西田 篤司

Substituted N and O heterocycles have been synthesized by the cycloisomerization of dienes using a ruthenium-carbene catalyst. The products obtained with and without trimethylsilyl vinyl ether differ (see scheme, Cy = cyclohexyl, Mes = 2,4,6-trimethylphenyl, Ts = p-toluenesulfonyl).

A simple and convenient method for the differentiation of alkoxy groups on aromatic rings is described. Niobium(V) is found to possess a strong Lewis acid property to transform alkyl arylethers smoothly to the corresponding phenols in high yields. The excellent regioselectivity was also observed in dialkoxy benzene derivatives under mild conditions.

A new palladium-catalyzed cyclization of N-alkenyl-o-haloanilines with selective isomerization of a double bond followed by 5-endo cyclization was developed and used to synthesize fused indoles.

Various (2S,3S)-23-bisarylmethoxy-1,4-butanediols 3a-h were synthesized from L-(+)-tartrate through bisallylether 12. Protection of the primary alcohol as an allyl ether was essential for selective deprotection in the presence of reactive arylmethyl ethers.

A key intermediate in the first asymmetric synthesis of the marine alkaloid (-)-nakadomarin A (1), isolated from the marine sponge Amphimedon sp., was the optically active hydroisoquinoline 2. Two separate ring-closing-metathesis reactions were crucial to the construction of the 15- and 8-membered rings.

A method for synthesizing substituted quinolines using ruthenium-catalyzed ring-closing metathesis as a key step has been developed. Substituted 1,2-dihydroquinolines, 4-silyloxy-1,2-dihydroquinoline and 4-methoxy-1,2- dihydroquinoline, were successfully synthesized in excellent yields via ene-ene metathesis and silyl or alkyl enol ether-ene metathesis, respectively. The synthetic intermediates of the antimalarial agents quinine, chloroquine, and PPMP-quinine hybrid were efficiently synthesized by this methodology. © 2004 Elsevier Ltd. All rights reserved.

A simple method for the diastereoselective synthesis of racemic 1,2-diol mediated by low-valence niobium generated in situ is described. A 1,4-dioxane-toluene solvent system was found to be essential to achieve higher selectivities and to prevent other reactions of pinacols, such as deoxygenation and acetal formation. Aromatic aldehydes and ketones were converted to the corresponding pinacols with up to 97 and 85% de, respectively. © 2004 Pharmaceutical Society of Japan.

The one-pot (three steps) synthesis of α-diazo-β-hydroxyesters from tosyl chloride under phase-transfer catalysis is described. The catalytic asymmetric aldol reaction between a diazoester and aldehydes was also investigated and gave moderate to good enantioselectivity. © 2003 Elsevier Ltd. All rights reserved.

Since manzamine B (1) have been isolated from Okinawan marine sponge Haliclona sp. By Higa and co-workers in 1987, its pentacyclic structure involving large membered rings have been attractive as a synthetic target. While its interesting biological activities, such as cytotoxicity against P388 mouse leukaemia cells (IC_<50> 6μg/mL) and antitumor activity, have been reported, complete survey and further investigation have been prevented due to its limited availability. Herein, we report our synthetic approach of 1. Initially, we set the compound 7 as a key intermediate. In order to obtain 7 as an optically active form, asymmetric Diels-Alder reaction between 8 and aminodiene (9) using chiral-Cr-Salen complex was studied. After screening to reaction conditions, we have realized that 7a was obtained in 30% yield with up to 88% ee using carbamate-type aminodiene (9a). Amide-type aminodiene (9d) gave 7d in 37% with up to 81% ee, respectively. Next, construction of C-ring was investigated. Alkylation of formyl group of 7d, readily available by deprotection of N-allyl group with Pd (0), proceeded by Peterson reaction in 80% yield. After conversion of silyl enol ether to the corresponding ketal (23d), removal of N-chloroacetyl group was accomplished in pyridine under reflux conditions. Further transformation is currently under investigation.

