Tsubasa Inokuma

Bifunctional hydrogen-bond donors that bear a quinazoline or benzothiadiazine skeleton for asymmetric organocatalysis.

Hydrogen-bond (HB)-donor catalysts that bear a 2-aminoquinazolin-4-(1H)-one or a 3-aminobenzothiadiazine-1,1-dioxide skeleton have been developed, and it has been shown that these catalyst motifs act similarly to other HB-donor catalysts such as thioureas. The highly enantioselective hydrazination of 1,3-dicarbonyl compounds was realized even at room temperature with up to 96% ee for 2-aminoquinazolin-4-(1H)-one-type catalysts, which were more effective than the corresponding urea and thiourea catalysts. In addition, benzothiadiazine-1,1-dioxide-type catalysts were shown to promote the isomerization of alkynoates to allenoates with high enantioselectivity. To overcome the problem that the products were obtained as mixtures with the starting alkynoates, we developed the tandem isomerization and cycloaddition of alkynoates for the synthesis of advanced chiral compounds such as bicyclo[2.2.1]heptenes and 3-alkylidene pyrrolidine without a significant loss of enantioselectivity.

Facile and Stabile Linkages through Tyrosine: Bioconjugation Strategies with the Tyrosine-Click Reaction

The scope, chemoselectivity, and utility of the click-like tyrosine labeling reaction with 4-phenyl-3H-1,2,4-triazoline-3,5(4H)-diones (PTADs) is reported. To study the utility and chemoselectivity of PTAD derivatives in peptide and protein chemistry, we synthesized PTAD derivatives possessing azide, alkyne, and ketone groups and studied their reactions with amino acid derivatives and peptides of increasing complexity. With proteins we studied the compatibility of the tyrosine click reaction with cysteine and lysine-targeted labeling approaches and demonstrate that chemoselective trifunctionalization of proteins is readily achieved. In particular cases, we noted that PTAD decomposition resulted in formation of a putative isocyanate byproduct that was promiscuous in labeling. This side reaction product, however, was readily scavenged by the addition of a small amount of 2-amino-2-hydroxymethyl-propane-1,3-diol (Tris) to the reaction medium. To study the potential of the tyrosine click reaction to introduce poly(ethylene glycol) chains onto proteins (PEGylation), we demonstrate that this novel reagent provides for the selective PEGylation of chymotrypsinogen, whereas traditional succinimide-based PEGylation targeting lysine residues provided a more diverse range of PEGylated products. Finally, we applied the tyrosine click reaction to create a novel antibody-drug conjugate. For this purpose, we synthesized a PTAD derivative linked to the HIV entry inhibitor aplaviroc. Labeling of the antibody trastuzumab with this reagent provided a labeled antibody conjugate that demonstrated potent HIV-1 neutralization activity demonstrating the potential of this reaction in creating protein conjugates with small molecules. The tyrosine click linkage demonstrated stability to extremes of pH, temperature, and exposure to human blood plasma indicating that this linkage is significantly more robust than maleimide-type linkages that are commonly employed in bioconjugations. These studies support the broad utility of this reaction in the chemoselective modification of small molecules, peptides, and proteins under mild aqueous conditions over a broad pH range using a wide variety of biologically acceptable buffers such as phosphate buffered saline (PBS) and 2-amino-2-hydroxymethyl-propane-1,3-diol (Tris) buffers as well as others and mixed buffered compositions.

NHC-catalyzed thioesterification of aldehydes by external redox activation

The NHC-catalyzed thioesterification of aromatic or aliphatic aldehydes with a range of thiols was developed in the presence of a stoichiometric amount of an organic oxidant. Among the oxidants examined, phenazine was shown to give the best results in terms of chemical yield and compatibility with thiols.

Hydroxyl group-directed organocatalytic asymmetric Michael addition of alpha,beta-unsaturated ketones with alkenylboronic acids.

The organocatalytic asymmetric Michael addition of organoboronic acids to gamma-hydroxy enones in the presence of an iminophenol-type thiourea catalyst is demonstrated. The hydroxyl group in the substrates plays a critical role in this reaction.

A Powerful Hydrogen‐Bond‐Donating Organocatalyst for the Enantioselective Intramolecular Oxa‐Michael Reaction of α,β‐Unsaturated Amides and Esters

Tuning the organocatalyst: An unprecedented enantioselective intramolecular oxa-Michael reaction of unactivated α,β-unsaturated amides and esters catalyzed by a powerful hydrogen-bond-donating organocatalyst has been developed. Furthermore, the products obtained from this reaction have been used for the straightforward asymmetric synthesis of several natural products and biologically important compounds.

