Synthesis and biological evaluation of coprinoferrin, an acylated tripeptide hydroxamate siderophore.

Coprinoferrin (CPF), originally isolated from a genetically engineered strain (ΔlaeA) of the mushroom fungus Coprinopsis cinerea, is an acylated tripeptide hydroxamate consisting of tandem aligned N5-hexanoyl-N5-hydroxy-L-ornithine with modifications of N-acetyl and C-carboxamide. These unique chemical properties make CPF an iron(III) binder (siderophore), which helps in iron acquisition from the environment and promotes hyphal growth as well as fruiting body formation in C. cinerea. However, CPF's detailed mode of action remains enigmatic. In this study, we have accomplished the synthesis of CPF from N-Boc-L-glutamic acid 5-benzyl ester. The physicochemical characteristics, spectroscopic features, and biological activity observed in the synthetic CPF closely match those of natural CPF. This alignment provides unequivocal confirmation of the proposed chemical structure, facilitating a deeper understanding of its physiological role in nature, particularly in fruiting body formation.

Annulative coupling of vinylboronic esters: aryne-triggered 1,2-metallate rearrangement.

A stereoselective annulative coupling of a vinylboronic ester ate-complex with arynes producing cyclic borinic esters has been developed. An annulation reaction that proceeded through the formation of two C-C bonds and a C-B bond was realized by exploiting a 1,2-metallate rearrangement of boronate triggered by the addition of a vinyl group to the strained triple bond of an aryne. The generated aryl anion would then cyclize to a boron atom to complete the annulation cascade. The annulated borinic ester could be converted to boronic acids and their derivatives by oxidation, halogenation, and cross-coupling. Particularly, halogenation and Suzuki-Miyaura coupling proceeded in a site-selective fashion and produced highly substituted alkylboronic acid derivatives.

Toward the Synthesis of Paspaline-Type Indole-Terpenes: Stereoselective Construction of Core Scaffold with Contiguous Asymmetric Quaternary Carbon Centers.

The core scaffold of paspaline-type indole-terpenes was synthesized by using the House-Meinwald rearrangement as a key step. Rearrangement of the epoxide methyl group in the precursor with methylaluminum bis(4-bromo-2,6-di-tert-butylphenoxide) as a Lewis acid proceeded smoothly to construct contiguous asymmetric quaternary carbon centers by a 1,2-chirality transfer.

Synthesis of functionalized cyclopropylboronic esters based on a 1,2-metallate rearrangement of cyclopropenylboronate.

A procedure converting tribromocyclopropane to densely functionalized ß-selenocyclopropylboronic ester using the 1,2-metallate rearrangement of a boron ate-complex has been developed. Treatment of an in situ-generated cyclopropenylboronic ester ate-complex with phenylselenenyl chloride triggered stereospecific rearrangement to produce functionalized cyclopropanes. DFT calculations for 1,2-metallate rearrangement suggested that the reaction proceeds through a seleniranium intermediate.

Structure Optimization of Gatastatin for the Development of γ-Tubulin-Specific Inhibitor.

Gatastatin (O 7-benzyl glaziovianin A) is a γ-tubulin-specific inhibitor that is used to investigate γ-tubulin function in cells. We have previously reported that the unsubstituted phenyl ring of the O 7-benzyl group in gatastatin is important for γ-tubulin inhibition. To obtain further structural information regarding γ-tubulin inhibition, we synthesized several gatastatin derivatives containing a fixed O 7-benzyl moiety. Modifications of the B-ring resulted in drastic decrease in cytotoxicity, abnormal spindle formation activity, and inhibition of microtubule (MT) nucleation. In contrast, various O 6-alkylated gatastatin derivatives showed potent cytotoxicity, induced abnormal spindle formation, and inhibited MT nucleation. We had previously reported that O 6-benzyl glaziovianin A is a potent α/ß-tubulin inhibitor; thus, these new results suggest that the O 6-position restricts affinity for α/ß- and γ-tubulin. Considering that an O 7-benzyl group increases specificity for γ-tubulin, more potent and specific γ-tubulin inhibitors can be generated through O 6-modifications of gatastatin.

Dual Inhibition of γ-Tubulin and Plk1 Induces Mitotic Cell Death.