A manzamine alkaloid nakadomarin A (1) was isolated from Okinawan Marine sponge Amphimedon sp. by Kobayashi and co-workers in 1997. Although some interesting biological activities of 1 have been reported, its limited availability has prevented a complete survey of its biological activity. Recently, we accomplished the first total synthesis of rac- and ent-1. However, an optical resolution of the key carboxylic acid gave only undesired isomer efficiently. Therefore, we have developed a new synthetic route to natural form of 1. Since the stereocenters of nakadomarin A are as same as those of ircinal A, we planed a new synthetic route using the same intermediate 7 which was developed for our previous synthetic study of ircinal A. The key intermediate 7, which was obtained by Diels-Alder reaction of 8 and 9, gave the tricyclic intermediate 10 via allylic cation intermediate (S_N' reaction) under the acidic conditions. Ozonolysis of 11, followed by aldol condensation with TAMA gave ring contracted intermediate 12, ABD rings. The furan ring (C ring) was constructed from endoperoxide 20 which was prepared by oxidation of 1,3-diene 19 with singlet oxygen. A presence of alkynyl side chain is essential to prevent isomerization of a terminal unsaturated bond under strong acidic conditions. We have observed that a dicobalt hexacarbonyl complex was useful as the protection of alkyne under RCM conditions. E ring was constructed using second-generation Grubbs catalyst. F ring was constructed by reduction of a dicobalt hexacarbonyl complex into an olefin, followed by the second RCM. Finally reduction of bislactum has accomplished the first asymmetric total synthesis of natural (-)-1.

A novel series of acylides, 3-O-(aryl)acetylerythromycin A derivatives, were synthesized and evaluated. These compounds have significant potent antibacterial activity against not only Gram-positive pathogens, including inducibly macrolide-lincosamide-streptogramin B (MLSB)resistant and efflux-resistant strains, but also Gram-negative pathogens, such as H. influenzae. 6,9:11,12-Dicarbonate acylide 47 (FMA0122) was twice as active against H. influenzae than azithromycin, whereas it showed only moderate in vivo efficacy in mouse protection tests. However, the 11,12-carbamate acylide 19 (TEA0929), which showed potent antibacterial activity against almost all of the main causative pathogens of community-acquired pneumonia tested, exhibited excellent in vivo efficacy comparable to those of second-generation macrolides.

A novel combined system of Yb(OTf)3 with TMSCl or TMSOTf catalyzed an imino ene reaction. The reaction of N-tosylbenzaldimine (1) with α-methylstyrene (2) proceeded smoothly to give homoallylic amine 3 in the presence of a catalytic amount of Yb(OTf)3 and TMSCl. This catalytic system was successfully applied to the imino ene reactions of various aldimines with alkenes. This new imino ene reaction provides a unique method for the three-component coupling reaction of an aldehyde, tosylamide, and α-methylstyrene in the presence of Yb(OTf)3 and TMSOTf, to give the corresponding homoallylic amine.

A variety of (3-indolyl)heteroaromatic compounds were synthesized by Suzuki-Miyaura coupling of 3-indolylboronic acid and halogenated heteroaromatics. 2-(3-Indolyl)thiophene showed potent inhibitory activity against lipid peroxidation by rat liver microsome.

A highly diastereoselective Pictet-Spengler reaction using chiral tryptamine carbamates has been developed. The reaction proceeds using aromatic and aliphatic aldehydes in the presence of trimethylchlorosilane. © 2003 Elsevier Science Ltd. All rights reserved.

Aruthenium complex, generated from the Grubbs carbene catalyst with vinyloxytrimethylsilane, catalyzed the isomerization of terminal alkenes RCH2-CH=CH2 to internal alkenes RCH=CH-CH3. Application of this olefin isomerization to 2-(N-allylamino)styrene gave the corresponding enamines, which were converted into indoles by a standard ring-closing metathesis, see scheme (Ts = tosyl).

A new synthetic route of (-)-TAN1251A possessing an antimuscarinic activity was developed on the basis of alkylation of a trans-4-hydroxy-L-proline derivative and the subsequent construction of an azaspiro ring as key steps. (C) 2002 Published by Elsevier Science Ltd.

