Total Synthesis of (±)-3-Deoxy-7,8-dihydromorphine, (±)-4-Methoxy-N-methylmorphinan-6-one and 2,4-Dioxygenated (±)-Congeners

A total synthesis of racemic 3-deoxy-7,8-dihydromorphine ((±)- 2 ) and 4-me-thoxy-ALmethylmorphinan-6-one ((±)- 3 ) is described. The key intermediate was 2,4-dihydroxy-N-formylmorphinan-6-one (11) , obtained from 3,5-dibenzyloxy-phenylacetic acid (4) in 41.8% overall yield. Bromination of 11 , and treatment with aqueous N_aOH-solution afforded, after N-deblocking and reductive N-methylation with concomitant removal of the aromatic bounded Br-atom, the morphinanone 14. Elimination of the HO–C(2) group in 14 was accomplished by hydrogenolysis of its N-phenyltetrazolyl ether 15 , to give 3-deoxy-6,0-didehydro-7,8-dihydromorphine (16). Reduction of 16 with L-Selectride at low temperature provided (±)- 2 in high yield. The ether 15 directly afforded, under more vigorous reduction conditions, 4-hydroxy-N-methylmorphinan-6-one (17). and after O-methylation of 17 , the methyl ether (±)- 3 was obtained. A (1:l)-mixture of 4-hydroxy-2-methoxy-N-methylmor-phinan-6-one (28) and its 2-hydroxy-4-methoxy isomer 30 svere obtained by Grewe-cyclization of a mono-methoxylated aromatic precursor similar to that which afforded 11. The 2,4-dioxygenated N-methylmorphinan-6-ones 29 , 31 and 38 were also prepared and characterized.     

Probes for a Regulatory Site on the Nicotinic Acetylcholine Receptor-Channel. Synthesis of (±)-7-Debutylperhydrohistrionicotoxin, (±)-2-Depentyl-7-debutylperhydrohistrionicotoxin,and their Analogues

Reaction of glutarimide with pent-4-enylmagnesium bromide, followed by cyclization of intermediate ketoamide, and hydrolysis of the formates 10 and 13 led to the mixture of the hydroxylactams 11 (cis) and 14 (trans) which could be separated via their benzenecarbamates. Reduction of cis-hydroxylactam 11 with LiAlH₄ yielded 2-depentyl-7-debutylperhydrohistrionicotoxin ( 6 ), whereas reduction of trans-isomer 14 gave the epimeric alcohol 9 . cis-Hydroxylactam 11 was converted via thiolactam 17 and the methylthio derivative 18 to ketimine 19 which was reduced with NaBH₄ yielding a mixture of natural 4 and unnatural 7 , analogues of perhydrohistrionicotoxin ( 2 ). Reduction of 4 with H₂ in the presence of Pd/C yielded (±)-7-debutylperhydrohistrionicotoxin ( 5 ).     

An Alternative Access to (±)-α-Irones and (±)-β-Irone via Acid-Mediated Cyclisation

Acid-mediated cyclisation of trienone 8 , readily available from 2,3-dimethylbutanal ( 1 ; five steps: 47% yield), using fluorosulfonic acid (6.8 mol-equiv.) in 2-nitropropane at ?70°, afforded a 14:9:1 mixture (70% yield) of (±)-cis-α-irone ( 9 ), (±)-trans-α-irone ( 10 ), and (±)-β-irone ( 11 ). Other acidic conditions examined, using 95% aq. H₂SO₄ solution, 85% aq. H₃PO₄ solution, or SnCl₄, gave inferior results.     

CHARACTERIZATION OF CIS- AND TRANS-DINITROBIS-(l-CYCLOHEXANEDIAMINE)-COBALT(III) CHLORIDE1

Abstract

Two geometrical isomers of [Co(l-chxn)₂(No₂)₂]Cl have been isolated. The trans-isomer is eluted first from a cellulose ion exchange column as a single isomer. The cis-isomer corresponds to the complex previously reported as the trans-isomer. The cis-isomer with the same CD sign pattern as for the trans-isomer is stereoselectively favored, but a small amount of the second cis-isomer separates using Cellex CM ion exchange cellulose. The CD spectra of the cis- and trans- isomers are similar to those of the corresponding isomers of the l-pn complex.     

