1.Heterobimetallic Catalysis in Asymmetric 1.4-Additionof O-Alkylhydroxylamine to αβ-UnsatUrated N-Acylpyrrole

My first project was the development of a catalytic asymmetric aza-Michael reaction using rare earth metal-lithium-binaphthol (RELB) complexes. When I joined the group, my co-workers have established aza-Michael reaction using enones and RELB catalyst. Use of carboxylic acid derivatives was, however, difficult at that time. Therefore I chose my theme as to broaden the substrate scope of the reaction to carboxylic acid derivatives.If the reaction scope was expanded, it leads to the synthesis of various useful chiral β-amino acid derivatives.

I planned my research strategy by considering following factors. 1) αβ-Unsaturated esters are unsuitable due to their high LUMO energy (poor reactivity). Activated carboxylic acid surrogates should be utilized. 2) Because RELB catalyst has suitable chiral environment towards enones that favor monodentate coordination mode, the use of monodentate carboxylic acid surrogate is desirable. Therefore, I selected α,β-unsaturated N-acylpyrrole as a candidate.Due to aromaticity of pyrrole ring, the reactivity of N-acylpyrrole is supposed to be much higher than ester, amide and be as good as enones. Coordination mode of α,β-unsaturated N-acylpyrrole is also similar to enones. As expected, YLB (Y-Li-BINOL) and DyLB (Dy-Li-BINOL) (Figure 1) complexes promoted aza-Michael reactions of methoxylamine and α,β-unsaturated N-acylpyrroles, affording products in up to 96% yield and 94% ee (Scheme 1).1The product was successfully converted into β-amino esters and aziridines as shown in Scheme 1(b). I also established a new efficient method for the synthesis of various α,β-unsaturated N-acylpyrroles using HWE reaction.

2. Bismuth- and Hafnium-Catalyzed Intermolecular Hvdroamination of 1,3-Dienes and Vinyl Arenes with Carbamates, Sulfonamides, and Carboxamides

Catalytic intermolecular hydroamination of olefins is an atom-economical method to provide nitrogen-containing building blocks. When I started this project, hydroamination of 1,3-diene investigated were limited to alkyl amines and aromatic amines. There was no report of intermolecular hydroamination reaction of 1,3-diene with weak nucleophiles like sulfonamides, carbamates, benzamides. Because 1,3-dienes readily polymerize, the key point of designing an efficient hydroamination of 1,3-dienes is how to suppress the polymerization, while promoting the desired 1:1 addition chemo-selectively. I planned to perform the reaction based on a new Lewis acid- π -acid dual controlling concept If some metal complex can activate 1,3-dienes, and at the same time, locate amide close to the activated diene, the desired reaction would proceed faster than undesired polymerization (proximity-effect-control). After numerous investigations, combination of Bi(OTf)3 and Cu(CH3CN)4PF6 was found to be suitable, giving desired products in up to 96% yield (Table 1).2 Detailed mechanistic studies showed that the exchange of PF6 anion and OTf anion gave more cationic Bi(OTf)2PF6 species which plays a significant role in the proposed catalytic cycle in Figure 2. Bi(011)2PF6not only activates 1,3-dienes to generate cationic species, but also interacts with amides to fix amides in close proximity.

Considering the allylic bismuth species (0) in Figure 2, the reaction with vinyl arenes can also form similar bismuth species. Therefore, I speculated that the bismuth catalyst would catalyze the hydroamination of vinyl arenes. When 2-oxazolidone was used, however, yield was poor using the bismuth catalyst.Further metal screening revealed that Hf(OTf)4 was more reactive than Bi(OTf)3. Mf(OTf)4/Cu(CH3CN)4PF6 system promoted the reaction with 2-oxazolidone nicely in good yield. The Hf(OTf)4/Cu(CH3CN)4PF6 system was applicable to the hydroamination of wide range of vinyl arenes, including less reactive vinyl arenes with electron-withdrawing groups and a readily Polymerizable vinyl arene with an electron-donating group. In case of a vinyl arene with an electron-donating group, reaction was performed at 8 °C to avoid self-polymerization.

3. Bismuth-Catalyzed Direct Substitution of the Hydroxyl Group in Alcohols with Sulfonamides Carbamates and Carboxamides

Substitution of the hydroxyl group in alcohols by amine nucleophiles generally requires pre-activation of the alcohols because of the poor leaving ability of the hydroxyl group. Alcohols are generally transformed into corresponding halides, carboxylates, or related compounds with good leaving ability. The process inevitably produces stoichiometric amounts of salt-waste. Substitution of the halides and related compounds also produces salt-waste and requires stoichiometric amounts of base. Therefore, direct catalytic substitution of alcohols with amines is desirable. In part 2, the Bi(OTf)3/MPF6 (M = K or Cu) system not only activates 1,3-dienes as π-acid, but also controls the position of amide nucleophiles as a Lewis acid. I hypothesized that bismuth catalysis would also be suitable for activation of allylic and propargylic alcohols.

