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Eudistomins L, K, C, E (30) and F (33) were synthesized from the corresponding N-hydroxytryptamine 21 and the D-cysteinal 23. A bromine of eudistomin L was biomimetically introduced onto the pyrroloindolic intermediate 8. Other eudistomins were prepared from substituted indoles 17. A modified Pummerer reaction was used to obtain the oxathiazepine ring.

Formation of the oxathiazepine ring in eudistomins 1 was investigated. Thiazolidinyl-β-carboline 5 was successfully transformed into thiaindoloquinolizidine 7, but attempted oxidative transformation of 7 to 1 was not successful. The oxidative cyclization of 1-substituted-2 hydroxy-β-carboline 24 with NCS or the acid-catalyzed cyclization of the corresponding S-oxide 26 with TsOH gave oxathiazepine 25, which was readily converted to (+)-debromoeudistomin L (+)-1f. (−)-Debromoeudistomin L (−)-1f was prepared from N-hydroxytryptamine 11 and the D-cysteinal 30.

A transient left ventricular apical ballooning (so-called "ampulla" or "Takotsubo-shaped" cardiomyopathy) with type I CD36 deficiency is described in a 71-year-old woman. The patient was referred because of chest pain and worsening of dyspnea. Electrocardiogram showed T-wave inversions on the precordal leads, and acute coronary syndrome was suspected. Left ventricular apical ballooning was observed by echocardiogram and left ventriculography, and coronary arteriography did not reveal any significant stenosis. Left ventricular motion normalized at the follow-up period and there were no increases in specific markers for myocardial damage, such as myocardial band fraction of creatine kinase and troponin T, through out the admission. 123I-metaiodobengylguanidine myocardial single photon emission computed tomography (SPECT) revealed decreased accumulation areas at the apex, while 201Tl SPECT showed normal accumulation. An abnormal metabolism of cardiac free fatty acid was suggested by lack of accumulation of 123I beta-methyliodophenyl pentadecanoic acid (BMIPP) SPECT. No CD36 expression in either platelets or monocytes/macrophages was shown using flow cytometer analysis and type I CD36 deficiency was diagnosed. DNA sequencing showed that the patient had compound heterozygosity of the CD36 gene (a nucleotide change in C478T and an adenine insertion at nucleotide 1159 in exon 10). Although CD36 deficiency is thought to be involved with many cardiovascular disease and metabolic abnormalities, Takotsubo-shaped cardiomyopathy with CD36 deficiency had not been reported. Further studies of Takotsubo-shaped cardiomyopathy and CD36 deficiency may reveal an association between this cardiomyopathy and specific genetic profiles.

Manzamine C congeners with modified azacyclic rings were synthesized using a DPPA-promoted conjunction of the β-carboline-1-acetate salt with various amines as a key reaction. A preliminaly biological evaluation revealed that these analogues retained similar activities as Manzamine C.

Synthesis of the tetracyclic core ( 19 ) of manzamine A ( 1 ) was achieved via Diels-Alder reaction of the dihydropyridinones ( 5 , 6 ). Conversion of the two D-A products ( 7 , 8 ) to the key tricyclic ketone ( 10 ) was conducted through a conventional pathway (Scheme III) as well as a new pathway developed (Scheme IV). For effective construction of the required azocine ring systems, model studies were carried out to find intramolecular amide formation by pentafluorophenyl ester and DPPA methods, which were successfully applied to the real substrate to furnish the titled core structure ( 19 ).

Recently many bioactive indole alkaloids have been isolated from marine organisms. Many of them have novel ring systems which are not found in the indole alkaloids isolated from higher plants and molds on the land. We have chosen β-carboline alkaloids, eudistomins and manzamines, as targets for total synthesis

A construction of the central tetracyclic core ( 19 ) of manzamine A ( 1 ) was successfully achieved by a highly efficient Diels-Alder reaction of the suitably protected dihydropyridinones ( 5 ) and Danishefsky's diene as a key strategy. Expedient conversion of the D-A product ( 7 ) to the precursor ( 15 ) was followed by the azocine lactam ring closure to furnish the titled core.

Asymmetric reduction of imines were studied using dialkoxyborane 1 . Dihydro-β-carboline 5a showed moderate (42%ee) and N -phenylketimine 10 higher enantioselectivity (73%ee). Asymmetric reduction of ketones with oxazaborolidine 33 showed high ennatioselectivities.

