Allylic Amination

103

Catalyst and substrate studies have been performed on the rhodium-catalyzed asymmetric ring opening reaction. A working model is advanced that involves oxidative insertion with retention to form an organorhodium intermediate that then undergoes nucleophilic attack with inversion. Kinetic and competition experiments have uncovered evidence for a proton transfer step in the catalytic cycle that may activate both the allylrhodium intermediate and the nucleophile. We have also conducted experiments designed to understand which properties of the PPF-P t Bu2 ligand contribute to the high reactivities and enantioselectivities.W e have previously reported that chiral rhodium(I) catalysts induce ring opening oxa-and azabicyclic alkenes with a variety of soft nucleophiles such as alcohols, phenols, amines, anilines, malonates, and carboxylates in high yield and enantioselectivity (1-8). The products are generated by an S N 2Ј nucleophilic displacement of the bridgehead leaving group with inversion providing the 1,2-trans product as one regio-and diastereomer. The formation of the 1,2-trans products is atypical for ring opening reactions of oxabicyclic alkenes, which usually generate the syn-1,2 diastereomers via exo nucleophilic attack (1, 2). Furthermore, regio-and stereochemical results diverge from previously documented rhodium-catalyzed reactions with allylic carbonates (9-18). The observations obtained with oxabicyclic alkenes find little precedent when compared to other allylic functionalizations including those catalyzed by Pd (refs. 19 In this report we describe catalyst and substrate studies and advance a mechanistic working model that rationalizes the stereochemical outcome and other experimental observations (Scheme 1). We have also conducted experiments designed to understand the properties of the PPF-P t Bu 2 ligand that contribute to high reactivities and enantioselectivities.Experimental procedures and characterization data can be found in Supporting Text, which is published as supporting information on the PNAS web site. Ligand Studies: Variations on the Josiphos Template and Other Ligand MotifsSeveral structural elements are present on the PPF scaffold that could contribute to its successful application in these reactions (51-53). PPF has elements of central and planar chirality as well as two phosphine atoms that differ both sterically and electronically. Two methods were used to determine the influence of the ligand on the rate. In cases where a significant difference in rate was observed, percent conversion vs. time, as determined by crude 1 H NMR, was used to quantify the reactivity of the catalyst. In cases where a more precise measurement of rate was desired, kinetic runs were performed.By comparing the reactivity and enantioselectivity of ligands 3 and 4, two trends emerge (Scheme 2). First, by increasing the steric bulk ( t Bu Ͼ Cy) the enantioselectivity is increased from 88% with 3 to 96% enantiomeric excess (ee) with the bulkier t Bu 2 P ligand 4. This increase in enantioselectivity comes at ...

Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Section: Influence Of Remote Substitution On the Oxabicyclic Alkene Omentioning

confidence: 99%

See 1 more Smart Citation

Rhodium-catalyzed asymmetric ring opening reactions of oxabicyclic alkenes: Catalyst and substrate studies leading to a mechanistic working model

Lautens

Fagnou²

2004

103

“…The possible transformations of these important compounds are numerous and proceed often with excellent stereoinduction (1)(2)(3). Consequently, optically active allylic alcohols and amines have appeared innumerable times as key intermediates in asymmetric total syntheses, showing the need for efficient and benign methods of their formation.…”

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confidence: 99%

Simple strategy for synthesis of optically active allylic alcohols and amines by using enantioselective organocatalysis

