Yoshitaka Hamashima

Copper-Catalyzed Trifluoromethylation of Allylsilanes†

The trifluoromethyl group is of interest in the pharmaceutical and agrochemical fields because it is lipophilic, hydrophobic, and metabolically stable; thus, great efforts have been made to develop reactions to introduce this group into organic molecules. The formation of Csp2 CF3 bonds is now a well-developed field of study. On the other hand, Csp3 CF3 bond formation is still generally achieved only through carbonyl groups, by one of a variety of protocols. New synthetic methods are still needed for the construction of Csp3 CF3 bonds in a wider range of molecular contexts. In 2010, we reported the trifluoromethylation of indole derivatives using Cu and Togni s reagent 2 (1-trifluoromethyl-1,2-benziodoxol-3-(1H)-one) in MeOH (Scheme 1 a). As an extension of that work, we next focused on C=C bond trifluoromethylation. Groups led by Buchwald, Liu, and Wang have recently reported the trifluoromethylation of unactivated olefins with a copper (I) salt and either Togni s reagent 2 or Umemoto s reagent 2’ (Scheme 1b). Although these reactions can provide structures bearing a trifluoromethyl group at the allylic position, the reported substrates are mostly limited to monosubstituted terminal olefins. We also independently investigated the trifluoromethylation of unactivated olefins, but when we applied our original Cu/2/MeOH system to the trifluoromethylation of unactivated olefins, we also found the substrate scope to be limited. To overcome this problem, we focused on allylsilanes as substrates, anticipating that they would be more nucleophilic than unactivated olefins. Herein, we disclose the trifluoromethylation of allylsilanes to afford either gem-disubstituted terminal olefins or vinylsilanes bearing a trifluoromethyl group in the allylic position (Scheme 1c). We initially examined the reaction of (2-phenylallyl)trimethylsilane 1 a with CuOAc and Togni s reagent 2 in MeOH. The desired trifluoromethylation product was obtained in low yield along with the recovery of 65 % of the starting material (Table 1, entry 1). Other copper (I) salts were examined in order to increase the effectiveness of this reaction. The use of [Cu(CH3CN)4]PF6 or CuCl gave slightly better results, but the yield was still low (entries 2 and 3). However, CuI was found to afford the desired product 3a in Scheme 1. Cu-catalyzed trifluoromethylation. CuTc = Copper(I)-thiophene2-carboxylate, DMAc= N,N-dimethylacetamide, OTf= trifluoromethanesulfonate.

Total Synthesis of (+)-Chaetocin and its Analogues: Their Histone Methyltransferase G9a Inhibitory Activity

The first total synthesis of (+)-chaetocin has been accomplished in nine steps starting from known N-Cbz-N-Me-serine using radical alpha-bromination reaction of diketopiperazine 10 and Co(I)-mediated reductive dimerization reaction of 12 as key reactions. The enantiomers show comparable inhibitory activity toward histone methyltransferase (HMT) G9a, but analogues without the sulfur functionality are inactive.

Diastereo- and Enantioselective Conjugate Addition of α-Ketoesters to Nitroalkenes Catalyzed by a Chiral Ni(OAc)2 Complex under Mild Conditions

A highly efficient, catalytic, diastereo- and enantioselective conjugate addition of alpha-ketoesters to nitroalkenes has been devised. The reaction was applicable to various substrates. Notably, the combination of endogenous and exogenous bases was effective, allowing a small amount of the catalyst (0.1-1 mol % Ni) to promote the reaction efficiently. The synthetic utility of this reaction was demonstrated in the synthesis of substituted pyrrolidine derivatives, whose stereochemistry is closely related to biologically important natural products such as kainic acid.

Catalytic Desymmetrization of Cyclohexadienes by Asymmetric Bromolactonization

Asymmetric bromolactonization of prochiral cyclohexadiene derivatives with N-bromosuccimide proceeded in the presence of (DHQD)(2)PHAL as a chiral catalyst to afford the corresponding bromolactones with up to 93% ee. This reaction was also applicable to the kinetic resolution of a racemic cyclic ene-carboxylic acid, where the starting material was recovered with high enantioselectivity.

