1. Direct Catalytic Asymmetric Addition of Allylic Cyanides to Ketoimines

Construction of stereogenic center through catalyst-controlled asymmetric C-C bond formation is regarded as the most efficient methodology for the synthesis of optically active compounds. In particular, the "direct reactions" which proceed under proton transfer conditions without preactivation of pronucleophile are desirable in terms of atom and step economy. However, in situ catalytic generation of active carbon nucleophiles coupled with subsequent asymmetric intermolecular C-C bond formation via proton transfer remains a formidable task in modem organic chemistry, especially for the catalytic asymmetric access to tetrasubstituted stereogenic center. Asymmetric additions of carbon nucleophiles to simple ketones and ketoimines are most efficient and straightforward approach to this important class of compounds bearing oxygen or nitrogen functionality. In contrast to a number of reported examples of asymmetric additions to aldehydes and aldimines, relatively few exist for ketones and ketoimines counterpart because of their attenuated reactivity and lesser steric dissimilarity of the substituents at the prochiral sp2 carbons.

In this context, I envisioned to use allylic cyanides 1 as potential pronucleophiles for the asymmetric addition to ketones and ketoimines because (1) the minimal steric bias of the nitrile group is beneficial for the highly congested transition state anticipated for the reaction with ketones and ketoimines; (2) the soft Lewis basic character of the nitrile functionality allows for chemoselective activation in the presence of a soft Lewis acid; (3) the adjacent vinyl group enhances the acidity of the a-hydrogen of the nitrile to facilitate deprotonation under mild basic conditions; and (4) divergent transformation of nitrile functionality serves as a useful handle for further elaboration of the reaction products (Scheme 1).

Intensive studies on reaction conditions identified that the combined use of a soft Lewis acidic [Cu(CH3CN)4]C104/(R,R)-Ph-BPE complex with a hard Bronsted basic LiOAr exhibited excellent performance in chemoselective activation of allylic cyanides 1, allowing for the subsequent addition to ketoimines 2 to afford the a-adducts which rapidly isomerized to give α,β-unsaturated nitrites 3 with high enantioselectivity (Scheme 2).1

2. Direct Catalytic Asymmetric Addition of Allylic Cyanides to Ketoines

In contrast to the a-addition reaction to ketoimines, the reaction with ketones 4 altered the reaction mode of allyl cyanide la to afford the corresponding 7-adduct 5 exclusively under the same catalyst system, demonstrating that 1 serves as ambident nucluephile (Scheme 3).2

Although I succeeded in developing direct catalytic asymmetric addition of allylic cyanides la for the construction of tetrasubstituted stereogenic center, relatively high catalyst loading (5-10 mol%) and mandatory use of excess allylic cyanide 1 (5-10 equiv) for satisfactory conversion deflate the value as the direct catalytic process. To develop more efficient synthetic methodology, detailed mechanistic investigations including kinetic studies in the addition reaction to ketone were conducted and revealed that the rate-determining step is the deprotonation step of allyl cyanide la and that the actual Bronsted base is LiOAr, which is in equilibrium with [Cu/(R,R)-Ph-BPE]CIO4 and LiOAr. My strategy to accelerate this deprotonation step was employment of a hard Lewis base that would enhance the Bronsted basicity of LiOAr through hard-hard interaction with lithium cation. Addition of the hard Lewis basic phosphine oxide 6 that effectively coordinates to the hard lithium cation enhanced the Bronsted basicity, leading to efficient deprotonative activation under one-tenth the catalyst loading and one-fifth the amount of allyl cyanide la (0.5-1 mol% catalyst loading and 2 equiv of allyl cyanide) (Scheme 4).3

3. Direct Catalytic Asymmetric Mannich-type Reaction of Thioamides

In principle, the soft Lewis acid/hard Bronsted base cooperative catalyst system can be operative for other soft Lewis basic pronucleophiles. I focused on the use of soft Lewis basic thioamides, prepared from corresponding amides with Lawesson's reagents, as carbon pronucleophiles in asymmetric Mannich-type reaction. Thioamides are in carboxylic acid oxidation state and catalytic generation of thioamide enolates remained uncovered due to the lower acidity of a-proton compared with aldehydes and ketones. The same catalyst system comprising [Cu(CH3CN)4]ClO4/(R,R)-Ph-BPE complex with hard Bronsted basic LiOAr turned out to be effective in the reaction of aldimine 7 and thioamides 8 to afford Mannich adduct 9 with relatively high enantioselectivity. Further optimization of reaction conditions was conducted by me and my coworker, revealing that the reaction can be performed with as little as 1 mol% of catalyst to achieve high enantioselectivity (Scheme 5).4 The divergent functional group transformation of thioamide functionality into thioester, amide, amine, and amidine highlights the synthetic utility of the products.

