Total Synthesis of Putative Melognine.

Total synthesis of melognine was accomplished. A 10-membered cyclic alkyne was prepared via an intramolecular SN2 reaction of a nosylamide. Enyne metathesis of the cyclic alkyne under an atmosphere of ethylene afforded a 1,3-diene. Intramolecular cycloaddition of a nitrone and an azomethine ylide with the 1,3-diene moiety constructed the characteristic highly fused skeleton. Further transformation, including ring-closing metathesis, resulted in the synthesis of melognine, whose NMR spectra did not match the reported data. Close inspection of the spectra of melognine in the literature suggested that the structure of melognine might be identical with that of a known alkaloid, melodinine L.

Deep learning driven de novo drug design based on gastric proton pump structures.

Existing drugs often suffer in their effectiveness due to detrimental side effects, low binding affinity or pharmacokinetic problems. This may be overcome by the development of distinct compounds. Here, we exploit the rich structural basis of drug-bound gastric proton pump to develop compounds with strong inhibitory potency, employing a combinatorial approach utilizing deep generative models for de novo drug design with organic synthesis and cryo-EM structural analysis. Candidate compounds that satisfy pharmacophores defined in the drug-bound proton pump structures, were designed in silico utilizing our deep generative models, a workflow termed Deep Quartet. Several candidates were synthesized and screened according to their inhibition potencies in vitro, and their binding poses were in turn identified by cryo-EM. Structures reaching up to 2.10 Å resolution allowed us to evaluate and re-design compound structures, heralding the most potent compound in this study, DQ-18 (N-methyl-4-((2-(benzyloxy)-5-chlorobenzyl)oxy)benzylamine), which shows a Ki value of 47.6 nM. Further high-resolution cryo-EM analysis at 2.08 Å resolution unambiguously determined the DQ-18 binding pose. Our integrated approach offers a framework for structure-based de novo drug development based on the desired pharmacophores within the protein structure.

Total syntheses of macleanine and lycoposerramine-S.

Total syntheses of fawcettimine-class Lycopodium alkaloids having an imino bridge between C5 and C13 were accomplished. Fawcettimine was first prepared in 10 steps from a known compound, and the characteristic structures, including the imino bridge, were constructed via the formation of a bridgehead imine.

Total Syntheses of Malettinins C and E.

The total syntheses of tropolone-containing natural products malettinins C and E were accomplished. A nitro compound and a chiral enone were prepared by using palladium-mediated nitromethylation and an organocatalyst-mediated asymmetric aldol reaction, respectively, and were connected via a Michael reaction. Oxidative dearomatization of a phenol having a cyclic acetal moiety produced a spirocyclic dienone, which could be converted into a tropolone via a base-mediated ring-expansion reaction, with elimination of the nitro group, providing entry to malettinins C and E.

Construction of the tetracyclic ring system of diterpene alkaloids via cationic [5 + 2] cycloaddition.

The ABCD ring system of C18/C19 diterpene alkaloids was constructed via cationic [5 + 2] cycloaddition to forge a bicyclo[3.2.1]octane, an intramolecular aldol reaction to form a seven-membered ring, oxidation of a phenol at the para-position, and introduction of a one-carbon unit via Stille coupling followed by oxidative cleavage of a furan ring.

Total Synthesis of Kopsone.

A total synthesis of kopsone was achieved, featuring stereoselective preparation of an acyclic aldehyde having a protected hydroxylamine moiety via Ireland-Claisen rearrangement and intramolecular cycloaddition of an eight-membered cyclic nitrone to form the 2-azabicyclo[3.3.1]nonane skeleton.

Fluorinated 2,6-Xylenesulfonyl Group: A Protective Group for Amines.

We have developed a fluorinated 2,6-xylenesulfonyl group (fluorinated xysyl, fXs) as a protective group for amines. The sulfonyl group could be attached to amines by reactions with the corresponding sulfonyl chloride, and survived various conditions, including acidic, basic, and even reductive conditions. The fXs group could be cleaved by treatment with a thiolate under mild conditions.

Convergent synthesis of the [5-7-6-3] tetracyclic core of premyrsinane diterpenes.