Mechanistic Studies on the Catalytic Asymmetric Mannich-Type Reaction with Dihydroisoquinolines and Development of Oxidative Mannich-Type Reactions Starting from Tetrahydroisoquinolines

Detailed mechanistic studies on our recently reported asymmetric addition reactions of malonates to dihydroisoquinolines (DHIQs) catalyzed by chiral Pd(II) complexes were carried out. It was found that an N,O-acetal was generated in situ by the reaction of DHIQ with (Boc)2O, and cooperative action of the Pd(II) complex as an acid-base catalyst allowed the formation of a chiral Pd enolate and a reactive iminium ion via alpha-fragmentation. The iminium ion was also accessible via oxidation with DDQ as an oxidant, and a catalytic asymmetric oxidative Mannich-type reaction was achieved with tetrahydroisoquinolines (THIQs) as starting materials. This oxidation protocol was applicable to N-acryloyl-protected THIQs, allowing the efficient synthesis of optically active tetrahydrobenzo[a]quinolizidine derivatives via intramolecular Michael reaction.

Catalytic Asymmetric Mono‐Fluorination of α‐Keto Esters: Synthesis of Optically Active β‐Fluoro‐α‐Hydroxy and β‐Fluoro‐α‐Amino Acid Derivatives

In the field of medicinal chemistry, it is widely recognized that the replacement of a hydrogen atom or a hydroxy group with a fluorine atom often improves the pharmacological activity of the parent compound. Although fluorine substitution on aromatic rings is a common tactic, several drug candidates with fluorine on a stereogenic carbon center have appeared in recent years. Consequently, the development of effective methods for the preparation of optically active fluorinated compounds is attracting considerable attention. We and others have already devised elegant systems for catalytic asymmetric fluorination reactions of carbonyl compounds, including b-keto esters, b-keto phosphonates, a-cyano phosphonates and a-cyano acetates, oxindoles, 7] acid derivatives, and aldehydes. As an extension of our acid–base catalytic system using late transition metal complexes, we recently reported the first example of catalytic diastereoand enantioselective conjugate addition of a-keto esters to nitroolefins. Focusing on a-keto esters as useful nucleophiles, we next became interested in asymmetric fluorination (Scheme 1). As the keto group in the product provides a good handle for further transformations, such reactions are expected to be useful for producing medicinally important chiral building blocks. Among them, b-fluoro-a-hydroxy and b-fluoro-a-amino acid derivatives are potentially useful as synthons for obtaining novel bioactive compounds and may contribute to pharmaceutical and chemical biology research. However, to date there is no example of an asymmetric reaction to access these compounds, because it has generally been believed that the monofluorinated products would tend to undergo facile enolization, resulting in the loss of optical purity. Difluorinated compounds might also be formed, albeit with difficulty. Based on our previous results, we envisaged that the use of mildly basic catalysts would permit the asymmetric fluorination of a-keto esters. Herein we report the first example of highly enantioselective mono-fluorination of a-keto esters catalyzed by Pd-m-hydroxo complexes 1. The resulting fluorinated products were successfully converted into chiral b-fluoro-a-hydroxy esters and b-fluoro-a-amino esters. As there are few generally applicable methods for the preparation of a substituted b-fluoro carboxylic acids, the present procedure is expected to be useful in medicinal chemistry research. Initially, we investigated the reaction of commercially available ethyl ester 2a with N-fluorobenzenesulfonimide (NFSI). Though our Pd-catalyzed fluorination reactions of 1,3-dicarbonyl compounds proceeded well in ethanol, no reaction was observed with a-keto ester 2a in this solvent (Table 1, entry 1). Careful solvent screening resulted in identification of methyl tert-butyl ether (MTBE) and cyclopentyl methyl ether (CPME) as the best solvents for the reaction. The yields and enantioselectivities obtained in the two solvents were comparable, but the fluorination reaction at 20 8C reached completion in 12 h in CPME, while it required 22 h in MTBE (Table 1, entries 8 and 9). Thus, CPME became our solvent of choice. As the corresponding fluorinated a-keto ester 3a was readily converted into the hydrate form during purification, the product was isolated after in situ reduction with diisobutylaluminium hydride (DIBAL-H). The low diastereoselectivity shown in Table 1 was later improved (see below). Furthermore, as the tert-butyl Scheme 1. Enantioselective mono-fluorination of a-keto esters. OTf = trifluoromethanesulfonate.

