2012

ABSTRACT:

Tertiary amines were readily converted into secondary amines through a photoredox-catalyzed N-demethylation, a bioinspired procedure that resembles nature’s enzymatic pathways. Furthermore, the selective oxidation of primary amines as well as primary and secondary alcohols was achieved using photoredox catalysis. The protocols feature low catalyst loadings (1–2 mol %) and offer access to diverse imines and carbonyl compounds. We succeeded in expanding the repertoire of photoredox catalysis with protocols that allow the synthesis of valuable compounds under mild reaction conditions. A visible light photoredox catalytic process for the deprotection of various tertiary amines leading to secondary amines was presented. The photoredox N-deprotection method mimics the cytochrome P-450 oxidation of tertiary amines. Further studies expanding the scope of this N-deprotection using more reactive catalysts are currently underway. In addition, a convenient procedure was developed for the synthesis of various imines starting from readily available primary amines. A synthetically useful protocol for the photoredox catalyzed oxidation of primary and secondary alcohols with low catalyst loadings is also provided. A wide range of substrates is tolerated under these conditions, yielding the corresponding carbonyl compounds with full conversion in most cases. The use of inexpensive household light and the easy of handling make the developed methods particularly attractive for applications in synthesis.

ABSTRACT:

The proline-catalyzed addition of various aliphatic aldehydes to sterically hindered 2-aryl-substituted 3H-indol-3-ones affords 2,2-disubstituted 2,3-dihydro-1H-indol-3-one derivatives with excellent enantioselectivities. In addition, the synthesis of a chiral derivative, (S)-2-(2-bromophenyl)-2,3-dihydro-2-(2-hydroxyethyl)-1H-indol-3-one, which can be used as an intermediate for the preparation of the natural product hinckdentine A was accomplished with a high level of enantioselectivity.

ABSTRACT:

A new chiral Brønsted acid-catalyzed aza-Diels–Alder reaction of cyclic C-acylimines with cyclopentadiene has been developed. The reaction provides optically active aza-tetracycles in good yields with high diastereo- and enantioselectivities under mild reaction conditions. We have developed an enantioselective Brønsted acid catalyzed aza-Diels–Alder reaction of C-acylimines with cyclopentadiene. The corresponding aza-tetracycles were obtained in high yields and with excellent enantio- and diastereoselectivities under mild reaction conditions. The results reported not only show that chiral BINOL derived phosphoric acid diesters can be efficient catalysts for [4 + 2] cycloadditions involving less-electron-rich dienes but additionally demonstrate the high potential of these acidic Brønsted acids in asymmetric catalysis.

ABSTRACT:

The enantioselective synthesis of 2-aryl-substituted 2,3-dihydroquinolin-4-ones, a class of hetero-cyclic compounds with interesting biological activities, has been achieved through a Brønsted acid-catalyzed enantioselective intramolecular Michael addition. The products are available in moderateto high yields and with good enantioselectivities. We have developed a catalytic route to various N-allyl- and N-benzyl-protected 2-arylsubstituted dihydroquinolin-4-one derivatives. The products have become available in moderate to high yields and with good enantiomeric ratios. The results reported not only demonstrate that chiral Brønsted acids can be efficient catalysts for enantioselective intramolecular Michael additions, but also show the high potential of highly acidic N-triflyl phosphoramides in asymmetric catalysis

ABSTRACT:

A Brønsted acid-catalyzed asymmetric Nazarov cyclization of acyclic α-alkoxy dienones has been developed. The reaction offers access to chiral cyclopentenones in a highly enantioselective manner. The reaction is complementary to our previously reported Brønsted acid-catalyzed electrocyclization reactions, which provided differently substituted optically active cyclopentenones with a fused tetrahydropyrane ring in good yields and with excellent enantioselectivities. We have presented a new Brønsted acid-cata-lyzed asymmetric Nazarov cyclization ofa-alkoxy divinylketones to afford optically active cyclopentenones. This effi-cient electrocyclization reaction proceeds under mild reac-tion conditions and leads to various substituted aromatica-hydroxyenones with excellent enantioselectivities (88–99%ee). Further studies to expand the generality of asymmetricBrønsted acid-catalyzed Nazarov reactions are anticipated.

