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.

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.

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.

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.

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.

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.

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.

Synthesis of multisubstituted cycloalkenes through carbomagnesiation of strained cycloalkynes.

An efficient synthetic method of seven- and six-membered cycloalkenes through the generation of strained cycloalkynes and following carbomagnesiation is described. Further bond formations of the resulting cycloalkenylmagnesium intermediates with a wide variety of electrophiles enabled us to prepare diverse cycloalkene derivatives including benzoxepine analogs having a fully substituted alkene structure.

Synthesis of benzyl sulfides via substitution reaction at the sulfur of phosphinic acid thioesters.

An ambident electrophilicity of phosphinic acid thioesters is disclosed. Unexpected carbon-sulfur bond formation took place in the reaction between phosphinic acid thioesters and benzyl Grignard reagents. The developed method for benzyl sulfides has a wide substrate scope and was applicable for the synthesis of a drug analog.

A facile preparation of functional cycloalkynes via an azide-to-cycloalkyne switching approach.

A facile method for preparing various functional cycloalkynes, including proteins incorporated with a cycloalkyne moiety, from the corresponding azides is developed. Treatment of diynes bearing strained and terminal alkyne moieties with a copper salt enabled terminal alkyne-selective click conjugation with azides, whereas a more azidophilic strained alkyne moiety was transiently protected from the click reaction via complexation with copper.

Further enhancement of the clickability of doubly sterically-hindered aryl azides by para-amino substitution.

Introduction of an amino group at the para position of doubly sterically-hindered aryl azides significantly enhances the reactivity with cyclooctynes. The distortability of the azido group is synergistically enhanced by the para-electron-donating group and two bulky ortho substituents, which increases the HOMO energy level and provoke the steric inhibition of resonance, respectively.

Synthesis of Cardiopetaline via a Wagner-Meerwein Rearrangement without Preactivation of the Pivotal Hydroxy Group.

A synthesis of cardiopetaline has been accomplished via a Wagner-Meerwein rearrangement of a diol having the denudatine skeleton. The Wagner-Meerwein rearrangement could be facilitated simply by heating the diol with p-toluenesulfonic acid in pivalic acid, without preactivating the pivotal hydroxy group. This strategy does not require differentiation of several hydroxy groups in the substrate for the Wagner-Meerwein rearrangement and could be applied to the synthesis of more highly oxygenated aconitine-type diterpenoid alkaloids.

Synthesis of Unsymmetrical Tertiary Phosphine Oxides via Sequential Substitution Reaction of Phosphonic Acid Dithioesters with Grignard Reagents.

A facile synthetic method for unsymmetrical tertiary phosphine oxides is reported. Sequential treatment of phosphonodithioic acid S,S-di(p-tolyl) esters with two Grignard reagents enabled the stepwise introduction of different carbon substituents on the phosphorus atom. The chemical stability of dithioesters and monosubstituted thioesters has enhanced the utility of this method, rendering a wide range of organophosphorus compounds easily available.

Thiazolobenzyne: a versatile intermediate for multisubstituted benzothiazoles.

Thiazolobenzyne, which is a benzyne species fused with a thiazole ring, was efficiently generated via an iodine-magnesium exchange reaction of an ortho-iodoaryl triflate-type precursor using a trimethylsilylmethyl Grignard reagent as an activator. A wide range of arynophiles reacted efficiently with the thiazolobenzynes generated by this method to afford various multisubstituted benzothiazoles.

Total Synthesis of (-)-Cardiopetaline.

The total synthesis of (-)-cardiopetaline, an aconitine-type natural product, has been accomplished. Our synthesis involved a Wagner-Meerwein rearrangement of a sulfonyloxirane that enabled, in a single step, the construction of the bicyclo[3.2.1] system in the aconitine skeleton and effective introduction of oxygen functional groups at the appropriate positions.

A mild and facile synthesis of aryl and alkenyl sulfides via copper-catalyzed deborylthiolation of organoborons with thiosulfonates.

An efficient deborylthiolation of aryl- and alkenylborons with thiosulfonates has been achieved under mild conditions using a copper catalyst. All steps of the experimental process were free from unpleasant odors. The mild reaction conditions as well as ready availability of boron compounds and thiosulfonates enabled easy access to an array of sulfides, including those bearing sensitive functional groups.

New photocleavable linker: α-thioacetophenone-type linker.

Photocleavable linkers are advantageous over the common linkers because they could be cleaved without using reagents. A novel photocleavable linker with an α-thioacetophenone moiety has been developed. This linker, which can be cleaved upon irradiation at 365 nm via the Norrish type II reaction, is applicable to a protein affinity purification system, allowing target proteins to be effectively isolated. This novel linker would serve as an effective tool in chemical biology.

Total synthesis of (-)-lepenine.

The first asymmetric total synthesis of lepenine has been accomplished. The synthesis features a tethered intramolecular Diels-Alder reaction, an intramolecular Mannich reaction, and a Diels-Alder reaction between an ortho-quinone monoketal and ethylene, resulting in stereoselective construction of the unique hexacyclic system.

Activity-dependent proteolytic cleavage of neuroligin-1.

Neuroligin (NLG), a postsynaptic adhesion molecule, is involved in the formation of synapses by binding to a cognate presynaptic ligand, neurexin. Here we report that neuroligin-1 (NLG1) undergoes ectodomain shedding at the juxtamembrane stalk region to generate a secreted form of NLG1 and a membrane-tethered C-terminal fragment (CTF) in adult rat brains in vivo as well as in neuronal cultures. Pharmacological and genetic studies identified ADAM10 as the major protease responsible for NLG1 shedding, the latter being augmented by synaptic NMDA receptor activation or interaction with soluble neurexin ligands. NLG1-CTF was subsequently cleaved by presenilin/γ-secretase. Secretion of soluble NLG1 was significantly upregulated under a prolonged epileptic seizure condition, and inhibition of NLG1 shedding led to an increase in numbers of dendritic spines in neuronal cultures. Collectively, neuronal activity-dependent proteolytic processing of NLG1 may negatively regulate the remodeling of spines at excitatory synapses.