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The use of chiral ligand-modified metal nanoparticles is a promising strategy for constructing active and robust asymmetric catalyst systems. A recent advance in such catalyst systems for C–C bond-forming reactions is highlighted, and the characteristics of the active species are discussed. Several studies suggested that a redox event between nanoparticles and reagents might be a key to generating active species from nanoparticles.

Diaza [1,4] Wittig-type rearrangement of N-allylic-N-Boc-hydrazines into γ-amino-N-Boc-enamines was demonstrated. The scope and limitation, experimental mechanistic studies, and a proposed reaction mechanism were also described.

Cooperative catalysts consisting of chiral Rh/Ag nanoparticles and Sc(OTf)3 have been developed that catalyze asymmetric 1,4-addition reactions of arylboronic acids with α,β-unsaturated amides efficiently. The reaction has been considered one of the most challenging reactions because of the low reactivity of the amide substrates. The new catalysts provide the desired products with outstanding enantioselectivities (>98 % ee) in the presence of low loadings (

Palladium nanoparticle (Pd NP) catalysts immobilized in a polymer with an N-heterocyclic carbene (NHC) moiety (PICB-NHC-Pd) have been developed, wherein the NHC moiety plays dual roles as a crosslinker and a ligand to activate the Pd NPs. The presence of both Pd NPs and NHC was confirmed by STEM/EDS and SR-MAS NMR analyses, respectively. This PICB-NHC-Pd catalyst showed excellent activity in the Suzuki–Miyaura coupling reaction without leaching of Pd. Excellent results were obtained in gram-scale synthesis, and catalyst recovery/reuse experiments were completed without loss of catalyst activity.

An unprecedented and convenient synthetic approach to 2,3-dihydro-1H-isoindol-1-one (isoindolinone) derivatives has been developed. The key and final step of the method is the reaction of N-alkyl-N-(o-bromobenzyl)benzamides with butyllithium in THF at −78 °C. The corresponding 2-alkyl-3-aryl-2,3-dihydro-1H-isoindol-1-ones were produced in moderate-to-fair yields, probably via oxidation of the initially formed corresponding 2H-isoindole derivatives with air during workup.

Lactone-moiety-attached 2-cyclohexylideneethyl picolinate was prepared through the OH-directed epoxidation (98% ds) of (R)-3-methylcyclohex-2-en-1-ol (99% ee), Horner–Wadsworth–Emmons olefination, conversion to the allylic moiety, and epoxide ring opening with Et2AlCH2CO2 t-Bu. The allylic substitution of the picolinate with Me2CuMgBr·MgBr2 furnished a quaternary carbon center with 92% ds. Finally, the lactonization of the product, the tert-butyl ester of the seco acid, under acidic conditions, afforded (–)-anastrephin.

The first intermolecular asymmetric Michael addition of nitrogen-nucleophiles to α,β-unsaturated carboxylic acids was achieved through a new type of arylboronic acid equipped with chiral aminothiourea. The use of BnONH2 as a nucleophile gives a range of enantioenriched β-(benzyloxy)amino acid derivatives in good yields and with high enantioselectivity (up to 90% yield, 97% enantiomeric excess (ee)). The obtained products are efficiently converted to optically active β-amino acid and 1,2-diamine derivatives.

New bisindole alkaloids, hyrtinadines C (1) and D (2), have been isolated from an Okinawan marine sponge Hyrtios sp. The structures of hyrtinadines C (1) and D (2) were elucidated based on analyses of the spectral data. Hyrtinadines C (1) and D (2) were the relatively rare alkaloids possessing a 3,4-fused azepinoindole skeleton. Hyrtinadines C (1) and D (2) showed antimicrobial activity.

In the course of searching for selective growth inhibitors of the cancer cells adapted to nutrient starvation, a new 3-alkylpyridine alkaloid named N-methylniphatyne A (1) was isolated from an Indonesian marine sponge of Xestospongia sp. The chemical structure of 1 was determined on the basis of the spectroscopic analysis and comparison with the synthesized 1 and its analogues. Compound 1 showed the cytotoxic activity against PANC-1 cells under the condition of glucose starvation with IC50 value of 16 µM, whereas no growth-inhibition was observed up to 100 µM under the general culture conditions.