Sphingosine-1-phosphate (S1P) is an intracellular second messenger and an extracellular mediator through endothelial differentiation gene (EDG) receptors, which are a novel class of G-protein-coupled receptors. Although EDG has attracted much attention because of its various roles, no selective agonists or antagonists have yet been developed. This could account for the delay in clarifying the physiological roles of members of the EDG family. Because precise structural information on EDG receptors is not yet available, pharmacophore models were generated based on structural information for S1P using the rational drug design software Catalyst. Novel antagonists, 2-alkylthiazolidine-4-carboxylic acids, were retrieved from a three-dimensional database search using the pharmacophore models, and these showed activity for EDG3. On the basis of their nonphosphoric acid structure, more potent antagonists, 2-(m- or p-heptylphenyl)thiazolidine-4-carboxylic acid, were developed.

The Pictet-Spengler reaction of nitrones and imines prepared from N-hydroxytryptamine and tryptamine gave the corresponding tetrahydro-β-carbolines in excellent yields in the presence of Yb(OTf)3-TMSCl in a mixture of CH2Cl2 and THF.

A novel protocol to effect the efficient selective halogenation of 1,1-disubstituted alkenes with NXS catalyzed by Yb(OTf)3-TMSCl, which affords the corresponding allyl halides in high yield, including allyl bromide, chloride, iodide and fluoride, is described. A remarkable feature of Yb(OTf)3-TMSCl-catalyzed halogenation is that, unlike conventional radical halogenation with N-halosuccinimides, the reaction discriminates between the allylic and benzylic positions. The reaction occurs selectively at the allylic position to give allylic halides, but not at the benzylic position. © 2002 Elsevier Science Ltd. All rights reserved.

Ring-closing olefin metatheses (RCM) of various tethered dihexenoyl derivatives were examined under various conditions. The E: Z ratios of the resulting double bonds of the cyclic products were determined. The stereochemistry of the resulting olefins was influenced largely by the effects of the template used. © 2002 The Royal Society of Chemistry.

The asymmetric Diels-Alder reaction of dihydropyridin-2-one with 2triethylsilyloxy-1,3-pentadiene was studied in the presence of chiral aluminum reagents. Menthyloxyaluminum dichloride was the most effective catalyst and gave a hexahydroisoquinolin-2-one derivative in 44% ee as an endo-product after desilylation.

Introduction of an acyl group to the 3-O-position of erythromycin A derivatives instead of L-cladinose led to a novel class of macrolide antibiotics that we named "acylides". The 3-O-nitrophenylacetyl derivative TEA0777 showed significantly potent activity against not only erythromyc-insusceptible Gram-positive pathogens but also inducibly macrolides-lincosamides-streptogramin B (MLSB)-resistant Staphylococcus aureus and efflux-resistant Streptococcus pneumoniae. These results indicated that acylides have potential as next-generation macrolide antibiotics.

The alkaloid, nakadomarin A has been isolated from the okinawan marine sponge Amphimedon sp. by Kobayashi in 1997. Although nakadomarin A is a member of manzamine family, it has a unique structure consisting of unprecedented 8/5/5/5/15/6 ring system containing a furane ring. Because of our interest to its unique ring system and also a need for enough quantity for full biological test, we started the synthesis of nakadomarin A. Two our synthetic approaches to the central core ring system of nakadomarin A will be reported. Route A consists of Diels-Alder reaction of chiral dienophile 9 and siloxydiene 2 to give a 6/6 AB ring system (10), followed by conversion to 5/5/6 ABD ring system (17) by ozonolysis and intramolecular aldol reaction. Route B is an efficient route for the synthesis of racemic ABCD ring system (31 and 37). A key step was intramolecular cyclization of a furane ring to acyl iminium cation. Ring closing metathesis of diene 39 to construct ring F will also be discussed.

A new skeletal rearrangement of cyclopentanones with pentynyl side chains into hydroazulene compounds via a radical process was developed. The presence of a triethylsilyloxy group at the α-position of the cyclopentanone was found to increase the reactivity. Except for this, there was no limitation of the reaction: The reaction was also applied to synthetic studies of damsinic acid, which was isolated from Ambrosia ambrosioides (Cav.) Payne along with damsin. (C) 2000 Elsevier Science Ltd.

New chiral auxiliaries, trans-2-(N-arylsulfonyl-N-benzyl)cyclohexanols, were prepared and applied to an asymmetric radical cyclization. Copyright (C) 2000 Elsevier Science Ltd.

