1. Scale-up Studies of a Barium-Catalyzed Asymmetric-Diels-Alder Reaction for the Synthesis of Tamifiu1

Our latest synthetic route of Tamiflu started from a novel barium-catalyzed asymmetric Diels-Alder reaction, which is conceptually distinct from classical Lewis acid catalysis. Labile diene 1, which was easily polymerized in the presence of chiral Lewis acid catalysts, was successfully activated by chiral Ba-F,-FujiCAPO complex and CsF to afford a reactive barium dienolate.2 This reaction was initially problematic, however, with regard to reproducibility. After careful optimization, 1 establishpd reliable conditions using degassed solvent. Finally, the reaction was successfully performed on 58-gram scale using 2.5 mol% catalyst, with high diastereoseictivity and excellent enantioselectivity (Scheme 1). Furthermore, the catalyst loading was reduced to 1 mol% of barium and 1 mol% of F2-FujiCAPO affording constant results. In short, a practical catalytic asymmetric Diels-Alder reaction was established, which is the key methodology used for the Tamiflu synthesis.

2. Nucleophile Generation via Decarboxylation: Asymmetric Construction of Contiguous Quaternary-Tdsubsfituted Stereocenters through a Cu(1)-Catalyzed Decarboxylative Mannich-Type Reaction3

Catalytic asymmetric construction of contiguous trisubstituted and all-carbon quaternary stereocenters, represents a particularly difficult challenge. There are two obvious obstacles involved in construction of such carbon centers, which lead to few successful examples available. The first is the enhanced steric hindrance. The second is the similarity between the nonhydrogen substituents on a prochiral carbon. The catalytic carbon-carbon bond-formation with high diastereo- and enantio-control using sterically congested substrates is prerequisite for the success of the targeted methodology. Aimed at expanding the scope ofasymmetric catalysis, I investigated the asymmetric synthesis of linear B-amino-a,a-disubstituted carboxylic acids (B2'2'3-amino acids) containing contiguous a-quaternary andB-trisubstituted chiral carbons. These amino acids and their derivatives are important chiral building blocks for biologically active molecules.

In our group, previous studies revealed that Cu(I)-catalyzed deprotonation of nitriles is a valuable nucleophile activation method for asymmetric carbon-carbon bond-formation at sterically hindered positions (tetrasubstituted carbon synthesis). I initially studied a catalytic asymmetric direct Mannich-type reaction between aldimine 4 and 2-phenylpropionitrile using nucleophile generation via chiral CuO'Bu complex-catalyzed deprotonation. Product 6 was obtained in moderate yield, but the diastereo- and enantioselectivity were quite low (1: 1.6 dr and less than 5% ee of 6) using (R)-DTBM-SEGPHOS as ligand.

Inspired by GooBen's report about the synthesis of biaryls via decarboxylative coupling using a catalytic combination of copper and palladium, I independently studied CN-contained nucleophile generation via copper-catalyzed decarboxylation of cyanoacetic acids. Although this type of nucleophile generation is a well-known process in nature, it has not been utilized in artificially catalyzed asymmetric carbon-carbon bond-formation. The reaction between 4 and 5 smoothly proceeded in the presence of 5 mol% copper complex to afford adducts with both excellent yield and high stereoselectivity (Scheme 2). As for the imines (4), aromatic imines as well as aliphatic imines containing acidic a-protons and thus susceptible under basic conditions were competent substrates in this decarboxylative Mannich-type reaction. As for the cyanocarboxylic acids (5), the enantio- and diastereoselectivity decreased slightly according to the size of the a-substituents. Nevertheless, products containing a synthetically useful allyl group at the quaternary center were produced with meaningful efficiency. It is also noteworthy that this method was applicable to cyanoacetic acid without an aromatic substituent (R2 vinyl, R3=CH3), affording the products with reasonable enantioselectivity. To our knowledge, this is the first general catalytic asymmetric method to access 132'2'3-amino acid derivatives with both aromatic and aliphatic substituents at the a- and/or f3-position(s).

The products were converted to enanti omeri cal ly- enri ch ed 132'2'3-amino amides without any racemization and epimerization through hydrolysis of N-diphenylphosphinoyl moiety and cyano group under acidic conditions.

Preliminary mechanistic investigation revealed that the soft-soft interaction important for facile nucleophile generation via decarboxylation (Schemebetween Cu(I) and nitrile is 3). Obviously, my newlydeveloped system showed a superior effect in this Mannich-type reaction and complemented to the previous basic deprotonation system using Cu(I)-conjugated base.

3. Asymmetric Intramolecular Aryl-Transfer Reaction from Aryl Triflates to Ketones Catalyzed by a Palladium-DIFLUOROPHOS Complex4

The electrophilic nature of aryl and vinyl organopalladium intermediates, which are generated from aryl and vinyl halides or triflates via an oxidative addition process with a Pd(0) species, is widely employed in organic synthesis. However, its nucleophilic nature received much less attention. Palladium-catalyzed nucleophilic reactions of organic halides and triflates to ketones and aldehydes are not studied extensively, although such additions are frequently encountered in traditional main-group metal chemistry. Furthermore, asymmetric versions of such reactions have not been reported yet.

