Hydrogen Bond Mediated Enantioselectivity of Radical Reactions

Abstract

The renaissance in radical chemistry during the last years and decades can be explained in large part by the improved prediction and control of the important parameters chemo-, regio-, and stereoselectivity.[1] Recent investigations show that radical reactions can be carried out enantioselectively without an auxiliary being attached covalently to the substrate.[2] Two different strategies have been reported. On the one hand, it is possible to differentiate the enantiotopic faces of a prochiral radical with chiral reagents (reagent control). For this purpose chiral hydrogen-atom donors have been used most often. [3] On the other hand, face differentiation is possible by a Lewis acid, which forms a chelate complex with the substrate, and which is in turn coordinated to chiral ligands.[4] Alternative chiral templates that are based upon noncovalent interactions and are similarly effective have, to the best of our knowledge, not yet been established. In a recent study we were able to show that high enantioselectivity (up to 84 % ee) in radical reactions can be achieved with the help of a hydrogenbonding chiral template. Our preliminary results are presented in this communication.We investigated the enantioselectivity of the reductive radical cyclization of 3-(w-iodoalkylidene)piperidin-2-ones (1). These compounds can be synthesized by the aldol condensation of N-tert-butyloxycarbonyl(Boc)piperidin-2-one with w-tert-butyldimethylsilyl(TBDMS)oxyaldehydes followed by conversion of the protected hydroxy group into an iodo group (1. tetrabutylammonium fluoride (TBAF), THF; 2. PPh 3 , imidazole, I 2 ). [5] In the presence of an initiator and Bu 3 SnH the alkenyl iodides reacted in a 5-or 6-exo-trig-cyclization [1, 6] (e.g. 2 a! 3 a, Scheme 1). The intermediate radicals 3 exhibit a prostereogenic center in a-position to the carbonyl function which is transformed by an intermolecular reaction with Bu 3 SnH to a stereogenic saturated carbon atom. In the case of the alkenyl iodide 1 a both enantiomeric cyclization products 4 a and ent-4 a are formed during the reaction.The reaction proceeded smoothly for the three substrates investigated. The appropriate cyclization products were

Asymmetrische Katalyse durch chirale Wasserstoffbrückendonoren

“…Zu den enantioselektiven Reaktionen, die durch das Lactam 10 vermittelt werden, gehören asymmetrische photochemische [2+2]‐54 und [4+2]‐Reaktionen,55 Norrish‐Yang‐56 und 6π‐Photocyclisierungen57 und asymmetrische radikalische Cyclisierungen (Schema ) 58. Obwohl in diesen Reaktionen stöchiometrische Mengen des chiralen Promotors benötigt werden, handelt es sich um die derzeit besten Methoden für derartige Transformationen, und sie könnten als Ausgangspunkt für die Entwicklung katalytischer Varianten dienen 59…”

Enantioselective Radical Reactions

“…An interesting intramolecular radical cyclization followed by enantioselective hydrogen atom transfer has recently been reported (Scheme 11) [40]. This reaction is carried out in the presence of a chiral complexing agent 38, which Scheme 11 Enantioselective H-atom transfer reaction with hydrogen bonding catalyst can hydrogen bond to an appropriate acceptor.…”

Cascade radical reactions via carbon-carbon/heteroatom bond-forming process

“…Compared with the stereocontrol studies on intermolecular radical reactions, the enantiocontrol in radical cyclizations still remains a major challenge [45][46][47][48][49][50][51][52]. Therefore, we have started investigating the new type of chiral Lewis acid-mediated cyclization approach [53][54][55].…”