Reaction of sulphoximides with diazomalonate in the presence of Cu-salt : A new synthesis and stereochemistry of optically active oxosulphonium ylides

Sulphoximides (Ia–Ie) were found to react with dimethyl diazomalonate (DDM) in the presence of a catalytic amount of Cu-salts affording the corresponding oxosulphonium ylides in moderate yields. The reaction did not proceed at all under irradiation of UV light. (?)-Methylphenyloxosulphonium bis(methoxycarbonyl)-methylide ((?)-IIb) was obtained from (+)-(S)-methylphenylsulphoximide ((+)-(S)-Ib) together with (?)-(S)-methyl phenyl sulphoxide ((?)-(S)-IIIb) by this reaction. Hydrolysis of (?)-IIb gave (+)-methylphenyloxosulphonium methoxycarbonylmethylide ((+)-IIf) which was converted to (?)-(S)-IIIb upon treatment with dibenzoylethylene. Stereochemical cycle starting from (+)-(S)-Ib to (?)-(S)-IIIb was established and the absolute configurations of both ylides, (?)-IIb and (+)-IIf were assigned as (R)-configuration. The stereochemical courses, namely from (+)-(S)-Ib or (?)-(S)-IIIb to (?)-(R)-IIb or (+)-(R)-IIf to (?)-(S)-IIIb were determined as retention processes. The optical purities of the oxosulphonium ylides obtained from both reactions, (+)-(S)-Ib→(?)-(R)-IIb and (?)-(S)-IIIb→(?)-(R)-IIb, were almost equal. These results indicate that the mechanism of the reaction of sulphoximides with carbenes (or carbenoids) involves the initial formation of the sulphoxides which react subsequently with carbenes to afford the final products.     

Photochemische Umsetzung von optisch aktiven 2-(1′-Methylallyl)anilinen mit Methanol

Photochemical Reaction of Optically Active 2-(1′-Methylallyl)anilines with Methanol It is shown that (?)-(S)-2-(1′-methylallyl)aniline ((?)-(S)- 4 ) on irradiation in methanol yields (?)-(2S, 3R)-2, 3-dimethylindoline ((?)-trans- 8 ), (?)-(1′R, 2′R)-2-(2′-methoxy-1′-methylpropyl)aniline ((?)-erythro- 9 ) as well as racemic (1′RS, 2′SR)-2-(2′-methoxy-1′-methylpropyl) aniline ((±)-threo- 9 ) in 27.1, 36.4 and 15.7% yield, respectively (see Scheme 3). By deamination and chemical correlation with (+)-(2R, 3R)-3-phenyl-2-butanol ((+)-erythro- 13 ; see Scheme 4) it was found that (?)-erythro- 9 has the same absolute configuration and optical purity as the starting material (?)-(S)- 4 . Comparable results are obtained when (?)-(S)-N-methyl-2-(1′-methylallyl)aniline ((?)-(S)- 7 ) is irradiated in methanol, i.e. the optically active indoline (+)-trans- 10 and the methanol addition product (?)-erythro- 11 along with its racemic threo-isomer are formed (cf. Scheme 3). These findings demonstrate that the methanol addition products arise from stereospecific, methanol-induced ring opening of intermediate, chiral trans, -(→(?)-erythro-compounds) and achiral cis-spiro [2.5]octa-4,6-dien-8-imines (→(±)-threo-compounds; see Schemes 1 and 2).     

Asymmetric synthesis of optically pure (R)(−)-2-acetyl-5,8-dimethoxy-1,2,3,4-tetrahydro-2-naphthol,a key intermediate for optically active anthracyclinone synthesis

Asymmetric reduction of 2-acetyl-5,8-dimethoxy-3,4-dihydronaphthalene(3) with lithium aluminum hydride partially decomposed with (?)-N-methylephedrine and N-ethylaniline was found to give the optically active allylic alcohol((?)-4) in 92% optical yield. Optically pure (?)-4 obtained in 87% yield based on 3 by recrystallization, was elaborated to the title compound((R)(?)-1) according to the reaction scheme exploited in the preceding paper.     