Synthesis of Ethyl (2RS,3SR)-1-Tosyl-3-Vinylazetidine-2-carboxylate and ethyl (2RS,E)-3-ethylidene-1-tosylazetidine-2-carboxylate (=rac-ethyl N-tosylpolyximate)

The synthesis of 3-ethylideneazetidine-2-carboxylic acid (=polyoximic acid; 3 ) is a approached in two different ways leading to potential precursors of 3 . The first way involved a ring closure to a vinyl-subsatituted azetidin. Thus, Ireland-Claisen rearrangement of the Boc-glycinates 6 and 10 of (Z)- and (E)-2-butene-1,4-diol afforded, after exchange of the N-protecting groups, the isomeric 2-(tosylamino)-3-vinylbutanolides 13 and 14 with high stereoselectivity. Only the cis-isomer 14 could be further transformed to 3-(bromomethyl)-2-(tosylamino)-4-pentenoate 17 , and in a smoth cyclization with K₂CO₃, to trans-3-vinylazetidtene-2-carboxylaze 18 (Scheme 2). In the second approach, the 3-ethylidene isomer 19 of 18 was obtained more directly by a [2+2] cycloaddition, together with the two isomers 23 and 24 , from methlallene 20 and (tosyliminno)acetate 21 (Scheme 3). The main product of this reaction was, however, 2-(tosylamino)-4-hexinoate 22 , the product of an ene reaction.     

First Total Synthesis of (±)‐Celaphanol A

The first total synthesis of (±)‐Celaphanol A was accomplished starting from α‐cyclocitral and 3,4‐dimethoxy benzyl chloride in six steps. The intramolecular cyclization with BF₃·Et₂O and enolization in t‐BuOK/t‐BuOH were the key steps. The process of intramolecular cyclization afforded an all‐cis isomer intermediate for synthesis of aromatic tricyclic diterpenes.     

Synthese von (±)-α-Chamigren. Vorläufige Mitteilung

Synthesis of (±)-α-Chamigrene Cis- and trans-β-ionol (cis and trans- 1 ) underwent acid catalysed dehydration to a mixture of the tetraenes 2–5 in 70–80% yield (Table 1). Irradiation of this mixtures made the 6-(Z), 8-(Z)-isomer 5 accessible (columns 3 and 4 in Table 1). Pyrolysis of the different mixtures at 170° showed, that both isomers, 3 and 5 respectively undergo electrocyclization to dehydrochamigrene ( 6 ). The latter was reduced to α-chamigrene ( 7 ) by hydrogen on Lindlar catalyst.     

Synthese von (±)-Diplodialid B und A

Synthesis of (±)-Diplodialide B and A Two steroid hydroxylase inhibitors, diplodialide B (1) and A (2) have been synthesized in the following way: The lithium enolate 5 of S-t-butyl thioacetate (4) was added to (E)-7-(2′-tetrahydropyranoxy)-2-octen-1-al (8) and the newly formed 3-hydroxy group in the product 9 was protected as t-butyl-diphenyl silyl ether followed by selective hydrolysis of the tetrahydropyranyl ether to give 10. Treatment with AgNO₃/H₂O cleaved the S-t-butyl ester group in 10 to give the corresponding hydroxy carboxylic acid which was converted into the S-2-pyridyl thioester by treatment with di(2-pyridyl)disulfide and triphenyl phosphine and cyclized with AgClO₄ to give the (4E,3,9-trans)- and (4E,3,9-cis)-lactone 11 and 12 (R?t-Bu(C₆H₅)₂Si) in 67% yield. Chromatographic separation of 11 and 12 and cleavage of the t-butyl-diphenyl silyl ether with tetrabutyl ammonium fluoride yielded (±)-diplodialide B (1) with (4E,3,9-trans)-configuration and the (4E,3,9-cis)-isomer 12 (R?H). Both isomers could be oxidized to diplodialide A (2) with manganese dioxide. The synthesis described above has also been carried out via the intermediates 10 , 11 and 12 with R?COOCH₂CH₂Si(CH₃)₃.     