The synthesis of the enantiomer allows the determination of the absolute configuration in the natural product, identified as an anticancer agent.

Asymmetric arylation of aldimines catalyzed by heterogeneous chiral rhodium nanoparticles has been developed. The reaction proceeded in aqueous media without significant decomposition of the imines by hydrolysis to afford chiral (diarylmethyl)amines in high yields with outstanding enantioselectivities. This catalyst system exhibited the highest turnover number (700) in heterogeneous catalysts reported to date for these reactions. The reusability of the catalyst was also demonstrated.

We undertook a systematic study of Grignard reactions using cyclopentyl methyl ether (CPME) as a reaction solvent. Diisobutylaluminum hydride was found to be the most appropriate activator of magnesium and a number of Grignard reagents could be prepared as homogeneous or heterogeneous solutions in CPME. The CPME used in the Grignard reaction was efficiently recycled without affecting the reaction yield of the second experiment. GC–MS analysis of the recovered solvent revealed that CPME was stable under the Grignard conditions. Some of the Grignard reagents in CPME were stable for at least several months and therefore these solutions could replace existing commercial reagents. Tramadol hydrochloride, an analgesic that is used worldwide, and tamoxifen, an anti-estrogenic drug for estrogen-receptor-positive breast cancer were synthesized using Grignard reactions in CPME.

Highly efficient catalytic asymmetric [3 + 2] cycloadditions using a chiral copper amide are reported. Compared with the chiral CuOTf/Et3N system, the CuHMDS system showed higher reactivity, and the desired reactions proceeded in high yields and high selectivities with catalyst loadings as low as 0.01 mol %.

Natural products are well recognized as an important source of lead compounds in drug development. During the past >30 years, we have discovered >1000 novel bioactive natural products from Okinawan marine organisms (sponges, tunicates, cone shells, etc.) and microorganisms (fungi, bacteria, dinoflagellates, etc.). Some of them are used as bioprobes useful for basic studies of life sciences, while others are expected to be candidates of drug leads.

In our continuing study for structurally and biogenetically interesting natural products from marine organisms, Okinawan marine sponges Agelas spp. were investigated, resulting in the isolation of 18 unique alkaloids including five dimeric bromopyrrole alkaloids (1-5), ten monomeric bromopyrrole alkaloids (6-15), and three conjugates of monomeric bromopyrrole alkaloid and hydroxykynurenine (16-18). In this mini-review, the isolation, structure elucidation, and antimicrobial activities of these alkaloids are summarized.

The efficient protocol tolerates various alkenes, such as 1-substituted and 1,1-disubstituted styrene derivatives and cyclic alkenes.

Substitution of secondary allylic phosphates with the anions derived from Ar2CH2 with BuLi or LDA proceeded regioselectively and stereoselectively without a metal catalyst, affording inversion products in good yield. Similarly, propargylic phosphates gave propargylic products selectively.

A novel approach to chiral anti-α,β-diamino acid derivatives through tandem orthogonal organocatalysis has been developed. Chiral phosphoric acid catalysts control the chemo-, regio-, and stereoselective addition of hydroxylamines to alkylideneoxazolones, while a phosphine catalyst promotes the isomerization of Z- alkylideneoxazolones to the more reactive E- alkylideneoxazolones.

The allylic substitution of γ,γ-disubstituted secondary allylic picolinates (esters of 2-PyCO2H) with aryllithium-based copper reagents was carried out in order to construct quaternary carbons. Initially, 2-methyl-7-phenylhept-2-en-4-yl picolinate was reacted with phenyl copper reagents derived from phenyllithium with Cu(acac)2, Cu(OMe)2, CuBr·Me2S, and CuCN in 1–3:1 ratios in the presence of excess magnesium bromide. Although the SN2′ product with a quaternary carbon was formed, the regioselectivity was 90% at most. Instead, phenyllithium/copper(I) thiophene-2-carboxylate/magnesium bromide (Ph/Cu = 1.5–2:1, Mg/Li = >1) was found to produce >98% regioselectivity and sufficient reactivity. This system was successful with eight aryllithium based copper reagents possessing sterically congested, electron-donating, or electron-withdrawing substituents. The anti stereochemical course was established by using an enantiomerically enriched geranaldehyde-derived picolinate.

