西田 篤司

© 2019 Society of Synthetic Organic Chemistry. All rights reserved. Since a cyano group can be transformed to carboxylic acids, amino- and hydroxymethyl groups as well as aldehydes, its installation, particularly catalytic protocol, has been one of the challenging issues in synthetic chemistry. Hydrocyanation of non-activated C-C multiple bonds has been one of the most powerful methods to install a CN group although selectivity control in products has been major challenge because simple olefin such as styrene derivatives is the only substrate to give higher regioselectivity in HCN addition process. In this review, the authors summarize.

© 2018 Society of Synthetic Organic Chemistry. Lundurines A-D were isolated in 1995 from the Malayan plant Kopsia tenuis, which has been used in folk medicine and is a rich source of biologically active alkaloids. Their intriguing hexacyclic framework includes an unprecedented cyclopropa [b] indole that has only ever been identified in lundurines. While these structural features have been attractive as synthetic targets, the first total synthesis was not reported until 2014. While lundurine B and D exhibit appreciable toxicity toward B16 melanoma cells and also reverse multidrug resistance in vincristine-resistant KB cells, their limited availability has prevented further studies for drug development. Therefore, the synthetic studies for these alkaloids and clarify the mechanism of their biological activity should contribute to medicinal chemistry. This review summarizes recent synthetic efforts in the total synthesis of lundurines and related alkaloids.

© 2017 Elsevier Inc. This review focuses on the total synthesis of lundurines A–C. Their main structural feature is a unique cyclopropa[b]indole core that has been found only in these alkaloids. In addition to this characteristic structure, the biological activity makes them as attractive synthetic targets. However, almost two decades passed from their isolation and structural determination in 1995 to their first total synthesis. The first part of this review summarizes the synthetic approaches to the tri- and tetracyclic ring systems of lundurine as well as an inter- and intramolecular cyclopropanation strategy that gives the cyclopropa[b]indole core. The second part presents a detailed description of four total syntheses that were reported from 2014 to 2016. In addition, the asymmetric total synthesis of the related alkaloids grandilodine C and lapidilectine B is described.

We have established aromatic enamide-ene metathesis to give highly substituted indole derivatives. This is a new method for the preparation of chiral 2-trans-cyclopropyl indoles, which successfully led to our H 4 antagonist candidates. Based on this findings, we also designed and synthesized conformationally restricted analogues and regioisomers of the nonsteroidal anti-inflammatory drug indomethacin. Evaluation of the inhibitory effects of these compounds on COX, P-glycoprotein, and multidrug-resistance indicated that NSAIDS modulation of multidrug resistant P-glycoprotein and multidrug-resistant protein-1 is not associated with COX-1 and COX-2 inhibitory activities.

Danishefsky diene (1-methoxy-3-trialkylsiloxy-1,3-butadiene) is known as a reactive and useful substrate for Diels-Alder reaction to give highly functionalized cyclohexenes. However, the diene is so unstable under acidic conditions that applicable Lewis acid to activate dienophile is quite limited. We developed Yb(OTf)₃/BINAMIDE or BINUREA/DBU catalyst, which realized the first example of catalytic asymmetric Diels-Alder reaction of Danishefsky diene and electron-deficient olefins. The Diels-Alder reaction of several types of dienophiles with Danishefsky diene was efficiently facilitated by the catalyst to give exclusively exo adducts. The Diels-Alder adduct can be transferred to various synthetic intermediates. Apparent (+)-non-linear effects between asymmetric induction and the enantiomeric composition of BINAMIDE may suggest the possible formation of a reservoir of non-reactive aggregates. A structure of ytterbium salt was discussed.

JSPS Asian Core Program: Cutting-Edge Organic Chemistry in Asia and IUPAC Strategic Planning for a New East and Southeast Asian Network for Organic Chemistry. Copyright © 2011 WILEY-VCH Verlag GmbH &amp Co. KGaA, Weinheim.

Asymmetric total synthesis of marine natural product, nakadomarin A, is described and as further extension, a novel synthesis of quinoline and indole ring system by ring closing metathesis is also described.

We have already successeded the formal total synthesis of (±)-manzamine A (1) via key intermediate (3). For asymmetric total synthesis of (+)-manzamine A, we established effective asymmetric synthesis to key intermediate (+)-3 (Scheme 6). Catalytic allylation of 20 using only 0.15mol% [PdCl(allyl)]_2 and 0.36mol% ligand 23 gave 21 in 83% yield with 81% ee. Intramolecular Michael reaction of 28 which has β-TIPS ether proceeded with high diastereoselectivity. Therefore, optically pure (+)-3 was synthesized from ethyl 4-oxopiperidine-3-carboxylate in 12 steps and in 38% over all yield. Further investigation toward the asymmetric total synthesis of (+) manzamine A (1) from (+)-3 will be discussed.