α/ß-Tubulin inhibitors that alter microtubule (MT) dynamics are commonly used in cancer therapy, however, these inhibitors also cause severe side effects such as peripheral neuropathy. γ-Tubulin is a possible target as antitumor drugs with low side effects, but the antitumor effect of γ-tubulin inhibitors has not been reported yet. In this study, we verified the antitumor activity of gatastatin, a γ-tubulin specific inhibitor. The cytotoxicity of gatastatin was relatively weak compared with that of the conventional MT inhibitors, paclitaxel and vinblastine. To improve the cytotoxicity, we screened the chemicals that improve the effects of gatastatin and found that BI 2536, a Plk1 inhibitor, greatly increases the cytotoxicity of gatastatin. Co-treatment with gatastatin and BI 2536 arrested cell cycle progression at mitosis with abnormal spindles. Moreover, mitotic cell death induced by the combined treatment was suppressed by the Mps1 inhibitor, reversine. These findings suggest that co-treatment with Plk1 and γ-tubulin inhibitors causes spindle assembly checkpoint-dependent mitotic cell death by impairing centrosome functions. These results raise the possibility of Plk1 and γ-tubulin inhibitor co-treatment as a novel cancer chemotherapy.

Formal Total Synthesis of Manzacidin B via Sequential Diastereodivergent Henry Reaction.

A formal total synthesis of manzacidin B is described. ß,ß-Disubstituted γ-hydroxy-ß-aminoalcohol, the key structure of manzacidin B, is stereoselectively constructed via sequential Henry reactions. By taking advantage of noncovalent interactions, such as intramolecular hydrogen bonding and chelation, we could diastereodivergently control the stereoselectivity of the Henry reaction.

Toward the Synthesis of SB-203207: Construction of Four Contiguous Nitrogen-Containing Stereogenic Centers.

SB-203207 is an altemicidin-type alkaloid that potently inhibits isoleucyl tRNA synthetase activity. Its main structural feature is a hexahydro-6-azaindene framework containing a unique ß-hydroxy α,α-disubstituted α-amino acid moiety on the cyclopentane portion. Herein we have established a method for constructing the four contiguous nitrogen-containing stereogenic centers of SB-203207 by using as key steps the stereoselective alkylation of bowl-shaped tricyclic lactone to construct a quaternary carbon at C1, the stereoselective hydroboration-oxidation reaction to install the C2 hydroxy group, and the Curtius rearrangement to introduce a nitrogen atom onto the C1 quaternary carbon.

Toward the Synthesis of Yuzurimine-Type Alkaloids: Stereoselective Construction of the Heterocyclic Portions of Deoxyyuzurimine and Macrodaphnine.

The heterocyclic portions of yuzurimine-type alkaloids, such as deoxyyuzurimine and macrodaphnine, were synthesized by using a stereoselective hydroboration-oxidation reaction to install the C20 methyl group, the intramolecular Mitsunobu reaction to construct the E-ring portion, and the intramolecular SN2 reaction to construct the F-ring portion as key steps.

Thioureas as Highly Active Catalysts for Biomimetic Bromocyclization of Geranyl Derivatives.

Thioureas bearing electron-deficient aryl groups show high catalytic activity in the biomimetic bromocyclization of geranyl derivatives. The reaction of geranyl derivatives with N-bromosuccinimide (NBS) proceeds rapidly in CH2Cl2 to give the corresponding bromocyclization products in high yields as a ca. 1:1 mixture of endo- and exo-isomers. The reactivity of geranyl derivatives highly depends on the terminal substituent: electron-donating substituents increase the reactivity, while electron-withdrawing substituents decrease the reactivity.

Catalytic enantioselective Hosomi-Sakurai reaction of α-ketoesters promoted by chiral copper(ii) complexes.

A catalytic enantioselective Hosomi-Sakurai reaction of α-ketoesters has been developed. A copper(ii) complex with a chiral bis(oxazoline) ligand bearing methanesulfonamide groups shows excellent catalytic activity to give α,α-disubstituted α-hydroxyesters in high yields with high enantioselectivities. This is the first successful method for the catalytic enantioselective 1,2-addition of α-ketoesters with allylic silanes.

Enantioselective aza-Friedel-Crafts reaction of furan with α-ketimino esters induced by a conjugated double hydrogen bond network of chiral bis(phosphoric acid) catalysts.

