Stereocontrolled Synthesis of Bicyclic Sulfamides via Pd-Catalyzed Alkene Carboamination Reactions. Control of 1,3-Asymmetric Induction by Manipulating Mechanistic Pathways

Abstract

A new annulation strategy for the synthesis of trans-bicyclic sulfamides is described. The Pd-catalyzed alkene carboamination reactions of 2-allyl and cis-2,5-diallyl pyrrolidinyl sulfamides with aryl and alkenyl triflates afford the fused bicyclic compounds in good yields and with good diastereoselectivity (up to 13:1 dr). Importantly, by employing reaction conditions that favor an anti-aminopalladation mechanism, the relative stereochemistry between the C3 and C4a stereocenters of the products is reversed relative to related Pd-catalyzed carboamination reactions that proceed via syn-aminopalladation.

Asymmetric Palladium‐Catalyzed Alkene Carboamination Reactions for the Synthesis of Cyclic Sulfamides

“…[7,8] We reasoned that an asymmetric variant of this transformation could provide straightforward access to enantiomerically enriched cyclic sulfamides. However, our prior studies had illustrated that the sulfamide-forming carboamination reactions may proceed via either syn - or anti -aminopalladation of the alkene depending on catalyst structure and reaction conditions.…”

“…However, our prior studies had illustrated that the sulfamide-forming carboamination reactions may proceed via either syn - or anti -aminopalladation of the alkene depending on catalyst structure and reaction conditions. [7] Since the two different C–N bond forming (and potentially enantiodetermining) aminopalladation pathways proceed through very different transition states, it seemed likely that achieving high selectivity for one pathway over the other would be critical for asymmetric induction. [9,10] …”

Synthesis of 2,3-dihydrobenzofurans via the palladium catalyzed carboalkoxylation of 2-allylphenols

“…We have recently demonstrated that Pd-catalyzed alkene carboamination reactions of electron-poor nucleophiles that fail under typical conditions can be conducted in high yield when reaction conditions that favor an anti-aminopalladation mechanistic pathway are employed. xv,xvi,xvii In this communication we describe the application of these conditions to the Pd-catalyzed synthesis of dihydrobenzofurans from 2-allylphenols, which proceeds through a key anti-oxypalladation of the substrate's pendant alkene. xviii …”

“…xv-xvii We were pleased to observe that a number of biaryl phosphine ligands provided the desired product 4a , with CPhos proving optimal to afford 85% yield of 4a .…”

“…xix This further illustrates the impact of reaction conditions on the stereochemistry of the heteropalladation step in Pd-catalyzed alkene difunctionalization reactions. xv–xvii,xx …”