Makoto Furutachi

Catalytic Asymmetric Synthesis of 3-Aminooxindoles: Enantiofacial Selectivity Switch in Bimetallic vs Monometallic Schiff Base Catalysis

A highly enantioselective catalytic asymmetric access to 3-aminooxindoles with a tetrasubstituted carbon stereocenter is described. 1-2 mol % of homobimetallic (R)-Ni(2)-Schiff base 1 catalyzed the asymmetric amination of 3-substituted oxindoles with azodicarboxylates to give (R)-products in 99-89% yield and 99-87% ee. Reversal of enantiofacial selectivity was observed between bimetallic and monometallic Schiff base complexes, and monometallic (R)-Ni-Schiff base 2c gave (S)-products in 98-80% ee. Transformation of the products into an optically active oxindole with a spiro-beta-lactam unit and a known key intermediate for AG-041R synthesis is also described.

A homodinuclear Mn(III)2-Schiff base complex for catalytic asymmetric 1,4-additions of oxindoles to nitroalkenes.

Catalytic asymmetric 1,4-additions of 3-substituted oxindoles to beta-aryl, beta-heteroaryl, and beta-alkenyl nitroalkenes are described. A new homodinuclear Mn(2)(OAc)(2)-Schiff base 1 complex was required to realize high diastereo- and enantioselectivity. Mn(2)(OAc)(2)-1 (1-5 mol %) promoted the 1,4-additions in 99-83% yield, 96-85% ee, and >30:1-5:1 dr at room temperature, providing useful chiral building blocks for the synthesis of beta-aminooxindoles with vicinal quaternary/tertiary carbon stereocenters.

A Stable Homodinuclear Biscobalt(III)–Schiff Base Complex for Catalytic Asymmetric 1,4‐Addition Reactions of β‐Keto Esters to Alkynones

Two metal cooperation: A homodinuclear Co(2)-Schiff base complex Co(2)(OAc)(2)-1 promoted the asymmetric 1,4-addition of beta-keto esters to alkynones under solvent-free conditions in air (see scheme). The reactions proceeded without air or moisture sensitivity in high yields and with high enantioselectivities (99-91% ee) at room temperature under highly concentrated conditions (neat-20 M) with 0.1-2.5 mol % catalyst loading.

A heterobimetallic Ni/La-salan complex for catalytic asymmetric decarboxylative 1,4-addition of malonic acid half-thioester.

Thioesters are synthetically versatile building blocks that can be transformed to aldehydes, ketones, amides, and other functional groups under mild reaction conditions. The use of malonic acid half-thioesters (MAHTs) as thioester enolate equivalents is an attractive method to mimic the biosynthesis of fatty acids and polyketides. A highly enantioselective catalytic asymmetric decarboxylative aldol reaction of MAHT using a Cu/box catalyst was realized by Shair and co-workers. Recently, the first organocatalytic enantioselective decarboxylative 1,4-addition of MAHTs to nitroalkenes was also developed by Wennemers and co-workers. The method provides straightforward access to the g-amino acids found in many pharmaceuticals, such as rolipram and pregabalin. The enantioselectivity of the reaction, however, remains unsatisfactory, because only one substrate had greater than 90 % ee. Thus, the development of new catalysts to achieve high enantioselectivity in decarboxylative 1,4-addition of MAHTs is highly desirable for the efficient short synthesis of pharmaceuticals. Herein, we report our efforts to address this issue. A new heterobimetallic Ni/Lasalan complex (Figure 1) was developed for catalytic asymmetric decarboxylative 1,4-addition of MAHT to nitroalkenes. The Ni/La-salan complex (10 mol %) gave products in up to 99 % yield and 94 % ee. A short synthesis of rolipram was also achieved. The stability of chiral metal complexes is important for realizing a highly enantioselective metal-catalyzed reaction using MAHTs. Chiral metal complexes should be tolerant to stoichiometric amounts of carboxylic acids (=MAHTs). We hypothesized that bimetallic Schiff base 1 complexes (Figure 1), which we recently developed, could be applied for the reaction of MAHTs because dinucleating Schiff bases work as tetradentate ligands to form stable bimetallic complexes. We first screened previously reported bimetallic Schiff base complexes, such as Cu/Sm-1 a, Pd/ La-1 a, Ni2-1 c, [12a,b] and Co2-1 c, [12c] and a heterobimetallic system containing a rare earth metal gave promising results. The optimization studies using MAHT 3 and nitroalkene 4 a are summarized in Table 1. Screening of metal combinations using ligand 1 a (entries 1–5) revealed that Ni/La gave the best reactivity and selectivity (entry 5). Thus, further optimization was performed using the Ni/La combination. Modification of the diamine moiety in Schiff bases 1 was effective (entries 5–8), and Schiff base 1 d gave product 5 a in 75 % ee, [a] M. Furutachi, S. Mouri, Dr. S. Matsunaga, Prof. Dr. M. Shibasaki Graduate School of Pharmaceutical Sciences The University of Tokyo Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan) Fax: (+81) 3-5684-5206 E-mail : smatsuna@mol.f.u-tokyo.ac.jp [b] Prof. Dr. M. Shibasaki Institute of Microbial Chemistry, Tokyo Kamiosaki 3-14-23, Shinagawa-ku, Tokyo 141-0021 (Japan) Fax: (+81) 3-3447-7779 E-mail : mshibasa@bikaken.or.jp Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/asia.201000540. Figure 1. Structures of dinucleating Schiff bases 1-H4, dinucleating salantype ligand 2d-H4, and dinuclear M /M complexes.