Chiral C 2- and C 1-symmetric BINOL-derived bis(phosphoric acid) catalysts, which have OP([double bond, length as m-dash]O)(OH)2/OP([double bond, length as m-dash]O)(OH)(OR) moieties at the 2,2'-positions, were developed and used for the enantioselective aza-Friedel-Crafts reaction of 2-methoxyfuran with α-ketimino esters for the first time. The intramolecular conjugated double hydrogen bond network is a key to increasing the Brønsted acidity and preventing deactivation of the catalysts. Highly functionalized α-amino acid derivatives with a chiral quaternary carbon center could be transformed into versatile optically active N- and O-heterocycles and an α-aryl-substituted serine.

Discovery of O6-benzyl glaziovianin A, a potent cytotoxic substance and a potent inhibitor of α,ß-tubulin polymerization.

We have discovered O6-benzyl glaziovianin A, which showed stronger inhibition of microtubule polymerization (IC50=2.1µM) than known α,ß-tubulin inhibitors, such as colchicine and glaziovianin A. Also, we performed competition binding experiments of O6-benzyl glaziovianin A and revealed that O6-benzyl glaziovianin A binds to the colchicine binding site with high affinity. It is interesting that glaziovianin A derivatives change their mode of action in benzylation at the O6 (α,ß-tubulin inhibitor) or O7 (γ-tubulin-specific inhibitor) position.

Enantioselective bromocyclization of 2-geranylphenols induced by chiral phosphite-urea bifunctional catalysts.

Chiral phosphite-urea bifunctional catalysts have been developed for the enantioselective bromocyclization of 2-geranylphenols with N-bromophthalimide (NBP) for the first time. The chiral triaryl phosphite moiety activates NBP to generate a bromophosphonium ion. On the other hand, the urea moiety interacts with a hydroxyl group of the substrate through hydrogen bonding interactions. Enantioselectivity is effectively induced through two-point attractive interactions between the catalyst and the substrate.

Stereoselective Electrophilic Cyclization.

Electrophilic cyclizations of unactivated alkenes play highly important roles in the synthesis of useful building blocks. This account describes our contributions to the rational design of monofunctionalized chiral Lewis base catalysts for enantioselective iodo- and protocyclizations. For the stereoselective promotion of electrophilic bromocyclizations, nucleophilic phosphite-urea cooperative catalysts have been designed.

Enantioselective 1,3-dipolar cycloaddition of azomethine imines with propioloylpyrazoles induced by chiral π-cation catalysts.

We developed 1,3-dipolar cycloadditions of azomethine imines with propioloylpyrazoles catalyzed by a chiral copper(II) complex of 3-(2-naphthyl)-l-alanine amide. The asymmetric environment created by intramolecular π-cation interaction and the N-alkyl group of the chiral ligand gives the corresponding adducts in high yields with excellent enantioselectivity. This is the first successful method for the catalytic enantioselective 1,3-dipolar cycloaddition of azomethine imines with internal alkyne derivatives to give fully substituted pyrazolines.

Cooperative activation with chiral nucleophilic catalysts and N-haloimides: enantioselective iodolactonization of 4-arylmethyl-4-pentenoic acids.

Chiral triaryl phosphates promote the enantioselective iodolactonization of 4-substituted 4-pentenoic acids to give the corresponding iodolactones in high yields with high enantioselectivity. N-Chlorophthalimide (NCP) is employed as a Lewis acidic activator and oxidant of I2 for the present iodolactonization. In combination with 1.5 equivalents of NCP, only 0.5 equivalents of I2 are sufficient to generate the iodinating reagent.

Catalytic enantioselective inverse electron demand hetero-Diels-Alder reaction with allylsilanes.

The first diastereo- and enantioselective inverse electron demand hetero-Diels-Alder reaction of ß,γ-unsaturated α-ketoesters with allylsilanes is described. Chiral copper(II) catalysts successfully activate the ß,γ-unsaturated α-ketoesters and promote the reaction with allylsilanes with excellent enantioselectivities. This process represents a new entry to chiral oxanes.

Selective bromocyclization of 2-geranylphenols promoted by phosphite-urea cooperative catalysts.

Nucleophilic phosphite-urea cooperative catalysts are highly efficient for the bromonium-induced cyclization of 2-geranylphenols. Phosphite-N,N'-dimethylurea catalysts also show moderate activity, probably due to the steric effect of their bent conformation.