Recently, I have successfully developed an asymmetric intramolecular aryl-transfer reaction from aryl triflates or iodides to ketones using a palladium-DIFLUOROPHOS complex as chiral catalyst with acceptable yields and excellent enantioselectivity. Optimized conditions were determined as shown in Scheme 4 by screening protecting groups on amide, Pd species, ligands (including phosphine ligands and BOX-type ligands), bases, temperature and the amount of Et3N. The catalyst loading (R/=H, R2=phenyl) was decreased to 1.25 mol% with maintained yield, despite slightly decreased enantioselectivity and prolonged reaction time (120 h). In the presence of 5 mol% catalyst, a series of oxindoles containing tetrasubstituted carbon at 3-position were constructed. Substrates both with electron-donating and electron-withdrawing groups were competent. Furthermore, substrate with a heteroaromatic (R2=heteroaromatic) ring such as thiophene was a good substrate under the optimized conditions. Vinyl-contained substrate (R2=vinyl) showed excellent enantioselectivity with moderate yield. It was noteworthy that aliphatic ketones (R,=alkyl) afforded corresponding oxindoles in moderate yield and acceptable enantioselectivity. Expansion of current methodology to construct a six-member ring is now on going.

Schethe1Scale-up Studies of the Catalytic Asymmetric Diels-Alder Reaction for a Practical Synthesis of Tamiflu

Scheme 2. Development of the First Catalytic Asymmetric Decarboxylative Mannich-Type Reaction for the Construction of Contiguous Quaternary-Trisubstituted Carbons

Scheme 3. Decarboxylation facilitated by Soft-Soft Interation between CM and Nitrile

Scheme 4. Catalytic Asymmetric Intramolecular Aryl-Transfer Reaction from Aryl Triflates to Ketones Catalyzed by a Palladium-DIFLUOROPHOS Complex

股は「新概念に基づく不斉触媒反応の開発:バリウム触媒による不斉Diels-Alder反応のスケールアップ研究とソフトメタル触媒を用いた不斉四置換炭素合成」というタイトルで、以下の3つの研究を遂行した。

1.抗インフルエンザ薬タミフル合成の基盤となる触媒的不斉Diels-Alder反応のスケール

当研究室が開発したタミフル合成は、不斉配位子F2-FujiCAPOとバリウムの錯体を触媒とする不斉Diels-Alder反応を起点とするものである。研究を開始した当初、最高で90%ee以上の高いエナンチオ選択性が得られる場合があるにもかかわらず、この結果を再現することがなかなか困難であった。この問題点を解決する目的で、股は反応の細部にわたる条件を子細に検討し直した。その結果、触媒調製時に副生するイソプロパノールを完全にポンプアップで除去することと、脱気した反応溶媒(THF)を用いることにより、完全に再現のとれる反応条件を確立した。本条件を用いることにより、触媒量を1mol%まで減量することが可能となり、さらに原料509以上の研究室における大量スケールでも優れた反応結果が得られることを明らかとした(触媒量2.5mo1%;Scheme1)。

2.キラル1銅触媒による脱炭酸を経由する求核1活性化を活用した三置換-四級連続不斉炭素構築型Mannich反応め開発

β一アミノ酸は定まった三次元構造を発現するペプチドの構成要素として、創薬分野において注目を集めている。一方で、キラルβ-アミノ酸の触媒的不斉合成1函現在においても挑戦的な課題である。股は、容易に合成可能なα-ジ置換シアノカルボン酸が、ソフト金属である1価銅の存在下で脱炭酸をおこし、キラル銅エノラート等価体を触媒的に生成することを見出した。この求核剤活性化法を基盤として、三置換-四級連続不斉中心を有するβ一アミノ酸等価体を温和な条件下で生成する触媒的不斉Mannich反応を確立した(Scheme2)。効率的な脱炭酸求核剤活性化には、ソフトな銅とソフトなニトリルとの相互作用が必須であることを、実験的に明らかとした。

3.アリールトリフラートからの極性転換を経る求核剤活性化を活用したヒドロキシオキシインドールの触媒的不斉合成法の確立

ヒドロキシオキシインドールは、様々な生物活性天然物や医薬に数多く見られる重要なキラルビルディングブロックである。いくつかの触媒的不斉合成法が過去に発表されているものの、特に不斉炭素上にアルキル置換基を有する化合物を合成する反応には大きなリミテーションが存在していた。股は、アニシジンとα一ケトカルボン酸の縮合に引き続く0一トリフルオロメタンスルホニル化により簡便に合成できる基質を用いて、これをキラルなパラジウム触媒とトリエチルアミンの存在下に付すことにより、高い基質一般性とエナンチオ選択性で光学活性オキシインドールを与える反応を開発した(Scheme3)。股の反応を用いると、従来困難であったアルキル置換オキシインドールも高エナンチオ選択的に合成できる。独自に開発した触媒的不斉反応を鍵工程として、抗菌剤リードであるEci8の合成を達成した。

以上の業績は、光学活性医薬およびそのリード化合物群の効率的合成の分野に顕著に寄与するものであり、博士(薬学)の授与にふさわしいものと判断した。