Minami Odagi

Origin of stereocontrol in guanidine-bisurea bifunctional organocatalyst that promotes α-hydroxylation of tetralone-derived β-ketoesters: asymmetric synthesis of β- and γ-substituted tetralone derivatives via organocatalytic oxidative kinetic resolution.

The mechanism of asymmetric α-hydroxylation of tetralone-derived β-ketoesters with guanidine-bisurea bifunctional organocatalyst in the presence of cumene hydroperoxide (CHP) was examined by means of DFT calculations to understand the origin of the stereocontrol in the reaction. The identified transition-state model was utilized to design an enantioselective synthesis of β- or γ-substituted tetralones by catalytic oxidative kinetic resolution reaction of tetralone-derived β-ketoesters. This kinetic resolution reaction proceeded with high selectivity, and selectivity factors (s value) of up to 99 were obtained. The potential utility of this oxidative kinetic resolution method for synthesis of natural products was confirmed by applying it to achieve an enantioselective synthesis of (+)-linoxepin (13) from β-substituted tetralone rac-7 in only six steps.

Asymmetric α-Hydroxylation of Tetralone-Derived β-Ketoesters by Using a Guanidine–Urea Bifunctional Organocatalyst in the Presence of Cumene Hydroperoxide

Highly enantioselective catalytic oxidation of 1-tetralone-derived β-keto esters was achieved by using a guanidine-urea bifunctional organocatalyst in the presence of cumene hydroperoxide (CHP), a safe, commercially available oxidant. The α-hydroxylation products were obtained in 99% yield with up to 95% enantiomeric excess (ee). The present oxidation was successfully applied to synthesize a key intermediate of the anti-cancer agent daunorubicin (2).

Asymmetric α‐Hydroxylation of a Lactone with Vinylogous Pyridone by Using a Guanidine–Urea Bifunctional Organocatalyst: Catalytic Enantioselective Synthesis of a Key Intermediate for (20S)‐Camptothecin Analogues

We have developed a catalytic asymmetric synthesis of (S)-4-ethyl-6,6-(ethylenedioxy)-7,8-dihydro-4-hydroxy-1H-pyrano[3,4-f]indolizine-3,10(4H)dione (5 a), a synthetic intermediate for (20S)-camptothecin analogues. A key step in this synthesis is an asymmetric α-hydroxylation of a lactone with a vinylogous pyridone structure (8 a) by using a guanidine-urea bifunctional organocatalyst. The present oxidation was successfully applied to the synthesis of C20-modified derivatives of (+)-C20-desethylbenzylcamptothecin (13).

Development of Novel Guanidine–Bisurea Bifunctional Organocatalysts and their Application to Asymmetric α-Hydroxylation of Tetralone-derived β-Keto Esters

A series of guanidine–bisurea bifunctional organocatalysts 4, with chiral centres located outside the urea groups, were synthesized. The novel catalyst 4 is conformationally more flexible than the original catalyst 1. In α-hydroxylation of tetralone- derived β-keto esters, 4 afforded the corresponding alcohols in high yields with moderate enantioselectivity.

Targeting STUB1–tissue factor axis normalizes hyperthrombotic uremic phenotype without increasing bleeding risk

Targeting mediators of the uremic thrombosis axis reverts the uremic hyperthrombotic phenotype without altering the bleeding risk. Striking a balance for anticoagulation Patients with chronic kidney disease can present a therapeutic conundrum because they are not only at increased risk of blood vessel thrombosis but also more likely to experience bleeding complications when treated with anticoagulants. Shashar et al. examined the mechanism of thrombosis in mouse models of renal disease and found a potential therapeutic target in a protein called STUB1. STUB1 is a ubiquitin ligase that interacts with tissue factor, a vascular wall protein that triggers the coagulation signaling cascade. The authors demonstrated that increase in STUB1 can prevent thrombosis but does not prolong bleeding in mouse models of kidney disease, suggesting that this may be a viable approach to antithrombotic management of patients. Chronic kidney disease (CKD/uremia) remains vexing because it increases the risk of atherothrombosis and is also associated with bleeding complications on standard antithrombotic/antiplatelet therapies. Although the associations of indolic uremic solutes and vascular wall proteins [such as tissue factor (TF) and aryl hydrocarbon receptor (AHR)] are being defined, the specific mechanisms that drive the thrombotic and bleeding risks are not fully understood. We now present an indolic solute–specific animal model, which focuses on solute-protein interactions and shows that indolic solutes mediate the hyperthrombotic phenotype across all CKD stages in an AHR- and TF-dependent manner. We further demonstrate that AHR regulates TF through STIP1 homology and U-box–containing protein 1 (STUB1). As a ubiquitin ligase, STUB1 dynamically interacts with and degrades TF through ubiquitination in the uremic milieu. TF regulation by STUB1 is supported in humans by an inverse relationship of STUB1 and TF expression and reduced STUB1-TF interaction in uremic vessels. Genetic or pharmacological manipulation of STUB1 in vascular smooth muscle cells inhibited thrombosis in flow loops. STUB1 perturbations reverted the uremic hyperthrombotic phenotype without prolonging the bleeding time, in contrast to heparin, the standard-of-care antithrombotic in CKD patients. Our work refines the thrombosis axis (STUB1 is a mediator of indolic solute–AHR-TF axis) and expands the understanding of the interconnected relationships driving the fragile thrombotic state in CKD. It also establishes a means of minimizing the uremic hyperthrombotic phenotype without altering the hemostatic balance, a long-sought-after combination in CKD patients.

