On the Scope of a Prins‐Type Cyclization of Oxonium Ions

The Prins cyclization of an aldehyde 1 with a homoallylic alcohol 2 , affording tetrahydro‐2H‐pyrans 4 via the oxonium ion 3 as central intermediate, was conceptually transferred to (alk‐3‐enyloxy)acrylates 6 , which form a related oxonium ion 7 upon treatment with acids (Scheme 1). The scope and utility of this modification of the Prins‐type cyclization of oxonium ions is discussed exemplarily by means of the syntheses of ten tetrahydro‐2H‐pyran and tetrahydrofuran derivatives, featuring diverse substitution patterns as well as different degrees of molecular complexity. These target structures include (±)‐ethyl (2RS)‐2‐[(2RS,4SR,6RS)‐ and (2SR,4RS,6SR)‐2‐tetahydro‐4‐hydroxy‐6‐methylpyran‐2‐yl]propanoate ( 23 ), (±)‐ethyl [(2RS, 3RS)‐tetrahydro‐3‐isopropenylfuran‐2‐yl]acetate ( 32 ), (±)‐ethyl (2Z)‐3‐(tetrahydro‐2,2‐dimethylfuran‐3‐yl)acrylate ( 37 ), (±)‐(3aRS,6RS, 7aRS)‐octahydro‐7a‐methylbenzofuran‐6‐yl formate ( 42 ), (±)‐ethyl (2RS,3RS,4aRS,8SR,8aRS)‐hexahydro‐2,5,5,8‐tetramethyl‐7‐oxo‐2H,5H‐pyrano[4,3‐b]pyran‐3‐carboxylate ( 48 ), and (±)‐ethyl (2RS,3RS,6SR)‐tetrahydro‐6‐(2‐methoxy‐2‐oxoethyl)‐3‐methyl‐2H‐pyran‐2‐carboxylate ( 53 ) (see Schemes 3 and 5–8). Besides the stereochemistry and mechanistic details of this versatile oxonium‐ion cyclization, the synthesis of suitable starting materials is also described.     

Total Synthesis of Racemic and Optically Active Compounds Related to Physostigmine and Ring-C Heteroanalogues from 3-[2′-(dimethylamino)ethyl]2,3-dihydro-5-methoxy-1,3-dimethyl-1H-indo l-2-ol

Oxindole 11 , obtained on 3-[2′-(dimethylamino)ethyl]alkylation of oxindole 12 , yielded, on stereoselective reduction with sodium dihydridobis(2-methoxyethoxy)aluminate, aminoalcohol 8 (Scheme 2). The quaternary methiodide 10 , obtained from 8 with MeI, gave, in nucleophilic displacements concurring with a Hofmann elimination, (±)-esermethole 6 , (±)-5-O-methylphysovenol ( 14 ), (±)-5-O-methyl-1-thiaphysovenol ( 15 ), and (±)-1-benzyl-1-demethylesermethole ( 16 ). Syntheses of (±)-1-benzyl-1-demethylphenserine ( 18 ), (±)-1-demethylphenserine ( 19 ), and (±)-phenserine ( 4 ) from 6 and 16 are described. Optically active 8a and 8b , obtained by chemical resolution, similarly gave the enantiomers 6a and 14a–16a of the (3aS)-series (prepared earlier from physostigmine ( 1a )) and their (3R)-enantiomers. The anticholinesterase activity of (±)- 4 , (±)- 18 , and (±)- 19 was compared with that of their optically active enantiomers.     

1,6-Dihydro-3 (2H)-pyridinones as synthetic intermediates. Formal synthesis of (±)-tabersonine and (±)-catharanthine

Formal synthesis of (±)-tabersonine (3) and (±)-catharanthine (4) has been achieved starting from ethyl 1,6-dihydro-3 (2H)-pyridinone-1-carboxylate (1a) as a common synthon.     