Rogiolenyne D,the likely immediate precursor of rogiolenyne A and B,branched C15 acetogenins isolated from the red seaweed Laurencia microcladia of II Rogiolo. Conformation and absolute configuration in the whole series

It is shown that in the red seaweed Jaurencia microcladia, collected in the Mediterranean off the torrent Il Rogiolo, the new branched C₁₅ acetogenin rogiolenyne D ( = (+)-(2S,3S,7R))-3-(bromomethyl)-7-[(Z)-1-chlorohexen-3-en-5-nyyl)]-2-ethyl-2,3,6,7-tetrahydrooxepin; (+)- ?3 co-occurs with the already reported rogiolenyne A ((?)- 1 ) and B ((?)- 2a , suggesting the lineage (+)- 3 →(?)- 1 (?)- 2a ,Which is realized here chemically. The relative configurations are established via NMR analysis and chemical transformations as regards the seven-membered ring, while recourse is made to conformational analysis for the side chain. The absolute configuration is established via the Mosher's NMR method applied to the MPTA esters of (?)- 2a .     

Synthesis of Aristotelia-Type Alkaloids. Part XII. Total synthesis of (−)-tasmanine. Stereoelectronic factors that control the rearrangement of 3H-indol-3-ol derivatives to oxindoles ( = 1,3-dihydro-2H-indol-2-ones) or to pseudoindoxyls ( =1,2-dihydro-3H-indol-3-ones)

The oxidative transformation of (+)-aristoteline ((+)- 5 ) into its metabolites, the recently synthesized indole alkaloids (?)-serratoline ((?)- 6 ), (+)-aristotelone ((+)- 2 ), and (?)-alloaristoteline ((?)- 22 ), was investigated in more detail. It was demonstrated that the diastereoface selectivity of the reaction of (+)- 5 with 3-chloroperbenzoic acid can be altered by variation of the solvent as well as by addition of CF₃COOH. The chemoselectivity of the 1,2-rearrangement of the intermediate 3H-indol-3-ol derivatives could be controlled as follows: treatment of 3H-indol-3-ols with aqueous polyphosphoric acid led to the pseudoindoxyl ( = 1,2-dihydro-3H-indol-3-one) derivatives, whereas an analogous treatment of the corresponding O-benzoates furnished exclusively the corresponding, constitutionally isomeric 2-oxindole ( = 1,3-dihydro-2H-indol-2-one) products. Exploitation of these and related findings led to efficient total syntheses of the Aristotelia alkaloid (?)-tasmanine ((?)- 1 ) and of the corresponding unnatural epimer (+)- 12 , as well as of the two pseudoindoxyls (+)-aristotelone ((+)- 2 ) and (?)-2-epiaristotelone ((?)- 11 ). All these transformations were carried out with synthetic (+)-aristoteline ((+)- 5 ) as the single indole alkaloid precursor.     

Neue Synthese von (−)-(R)-Cembren A,Synthese von (+)-(R)-Cembrenen und (+)-(S)-Cembren

Novel Synthesis of (?)-(R)-Cembrene A, Synthesis of (+)-(R)-Cembrenene and (+)-(S)-Cembrene A novel synthesis of (?)-(R)-cembrene A ((?)- 3 ) was developed using the Sharpless epoxidation for the introduction of the chiral center. Furthermore, the synthesis of (+)-(R)-cembrenene ((+)- 4 ) showed that this cembranoid must have the (R)-configuration and not, as previously reported, the (S)-configuration. Selective hydrogenation of (+)- 4 afforded (+)-(S)-cenibrene ((+)- 5 ).     

Stereoselective Conversion of Campholene- to Necrodane-Type Monoterpenes. Novel Access to (−)-(R,R)- and (R,S)-α-Necrodol and the Enantiomeric γ-Necrodols

Naturally occurring (?)-(R,R)-α-necrodol ((?)- 1 ) and its C(4)-epimer (?)- 2 are obtained in 84 and 44% yields, respectively, by lithium ethylenediamide (LEDA) treatment of the corresponding β-necrodols (?)- 3 and (?)- 4 (Scheme 1, Table), both readily available from (?)-campholenyl acetate ((?)- i ) by an efficient stereoselective synthesis. The thermodynamically preferred (?)-(R)-γ-necrodol ((?)- 5 ) becomes the major product (≥ 80% yield) after either prolonged treatment with LEDA or exposure of α- and β-necrodols to BF₃·Et₂O. In an alternative route, (+)- 5 is prepared starting from (+)-campholenal ((+)- ii ) via Pd-catalysed decarbonylation to (?)-(S)-1,4,5,5-tetramethylcyclopent-l-ene ((?)- 6 ) and subsequent application of an acid-catalysed CH₂O-addition/rearrangement sequence (Scheme 2).     