Der massenspektrometrische Zerfall isomerer Diacetamido-cyclo-hexane,ihrer N-Phenäthyl-Derivate und Bis (acetamidomethyl)cyclohexane. 32. Mitteilung über massenspektrometrische Untersuchungen,,

The Mass Spectral Decomposition of Isomeric Diacetamido-cyclohexanes, their N-Phenethyl-Derivatives and Bis(acetamidomethyl)cyclohexanes In the mass spectra of the six isomeric diacetamidocyclohexanes 2--4 (cis and trans each, Scheme 2) as well as of the six isomeric bis(acetamidomethyl)cyclohexanes 6--8 (cis and trans each, Scheme 5) are clear differences between the constitutional isomers, whereas cis/trans isomers show very similar spectra. The lack of stereospecific fragmentations is explained by loss of configurational integrity of the molecular ion before fragmentation. However, the mass spectral fragmentation of epimeric diamidocyclohexanes becomes very stereospecific by the introduction of a phenethyl group on one of the nitrogen atoms: this group avoids epimerization of the molecular ion prior to fragmentation. In the N-phenethyl derivatives 10, 11, 13 and 14 (Scheme 8) the typical fragmentations of the cis-isomer after loss of ·C₇H₇ from the molecular ion are the elimination of CH₂CO by formation of cyclic ions, and the loss of p-toluenesulfonic acid or benzoic acid, respectively, with subsequent elimination of CH₃CN (Scheme 9). In the trans-isomer the typical fragmentations are the loss of the side chain bearing a tertiary nitrogen atom, and the elimination of the tosyl or benzoyl radical, respectively, with subsequent loss of CH₃CONH₂ (Scheme 10).     

Synthesis and reactions of a monosubstituted dithiirane 1-oxide, 3-(9-triptycyl)dithiirane 1-oxide

A 3-monosubstituted dithiirane 1-oxide, 3-(9-triptycyl)dithiirane 1-oxide, was prepared for the first time, by the reaction of (9-triptycyl)diazomethane and S₈O. The dithiirane 1-oxide was obtained as cis- and trans-isomers, and the structure of the trans-isomer was verified by X-ray crystallography. The cis-isomer isomerized gradually to the trans-isomer in solution. The divalent sulfur atom of the cis- and trans-dithiirane 1-oxides were removed on treatment with triphenylphosphine to give the corresponding Z- and E-sulfines, respectively. The reaction of the trans-dithiirane 1-oxide with (Ph₃P)₂Pt(C₂H₄) provided the (sulfenato-thiolato)Pt^II complex, and that with Lawesson's reagent yielded the 1,3,4,2-trithiaphospholane and 1,2,4,5,3-tetrathiaphosphorinane derivatives.     

Synthesis of eleven-membered carbocycles via a homo-Cope type of five-carbon ring expansion reaction utilized β-(hydroxymethyl)allylsilane

Eleven-membered carbocycles were synthesized from six-membered compounds fitted with a β-(hydroxymethyl)allylsilane unit via the title reaction. Namely, trans- and cis-(E)-2-(trimethylsilylmethyl)-3-(2-vinylcyclohex-1-yl)prop-2-en-1-ol were treated with Tf₂O in CH₂Cl₂ in the presence of 2,6-lutidine to afford (1E)-3-methylenecycloundeca-1,6-diene in good yield. The geometry of the product was shown to depend upon the trans- and cis-substitution pattern on the cyclohexane ring of the substrates; i.e. trans-isomer afforded (6E)-product exclusively and cis-isomer afforded the mixture of (6E)- and (6Z)-product in 1:2 ratio. The (Z)-substrate with respect to allylsilane moiety afforded the same ring expansion product, however, the yield was lower than the reaction with the (E)-substrate. The substrates bearing t-butyl or benzyloxy substituents on the cyclohexane ring also afforded the product analogously, indicating that the reaction depends upon the conformation of the substrate. On the other hand, the substrate bearing isopropenyl group instead of a simple vinyl group did not afford the ring expansion product but produced bicyclo[5.4.0]undecane via the ene reaction.     

