1. Development of New Modular Chiral Bisphosphine Ligands (ShrimP*): Design, Synthesis and Their Application in Cu(I)-Catalyzed Asymmetric Allylation and Propargylation of Ketones1

Chiral phosphines play crucial roles in asymmetric catalysis. Many privileged chiral phosphines have been developed. Continuous structural improvement and diversification are still necessary, however, to achieve high asymmetric induction in difficult-to-control C-C bond formations, such as tertiary alcohols constructions. Synthesis of chiral phosphines is generally laborious, which has hampered their intensive structural optimization. Modular approaches allowing for rapid synthesis and systematic optimization of ligand structure will facilitate the development of chiral phosphines. Herein, I report the development of new modular chiral bisphosphine ligands (ShrimP*, Figure 1) and their application in construction of two kinds of chiral tertiary alcohols.

(1) Development of ShrimP* and its Application in Cu(I)-Catalyzed Asymmetric Allylation of Ketones

Catalytic asymmetric allylation of ketones constructing chiral tertiary alcohols represents a challenging reaction. Although many efforts have been devoted to this reaction, there are still several drawbacks in the known methodologies, such as high catalyst loadings, narrow substrate generalities, and requirement of unstable allylating reagents. Our group previously developed the first asymmetric allylboration of ketones catalyzed by a CuF-iPr-DuPHOS complex2. AIthough the products were obtained in high yields, the enantioselectivity was not necessarily satisfactory, even after intensive screening of commercially available chiral phosphines. Therefore, efficient catalysts with excellent enantio-induction ability to facilitate the asymmetric allylation of ketones are in high demand.

With these considerations in mind, I started to develop original modular chiral phosphines. The intensive optimization of a series of readily synthesized phosphines in the catalytic enantioselective allylation of acetophenone led me to identify Shrimp* as the best ligand. ShrimP* was easily prepared in multigram scale in high yield via three facile transformations (O-alkylation, bisaminal formation, and phosphination) using commercially available reagents. Further optimization of reaction conditions revealed that the addition of co-catalyst LiO'Pr and protonic additive isopropanol significantly improved the reactivity. As a result, the optimal reaction conditions were developed as shown in Scheme 1.

In general, the allylation reaction proceeded smoothly in the presence of 2 mol % of catalyst, affording the product in high yield and excellent enantioselectivity. Compared with our previous reaction using iPr-DuPHOS2, the enantioselectivity and catalyst activity were significantly improved. The crotylation reaction also proceeded with improved diastereo- and enantioselectivity. Notably, in the case of tetralone as substrate, using as low as 0.1 mol % of CuOAc―ShrimP* catalyst afforded the product in excellent enantioselectivity (95% ee) and high yield (85%). These facts clarified that Cu―ShrimP* possesses high activity and excellent enantio-control ability.

(2) Application of ShrimP* to the First Cu(11)―Catalyzed Asymmetric Propargylation of Ketones

To further demonstrate the utility of Shrimp*, I applied the CuOAc―ShrimP* catalyst to an enantioselective propargylation of ketones using allenylboronate (Scheme 2). Homopropargyl tertiary alcohols were produced with high enantioselectivity from a range of ketones, including aryl, heteroaryl, a13-unsaturated and alkyl ketones. The reaction proceeded with perfect regioselectivity (7-addition), and the corresponding allenyl alcohol isomers (a-adducts) were not detected in any case. Due to the synthetic versatility of terminal alkynes, various product conversions, such as Sonogashira coupling and one-pot propargylation―Huisgen cycloaddition, were successfully performed. Therefore, this reaction produces a synthetically independent family of chiral building blocks for allylation. It's noteworthy that this is the first catalytic enantioselective propargylation of ketones.

