Total Synthesis of Leptosperol B through Stereocontrolled Intramolecular 1,4-Addition to Construct the Octahydronaphthalene Framework.

Leptosperol B, possessing a unique octahydronaphthalene framework and 5-substituted aromatic ring, was isolated from the leaves of Leptospermum scoparium in 2020. The asymmetric total synthesis of leptosperol B was accomplished in 12 steps from (-)-menthone. The efficient synthetic scheme involves regioselective hydration and stereocontrolled intramolecular 1,4-addition to construct the octahydronaphthalene skeleton, followed by the introduction of the 5-substituted aromatic ring.

Total Synthesis of Lucidumone through Convenient One-pot Preparation of the Tetracyclic Skeleton by Claisen Rearrangement and Subsequent Intramolecular Aldol Reaction.

The total synthesis of lucidumone (1), a Ganoderma meroterpenoid, was accomplished in racemic form from easily prepared 6 and 7 in 10 steps as the longest linear sequence. The synthesis was completed through one-pot preparation of the tetracyclic core skeleton by Claisen rearrangement followed by an intramolecular aldol reaction. The intramolecular aldol reaction allowed for the stereocontrolled construction of the bicyclo [2.2.2] octane skeleton fused to an indanone structure. The enantioselective total synthesis of 1 was also described via a chiral transfer strategy in the Claisen rearrangement.

Discovery of ASP5878: Synthesis and structure-activity relationships of pyrimidine derivatives as pan-FGFRs inhibitors with improved metabolic stability and suppressed hERG channel inhibitory activity.

Fibroblast growth factor receptor 3 (FGFR3) is an attractive therapeutic target for the treatment of bladder cancer patients harboring genetic alterations in FGFR3. We identified pyrimidine derivative ASP5878 (27) with improved metabolic stability and suppressed human ether-á-go-go related gene (hERG) channel inhibitory activity by the optimization of lead compound 1. Based on prediction of the metabolites of 1, an ether linker was introduced in place of the ethylene linker to improve metabolic stability. Moreover, conversion of the phenyl moiety into the pyrazole ring resulted in the suppression of hERG channel inhibitory activity, possibly due to the weaker π-π stacking interaction with Phe656 in the hERG channel by a reduction in π-electrical density of the aromatic ring. ASP5878 showed potent in vitro FGFR3 enzyme and cell growth inhibitory activity, and in vivo FGFR3 autophosphorylation inhibitory activity. Moreover, ASP5878 did not affect the hERG current up to 10 µM by in vitro patch-clamp assay, and a single oral dose of ASP5878 at 1, 10, and 100 mg/kg did not induce serious adverse effects on the central nervous, cardiovascular, and respiratory systems in dogs. Furthermore, ASP5878 exhibited lower total clearance than hepatic blood flow and high oral bioavailability in rats and dogs, and moderate brain penetration in rats.

Synthesis and structure-activity relationships of pyrimidine derivatives as potent and orally active FGFR3 inhibitors with both increased systemic exposure and enhanced in vitro potency.

Fibroblast growth factor receptor 3 (FGFR3) is an attractive therapeutic target for the treatment of patients with bladder cancer harboring genetic alterations in FGFR3. We identified pyrimidine derivative 20b, which induced tumor regression following oral administration to a bladder cancer xenograft mouse model. Compound 20b was discovered by optimizing lead compound 1, which we reported previously. Specifically, reducing the molecular size of the substituent at the 4-position and replacing the linker of the 5-position in the pyrimidine scaffold resulted in an increase in systemic exposure. Furthermore, introduction of two fluorine atoms into the 3,5-dimethoxyphenyl ring enhanced FGFR3 inhibitory activity. Molecular dynamics (MD) simulation of 20b suggested that the fluorine atom interacts with the main chain NH moiety of Asp635 via a hydrogen bond.

Highly stereocontrolled total synthesis of secodolastane diterpenoid isolinearol.

