Eine neue Synthese von (±)-Dihydrorecifeiolid

A New Synthesis of (±)-Dihydrorecifeiolide Ethyl 1-(2′-formylethyl)-2-oxocyclooctane-1-carboxylate ( 2 ) prepared by Michael reaction of ethyl 2-oxocyclooctane-1-carboxylate ( 1 ) was regioselectively methylated at the aldehyde group with (CH₃)₂Ti[OCH(CH₃)₂]₂ to give 3 (Scheme 1). The alcohol 3 was treated with Bu₄NF to give the deethoxycarbonylated product 4 which by distillation gave the bicyclic enol ether 5 . Oxidation (m-chloroperbenzoic acid) of 5 and reduction of the resulting oxolacton 6 yielded the title compound (±)-dihydrorecifeiolide ( 7 ) in an overall yield of nearly 50 %. Methylation of the aldehyde 2 with MeLi gave the ring-enlarged lacton 9 in poor yield (13 %). The deethoxycarbonylation reaction 3 → 4 was studied in more detail (Scheme 3).     

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 Synthesis of (±)-11-Deoxydaunomycinone via Regioselective Tandem Diels-Alder Reactions

The 2,5-dimethylidene-3,6-bis[(Z)-(2-nitrophenyl)sulfenylmethylidene]-7-oxabicyclo[2.2.1]heptane ( 13 ) can be used to generate polyfunctional and multicyclic molecules with high regio- and stereoselectivity via two successive Diels-Alder additions using two different dienophiles. This principle has been applied to the synthesis of (±)-11-deoxydaunomycinone ( 7 ), the aglycone of an important antitumor drug. The 2,3-didehydroanisole adds to 13 and gives the monoadduct 14 with high regioselectivity. No trace of bis-adduct is observed. The 1,4-epoxy-1,2,3,4-tetrahydro-5-methoxy-3-methylidene-2-[(Z)-(2-nitrophenyl)sulfenylmethylidene]anthracene ( 15 ) obtained on treating 14 with K₂CO₃ adds to methyl vinyl ketone to give [(1RS, 2SR, 5RS,12RS)-5,12-epoxy-1,2,3,4,5,12-hexahydro-7-methoxy-1-(2-nitrophenyl)sulfenyl-2-naphthacenyl]methyl ketone ( 16 ) with high regio- and stereoselectivity. The acid-catalyzed 7-oxanorbornadiene→phenol rearrangement of 16 is regioselective and gives (5-acetoxy-3,4-dihydro-7-methoxy-2-naphthacenyl) methyl ketone ( 20 ) which was transformed into (±)-7,11-dideoxydaunomycinone ((±)- 24 ), a known precursor of 7 .     

Highly Stereoselective Total Syntheses of (±)-Chelidonine and of (±)-Norchelidonine by an Intramolecular o-Quinodimethane/Nitrostyrene-Cycloaddition

Conversion of 2-bromomethylstyrene 22 and benzocyclobutenyl carbamate 28 to the benzophenanthridine alkaloids (±)-chelidonine ( 1 , five steps, 25% from 28 ) and to (±)-norchelidonine ( 2 , six steps, 24% from 28 ) are described. The key step 29 → 31 involves a highly regio- and stereocontrolled intramolecular Diels-Alder reaction of the (E)-quinodimethane 30 .     

Synthesen makrocyclischer Lactone durch Ringerweiterung Herstellung von (±)-Phoracantholid I, (±)-Dihydrorecifeiolid und (±)-15-Hexadecanolid

Syntheses of Macrocyclic Lactones by Ring Enlargement Reaction Reaction. Preparation of (±)-Phoracantholide I, (±)-Dihydrorecifeiolide and (±)-15-Hexadecanolide A general procedure for the synthesis of macrocyclic lactones is described. The Michael adducts of 2-nitrocycloalkanones and acrylaldehyde were regiospecifically methylated with CH₃Ti[OCH(CH₃)₂]₃ or (CH₃)₂Ti[OCH(CH₃)₂]₂ at the aldehyde carbonyl group. Treatment of the so-formed alkohols with tetrabutylammonium fluoride gave the lactones enlarged by four ring members. This method was used to synthesize the 10-membered (±)-phoracantolide I ( 11 ), the 12-membered (±)-dihydrorecifeiolide ( 17 ), and (±)-15-hexadecanolide ( 24 ) in 52%, 26.5%, and 58.7% respectively.     

