Highly Enantioselective Formation of α‐Allyl‐α‐Arylcyclopentanones via Pd‐Catalysed Decarboxylative Asymmetric Allylic Alkylation

Abstract

A highly enantioselective Pd-catalysed decarboxylative asymmetric allylic alkylation of cyclopentanone derived α-aryl-β-keto esters employing the (R,R)-ANDEN-phenyl Trost ligand has been developed. The product (S)-α-allyl-α-arylcyclopentanones were obtained in excellent yields and enantioselectivities (up to >99.9 % ee). This represents one of the most highly enantioselective formations of an all-carbon quaternary stereogenic center reported to date. This reaction was demonstrated on a 4.0 mmol scale without any deterioration of enantioselectivity and was exploited as the key enantioselective transformation in an asymmetric formal synthesis of the natural product (+)-tanikolide.

Recent Advances in Enantioselective Pd-Catalyzed Allylic Substitution: From Design to Applications

“…Guiry and co-workers exploited the DAAA for the highly enantioselective formation of α-allyl-α-aryl cyclopentanones ( Scheme 209 ). 570 α-Aryl β-keto allyl ester substrates afforded sterically hindered products in excellent ee values with Trost-type ligands. While the ( R,R )-Ph-DACH ligand afforded an 86% ee for the 2,4,6-trimethoxyphenyl-containing model substrate, the ( R,R )-ANDEN phenyl Trost ligand L23 gave exceptional levels of selectivity for the enantioselective synthesis of an all-carbon quaternary stereocenter (up to 99.9% ee ).…”

“…Guiry and co-workers extended their previous work on Pd-catalyzed DAAA of sterically hindered α-aryl β-keto allyl ester substrates 570 to include α-aryl β-oxo-allyl lactone derivatives ( Scheme 225 ). 600 Studies to optimize this process with dihydrocoumarin and δ-valerolactone-derived α-aryl β-oxo-allyl esters possessing a 2,4,6-trimethoxyphenyl substituent, found Trost’s ligand ( R,R )- L23 to be the optimal for these sterically hindered substrates.…”

Palladium‐Catalyzed Decarboxylative Asymmetric Allylic Alkylation: Development, Mechanistic Understanding and Recent Advances

“…Guiry published a highly enantioselective formation of α‐allyl‐α‐arylcyclopentanones 43 via DAAA (Scheme ) . Sterically hindered α‐aryl β‐keto allyl esters 42 gave allylated products 43 in high enantioselectivities using Trost‐type ligands.…”

“…Guiry reported the development of a Pd‐catalyzed DAAA for sterically hindered α‐aryl‐β‐oxo‐allyl lactone 109 , dihydrocoumarin 111 and isochromanone 113 ‐derived substrates (Scheme ) . Optimization studies using dihydrocoumarin and δ‐valerolactone‐derived α‐aryl‐β‐oxo‐allyl esters with 2,4,6‐trimethoxyphenyl as the aryl substituent, led to the identification of ( R,R )‐ANDEN‐phenyl Trost ligand 11 as the optimal ligand for this substrate class.…”

Divergent synthesis of (+)-tanikolide and its analogues employing stereoselective rhodium(II)-catalyzed reaction

“…In terms of potent biological activities and structural features of (+)-tanikolide and (−)-malyngolide, there have been a large number of reports on the total syntheses of these natural products [3][4][5][6][7][8][9][10][11][12][13] and their analogues. 6n,o One of the key steps is the stereoselective construction of the quaternary carbon center at C5, which has been accomplished using several different approaches, such as aldol reactions, 3 allylation of ketones such as Keck allylation, 4 addition of Grignard reagents to ketones, 5 epoxidation-epoxide opening, 6 Sharpless asymmetric dihydroxylation, 7 sigmatropic rearrangement, 8 1,3-dipolar cycloaddition of nitronate and acrolein, 9 asymmetric intramolecular cyclopropanation, 10 bromolactonization, 11 asymmetric allylic alkylation, 12 and others. 13 However, most of these examples are application and demonstration of synthetic methodologies to construct a synthetically challenging quaternary carbon center.…”