4. Direct Catalytic Asymmetric Addition of Terminal Alkynes to a,,I3-Unsaturated Thioamides

Copper alkynides have been utilized in numerous useful reactions including C(sp)-C(sp2) coupling reaction such as Sonogashira reaction. In general, copper alkynylides exhibit low nucleophilicity as exemplified by conjugate addition of organocuprates, where alkynes serves as dummy ligands for selective addition of more reactive alkyl groups. I turned my attention to the use of a.,!3-unsaturated thioamides as electrophilic partner in the direct addition of terminal alkynes. The simultaneous activation of both terminal alkyne and soft Lewis basic a,13-unsaturated thioamide holds promise for overcoming low reactivity of transition metal alkynylide to engage the enantioselective coupling of them under proton transfer conditions. Ligand screening identified that (R)-MeO-BIPHEP (13) bearing sterically bulky substituents on phosphorous atom and (R)-DTBM-Segphos (14) matched best for soft Lewis acid/hard Bronsted base catalytic system in catalytic asymmetric conjugate addition of terminal alkynes 11 to a,I3-unsaturated thioamides 10, affording P-alkynyl thioamides 12 in a highly enantioselective manner (Scheme 5).

The reaction with aliphatic terminal alkynes afforded moderate enantioselectivity even after ligand screening, in which the employment of a chiral phosphate anion as an additional stereocontrolling element instead of PF6- was beneficial to improve enantioselectivity (Scheme 6).5

Developed catalytic asymmetric conjugate addition reaction was applied for the enantioselective synthesis of potent GPR40 agonist AMG 837 (15) employing TMS acetylene as an acetylene equivalent nucleophile (Scheme 7).

Scheme 1. Allylic Cyanide as Ambident Nucleophile

Scheme 2. Direct Catalytic Asymmetric Addition of Allylic Cyanides to Ketoimines

Scheme 3. Direct Catalytic Asymmetric Addition of Allylic Cyanides to Ketones

Scheme 4. Soft Lewis Acid/Hard Brosted Base/Hard Lewis Base Cooperative Catalysis

Scheme 5. Direct Catalytic Asymmetric Mannich-type Reaction of Thioamides

Scheme 5. Direct Catalytic Asymmetric Conjugate Addition of Terminal Alkynes to a,13-Unsaturated Thioamides

Scheme 6. Chiral Counteranion Catalysis

Scheme 7. Enantioselective Synthesis of AMG 837.

矢崎亮は、「ソフトLewis酸/ハードBronsted塩基協奏触媒を用いた直接的不斉炭素-炭素結合形成反応」というタイトルで、以下の4点に関する博士課程の研究を行った。

(1)アリルシアニドのケトイミンへの直接的触媒的不斉付加反応

ソフトLewis酸として[Cu(CH3CN)4]CIO4/(R,R)-Ph-BPE、ハードBrensted塩基としてLiOArを用いることで、高収率かつ高エナンチオ選択的にケトミンに対するアリルシアニドの付加反応が進行することを見出した(Scheme1)。本反応ではOL一付加、続く異性化によりα,β-不飽和ニトリルが得られている。

(2)アリルシアニドのケトンへの直接的触媒的不斉付加反応

ケトイミンへの付加反応で有効であった触媒系をケトンへと適用した.その結果、ケトイミンとは異なり高エナンチオ選択的にγ-付加体が得られたことより、アリルシアニドがアンビデント求核剤として機能することが分かった。

さらなる反応機構解析の結果、反応律速段階がアリルシアニドの脱プロトン化過程であることが示唆されたため、Brinsted塩基として機能するLiOArの塩基性を向上させるためハードLewis塩基6を添加することで触媒量及びアリルシアニドの等量の低減化に成功した(Scheme2)。

(3)チオアミドを求核剤として用いる直接的触媒的不斉Mannich型反応

上述した触媒系は他のソフトLewis塩基部位を有する基質においても適用可能であると考え、求核剤として「チオアミド」に着目した。モデル反応としてMannich型反応を選択し、開発した触媒系を用いたところしたところ予想通り反応は円滑に進行することが分かった。エナンチオ選択性も良好であったため配位子を固定し、各種反応条件の最適化を行なうことで1mol%の触媒存在下においても反応は円滑に進行し、高エナンチオ選択的に対応する付加体を与えることを見出した(Scheme3)。

(4)チオアミドを求電子剤として用いる末端アルキンの直接的触媒不斉共役付加反応

遷移金属アセチリドは薗頭反応をはじめとして多くの炭素一炭素結合形成反応において汎用されている。しかしながら、アルカリ金属より調製したアセチリドと比して低い求核性のため、末端アルキンを反応系中でメタル化し、プロトン移動のみによる触媒的不斉共役付加反応の例は極めて少ないのが現状である。そこで求電子剤としてソフトなLewis塩基部位を有し、カルボン酸と同様の酸化状態にあるα,β-不飽和チオアミドを用いることで、ソフトLewis酸/ハードBznsted塩基/ハードLewis塩基協奏触媒存在下、両反応基質の同時活性化により遷移金属アセチリドの低反応性を打開し、効率的な光学活性β-アルキニルカルボン酸誘導体の合成法を確立した(Scheme4)。

以上のように、矢崎の業績は触媒的不斉反応の進歩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。