Total Synthesis of (+)-Gracilamine Based on an Oxidative Phenolic Coupling Reaction and Determination of Its Absolute Configuration

The enantioselective total synthesis of (+)-gracilamine (1) is described. The strategy features a diastereoselective phenolic coupling reaction followed by a regioselective intramolecular aza-Michael reaction to construct the ABCE ring system. The configuration at C3a in 1 was controlled by the stereocenter at C9a, which was selectively generated (91 % ee) by an organocatalytic enantioselective aza-Friedel-Crafts reaction developed by our research group. This synthesis revealed that the absolute configuration of (+)-gracilamine is 3aR, 4S, 5S, 6R, 7aS, 8R, 9aS.

Asymmetric α-amination of β-keto esters using a guanidine–bisurea bifunctional organocatalyst

Summary An asymmetric α-amination of β-keto esters with azodicarboxylate in the presence of a guanidine–bisurea bifunctional organocatalyst was investigated. The α-amination products were obtained in up to 99% yield with up to 94% ee.

Synthetic studies of (23S,25R)-1α,25-dihydroxyvitamin D3 26,23-lactone (calcitriol lactone) and its derivatives

(23S,25R)-1α,25-Dihydroxyvitamin D3 26,23-lactone (calcitriol lactone) is a major metabolite of 1α,25-dihydroxyvitamin D3 that binds to vitamin D receptor (VDR) and exhibits various biological activities. This lactone and its derivatives are considered to have potential as drug candidates to treat VDR-related diseases, but their biological activities have not yet been fully characterized, mainly because of their limited availability by chemical synthesis. This review deals with synthetic studies of calcitriol lactone, and its derivatives, i.e., methylene lactones (TEI-9647 and its derivatives) and calcitriol lactams (DLAMs). We also discuss their biological activities, VDR-binding affinity and structure-activity relationships.

Development of Guanidine-Bisurea Bifunctional Organocatalyst Bearing Chirality at the Inner and Outer Sides of the Urea Groups, and Application to Enantioselective α-Hydroxylation of Pyranoindolizine Intermediate for Camptothecin Synthesis

Pyranoindolizine is a tricyclic structure found in various biologically active compounds, such as camptothecin (CPT) and its derivatives. In the case of CPTs, the chirality at the α-position in the α-hydroxyl lactone moiety of pyranoindolizine is important for the antitumor activity. This paper deals with enantioselective oxidation of the α-position in pyranoindolizine lactone, which corresponds at C20 in CPT, with cumene hydroperoxide (CHP) in the presence of newly synthesized guanidine-bisurea bifunctional organocatalysts bearing chirality on both the inner and outer sides of the urea groups.

Conformationally Flexible Guanidine–(Thio)Urea Bifunctional Organocatalysts

Enzymes can exhibit diverse catalytic functions by exploiting conformational changes in response to various external stimuli. An intriguing property of enzymes is that they can attain rate acceleration relative to competing reaction pathway occurring via other conformations. Inspired by these flexible but well-regulated functions of enzymes, we have developed the conformationally flexible guanidine-(thio)urea bifunctional organocatalyst. In this chapter, we describe some asymmetric reactions and very unique entropy-driven reactions catalyzed by guanidine-(thio)urea bifunctional organocatalyst.