Late stages in the biosynthesis of abnormal erythrina alkaloids

The incorporation of (±)-, N-norprotosinomenine, N-nor-orientaline, N-nor-reticuline, norlaudanosoline, protosinomenine, and N-[2-(3-hydroxy-4-methoxyphenyl)ethyl]-2-(4-hydroxyphenyl) ethylamine into coccuvine has been studied, and the specific utilisation of the (±)-norprotosinomenine demonstrated. A double labelling experiment with (±)-[1-³H,4'-methoxy-¹⁴C]-N-norprotosinomenine showed that the 4'-O-Me group of the precursor is retained in the bioconversion and the erythrinan ring system is not formed by addition of secondary amino function onto an ortho-quinone system. Feeding of (±)-[1-³H, 7-methoxy-¹⁴C]norprotosinomenine established that O-demethylation is the terminal step in the biosynthesis of coccuvine. Feeding of labelled abnormal Erythrina alkaloids revealed that isococculidine is converted into coccoline via coccuvinine and isococculine into coccolinine via coccuvine.     

Novel,racemic or nearly-racemic antibacterial bromo- and chloroquinols and γ-lactams of the verongiaquinol and the cavernicolin type from the marine sponge Aplysina (= Verongia) cavernicola

Butanolic extracts of the Mediterranean sponge Aplysina (= Verongia) cavernicola have given, by reverse-phase HPLC, the antibacterial quinols (±)-3-bromoverongiaquinol (= (±)-3-bromo-1-hydroxy-4-oxo-2,5-cyclohexadine-1-acetamide; 1d) and (±)-3-bromo-5-chloroverongiaquinol (= (±)-3-bromo-5-chloro-1-hydroxy-4-oxo-2,5-cyclohexadine-1-acetamide; 1c ) besides the products of their formal cyclization 5-chlorohexadiene-1-acetamide; 1c ) besides the products of their formal cyclization 5-chlorocavernicolin (= 5-cloro-3,3a,7,7aβ-tetrahydro-3aβ-hydroxy-2,6(1H)-indoledione; 6) , the C(7)-epimerizing 7β-bromo-5-chlorocavernicolin (=7 β-bromo-5-chloro-3,3a,7,7aβ-tetrahydro-3aβ-hydroxy-2,6(1H)-indoledione; 4a and 7α-bromo-5-chlorocavernicolin (4b) , and the C(7)-epimerizing 5-bromo-7β-chlorocavernicolin ( = 5-bromo-7β-chloro-3,3a,7,7aβ-tetrahydro-3aβ-hydroxy-2,6(1H)-indoledione; 5a) and 5-bromo-7α-chlorocavernicolin (5b) . The latter four were isolated as mixtures of C(7)-epimerizing monoacetates 4a′/4b′ and 5a′/5b′. Both 1 and 1c proved to be racemic from NMR examination of their esterification products with (–)-methyl-oxyacetic acid, whilst 6 had a ca. 6% enantiomeric purity as shown by a ¹H-NMR study of its monoacetate 6′ in the presence of a chiral shift reagent. These chiroptical data of the first chiral quinols from the Verongida and of 6 suggest phenol oxidative routes from tyrosine precursors for their formation. In view of their bioactivities, 1d and 1c have been synthesized from (p-hydroxyphenyl)acetic acid byt phenol oxidative routes.     

The biosynthesis of laurifinine

The incorporation of (±)-nor-laudanosoline, (±)-N-nor-protosinomenine, (±)-N-nor-orientaline, (±)-N-nor-reticuline, and N-[2-(3-hydroxy-4-methoxyphenyl) ethyl]-2-(4'-hydroxyphenyl) ethylamine into laurifinine has been studied and the specific utilisation of the (±)-N-norprotosinomenine demonstrated. Double labelling experiments with (±)-[1-³H, 4'-methoxy-¹⁴C]-, and (±)-[1-³H, 7-methoxy-¹⁴C]-N-norprotosinomenines showed that 4' and 7, OMe groups and the H atom at the asymmetric centre of the precursor are retained in the bioconversion into laurifinine. Parallel experiments with (+)- and (-)-N-norprotosinomenine demonstrated specific utilisation of (+)-isomer into laurifinine.     