(3) Mechanistic Studies

To gain some insight into the origin of the high catalyst activity and enantioselectivity of the CuOAc-ShrimP* complex, I elucidated the X-ray crystal structure of the complex. The observed bite angle was extraordinarily wide (〓PCuP = 137.8°), resulting in the stabilization of the catalytically active monomeric Cu complex. This hypothesis was confirmed by comparison of the catalytic activity and - aggregation state of the Cu-bisphosphine (ShrimP*, iPr-DuPHOS, and XantPHOS) complex. Furthermore, through DFT calculation for transition state structures of the allylation of acetophenone, it was observed that the carbonyl oxygen in acetophenone formed non-conventional C-H・・・O=C hydrogen bonds with the bisaminal protons (H19, H28) and aryl-H (H90) on the phosphorous atom (Figure 2), leading to a distortion of the tetrahedral copper atom geometry. Therefore, I tentatively proposed that the significant stabilization by hydrogen bond network formation in the transition state, as well as the extraordinarily wide bite angle, is responsible for the high catalyst activity and enantioselectivity of the CuOAc-ShrimP* complex.

2. Direct Asymmetric Synthesis of Dihydropyranones via a Soft Metal Catalyzed Sequential Aldol-oxy-Michael Reaction Using α,β-Unsaturated Ynones 6

Chiral dihydropyranones are versatile skeletons of various biologically active molecules. Catalytic asymmetric hetero-Diels-Alder reactions between carbonyl compounds and activated dienes (typically, Danishefsky's dienes) is a conventional method to access them.3'4 However, preparation of labile dienes is a cumbersome process. Thus, I envisioned that an asymmetric hetero-Diels-Alder reaction to produce dihydropyanones via a sequential aldol-oxy-Michael reaction using enolates generated in situ by a chiral base catalyst from stable and easily available ynones will be advantageous.

Despite the presumable fascinating efficiency, developing such a reaction is particularly challenging due to two reasons: 1) there are possible side reactions in a base-catalyzed direct aldol reaction, such as retro-aldol reaction, homo-aldol reaction of substrates, and dehydration of aldol adducts; 2) the corresponding intramolecular oxy-Michael reactions to ynones are not studied extensively.

To overcome these difficulties, I assumed a soft metal-conjugated base would facilitate the sequential aldol-oxy-Michael reaction. My designed process relies on two distinct soft metal-soft π electron interactions: 1) chemoselective deprotonative activation of ynones through soft metal-soft ynone interaction in the presence of (enolizable) aldehydes to promote the aldol reaction;5 2) electrophilic activation of thus-generated aldol adducts (β-hydroxyynones) via soft metal-soft ynone interaction to promote the oxy-Michael reaction. As expected, after intensive screening, I successfully developed a direct asymmetric synthesis of dihydropyanones via a sequential aldol-oxy-Michael reaction catalyzed by a Cu(I)-DTBM-SEGPHOS complex and AgOTf, respectively (Scheme 3).6 Chiral 2,6-disubstituted dihydropyranones were produced in moderate to excellent enantioselectivity and good yields with high substrate generality. One example for asymmetric synthesis resulted in high diastereo- and enantioselectivity.

It's notable that the highly chemoselective deprotonative activation of ynones allows for a direct aldol-cyclization reaction of a-nonbranched aliphatic aldehydes, which are susceptible to self-condensation. Furthermore, a series of functional groups was compatible, such as ketone, ester and unprotected hydroxyl group. Expansion of substrate scope in the diastereoselective reaction, as well as application of the current methodology to a catalytic asymmetric synthesis of Relenza (an antiviral drug) is now ongoing.

