Introduction

Although water is cheap, safe, and environmentally friendly compared to organic solvents, most organic reactions have been conducted in organic solvents. On the other hand, unique reactivity and selectivity are sometimes observed in aqueous solvents. In this content, our laboratory has investigated organic reactions in aqueous media, and among them, I have focused on the use of metal hydroxides as catalysts in water (aqueous media) and aqueous ammonia as a nitrogen source in organic synthesis. In this work, I developed two kinds of catalytic asymmetric reactions in aqueous solvents.

Zinc Hydroxide (Zn(OH)2)-Catalyzed Asymmetric α-Selective Allylation of Aldehydes in Aqueous Media

Catalytic asymmetric allylation of aldehydes provides optically active homoallylic alcohols, which are useful intermediates for the synthesis of natural products and biologically important compounds. When allylboronates are used as reagents for allylation of aldehydes, most reactions are conducted under anhydrous conditions because most chiral reagents/catalysts are easily decomposed in the presence of even a small amount of water. In addition, most asymmetric reactions are carried out at low temperature (mostly at –78 ℃) because allylboration of aldehydes proceeds spontaneously without catalyst. On the other hand, it is well known that allylboration of aldehydes proceeds through a cyclic six-membered transition state to afford γ-addition products. γ-Addition products are also obtained in the catalytic asymmetric allylboration of aldehydes.

On the other hand, I have already developed α-selective allylation of aldehydes with α-substituted allylboronates catalyzed by 5 mol% of Zn(OH)2 and 6 mol% of 2,9-dimethyl-1,10-phenantroline (dmp) in aqueous media.(1)) I also applied this catalytic system to asymmetric variant by using a chiral ligand. The reaction of benzaldehye (1) with α-methylallylboronate (2) in the presence of 10 mol% of Zn(OH)2 and 12 mol% of chiral bipyridine ligand (L1) at 0 ℃ afforded the α-addition product (3) in 83% yield with high syn-selectivity (syn/anti = 94/6) and 71% ee (syn-isomer) along with γ-addition product (4) (Scheme 1).

During my Ph.D. studies, I firstly examined the addition modes of the reagents to suppress the formation of the γ-adduct. As a result, when benzaldehyde was slowly added over 1 h, only α-adduct was obtained in 92% yield with keeping high syn-selectivity (syn/anti = 91/9) and good enantioselectivity (71% ee). Substrate generality was then surveyed under the optimized conditions (Table 1). The reactions proceeded smoothly using 2–10 mol% of the catalyst, and in all cases exclusive α-selectivity was observed. When aliphatic aldehydes were employed, the desired products were obtained with high enantioselectivities, although diastereoselectivities were little decreased (entries 2-4). Not only α-methylallylation but also other α-alkylallylations proceeded smoothly, and moderate to excellent syn-selectivities and high to excellent enantioselectivities were obtained (entries 5-7). Moreover, α-benzyloxyallylation also proceeded well, and high diastereo- and enantioselectivities were attained using both aromatic and aliphatic aldehydes (entries 8-9). This catalytic system was also applicable to asymmetric α-chloroallylation. Aromatic as well as aliphatic aldehydes bearing some functional groups worked efficiently to afford the desired products in high to excellent yields with high to excellent diastereo- and enantioselectivities (entries 10-14). The reaction also proceeded smoothly in the presence of 2 mol% of the catalyst (entriy 13). Some of the products were directly used for the synthesis of natural products, such as disparlure (entriy 13) and spirastrellolide A (entriy 14).

As for the mechanism of this catalytic process, because α-addition products were obtained exclusively, I assumed the double γ-addition mechanism (Figure 1). The catalytic cycle is initiated by boron-to-zinc transmetalation to form the γ-substituted allylzinc A, which can react smoothly with aldehydes via a γ-addition fashion. In order to examine more detail of the reaction mechanism, I initially tried to detect the allylzinc A directly. When Zn(OH)2, dmp and α-methylallylboronate were combined in H2O/MeCN (1/4), the major signals of the crotylzincate B were detected by ESI-MS analysis (Figure 2(a)). The isotope pattern was identical with the calculated one (Figure 2(b)). It was found that this crotylzincate B was not stable and gradually decomposed in aqueous media. This decomposition was successfully monitored by online ESI-MS analysis (Figure 2(c)).

