intermediate is favored through hyperconjugation [28]
Summary
Ring-closing metathesis (RCM) [16], halo etherification [17], reductive etherification [18,19], and metal-mediated cyclization [20,21], etc. are the most frequent strategies utilized for THP ring construction (Scheme 1). A strategy involving BiCl3-catalyzed microwave-assisted Prins cyclization of homoallylic alcohol with an aldehyde was successfully employed for the synthesis of 4-chloro-cis-2,6disubstituted tetrahydropyran as a single diastereomer [57], as shown in Scheme 23.
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