With the Bi(OTf)3/MpF6(M = K or Cu) system, various allyl alcohols and propargyl alcohols were efficiently transformed into corresponding allylic and propargylic amides in good yield (Table 2)4. Mechanistic studies showed that even with co-existence of base like K2CO3, the reaction proceeded without any problem to give desired product at similar efficiency. When using chiral allyl and propargyl alcohols, racemic allylic amides were obtained, implying the formation of carbenium intermediate.

1.ヘテロビメタリック触媒を用いたα,β一不飽和酔アシルピロールの触媒的不斉アザマイケル反応:

キラルなβ一アミノ酸類は、種々の天然物や医薬品、不斉配位子等を構築する重要なビルディングユニットである。触媒的不斉アザマイケル反応はキラルβ一アミノ酸を与える有用な手法となりうるが、これまで、カルボン酸誘導体を基質とした場合にはエノンと比べて反応性が低下するため成功例が限られており、また基質一般性にも問題点を残していた。柴崎研究室でもヘテロビメタリック触媒を用いたエノンの触媒的不斉アザマイケル反応は既に成功していたもりの、カルボン酸誘導体への展開が課題として残されていた。秦紅波はカルボン酸誘導体の触媒的不斉アザマイケル反応を達成するべく研究に着手した。

すでにエノンで良好な結果を与える触媒系が存在したことから、同じ触媒系に適用可能な基質を選択することとした。エノンが単座配位形式を取ることを念頭におき、α,β一不飽和酢アシルピロールα,β一不飽和酢アシルピロールを活性化エステル等価体として選択し、検討を行った。その結果、触媒としてYLBあるいはDyLB(Figure1)を用いた場合にメトキシルアミンの1,4一付加反応が円滑に進行し、生成物を最高96%収率、94%eeにて得ることに成功した(Scheme1)。また得られた生成物はキラルアジリジン、β一アミノエステルへと変換可能であった。また、秦紅波はβ一アルキル置換α,β一不飽和N-アシルピロールの効率的合成法もあわせて開発した。

2.ビスマスおよびハフニウム触媒によるアミドを求核剤とする1,3一ジエン、ビニルアレーン類の触媒的分子問ヒドロアミノ化反応:

スルホンアミド、カーバメート、アミドなどの求核性の弱い反応剤を用いた分子間ヒドロアミノ化反応では、1,3一ジエンあるいはビニルアレーンのポリマー化を抑制しつっ、望みの1:1付加反応のみをケモ選択的に進行させる触媒が必要となる。秦紅波はこの課題に対して、「近接効果制御」という概念に基づいた触媒系の開発を行った。すなわち、ある金属触媒が1,3一ジエンあるいはビニルアレーンを活性化する際に、同時にスルホンアミド、カーバメート、アミドなどの反応剤を同じ金属上に位置固定しておくことができれば、擬似的に分子内反応と同じ様に二つの反応剤が近接位に配置された状態を作り出すことが可能となる。秦紅波はこのような機能を満たす触媒系の探索を行い、その結果、Bi(oTf)3とcu(cH3cN)4PF6を混合することで生じるカチオン性のビスマス触媒が1,3一ジエンの分子間ヒドロアミノ化反応に適した触媒であることを見いだした。Table1に示す様に種々のスルホンアミド、カーバメート、アミドが有効でありぐ最高96%収率で望みの付加体を与えた.また、詳細な反応機構解析も行った結果、カチオン性のビスマス種が触媒活性種であると推察され、Figure2に示すような触媒サイクルが提唱された。また、同様にビニルアレーン類の分子間ヒドロアミノ化反応も検討した結果、より高活性な触媒としてHf(OTf)4/Cu(CH3CN)4PF6系が見いだされた(Scheme2)。

3.ビスマス触媒によるアミドを求核剤とするアルコール水酸基の直接的置換反応:

アルコール水酸基の置換反応では通常、水酸基の良い脱離基への変換ないしは化学量論量の活性化剤を添加した条件での反応が行われる。これらの反応では必然的に化学量論量の廃棄物を生じることになる。アルコ-ル水酸基を直接置換することができれば副生するものは水だけであり、廃棄物を再少量に抑えることができる。秦紅波はカチオン性ビスマス触媒がアリルアルコール及びプロパルギルアルコールめスルホンアミド、カーバメート、アミドなどの求核剤による置換反応に極めて有効であることを見いだした。Bi(OTf)3/KPF6混合系を用いることで反応は短時間で進行し、最高99%収率で生成物を与えた(Scheme3)。

以上の結果は、医薬品合成研究に対して重要な貢献をすると考え、博士(薬学)に十分相当する研究成果と判断した。