The skeletal rearrangement of five types of epoxydecalin thiocarbonylimidazolides was investigated. This reaction proceeded via a 10-membered cyclic carbon radical formed by β-cleavage of alkoxy radicals, and produced two types of skeletal rearranged products; i.e. bicyclo[6.3.0]undecanones and bicyclo[5.3.1]undecanones. The ratio of the products strongly depended on the character and stereochemistry of the substituents. (C) 2000 Elsevier Science Ltd.

A series of 5-(3-indolyl)oxazoles were prepared by solid-support synthesis. Oxidative cyclization of an immobilized dipeptide containing tryptophan gave these oxazoles efficiently. (C) 2000 Elsevier Science Ltd.

(Equation Presented) Physostigmine A new and efficient synthetic route to physostigmine is described. Corey-Kim reagent reacted with tryptamine or tryptophan carbamates to give 3a-(methylthiomethyl)hexahydropyrrolo[2,3-b]indole skeletons. Formal total synthesis of racemic and chiral physostigmine was accomplished in excellent overall yields, in short steps.

(equation presented) Ytterbium trifluoromethanesulfonate [Yb(OTf)3] catalyzed the imino ene reaction of N-tosyl aldimine with α-methylstyrene to give a homoallylamine in moderate yield. Furthermore, addition of a catalytic amount of chlorotrimethylsilane (TMSCI) dramatically enhanced the imino ene reaction.

An efficient synthetic method for the preparation of optically active pyrroloazocine, pyrroloazepine, quinolizidine, indolizidine using ring closing olefin metathesis (RCM) is described.

New axially chiral macrolactams are effectively synthesized by ring- closing metathesis (RCM).

The diastereoselective nucleophilic addition of alkyllithium to N- alkylidene-α-naphthylethylamine was carried out. In the presence of Lewis acids or Lewis bases, organolithiums reacted smoothly with imines to give the corresponding amines in high stereoselectivity (up to 100% de). Furthermore, the resulting optically active amines were found to be useful for asymmetric reactions as chiral ligands.

Manzamine alkaloids constitute a novel family of several marine sponge metabolites that exhibit significant cytotoxic activity against leukemia and antibiotic activity. The unprecedented structures of these highly functionalized heterocyclic ring system and remarkable biological properties have attracted much attention as a challenging synthetic targets. While the simplest congener manzamine C (3) and related compounds have been previously synthesized by us and Langlois' group, the more complex manzamine A (1) has been more challenging target. Quite recently, Winkler, Martin and their coworkers have succeeded in total synthesis of manzamine A and its related compounds. We have also been interested in developing efficient routes to tetraazacyclic intermediate 5 based on the initial construction of tricyclic intermediate 20 by an intermolecular Diels-Alder reaction of functionalized dihydropyridinone 10 as a dienophile with siloxydiene, leading to the construction of a cis relationship in the central AB ring system of this unique structure. Using this strategy, we could synthesize advanced key intermediates 30 and 36. Details of the synthsis and further conversion to ircinal A (4) and manzamine A will be discussed.

The alkylation of 4-hydroxyproline derivatives 7 and 12 with a range of alkylating reagents was examined. The stereoselectivity was found to be dependent on the reagent and the N-protecting group. This was explained by a concept based on the stereoelectronic effect and π-interaction.

A new axially chiral ligand, 1,1'-(2,2'-bisacylamino)binaphthalene, was found to be effective in the ytterbium-catalyzed asymmetric Diels-Alder reaction between cyclopentadiene and crotonyl-1,3-oxazolidin-2-one. The Diels-Alder reaction using 15 mol% of 1,1'-(2,2'- bisbenzoylamino)binaphthalene · Yb(OTf)3 · 2i-Pr2NEt afforded the adduct with high enantioselectivity (97% yield, endo/exo=9 1/9, >98% ee for the endo adduct).

The highly stereoselective synthesis of the optically active tetracyclic core 2 of Manzamine A 1 was achieved via the Diels-Alder reaction of dihydropyridinone 12b, derived from L-serine, with siloxydienes, followed by sequential new and conventional pathways.