(+)- and (-)-1-0, 4-0-bis(p-chlorobenzyl)threitol as novel resolving agents for optically active anthracyclinone synthesis: an efficient synthesis of optically pure 4-demethoxydaunomycinone

(±)-7-Deoxy-4-demethoxydaunomycinone(±)-$\text{3}$) was cleanly resolved by forming a mixture of the diastereomeric acetals ((?)-$\text{9}$ and (+)-$\text{10}$ or (+)-$\text{9}$ and (?)-$\text{10}$ with the title $\text{vicinal}$-diol((+)- or (?)-$\text{5}$) to give optically pure (R)(?)-$\text{3}$. The method for racemizing the undesired enantiomer((S)(+)-$\text{3}$) was also explored. Optically pure (+)-4-demethoxydauno-mycinone ((+)-$\text{2b}$) was elaborated from (R)(-)-$\text{3}$ according to the reported reaction scheme.     

Biosynthese der Verrucarine und Roridine. Teil 5. Synthese von zwei Diastereoisomerenpaaren des [1,8-14C]-α-Bisabolols und Versuche zu deren Einbau in Verrucarol Verrucarine und Roridine, 32. Mitteilung [1]

The diastereoisomeric (+)-[1,8-¹⁴C]-(1'R,6R, S)-α-bisabolol ( 2a ) and (?)-[1,8-¹⁴C]-(1′S, 6R, S)-α-bisabolol ( 2b ) were synthesized by reaction of the Grignard compound of [1,6-¹⁴C]-5-bromo-2-methyl-2-pentene ( 12 ) with (+)-(R)- and (?)-(S)-4-acetyl-1-methyl-1-cyclohexene, ( 6a ) and ( 6b ) respectively. For the preparation of compound 12, cyclopropyl methyl ketone was treated with [¹⁴C]-methyl magnesium iodide to form the carbinol 11, which was cleaved by HBr. Compounds 6a and 6b were synthesized from (+)-(R)- and (?)-(S)-limonene, ( 4a ) and ( 4b ), via the derivatives 5a , 6a and 5b , 6b respectively. - This synthesis established the absolute configuration at C(1′) of the natural α-bisabolols: (R) for (+)-α-bisabolol and (S) for (?)-α-bisabolol. - Feeding experiments with cultures of Myrothecium roridum and radioactive (+)-(1′R, 6R, S)- and (?)-(1′S, 6R, S)-α-bisabolol ( 2a ) and ( 2b ) gave negative results. These findings indicate that bisabolane derivatives are not intermediates in the biosynthesis of verrucarol (3).     

Absolute configuration and conformational stability of (+)-2,5-dimethylthiolane and (-)-2,5-dimethylsulfolane

Enantiopure (+)-2,5-dimethylthiolane and (-)-2,5-dimethylsulfolane were prepared using literature procedures and investigated using vibrational circular dichroism (VCD). Experimental absorption and VCD spectra of (+)-2,5-dimethylthiolane and (-)-2,5-dimethylsulfolane in CCl(4) solution in the 2000-900 cm(-)(1) region were compared with the ab initio predictions of absorption and VCD spectra obtained with density functional theory using the B3LYP/6-311G(2d, 2p) basis set for different conformers of (2R,5R)-2,5-dimethylthiolane and (2R,5R)-2,5-dimethylsulfolane. This comparison indicates that (+)-2,5-dimethylthiolane is of the (2R,5R)-configuration and has two predominant conformations in CCl(4) solution. In addition, (-)-2,5-dimethylsulfolane is of (2R,5R)-configuration and has only one predominant conformation. The stereochemical assignment is in agreement with literature.     

Synthesis of (−)-Conduritol C (1L-Cyclohex-5-ene-1,2,3/4-tetrol)

(1R, 2R, 4R)-2-endo-Cyano-7-oxabicyclo[2.2.1]hept-5-en-2-yl acetate ((?)-7) has been transformed into the all-cis-configurated 4L -4,5,6/0-trihydroxycyclohex-2-en-1-one derivatives (?)- 12 and (?)- 19 . (?)-Conduritol C ((?)- 3 ) was derived in a stereospecific manner from (?)- 12 .     