A new general procedure for the alkylation of the C=N double bond of 3, 4-dihydro-β-carboline has been developed with amphiphilic reaction systems such as BF3·OEt2/RLi, RMgX, R2CuLi or trimethylsilyl trifluoromethane-sulfonate/RLi, RMgX to give the corresponding 1-substituted-1, 2, 3, 4-tetrahydro-β-carbolines.

The 1H- and 13C-NMR spectra of harman (2) and N-methylharman (3) have been reinvestigated, and definitive assignments of all the protons and carbons of 2 in CDCl3, DMSO-d6, and CD3OD were obtained by the use of DEPT, HC-COSY (or HMQC), COLOC (or HMBC), and CNOEDIF techniques.

The cyclic tautomer (5) of N b -methyl-3-indoleacetamide (4) has been prepared by dissolving 4 in phosphoric acid. The bromination of 5 with 1 or 2 mol of N-bromosuccinimide (NBS) or 2,4,4,6-tetrabromo-2,5-cyclohexadienone (TABCO) gave the 5-bromo- (8) and the 5,7-dibromo (9) derivatives. On the other hand, the 5-bromo derivative (11) was the major product of the bromination of the N-acetyl cyclic tautomer (6) even with 2 mol of NBS. The 5-nitro derivative (17) was obtained in excellent yield by the nitration of 6 with ammonium nitrate in trifluoroacetic anhydride (TFAA). Reduction of 17 followed by bromination gave the 4,6-dibromo derivative (19), which gave the tribromide (20) in the Sandmeyer reaction. The 4,5,6-tribromo-3-indoleacetamide (7), which is the indole moiety of a marine indole alkaloid, chartelline A, was obtained by the ring opening of 20. Furthermore, the oxidation of 5 with lead tetraacetate followed by acetylation gave the 5-acetoxy derivative (22). The selective hydrolysis and bromination of 22 gave the 4,6-dibromo-5-hydroxy derivative (24)

Alkylation of 3,4-dihydro-β-carboline has been accomplished with organo-copper and -lithium reagents by activation of BF3·OEt2 or trimethylsilyl trifluoromethanesulphonate.

Manzamine C (1) has been synthesized from silyloxyscetylene (3) along the line: 4→5→8→18→1. The overall yields is 21%. Thr β-carboline segment (11) was obtained by the Bischler-Napieralski reaction of 14 followed by dehydregenation. By the similar procedure, the trans isomer 2 and dihydromanzamine C (21) have been synthesized.

The asymmetric reduction of imines with chiral dialkoxyboranes was investigated and gave an optically active amine up to 73%ee in the presence of MgBr2·OEt2.

Bicyclic 5-hydroxy-2-pyrrolidinones (2a - f) were synthesized with high enantioselectivity by the reduction of meso-cyclic-1,2-dicarboximides (1a - f) with lithium aluminum hydride (LiAlH 4 )-methanol (MeOH)-1,1'-bi-2-naphthol complex (BINAL-H). Treatment of 2a - f with triethylsilane (Et 3 SiH) and trifluoroacetic acid(CF 3 CO 2 H) gave optically active 2-pyrrolidinones (3a - f) in quantitative yields. For the absolute configuration correlation, 2a - d were converted into known lactones (4a - d)

Asymmetric reduction of imines were studied using dialkoxyborane 1 . Dihydro-β-carboline 5a showed moderate (42%ee) and N -phenylketimine 10 higher enantioselectivity (73%ee). Asymmetric reduction of ketones with oxazaborolidine 33 showed high ennatioselectivities.

For the construction of the tricyclic core of manzamine A (1), the Diels-Alder reactions of some dihydropyridinones were surveyed. The N-protecting group of the dihydropyridinone played an important role in achieving a successful Diels-Alder reaction. In view of its electron-withdrawing character as well as its thermal stability, the p-toluenesulfonyl protecting group was found to be best in our synthesis. An effective method for the preparation of 3-alkyldihydropyridinones via the Michael addition to dehydroalanine derivatives has also been devised

Efficient methods for the Michael addition reactions of N-arylsulfonyl-3-phenylthiopiperidones (1) with both the protected amidoacrylates (4, 9) and the simple acrylates (12) have been developed. These reactions offer an efficient route to the 3-alkyl-substituted dihydropyridinones (3, 11), the dienophiles employed in the natural product synthesis

Recently many bioactive indole alkaloids have been isolated from marine organisms. Many of them have novel ring systems which are not found in the indole alkaloids isolated from higher plants and molds on the land. We have chosen β-carboline alkaloids, eudistomins and manzamines, as targets for total synthesis

Convenient synthetic routes were devised for the preparation of the optically active azocine derivative from the protected serinal (1), which will be useful in manzamine synthetic study.

