A Highly Stereoselective Synthesis of Tetrahydrofurans

Abstract

The development of a direct and highly stereoselective synthesis of 2,3,5‐substituted tetrahydrofurans has been accomplished through a combination of batch‐ and microchip‐MS‐experiments. This sequential transformation comprises a Lewis acid‐mediated reaction of bis(silyl) dienediolate 1 and a broad range of aldehydes, furnishing products with three new σ‐bonds and three stereogenic centers in a one‐pot process with typically good yields and excellent stereoselectivity. Key steps which have been elucidated primarily with microchip‐MS‐experiments include a vinylogous aldol reaction and a Prins‐type cyclization. Furthermore, a titanium BINOL complex is a powerful chiral catalyst for this process. The products were further converted into bi‐ and tricylic products by carbonyl–ene reactions, proceeding with excellent yields and diastereoselectivity.

Continuous Flow Synthesis of Highly Substituted Tetrahydrofurans

“…By way of comparison all reactions were also carried out under batch conditions following our optimized procedure previously reported. [5a] Several aromatic, heteroaromatic and aliphatic aldehydes were used for the VMAR, while maintaining n ‐hexanal for the second step ( 3a – 3e ). For the flow chemical synthesis, higher yields and selectivities were obtained for most of the reactions.…”

“…We recently reported a highly diastereoselective BF 3 · OEt 2 mediated, novel, one‐pot synthesis of 2,3,5‐trisubstituted tetrahydrofurans employing the readily available bis(silyl)dienediolate 1 recently established in our group …”

“…Even under optimized conditions, a significant amount of the 2,5‐equally substituted side product 4a was formed. With detailed insight into the mechanism of the reaction, which we were able to obtain using lab‐on‐a‐chip technology,[5a] we determined the first step of the reaction, the VMAR, to be crucial for the product selectivity, as a slight excess of aldehyde already triggered the Prins‐type cyclization reaction. In order to reduce the amount of the side product that is formed during the reaction, we envisioned flow chemistry to be of advantage both due to more efficient mixing of the reactants as well as the accurate control of reaction parameters that can be achieved ,…”

Stereoselective Synthesis of 2,3,5-Trisubstituted Tetrahydrofurans Initiated by a Titanium–BINOLate-Catalyzed Vinylogous Aldol Reaction

“…The nucleophile 1 was prepared using an improved procedure established in our group. 14 1 H and 13 C NMR spectra were recorded in CDCl 3 at 26 °C using a Mercury Plus 300 MHz and a Bruker Avance DRX 400 MHz spectrometer. Spectra were referenced to residual chloroform (7.26 ppm, 1 H; 77.16 ppm, 13 C).…”

Diastereoselective Synthesis of Highly Substituted, Amino‐ and Pyrrolidino‐Tetrahydrofurans as Lead‐Like Molecular Scaffolds

“…[5,6] Within the large family of oxygen heterocycle-containing natural productst hat occupy biologically relevantc hemical space, [5] the tetrahydrofuran (THF) ring systema ssumesa ni mportant place.I ti sf ound in myriadn atural products, [7] biologically active small molecules [8] and FDA-approved drugs. [9] The significance of the THF moiety in medicinal chemistry continues to inspire the developmento fm ethods for the de novo synthesis of functionalised variants and THF-containing natural products, [10,11] as well as methodsf or selectiveC ÀHf unctionalisationo ft he ring itself. [12] As part of our contributions [13] to the European Lead Factory (ELF) drug discovery initiative, [14] we were interested in the designa nd synthesiso fn ew THF scaffolds bearing an amino substituent on the heterocycle backbone( i.e.,a tC -3 or C-4).…”