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 .     

The SO2(3B1) photosensitized isomerization of cis- and trans-1,2-dichloroethylene

The photolysis of SO₂ at 3712 Å in the presence of the 1,2-dichloroethylenes has been investigated at 22deg;C. The data are consistent with the SO₂(³B₁) photosensitized isomerization of the 1,2-dichloroethylene isomer. A kinetic treatment of the initial quantum yield data was consistent with the formation of a polarized charge-transfer intermediate whenever SO₂(³B₁) molecules and one of the 1,2-dichloroethylene isomers collide which ultimately decays unimolecularly to the cis-isomer with a probability of 0.70 ± 0.26 and to the trans-isomer with a 0.37 ± 0.16 probability. Quenching rate constants for removal of SO₂(³B₁) molecules by cis- and trans-1,2-dichloroethylene have been estimated from quantum yield data and from laser excited phosphorescence lifetimes using an excitation wavelength of 3130 Å. Estimates of the quenching rate constant (units of 1./mole ± sec) are for the cis-isomer, (1.63 ± 0.71) × 10¹⁰, quantum yield data, and (2.44 ± 0.11) × 10¹⁰, lifetime data; and for the trans-isomer,(2.59 ± 0.09)×10¹⁰, lifetime data, and (2.35 ±0.89) × 10¹⁰, quantum yield data. An experimentally determined photostationary composition,[cis-C₂Cl₂H₂]/[trans-C₂Cl₂H₂] = 1.8 - 0.1, was in good agreement with a value of 2.00 - 1.15 which was predicted from rate constants derived in this study.     

Synthesis and amoebicid properties of emetin analogs. Analysis of the new compounds by 13C-NMR. B/C-cis or trans-fused (+/-) 1-alkyl-3-desethyl-emetin (author's transl)]

Synthesis and amoebicid properties of emetin analogs. Analysis of the new compounds by ¹³C-NMR. B/C-cis or trans-fused (±) 1-alkyl-3-desethyl-emetin. New 1-alkyl-3-desethyl-emetines were prepared for pharmacological purposes. The usual emetine synthesis sequence applied to cis-1-alkylbenzo [a]quinolizidin-2-ones afforded new cis-1-alkyl-3-desethyl-emetines. The trans-fused isomers were also prepared. The relative configuration are determined by ¹H- and ¹³C-NMR. spectra.     

Adiabatic <Emphasis Type="Italic">trans-cis</Emphasis> photoisomerization and photocyclization of 8-styrylquinoline

Kinetics of the photocyclization of trans-8-styrylquinoline into 10a,10b-dihydronaphtho[1,2-h]quinoline (4-azachrysene) was studied in hexane. It was found that in addition to the expected two-step (two-quantum) route with trans-cis photoisomerization occurring in the first step with a quantum yield of φ_tc = 0.13 with consequent photocyclization of the cis-isomer with a quantum yield of 0.23. The direct singlequantum photocyclization of the trans-isomer with a quantum yield of 0.009 is also observed. The latter observation indicates that the excited trans-isomer isomerizes without loss of excitation to the excited cis-isomer, which then undergoes cyclization, i.e., the trans-cis photoisomerization proceeds partially by adiabatic mechanism t* → c*.     

