Chiral y-amino acids and their derivatives are very important building blocks being the key structural motifs in natural products and pharmaceuticals. However, catalytic enantioselective methods leading to these compounds are still rare. Herein, I report direct catalytic asymmetric Mannich-type reactions and aldol-type reactions by utilizing the multifunctionality of a-keto anilides (Figure 1) toward the synthesis of chiral y-amino amides and azetidine derivatives. In case of Mannich-type reactions, a-keto anilides functioned as the nucleophiles, providing either syn- or anti-Mannich adducts stereoselectively by using different types of bifunctional Lewis acid-Bransted base catalyst Transformations of Mannich adduct provided efficient accesses to chiral y-amino amides and azetidine derivatives. On the other hand, a-keto anilides functioned as the electrophiles in catalytic asymmetric aldol-type reactions with a ketoimine as the nucleophile.

1. Direct Catalytic Asymmetric Mannich-Type Reactions Using a-Keto Anilides as Nucleophile

(1) syn-Selective Mannich-Type Reactions1

Direct catalytic asymmetric Mannich-type reaction using a-keto esters as nucleophiles was reported by Jorgensen et al.2 After diastereoselective reduction of a-keto unit in Mannich adduct, a highly functionalized y-amino ester with three contiguous stereocenters was obtained with excellent enantio- and diastereoselectivity. However, the method was limited to the use of N-Ts a-imino ester as the only electrophile. Therefore, the development of other new method to enable the use of imines with various substituents for y-amino acid derivative synthesis is in high demand.

Initially, I also examined the feasibility of using a-keto ester as nucleophile for Mannich-type reactions with imines activated by various protecting groups, and found that partial cyclization always occurred after C-C bond formation. Then, I turned my attention to using a-keto anilides as nucleophiles. The Mannich adducts were easily obtained in high yield. After screening several chiral catalysts developed in our group, I found heterobimetallic La-aryloxide/Li-aryloxide/pybox complex3 to be the most effective for providing syn-form Mannich adducts when using N-2-thiophenesulfonyl imines as electrophiles. Finally, La(OAr)3/LiOAr/sBu-pybox catalyzed direct Mannich-type reactions of various aryl, heteroaryl and alkyl N-thiophenesulfonyl imines to give products in >99-66% yield, 95-70% ee, and >97:3-77:23 syn-selectivity (Scheme 1). Both La and Li were important in present system. The real catalyst was supposed to be a bifunctional basic ate-complex, in which one La-aryloxide moiety functioned as Brsnsted base for deprotonating of a-keto anilide while La or Li functioned as Lewis acid for activating the substrate.

(2) anti-Selective Mannich-Type Reactions4 (Co-worked with Yingjie Xu, M2 student)

Because the control of diastereoselectivity in asymmetric catalysis is a very important issue, therefore, after establishment of syn-selective Mannich-type reactions using a-keto anilides as nucleophiles, I considered how to achieve the anti-selectivity using the same substrates.

I examined the reactions using La(OAr)3/phosphine dioxide as catalyst.5 However, poor reactivity along with poor enantioselectivity was observed, albeit sometimes with high anti-selectivity. Then I found that bimetallic-Schiff base complex could promote the reaction of a-keto anilide and N-2-thiophenesulfonyl imine in anti-selectivity and with good yield. However, just by changing metals or the upper part of Schiff base ligand, both diastereo- and enantioselectivity would be affected greatly. A homodinuclear Ni2-Schiff base complex was found to be the most promising candidate. However, the reproducibility was not so good. After that time, the optimal reaction conditions were successfully established by co-worker, Yingjie Xu, who found that careful washing of the complex without using water in catalyst preparation process is the key point for high enantioselectivity. Finally, Ni2-Schiff base complex catalyzed direct Mannich-type reaction of a-keto anilides with various aryl, heteroaryl and alkyl imines which were activated by an N-ortho-nitrobenzenesulfonyl group, giving products in 99-76% yield, 95-91% ee, and >50:1-10:1 anti-selectivity (Scheme 2). In the homodinuclear Ni2-Schiff base complex, one Ni-aryloxide moiety is supposed to function as Brcnsted base for deprotonating of a-keto anilide, another Ni is supposed to function as Lewis acid for activating imine substrate.