Synthesis of the Bretonins,Polyolefinic Esterified Glyceryl Ethers of an Unidentified Sponge from the North-Brittany Sea: Absolute Configuration and Novel Structure Assignment

The absolute configurations of acetylated bretonin A (= (+}-( R )-1-[(acetoxy)methyl]-2-{[(4E,6E,8E)-dodeca-4,6,8-trienyl]oxy}ethyl 4-acetoxybenzoate; (?)- 1b ) and isobretonin A (= (+)-(S)-3-{[(4E,6E,8E)-do-deca-4,6,8-trienyl]oxy}-2-hydroxypropyl 4-hydroxybenzoate; (+)-2), previously isolated from an undetermined sponge of the North Brittany sea, were established by comparison with synthetic (+)- lb and (+)- 2 , obtained from the condensation of commerical (?)-(R)-2,2-dimethyl-1,3-dioxolan-4-yl p-toluenesuifonate ((?)-(R)- 15 ) with a mixture of (4E,6E,8E)- ( 14e ) and (4E,6Z,8E)-dodeca-4,6,8-trien-1-ol ( 14z ). This also allowed confirming the structure and configuration of bretonin B (= (S)-2-{[(4E,6Z,8E)-dodeca-4,6,8-trienyl]oxy}-1-(hydroxy-methyl)ethyl 4-hydroxybenzoate; 3 ) which was also isolated from the same sponge, albeit in a too small amount for a complete study. As concerns the glyceryl ethers precursors of the bretonins, co-occurrence of the usual (S)-con-figuration (from 1a ) with the unusual (R)-configuration (from (+)- 2 )) poses intriguing biogenetic problems.     

Rogiolenyne A,B, and C: The First Branched Marine C15 Acetogenins. Isolation from the Red Seaweed Laurencia microcladia or the Sponge Spongia zimocca of II Rogiolo

It is shown here that the red seaweed Laurencia microcladia, collected off the torrent II Rogiolo, south of Livorno, contains rogiolenyne A (= (?)-(1R*,2S*,3R*,5S*,7S*)-2-(bromomethyl)-5-[(Z)-1-chlorohex-3-en-5-ynyl]-3-ethyl-4,8-dioxabicyclo[5.1.0]octane; (?)- 1 ) while the sponge Spongia zimocca, which grows in the same small area, contains rogiolenyne B (= (?)-(2R*3R*,4R*,5R*,7S*)-3-(bromomethyl)-5-chloro-7-[(Z)-1-chlorohex-3-en-5-ynyl]-2-ethyloxepan-4-ol; (?)- 4a ) and its acetate, rogiolenyne C((?)- 4b ). These structures, which are based on extensive NMR and MS data and on chemical transformation, are the first examples of branched marine C₁₅ acetogenins. Biogenesis of (?)- 1 in L. microcladia is thought to involve C(12) extrusion form a C₁₅ linear tetraen-1-yne precursor via H⁺-induced cyclopropane ring closure, followed by Br⁺-induced cyclopropane ring opening, aided by C–O^? attack (Scheme 2). It is also proposed that transfer of (?)- 1 to S. zimocca is followed by epoxide ring opening by Cl^? to give (?)- 4a and acetylation to give (?)- 4b .     

Conformationally tailored N-[(2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)carbonyl]proline templates as molecular tools for the design of peptidomimetics. Design and synthesis of fibrinogen receptor antagonists

The proline peptide bond was shown by 2D proton NMR studies to exist exclusively in the trans conformation in benzyl (2S)-1-[[(2S)-2-methyl-6-nitro-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl]carbonyl]-2-pyrrolidinecarboxylate [(S,S)-11], benzyl (2S)-1-[[(2S)-2-methyl-7-nitro-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl]carbonyl]-2-pyrrolidinecarboxylate [(S,S)-9], and in the corresponding 6-amino and 7-amino carboxylic acids (S,S)-3 and (S,S)-4. On the other hand, the diastereomers (R,S)-11 and (R,S)-9 containing an (R)[2-methyl-6/7-nitro-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl]carbonyl moiety, and the diastereoisomers (R,S)-3 and (R,S)-4 incorporating an (R)[6/7-amino-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl]carbonyl moiety were found to exist as equilibria of trans(63-83%) and cis(17-37%) isomers. These conformationally defined templates were applied in the construction of RGD mimetics possessing antagonistic activity at the platelet fibrinogen receptor.     

Highly stereocontrolled substitution of phenols with pyruvic esters. A viable route to ortho-hydroxyatrolactic esters of (2R)- and (2S)-configuration

Treatment of phenols with optically active (+)- and (?)-menthyl pyruvate assisted by Al(III)- or Ti(IV)-based promoters leads to the formation of $\text{ortho}$-hydroxyatrolactic esters of (2R)- and (2S)-configuration. The use of suitable menthol-based promoters augments markedly (up to 96% d.e.) the intrinsic stereochemical bias of the chiral pyruvate.     