A strong C—H acidic compound (TCA) is described as catalyst for the sequential Mukaiyama—Michael aldol reaction of α-pyrone derivatives with the silyl ketene acetal (II) and ketones or different α,β-unsaturated ketones.

The study of an all-solid-state TiH2/orthorhombic-La2LiHO3/Ti cell provides conclusive evidence of pure H- conduction.

The novel 9,11-secosteroid, haebaruol, was isolated from the soft coral Clavularia sp. collected from the Ishigaki Island, Okinawa, Japan. The planar structure of haebaruol was elucidated by NMR sp...

The first total synthesis of (±)-naupliolide has been achieved. The synthetic method includes a Simmons-Smith cyclopropanation of an allyl alcohol, diastereoselective cleavage of a benzylidene acetal group, radical cyclization of an aldehyde with a cyclopropane ring, and construction of an eight-membered ring by ring-closing metathesis.

An efficient one-pot procedure for the preparation of 3-substituted 3,4-dihydro-1,2,3-benzotriazines 2, 3, and 4 from o-bromobenzyl azides 1 is described. The reaction of these azides with BuLi in THF at −78° generates o-lithiobenzyl azides via the Br/Li exchange. These lithium compounds immediately undergo intramolecular cyclization to give the corresponding (dihydro-1,2,3-benzotriazinyl)lithium intermediates, which are trapped with a variety of acylating agents or BnBr at N(3) exclusively to provide the desired products in moderate to good yields.

NHC-rhodium complexes (NHC=N-heterocyclic carbenes) have been widely used as efficient catalysts for hydrosilylation reactions. However, the substrates were mostly limited to reactive carbonyl compounds (aldehydes and ketones) or carbon-carbon multiple bonds. Here, we describe the application of newly-developed chelating bis(tzNHC)-rhodium complexes (tz=1,2,3-triazol-5-ylidene) for several reductive transformations. With these catalysts, the formal reductive methylation of amines using carbon dioxide, the hydrosilylation of amides and carboxylic acids, and the reductive alkylation of amines using carboxylic acids have been achieved under mild reaction conditions.

Previously inaccessible N-Boc-protected propargylic and allylic amines were synthesized by the reaction between N-Boc-aminals and organomagnesium reagents through the in situ generated N-Boc-imine intermediates. The obtained N-Boc-propargylic amines could be readily converted into unprecedented N-Boc-ketimines by oxidation with manganese dioxide.

An In(O-Ac)3—Ph-SiHMe2 system simultaneously promotes the hydrosilylation of the ketone and carboxylic acid functionality in 3-benzoylpropionic acids as well as the subsequent intramolecular cyclization of the iodinated intermediate formed furnishing tetralin derivatives in good to excellent yields.

Acicular purplish crystals were obtained from Cu(acac)2 and a chiral bipyridine ligand. Although the crystals were not soluble, they nevertheless catalyzed asymmetric silyl conjugate addition of lipophilic substrates in water. Indeed, the reactions proceeded efficiently only in water; they did not proceed well either in organic solvents or in mixed water/organic solvents in which the catalyst/substrates were soluble. This is in pronounced contrast to conventional organic reactions wherein the catalyst/substrates tend to be in solution. Several advantages of the chiral Cu(II) catalysis in water over previously reported catalyst systems have been demonstrated. Water is expected to play a prominent role in constructing and stabilizing sterically confined transition states and accelerating subsequent protonation to achieve high yields and enantioselectivities.

The title reaction affords tertiary allenyl (III) and homopropargyl alcohols (IV) in high selectivities from the same starting materials (I), simply by changing the reaction conditions.

TPEN, N,N,N′,N′-tetrakis(2-pyridylmethyl)-1,2-ethylenediamine, recognized as a multidentate ligand with six nitrogen donors for coordination with various metal ions, is employed as an extracting ag...

