Catalytic asymmetric synthesis of molecules containing tetrasubstitued carbons is an important topic in organic synthesis. 1 These molecules can be important precursors of complex molecules or pharmaceutical leads. Among various methodologies, catalytic asymmetric addition of versatile nucleophiles to ketones and β-disubstituted enones are direct methods toward the construction of chiral tetrasubstituted carbons. I would like to present my achievement about the construction of tetrasubstituted carbons through chiral copper(I)-catalysis.

1. Copper(I)-Catalyzed Hetero-Diels-Alder Reaction between Danishefsky-Type Siloxy Dienes and Ketones.2

Dihydropyranones are versatile skeletons of various biologically active compounds. A direct method for the synthesis of dihydropyranones is the hetero-Diels-Alder reaction between Danishefsky's siloxy diene and carbonyl compounds. Various chiral catalysts have been developed for this reaction, but the substrate scope was limited to aldehydes and α-ketoesters. The corresponding development using simple ketones to synthesize dihydropyranones containing tetrasubstituted carbons was still unsatisfactory due to the attenuated reactivity of simple ketones compared with aldehydes and α-ketoesters. Therefore, it is a challenging task to achieve the catalytic hetero-Diels-Alder reaction with simple ketones even in a racemic system.

Based on our previous investigation and realization of copper(I)-catalyzed aldol reaction of simple ketones,3 we hypothesized that a copper-dienolate species would be generated in situ through transmetalation between copper(I) complex and Danishefsky's diene (Figure 1). This copper dienolate, furthermore, would be reactive enough to achieve the synthesis of dihydropyranones containing tetrasubstituted carbons by using simple ketones. The results showed high substrate generality and proved that our concept was vaible (Scheme 1).

At this stage, I was still unsatisfied with the consumption of a stoichiometric amount of (EtO)3SiF from the aspect of atom economy, so another type of siloxyl diene, 1b, was designed based on the reaction mechanism. New diene 1b was prepared in gram scale by the similar procedure of Danishefsky's diene 1a (eq. 1). The copper(I)-catalyzed hetero-Diels-Alder reaction between ketones and 1b proceeded smoothly in the absence of (EtO)3SiF without losing any reactivity.

Then we extended this platform to develop an asymmetric version. Screening of chiral phosphines led us to identify Walphos type diphosphines as the optimized chiral ligand. Use of ethyl acetate as a solvent afforded better results than THF. By using these conditions, various tetrahydropyranones were obtained with high to moderate selectivities, Table 1. In conclusion, this is the first example of catalytic asymmetric hetero-Diels-Alder reaction between Danishefsky-type diene and simple ketones.

2. Catalytic Asymmetric Synthesis of Chiral Tertiary Organoboronic Esters through Conjugate Boration of β-Disubstituted Cyclic Enones.4

Conjugate addition is a fundamental method to establish a stereocenter at the β-position of electron-withdrawing groups. Although various catalytic asymmetric conjugate additions for β-monosubstituted substrates have been well developed, addition to β-disubstituted unsaturated electron-poor olefins for the construction of tetrasubstituted chiral centers was still limited. Two important reasons are that the reaction is difficult to promote due to great steric hindrance, and that the enantioselectivity is hardly controlled by the small steric difference between two substituents at theβ-position in the addition step.

Recently, chiral organoboronic acids exhibiting unique biological activities are identified, in addition to the fact that organoboron compounds are versatile synthetic intermediates. Catalytic asymmetric synthesis of chiral tertiary organoboron compounds had not been developed yet. We hence focused on the catalytic asymmetric synthesis of chiral tertiary organoboronic esters through conjugate addition to β-disubstituted cyclic enones.

In the initial study, the conditions developed by Yun's group5 for the reactions of β -monosubstitued substrates was employed for 3-phenylcyclohexenone, but it just afforded the desired chiral organoboronic ester in low yield. I then optimized the reaction conditions. Use of polar solvent such as DMSO and lithium alkoxide as copper(I) alkoxide catalyst generating reagent gave better yields for this reaction. QuinoxP* containing Pchirality was the best ligand to afford excellent reaction yield and enantioselectivity. The investigation of substrate scope was then conducted as shown in Table 2. Excellent enatioselectivities were obtained with β-aromatic-substutied enones, and stereoselectivities were almost not influenced by substituents on the aromatic rings. β - Alkyl-substituted substrates also afforded highly enantiomerically-enriched products. Moreover, β -substituted-5 and 7-membered cyclic enones produced synthetically useful enantioselectivity.

