Keiji Maruoka

Phosphonium Salts as Chiral Phase‐Transfer Catalysts: Asymmetric Michael and Mannich Reactions of 3‐Aryloxindoles

Its a PTC: A highly efficient reaction of 3-aryloxindoles in an asymmetric Michael addition was achieved by using a quaternary tetraalkylphosphonium salt as a chiral phase-transfer catalyst (PTC). The products were obtained in quantitative yields high ee values. The reaction of 3-aryloxindoles in an asymmetric Mannich reaction using the same catalyst also proved to be feasible.

Enantioselective base-free phase-transfer reaction in water-rich solvent.

The development of enantioselective phase-transfer catalysis for preparing important natural products or physiologically active compounds is quite attractive and challenging in terms of environmental consciousness. Although quaternary ammonium salts as phase-transfer catalysts are believed to require base additives for phase-transfer reactions, we have discovered that even without any base additives, the enantioselective phase-transfer conjugate addition of 3-phenyloxindole to beta-nitrostyrene proceeded smoothly in the presence of a chiral bifunctional ammonium bromide under neutral conditions in water-rich solvent with both high diastereo- and enantioselectivity.

Asymmetric inverse-electron-demand 1,3-dipolar cycloaddition of C,N-cyclic azomethine imines: an umpolung strategy.

The catalytic asymmetric 1,3-dipolar cycloaddition (1,3-DC) has now become one of the most established methods for the stereoselective synthesis of five-membered heterocycles having contiguous stereogenic centers, concurrent with the development of chiral Lewis acids and organocatalysts. As a reaction mode for 1,3-DCs, normal-electron-demand (NED) 1,3-DCs proceed by the interaction of a catalytically activated LUMO of electron-deficient alkenes with the HOMO of the 1,3-dipoles; alternatively, the inverse-electron-demand (IED) 1,3-DCs are facilitated by the interaction of the LUMO of an acid-activated 1,3-dipole and the HOMO of electron-rich alkenes. Although synchronous development of both features in the realm of asymmetric catalysis would be highly desirable to produce a diverse array of cycloadducts, IED 1,3-DCs are far less developed to date and remain a challenge in contrast to the sophistication and diversification of their NED counterparts. 3, 5h–j,11a] We recently succeeded in shedding light on the as of yet unexplored utility of C,N-cyclic azomethine imines 1 in the titanium/binolate catalyzed NED 1,3-DC using enals as dipolarophiles (Scheme 1). 5] As the next step of the study, we set out to investigate the asymmetric IED 1,3-DC of these 1,3-dipoles, coupled with the fact that the related methods for catalytic asymmetric diand tetrahydroisoquinoline syntheses by the nucleophilic addition to (dihydro)isoquinoline derivatives are still far from established in terms of the generality and selectivity. We report herein the investigation toward this end using vinyl ether as a conventional electron-rich dipolarophile and the axially chiral dicarboxylic acid originally developed in our group as a chiral Brønsted acid catalyst, which succeeded in attaining a remarkably broad substrate scope to give a variety of C1-chiral tetrahydroisoquinolines with excellent enantioselectivity irrespective of the position and electronic nature of the substituents. In addition, unique Lewis acid catalyzed functionalizations of the cycloadducts were disclosed in which tetrahydroisoquinolines with additional chiral stereocenter at the C1 side chain could be generated stereoselectively. This accomplishment prompted us to introduce a new concept called the IED umpolung 1,3-DC, which gives cycloadducts regioisomeric to the products of the previously reported titanium/binolate-catalyzed NED 1,3-DC starting from the same enals. This tactic could be realized by the umpolung nature of enals imposed by the formation of the corresponding N,N-dialkylhydrazones, also known as vinylogous azaenamines (Scheme 1). A clue to the development of asymmetric IED 1,3-DCs of C,N-cyclic azomethine imines with vinyl ether was provided from our early observation that these 1,3-dipoles easily form stable protonated salts in the presence of a hydrobromic acid. This fact naturally led us to the use of a chiral Brønsted acid, which has recently emerged as a powerful tool for numerous stereoselective organic transformations. 11] As we have been intensively working on the development of axially chiral dicarboxylic acids as a class of chiral Brønsted acid catalysts, we commenced the study of the asymmetric IED 1,3-DC between C,N-cyclic azomethine imine 1a and tertbutyl vinyl ether using the most general axially chiral dicarboxylic acid (R)-3a that bears 2,6-Me2-4-tBu-C6H2 groups as key 3,3’ substituents. As anticipated, (R)-3a facilitated the reaction in CH2Cl2 at 0 8C to give the exo and endo adducts in 78% and 18% yields, respectively, but the enantioselectivities were disappointingly low (Table 1, entry 1). Screening of a series of catalysts bearing different aryl substituents resulted in unsatisfactory selectivities (entries 2–4). A breakthrough came when we developed the new catalyst (R)-3e having diphenylmethyl groups at the 3,3’positions, with which the cycloadduct was furnished with a drastically improved enantioselectivity and exo/endo ratio (entry 5). Replacement of the phenyl group by a 2-naphthyl group further enhanced the enantioselectivity to 82% (entry 6). Finally, by changing the solvent to CHCl3 and lowering the reaction temperature to 30 8C, the exo-adduct 2a could be obtained exclusively in 98% yield and 95 % ee Scheme 1. Normaland inverse-electron-demand 1,3-dipolar cycloadditions of C,N-cyclic azomethine imines. binol= 2,2’-dihydroxy-1,1’binaphthyl, Bz = benzoyl.