Figure 1. ShrimP*: Ar = p-F-Ph

Scheme 1. CuOAc-ShrimP* complex catalyzed asymmetric allylation of ketones

Scheme 2. CuOAC-ShrimP* complex catalyzed asymmetric propargylation of ketones

Figure 2. DFT calculation for transition state structure of the catalytic asymmetric allylation of acetophenone

Scheme 3. Direct asymmetric synthesis of dihydropyranones via a soft metal catalyzed sequential aldol-oxv-Michael reaction using a, fl-unsaturated ynones

施世良は、「一価銅触媒による3級アルコールおよびジヒドロピラノン類の不斉合成」というタイトルで、以下の述べる2種類の研究を行った。

(1)独自のキラルボスフィン配位子ShrimP*の創製

キラルポスフィン配位子は、不斉触媒のエナンチオ選択性と活性を直接的に左右するため、その開発は不斉触媒化学の中核をなす。様々なキラルボスフィン配位子が開発されているものの、不斉四置換炭素構築に代表される困難な立体化学制御を実現するためには、更なる新規骨格が必要である。施は、モジュールからキラルポスフィン配位子を構築する概念に基づき、ケトンに対する触媒的不斉アリル化反応とプロパルギル化反応に有効な独自の不斉配位子ShrimP*(Figure1)を見出した。ShrimP*は、トリアリールポスフィン部位を金属への配位モジュールとして、市販の比較的安価なアミノジオールをキラリティー制御モジュールとしてそれぞれ有しており、これらをアミナールで縮合することで合成できる。実際、市販の4つの化合物から3工程、60%程度の総収率でShrimP*は合成できる。そのため各モジュールをそれぞれ最適化しこれらを組み合わせることにより、多様な構造を有するキラルボスフィンが迅速に合成できる。この特徴は、不斉反応を最適化する場合に大きなメリットとなる。

まず初めに施は、ShrimP*を当研究室で開発したケトンに対する触媒的不斉アリル化反応で最適化し、適用した(Scheme1)。その結果、酢酸銅とShrimP*の錯体を不斉触媒として、LiOiPrとイソプロパノールを共存させることで、高い基質一般性と触媒活性が発現することを見出した。最適な基質に対しては、約1000回の触媒回転と90%ee以上の高いエナンチオ過剰率が得られた。また、エナンチオ選択性制御に加えてジアステレオマー選択性制御も必要なクロチル化でも良好な結果が得られた。これらは、市販の最適なキラルポスフィンであるiPr-DuPHOSに比較して、格段に優れた結果である。触媒のX線結晶解析や質量分析を用いた構造的解析から、高い触媒活性とエナンチオ選択性を与える要因の仮説を構築した。

ShrimP*の持つ非常に大きなバイトアングルにより触媒活性種である単量体銅錯体が安定化されることが、高い触媒活性の主たる原因であり、またアセタールプロトンと近傍に存在するオキシアニオン(酢酸アニオンやアリル基がケトンと反応するときに生成するオキシアニオン)とが非古典的水素結合を形成することが、エナンチオ選択性発現の要因であろうことを提唱した。

銅一ShrilnP*錯体の高い触媒活性を活かして、ケトンに対する触媒的不斉プロパルギル化にも成功した(Scheme2)。本反応は、市販のアレニルホウ素化合物を求核剤として用いて、完全な位置選択性と高いエナンチオ選択性が得られる点が特徴である。末端アルキンの合成的有用性を活かして、薗頭カップリングやclick反応など、冒アリル基とは異なる合成展開が可能であった。

(2)イノンを求核剤とする触媒的不斉アルドール反応一オキシMichael環化によるキラルジヒドロピラノン類の触媒的不斉合成法の確立

当研究室が有するソフトメタルである1価銅とソフトな官能基の選択的相互作用による活性化の知見を活かして、イノンをキラル銅アルコキシド触媒により選択的に脱プロトンして活性化し、生じるキラル銅エノラートをアルデヒドに不斉付加させる反応を見出した。更に、ソフト金属のアルキン活性化能を活かして、生成物をワンポットで環化させ、医薬ビルディングブロックとして汎用性の高いジヒドロピラノンへと導くプロセスを確立した(Scheme3)。本触媒的不斉反応は、様々な糖誘導体の合成に有用であると考えられる。

以上のように、施の業績は新しい不斉触媒反応の開発と医薬品等の生物活性化合物の触媒的不斉合成に有意に貢献するものであり、博士(薬学)の授与に相当するものと判断した。