Lead tetraacetate assisted formation of bis(acetoxy)acetic acid derivative from carvone

R-Carvone on heating with Pb(OAc)₄ in benzene gives (2RS)-2-hydroxy-2-[(1S)-4-methyl-5-oxocyclohex-3-en-1-yl)]-prop-1-yl bis(acetoxy)acetate. Alkaline hydrolysis of this compound affords the corresponding diol which under acidic catalysis is transformed into bis-hydroxy ether and 1,4-dioxane derivatives.     

A chiral cyclohex-2-enone carrying a hexofuranosyl substituent which directs highly stereoselective 1,4-conjugate additions

The reaction of (Z)-3-deoxy-3-C-[(hydroxymethyl)methylene]-1,2:5,6-di-O-isopropylidene-α-D-ribo-hexo-furanose, prepared from D-glucose, with 1,1-dimethoxycyclohexane in the presence of propanoic acid at 135°C, then at 200°C, provided two Claisen rearrangement products, namely (2R,3R,4S,5S)-2,3-(isopropylidene)dioxy-5-[(1R)-1,2-(isopropylidene)dioxyethyl]-4-[(1S)- and (1R)-2-oxocyclohexyl]-4-vinyltetrahydrofuran in a ratio of 3.3:1. L-Selectride^® reduction of the major product gave the corresponding (S)-cyclohexanol exclusively. In contrast, the Claisen rearrangement of the aforementioned allylic alcohol with 3,3-dimethoxycyclohexene proceeded with complete stereoselectivity to provide the corresponding 4-[(1S)-2-oxocyclohex-3-enyl]-4-vinyltetrahydrofuran exclusively. The 1,4-conjugate additions to the thus formed cyclohexenone derivative with dimethyl and divinylcuprates proceeded with complete π-facial selection to provide the 3-methylated and 3-vinylated cyclohexanone derivatives, both in high yields.     

Synthesis of (±)-O-methylcannabichromene and some homologues

A facile novel synthesis of (±)-O-methylcannabichromene ( 5d ) together with (±)-2-methyl-2-(4-methyl-3-pentenyl)-5-methoxy-2H-benzopyran ( 5a ) and its 7-methyl ( 5b ) and 7-propyl ( 5c ) homologues, using organolithium salts is described.     

Synthesis and Stereochemistry of Thiapyranothiazoles as Diels-Alder Adducts Obtained from Spirodimers of 1,3-Thiazolidines with Cinnamic Acid and its Ester

Thiation of 5-Arylmethylene-3-phenyl-2-thioxo-1,3-thiazolidin-4-ones ( 1a and b ) with either P 4 S 10 1 or Lawesson's reagent 2 , gave mainly the spirodimers 3'phenyl-2'-thoxo-1',3'-thiazolidino[2,3-d]-spiro[6',7' diaryl-5,5'-perhydrothiapyrano]-3-phenyl-1,3-thiazolidin-4-thiones ( 3a and b ) beside, 5-(3-bromo-4-methoxyphenylmethylene)-3-phenyl-1,3-thiazolidin-2,4-dithione ( 2b ) as a mixture with 3b . 2b was allowed to react with ethyl cinnamate as a dienophile producing 4b and 5b . Moreover, prolonged heating of either 3b or 3a with ethyl cinnamate gave a mixture contains 40% of 4b and a mixture of 4a and 5a respectively. Furthermore, the dimer 3b reacted with cinnamic acid in glacial acetic acid to give the Diels-Alder-adduct 6b and 7b . Structures and stereo-chemistry of obtained compounds have been studied.     