ABSTRACT:

A synergistic catalytic system for the first asymmetric addition of aldehydes to in situ generated prochiral oxocarbenium ions has been developed. The dual catalytic protocol allows the simultaneous activation of both electrophile and nucleophile and provides access to a variety of valuable chiral 2H-chromenes with excellent enantioselectivities. We descirbe the first asymmetric addition of aldehydes to prochiral oxocarbenium ions yielding valuable chiral 2H-chromene derivatives. Given the difficulties that typically arise from the in situ formation of highly reactive oxocarbenium ions and the side reactions that can occur, the results presented here are very encouraging. A catalytic system consisting of an achiral Lewis acid and a chiral imidazolidinone catalyst which simultaneously activates the electrophile and nucleophile, was key to afford the products with excellent enantioselectivities. The resulting optically active aldehydes can be subjected to different functional group transformations to form the corresponding alcohols, enal esters and acids. The stereochemical outcome of this combined metal and organocatalyzed reaction provides the basis for further extensions. Together with previously reported amine catalyzed additions of aldehydes to imines, carbonyl groups, and carbocations, the addition to oxocarbenium ions presented here not only expands the repertoire of Lewis base catalysis but also provides fast and ready access to valuable chromenes and chromans in a highly enantioselective fashion. It is anticipated that this new mode of activation will find application in related reactions of oxocarbenium ions and is the focus of ongoing research.

ABSTRACT:

The diarylprolinol TMS ether catalyzed enantioselective addition–acetalization cascade reaction of 1,3-diketones with α,β-unsaturated aldehydes provides access to biologically active hydroxychromenone derivatives. These chromenones can be converted into the corresponding lactones, oxadecalinones, and benzopyranes in good yields without loss of enantiomeric excess. The usefulness of this newly developed methodology was demonstrated in the synthesis of the core structure of a Δ9-tetrahydrocannabinol analog. A highly general, efficient diarylprolinolether catalyzed enantioselective reaction of 1,3-diketones with a,b-unsaturated aldehydes providing access to a wide range ofchromenone derivatives is described. Diverse aliphatic and aromatica,b-un-saturated aldehydes and various 5-substituted 1,3-cyclohexane-diones were used in this addition–acetalization cascade reac-tion. Furthermore, it is possible to synthesize the correspond-ing lactones, oxadecalinones, and benzopyranes from the opti-cally active hydroxychromenone derivatives obtained in this re-action. No changes in the enantiomeric excesses wereobserved and good yields were obtained. The synthetic utilityof the protocols was demonstrated in the synthesis of the corestructure of aD9-tetrahydrocannabinol analog.

ABSTRACT:

The first asymmetric calcium-catalyzed addition reactions of styrene as well as indole derivatives to trifluoropyruvates have been reported. The corresponding products are obtained in high yields and with good to excellent enantioselectivities. The procedure allows direct access to biologically relevant fluorine-containing molecules, which are of interest for medicinal and agrochemical chemistry. The synthesis of quaternary stereocenters still remains a challenge in organic synthesis. Thus, the newly developed transition-metal-free protocol addresses this challenge and provides a valuable and mild method for the generation of esters comprising an α-trifluoromethyl as well as α-hydroxy moiety, a substitution pattern which mimics a carboxylic acid. In this asymmetric calcium-catalyzed addition reactions the calcium salt of a chiral BINOL-phosphoric acid, Brønsted acid, has successfully been applied.