Preparation of the 1-methoxycarbonyl-3-phenylthio-2-quinolinone (10) from dihydro-2-quinolinone (5) and its Diels-Alder reaction with 2-trimethylsilyloxy-1, 3-butadiene under Lewis acid catalyst is described. Conversion of the D-A adduct (11) to 9-phenenthridinone ketal (16) will open a new synthetic route to a dynemicin A core structure.

Manzamine C congeners with modified azacyclic rings were synthesized using a DPPA-promoted conjunction of the β-carboline-1-acetate salt with various amines as a key reaction. A preliminaly biological evaluation revealed that these analogues retained similar activities as Manzamine C.

For the construction of the tricyclic core of manzamine A (1), the Diels-Alder reactions of some dihydropyridinones were surveyed. The N-protecting group of the dihydropyridinone played an important role in achieving a successful Diels-Alder reaction. In view of its electron-withdrawing character as well as its thermal stability, the p-toluenesulfonyl protecting group was found to be best in our synthesis. An effective method for the preparation of 3-alkyldihydropyridinones via the Michael addition to dehydroalanine derivatives has also been devised

The asymmetric reduction of imines with chiral dialkoxyboranes was investigated and gave an optically active amine up to 73%ee in the presence of MgBr2·OEt2.

Manzamine C (1) has been synthesized from silyloxyscetylene (3) along the line: 4→5→8→18→1. The overall yields is 21%. Thr β-carboline segment (11) was obtained by the Bischler-Napieralski reaction of 14 followed by dehydregenation. By the similar procedure, the trans isomer 2 and dihydromanzamine C (21) have been synthesized.

The effect of temperature on the Pictet-Spengler reaction of Nb-hydroxytryptamines (1) and cysteinals (2) has been examined. The optically active nitrones (3), obtained from 1 and 2, gave the corresponding Nb-hydroxy-β-carbolines (4α and 4β) exclusively at -78°C in the presence of an excess of trifluoroacetic acid. The mechanism is discussed in relation to the stereochemistry.

The first total synthesis of symbioramide (1) is described and simultaneously established the complete stereostructure of 1 to be (2S,3R,2′R,3′E)-N-(2′-hydroxy-3′-octadecenoyl)-dihydrosphingosine.

The cyclic tautomer (5) of N b -methyl-3-indoleacetamide (4) has been prepared by dissolving 4 in phosphoric acid. The bromination of 5 with 1 or 2 mol of N-bromosuccinimide (NBS) or 2,4,4,6-tetrabromo-2,5-cyclohexadienone (TABCO) gave the 5-bromo- (8) and the 5,7-dibromo (9) derivatives. On the other hand, the 5-bromo derivative (11) was the major product of the bromination of the N-acetyl cyclic tautomer (6) even with 2 mol of NBS. The 5-nitro derivative (17) was obtained in excellent yield by the nitration of 6 with ammonium nitrate in trifluoroacetic anhydride (TFAA). Reduction of 17 followed by bromination gave the 4,6-dibromo derivative (19), which gave the tribromide (20) in the Sandmeyer reaction. The 4,5,6-tribromo-3-indoleacetamide (7), which is the indole moiety of a marine indole alkaloid, chartelline A, was obtained by the ring opening of 20. Furthermore, the oxidation of 5 with lead tetraacetate followed by acetylation gave the 5-acetoxy derivative (22). The selective hydrolysis and bromination of 22 gave the 4,6-dibromo-5-hydroxy derivative (24)

An expeditious preparation of the central pyrroloisoquinoline skeleton of manzamine A ( I ) was achieved via the high-pressure Diels-Alder reaction of 3-alkyl-5,6-dihydro-2-pyridinone ( 1 0) with Danishefsky diene followed by deprotection and spontaneous pyrrolidine ring clousure.

