A Modular Strategy for the Direct Catalytic Asymmetric α-Amination of Carbonyl Compounds

Although trifluoromethylthiolated compounds have privileged applications in pharmaceuticals and agrochemicals, efficient strategies for the asymmetric construction of Csp3–SCF3 bonds are limited. S...

We have developed Cu(II)-catalyzed enantioselective conjugate-addition reactions of boron to α,β-unsaturated carbonyl compounds and α,β,γ,δ-unsaturated carbonyl compounds in water. In contrast to the previously reported Cu(I) catalysis that required organic solvents, chiral Cu(II) catalysis was found to proceed efficiently in water. Three catalyst systems have been exploited: cat. 1: Cu(OH)2 with chiral ligand L1; cat. 2: Cu(OH)2 and acetic acid with ligand L1; and cat. 3: Cu(OAc)2 with ligand L1. Whereas cat. 1 is a heterogeneous system, cat. 2 and cat. 3 are homogeneous systems. We tested 27 α,β-unsaturated carbonyl compounds and an α,β-unsaturated nitrile compound, including acyclic and cyclic α,β-unsaturated ketones, acyclic and cyclic β,β-disubstituted enones, acyclic and cyclic α,β-unsaturated esters (including their β,β-disubstituted forms), and acyclic α,β-unsaturated amides (including their β,β-disubstituted forms). We found that cat. 2 and cat. 3 showed high yields and enantioselectivities for almost all substrates. Notably, no catalysts that can tolerate all of these substrates with high yields and high enantioselectivities have been reported for the conjugate addition of boron. Heterogeneous cat. 1 also gave high yields and enantioselectivities with some substrates and also gave the highest TOF (43,200 h(-1) ) for an asymmetric conjugate-addition reaction of boron. In addition, the catalyst systems were also applicable to the conjugate addition of boron to α,β,γ,δ-unsaturated carbonyl compounds, although such reactions have previously been very limited in the literature, even in organic solvents. 1,4-Addition products were obtained in high yields and enantioselectivities in the reactions of acyclic α,β,γ,δ-unsaturated carbonyl compounds with diboron 2 by using cat. 1, cat. 2, or cat. 3. On the other hand, in the reactions of cyclic α,β,γ,δ-unsaturated carbonyl compounds with compound 2, whereas 1,4-addition products were exclusively obtained by using cat. 2 or cat. 3, 1,6-addition products were exclusively produced by using cat. 1. Similar unique reactivities and selectivities were also shown in the reactions of cyclic trienones. Finally, the reaction mechanisms of these unique conjugate-addition reactions in water were investigated and we propose stereochemical models that are supported by X-ray crystallography and MS (ESI) analysis. Although the role of water has not been completely revealed, water is expected to be effective in the activation of a borylcopper(II) intermediate and a protonation event subsequent to the nucleophilic addition step, thereby leading to overwhelmingly high catalytic turnover.

A practical sequence involving three consecutive palladium(0)-catalyzed reactions has been developed for synthesizing 3-alkyl-3-aryloxindoles in high enantiopurity. The Heck cyclization precursors 10 and 11a-k are generated in one step by chemoselective Stille cross-coupling of 2'-triflato-(Z)-2-stannyl-2-butenanilide 9 with aryl or heteroaryl iodides. The pivotal catalytic asymmetric Heck cyclization step of this sequence takes place in high yield and with high enantioselectivity (71-98% ee) with the Pd-BINAP catalyst derived from Pd(OAc)(2) to construct oxindoles containing a diaryl-substituted all-carbon quaternary carbon center. A wide variety of aryl and heteroaryl substituents, including ones of considerable steric bulk, can be introduced at C3 of oxindoles in this way (Table 4). The only limitations encountered to date are aryl substituents containing ortho nitro or basic amine functionalities and the bulky N-alkyl-7-oxindolyl group. Asymmetric Heck cyclization of butenalide 22 having an o-(N-acetyl-N-benzylamino)phenyl substituent at C2 provided a approximately 1:1 mixture of amide atropisomers 23 and 24 in high yield and high enantioselectivity. These atropisomers are formed directly upon Heck cyclization of 22 at 80 degrees C, as they interconvert thermally to only a small extent at this temperature.

Nickel-Catalyzed Regiodivergent Asymmetric Cycloadditions of α,β-Unsaturated Carbonyl Compounds

For Abstract see ChemInform Abstract in Full Text.

SummaryOver the past decades, asymmetric catalysis has been intensely investigated as a powerful tool for the preparation of numerous chiral biologically active compounds. However, developing general and practical strategies for preparation of both enantiomers of a chiral molecule via asymmetric catalysis is still a challenge, particularly when the two enantiomers of a chiral catalyst are not easily prepared from natural chiral sources. Inspired by the biologic system, we report herein an unprecedented catalytic enantiodivergent Michael addition of pyridazinones to enones by subtle adjustment of achiral amino moiety of dipeptide phosphine catalysts. These two dipeptide phosphine catalysts, P5 and P8, could deliver both enantiomers of a series of N2-alkylpyridazinones in good yields (up to 99%) with high enantioselectivities (up to 99% ee) via the catalyst-controlled enantiodivergent addition of pyridazinones to enones.

