Highly diastereoselective 1,3-dipolar cycloaddition reactions of trans-2-methylene-1,3-dithiolane 1,3-dioxide with 3-oxidopyridinium and 3-oxidopyrylium betaines: a route to the tropane skeleton

Abstract

The C2-symmetric vinyl sulfoxide, trans-2-methylene-1,3-dithiolane 1,3-dioxide, was found to react with a range of 3-oxidopyridinium betaines (bearing different substituents on nitrogen) in high yield and with total diastereoselectivity. A 2.3:1 mixture of regioisomers was formed with all of the 3-oxidopyridinium betaines but the ratio was found to change over prolonged periods of time due to reversibility of the minor regioisomer. 3-Oxidopyridinium betaines bearing methyl substituents at either the 2- or 6-position were also tested in the cycloaddition process. Improved regioselectivity (8:1) and again high diastereoselectivity were observed with the betaine having an additional substituent at the 2-position, but with betaines having a substituent in the 6-position although high regioselectivity was observed (9.9:1), the major isomer was formed with low diastereoselectivity (5.5:4.4). The origin of the regio- and diastereo-selectivity with all the betaines is discussed. Finally, the C2-symmetric vinyl sulfoxide, trans-2-methylene-1,3-dithiolane 1,3-dioxide was reacted with an oxidopyrylium betaine in moderate yield. Good regioselectivity and moderate diastereoselectivity were observed.

Structure‐Pattern‐Based Total Synthesis

“…The above mentioned functional group pattern, which is present in all three natural product families, was readily introduced by an elegant [5+2] cycloaddition of oxidopyridinium ion 42 with bissulfoxide 41 , which constitutes the key step in the syntheses (Scheme ) . Both cycloaddition components were readily prepared, and the syntheses proceeded in four literature‐known steps from commercially available 2‐((benzyloxy)methyl)‐1,3‐dioxolane for the dipolarophile 41 , and in one step from 3‐hydroxypyridine for dipoles 42 a and 42 b . The cycloaddition proceeded smoothly at room temperature to give, after reduction of the bissulfoxide to the corresponding dithiolane, “privileged intermediate” 40 as the major regioisomer in a ratio of 2.5:1 to 5.4:1 (Scheme ).…”

“…The cage‐like structure of tetracyclic ketone 47 could be obtained by a Pd‐catalyzed enolate coupling reaction starting from tricycle 48 . Finally, the latter could be derived from the [5+2]‐oxidopyridinium cycloaddition reaction of 41 and 42 b …”

“…[21] Both cycloaddition components were readily prepared,a nd the syntheses proceeded in four literature-known steps from commercially available2 -((benzyloxy)methyl)-1,3-dioxolane for the dipolarophile 41, [22] and in one step from 3-hydroxypyridinef or dipoles 42 a and 42 b. [23,24] The cycloaddition proceeded smoothly at room temperature to give, after reduction of the bissulfoxide to the corresponding dithiolane, "privileged intermediate" 40 as the major regioisomer in ar atio of 2.5:1 to 5.4:1 (Scheme 5). Thist ype of cycloaddition reaction with enantiopure 41 was established by Aggarwal and co-workers and also tolerates variations of substituents R 1 and R 2 .…”

“…[29] The cage-likes tructure of tetracyclic ketone 47 could be obtainedb yaPd-catalyzed enolate coupling reactions tarting from tricycle 48.F inally,t he latter could be derived from the [5+ +2]-oxidopyridinium cycloaddition reaction of 41 and 42 b. [22,24,30] Our synthesis started with the [5+ +2]-oxidopyridiniumi on cycloaddition reaction of bissulfoxide 41 andp yridinium salt 42 b under basic conditions (Scheme7). The so-obtained regioisomers 56 andr egio-56 could not be separated until after reduction of the bissulfoxide to the corresponding dithiolanew as carried out using triflouroacetic anhydridea nd sodium iodide.…”

Enantioselektive schutzgruppenfreie Totalsynthese von Sarpagin‐ Alkaloiden – ein generalisierter Zugang

“…Cycloadditionen eingehen und dass dabei Regioselektivitäten von ca. 2:1 auftreten [10]. Glücklicherweise war das Regioisomer 12 auch in dieser Arbeit nicht nur das Haupt-sondern auch das gewünschte Produkt.…”