The first example of a reagent-controlled enantioselective Pictet-Spengler reaction is demonstrated. Using diisopinocampheylchloroborane as a chiral Lewis acid catalyst, the Pictet-Spengler reaction of Nb-hydroxytryptamine with aldehydes gave the corresponding 2-hydroxytetrahydro-β-carbolines in up to 90% ee. The enantioselective Pictet-Spengler reaction catalyzed by chiral binaphthol-derived Brønsted acid-assisted Lewis acids, with up to 91% ee, is also demonstrated.

Ircinal A (1) was isolated from Okinawan marine sponges by Kobayashi. Ircinal A (1) and Manzamine A (2) have been the subject of recent synthetic investigations owing its unique molecular structure and remarkable biological properties including antitumor and antibacterial activities. We have already accomplished a synthesis of key tetracyclic intermediate (ABCD ring) for 1 and 2 in a racemic form. For the synthesis of optically active 1 and 2, several optically active dienophiles (11, 16, 17, 26) were prepared and subjected to Diels-Alder reaction with Danishefsky diene. The D-A adduct, obtained by the reaction of dienophile (16), was successfully converted to the tetracyclic intermediate (3), in an optically active form.

Novel-type alkaloids, TAN1251 A, B, C and D, were isolated from a culture of Penicillium thomii RA-89 by the research group of Takeda Chemical Industries Ltd. The structures involve a unique tricyclic skeleton which consists of a 1,4-diazabicyclo[3,2,1]octane ring and a cyclohexanone ring through a spiro bond. The skeleton is linked to a long side chain through a Z-double bond. The compounds have been found to show cholinergic activity on the basis of the radio ligand receptor binding assay by using 3H-quinuclidinyl benzilate (QNB) and microsomal fractions of rat cerebral cortex. Especially, the affinity of TAN1251B to a muscarinic acetylcholine receptor is stronger than that of atropine. TAN1251A was selective to the M1 subtype of muscarinic receptor. Such structural complexity and interesting biological activity provided us the stimulus for elaborating the synthetic study of TAN1251 derivatives. We wish to report here the first total synthesis of racemic TAN1251A and the formal asymmetric synthesis of the compound.

The first total synthesis of martefragin A, a potent inhibitor of lipid peroxidation isolated from sea alga, has been accomplished and the absolute configurations of two stereogenic centers were determined. Synthetic martefragin A, its stereo isomers, and some analogs showed strong inhibitory activity against lipid peroxidation rat liver microsome.

The first synthesis of novel type alkaloid (±)-TAN1251A possessing an antimuscarinic activity was achieved.

Both L-threo and D-erytho-1-phenyl-2-palmitoylamino-3-morpholino-1-propanol (PPMP) were synthesized stereoselectively from L-serine.

An efficient protocol was devised for the synthesis of the chiral dihydropyridinone derivative (19), which involves an aldol-type coupling reaction between N-alkylpiperidin-2-one and Garner aldehyde followed by a silane-Rh-mediated olefin isomerization.

The radical reaction of three epoxydecalin thiocarbonylimidazolides was investigated using nBu3SnH and AIBN. Two types of rearrangement from a ten-membered cyclic carbon radical, which was formed by β-cleavage of alkoxy radicals, were observed.

Martefragin A (1) is a new type of indole alkaloid of marine origin, which was isolated from the marine red alga Martensia fragilis collected at Toyama Bay, and exhibits potent antiperoxidation activity of lipid. We focused our interest on the asymmetric synthesis of four possible stereo isomers of 1 in order to determine the absolute configuration of 1 as well as to investigate the structure-activity relationship. Here we present the first efficient and highly enantioselective synthesis of 1. Starting from the chiral (S)-2-methylbutyl iodide, we developed a four step route to generate (S)-4-methylhexanoyl chloride, which was converted to 7a via 14 by use of Evans methodology. The oxidative cyclization of the dipeptide 16, obtained from 7c and L-tryptophan benzyl ester, was accomplished using DDQ to give 17 (63%). Further synthetic manipulations involve deprotection of the nitrogen, dimethylation of amino group and hydrogenolysis of the benzyl ester to afford the martefragin A, (1"S, 3"S)-1. The absolute configuration of 18 was established by X-ray structure analysis. The synthesis of other isomers of 1 and related compounds, and structure-activity relationship will be presented.