Triaziridine. II. Erste Beispiele: 2, 3-Dialkyl-triaziridin-1-carbonsäurealkylester

Triaziridines. II. First Examples: Alkyl 2,3-Dialkyl-triaziridine-1-carboxylates The first examples of substituted triaziridines 2 are described; they carry an alkoxycarbonyl and two alkyl groups (as in 4 ). The preparation of these novel threemembered nitrogen homocycles was achieved by photolysis of 1-alkoxycarbonylazimines 3c. In this way, methyl 2, 3-(cis-1, 3-cyclopentylene)triaziridine-1-carboxylate ( 6a ), methyl trans-2, 3-diisopropyl-triaziridine- 1 -carboxylate ( 8a ) and their ethyl ester analogues 6b and 8b were obtained in 50, 18, 65 and 21 % yield, respectively. The structure of the triaziridines 6 and 8 was deduced from their spectroscopic properties which reveal several interesting features: 1) N (2) and N (3), carrying alkyl groups, are pyramidal and invert slowly; 2) the isopropyl groups of 8 are situated trans to each other on the three-membered ring, whereas the two alkyl groups of 6 are cis as forced by the C-ring system; 3) N (1) is also pyramidal, despite its «amidic» nature; it inverts with an activation energy of 62 (± 4) kJ/mol; 4) the alkoxycarbonyl, group does not conjugate with N (1) and rotates rapidly. The triaziridines 6 and 8 are thermally labile, isomerizing slowly at room temperature into the corresponding azimines 5 and 7 by cleavage of one of the bonds to N (1 ). The velocity of this ring opening reaction is almost the same for 6 and 8 , so that a dependence on the relative configuration at N (2) and N (3) is not evident. The Arrhenius activation energy for the isornerization of 6a to the corresponding azimine 5a and the enthalpy difference between 6a and 5a were both determined as 100 (± 4) kJ/mol. The photolysis of 1-alkoxycarbonyl-2, 3-diisopropyl-azimines ( 7 ) in diethyl ether was accompanied by a side reaction leading to methyl and ethyl N-(1-ethoxyethyl)carbamate ( 9a and 9b , resp.), presumably by insertion of the alkoxycarbonylnitrene, generated by photofragmentation of the azimines, into the ethereal solvent.     

Synthesis,cytotoxic, and carbonic anhydrase inhibitory effects of new 2-(3-(4-methoxyphenyl)-5-(aryl)-4,5-dihydro-1H-pyrazol-1-yl)benzo[d]thiazole derivatives

2-(3-[4-Methoxyphenyl]-5-aryl-4,5-dihydro-1H-pyrazol-1-yl)benzo[d]thiazoles ( 1b-7b ) were synthesized for the first time except 1b , and spectral methods such as ¹H NMR, ¹³C NMR and HRMS were utilized to illuminate the chemical structures of the synthesized compounds. Phenyl ( 1b ), 2-methoxyphenyl ( 2b ), 4-methoxyphenyl ( 3b ), 4-methoxy-3-hydroxyphenyl ( 4b ), 2,5-dimethoxyphenyl ( 5b ), 3,4,5-trimethoxyphenyl ( 6b ), or thiophene-2-yl ( 7b ) was used as a aryl part. The inhibitory effects of the compounds were evaluated toward human carbonic anhydrase I and II enzymes (hCA I and hCA II). In vitro cytotoxic effects of the compounds against human oral squamous carcinomas and human normal oral cells were carried out via MTT. The compounds ( 1b-7b ) had Ki values of 36.87 ± 11.62-66.24 ± 2.99 μM (hCA I) and 22.66 ± 1.41-89.95 ± 6.25 μM (hCA II). Compounds 1b (Ki = 36.87 ± 11.62 μM) toward hCA I, 6b (Ki = 22.66 ± 1.41 μM) toward hCA II had significant enzyme inhibitory potency. Compound 6b had the highest tumor selectivity (TS = 29.3) and potency selectivity expression (PSE = 272.3) values. Therefore, compounds 1b and 6b with CAs inhibition effect and compound 6b with the cytotoxicity may be forwarded to further studies as potent compounds.     

