Dynamic Ligand Exchange of the Rare-Earth Metal Complex

On the basis of the nature of the rare-earth metal complexes, such as moderate Lewis acidity, multifunctionality, large coordination numbers, and fast ligand exchange ability, I anticipated that subsequent addition of other reagents would alter the structure and function of the rare-earth complex in situ through dynamic ligand exchange to promote different reactions successively. In this regard, the rare-earth-BINOL complex appeared to be a suitable catalyst. Our group reported a general and highly enantioselective epoxidation of α,β-unsaturated simple amides 2 catalyzed by the Sm-（S）-BINOL-Ph3As=O complex 1, prepared from Sm（OiPr）3, （S）-BINOL, and Ph3As=O in a ratio of 1:1:1.1 The highly enantioenriched α,β-epoxy amides 3 （up to >99% ee）, in particular α,β-epoxy morpholinyl amides,2,3 are versatile intermediates because a ring-opening of the epoxide and a modification of the amide moiety provide efficient access to useful chiral building blocks. I assumed that the subsequent addition of another reagent （R3Si-Nu） after the asymmetric epoxidation would generate another highly reactive complex （X2Sm-Nu） to promote the catalytic epoxide-opening in one reaction vessel（Scheme 1）.

Initial investigation began with the ring-opening reaction of α,β-epoxy amide （Table 1）. As expected, treatment of α,β-epoxy amide 3a with Me3SiN3 in the presence of 5 mol % of Sm（OiPr）3 led to a cleanepoxide-opening within 1 h at room temperature, affording the corresponding anti-β-azido-α-hydroxyamide 4a in 99% yield （entry 1）. Reduced catalyst loading （0.2 mol %） was sufficient （99%; entry 2）. The use of 5 mol % of the （S）-Sm complex 1 also completed the reaction （entry 3）. In contrast, the reaction with 10 mol % of Sm（OTf）3, a much stronger Lewis acid, proceeded sluggishly to give 4a in 21% yield after 24 h. （entry 4）.

Encouraged by the above results, I examined the extension to a one-pot sequential process. After completion of the catalytic asymmetric epoxidation of 2a in the presence of 5 mol % of the （S）-Sm complex 1, Me3SiN3 was directly added to the reaction mixture. The epoxide-opening proceeded smoothly without adverse effects （99%, 99% ee; Table 2, entry 1）. As summarized in Table 2, the present one-pot sequential process had broad substrate generality, and especially noteworthy was the complete regioselectivity of the β-aliphatic substrates （entries 8.12）.

Having established the above new one-pot sequential process, the utility was demonstrated by short syntheses of the side chain of the anticancer drug, taxol and a novel cytokine modulator, （.）-cytoxazone （Scheme 2）.

Mechanistic Study: I performed spectroscopic experiments to gain precise information of the anticipated rare-earth azide complex, which has never been characterized. When Sm（OiPr）3 （1 mol equiv） and Me3SiN3 （5 mol equiv） were mixed in THF-d8, the generation of Me3SiOiPr was observed on 1H and 13C NMR spectra, suggesting that a ligand exchange occurs from the isopropoxide to the azide on the samarium metal. Next, I measured in situ IR spectra. When Me3SiN3 （20 mol equiv） was treated with Sm（OiPr）3 （1 mol equiv） in THF, a new peak appeared around 2100 cm-1 on in situ IR spectra （Figure 1）. Treatment of Me3SiN3 with the （S）-Sm complex 1 instead of Sm（OiPr）3 gave similar spectra. DFT calculation （B3LYP/LanL2DZ level） suggested that Sm（N3）3 has an absorption at 2093 cm-1 （N=N stretch）. On the other hand, there were no new peaks observed when treated with Sm（OTf）3 in THF. These results indicate that Sm（OiPr）3 or the （S）-Sm complex 1 works in the epoxide-opening reaction, not simply as a Lewis acid, but as the active azidation reagent by formation of the highly reactive samarium azide complex. This is the first investigation of the physical property of the rare-earth azide complex.

In stark contrast to the success using α,β-epoxy amides, α,β-epoxy ketones and α,β-epoxy esters remained almost unchanged under the reaction conditions shown in Table 1. These facts suggested that the Lewis basicity of the carbonyl moiety has a key role in the epoxide-opening reaction. To investigate the origin of the dramatic difference in reactivity, I performed the ring-opening reaction of α,β-epoxy anilides 9a-e, where the Lewis basicity of the carbonyl moiety was tuned by a para-substituent （X） on the benzene（v） of Step B increased as the electron-donating ability of X increased. Remarkably, a similar tendency was observed in the initial rate of the asymmetric epoxidation （Step A）. These results suggested that more Lewis-basic amide carbonyl coordinates to the samarium more efficiently and enhances the nucleophilicity of the active samarium.nucleophile complex. In the asymmetric epoxidation of α,β-unsaturated simple amides, the enhancement would be effective enough to overwhelm the potentially low reactivity that derives from the high LUMO energy level, thus achieving the high reactivity.

Exploring other nucleophiles for the sequential process revealedthat the use of PhSSiMe3 or PhSH waseffective （Scheme 4）. Samarium thiolate should be generated through dynamic ligand exchange and act as the active species

I developed a mild and efficient one-pot sequential catalytic asymmetric epoxidation-regioselectiveepoxide-opening process promoted by the Sm-BINOL-Ph3As=O complex. The key to the success was the in situ generation of the highly reactive samarium-nucleophile complex through dynamic ligand exchange.4

Catalytic Asymmetric Synthesis of Tertiary Nitroaldols

The enantioselective construction of tetrasubstituted carbon centers represents an attractive area in synthetic organic chemistry because they are ubiquitous motif in pharmaceuticals and biologically significant molecules. Catalytic asymmetric Henry reaction （nitroaldol reaction） of ketones would lead to chiral tertiary nitroaldols, which are very useful intermediates. There are, however, no reports on general asymmetric synthesis of tertiary nitroaldols, and very few methodologies even for the racemic version. The difficulty presumably arises from the attenuated reactivity of simple ketones and a strong tendency toward retro-Henry reaction, which makes this subject quite challenging.