The Pictet-Spengler reaction of N-hydroxytryptamine (6) with various aldehydes was examined. Reduction of 3-(2-nitroethyl) indole (5) with aluminum amalgam gave 6, which was not so stable and was readily oxidized to the azoxy compound (10) in solution under an oxygen atmosphere. Reaction of 6 with saturated aldehydes gave the corresponding nitrones (11b, c) without an acid catalyst at room temperature, while the reaction with α, β-unsaturated aldehydes provided nitrones (11d, e, f) in the presence of trifluoroacetic acid. Cyclization of the nitrones with trifluoroacetic acid in methylene chloride gave the 2-hydroxy-1, 2, 3, 4-tetrahydro-β-carbolines (2) in good yields. The cyclization of the saturated nitrones proceeded rapidly, whereas the similar reaction of the unsaturated nitrones was slow. Direct Pictet-Spengler reaction of 6 with aldehydes in methylene chloride in the presence of trifluoroacetic acid gave 2a, b, c in excellent yields. Dehydration of the 2-hydroxy-β-carboline (2b) with trifluoroacetic anhydride in benzene gave the 3, 4-dihydro-β-carboline (15). 6-Bromo-5-methoxy-N-hydroxytryptamine (25) was prepared from 3-bromo-4-methyoxyaniline (17) via the indole (22). The Pictet-Spengler reaction of 25 with isovaleraldehyde gave the 2-hydroxy-tetrahydro-β-carboline (26).

Preparation of the 1-methoxycarbonyl-3-phenylthio-2-quinolinone (10) from dihydro-2-quinolinone (5) and its Diels-Alder reaction with 2-trimethylsilyloxy-1, 3-butadiene under Lewis acid catalyst is described. Conversion of the D-A adduct (11) to 9-phenenthridinone ketal (16) will open a new synthetic route to a dynemicin A core structure.

5,6-Dihydro-2H-Pyran-2-one and 2H-Pyran-2-one product: 5,6-dihydro-2H-pyran-2-one reactant: 18.6 g. (0.105 mole) of N-bromosuccinimide product: 2H-pyran-2-one Keywords: annulation, heterocyclic-[6]; elimination, dehydrohalogenation; halogenation, bromination; N-bromosuccinimide; triethylamine

Formation of the oxathiazepine ring in eudistomins 1 was investigated. Thiazolidinyl-β-carboline 5 was successfully transformed into thiaindoloquinolizidine 7, but attempted oxidative transformation of 7 to 1 was not successful. The oxidative cyclization of 1-substituted-2 hydroxy-β-carboline 24 with NCS or the acid-catalyzed cyclization of the corresponding S-oxide 26 with TsOH gave oxathiazepine 25, which was readily converted to (+)-debromoeudistomin L (+)-1f. (−)-Debromoeudistomin L (−)-1f was prepared from N-hydroxytryptamine 11 and the D-cysteinal 30.

Eudistomins L, K, C, E (30) and F (33) were synthesized from the corresponding N-hydroxytryptamine 21 and the D-cysteinal 23. A bromine of eudistomin L was biomimetically introduced onto the pyrroloindolic intermediate 8. Other eudistomins were prepared from substituted indoles 17. A modified Pummerer reaction was used to obtain the oxathiazepine ring.

A historical development of the chemistry of cyclic tautomer of tryptophan is reviewed. The cyclic tautomer of tryptophan, pyrrolo [2,3-b]indole-2-carboxylic acid, was prepared by dissolving N-methoxycarbonyltryptophan ester derivatives in 85% phosphoric acid or trifluoroacetic acid. The cyclic tautomer can be reverted to the indolic form with a dilute acid. The cyclic tautomer is an aniline derivative and the enamine reactivity of the indole ring in tryptophan is protected. The electrophilic substitution and oxidation of these cyclic tautomers opened a new method to prepare 5-substituted and/or 6-substituted tryptophan derivatives such as 5-bromo-, 5-hydroxy, and 6-methoxy-tryptophans. The formation and reactions of cyclic tautomers of diketopiperazines containing tryptophan and 3-indoleacetamide are also discussed. Some indole alkaloids having substituents at the benzene ring such as fumitremorgins, flustramine B, and eudistomines were synthesized by the use of these reactions. Furthermore, enantioselective alkylations of the carbanion at the 2-position of the cyclic tautomer established a new route to optically pure alpha-substituted tryptophans. The 2,3-dehydro derivative of the cyclic tautomer is an alpha, beta-unsaturated ester and was found to be a good precursor of optically pure beta-substituted tryptophans. The 3a-position of the cyclic tautomer is a benzylic position and subjected to radical reactions to give 3a-substituted-pyrroloindoles.

Coupling reaction of the indoles (I) and (VII) with the alkynecobalt complexes (II) and (X) followed by demetalation yields the dimethylpropargylindoles (V) and (IX) or the dimethylpropargylhexahydropyrrolo-(2,3-b)indole (XII).