A series of alkyl- and aryl-substituted iminopyridine Fe(II) complexes 1a–7a and Co(II) complexes 2b, 3b, 5b, and 6b were synthesized. The activator effect, influence of temperature, and, particularly, the alkyl and aryl substituents’ effect on catalytic activity, polymer molecular weight, and regio-/stereoselectivity were investigated when these complexes were applied in isoprene polymerization. All of the Fe(II) complexes afforded polyisoprene with high molecular weight and moderate cis-1,4 selectivity. In contrast, the Co(II) complexes produced polymers with low molecular weight and relatively high cis-1,4 selectivity. In the iminopyridine Fe(II) system, the alkyl and aryl substituents’ effect exhibits significant variation on the isoprene polymerization. In the iminopyridine Co(II) system, there is little influence observed on isoprene polymerization by alkyl and aryl substituents.

Organoselenium compounds, due to their high structural diversity, special function, and biological activities, have drawn attention in synthetic chemistry. Herein, a novel example of chiral N,N′-di...

We successfully developed an enantioselective trifluoromethylthiolation of structurally diverse carbonyl compounds. Trichloroisocyanuric acid and AgSCF3 were employed to generate active electrophilic trifluoromethylthio species in situ for asymmetric C-SCF3 bond formation. A broad variety of chiral SCF3-carbon nucleophiles (pyrazolones, β-keto esters, and β-keto amides) were obtained in excellent yields with high enantioselectivities (up to 92% ee) by Cinchona alkaloid derived squaramide catalysts. The reaction exhibits high efficiency, good enantioselectivity, and high functional group tolerance, which provided a novel and efficient way for asymmetric synthesis of trifluoromethylthiolated carbonyl compounds.

Two platinum(II)‐catalyzed heterocyclization‐migration reactions that provide five‐membered heterocycle products are described. With 5 mol‐% of PtCl2 as a catalyst, 2‐alkynyl‐2‐hydroxy carbonyl compounds 1 are converted into 3(2H)‐furanones 2 at 80 °C in moderate to excellent yields under very mild reaction conditions. The reaction is proposed to proceed through an oxonium ion intermediate B, which triggers a stereospecific 1,2‐shift analogous to an α‐ketol rearrangement. When exploited in a different manner, the 2‐alkynyl‐2‐hydroxy carbonyl compounds 1 afford 3‐pyrrolones 3 in 33–81 % yield. For this purpose, the starting compounds 1 are treated with primary amines in the presence of 5 mol‐% of PtCl2 at 100 °C in a convenient one‐pot process. These cyclization‐migration reactions give novel access to 3(2H)‐furanones and 3‐pyrrolones in which the 2‐position bears aryl or alkyl substituents. Synthetically challenging spirocyclic compounds can be prepared in this fashion by ring contraction. Studies that define the scope and limitations of the cyclization‐migration synthesis of heterocyclic systems are also described. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

Azaarenes are attractive structural units widely found in chiral pharmaceuticals, agrochemicals, and biologically active natural products. An ongoing strategy has been the construction of new chira...

Because of the tremendous effort of a great number of researchers, the catalytic asymmetric dialkylzinc addition to aldehydes has become a mature method. Ligands of diverse structures have been obtained, and high enantioselectivity for all different types of aldehydes have been achieved. Among the representative excellent catalysts are compounds 1, 8, 120, 325, 352, and 360 discussed above. However, compared to the well-developed dialkylzinc addition, the catalytic asymmetric reactions of aryl-, vinyl-, and alkynylzinc reagents with aldehydes are still very much under developed. Although catalysts such as (S)-402 and 210 prepared by Pu and Bolm have shown good enantioselectivity for the reaction of diphenylzinc with certain aromatic and aliphatic aldehydes, the generality of these catalysts for other [formula: see text] arylzinc reagents have not been studied. The vinylzinc additions using ligands 1 and 412 reported by Oppolzer and Wipf were highly enantioselective for certain aromatic aldehydes but not as good for aliphatic aldehydes. Carreira discovered highly enantioselective alkynylzinc additions to aldehydes promoted by the chiral amino alcohol 415, but this process was not catalytic yet. Ishizaki achieved good enantioselectivity for the catalytic alkynylzinc addition to certain aldehydes by using compounds 160, but the enantioselectivity for simple linear aliphatic aldehydes was low. Another much less explored area is the organozinc addition to ketones. Yus and Fu showed very promising results by using ligands 381 and 406 for both dialkylzinc and diphenylzinc additions to ketones, but the scope of these reactions were still very limited. Therefore, more work is needed for the aryl-, vinyl-, and alkynylzinc additions and for the organozinc addition to ketones, although many good catalysts have been obtained for the dialkylzinc addition to aldehydes. Development of these reactions will allow the catalytic asymmetric synthesis of a great variety of functional chiral alcohols that are either the structural units or synthons of many important organic molecules as well as molecules of biological functions. Macromolecular chiral catalysts have become a very attractive research subject in recent years because these materials offer the advantages of simplified product isolation, easy recovery of the generally quite expensive chiral catalysts, and potential use for continuous production. Three types of macromolecules including flexible achiral polymers anchored with chiral catalysts, rigid and sterically regular main chain chiral polymers, and chiral dendrimers have been used for the asymmetric organozinc addition to aldehydes. Among these materials, the binaphthyl-based polymers such as (R)-451 developed by Pu have shown very high and general enantioselectivity. Study of the binaphthyl polymers in the asymmetric organozinc addition has demonstrated that it is possible to systematically modify the structure and function of the rigid and sterically regular polymer for the development of highly enantioselective polymer catalysts. The catalytic properties of highly enantioselective monomer catalysts can also be preserved in the rigid and sterically regular polymer provided the catalytically active species of the monomer catalyst is not its aggregate. The TADDOL-based polymers and dendrimers prepared by Seebach showed very high and stable enantioselectivity for the diethylzinc addition to benzaldehyde even after many cycles. These studies on macromolecular chiral catalysts demonstrate that these materials are potentially very useful for practical applications.