In the early 1990s, our group reported the first example of the catalytic asymmetric Henry reaction of aldehydes promoted by the heterobimetallic LaLi3tris（binaphthoxide） complex （LLB）. To address the above-mentioned issue, I initially tested LLB for the Henry reaction of ketone 12. Notably, the reaction proceeded at -40℃ in the presence of 5 mol % of （R）-LLB, affording the corresponding tertiary nitroaldol （S）-13 with 89% ee although the catalytic efficiency was unsatisfactory （20%; Scheme 5, eq 1）. Assuming that the low chemical yield was due to fast retro-Henry reaction, I turned my attention to kinetic resolution of racemic 13, expecting that （R）-LLB would preferentially convert the matched enantiomer （S）-13 into 12 and leave the mismatched enantiomer （R）-13 unchanged. As a result, the retro-Henry reaction of （±）-13 proceeded at -40℃ in the presence of catalytic （R）-LLB, giving （R）-13 with 82% ee at 51% conversion. Raising temperature to -20℃ increased the reaction rate （eq 2）. Further optimization of the reaction conditions and examination of substrate scope are currently in progress.

Scheme 1. Dynamic Ligand Exchange of the Rare-Earth Complex and Strategy for One-Pot Sequential Process

Table 1. Regioselective Ring-Opening of α,β-Epoxy Amide

Table 2. One-Pot Sequential Process

Scheme 2. Transformations

Figure 1. In Situ IR Spectra

Scheme 3. Hammett Plot

Scheme 4. Application to Sulfur Nucleophile

Scheme5. Catalytic Asymmetric Synthesis of Tertiary Nitroaldols

希土類金属錯体の動的リガンド交換

希土類金属錯体はルイス酸性、多機能性、高い配位数をとりリガンド交換を起こしやすいといった特徴を有している。戸崎はこういった希土類金属錯体の特徴をもとにして、連続的な試薬の添加により、動的リガンド交換を経て希土類金属錯体の構造と機能が変化し、異なる複数の反応がワンポットにて進行しうるのではないかと考え研究に着手した。Sm-（S）-BINOL-Ph3As=O錯体1によるα,β-不飽和アミドの触媒的不斉エポキシ化反応ののち、第二の試薬（R3Si-Nu）を添加することで新たな高活性な錯体（X2Sm-Nu）が生成しエポキシド開環反応を進行させうると予測し、検討を開始した（Scheme 1）。

最初にTable 1に示すようにα,β-エポキシアミドの開環反応の検討を行ったところ、触媒量のSm（OiPr）3または（S）-Sm錯体1存在下Me3SiN3を用いた場合に開環反応が室温下にて円滑に進行し、対応する生成物4aが99%収率にて得られることが分かった（entry 1-3）。一方強力なルイス酸であるSm（OTf）3を用いた場合には低収率にとどまった（entry 4）。

次に、実際のワンポット反応を試みたところ、触媒的不斉エポキシ化反応終了後の反応溶液に直接Me3SiN3を添加したところ、この場合も開環反応が円滑に進行し、99%収率、99%eeにて望みの開環生成物が得られた（Table 2,entry 1）。Table 2に示すように、本ワンポットプロセスは広い基質一般性を有しており、特にβ位がアルキル鎖で置換された基質においても完全な位置選択性で開環生成物が得られることがわかった（entries 8-12）。

さらに上述のように開発した新規のワンポットプロセスを活用し、抗がん剤のタキソールの側鎖部位および免疫調節活性を有する天然物cytoxazoneの合成にも成功した（Scheme 2）。

3級ニトロアルドールの触媒的不斉合成

不斉四置換炭素の構築は近年注目を集めているが、単純ケトンに対する触媒的不斉ヘンリー反応（ニトロアルドール反応）はキラルな3級ニトロアルドールを与えうる非常に有用な反応であるにもかかわらずその不斉合成はこれまでにまったく報告例がなく、ラセミ体合成ですら極めて限られた方法論が報告されているのみであった。

戸崎は、アルデヒドの触媒的不斉ヘンリー反応において有効であったLaLi3tris（binaphthoxide）錯体（LLB錯体）を用いてケトン8のヘンリー反応を試みたところ、5mol%の（R）-LLB錯体存在下、-40℃にて反応が進行し、20%収率,89%eeにて生成物（S）-9が得られることを見出した（Scheme 3,eq1）。さらに、競合的に起こる速いレトロ反応に着目しラセミ体（±）-9を出発原料として-40℃にて触媒量の（R）-LLB錯体を作用させたところレトロヘンリー反応が進行し、51%変換率において82%eeにて（R）-9が得られることを見出した。また反応温度を-20℃に上昇させたところ反応速度が増大し、同程度のエナンチオ選択性で目的物が得られることがわかった（Scheme 3,eq2）。

以上の研究成果は、今後の医薬合成に重要な知見を与えている。博士（薬学）に十分相当すると判断した。

Scheme 1. Dynamic Ligand Exchange of the Rare-Earth Complex and Strategy for One-Pot Sequential Process

Table 1. Regioselective Ring-Opening of α,β-Epoxy Amide

Table 2. One-Pot Sequential Process

Scheme 2. Transformations

Scheme 3. Catalytic Asymmetric Synthesis of Tertiary Nitroaldols