Catalytic Asymmetric 1,4-Additions of β-Keto Esters to Nitroalkenes Promoted by a Bifunctional Homobimetallic Co2-Schiff Base Complex

Catalytic asymmetric 1,4-addition of β-keto esters to nitroalkenes is described. 2.5 mol % of a homobimetallic Lewis acid/Brønsted base bifunctional Co2-Schiff base complex smoothly promoted the reaction in excellent yield (up to 99%), diastereoselectivity, and enantioselectivity (up to >30:1 dr and 98% ee). Catalyst loading was successfully reduced to 0.1 mol %. Mechanistic studies suggested that intramolecular cooperative functions of the two Co-metal centers are important for high catalytic activity and stereoselectivity.

Two approaches toward the formal total synthesis of oseltamivir phosphate (Tamiflu): catalytic enantioselective three-component reaction strategy and L-glutamic acid strategy.

Two independent formal total syntheses of oseltamivir phosphate were successfully achieved: the first utilized a copper-catalyzed asymmetric three-component reaction strategy, and the second utilized L-glutamic acid γ-ester as a chiral source to install the correct stereochemistry. Both strategies used Dieckmann condensation to construct a six-membered ring core, after which manipulation of the functional groups and protecting groups accessed Coreys intermediate for the synthesis of oseltamivir phosphate. While the first synthesis was accomplished via four purification steps in 25.7% overall yield, albeit with moderate optical purity (76% ee), the second strategy achieved the synthesis via six purification steps in 19.8% overall yield with perfect enantiocontrol.

Unique physicochemical and catalytic properties dictated by the B3NO2 ring system

The expansion of molecular diversity beyond what nature can produce is a fundamental objective in chemical sciences. Despite the rich chemistry of boron-containing heterocycles, the 1,3-dioxa-5-aza-2,4,6-triborinane (DATB) ring system, which is characterized by a six-membered B3NO2 core, remains elusive. Here, we report the synthesis of m-terphenyl-templated DATB derivatives, displaying high stability and peculiar Lewis acidity arising from the three suitably arranged boron atoms. We identify a particular utility for DATB in the dehydrative amidation of carboxylic acids and amines, a reaction of high academic and industrial importance. The three boron sites are proposed to engage in substrate assembly, lowering the entropic cost of the transition state, in contrast with the operative mechanism of previously reported catalysts and amide coupling reagents. The distinct mechanistic pathway dictated by the DATB core will advance not only such amidations, but also other reactions driven by multisite activation.

An enantioselective synthesis of voriconazole.

A new seven-step sequence to access voriconazole, a clinically used antifungal agent, was developed. The initial catalytic asymmetric cyanosilylation is the key to constructing the consecutive tetra- and trisubstituted stereogenic centers. The fluoropyrimidine unit frequently triggered unexpected side reactions, but careful amendment of the reaction sequence allowed for the concise enantioselective synthesis.