A new approach for asymmetric synthesis of (R)-3-methylpyrrolidine alkaloids from (S)-malic acid

Diastereoselective methylation of dimethyl (S)-malate 7, followed by two, three-step reductive de-hydroxylation procedures afforded dimethyl (R)-2-methylsuccinate 11 in 80.2% e.e. and 84.7% e.e., respectively. The latter compound was further transformed into the natural enantiomers of the ant venom alkaloids (R)-leptothoracine 1 and (R)-3-methyl-N-(2-phenylethyl)-pyrrolidine 2.     

Synthese von (−)-(R)-Nephthenol und (−)-(R)-Cembren A

Synthesis of (?)-(R)-Nephthenol and (?)-(R)-Cembren A Starting for L -serine,(?)-(R)-nephthenol((?)- 2 ) and (?)-(R)-cembren A((?)- 3 ) were synthesized.     

Isolation from the Mediterranean Stolonifern Coral Sarcodictyon roseum of Sarcodictyin C,D, E,and F,novel diterpenodic alcohols esterified by (E)- or (Z)-N(1)-methylurocanic acid. Failure of the carbon-skeleton type as a classification criterion

It is shown here that the stoloniferan coral Sarcodictyon roseum of east Pyrenean waters contains four novel diterpenoids, sarcodictyin C ((?) -3 ), D ((?) -4 ), E ((+)- 5 ), F ((+)- 6 ), which are related to sarcodictyin A ( = (?)-(4R,4aR,7R,10S,11S,12aR,1Z,5E,8Z-7,10-epoxy-3,4,4a,7,10,11,12,12a-octahydro-7-hydroxy-6-(methyoxycarbonyl)-1,10-dimethyl-4-(1-methylethyl)-benzocyclodecen-11-yl (E)-N¹-methylyrocanate; ((?)? 1 ), previously isolated from the same coral. Sarcodictyin C ((?) -3 ) and D ((?) -4 ) and the 3α-hydroxy and 3α-acetoxy derivatives of (?) -1 ), sarcodictyin E ((+) -5 ) is the (Z)-urocanate isomer of (?) -3 ), and sarcodictyin F ((+) -6 ) is the 1α-hydroxy-2-ene isomer of (?) -3 . In all cases, the nine-membered ring is locked, and the molecule stabilized, by the urocanic appendage; when this is removed in MeOH/KOH, the C(11)–O^? function is free to attack at C(5), and retro-condensations then lead to the ring-contracted butenolides 11 (from (?) -3 ) or 10 (from(?) -1 ) with extrusion of the hydroxyfuran nucleus (Scheme 3). Under the same conditions, with (?) -3 , the C(3)-O^? group competitively attacks at C(5), the hydroxyfuran nucleus is expelled, and aldehyde 14 is formed. Peculiarly, in the reaction of (?) -3 with MeOD/KOD, the ring-contracted butenolide 17 contains D at the 4′-ax position. The sarcodictyins are unique in these chemical properties, not shared by the cladiellanes which have the same C-skeleton.     

Enantioselective Synthesis of 3- Azabicyclo[4.3.0]nonane Alkaloids

The stereospecific synthesis of the monoterpene alkaloids (?)-α-skytanthine ((?)- 2 ), (?)-N -demethyle-δ-sky-tanthine((?)- 7 ), and (+)-epidihydrotecomanine (+)- 4 was achieved from a common intermediate 22 , which in turn was obtained from (1R,4S,1′S)-2-(1′-phenylethyl)-2-azabicyclo[2.2.1]hept-5-ene (10) ,via a ketene aza-Claisen rearrangement. The piperidine derivative (+)- 31 , formally the aza-analogue of (+)-isoiridomyrmecin, was also obtained from the same intermediate 22 .     

Stereospezifität der neuroleptischen Wirkung und Chiralität von (+)-3-{2-[4-(8-Fluor-2-methyl-10,11-dihydrodibenzo[b,f]thiepin-10-yl)-1-piperazinyl]-äthyl}-2-oxazolidinon (16). 4. Mitteilung über tricyclische Antidepressiva und Neuroleptica

Stereospecifity of the neuroleptic activity and chirality of (+)-3-{2-[4-(8-fluoro-2-methyl-10, 11-dihydrodibenzo[b,f]thiepin-10-yl)-1-piperazinyl]ethyl}-2-oxazolidinone (16). The synthesis and stereospecific neuroleptic action in animals of the (+)-enantiomer of 3-{2-[4-(8-fluoro-2-methyl-10,11-dihydrodibenzo [b,f]thiepin-10-yl)-1-piperazinyl]ethyl}-2-oxazolidinone ( 16 ) are briefly described. The (10S)-configuration of this compound was determined by X-ray diffraction.