The [5-7-6-3] tetracyclic core of premyrsinane diterpenes was convergently synthesized via the stereoselective three-component coupling of a 2-propenyl unit, an enone, and an aldehyde, followed by the relay ring-closing metathesis with conformation control of the substrate to construct the 7-membered ring.

Construction of the [7-5-5] Tricyclic Core of Daphniphyllum Alkaloids via a Cationic Cascade Reaction.

The [7-5-5] tricyclic core of daphniphyllum alkaloids, containing contiguous stereogenic centers at C14 and C15 and a tetrasubstituted alkene moiety between C9 and C10, was constructed via a cascade reaction that involved an electrocyclic reaction of a pentadienyl cation and intramolecular interception of the resultant cyclopentenyl cation.

Formal Synthesis of Ecteinascidin 743 via an Intramolecular Cascade Heck Reaction to Construct the Diazabicyclo[3.3.1]nonane Framework.

A synthetic route to ecteinascidin 743 has been established via an intramolecular cascade Heck reaction to construct the diazabicyclo[3.3.1]nonane skeleton while controlling the two contiguous stereogenic centers. The strategically formed five-membered ring was oxidatively cleaved to generate a dialdehyde intermediate, from which the B ring of ecteinascidin 743 was constructed.

Anticancer Approach Inspired by the Hepatotoxic Mechanism of Pyrrolizidine Alkaloids with Glycosylated Artificial Metalloenzymes.

Metabolic oxidation of pyrrolizidine alkaloids (PAs) from herbal and dietary supplements by cytochrome P450 produces dehydro-PAs (DHPs), which leads to toxicities. A highly reactive cation species generated from the active pyrrole ring of DHPs readily reacts with various cellular components, causing hepatotoxicity and cytotoxicity. Inspired by PA-induced hepatic damage, we developed a therapeutic approach based on a cyclization precursor that can be transformed into a synthetic DHP under physiological conditions through gold-catalyzed 5-endo-dig cyclization using a gold-based artificial metalloenzyme (ArM) instead of through metabolic oxidation by cytochrome P450. In cell-based assays, the synthesis of the DHP by a cancer-targeting glycosylated gold-based ArM substantially suppressed cell growth of the targeted cancer cells without causing cytotoxicity to untargeted cells, highlighting the potential of the strategy to be used therapeutically in vivo.

Substitution of α-Azido Sulfones with Thiolates to Form α-Azido Sulfides.

Upon treatment of α-azido sulfones with a thiol in the presence of 1,1,3,3-tetramethylguanidine, substitution of the sulfonyl group with a thiolate occurred, resulting in the formation of α-azido sulfides. Based on experimental results and DFT calculations, a reaction mechanism that involves the addition of a thiolate to the azido group and generation of an alkylidene triazene is proposed.

Photoinduced rearrangement of α-(2-nitrophenyl)ketones.

Photoirradiation of α-(2-nitrophenyl)ketones produced cyclic hydroxamates. The reaction proceeded via photoinduced oxygen transfer from the nitro group to the benzylic position, forming an α-hydroxyketone having a nitroso group. Subsequent addition of the nitroso group to the ketone moiety and the concomitant cleavage of the C-C σ bond between the carbonyl group and the benzyl position produced hydroxamic acid, which underwent formation of a hemiacetal to give cyclic hydroxamate.

Photo-oxygenation by a biocompatible catalyst reduces amyloid-ß levels in Alzheimer's disease mice.

Amyloid formation and the deposition of the amyloid-ß peptide are hallmarks of Alzheimer's disease pathogenesis. Immunotherapies using anti-amyloid-ß antibodies have been highlighted as a promising approach for the prevention and treatment of Alzheimer's disease by enhancing microglial clearance of amyloid-ß peptide. However, the efficiency of antibody delivery into the brain is limited, and therefore an alternative strategy to facilitate the clearance of brain amyloid is needed. We previously developed an artificial photo-oxygenation system using a low molecular weight catalytic compound. The photocatalyst specifically attached oxygen atoms to amyloids upon irradiation with light, and successfully reduced the neurotoxicity of aggregated amyloid-ß via inhibition of amyloid formation. However, the therapeutic effect and mode of actions of the photo-oxygenation system in vivo remained unclear. In this study, we demonstrate that photo-oxygenation facilitates the clearance of aggregated amyloid-ß from the brains of living Alzheimer's disease model mice, and enhances the microglial degradation of amyloid-ß peptide. These results suggest that photo-oxygenation may represent a novel anti-amyloid-ß strategy in Alzheimer's disease, which is compatible with immunotherapy.