Stereoselective synthesis of (1R,2S)- and (1S,2R)-1-amino-cis-3-azabicyclo[4.4.0]decan-2,4-dione hydrochlorides: bicyclic glutamic acid derivatives

Asymmetric synthesis of (1R,2S)- and (1S,2R)-1-amino-cis-3-azabicyclo[4.4.0]decan-2,4-diones has been achieved. The underlying second generation asymmetric synthesis proceeds via a Strecker reaction with commercially available (R)-1-phenylethylamine (1-PEA) as chiral auxiliary, TMSCN as cyanide source and racemic ethyl 2-(2-oxocyclohex-1-yl)ethanoate. A ring closure addition-elimination reaction between an amide nitrogen and the ester functionality leads to the 1-amino-3-azabicyclo[4.4.0]decan-2,4-diones. The absolute configurations of the title compounds have been assigned based on detailed NMR-spectroscopic analysis and X-ray data.     

A New Approach to Sesquiterpene Arenes of the 9,11‐Drimenyl Type (= [(1E,2RS,4aRS,8aRS)‐Octahydro‐2,5,5,8a‐tetramethylnaphthalen‐1(2H)‐ylidene] methyl Type)

A new reaction sequence for the synthesis of the sesquiterpene arenes (±)‐wiedendiol B ((±)‐ 1 ) and the siphonodictyal B derivative (±)‐ 21 consists in the coupling of (±)‐drimanoyl chloride ((±)‐ 3 ) with lithiated and appropriately substituted aromatic synthons to furnish the ketones (±)‐ 7 and (±)‐ 17 which were reduced to the benzyl alcohols (±)‐ 8a,b and (±)‐ 18a,b , respectively (Schemes 5, 4, and 12). The 9,11‐double bond of the drimenes (±)‐ 9 and (±)‐ 19 was formed by elimination of H₂O from the benzyl alcohols (±)‐ 8a,b and (±)‐ 18a,b (Schemes 6 and 12). New alternatives were applied to this elimination reaction involving either the pyridine ? SO₃ complex or chloral as reagents.     

A Flexible Stereoselective Synthesis of the Spirosesquiterpenes (±)-β-Acorenol, (±)-β-Acoradiene, (±)-Acorenone-B and (±)-Acorenone via an Intramolecular Ene-Reaction

The racemic spirosesquiterpenes β-acorenol ( 1 ), β-acoradiene ( 2 ), acorenone-B ( 3 ) and acorenone ( 4 ) (Scheme 2) have been synthesized in a simple, flexible and highly stereoselective manner from the ester 5 . The key step (Schemes 3 and 4), an intramolecular thermal ene reaction of the 1,6-diene 6 , proceeded with 100% endo-selectivity to give the separable and interconvertible epimers 7a and 7b . Transformation of the ‘trans’-ester 7a to (±)- 1 and (±)- 2 via the enone 9 (Scheme 5) involved either a thermal retro-ene reaction 10 → 12 or, alternatively, an acid-catalysed elimination 11 → 13 + 14 followed by conversion to the 2-propanols 16 and 17 and their reduction with sodium in ammonia into 1 which was then dehydrated to 2 . The conversion of the ‘cis’-ester 7b to either 3 (Scheme 6) or 4 (Scheme 7) was accomplished by transforming firstly the carbethoxy group to an isopropyl group via 7b → 18 → 19 → 20 , oxidation of 20 to 21 , then alkylative 1,2-enone transposition 21 → 22 → 23 → 3 . By regioselective hydroboration and oxidation, the same precursor 20 gave a single ketone 25 which was subjected to the regioselective sulfenylation-alkylation-desulfenylation sequence 25 → 26 → 27 → 4 .     