I then conducted kinetic investigation in the reaction of 3-phenylpropanal with α-methylallylboronate. As a result, a first-order dependence on the allylboronate and a zero-order dependence on the 3-phenylpropanal were observed, respectively. These observations conclude that transmetalation from B to Zn is the rate determining step in this reaction. I also evaluated chiral ligands L2 and L3 in the reaction of 3-phenylpropanal with α- chloroallylboronate under the standard conditions (Table 2). Interestingly, the reactions proceeded smoothly in the presence of L2 and L3 to provide α-addition products exclusively. However, while high diastereo- and enantioselectivities were observed using L2, almost no selectivity was observed in the case of L3. In addition, our group already obtained X-ray crystallgraphical data of the ZnBr2 and L1 complex, and it adopts a square-pyramidal structure, in which the two pyridine nitrogen atoms and one of the two hydroxy groups of L1 coordinate to zinc. These data suggested that one face of the allylzinc moiety could be shielded by the fixed tert-butyl group.

Palladium-Catalyzed Asymmetric Allylic Amination Using Aqueous Ammonia

To use aqueous ammonia as a N1 source in organic chemistry is one of the most attractive methods for the synthesis of primary amines. However, in the use of ammonia for metal-catalyzed processes, many kinds of transition metals are deactivated by ammonia to give stable amine complexes. Moreover, when a primary amine is formed, this product is more reactive than ammonia and causes overreactions to provide secondary amines. On the other hand, we have already developed the first palladium-catalyzed allylic amination using aqueous ammonia for the preparation of primary amines.(2)) The reactions proceeded smoothly in the presence of 10 mol% of Pd(PPh3)4 to afford the desired primary amines with high selectivities.

I found that when the reaction was conducted with 2 mol% of [PdCl(allyl)]2 and 6 mol% of (R)-BINAP, enantioselective allylic amination proceeded smoothly (Scheme 2).

Conclusion

Catalytic asymmetric synthesis using aqueous solvents was investigated. First, Zn(OH)2-catalyzed α-selective asymmetric allylation of aldehydes with α-substituted allylboronates was achieved. Various aldehydes were converted to optically active homoallylic alcohols in the presence of catalytic amounts of Zn(OH)2 and L1 in aqueous media with exclusive α-selectivity. It is noted that this method does not require strictly anhydrous reaction conditions and low temperature. Second, palladium-catalyzed asymmetric allylic amination using aqueous ammonia has been accomplished. These reactions only proceed in aqueous media or the optimal selectivities are observed only in aqueous media. In both cases, water plays a key role for the reactivity and selectivity.

Scheme 1. Initial investigation on asymmetric allylation

Table 1. Substrate scope of asymmetric allylation

Figure 1. Assumed catalytic cycle

Figure 2. ESI-MS analysis

Table 2. Effect of chiral ligands

Scheme 2. Catalytic asymmetric allylic amination

本論文は、水溶媒中でのカルボニル化合物の触媒的不斉アリル化反応およびアリル位アミノ化反応の開発について、6章に渡って述べたものである。

一般に有機合成反応を行う場合有機溶媒が用いられるが、有機溶媒の中には人体や環境に有害なものもあり、その使用はなるべく限定することが望ましい。そこで近年、有機溶媒に代わる溶媒として水が注目を集め、水を溶媒とする有機合成反応の開発が活発に行われている。水は高い誘電率や水素結合能などの特性を有しているため、有機溶媒中では見られない反応性や選択性を示すことも明らかになっている。本論文では、水系溶媒中で有効に機能する触媒としての金属水酸化物、およびアンモニア水を窒素源とした有機合成反応に着目し、水系溶媒中での触媒的不斉合成反応の開発を行っている。