Nitrone Formation by Reaction of an Enolate with a Nitro Group.

Ketones with a 2-nitrophenyl group at the α-position were treated with sodium hydroxide in methanol at 60 °C. Under these conditions, enolates derived from the ketones intramolecularly reacted with the nitro group to form a variety of nitrones. Additional experimental results, including the unexpected isolation of N-hydroxyindolinone as a byproduct, led to a proposed reaction mechanism, occurring via an α-hydroxyketone. The resultant nitrones underwent inter- and intramolecular 1,3-dipolar cycloaddition with olefins to afford polycyclic isoxazolidines.

Copper-Mediated Conversion of Alkynes into Nitriles via Iodotriazoles.

We disclose our studies on a copper-mediated reaction of alkynes with trimethylsilyl azide to afford nitriles, and proposed a reaction mechanism, which involves an iodoalkyne and an iodotriazole as intermediates.

Total Synthesis of Haliclonin†A.

The total synthesis of haliclonin A was accomplished. Starting from 3,5-dimethoxybenzoic acid, a functionalized cyclohexanone fused to a 17-membered ring was prepared through a Birch reduction/alkylation sequence, ring-closing metathesis, intramolecular cyclopropanation, and stereoselective 1,4-addition of an organocopper reagent to an enone moiety. Reductive C-N bond formation via an N,O-acetal forged the 3-azabicyclo[3.3.1]nonane core. The allyl alcohol moiety was constructed by a sequence involving stereoselective α-selenylation of an aldehyde via an enamine, syn-elimination of a selenoxide, and allylation of the aldehyde with an allylboronate. Formation of the 15-membered ring containing a skipped diene was achieved by ring-closing metathesis, and final transformations led to the synthesis of haliclonin A.

A novel translation inhibitor, mersicarpine, inhibits S-phase progression and induces apoptosis in HL60 cells.

Mersicarpine is an aspidosperma alkaloid isolated from the Kopsia genus of plants. Its intriguing structural features have attracted much attention in synthetic organic chemistry, but no biological activity has been reported. Here, we report the effects of mersicarpine on human leukemia cell line HL60. At concentrations above 30 µm, mersicarpine reversibly arrested cell cycle progression in S-phase. At higher concentrations, it induced not only production of reactive oxygen species, but also apoptosis. Macromolecular synthesis assay revealed that mersicarpine specifically inhibits protein synthesis. These results suggest that mersicarpine is a novel translation inhibitor that induces apoptosis.

Structure-Activity Relationship Study of Majusculamides A and B and Their Analogues on Osteogenic Activity.

We discovered that majusculamide A (1) and majusculamide B (2), isolated from a marine cyanobacterium collected in Okinawa, induced osteoblast differentiation in MC3T3-E1 cells. Although majusculamide A (1) has a different configuration only at the C-19 stereocenter, bearing a methyl group, compared to majusculamide B (2), the effect of 1 was stronger than that of 2. We synthesized some analogues of the majusculamides (3-15) and evaluated osteogenic activities of these analogues. The structure-activity relationship study of majusculamide analogues suggested that the number of methyls and configuration at C-19 and the nature of the substituent at C-20 of majusculamide A (1) may be important for the osteoblast differentiation-inducing effect of 1.

Total Synthesis of Tetrodotoxin.

A total synthesis of tetrodotoxin was accomplished. A Diels-Alder reaction between a known enone and a siloxy diene gave a tricyclic product, the steric bias of which was used to construct the remaining stereogenic centers. A nitrogen atom was introduced either by a four-step sequence involving a Curtius rearrangement, or a three-step sequence featuring a newly developed transformation of a terminal alkyne into a nitrile. Introduction of the guanidine moiety followed by the formation of the heterocyclic system by cascade reactions led to tetrodotoxin.