(3) Synthesis of Chiral y-Amino Amides and Azetidine Derivatives6

To demonstrate the synthetic utility of syn- or anti-Mannich adducts obtained via above protocols, transformations of them into various chiral y-amino amides and azetidine derivatives were investigated (Scheme 3). Various B-alkyl-y-amino-a-hydroxy amides with three contiguous chiral centers were successfully obtained by diastereoselective reductions of a-keto moiety using K-Selectride, KBH4, or Super-Hydride. y-Amino amides containing one tetrasubstituted carbon unit were also synthesized by diastereoselective additions of various Grignard reagents to a-keto moiety. Finally, N-2-thiophenesulfonyl group was easily removed by Na/naphthalene for the first time. On the other hand, these y-amino amides became good precursors for fully substituted azetidine-2-amides/esters, which are quite useful non-natural amino acid derivatives for medicinal chemistry but still rarely reported. As a result, intramolecular Mitsunobu cyclization proceeded and optically active azetidine-2-amides were obtained in high yield. As a potential ester equivalent, anilide moiety was easily converted into ester group under mild conditions without any epimerization.

2. Direct Catalytic Asymmetric Aldol-Type Reactions Using a-Keto Anilides as Electrophiles

Chiral tertiary alcohols or a-tertiary amines are very important building blocks of naturally occurring and artificial biologically active molecules. Based on the results as described in above section, I envisaged the possibility of asymmetric Mannich-type addition of a-keto anilides to ketoimines, which would possibly construct 7-amino amides with a tetrasubstituted chiral carbon unit after reducing C=O bond. However, preliminary racemic reaction between a-keto anilide and ketoimine in the presence of LiOAr only afforded the product with a tertiary alcohol moiety quantitatively, which suggested an inversion pathway-ketoimine worked as a nucleophile, while a-keto anilide worked as an electrophile. Upon treatment with H-, R- orH3O+, C=N bond in product would potentially present to be a reactive site for synthesizing y-amino-a-hydroxy amide or a-hydroxy-y-keto amide that contains one or two tetrasubstituted carbon centers. Therefore, I started to investigate direct catalytic asymmetric aldol-type reactions of ketoimines using a-keto anilides as electrophiles. Moreover, using achiral ketoimines as nucleophiles for the direct asymmetric C-C bond-forming reactions is still challenging now.

At present, one promising result has already been obtained by using heterobimetallic Nd(OAr)3/LiOAr/iPr-pybox complex (Scheme 4). The aldol adduct was hydrolyzed into a-hydroxy-y-keto amide quantitatively. Further optimizations of reaction conditions to improve the reactivity and selectivity, as well as transformations of the aldol adducts into tetrasubstituted 7-amino-a-hydroxy amides are still under investigations.

Figure 1. Multifunctionality of a-keto anilid

Scheme 1. Heterobimetallic La/Li/pybox-catalyzed direct asymmetric Mannich-type reactions of a-keto anilides

Scheme 2. Homodinuclear Ni2-Schiff base complex-catalyzed direct asymmetric Mannich-type reactions of a-keto anilides

Scheme 3. Transformations of Mannich adducts: chiral y-amino amides and azetidine derivatives synthesis

Scheme 4. Heterobimetallic Nd/Li/pybox-catalyzed direct asymmetric aldol-type reaction of a-keto anilide

光学活性γ-アミノ酸は生物活性化合物に多く見られる重要な合成素子であり、多様性に富んだ光学活性γ-アミノ酸を効率的に得るための手法の開発が強く望まれている。盧剛は、α-ケトアニリドの特性を活用することで、様々な光学活性γ-アミノ酸の合成法が開発できると考え、研究に取り組んだ。