Jiang

Holub

Jørgensen

2010

A simple organocatalytic one-pot protocol for the construction of optically active allylic alcohols and amines using readily available reactants and catalyst is presented. The described reaction is enabled by an enantioselective enone epoxidation/aziridinationWharton-reaction sequence affording two highly privileged and synthetically important classes of compounds in an easy and benign way. The advantages of the described sequence include easy generation of stereogenic allylic centers, also including quaternary stereocenters, with excellent enantio-and diastereomeric-control and high product diversity. Furthermore, using monosubstituted enones as substrates, having moderate enantiomeric excess, the one-pot reaction sequence proceeds with an enantioenrichment of the products and high diastereoselectivity was achieved.asymmetric catalysis | allylic amines | enantioselectivity A llylic alcohols and amines represent two of the most abundant and fundamental building blocks in contemporary organic synthesis. The possible transformations of these important compounds are numerous and proceed often with excellent stereoinduction (1-3). Consequently, optically active allylic alcohols and amines have appeared innumerable times as key intermediates in asymmetric total syntheses, showing the need for efficient and benign methods of their formation.One of the traditional synthetic approaches to optically active allylic alcohols is the catalytic kinetic resolution applying enzymes (4). In addition, Sharpless and coworkers have successfully established an asymmetric titanium-catalyzed resolution of racemic secondary allylic alcohols via the Sharpless-Katsuki epoxidation (5), resulting in a mixture of epoxy-alcohols and optically active allylic alcohols (Scheme 1, expression 1). However, the fact that the resolution method is restricted to a theoretical yield of 50%, makes other direct routes to optically active allylic alcohols highly desirable. With the dynamic kinetic resolution (6), a procedure that allows full conversion of the starting compound to one desired product with excellent stereocontrol was established. In this process, a fast and efficient in situ racemization reaction of the undesired enantiomer of the starting material is the key to overcome the 50%-yield limit of the traditional resolution method. However, the scope of this reaction is limited to mainly acyclic substrates and the combined use of transition metal and enzyme is necessary (Scheme 1, expression 2).As an alternative to the resolution method, several different enantioselective reduction protocols of enones have been developed. Examples are the Corey-Bakshi-Shibata reduction (7), applying a borane-prolinol complex, and the catalytic enantioselective hydrogenation, applying BINAP [2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl]-diamine ruthenium complexes developed by Noyori and coworkers (8) (Scheme 1, expression 3). The needs of bulky functional groups, different substitution patterns at the enone functionality, and inert reaction conditions for obtain...

“…Transition metal-catalyzed reactions of nitrogen nucleophiles with allylic electrophiles (15) provide the opportunity to form the carbon-nitrogen bond in an amine with stereoselectivity that is based on a catalytic amount of a chiral ligand bound to the transition metal. In most cases, a palladium catalyst has been used for this transformation (16,17).…”

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confidence: 99%

Editing the stereochemical elements in an iridium catalyst for enantioselective allylic amination

Leitner

Shu

Hartwig

2004

Individual diastereomeric phosphoramidites and mixtures of diastereomeric phosphoramidites were evaluated in the iridiumcatalyzed amination of allylic carbonates. The original process was conducted with a phosphoramidite ligand containing a resolved 2,2-dihydroxy-1,1-binaphthyl (BINOL) group and a diastereomerically and enantiomerically pure bis(phenethyl)amino group. Evaluation of the structure of the active catalyst and relative rates for reactions in the presence of catalysts containing diastereomeric ligands led to the identification of a phosphoramidite that provided the amination product with enantiomeric excess similar to the original, more structurally and stereochemically complex ligand and that contains a racemic BINOLate and an N-benzylphenethylamino group on phosphorus.B iologically active molecules with stereocenters alpha to nitrogen range from single enantiomer pharmaceuticals to alkaloid natural products (1, 2). The classic routes to such chiral amines include resolution with chiral acids or initiation of the synthesis with a member of the existing optically active chiral pool that includes naturally occurring amino acids. However, the resolution typically requires disposal of at least half of the chiral amine, and many targets require a multistep synthesis from materials in the chiral pool. Thus, many synthetic approaches have been investigated for the preparation of ␣-chiral amines in an enantioselective manner.Two common approaches involve hydrogenation of an imine (3-5) and additions of nucleophiles to imines (6-12). The hydrogenation of imines is not yet a general process and can be used to form only primary or secondary amines. The addition of carbon nucleophiles to imines with high enantioselectivity has been limited also, and the highest selectivities typically require a chiral substituent at nitrogen that would ultimately be disposed or would require recycling (8). An alternative approach involves enantioselective formation of the carbon-nitrogen bond in the amine (6,7,13,14).Transition metal-catalyzed reactions of nitrogen nucleophiles with allylic electrophiles (15) provide the opportunity to form the carbon-nitrogen bond in an amine with stereoselectivity that is based on a catalytic amount of a chiral ligand bound to the transition metal. In most cases, a palladium catalyst has been used for this transformation (16,17). Although exceptions have been found (18), most palladium catalysts generate a terminal achiral allylic amine product from a linear allylic electrophile or a racemic branched allylic electrophile. Thus, a catalyst that would convert either a racemic branched allylic electrophile or an achiral terminal electrophile enantioselectively to a branched chiral amine product would provide a valuable synthetic tool (19-21). We recently reported an iridium complex containing a phosphoramidite ligand that catalyzes the reaction of amines with achiral linear allylic carbonates to form the branched allylic amine products with high enantioselectivity and regioselectivity (Eq. 1 and ...