Synthesis and spectral analysis of (±)-cis-N-[1-(2-hydroxy-2-phenyl-ethyl)-3-methyl-4-piperidyl]-N-phenylpropanamide and (±)-cis-N-[1-(2-hydroxy-1-phenylethyl)-3-methyl-4-piperidyl]-N-phenylpropanamide

Treatment of (±)-cis-N-(3-methyl-4-piperidyl)-N-phenylpropanamide (2) with styrene oxide (1) yielded a mixture of (±)-cis-N-[1-(2-hydroxy-2-phenylethyl)-3-methyl-4-piperidyl]-N-phenylpropanamide (3) and (±)-cis-N-[1-(2-hydroxy-1-phenylethyl)-3-methyl-4-piperidyl]-N-phenylpropanamide (4) . The structure of compound 3 was confirmed by an unambiguous synthesis via (±)-cis-N-[1-(2-oxo-2-phenylethyl)-3-methyl-4-piperidyl]-N-phenylpropanamide (6) . The proton and carbon-13 resonances of compounds 3 and 4 were assigned with the aid of two-dimensional heteronuclear correlation experiments.     

Preparation and structural analysis of (±)‐cis‐ethyl 2‐sulfanylidenedecahydro‐1,6‐naphthyridine‐6‐carboxylate and (±)‐trans‐ethyl 2‐oxooctahydro‐1H‐pyrrolo[3,2‐c]pyridine‐5‐carboxylate

Bicycle ring closure on a mixture of (4aS,8aR)‐ and (4aR,8aS)‐ethyl 2‐oxodecahydro‐1,6‐naphthyridine‐6‐carboxylate, followed by conversion of the separated cis and trans isomers to the corresponding thioamide derivatives, gave (4aSR,8aRS)‐ethyl 2‐sulfanylidenedecahydro‐1,6‐naphthyridine‐6‐carboxylate, C₁₁H₁₈N₂O₂S. Structural analysis of this thioamide revealed a structure with two crystallographically independent conformers per asymmetric unit (Z′ = 2). The reciprocal bicycle ring closure on (3aRS,7aRS)‐ethyl 2‐oxooctahydro‐1H‐pyrrolo[3,2‐c]pyridine‐5‐carboxylate, C₁₀H₁₆N₂O₃, was also accomplished in good overall yield. Here the five‐membered ring is disordered over two positions, so that both enantiomers are represented in the asymmetric unit. The compounds act as key intermediates towards the synthesis of potential new polycyclic medicinal chemical structures.     

Synthesis,separation, and resolution of cis- and trans-3-ethylproline

The synthesis, separation, and optical resolution of cis- and trans-3-ethylproline are described. Two different approaches were employed: (1) The Michael addition reaction of 2-pentenal with diethyl-N-carbobenzyloxyaminomalonate gave the intermediate 3-ethyl-5-hydroxy-N-benzyloxypyrrolidine. Hydrogenolysis of this intermediate followed by acid hydrolysis gave a mixture of cis- and trans-3-ethylproline. Separation of the isomers was accomplished by selective saponification of N-(p-toluenesulfonyl)-cis- and trans-3-ethylproline methyl esters using 0.25N methanolic sodium hydroxide. (2) The Michael condensation of diethyl acetamidomalonate with 2-pentenoic acid ethyl ether produced the intermediate 5,5-bis(ethoxycarbonyl)-4-ethylpyrrolidine. Partial saponification followed by decarboxylation afforded a mixture of cis- and trans-isomers of ethyl-3-ethylpyroglutamate. The diastereoisomers were separated using low temperature fractional crystallization. Reduction of these isomers and tosylation in situ afforded the corresponding N-(p-toluenesulfonyl)-cis- and trans-3-ethylprolinols. Chromic acid oxidation gave N-(p-toluenesulfonyl)-cis- and trans-3-ethylproline. Reaction of these tosylates with 30% hydrogen bromide in acetic acid gave cis- and trans-3-ethylproline. Both optically active isomers of D(+)-and L(-)-trans-3-ethylproline were successfully resolved using (+)-dibenzoyl-D -tartaric acid and (-)-dibenzoyl-L -tartaric acid as resolving agents. The absolute configurations of the optically active isomers were determined by circular dichroism spectroscopy.     

