Tetsu Tsubogo

Development of catalytic asymmetric 1,4-addition and [3 + 2] cycloaddition reactions using chiral calcium complexes.

Catalytic asymmetric 1,4-addition and [3 + 2] cycloaddition reactions using chiral calcium species prepared from calcium isopropoxide and chiral bisoxazoline ligands have been developed. Glycine Schiff bases reacted with acrylic esters to afford 1,4-addition products, glutamic acid derivatives, in high yields with high enantioselectivities. During the investigation of the 1,4-addition reactions, we unexpectedly found that a [3 + 2] cycloaddition occurred in the reactions with crotonate derivatives, affording substituted pyrrolidine derivatives in high yields with high enantioselectivities. On the basis of this finding, we investigated asymmetric [3 + 2] cycloadditions, and it was revealed that several kinds of optically active substituted pyrrolidine derivatives containing contiguous stereogenic tertiary and quaternary carbon centers were obtained with high diastereo- and enantioselectivities. In addition, optically active pyrrolidine cores of hepatitis C virus RNA-dependent polymerase inhibitors and potential effective antiviral agents have been synthesized using this [3 + 2] cycloaddition reaction. NMR spectroscopic analysis and observation of nonamplification of enantioselectivity in nonlinear effect experiments suggested that a monomeric calcium species with an anionic ligand was formed as an active catalyst. A stepwise mechanism of the [3 + 2] cycloaddition, consisting of 1,4-addition and successive intramolecular Mannich-type reaction was suggested. Furthermore, modification of the Schiff base structure resulted in a modification of the reaction course from a [3 + 2] cycloaddition to a 1,4-addition, affording 3-substituted glutamic acid derivatives with high diasterero- and enantioselectivities.

Multistep continuous-flow synthesis of (R)- and (S)-rolipram using heterogeneous catalysts

Chemical manufacturing is conducted using either batch systems or continuous-flow systems. Flow systems have several advantages over batch systems, particularly in terms of productivity, heat and mixing efficiency, safety, and reproducibility. However, for over half a century, pharmaceutical manufacturing has used batch systems because the synthesis of complex molecules such as drugs has been difficult to achieve with continuous-flow systems. Here we describe the continuous-flow synthesis of drugs using only columns packed with heterogeneous catalysts. Commercially available starting materials were successively passed through four columns containing achiral and chiral heterogeneous catalysts to produce (R)-rolipram, an anti-inflammatory drug and one of the family of γ-aminobutyric acid (GABA) derivatives. In addition, simply by replacing a column packed with a chiral heterogeneous catalyst with another column packed with the opposing enantiomer, we obtained antipole (S)-rolipram. Similarly, we also synthesized (R)-phenibut, another drug belonging to the GABA family. These flow systems are simple and stable with no leaching of metal catalysts. Our results demonstrate that multistep (eight steps in this case) chemical transformations for drug synthesis can proceed smoothly under flow conditions using only heterogeneous catalysts, without the isolation of any intermediates and without the separation of any catalysts, co-products, by-products, and excess reagents. We anticipate that such syntheses will be useful in pharmaceutical manufacturing.

Asymmetric Carbon–Carbon Bond Formation under Continuous-Flow Conditions with Chiral Heterogeneous Catalysts

Catalytic asymmetric carbon-carbon bond-forming reactions provide one of the most efficient ways to synthesize optically active compounds, and, accordingly, many chiral catalysts for these reactions have been developed in the past two decades. However, the efficiency of the catalysts in terms of turnover number (TON) is often lower than that of some other reactions, such as asymmetric hydrogenation, and this has been one of the obstacles for industrial applications. Although there are some difficulties in increasing the efficiency, the issues might be solved by using continuous flow in the presence of chiral heterogeneous catalysts. Indeed, continuous-flow systems have several advantages over conventional batch systems. Here we summarize the recent progress in asymmetric C-C bond-forming reactions under continuous-flow conditions with chiral heterogeneous catalysts.

Calcium-Catalyzed Diastereo- and Enantioselective 1,4-Addition of Glycine Derivatives to α,β-Unsaturated Esters

The first highly diastereo- and enantioselective catalytic asymmetric 1,4-addition reactions of a glycine Schiff base to beta-substituted alpha,beta-unsaturated esters have been developed. The reaction pathway was successfully controlled, and the desired 1,4-addition products were exclusively obtained with high enantioselectivities. The product obtained was converted to a 3-substituted glutamic acid derivative by acid hydrolysis.

Chiral calcium catalysts with neutral coordinative ligands: enantioselective 1,4-addition reactions of 1,3-dicarbonyl compounds to nitroalkenes.