Manzamine alkaloid, (-) -nakadomarin A (1) was first isolated from the Okinawan marine sponge in 1997. Its structure consists of an unprecedented hexacyclic ring system (8/5/5/5/15/6) that includes a furan ring. We report here the first total synthesis of both enantiomers of nakadomarin A.<BR>The spiro-lactam 29, obtained from methyl 4-oxopiperidine carboxylate, was coupled with a furan ring by Suzuki-Miyaura reaction to give intermediate 30. Intramolecular cyclization of the furan ring to acyliminium cation afforded the central core of nakadomarin A, 32. Both 8- and 15-membered rings were constructed by ring closing metathesis (RCM) to give dioxonakadomarin A, 14 which was reduced to (&plusmn;) -1. Using chiral 23, obtained by optical resolution, the asymmetric synthesis of unnatural enantiomer, (+) -1 has been accomplished and the synthesis confirmed the absolute stereochemistry of (-) -1.<BR>A central ABD ring system 52, which has all stereocenters of (-) -1, was synthesized from chiral hydroisoquinolinone 49, derived from Diels-Alder reaction of chiral piperidinone 47 and siloxydiene 48. The intermediate 52 was converted to natural (-) -nakadomarin A by furan formation via endoperoxides followed by RCM.

The manzamine alkaloids such as manzamine A, B, and C belongs to a unique family of cyctotoxic β-carbline linked azacycles, which have been isolated from several marine sponges. Manzamine A has recently been shown to exhibit in vivo antimalarial activity against parasite Plasmodium berghei. Further progress was added recently by the isolation of the new and closely related members such as nakadomarin A, as well as an ingenious proposal for their biosynthetic pathway. Martefragin A, isolated from the Japan sea alga Martensia fragilis Harvey, has been shown to have a potent inhibitory activity against lipid peroxidation. Our recen. efforts to develop total synthesis entries to manzamine A, manzamine B, manzamine C, nakadomarin A, and martefragin A are presented.

By merging the disciplines of organometallic chemistry and surface nanotechnology, we have studied a novel material that combines tetrakistriphenylphosphine palladium (Pd(PPh3)4), a useful organometallic catalyst for producing pharmaceutical substances, with a sulfur-terminated GaAs(001) substrate grown by molecular beam epitaxy. This organopalladium catalyst is reusable in the Heck reaction and Suzuki coupling.

The total synthesis of (±)-TAN1251A possessing an antimuscarinic activity was achieved. Carboxylic acid (1) was converted into carbamate (3) through a sequence of alkylation and Curtius rearrangement. After a few functional group interconversions of 3, the corresponding amine (9) was converted into an azaspiro molecule (18) through cyclization and installation of a C2 unit. Hydrolysis of 18 followed by lactam formation afforded tricyclic compound (20). Coupling of 20 with aldehyde (22) gave two epimeric adducts, (23A) and (23B), which were converted into TAN1251A by four steps. © 2002 Elsevier Science Ltd. All rights reserved.

A novel construction of hydroazulenones using skeletal rearrangement of epoxy-hydroindan derivatives via alkoxy radical was developed. The reaction was also found to proceed without damage of acetal or olefin group. © 2002 Elsevier Science Ltd. All rights reserved.

We describe a novel, practical method for synthesis of 2,3-dihydro-3-haloindole from an o-aminostyrene derivative via haloamination, in which the protective group on the nitrogen and α-alkyl substituents on styrene are critical.

An efficient synthesis of the tetracyclic core of nakadomarin A was accomplished starting from methyl 4-oxo-3-piperidinecarboxylate. The key steps were intramolecular cyclization of furan to N-acyliminium ions to construct the strained central cyclopentene ring. © 2001 Elsevier Science Ltd. All rights reserved.

We describe a novel and convenient method for quinoline synthesis using ring-closing olefin metathesis (RCM), ene-ene metathesis, and ene-enol ether metathesis. We also report the first example of enol silyl ether-ene metathesis to produce cyclic enol silyl ether. Using this method, versatile substituted quinoline derivatives were readily prepared in excellent yield from anthranilic acid derivatives. © 2001 Elsevier Science Ltd. All rights reserved.

An efficient synthesis of the tetracyclic core of nakadomarin A was accomplished starting from methyl 4-oxo-3-piperidinecarboxylate. The key steps were intramolecular cyclization of furan to N-acyliminium ions to construct the strained central cyclopentene ring. (C) 2001 Elsevier Science Ltd. All rights reserved.