Triaziridine. 9. Mitteilung. Ringöffnungen von Triaziridinen

Triaziridines. Ring Openings of Triaziridines Eleven triaziridine derivatives were heated at 60° in CDCl₃ to obtain information on the tendency towards, resp. the resistance to, ring opening of the N₃-homocycle by thermolysis. Among these triaziridines, there are three which contain, as one of the substituents, a methoxycarbonyl group (ester derivatives 1 , 5 and 16 ), three a methyl group (methyl derivatives 18 , 24 , and 26 ), three an H-atom ( 14 , 27 , and 30 ), and two a negative charge ( 31 and 32 ). The other two substituents in each of these four classes of triaziridines are trans-located i-Pr groups ( 1 , 18 , 27 , and 31 ), cis-located i-Pr groups ( 5 , 24 , 14 , and 32 ), and a 1,3-cis-cyclopentylidene group ( 16 , 26 , and 30 ). As major products these mild thermolyses, we isolated : from the trans-ester 1 and from the annellated ester derivative 16 , the 1-acyl-azimines 2 and 17 , respectively, from the cis-ester 5 , the 3-acyl-triazene 4 , from the trans-methyl derivative 18 , the (E)-diazene 19 , and hexamine 21 , from the cis-methyl derivative 24 the 2-methylazimine 25 , both from the trans- and cis-H-derivatives 27 , and 14 , respectively, the H- triazene 13 and, finally, both from the trans-and cis-anion 31 and 32 , respectively – after protonation the H-triazene 13 and – after methylation – the methyl-triazene 33 . The same thermolysis of the annellated methyl and H-derivatives 26 and 30 , respestively, resulted only in decomposition. These results can be uniformly interpreted with a primary opening of the triaziridine ring by rupture of one of the two types of N? N bonds lending to azimines or triazenide anions. Some of the azimines were isolable, namely 2 , 17 , and 25 , and one was spectroscopically observable as an intermediate, namely 11 on the way to the triazene 4 . The other azimines are plausible intermediates to the isolated products, namely 15 on the way to 13 , and 22 on the way to 19 and 21 . The triazenide anion 28 is the evident intermediate on the way to 13 or to 33 . The annellated azimines are assumed not be formed from 26 and 30 , or then to be be decomposed under the conditions of their formation. We conclude that the triaziridine derivatives 1, 16 , and 18 underwent thermal ring opening between N(1) and N(2), while the derivatives 5 , 14 , 24 , 27 , 31 , and 32 were ruptured between N(2) and N(3); no conclusion was possible on the ring opening of the derivatives 26 and 30 . The predominant formation of the (Z)-azimine 2 from the trans-triaziridine 1 , and of the (E)-isomer 3 – among the two azimines – from the cis-triaziridine 5 suggests a stereospecificity in the triaziridine ring openings. This would, however, not be expected to be observable in the products from the other triaziridines, since both N? N bonds of the azimine 25 and of the anion 28 probably rotate rapidly and since the secondary trans formations of the other primary products are not able to retain configurational information.     

Synthese von threo-cis/threo-trans- und erythro-cis/erythro-trans-Dihydropalustrin. 17. Mitteilung über Schachtelhalmalkaloide

Synthesis of threo-cis/threo-trans- and erythro-cis/erythro-trans-dihydropalustrin The first synthesis of a threefold protected spermidine, namely ³-benzyloxycarbonyl-N¹-phthaloyl-N²-tosylspermidin ( 9 ) is presented. Each of the protecting groups can be removed selectively. After hydrazinolysis the resulting N³-benzyloxy-carbonyl-N²-tosylspermidine ( 10 ) has been condensed with methyl (2 E)-cis-7,8-epoxy-2-decenoate to the threo-cis/trans piperidines 17 , and with methyl (2 E)-trans-7,8-epoxy-2-decenoate to the erythro-cis/trans piperidines 17 , respectively. After catalytic removal of the Z group, the resulting aminoesters 13 and 18 , in a melt with imidazole, underwent ring closure to the 13-membered lactames 14 and 19 , respectively. reductive deprotection of the N-tosyl group with sodium/ammonia led to the stereoisomeric palustrines 15 and 20 , respectively.