Alkaline earth metals are among the most promising metallic species in organic synthesis owing to their abundance and low toxicity. Since the first report of their use as a chiral catalyst in 1998, there have been several reports of their use in asymmetric catalysis; however, their reactivity and selectivity are lower in most cases compared with those of other chiral metal-catalyzed reactions. Recently, we developed the 1,4-addition and the [3+2]-cycloaddition reactions of glycine Schiff bases using chiral calcium catalysts. We also reported the chiral strontium-catalyzed Michael reactions of malonates with chalcone derivatives, in which high reactivities and selectivities were attained. Salt formation is essential in the construction of chiral alkaline earth metal catalysts; it is required to successfully connect chiral ligands to the metal centers (Scheme 1). However, in those systems shown in Scheme 1, the Brønsted basicity of the catalyst is sometimes decreased owing to the acidic nature of the chiral ligands. During the course of our investigations to develop more efficient catalysts, we envisioned that a complex between an alkaline earth metal base and a chiral coordinative ligand might act as a stronger chiral Brønsted base species, although such examples have not been reported. Herein, we describe the use of chiral calcium catalysts, with neutral coordinative ligands, in 1,4-addition reactions of 1,3-dicarbonyl compounds to nitroalkenes. Asymmetric 1,4-addition reactions of 1,3-dicarbonyl compounds to nitroalkenes are one of the most important methods for the preparation of chiral g-nitro carbonyl compounds, which can be converted into various chiral amines by subsequent reduction. We began by investigating the reaction of malonate 4a with b-nitrostyrene (5a) in the presence of chiral catalysts, prepared from alkaline earth metal alkoxides and chiral ligands (Table 1). Although calcium complex of box ligand 1, and strontium complex of bis(sulfonamide) 2 unexpectedly gave very low enantioselectivities (Table 1, entries 1 and 2; Scheme 2), calcium pybox complex (pybox = pyridinebisoxazoline; 3a), a chiral complex with a neutral coordinative ligand, gave the desired

Asymmetric Mannich Reaction of Malonates with Imines Catalyzed by a Chiral Calcium Complex

A chiral calcium complex was found to be effective for the Mannich reactions of malonates with N-Boc imines. The desired adducts were obtained in excellent yields (up to 95%) with moderate to good enantioselectivities (up to 77% ee).

Chiral alkaline-earth metal catalysts for asymmetric bond-forming reactions

Recent developments in chiral alkaline-earth metal catalysts are summarized. Alkaline-earth metals are very attractive metal species because they are ubiquitous elements in nature, and form less harmful compounds compared with heavy transition metals. Several types of chiral ligands have been successfully employed for chiral modification of alkaline-earth metal catalysts, and high stereoselectivities have been achieved in asymmetric carbon–carbon bond forming reactions. These remarkable results indicate that chiral alkaline-earth metal catalysts show promise as useful tools in stereoselective synthesis.

Toward efficient asymmetric carbon-carbon bond formation: continuous flow with chiral heterogeneous catalysts.

A chiral Ca catalyst based on CaCl(2) with a chiral ligand was developed and applied to the asymmetric 1,4-addition of 1,3-dicarbonyl compounds to nitroalkenes as a model system. To address product inhibition issues, the Ca catalyst was applied to continuous flow with a chiral heterogeneous catalyst. The continuous flow system using a newly synthesized, polymer-supported Pybox was successfully employed, and the TON was improved 25-fold compared with those of the previous Ca(OR)(2) catalysts.

Calcium-Catalyzed Asymmetric Synthesis of 3-Tetrasubstituted Oxindoles: Efficient Construction of Adjacent Quaternary and Tertiary Chiral Centers

Chiral Ca-catalyzed asymmetric addition reactions of 3-substituted oxindoles with N-Boc-imines afford 3-tetrasubstituted oxindole derivatives bearing adjacent quaternary and tertiary chiral centers, which are key structures for biological activities. Ubiquitous and nontoxic Ca catalysts (1-10 mol %) work well in this reaction, and high yields (up to 99%) and selectivities (up to >99% ee) of the products with wide substrate scope have been attained. The structures of the chiral Ca catalysts and intermediary Ca enolates are also discussed.

Highly enantioselective Friedel-Crafts-type alkylation reactions of indoles with chalcone derivatives using a chiral barium catalyst.

Alkaline earth metals are abundant, nontoxic and inexpensive, and have high coordination numbers. Their salts have both Brønsted basicity and Lewis acidity. Despite these characteristic features, only recently have successful examples using alkaline earth metal compounds as catalysts in organic synthesis been reported. We have developed anionic chiral calcium catalysts prepared from calcium alkoxides or amides and chiral bisoxazoline (box) ligands and strontium catalysts prepared from strontium alkoxides or amides and chiral sulfonamides. These catalysts worked well as Brønsted bases for several catalytic asymmetric carbon carbon bond-forming reactions. We also found that a chiral coordinative ligand (pybox) was applicable for asymmetric 1,4-addition and Mannich-type reactions using a calcium catalyst. Herein, we report that chiral barium complexes prepared from barium amides and chiral ligands work well as efficient catalysts for asymmetric Friedel– Crafts–type alkylation reactions of indoles with chalcone derivatives. Enantioselective Friedel–Crafts–type alkylation reactions of indoles provide versatile methods for the preparation of optically active indole derivatives. As catalytic asymmetric reactions are ideal from a viewpoint of efficiency, some catalysts for these reactions have been developed recently; however, most are chiral Lewis acids or organocatalysts. To the best of our knowledge there are no examples of Brønsted base catalyzed asymmetric Friedel–Crafts– type reactions of indoles with enones. Moreover, in spite of their versatile synthetic utilities, the use of chalcone derivatives as enones has been limited. We considered that alkaline earth metal complexes might function as chiral Brønsted base catalysts in the Friedel– Crafts–type reactions of indoles. The reaction of indole 8 a with chalcone 9 a was selected as a model reaction, and several combinations of alkaline earth amides with chiral ligands were tested. First, we examined the combination of alkaline earth metal amides with taddols (a,a,a’,a’-tetraaryl1,3-dioxolan-4,5-dimethanoles) 1 in the model reaction (Figure 1). When barium amide (barium bis(hexamethyldi-