序論、これまでの研究(第2章)に続く第3章では、水酸化亜鉛を触媒とした水系溶媒中でのアルデヒドのα選択的不斉アリル化反応について述べている。アルデヒドとアリルホウ素試薬を用いたアリル化反応は、最も有用な炭素––炭素結合形成反応の一つあり、これまで数々の基礎的な研究が報告されているが、そのほとんどが有機溶媒中、厳密な無水条件下で行われ、また、六員環いす型遷移状態を経由したγ付加で進行することが広く知られている。

本論文では、本学修士論文の内容をさらに発展させ、水酸化亜鉛を触媒としたアルデヒドのα選択的アリル化反応の選択性の向上をはかり、アルデヒドを低速添加することで、反応はより円滑に進行し、α付加体のみが高いシン選択性および良好なエナンチオ選択性をもって得られることを明らかにしている。さらに本反応は、高い基質一般性を有することも示している。反応はいずれの場合も2-10 mol%の触媒存在下、水系溶媒中で円滑に進行し、α付加体のみの生成が確認されている。脂肪族アルデヒドを用いた場合、立体選択性はやや低下するが、高いエナンチオ選択性をもって目的化合物が得られること、また、α位にメチル基を有するアリルホウ素試薬だけでなく、種々のアルキル基、ベンジルオキシ基、クロロ基を有するアリルホウ素試薬を用い場合においても、α付加体のみが、高収率、高立体選択的、高エナンチオ選択的に得られることを明らかにしている。

続いて第4章では、詳細な反応機構の解析を行っている。有機溶媒中で行われる通常のアリル化反応とは異なり、本反応ではα付加体のみが得られたことから、2度のγ付加を経る反応機構を提唱している。すなわち、まず始めに水酸化亜鉛とアリルホウ素試薬との金属交換反応がγ付加で進行し、系中でクロチル亜鉛種が生成し、次にこのクロチル亜鉛種がアルデヒドと2度目のγ付加反応することによって、生成物の亜鉛アルコキシドが生成する。最後に水によってこの亜鉛アルコキシドが加水分解され、結果としてα付加体が生成し、水酸化亜鉛が再生されるものというものである。この機構を証明するために、 鍵となるクロチル亜鉛種の補足をESI-MS分析を用いて行い、クロチル亜鉛種に相当するピークの観測に成功している。また、またこのクロチル亜鉛種は水系溶媒中では不安定であり、徐々に水と反応し分解することを示している。さらに、本反応において水は必須であり、その役割の詳細について述べている。

第5章では、パラジウム触媒を用いるアンモニア水を窒素源とする不斉アリル位アミノ化反応について述べている。アンモニアは安価で入手も容易であることから、アンモニアを窒素源とした有機合成反応は非常に魅力的である。しかし、アンモニアの反応性が低いこと、生成する第1級アミンの求核性がアンモニアよりも高く、過剰反応が進行してしまうこと、また金属を触媒とした反応では、アンモニアが金属に強固に配位し、触媒が不活性化してしまうことなど、アンモニアを窒素源とした有機合成反応には多くの問題点が挙げられる。本論文はこれらの問題の解決を図り、パラジウムを触媒とし、アンモニア水を窒素源として用いた不斉アリル位アミノ化反応の開発に成功している。

以上のように、本論文は、カルボニル化合物の触媒的不斉アリル化反応及びアリル位アミノ化反応が水溶媒中で円滑に進行すること、また、その反応性、選択性は有機溶媒中ではみられないユニークなものであり、溶媒として用いた水が重要な働きをしていることを明らかにしたものである。なお、本論文は、小林 修、上野雅晴との共同研究であるが、論文提出者が主体となって分析及び検証を行ったもので、論文提出者の寄与が十分であると判断する。したがって、博士(理学)の学位を授与できると認める。