A Ag-based chiral catalyst promotes efficient and highly enantioselective aldol additions of ketone-derived enolsilanes to alpha-ketoesters in the presence of a readily available amino acid-based ligand and commercially available AgF2. alpha-Ketoester substrates may bear alkyl, alkenyl, and aryl substituents; reactions proceed to >98% conversion to afford the desired tertiary alcohols in 61->98% isolated yield and 60-96% ee. In contrast to previously reported approaches, highest enantioselectivities are observed with sterically demanding substrates, and reactions can be carried out in undistilled solvent, in air with as little as 1 mol % catalyst.

The catalytic enantioselective tandem reaction is an efficient synthetic methodology in which optically active compounds are assembled from simple prochiral substrates via two (or more) distinct catalytic processes taking place under the same conditions. The synthetic efficiency is enhanced by avoiding the time-intensive and yield-reducing isolation and purification of synthetic intermediates and by decreasing the amounts of chemicals and solvents used. The asymmetric catalytic reductive aldol reaction is an efficient tandem transformation involving conjugate reduction of a,b-unsaturated carbonyl compounds followed by aldol reaction of the enolate intermediate with aldehydes or ketones. Chiral transition-metal catalysts have been used to control the stereochemistry of these transformations. We recently reported that achiral phosphorus oxides function as Lewis base organocatalysts to promote both the conjugate reduction of enones with trichlorosilane and the reductive aldol reaction of enones with aldehydes. Herein we report that enantioselective catalysis of this tandem reaction by chiral Lewis bases provides good to high diastereoand enantioselectivities. Scheme 1 outlines the current catalytic method. Our previous study had shown that the Lewis base catalyzed conjugate reduction with trichlorosilane proceeds via a six-membered transition state with an enone in the s-cis conformation to give the (Z)-trichlorosilyl enolate exclusively. Therefore, high syn selectivity is expected for the subsequent aldol process, assuming that the reaction proceeds through a chair-like cyclic transition state. Moreover, high enantioselectivity could also be achieved by judicious selection of chiral Lewis base catalysts (LB*). We first examined various chiral Lewis base catalysts (Figure 1) for the reductive aldol reaction of chalcone (1a) and benzaldehyde (2a) with trichlorosilane at 78 8C (Table 1). With (S)-BINAPO, the reaction in dichloromethane gave aldol adduct 3a with respectable stereoselectivities (Table 1, entry 1). By simply changing the solvent from dichloromethane to propionitrile, both the stereoselectivities and chemical yield dramatically improved (Table 1, entry 2). Other Lewis base catalysts were then examined using this solvent (Table 1, entries 3–6). (R,R)-DIOPO showed a comparable activity to BINAPO to afford similar enantioselectivity with a slight loss of diastereoselectivity (Table 1, entry 3). Although structurally similar to BINAPO, (S)[a] Prof. Dr. M. Sugiura, N. Sato, Y. Sonoda, Prof. Dr. M. Nakajima Graduate School of Pharmaceutical Sciences Kumamoto University 5-1 Oe-honmachi, Kumamoto 862-0973 (Japan) Fax: (+81)96-362-7692 E-mail : msugiura@kumamoto-u.ac.jp (M. Sugiura) nakajima@gpo.kumamoto-u.ac.jp (M. Nakajima) [b] Prof. Dr. S. Kotani Priority Organization for Innovation and Excellence Kumamoto University 5-1 Oe-honmachi, Kumamoto 862-0973 (Japan) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/asia.200900450. Scheme 1. The enantioselective reductive aldol reaction with trichlorosilane catalyzed by a chiral Lewis base catalyst.

The preparation of various (R)-Sulfur-MOP ligands with aryl and alkyl substituents on sulfur, and the application of these ligands to Pd-catalyzed asymmetric allylic alkylation of indoles is reported. The sulfur substituent served as an effective stereocontrol element, and in the case of the 2-i-PrPh substituent on sulfur, the allylation products from an array of simple and substituted indoles were obtained with high enantioselectivity (up to 95% ee).