Synthese der Spermidin-Alkaloide (±)-Inandenin-10-ol,Inandenin-10-on und (±)-Oncinotin

Syntheses of the Spermidine Alkaloids (±)-Inandenin-10-ol, Inandenin-10-one, and (±)-Oncinotine New syntheses of the title compounds using two-ring-enlargement reactions are described. Starting from the aldehyde 1 , the corresponding 4′-aza derivative 15 could be obtained by reductive amination with the appropriate and protected spermidine derivative 14 (Scheme 4). Enlargement of the carbocyclic ring in 15 by five members gave, after further transformations, the hydroxylactam 18 . Transamidation of 18 , the second ring-enlargement step, led to (±)-inandenin-10-ol (7;22.9% overall yield) and, after oxidation, to inandenin-10-one ( 8 ; 22.5%, overall yield). (±)-Oncinotine 6 was synthesized by two pathways (Scheme 6): protection of the terminal NH₂ group by treatment with the Nefkens reagent and replacement of the OH group by Cl gave 24 , which by thermal transamidation followed by direct ring closure led to the oncinotine derivative 26 . The same intermediate could be obtained in higher yield via 28 by oxidation and protection of 18 followed by transamidation and reductive ring closure. Treatment of 26 with hydrazine finally gave (±)-oncinotine 6 in 15.9% overall yield.     

Synthesis of Aristotelia-type alkaloids. Part VIII. Synthesis of (±)-aristolasicone

The revised structure of the indole alkaloid aristolasicone ( 2 ) was confirmed through a convergent total synthesis of the racemic form of this metabolite. The key step involves a one-pot condensation/cyclization reaction between 1-(4-methoxyphenylsulfonyl)-1H-indole-2-acetaldehyde ( 9 ) and (±)-trans-5-(2,6-difluorobenzyloxy)-p-menth-l-en-8-amine ((±)-7). The resulting allohobartine derivative (±)- 13 , obtained in 84% yield, was deprotected and oxidized to (±)-alloscrratenone ((±)- 15 ) which cyclized smoothly to the target molecule (±)-2 upon exposure to BF₃ · Et₂O.     

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.     

A Short Synthesis of (±)-Muscone

(±)-Muscone ((±)-1) has been synthesised in three steps from 2-(2′-methylprop-2′-enyl)cyclododecan-1-one ( 2 ). The synthesis involves two key transformations: a Lewis-acid-mediated intramolecular ene reaction ( 2→3 ) and the β-cleavage of the bicyclic potassium alkoxide 3a′ to the macrocyclic enone (Z)- 11 .     

Formale Totalsynthese von (±)-Isocomen durch Anwendung der α-Alkinon-Cyclisierung

Formal Total Synthesis of (±)-Isocomen by Application of the α-Alkinon Cyclization A total synthesis of the racemic form of the sesquiterpene isocomene ( A ) was accomplished by application of the cyclopentenone anellation B→D (Scheme 1) which includes the α-alkynone cyclization C→D , a gas-phase flow thermolytic process. Starting with the known product 2 (Scheme 3) of the anellation B→D , the elaboration of ring C of A proceeded in 9 steps to the α-alkynone 16 (Scheme 5) which was cyclized at 540° selectively to give the angularly fused triquinane 4 (77%). A two-step procedure then led to 5 (Scheme 6), a last but one intermediate in a known total synthesis of (±)- A . The conversion of 16 to 4 also demonstrated the compatibility of an acetoxy function with the anellation sequence B→D .     

(±)-1-[(1R*,2R*,8aS*)-1,2,3,5,6,7,8,8a-Octahydro-1,2,8,8-tetramethylnaphthalen-2-yl]ethan-1-one: Isolation and Stereoselective Synthesis of a Powerful Minor Constituent of the Perfumery Synthetic Iso E Super®

(±)-1-[(1R*,2R*,8aS*)-1,2,3,5,6,7,8,8a-Octahydro-1,2,8,8-tetramethylnaphthalen-2-yl]ethan-1-one ( 5 ) was identified as a minor (ca. 5%) but very powerful (5 pg/l (air)) constituent of the important perfumery synthetic Iso E Super^®. Its structure was assigned by NMR spectroscopy and established by a stereoselective synthesis starting from α-ionone ( 10 ). Diastereoselective conjugate addition of Me₂CuLi to 10 was followed by a haloform reaction, esterification, and isomerization of the C=C bond by treatment with NaOCl (Schemes 3 and 4). The resulting allyl chloride 17 was ozonized and transformed into the trimethyl(vinyl)octahydrocoumarin 20 by diastereoselective Grignard reaction with ethynylmagnesium chloride, and subsequent Lindlar hydrogenation. Ireland-Claisen rearrangement of 20 followed by methylation with MeLi afforded the target molecule 5 that was identical with the material isolated from commercial Iso E Super^®.     