The first asymmetric total synthesis of isolinearol has been achieved with high stereoselectively. The synthetic method includes enatio- and diastereoselective reductive desymmetrization, stereocontrolled introduction of the methallyl group, regio- and stereocontrolled allylation and introduction of the side chain carbonyl group using olefin cross-metathesis with a pinacol vinyl boronic ester.

Structure-based drug design of 1,3,5-triazine and pyrimidine derivatives as novel FGFR3 inhibitors with high selectivity over VEGFR2.

Fibroblast growth factor receptor 3 (FGFR3) is an attractive therapeutic target for the treatment of bladder cancer. We identified 1,3,5-triazine derivative 18b and pyrimidine derivative 40a as novel structures with potent and highly selective FGFR3 inhibitory activity over vascular endothelial growth factor receptor 2 (VEGFR2) using a structure-based drug design (SBDD) approach. X-ray crystal structure analysis suggests that interactions between 18b and amino acid residues located in the solvent region (Lys476 and Met488), and between 40a and Met529 located in the back pocket of FGFR3 may underlie the potent FGFR3 inhibitory activity and high kinase selectivity over VEGFR2.

Total synthesis of (±)-chondrosterin I using a desymmetric aldol reaction.

The first total synthesis of racemic chondrosterin I was accomplished. The synthetic features include a Michael addition to incorporate a nitro alkane moiety, an oxidative Nef reaction, intramolecular cyclization of the γ-ketoester derivative, and a desymmetric intramolecular aldol reaction of the meso diketoester compound. The present strategy will be applicable to the synthesis of an optically active form by asymmetric desymmetrization.

Identification of potent lysophosphatidic acid receptor 5 (LPA5) antagonists as potential analgesic agents.

Lysophosphatidic acid (LPA) plays an important role in a variety of cellular functions. In particular, LPA5 receptor is highly expressed in spinal cord and dorsal root ganglion, which are associated with pain. This fact prompted us to hypothesize that LPA5 antagonists show analgesic effects. To search for potent LPA5 antagonists with blood brain barrier (BBB) permeability, we conducted high throughput screening (HTS). In HTS campaign, we found a 2H-isoquinoline-1-one scaffold showing antagonistic activity against LPA5 and synthesized a series of 2H-isoquinoline-1-one derivatives and evaluated their LPA5 activities. Among these compounds, compound 7e showed potent LPA5 activity with an IC50 value of 0.12 µM, and acceptable BBB permeability. Furthermore, it showed effective analgesic effect in a chronic constriction injury rat model. Therefore, 7e may have a potential as novel pain therapeutic approach.

Asymmetric Total Synthesis of (+)-Lemnardosinane A.

The asymmetric total synthesis of (+)-lemnardosinane A, a rare rearranged sesquiterpenoid, has been accomplished from (S)-carvone. Key features of the synthesis are the formation of a bicyclo[3.3.1]nonane skeleton using the intramolecular aldol reaction, the stereoselective introduction of an alkyne group, and the stereoselective formation of a tricyclic skeleton via intramolecular pinacol coupling.

Asymmetric Total Synthesis of (-)-Lemnalemnane A.

The asymmetric total synthesis of lemnalemnane A, a rare rearranged sesquiterpenoid, has been accomplished in 13 steps from (S)-carvone. The key features of the synthesis are the removal of the isopropenyl group derived from (S)-carvone via a radical intermediate, the formation of the bicyclo[3.3.1]nonane skeleton using the Dieckmann condensation, the stereocontrolled construction of five continuous chiral centers by chemo- and stereoselective reduction and stereoselective introduction of the alkyne group, and the formation of the spirolactone moiety via a hemiacetal intermediate.

Total synthesis of applanatumol A.

The first total synthesis of applanatumol A has been achieved in a highly stereocontrolled manner. The synthetic method includes assembly of the contiguous chiral centers by convergent Fráter-Seebach alkylation, construction of the seven-membered ring by intramolecular aldol reaction, and stereoselective tandem cyclization to form the tetracyclic skeleton.

Total Synthesis of Asperaculin A.

