Radical Reactions with Double Memory of Chirality (²MOC) for the Enantiospecific Synthesis of Adjacent Stereogenic Quaternary Centers in Solution: Cleavage and Bonding Faster than Radical Rotation

Abstract

The solution photochemistry of bis(phenylpyrrolidinonyl)ketones (R,R)-1b and (S,S)-1b exhibited a remarkably high memory of chirality. Stereospecific decarbonylation to products (R,R)-3b and (S,S)-3b, respectively, occurred with an ee of ca. 80%. The reaction is thought to occur along the single state manifold by sequential Norrish type-I α-cleavage decarbonylation, and radical–radical combination in a time scale that is comparable to that required for the radical intermediate to expose its other enantiotopic face by rotation about an axis perpendicular to that of the p orbital (ca. 3–7 ps). The absolute configuration of a key intermediate and that of ketone (R,R)-1b were determined by single-crystal X-ray diffraction and the ee values of the photochemical products with the help of chiral shift reagent (+)-Eu(tfc)3 and chiral LC-MS/ MS. On the basis of the ee and de values at 25 °C, it could be determined that ca. 70% of the bond forming events occur with double memory of chirality, ca. 21% occur after rotation of one radical to form the meso product (R,S)-3b, and only 9% occur after double rotation to form the opposite enantiomer. This report represents the first example of a doubly enantiospecific Norrish type-I and decarbonylation reaction in solution and illustrates potentially efficient ways to obtain compounds with adjacent stereogenic quaternary centers.

Principles, Concepts and Strategies of Stereoselective Synthesis

“…If at least one on those criteria mentioned during the memory of chirality process is not fulfilled, the enantioselectivity of the (S)-product will be decreased. Memory of chirality is an intriguing and powerful strategy in stereoselective organic synthesis [45][46][47][48][49][50] that has been applied to enolate chemistry, [51][52][53][54] radical and photochemical processes, [55][56][57] and reactions involving carbocation intermediates. 58,59 Several examples of MOC are provided in Scheme 1.3.…”

Solid‐State Asymmetric Photochemical Studies Using the Ionic Chiral Auxiliary Approach

“…Garcia‐Garibay and co‐workers have explored the generality of the decarbonylation reaction in the solid state and solution with a number of different examples 21–24…”

“…Garcia-Garibay and co-workers have explored the generality of the decarbonylation reaction in the solid state and solution with a number of different examples. [21][22][23][24] Now we turn to the discussion of the internal, built-in chiral auxiliary approach. This technique was first developed in the Scheffer laboratory at the University of British Columbia and has been applied successfully in photochemical asymmetric synthesis.…”

Discovery and Total Synthesis of a Bis(cyclotryptamine) Alkaloid Bearing the Elusive Piperidinoindoline Scaffold

“…Because of conformational restrictions imposed by the rigid reaction cavity of the crystal lattice, as illustrated by the dotted lines, the conversion of 9 to 7 was expected to occur with retention of stereochemistry. We have previously shown the success of such solid-state photodecarbonylation reactions in simpler systems. − Moreover, this key step would complement the elegant radical-based approach for accessing cyclotryptamine alkaloids pioneered by Movassaghi and co-workers . Ketone 9 would be prepared from acid chloride 10 and enolate 11…”