Regio‐ and Stereoselective Synthesis of Acetallic Tetrahydropyrans as Building Blocks for Natural Products Preparation, via a Tandem [4+3]‐Cycloaddition/Ozonolysis Process

Abstract

A highly versatile synthetic pathway is presented for the preparation of polyfunctionalized acetallic tetrahydropyrans from conveniently substituted 1‐methoxy‐8‐oxabicyclo[3.2.1]oct‐6‐en‐3‐one derivatives, as intermediates in the total synthesis of natural and unnatural products with structural, functional and/or biological importance. This synthetic methodology involves two key steps: a [4 + 3] cycloaddition reaction between an oxyallyl cation and 2‐methoxyfuran as a diene, followed by oxidative and/or reductive ozonolysis of the cycloheptenone subunit. This sequence renders polyfunctionalized 2‐methoxytetrahydropyranic products capable of being easily opened under acidic conditions. The key steps, cycloaddition and subsequent ozonolysis were both fully studied under different reaction conditions and using several substrates in order to optimize yields and stereoselectivities and to study the scope of the methodology. It is noteworthy that both reactions proceed with high diastereoselectivity and, in the case of the oxidative ozonolysis, outstanding regioselectivity as well. A chemical library of 14 polyfunctionalized tetrahydrofurans, having five or seven stereocenters, has been prepared using the detailed approach.

Scale-Up of Ozonolysis using Inherently Safer Technology in Continuous Flow under Pressure: Case Study on β-Pinene

“…In synthetic chemistry, the ozonolysis reaction is widely used . Ozone is a strong oxidant, reacting with unsaturated C–C bonds (among other reactive groups) and delivering oxidized products directly or with a tandem reaction, , which influences itself the formed final product. This reaction is considered green due to a couple of factors: the use of a clean reagent and the absence of metals .…”

(3 + 3) Cycloaddition of Oxyallyl Cations with Nitrones: Diastereoselective Access to 1,2-Oxazinanes

“…Oxyallyl cations are highly reactive electrophilic 2π systems that have been successfully engaged as 1,3-dipoles in numerous cycloaddition reactions. Since the pioneering work of Fort, the (4 + 3) cycloaddition between oxyallyl cations and dienes or furans has become a dependable tool for the preparation of seven-membered rings [Scheme , eq 1]. , This approach follows a symmetry-allowed [4π+2π] process and has been envisioned for numerous syntheses of biologically active natural products . Various five-membered ring carbocycles can also be accessed via a stepwise (3 + 2) cycloaddition with alkenes or alkynes [Scheme , eq 2]. − Recently, Chi and MacMillan reported an elegant application of oxyallyl cation chemistry to nucleophilic α-substitution of ketones before to develop an asymmetric version of this reaction [Scheme , eq 3] …”