Debenzylative Cycloetherification: An Overlooked Key Strategy for Complex Tetrahydrofuran Synthesis

Abstract

Tetrahydrofuran (THF) is a major structural feature found in many synthetic and natural products displaying a variety of biological properties. This review summarizes the main synthetic approaches that have been developed to construct tetrahydrofuran moieties involving debenzylative cycloetherification reactions (DBCE). Interestingly, this reaction is regio- and stereoselective without the requirement of a selective protection/deprotection strategy. Many applications of this process have been reported, including carbafuranoside synthesis, regioselective deprotection of the benzyl group positioned γ to an alkene, and total synthesis of natural products. The stereochemical outcome and the mechanism of these interesting transformations are also discussed.

Debenzylative Cycloetherification as a Synthetic Tool in the Diastereoselective Synthesis of 3,6-Disubstituted Hexahydro-2H-furo[3,2-b]pyrroles, PDE1 Enzyme Inhibitors with an Antiproliferative Effect on Melanoma Cells

“…Among the different synthetic strategies to build the tetrahydrofurane ring, debenzylative cycloetherification is an underexploited approach for the synthesis of tetrahydrofuran-containing molecules. In this context, the activation of alkenes in the δ position with respect to the benzyl ether by halogenation (usually iodination and occasionally bromination) or epoxidation leads to tetrahydrofurans through debenzylative cycloetherification (Scheme ).…”

Generation and Rearrangement of N,O‐Dialkenylhydroxylamines for the Synthesis of 2‐Aminotetrahydrofurans

“…[1] Due to the privileged nature of these heterocycles,m any methods have been developed to access these important scaffolds. [2] One strategy that has not yet been explored for the synthesis of tetrahydrofurans is the [3,3]-sigmatropic rearrangement of N,Odialkenylhydroxylamines followed by cyclization of the initial rearrangement product (Scheme 1A). [3] This approach is appealing because of the potential to simultaneously set several contiguous stereocenters in the tetrahydrofuran ring and the latent modularity of the precursor.A nalogous transformations have been reported for the synthesis of dihydrobenzofurans from O-aryloxime ethers,w hich are easily prepared via oxime arylation or condensation of the corresponding O-arylhydroxylamine with the appropriate ketone.…”

Solvent‐Free Conversion of Alcohols to Alkyl Iodides and One‐Pot Elaborations Thereof

“…A 1,6‐cyclization was achieved on 14 by addition of only a slight excess of DIPEA at a higher temperature after the first iodination step, to provide 1,6‐anhydrosugar 46 in high yield (entry 10), reasonably due to the higher acidity of the hemiacetal hydroxyl. It is worth noting that undesired generation of anhydrosugars was never detected in the herein described preparation and elaborations of saccharide iodides, though representing a frequent side‐process in standard synthetic elaborations of 6‐O‐sulphonyl or 6‐halo–6‐deoxy sugars ,…”