Organocatalytic Asymmetric Neber Reaction for the Synthesis of 2H-Azirine Carboxylic Esters

The first enantioselective Neber reaction of β-ketoxime sulfonates catalyzed by a bifunctional thiourea has been developed. The reaction proceeds stereoselectively with 5 mol % of the catalyst to give the 2H-azirine carboxylic esters in good yields with up to 93% ee. In addition, the resulting azirines can be successfully employed in the stereoselective synthesis of di- and trisubstituted aziridines.

Organocatalyzed Isomerization of α‐Substituted Alkynoates into Trisubstituted Allenoates by Dynamic Kinetic Resolution

Chiral allenes have gained increasing attention as interesting chiral building blocks in synthetic organic chemistry. Therefore, the development of the catalytic enantioselective synthesis of chiral allenes has received considerable attention in the field of organic synthesis. In particular, enantioselective isomerization of alkynoates is one of the most atom-economical ways to access this motif. In 2000, Shioiri et al. reported the first enantioselective isomerization of alkyne by using a strong base together with a chiral phase-transfer catalyst. More recently, catalytic highly enantioselective isomerization of alkynoates to allenoates has been reported. Tan and Huang et al. reported a chiral guanidine-catalyzed isomerization of tert-butyl alkynoates to give the corresponding allenoates in high enantioselectivities. We also found that several hydrogen bond (HB) donors, shown in Figure 1, could be used for

A dual arylboronic acid--aminothiourea catalytic system for the asymmetric intramolecular hetero-Michael reaction of α,β-unsaturated carboxylic acids.

A bifunctional aminoboronic acid has been used to facilitate for the first time the intramolecular aza- and oxa-Michael reactions of α,β-unsaturated carboxylic acids. The combination of an arylboronic acid with a chiral aminothiourea allowed for these reactions to proceed successfully in an enantioselective manner to afford the desired heterocycles in high yields and ees (up to 96% ee). The overall utility of this dual catalytic system was demonstrated by a one-pot enantioselective synthesis of (+)-erythrococcamide B, which proceeded via sequential Michael and amidation reactions.

Synthesis of optically active N-aryl amino acid derivatives through the asymmetric petasis reaction catalyzed by a novel hydroxy-thiourea catalyst.

Optically active nonproteinogenic amino acid derivatives have received considerable interest due to their biological activities and ability to serve as chiral building blocks in asymmetric synthesis. N-Aryl-substituted amino acid derivatives can act as a fibrinogen receptor antagonist, hepatitis C virus replication inhibitor, glycine antagonist or an angiotensin receptor antagonist as shown in Figure 1. In addition, it is known that some compounds of this class are protein kinase C (PKC) activators, N-methyl-d-aspartate (NMDA) receptor antagonists, and angiotensin converting enzyme (ACE) inhibitors. Others have been shown to have anti-ulcer and cyclosporine receptor-binding activity. Notably, some consist of more than one amino acid moiety. However, despite the great importance of these structures, existing methods for their preparation rely heavily on the copper-catalyzed Ullmann-type N-arylation of amino acids. For the synthesis of optically active derivatives, it is necessary to prepare the optically active parent aamino acids. In addition, suitable aryl donors are limited to relatively electron-deficient and sparsely substituted aromatic compounds. On the other hand, several groups have reported catalytic asymmetric approaches for the synthesis of N-aryl amino acid units by using the 1,2-addition of N-aryla-iminoesters with several nucleophiles. We considered that if a similar process was applied to N-aryl-a-imino amides instead of esters, it could be a direct and more useful method for the synthesis of peptides that contain Naryl amino acid moieties. Recently, Li et al. reported the racemic 1,2-addition of N-aryl-a-imino amides and organoboronic acids. However, to the best of our knowledge, an asymmetric version of this reaction has not yet been reported. The Petasis reaction is a powerful method for the synthesis of a-amino acid derivatives. However, to date, there have been only two reports on asymmetric catalytic Petasis reactions. We reported the Petasis reaction of quinolinium and vinyl boronic acids using a thiourea catalyst that contains an amino alcohol moiety. 17] The Schaus research group reported the three-component asymmetric organocatalytic Petasis reaction of ethyl glyoxylate, an aliphat[a] T. Inokuma, Y. Suzuki, Prof. Dr. T. Sakaeda, Prof. Dr. Y. Takemoto Department of Pharmaceutical Sciences Kyoto University Yoshida, Sakyo-ku, Kyoto, 606-8501 (Japan) Fax: (+81) 75-753-4569 E-mail : takemoto@pharm.kyoto-u.ac.jp Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/asia.201100453. Figure 1. Examples of N-aryl amino acid derivatives.

One-Pot/Sequential Native Chemical Ligation Using Photocaged Crypto-thioester

A practical and efficient methodology for the chemical synthesis of peptides/proteins using a one-pot/sequential ligation is described. It features the use of photocleavable S-protection on an N-sulfanylethylaniline moiety. Removal of the S-protecting ligated materials under UV irradiation provides a readily usable mixture for subsequent native chemical ligation.