Enantioselective Bromocyclization of Allylic Amides Catalyzed by BINAP Derivatives

A highly enantioselective bromocyclization of allylic amides with N-bromosuccinimide (NBS) was developed with DTBM-BINAP as a catalyst, affording chiral oxazolines with a tetrasubstituted carbon center in high yield with up to 99% ee. By utilizing the bromo substituent as a handle, the obtained compounds were converted to synthetically useful chiral building blocks.

Catalytic Enantioselective Aldol-type Reaction of β-Ketosters with Acetals†

Optically active β-oxycarbonyl compounds are useful intermediates in synthetic organic chemistry, and great efforts have been devoted to the development of catalytic asymmetric aldol reactions. Excellent methods have been developed with chiral Lewis acids and chiral secondary amines, in which ketones and their silyl derivatives react with aldehydes in a highly enantioselective manner. In contrast, readily enolizable 1,3-dicarbonyl compounds, such as β-keto esters and malonates have rarely been used as nucleophiles, probably because of insufficient nucleophilicity of the metal enolates of such compounds, although a plausible alternative explanation is that the products are unstable and readily undergo retro-aldol reaction (Scheme 1). Because of these general difficulties, there are only a few examples of the synthesis of optically active β-oxymalonates using π-allyl Pd chemistry, aldol reaction, and oxy-Michael reaction. As for catalytic aldol reactions of 1,3-dicarbonyl compounds, we recently reported a catalytic asymmetric hydroxymethylation of β-keto esters using paraformaldehyde as a C1 unit. However, reactions with less reactive aldehydes were difficult (vide infra), and we found no precedents in the literature. Previously, we showed that chiral Pd enolates were formed by the reaction of chiral Pd-bisphosphine complexes 1 with β-keto esters, being accompanied with the formation of a protic acid (Scheme 1). We envisaged that this proton might activate O,O-acetals to give an oxonium intermediate, so that aldol-type reactions with β-keto esters would proceed smoothly. Since the product is O-protected, we expected that the undesired retro-aldol reaction would be suppressed. The use of O,O-acetals as a synthetic equivalent of aldehydes has been extensively investigated in Lewis acid-mediated or catalyzed aldol-type reactions with silyl enolates. A general principle of these reactions is that chiral induction is hard to achieve, since the chiral Lewis acid interacts only weakly with the prochiral electrophile (Scheme 2). To our knowledge, no asymmetric version of such reactions has been reported. Here, we disclose the first example of a catalytic asymmetric aldol-type reaction of O,O-acetals using chiral Pd and Pt complexes, in which the chiral metal enolates of prochiral β-keto esters are the key intermediates.

Pd-II-catalyzed asymmetric addition reactions of 1,3-dicarbonyl compounds: Mannich-type reactions with N-Boc Imines and three-component aminomethylation

This paper describes catalytic asymmetric Mannich-type reactions of beta-ketoesters and malonates using chiral palladium complexes. Although readily enolizable, carbonyl compounds are attractive substrates, the use of such compounds as nucleophiles in Mannich-type reactions has not been extensively investigated. In the presence of chiral Pd aqua complexes (2.5 mol %), beta-ketoesters reacted with various N-Boc imines (Boc=tert-butoxycarbonyl) to afford the desired beta-aminocarbonyl compounds in good yield with high to excellent stereoselectivity (up to 96:4 d.r., 95-99 % ee in most cases). In these reactions, construction of highly crowded vicinal quaternary and tertiary carbon centers was achieved in one step. A chiral Pd enolate is considered to be the key intermediate. To elucidate the stereoselectivity observed in the reaction, possible transition-state models are discussed, taking into account steric and stereoelectronic effects. Furthermore, this catalytic system was applied to the Mannich-type reaction of malonates with N-Boc imine as well as one-pot classical aminomethylation of beta-ketoesters using benzylamine salt and formalin. The reactions proceeded smoothly, and the corresponding Mannich products were obtained in high yield with moderate to good enantioselectivity.

Acid-base catalysis using chiral palladium complexes

Chiral Pd aqua and µ-hydroxo complexes were found to act as mild Brønsted acids and bases, and chiral Pd enolates were generated from these complexes even under acidic conditions. Highly enantioselective Michael addition, Mannich-type reaction, fluorination, and conjugate addition of amines have been developed based on the acid-base character of these Pd complexes.