1.α-ケトアニリドを求核剤とする直接的触媒的不斉マンニッヒ型反応

1-1.syn-選択的な直接的触媒的不斉マンニッヒ型反応

近年、直接的触媒的不斉マンニッヒ型反応によるβ-アミノ酸の合成に関する研究が盛んに行われている。一方で、α-ケトエステルを求核剤とするマンニッヒ型反応は官能基化されたγ-アミノ酸を得るための効果的な手法となりうるが、Jorgensenらによる報告が1例あるのみであり、しかも、彼らの手法は求電子剤がα-イミノエステルに限定されているという問題点が残されていた。そこで、盧剛は、様々な置換基をもったイミンへと適用可能な反応系の開発を目指して検討を開始した。

当初、α-ケトエステルを求核剤として検討を進めたが、得られる生成物の安定性に問題が生じた。そこで、求核剤の検討を行い、α-ケトアニリドが最適であることを見いだした。様々な不斉触媒を探索した結果、La-アリールオキシド/Li-アリールオキシド/Pyboxを組み合せた触媒系が優れた選択性および反応性を示した。イミンとして2-チオフェンスルホニルイミンを用いた場合に最良の結果が得られ、syn-マンニッヒ体を>99~66%収率、95-70%ee、そして>97:3~77:23のsyn:anti比で得ることに成功した(Scheme 1)。コントロール実験の結果、La-アリールオキシドとLi・アリールオキシドの両方が高い反応性と選択性発現に必須であることが判明したことから、実際の活性種はScheme1右に示すようなアート錯体ではないかと想定された

1-2.anti-選択的な直接的触媒的不斉マンニッヒ型反応。

生成物の多様性を考えた場合、1-1と相補的なanti-選択的な反応の開発が望ましい。盧剛は、共同研究者の許応傑とともにanti-選択的な反応に適した触媒の探索を行った。希土類pybox触媒系ではanti-選択性を実現することは出来なかったが、2核性Schiff塩基触媒系を用いることで高いanti-選択性が実現できることが判明した。使用する金属および配位子の微調整を行った結果、最終的にビフェニルジアミンを母核とする複核Ni触媒系が最適であった。Scheme2に示すように、anti-マンニッヒ体を99~76%収率、95-91%ee、そして>50:1~10:1のanti-syn比で得ることに成功した。

1.3マンニッヒ生成励の変換

1-1および1-2で得られたマンニッヒ体を用い、官能基化された様々なγ-アミノ酸誘導体の合成を検討した(Scheme 3)。ケトン部の立体選択的還元は、syn体に関してはKBH4あるいはK-Selectride、anti体に関してはsuper hydrideあるいはK-Selectrideを用いることで高いジアステレオ選択性にて進行し、それぞれsyn-antiあるいはanti-antiの立体様式のβ-アルキル-γ-アミノ-α-ヒドロキシアニリドを高い収率にて与えた。各種グリニャール試薬の付加も立体選択的に進行し、tert-アルコールを有するγ-アミノアニリドを与えた。さらに、立体選択的還元により得られた生成物を光延反応の条件にて反応させたところ、分子内閉環反応が効率的に進行し、多置換アゼチジンアニリドおよびエステルを得ることにも成功した。光学活性多置換アゼチジンカルボン酸誘導体を立体を精密に制御して合成する手法は、立体障害のため困難とされており、本方法論は非常に有効な手法である。

2.αケトアニリドを求電子剤とする直接的触媒的不斉アルドール型反応

盧剛は、α-ケトアニリドが求核剤としてでなく、求電子剤としても有用であることを見いだした。すなわち、ケトイミンを求核剤とし、α-ケトアニリドを求電子剤とするアルドール型の反応が希土類/アルカリ金属触媒系により収率よく進行した。最適化の結果、Nd-アリールオキシド/Li-アリールオキシド/Pybox触媒系により72%eeにて生成物を得ることに成功した(Scheme4)。

以上の非天然型γ-アミノ酸誘導体およびアゼチジンカルボン酸誘導体の合成法の開発に関する研究成果は、医薬合成化学の分野に広く貢献するものであり、博士(薬学)の学位を授与するに値すると判断した。