Asymmetric ene reaction catalyzed by chiral organoaluminum reagent

Abstract The asymmetric ene reaction of prochiral aldehydes with alkenes has been effected by chiral organoaluminum reagent providing optically active homoallylic alcohols in both enantiomeric forms with high enantiomeric purity.

Catalytic Asymmetric Alkynylation of C1‐Substituted C,N‐Cyclic Azomethine Imines by CuI/Chiral Brønsted Acid Co‐Catalyst

Biologically active tetrahydroisoquinolines having a chiral stereocenter at the C1-position are commonly found in nature and also in synthetic molecules, and therefore, the catalytic asymmetric synthesis of these valuable building blocks has been explored as a worthwhile research area during the past decade. In addition to asymmetric hydrogenation, catalytic asymmetric C C bond formation by nucleophilic addition to dihydroisoquinolines or isoquinolines has been given much attention in this regard. Despite these efforts, there has been only one early report, by Shibasaki and co-workers in 2001, wherein dihydroisoquinolines having two different functionalities at the C1-position (tetrasubstituted carbon center) could be successfully generated in a catalytic asymmetric manner. Although a decade has passed since their pioneering discovery, no viable alternative to achieve this goal has emerged to date. During our studies on the use of C,N-cyclic azomethine imines (e.g. 1a ; Scheme 1) in the context of catalytic asymmetric 1,3-dipolar cycloadditions, we became aware of their unique ability to act as prochiral electrophiles to dihydroisoquinolines. Namely, the copper-catalyzed reaction of 1a with phenylacetylene furnished the alkynylation product and not the [3 + 2] cycloadduct, in contrast to the reaction of N,N’-cyclic azomethine imines, reported by Fu. Although the asymmetric alkynylation of N-alkyl and N-aryl dihydroisoquinolinium salts has already been reported as a comparable method by Schreiber and Taylor, and Li and coworkers, respectively, these studies exhibited rather limited substrate scope or only modest selectivity. What is even more important is the inability of this procedure to construct an asymmetric tetrasubstituted carbon center; Schreiber and Taylor only reported a racemic product, thus clearly leaving room for further development. We report herein, the exploration of our alkynylation as a novel direct catalytic asymmetric method to provide a variety of chiral C1-alkynyl tetrahydroisoquinolines. This investigation led to the discovery of a highly enantioselective alkynylation of azomethine imines catalyzed by a Cu/Phpybox complex (pybox = 2,6-bis(2-oxazolinyl)pyridine). This reaction has a remarkably broad substrate scope in terms of the aromatic substituents of the azomethine imines and the terminal alkynes. Although we faced the difficulty of attaining high enantioselectivity when using C1-substituted azomethine imines for the challenging formation of a tetrasubstituted carbon center, this issue could be successfully overcome by the addition of an axially chiral dicarboxylic acid, originally developed in this laboratory, as a key co-catalyst. We commenced the study by screening the commercially available chiral ligands that are commonly used in coppercatalyzed asymmetric transformations, for the reaction of C,N-cyclic azomethine imine 1a and phenylacetylene (Table 1). Among the chiral bis(oxazoline) and pybox ligands that were examined at 20 mol % catalyst loading, (R,R)-Ph-pybox L5 exhibited the best results, giving 2a in 90% yield with 95% ee (Table 1, entries 2–6). The amount of the catalyst could then be decreased to 5 mol% without compromising the yield or selectivity (Table 1, entry 7). The choice of the copper source also had a significant impact on