The racemic total synthesis of asperaculin A, a sesquiterpenoid lactone with an unprecedented structure, has been accomplished in 17 steps from 3-methyl-2-cyclopentenone. Key features of the synthesis are the construction of a central all-carbon quaternary center using the Johnson-Claisen rearrangement, stereocontrolled introduction of a cyano group, and acid-mediated γ-lactonization.

Total synthesis of highly oxygenated phomopsol B via acid-induced etherification to construct a bridged structure.

The first total synthesis of phomopsol B has been achieved in a racemic form. The synthesis comprises a deacetylative cyclization to construct a bicyclic skeleton followed by primary alcohol-assisted dihydroxylation, ether cyclization to construct a dioxabicyclo [3.2.1] skeleton and γ-lactone formation based on oxidation by TEMPO.

Total Synthesis of Stachyodin A via One-Pot Suzuki Coupling for Quick Construction of Carbon Skeleton.

Stachyodin A, possessing a unique spirotetrahydrofuran ring system, was isolated from the roots of Indigofera stachyodes in 2018. The first total synthesis of racemic stachyodin A was accomplished in 14 steps. The efficient stereoselective synthetic route involved one-pot Suzuki coupling and stereocontrolled epoxidation followed by reductive opening and spirocyclization.

Total Synthesis of Nesteretal A.

The enantioselective total synthesis of nesteretal A was achieved in 15 steps via biomimetic cascade hemiacetalizations at the final key step. Other key features of the total synthesis include Sharpless asymmetric dihydroxylation, diastereoselective 1,2-addition, Pd-catalyzed ene-type cyclization, and stereoselective epoxidation to construct a complex structure containing multiple quaternary carbons.

Total Synthesis of ent-Callilongisin B.

The first enantioselective total synthesis of tricyclic diterpenoid callilongisin B, which was isolated from Callicarpa longissima, has been achieved. The synthetic method includes a diastereoselective 1,4-addition and Hosomi-Sakurai allylation followed by Wacker oxidation, intramolecular aldol reaction to construct a six-membered ring, and oxidative dearomatization accompanied by diastereoselective δ-lactonization.

Enantioselective Total Synthesis of Mollebenzylanol A.

Mollebenzylanol A is a tyrosine phosphatase 1B inhibitor isolated from the leaves of Rhododendron molle in 2018 that has a highly functionalized structure. The first enantioselective total synthesis of mollebenzylanol A was achieved in 13 steps from a known chiral starting material. An efficient and practical synthetic scheme was disclosed in a stereocontrolled manner, including stereo/regioselective epoxidation, Eschenmoser-Claisen rearrangement, and stereocontrolled dihydroxylation.

Enantioselective Total Synthesis of Diocollettines A.

The first enantioselective total synthesis of diocollettines A was accomplished in only six steps from a known compound. A short and practical synthetic route was disclosed, featuring an intensive investigation of the stereoselective aldol reaction as a key step using an easily prepared aldehyde moiety and an enone derivative. The synthetic scheme also includes the efficient stereocontrolled construction of the tricyclic skeleton of diocollettines A by intramolecular acetal formation, stereoselective dihydroxylation, and intramolecular ether cyclization.

Total Synthesis of Applanatumol B.

The first total synthesis of the tricyclic meroterpenoid applanatumol B, isolated from Ganoderma applanatum, was accomplished in 14 steps from 2,5-dimethoxybenzaldehyde and 4-pentyn-1-ol. The synthetic features include an intramolecular Morita-Baylis-Hillman reaction, a stereoselective Michael addition, and efficient construction of the tricyclic skeleton under acidic conditions involving epimerization at the α-position of the ketone.

Asymmetric Synthesis and Structure Revision of Guignardone H and I: Development of a Chiral 1,3-Diketone Possessing C2 Symmetry.

A novel chiral 1,3-diketone possessing C2 symmetry was synthesized and utilized in the asymmetric synthesis of guignardone H and I by employing sequential condensation-6π-electrocyclization reactions with the novel 1,3-diketone followed by stereoselective hydrogenation as key steps. Although the synthetic compounds differed from natural guignardone H and I, we realized that the C4-epimers of the proposed structures for guignardone H and I were the actual structures.