Quinolizidines—IV: Total syntheses of (±)-ankorine and (±)-11-methoxyprotoemetinol

The first total synthesis of ankorine (4), an Alangium lamarckii alkaloid, has been accomplished in the form of a recemic modification by means of an initial condensation of 2-benzyloxy-3,4-dimethoxyphenacyl bromide with the lactim ether 6, derived from ethyl (±)-trans-5-ethyl-2-oxo-4-piperidineacetate (5), and succeeding steps proceeding through the intemediates 7a, 8a, 9a, 10a (X=Cl), 11a, and 12a. A parallel synthetic route starting with 3,4,5-trimethoxyphenacyl bromide and 6 gave (±)-11-methoxyprotoemetinol (12c) via the intermediates 7c, 8c, 9c, 10c (X =I,ClO₄), and 11c. The trimethyl ether 12c did not match the O-Me derivative (type 12e) of natural ankorine. Thus, the formula 4 defines the structure and relative stereochemistry of ankorine.     

Stereoselective synthesis of (±)-methyl homononactate and (±)-methyl 8-epi-homononactate

A stereoselective route to (±)-methyl homononactate (4b) and (±)-methyl 8-epi-homononactale (5b), synthetic precursors to the antibiotic tetranactin, is presented. Key steps involve employing the regioseleclive ring opening of l-(benzyloxy)but-3-ene oxide (8) with the dianion derived from methyl(2-methyl, 3-oxo)butanoate (9), and the stereoselective addition of dialkyl zinc species to a β-alkoxyaldehyde precursor (6). Conditions have been developed to enable the diethyl zinc addition to give either isomer with reasonable selectivity.     

Synthesis of 4-aryl-substituted β-lactam enantiomers by enzyme-catalyzed kinetic resolution

Enantiopure 4-phenyl- and 4-(p-tolyl)-2-azetidinones 3a, 3b, 4a and 4b (with e.e.s of ≥96%) were prepared through lipase-catalyzed asymmetric butyrylation of the primary OH group of N-hydroxymethylated β-lactams (±)-5 and (±)-6 at the (R)-stereogenic centre or by lipase-catalyzed asymmetric debutyrylation of O-butyryloxymethyl-2-azetidinones (±)-7 and (±)-8 at the (R)-stereogenic centre. The ring-opening of lactams 5a, 5b, 6b and 8a with HCl/EtOH afforded the corresponding β-amino ester enantiomers 9a, 9b, 10a and 10b with e.e.s of ≥92%.     

Studies for a Diastereoselective Synthesis of the Tetracyclic Diterpenic Diol Stemarin: A Model Study for a New Preparation of the Key Intermediate and the Synthesis of (+)-18-Deoxystemarin

Methods for a stereoselective preparation of compounds of type 2b , a key intermediate of a previous synthesis of the tetracyclic diterpene stemarin ( la ), have been tested on model compounds 5a, 5c , and 8a . Thus, (±)-(1RS,6SR,8SR,11SR)-hydroxytricyclo[6.2.2.0^l,6]dodecan-9-one ( 5a ) was transformed by the Mitsunobu reaction into (±)-(1RS,6SR,8SR,11RS)-11-(benzoyloxy)tricyclot[6.2.2.0^1,6]dodecan-9-one ( 6b ; Scheme 2). The latter was also obtained from (±)-(1RS,6SR,8SR,11RS)-11-[(4)-toluenesulfonyloxy]tricyclo[6.2.2.0^1,6]dodecan-9-one ( 5c ) by the action of Et₄N (PhCOO) in acetone. Compound 6b was then converted into (±)-(1RS,6RS,8RS,9RS)-tricyclo[6.2.2.0^1,6]dodecan-9-ol ( 8b ), a model for 2b . Compound 8b was also prepared from its epimer 8a by the Mitsunobu reaction via ester 7b . The inversion of configuration of bicyclo[2.2.2]octan-2-ols or derivates was not previously described. The model studies paved the way to the diastereoselective synthesis of (+)-18-deoxystemarin ( 1b ) via 12β-hydroxy-13-methyl-9β,13β-ethano-9β-podocarpan-15-one ( 10a ) and 13-methyl-9β,13β-ethano-9β-podpcarpan-12α-ol ( 11b ).