Trans-Selective Asymmetric Aziridination of Diazoacetamides and N-Boc Imines Catalyzed by Axially Chiral Dicarboxylic Acid

Axially chiral dicarboxylic acid (R)-1d catalyzed reaction of diazoacetamides and N-Boc imines provided a novel organocatalytic means for the formation of enantiomerically enriched N-Boc protected trans aziridines.

A Designer Axially Chiral Amino Sulfonamide as an Efficient Organocatalyst for Direct Asymmetric anti-Selective Mannich Reactions and syn-Selective Cross-Aldol Reactions

A direct asymmetric Mannich reaction using a novel axially chiral amino sulfonamide (S)-3 that is highly anti- and enantioselective has been developed. For instance, in the presence of a catalytic amount of (S)-3, the reactions between aldehydes and alpha-imino esters proceeded smoothly to give anti Mannich products with a significantly higher anti/syn ratio and enantioselectivity than previously possible. By utilizing N-Boc-protected aromatic imines instead of alpha-imino esters, the synthetically useful Boc protecting group and various aromatic or heteroaromatic substituents were installed into the anti Mannich products and consequently the substrate scope of the anti-selective Mannich reaction and the synthetic utility of the anti Mannich products have been expanded. The axially chiral amino sulfonamide (S)-3 has also been successfully applied to asymmetric direct cross-aldol reaction between two different aldehydes. The catalyst (S)-3 has the advantage of giving mainly syn products, whereas proline shows the opposite anti selectivity.

A Designer Axially Chiral Amino Sulfonamide as an Efficient Organocatalyst for Direct Asymmetric Mannich Reactions of N‐Boc‐Protected Imines

The moderate nucleophilicity of the axially chiral amino sulfonamide (S)-1 suppresses the problematic side reactions, including aldol reactions, in the asymmetric Mannich reaction of N-Boc-protected imines with aldehydes. The corresponding adducts are obtained in good yield and excellent stereoselectivity (see scheme; Boc = tert-butoxycarbonyl, Tf = trifluoromethanesulfonyl).

Direct Asymmetric Benzoyloxylation of Aldehydes Catalyzed by 2-Tritylpyrrolidine

A direct asymmetric benzoyloxylation of aldehydes with benzoyl peroxide was found to be catalyzed by (S)-2-(triarylmethyl)pyrrolidines (S)-2. This method provides a new approach for the preparation of optically active alpha-benzoyloxyaldehydes as useful chiral building blocks.

Phase-transfer-catalysed asymmetric synthesis of tetrasubstituted allenes

Allenes are molecules based on three carbons connected by two cumulated carbon-carbon double bonds. Given their axially chiral nature and unique reactivity, substituted allenes have a variety of applications in organic chemistry as key synthetic intermediates and directly as part of biologically active compounds. Although the demands for these motivated many endeavours to make axially chiral, substituted allenes by exercising asymmetric catalysis, the catalytic asymmetric synthesis of fully substituted ones (tetrasubstituted allenes) remained largely an unsolved issue. The fundamental obstacle to solving this conundrum is the lack of a simple synthetic transformation that provides tetrasubstituted allenes in the action of catalysis. We report herein a strategy to overcome this issue by the use of a phase-transfer-catalysed asymmetric functionalization of 1-alkylallene-1,3-dicarboxylates with N-arylsulfonyl imines and benzylic and allylic bromides.