The stereoselective synthesis of (E)-bromovinyloxazolidinones was developed by the three-component reaction of propargylic amines, carbon dioxide, and N-bromosuccinimide in the presence of a silver...

The concept of flow “fine” synthesis, that is, high yielding and selective organic synthesis by flow methods, is described. Some examples of flow “fine” synthesis of natural products and APIs are discussed. Flow methods have several advantages over batch methods in terms of environmental compatibility, efficiency, and safety. However, synthesis by flow methods is more difficult than synthesis by batch methods. Indeed, it has been considered that synthesis by flow methods can be applicable for the production of simple gasses but that it is difficult to apply to the synthesis of complex molecules such as natural products and APIs. Therefore, organic synthesis of such complex molecules has been conducted by batch methods. On the other hand, syntheses and reactions that attain high yields and high selectivities by flow methods are increasingly reported. Flow methods are leading candidates for the next generation of manufacturing methods that can mitigate environmental concerns toward sustainable society.

Review: [synthesis of heterasumanenes, and effects of the heteroatoms on the structures and optical properties; 40 refs.

The secondary metabolite, turkiyenine, is a probable bioactive component of the medicinal plant, Hypecoum procumbens L. Structurally, it is an isoquinoline-derived alkaloid composed of dihydrobenzofuran and 3-benzazepine-1-one moieties arranged in a unique spirocyclic structure. Yet despite the intriguing structure and medicinal relevance of benzofuran and benzazepine motifs, neither a synthetic study nor a biological evaluation of turkiyenine have been reported to date. Herein we communicate the first total synthesis of the proposed structure of turkiyenine, and on the basis of X-ray crystallography show that the proposed structure is incorrect. The key steps of our synthesis include an aza-spiro annulation onto a benzofuran using a rhodium–nitrenoid to construct a 3-alkyl-3-amino-2,3-dihydrobenzofuran, an acyl-alkylation of an aryne onto a β-ketolactam to form a 3-benzazepine-1-one, and chemoselective reduction of an amide in the presence of a ketone.

Catalytic asymmetric endo-selective [3+2] cycloaddition reactions of Schiff bases of α-aminophosphonates with olefins are described. While the efficient asymmetric synthesis of several phosphonate analogues of proline derivatives is important in bioorganic chemistry, a direct catalytic method to prepare optically active endo [3+2] cycloadducts of α-aminophosphonates with olefins has never been developed. We found for the first time that catalyst systems prepared from Group 11 metal amides with the (R)-FeSulphos ligand were effective for the asymmetric endo-selective [3+2] cycloaddition to afford the desired proline phosphonate analogues in high yields with high endo- and high enantioselectivities.

BaTiO2.5H0.5 (I) is used as a starting material in multistep low temperature topochemical routes to access mixed anion compounds.

Cellulose-supported chiral Rh nanoparticle (NP) catalysts have been developed. The Rh NPs, which were well dispersed on cellulose, catalyzed the asymmetric 1,4-addition of arylboronic acids to enones and enoates, one of the representative asymmetric carbon–carbon bond-forming reactions, in the presence of chiral diene ligands, providing the corresponding adducts in high yields with outstanding enantioselectivities without metal leaching. The solid-state NMR analysis of the chiral NP system directly suggested interactions between the Rh NPs and the chiral ligand on cellulose. This is the first example of using polysaccharide-supported chiral metal nanoparticles for asymmetric carbon–carbon bond-forming reactions.

Two new bromotyrosine alkaloids, tyrokeradines G (1) and H (2), have been isolated from an Okinawan marine sponge of the order Verongida. The structures of 1 and 2 were elucidated on the basis of spectroscopic data. Tyrokeradine G (1) is the first bromotyrosine alkaloid possessing a β-alanine unit, while tyrokeradine H (2) is a rare bromotyrosine alkaloid possessing a N-substituted pyridinium ring. Tyrokeradines G (1) and H (2) showed antifungal activity.

The key intermediate (I) for the synthesis of beraprost is obtained in 14 steps involving an enantioselective organocatalyzed asymmetric intramolecular oxo-Michael reaction of an unsaturated amide mediated by a newly developed benzothiadiazine catalyst.