ABSTRACT:

The first dual catalytic system that consists of a photoredox catalyst and a metal catalyst has been described. Besides the perfect interplay of both catalytic cycles the choice of reaction parameters, and notably the light source, the photoredox catalyst, and the metal catalyst are essential for the successful realization of this dual catalytic transformation, as many side reactions need to be circumvented. For instance, strongly reducing intermediates of the photoredox catalyst are passed throughout the photocatalytic cycle (e.g. [Ru(bpy)3]+), which can easily degrade the metal catalyst. In addition, the intermediate iminium ion can be degraded by oxidation to the undesired amide. We also demonstrated that a dual catalytic system can be realized in the oxidative alkynylation reaction. It features a highly modular catalytic system and mild reaction conditions. Reactions can be carried out using visible light as a source of energy for the oxidation of various tertiary amines, yielding valuable propargylic amines in good to excellent yields. Moreover, we were able to demonstrate for the first time that besides N-aryl amines also alkyl amines, namely glycinyl esters, can be subjected to this photoredox-catalyzed functionalization of sp3 C-H bonds. The high modularity of the catalytic system allows an easy adaption of this concept to other substrates. The realization of this concept is an important advancement in the area of both metal dual catalytic as well as photoredox catalytic transformations. Current investigations are focussed on extending the repertoire of dual metal-catalyzed transformations with visible light.

ABSTRACT:

A multicatalytic system consisting of tetrapropylammonium perruthenate/N-methylmorpholine N-oxide (TPAP/NMO) as oxidant, and diarylprolinol TMS-ether as chiral amine catalyst, has been developed and applied in the efficient construction of valuable chiral molecules. The one-pot domino reactions elaborated in the present study are based on the in situ generation of α,β-unsaturated aldehydes from allylic alcohols and their subsequent use in various asymmetric transformations (e.g., cyclopropanation, Michael addition, Michael addition/acetalization). TPAP as a substrate-selective redox catalyst is well tolerated by the amine catalyst and the domino reactions proceed in good yields and high enantioselectivities. The compatibility of metal and organocatalysis presented herein widens the scope of asymmetric iminium catalysis. e reactions are conducted with 6–20 % of TMS-prolinol ether and the TPAP loadings can be reduced to 1 mol %. Furthermore, the in situ oxidation can be conducted with environmentally benign terminal oxidants such as O2. The compatibility of one metal catalyst and one organic catalyst presented here clearly widens the scope of asymmetric iminium catalysis and combined catalysis in general.

ABSTRACT:

New protocols have been developed for efficient heterogeneous photocatalytic cross dehydrogenative coupling reactions using cheap, readily available and recyclable metal oxide catalysts. The heterogeneous catalysts are highly robust and can be applied to different carbon-carbon and carbon-phosphorous bond forming reactions to provide products, such as β-nitro amines, β-amino ketones, amino-nitriles or amino-phosphonates in high chemical yield. Furthermore, the catalysts can be simply recycled and reused which demonstrates that this environmentally friendly and economical protocol is an improvement over previously reported procedures. Additionally, no change in the chemical composition of the metal oxides was observed which underlines the robustness of the catalysts in light mediated cross dehydrogenative coupling reactions. The newly developed protocols for efficient heterogeneous photocatalytic cross dehydrogenative coupling reactions using cheap, readily available and recyclable metal oxide catalysts. The heterogeneous catalysts are highly robust and can be applied to different carbon-carbon and carbon-phosphorous bond forming reactions to provide products, such as b-nitro amines, b-amino ketones, amino-nitriles or amino-phosphonates in high chemical yield. Furthermore, the catalysts can be simply recycled and reusedwhich demonstrates that this environmentally friendly andeconomical protocol is an improvement over previously reported procedures. Additionally, no change in the chemical composition of the metal oxides, ZnO and TiO2 was observed which underlines the robustness of the catalysts in light mediated cross dehydrogenative coupling reactions.