Syntheses of (±)- and Enantiomerically Pure (+)-Longifolene and of (±)- and Enantiomerically Pure (+)-Sativene by an Intramolecular de Mayo Reaction

Starting from 2-cyclopentenoyl chloride ((RS)- or (S)- 8 ), the racemic as well as the enantiomerically pure (+)-sesquiterpenes longifolene ((±)- and (+)- 1 , resp.) and sativene ((±)- and (+)- 2 , resp.) were synthesized efficiently by a sequence of nine and ten steps, respectively. The key sequence 10 → 16 → 3 is the first strategic application of an intramolecular photoaddition/retro-aldolization sequence (intramolecular de Mayo reaction) in organic synthesis.     

Synthesis of (±)-Pyrenolide B

In the synthesis of the title compound 12 , the important intermediate 7 was obtained in good yield from the easily available ethyl 5, 5-ethylenedioxy-2-oxocyclohexane-1-carboxylate ( 1 ) via ring enlargement of the bicyclic enol ether 5 (Scheme). Its reduction (NaBH₄ in EtOH) and subsequent protection with (t-Bu)Me₂Si resulted in the highly functionalized ten-membered lactone 9 . Introduction of the (Z)-configurated double bond, followed by deprotection and elimination of H₂O, gave (±)-pyrenolide B ( 12 ) in 16% overall yield.     

A Short and Efficient Synthesis of (±)-Modhephene by a Stereoelectronically-Controlled Ene-Reaction

(±)-Modhephene ( 6 ) has been synthesized from the easily available trimethylpentalenone 1 in 6 steps in 26% overall yield (Scheme 2). The remarkably smooth 1,4-addition/enolate trapping 1 → 2 and subsequent selenoxide elimination after oxidation furnished the key intermediate 3 which underwent an expedient and highly stereoselctive intramolecular ene-reaction to give the propellane 4 , readily convertible to (±)- 6 .     

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.     

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.     

Total Synthesis of (±)-α-Acoradiene via Intramolecular Photoaddition and Reductive Cyclobutane Cleavage

(±)-α-Acoradiene (4) has been synthesized from 3-methoxy-2-cyclohexenone by a sequence of 8 steps. The key steps (Scheme 6) are the regio- and stereoselective photo[2+2]addition 7→6 and the reductive fragmentation 6→5 .     

Quenching of O2(1Δg) by aliphatic amines

The quenching rate constants of O₂(¹Δ_g) with n-butylamine, diethylamine, dipropylamine, dibutylamine, and tripropylamine have been determined in a discharge flow system. The rate constants are found to be (1.6 ± 0.2) × 10³, (8.5 ± 0.6) × 10⁴, (9.8 ± 0.5) × 10⁴, (2.1 ± 0.1) × 10⁵, and (8.6 ± 0.5) × 10⁵ 1 mol^?1 s^?1, respectively. The rate constants are found to increase in the order, tertiary amine → secondary amine → primary amine. The “inductive effect” of alkyl substitution is also found to increase the rate constant in a given series of amines.     

Total Syntheses of (±)‐Fawcettimine, (±)‐Fawcettidine, (±)‐Lycoflexine,and (±)‐Lycoposerramine‐Q

The total syntheses of four fawcettimine‐related Lycopodium alkaloids, (±)‐fawcettimine, (±)‐fawcettidine, (±)‐lycoposerramine‐Q, and (±)‐lycoflexine, were completed in a highly stereoselective manner. The Pauson–Khand reaction of 4‐methylidene‐6‐siloxyoct‐1‐en‐7‐yne followed by regio‐ and stereoselective hydrogenation led to the short‐step preparation of the bicyclo[4.3.0]nonenone intermediate bearing a methyl group with the required stereochemistry. The subsequent chemical manipulation of the bicyclic compound afforded the 6‐5‐9‐membered tricyclic dioxo compound, which was then transformed into the four targeted alkaloids in an alternative and more efficient fashion.     

Synthese von (±)-Muscopyridin über eine C-ZIP-Ringerweiterungsreaktion

Synthesis of (±)-Muscopyridine via C-ZIP Ring Enlargement Treatment of 4-(1-nitro-2-oxocyclododec-1-yl)butanal ( 1 ) and of its methyl derivative 5 with pentylamine in EtOH at room temperature gave the ring-enlarged aminomethylidene derivatives 6 and 7 , respectively (Scheme 1). After hydrolysis of the aminomethylidene group in 6 and 7 and deformylation followed by a reductive Nef-type reaction, the macrocyclic diketones 10 and 11 , respectively, were obtained. They were transformed by a modified Hantzsch procedure to the title compound (±)-muscopyridine ( 13 ) and normuscopyridine ( 12 ), respectively.