Using 28 chemically well-defined compounds containing D-erythro-sphingosine and its analogues, we analyzed structure-activity relationships for DNA primase inhibition. Biochemical studies demonstrated a positively charged amino group at C2 and a long aliphatic chain to be absolutely required for inhibition. Whereas C2-amino group is intact, sphingosine 1-phosphate was totally inactive. This result could be due to cancellation of positive charge of the amino group by the interaction with negatively charged C1-phosphate, since simulations with the software INSIGHT II showed these two groups to be close enough to interact. The hydroxyl group at C3 and trans-double bond at C4-C5 were also found to be important for the inhibition. Dehydroxylation of C3, as well as saturation or cis-conversion of the trans-double bond led to decrease of inhibitory activity. Despite saturation of the double bond, introduction of a hydroxyl group into C4 of dihydrosphingosine resulted in restoration of inhibition. Conversion of the double bond into a triple bond did not abolish but rather enhanced the inhibitory activity. Among sphingosine stereoisomers, the naturally occurring D-erythro-sphingosine proved to be the strongest inhibitor. To ascertain the contribution of the total conformation to the inhibition, especially of the long aliphatic chain, we constructed a 3D-quantitative structure-activity relationship model using the computer program Catalyst/HipHop on the basis of information described above. Analysis of the hypothesis model for active compounds revealed that the orientation of aliphatic chain, represented by the dihedral angle of C2-3-4-5, correlated well with the inhibition. Modifications such as deletion of the hydroxyl group at C3 or saturation of the C4-C5 double bond caused shifts in the dihedral angle of C2-3-4-5, with concomitant decrease in inhibitory activity.

New approaches to total asymmetric synthesis of ircinal A and manzamine A are described. The synthesis utilizes a highly efficient Diels-Alder reaction of the suitably functionalized dihydropyridinones and siloxydienes as a key step, followed by expedient conversion to manzamine A.

The generation and reaction of alkoxy radicals are discussed. The alkoxy radicals were useful for the radical transposition via skeletal rearrangement. Inter-and intramolecular β-Diastereoselective radical additions to chiral α,β-unsaturated esters were developed. The presence of a Lewis acid was necessary for high selectivity.

Two new radical reactions are reviewed.<BR>1) Skeletal rearrangement via alkoxy radical; a new radical rearrangement, initiated by radical cyclization between ketones and acetylenes followed by &beta;-cleavage of the alkoxy radical and subsequent radical-olefin cyclization was developed. This reaction realized a single-step conversion from cyclohexanone derivatives to bicyclic cyclooctenones and from cyclopentane derivatives to bicyclic cycloheptenenones. The efficiency of the conversion was greatly influenced by the substituents on the ring and on the side chain. Same type of rearrangement was also observed in the radical reaction of epoxydecalin thiocarbonylimidazolides prepared from 1-hydroxymethyl-1, 2, 3, 4, 4a, 5, 6, 7, 8-octahydronaphthalene derivatives.<BR>2) Asymmetric radical cyclization in the presence of Lewis acid : &beta;-diastereoselective radical cyclizations using &alpha;, &beta;-unsaturated 8-phenylmenthyl ester as a chiral radical acceptor was developed. Generally, higher diastereoselectivity was observed when bulky Lewis acid was used at low temperature. Co-ordination of the Lewis acid to the carbonyl oxygen fixed the conformation of &alpha;, &beta;-unsaturated ester as s-trans and activated the unsaturated ester as a radical acceptor, chiral (2-methylenecyclopentyl) acetate, (2-methylenecyclohexyl) acetate, (2-cyclopentnly) acetate, and (2-cyclohexenyl) acetate were prepared.

Two new radical reactions are reviewed. 1) Skeletal rearrangement via alkoxy radical ; a new radical rearrangement, initiated by radical cyclization between ketones and acetylenes followed by β-cleavage of the alkoxy radical and subsequent radical-olefin cyclization was developed. This reaction realized a single-step conversion from cyclohexanone derivatives to bicyclic cyclooctenones and from cyclopentane derivatives to bicyclic cycloheptenenones. The efficiency of the conversion was greatly influenced by the substituents on the ring and on the side chain. Same type of rearrange ment was also observed in the radical reaction of epoxydecalin thiocarbonylimidazolides prepared from 1-hydroxymethyl-1, 2, 3, 4, 4a, 5, 6, 7, 8-octahydronaphthalene derivatives. 2) Asymmetric radical cyclization in the presence of Lewis acid ; β- diastereoselective radical cyclizations using α,β-unsaturated 8-phenylmenthyl ester as a chiral radical acceptor was developed. Generally, higher diastereoselectivity was observed when bulky Lewis acid was used at low temperature. Co-ordination of the Lewis acid to the carbonyl oxygen fixed the conformation of α,β-unsaturated ester as s-trans and activated the unsaturated ester as a radical acceptor, chiral (2- methylenecyclopentyl) acetate, (2-methylenecyclohexyl) acetate, (2-cyclopentnly) acetate, and (2-cyclohexenyl) acetate were prepared.

The C1-C9 fragment of erythromycin A, which contains two sugar moieties, was prepared by the chemical degradation of erythromycin A. This fragment was a useful intermediate for the synthesis of erythromycin analogs, and two new macrolides were prepared. © 1995.