ABSTRACT:

The asymmetric organocatalytic hydrogenation of benzoxazines, quinolines, quinoxalines and 3H-indoles in continuous-flow microreactors has been developed. Reaction monitoring was achieved by using an inline ReactIR flow cell, which allows fast and convenient optimization of reaction parameters. The reductions proceeded well, and the desired products were isolated in high yields and with excellent enantioselectivities. We have demonstrated the potential of a microreactor setup coupled with FTIR inline analysis for monitoring asymmetric continuous-flow hydrogenations of benzoxazines, quinolines, quinoxalines and 3H-indoles. Following a real-time continuous-flow optimization, the corresponding products were obtained in good yields and with excellent enantioselectivities. By applying the FTIR inline monitoring, reaction parameters can be screened rapidly in a single reaction setup, and the optimal reaction conditions can be obtained much faster as compared to the classical sequence of conducting the reaction followed by analysis. Further work will include automated integration and feedback optimization of reaction parameters.

ABSTRACT:

Enantioselective oxidative domino reactions of allylic alcohols to functionalized aldehydes have been developed. The one pot domino oxidation-iminium activation represents a convenient strategy for the enantioselective addition of malonates to allylic alcohols and the asymmetric formation of formyl cyclopropanes. We developed enantioselective oxidative domino reaction pathway. The newly developed procedure prevents the necessary purification or distillation step associated with the use of aldehydes in asymmetric organocatalysis. The procedure allows the use of allylic alcohols, together with the cheap and readily available oxidant MnO2 which can be simply separated by filtration. Thus, the newly developed protocol represents a valuable alternative to recently reported oxidative procedures which employ aldehydes and more expensive or difficult to handle oxidizing reagents, such as IBX and DDQ. The domino oxidative iminium reaction is viable for the enantioselective formation of formyl cyclopropanes and addition of malonates to allylic alcohols. The corresponding valuable chiral aldehydes have been isolated in good yields with high enantioselectivities. In contrast to earlier reports, we were also able to demonstrate for the first time that cyclopropane aldehydes can further be manipulated to their corresponding esters in a highly chemoselective manner by using a carbene catalyst. The generally mild reaction conditions of the oxidative processes together with the operational simplicity and practicability render this approach not only a useful procedure for the synthesis of optically active chiral aldehydes and esters but, additionally, expands further the repertoire of enantioselective covalent catalysis.

ABSTRACT:

A direct catalytic azidation of primary, secondary, and tertiary allylic alcohols has been developed. This new azidation reaction affords the corresponding allylic azides in high to excellent yields and regioselectivities. The reaction provides straightforward access to allylic azides that are valuable intermediates in organic synthesis, including the preparation of primary amines or 1,2,3-triazole derivatives. Regarding the reaction mechanism, we propose a reaction pathway in which a carbocation intermediate is formed. Taking into consideration that Ag salts are reported to interact with C–C multiple bonds, coordination of the Ag(I) to the double bond cannot be ruled out.

ABSTRACT:

Alkylation reactions utilizing nontoxic Lewis acid catalysts and “green” alkylating reagents are of high interest due to the continuous need for environmentally benign C–C and C–X bond formation. This article shows recent advances in Bi(III)-catalyzed alkylations of arenes, 2,4-pentanediones and various oxygen- and nitrogen-containing nucleophiles. Instead of toxic alkyl halides, the electrophilic components for these transformations were benzyl and propargyl alcohols as well as substrates with activated double bonds such as styrenes. The fact that Bi(III) salts are capable of activating both σ- and π-donors highlights their unique character as versatile catalysts for catalytic alkylation reactions. In addition, Bi(III) salts are less toxic and cheaper than other Lewis acids that have been described for similar transformations.

ABSTRACT:

General metal-free highly enantioselective cycloaddition between hydrazones and alkenes has been developed that affords pyrazolidine and pyrazoline derivatives, which are valuable compounds with important biological activity. In contrast to the less acidic binol-derived phosphoric acids, the much more acidic N-triflylphosphoramide Brønsted acids proved to be very effective catalysts and promoted the highly enantioselective cycloaddition. The reaction can be performed with a broad range of hydrazones and alkenes and leads to high yields and excellent diastereo- and enantioselectivities. Notably, the resulting optically active pyrazolidines can undergo many chemical transformations, including the enantioselective synthesis of valuable 1,3-diamines.