This reaction is a useful platform for the synthesis of various chiral building blocks that are otherwise difficult to access (Scheme 2). Interesting β -hydroxy ketone 7 containing a tetrasubstituted carbon was easily obtained almost without losing enantioselectivity through the oxidation by sodium perborate (eq. 2). Chiral tertiary organoboronic acid 8 was produced through acid hydrolysis (eq. 3). This reaction system was extended to a catalytic asymmetric cascade three-component reaction. In situ generated chiral boron enolate was treated with benzaldehyde before quenching, and the resulting product was oxidized in one pot. Under these conditions, chiral diol 9 involving three contiguous stereogenic centers was obtained with good diastereoselectivity and enantioselectivity (eq. 4).

To this stage, the copper(I)-catalyzed conjugate boration of β-disubstituted cyclic enones was well developed. However, linear β-disubstituted enones did not produce good results by using the same conditions, affording desired product just with low enantioselectivity. The development of copper(I)-catalyzed conjugate boration of linear β-disubstituted enones would be a challenging topic, and related investigation is ongoing.

Figure 1. Hypothesis for the generation of copper dienolate based on the previous aldol reaction.

Scheme 1. Cu(I)-Catalyzed Hetero-Diels-Alder Reaction of Ketones

Table 1. Substrate Scope of Asymmetric Cu(I)-Catalyzed Hetero-Diels-Alder Reaction of Ketones

Table 2. Catalytic Enanotioselective Conjugate Boration of β -Disubstituted Cyclic Enones

Scheme 2. Synthetically Useful Conversions of the Products and Extension to a Catalytic Asymmetric Three-Component Reaction

陳は、「一価銅触媒を用いるケトンとβ-二置換エノンに対する不斉四置換炭素構築反応の開発」のタイトルで、主に以下の2 つのトピックスについて研究をおこなった。

1. 銅触媒を用いたDanishefsky 型ジエンとケトンとのヘテロDiels-Alder 反応

Danishefsky ジエンとカルボニル化合物とのヘテロDiels-Alder 反応は、生物活性化合物のビルディングブロックとして広く一般的に見られるジヒドロピラノン誘導体を与える合成的有用性の高い反応である。カルボニル化合物としてアルデヒドを用いた触媒的不斉ヘテロDiels-Alder反応については数多くの報告例があるのに対して、ケトンを用いた不斉四置換炭素を含有する生成物を与える触媒反応は、ラセミ体合成に関しても限られた例しか報告されていなかった。陳は、当研究室で見いだした銅触媒によるケトンに対する不斉アルドール反応の反応機構から論理的に類推して、Danishefsky ジエンからのトランスメタル化を介する求核剤活性化法を組み込んだ、一般性の高い触媒的ヘテロDiels-Alder 反応を確立した。想定反応機構を基にジエンを改良して、副生成物となるケイ素化合物の排出を極力抑えた反応条件の設定にも成功した。さらにキラルジホスフィンを導入することにより、世界初のケトンに対する触媒的不斉ヘテロDiels-Alder 反応を開発した(Table 1)。

2. 銅触媒を用いたエノンに対するホウ素の不斉共役付加反応による四置換炭素構築

炭素-ホウ素結合は酸化やクロスカップリング反応により炭素-酸素結合や炭素-窒素結合、炭素-炭素結合に比較的容易に変換することができるため、有機ホウ素分子は有機合成化学上汎用性の高い化合物群である。また、ホウ酸をカルボン酸ミミックとしたキラル医薬開発も精力的におこなわれている。エノンに対する触媒的不斉ホウ素共役付加反応は、カルボニルβ位にホウ素を導入する反応であり、銅アルコキシド触媒により促進されることが韓国のYun らの研究により知られていた。しかしながら、βジ置換のエノンに対してホウ素を導入する触媒的不斉反応は報告がなかった。陳は、反応溶媒としてDMSO を用い、Yun らの反応では必須であったプロトン源の添加をおこなわない、独自の反応条件を確立することで、世界初のβ四置換炭素を与えるホウ素の触媒的不斉共役付加反応の開発に成功した(Table 2)。

生成物は、さまざまな有用キラル合成中間体へと変換が可能であった。例えば、酸化により、エナンチオ過剰率の低下を最小限に抑えながら不斉四置換炭素を含有するアルドール体へ変換した(Scheme 1, eq. 1)。またホウ酸エステルの加水分解により、キラルホウ酸誘導体へと変換できた(eq. 2)。不斉共役ホウ素化反応の進行にプロトン源を必要としない点は陳の反応の一つのメリットであり、ホウ素共役付加反応後の生成物である活性ホウ素エノラートからは更なる変換反応が可能である。この特徴を活かして、触媒的不斉共役ホウ素化-アルドール反応-酸化の連続反応にも成功している(eq. 3)。この連続反応においては、連続する3 つのキラル中心の立体化学が高度に制御できている。また本テーマでの知見を活かして、直鎖状βジ置換エノンに対しても有効な反応条件を見い出している。

これらの業績は、特に薬学分野の有機合成化学反応開発に大きく貢献するものであり、博士(薬学)の授与にふさわしいものと判断した。