Palladium-catalyzed enantioselective C-3 allylation of 3-substituted-1H-indoles using trialkylboranes

We have developed a new enantioselective C-3 allylation of 3-substituted indoles using allyl alcohol and trialkylboranes. Asymmetric syntheses of 3,3-disubstituted indolines and indolenines in enantiomeric excesses up to 90% have been achieved using the bulky borane 9-BBN-C6H13 as the promoter of the reaction. The dependence of the selectivity on the nature of the borane suggests that the boron reagent has a role beyond promoting ionization of the allyl alcohol. A protocol for oxidation of indolenines to oxindoles has also been developed and led to a formal synthesis of (-)-phenserine.     

Dinuclear Zn-catalyzed asymmetric alkynylation of unsaturated aldehydes

Our recent development of a proline-derived bimetallic catalyst has led to a number of efficient, catalytic, enantioselective transformations. Herein, we report a practical and general alkynylation of aromatic and alpha,beta-unsaturated aldehydes using our zinc catalyst system.     

Palladium-catalyzed asymmetric allylic alkylation of meso- and dl-1,2-divinylethylene carbonate

The palladium-catalyzed asymmetric allylic alkylation of a 1:1 mixture of dl- and meso-1,2-divinylethylene carbonate is reported. For the first time, both the ionization and nucleophilic addition steps of the catalytic cycle act as enantiodiscriminating steps to give a single product in high enantiomeric excess. The reactions proceed in >98% ee to efficiently generate useful chiral building blocks from acrolein. The absolute and relative configurations of iso-cladospolide B and 11-epi-iso-cladospolide B were verified by total synthesis, solving an apparent discrepancy in the literature.     

A direct catalytic asymmetric Mannich-type reaction via a dinuclear zinc catalyst: synthesis of either anti- or syn-alpha-hydroxy-beta-amino ketones

The use of imines bearing a hydrolyzable nitrogen substituent in direct asymmetric Mannich reactions with alpha-hydroxyketones is developed. Previous work focused on the use of N-arylimines or nonenolizable imines, and the latter with only methoxy-substituted alpha-hydroxyacetophenones. Using a dinuclear catalyst devised from 2,6-di-(S)-2'-diphenylhydroxymethylpyrrolidino-N-methyl)-4-methylphenol and diethylzinc, a broad array of hydroxyacetylated aromatics, including phenyl, 2-furyl, 1-naphthyl, and 2-naphthyl, react well. In addition, the reactions focused on the use of enolizable imines. With the N-diphenylphosphinoyl, the reactions are anti selective with enantiomeric excesses ranging from 83 to 99%, except for the reaction of the 2-methoxy-2'-hydroxyacetylbenzene. With the N-Boc-imines, the reactions were syn selective with enantiomeric excesses from 90 to 94%. The dependence of the diastereoselectivity on the nature of the N-substituent presumably arises from the steric demands of the diphenylphosphinoyl group.     

Molybdenum-catalyzed asymmetric allylation of 3-alkyloxindoles: application to the formal total synthesis of (-)-physostigmine

The first example of Mo-catalyzed asymmetric allylation for the generation of quaternary stereocenters at a prochiral nucleophile is reported. A variety of 3-alkyl oxindoles can be alkylated with high yields and enantioselectivity. This method provides expedited access to (-)-physostigmine and its analogues.     

Palladium-catalyzed asymmetric allylic alkylation of electron-deficient pyrroles with meso electrophiles

Pyrroles can serve as competent nucleophiles with meso electrophiles in the Pd-catalyzed asymmetric allylic alkylation. The products from this transformation were obtained as a single regio- and diastereomer in high yield and enantiopurity. A nitropyrrole-containing nucleoside analogue was synthesized in seven steps to demonstrate the synthetic utility of this transformation.     

Palladium-catalyzed alkylation of 1,4-dienes by C-H activation

Activated: the title reaction proceeds with a broad range of nucleophiles and variously substituted 1,4-dienes under mild conditions, and provides direct access to the corresponding 1,3-diene-containing products with high regio- and stereocontrol (see scheme; 2,6-DMBQ=2,6-dimethylbenzoquinone, EWG=electron-withdrawing group). This is the first catalytic allylic C-H alkylation that proceeds in the absence of sulfoxide ligands.     

Development of Zn–ProPhenol‐Catalyzed Asymmetric Alkyne Addition: Synthesis of Chiral Propargylic Alcohols

The development of a general and practical zinc‐catalyzed enantioselective alkyne addition methodology is reported. The commercially available ProPhenol ligand ( 1 ) has facilitated the addition of a wide range of zinc alkynylides to aryl, aliphatic, and α,β‐unsaturated aldehydes in high yield and enantioselectivity. New insights into the mechanism of this reaction have resulted in a significant reduction in reagent stoichiometry, enabling the use of precious alkynes and avoiding the use of excess dimethylzinc. The enantioenriched propargylic alcohols from this reaction serve as versatile synthetic intermediates and have enabled efficient syntheses of several complex natural products.     

Pd and Mo Catalyzed Asymmetric Allylic Alkylation

The ability to control the alkylation of organic substrates becomes ever more powerful by using metal catalysts. Among the major benefits of metal catalysis is the possibility to perform such processes asymmetrically using only catalytic amounts of the chiral inducing agent which is a ligand to the metal of the catalyst. A unique aspect of asymmetric metal catalyzed processes is the fact that many mechanisms exist for stereoinduction. Furthermore, using the same catalyst system, many types of bonds including but not limited to C-C, C-N, C-O, C-S, C-P, and C-H can be formed asymmetrically. An overview of this process using palladium and molybdenum based metals being developed in my laboratories and how they influence strategy in synthesizing bioactive molecular targets is presented.     

An introduction to pathodynamics from the view of homeostasis and beyond

This presentation discusses how dynamic models and Brownian motion methods can be applied to the analysis of clinical measurements. This approach has the potential to facilitate the understanding of biological systems on a macroscopic scale, much like thermodynamics did for physical chemistry. (© 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)