ABSTRACT:

A highly efficient route for the synthesis of valuable 3,4-substituted chromenone derivatives by the reaction of 1,3-diketones with aldehydes in the presence of L-proline was developed. The reactions take advantage of readily available starting materials and follow a Knoevenagel condensation/Michael addition/hemiacetalization domino process. Chiral 3-substituted chromenones are obtained with high enantioselectivities when a chiral diarylprolinol TMS-ether is applied in the reaction.

ABSTRACT:

A catalytic asymmetric oxidative iminium–allenamine cascade allows the use of propargyl alcohols as stable substrates and yields valuable chiral bicyclic 4H-chromenes. we have succeeded in developing a cascade reaction combining a catalytic oxidation with an organocatalytic enantioselective domino process. For a complex one pot reaction sequence we chose a prolinol catalyzed iminium–allenamine cascade as an example since it would be a good demonstration for the viability of this combined process. We were able to show for the first time that the use of substrate-selective TPAP/NMO redox system is not only compatible with diarylprolinolsilyl ether catalysts, but also with different reactive functionalities and sensitive intermediates and chromene products. Thus, the in situ formed propargyl aldehydes could be further elaborated in the enantioselective domino process. The oxidative cycle in this combined catalytic procedure prevents the necessary purification or distillation step associated with the use of aldehydes in organocatalysis and should in particular be useful for reactions involving sensitive aldehydes as substrates. Hence, the reported procedure represents a valuable alternative to previously described procedures which do employ aldehydes and stoichiometric amounts of oxidants such as IBX or DDQ. Important 4H-chromene derivatives could be synthesized by this operationally simple cascade, under mild conditions, in good yields and with excellent enantioselectivities. By applying a subsequent domino iminium–enamine cascade, we were able to prepare new complex tricyclic 4H-chromenes. In this sequential cascade, four bonds were formed and three chiral centers were controlled, yielding highly functionalized structures from simple starting materials (i.e. a propargyl alcohol, a cinnamaldehyde and a nitrostyrene derivative). This first unification of metal catalyzed oxidation with organocatalysis expands the scope of asymmetric covalent catalysis and combined catalytic procedures and we are confident that future developments will soon arise.

ABSTRACT:

A convenient and highly effective Ir-catalyzed α-alkylation of ketones with subsequent reduction and deprotection/cyclization methodology for the synthesis of valuable 2,5-disubstituted tetrahydrofurans was developed. Notably, commercially available substituted acetophenones as well as solketal a readily available derivative of the bulk chemical glycerol are used in the atom-economic transfer hydrogen reaction, whereby water is the only by-product. The subsequent reduction and deprotection/cyclization proceed under mild reaction conditions and afford 2,5-disubstituted tetrahydrofurans in good to high overall yields. In addition, a more practical, one-pot three-step procedure has been developed.

ABSTRACT:

The first time a relay catalysis protocol for the C–H functionalization of glycine derivatives and glycine derived dipeptides by combining visible-light photoredox catalysis and Lewis acid catalysis was developed. Importantly the generation and activation of the imine intermediates can only be achieved by applying this combined catalysis approach and neither over oxidation to α-oxo esters nor peptide fragmentation has been observed. The results reported not only demonstrate the use of secondary amines in photoredox catalysis but also pave the way for the use of other nucleophiles for direct α-amino acid and peptide modification. The operational simplicity and practicability, as well as the mild reaction conditions using visible light as the energy source promote the protocol as an attractive way to functionalize amino acids and peptides. Further studies, employing different peptides and nucleophiles in this new combined photoredox and Lewis acid catalysis protocol, are currently in progress as it allows a convenient and efficient late-stage functionalization.