Wolff-Kishner Research Articles

Preparation and Chiroptical Properties of Optically Active Tetracyclic Cage-shaped Hydrocarbons; [m.0]Triblattanes and [m.1]Triblattanes

Abstract Horse liver alcohol dehydrogenase mediated reduction of tetracyclo[4.3.0.02,5.03,8]nonan-9-one ([1.0]triblattan-9-one) (17) gave (+)-17 and (−)-tetracyclo[4.3.0.02,5.03,8]nonan-9-ol(18). Hydrogenolysis of (+)-17 with 5% rhodium-alumina to (+)-(1R,3R,6R8R)-twist-brendan-9-ol with known absolute rotation allowed us to assign the 1S,2S,3R,5R,6R,8R absolute configuration to (+)-17 and to calculate the absolute rotation of (+)17. Wolff-Kishner reduction of (+)-17 gave (+)-[1.0]triblattane. BF3-Catalyzed diazomethane ring expansion of (+)-17 was followed by Wolff-Kishner reduction to afford optically active [m.0]triblattanes. (+)-Tetracyclo[5.2.12,6.04,8]decan-5-one ([1.1]triblattan-5-one) with known absolute configuration and absolute rotation was transformed to optically active [m.1]triblattanes by diazomethane ring expansion with BF3 etherate followed by Wolff-Kishner reduction. The known optical purities of our starting materials permitted calculation of the absolute molecular rotations of [m.0]triblattanes and [m.1]triblattanes. The chiroptical properties of triblattanes are discussed.

NEW STRATEGY FOR CHIRAL ALKALOID SYNTHESIS COMMENCING WITH A CARBOHYDRATE. SIMPLE SYNTHESIS OF (−)-ALLO-YOHIMBANE FROM LEVOGLUCOSENONE

Abstract An optically active allo-yohimbane was synthesized in 12 steps from levoglucosenone. The key steps are Diels–Alder cycloaddition for the E-ring construction followed by eliminative Wolff–Kishner reduction and selective double cyclization in the D- and C-ring formation.

Quinolizidines. XVII. A new access to 9,10-dimethoxy- and 8-hydroxy-9,10-dimethoxybenzo(a)quinolizidine-type Alangium alkaloids from 3-acetylpyridine.

New syntheses of the ipecac and Alangium alkaloids possessing the 9, 10-dimethoxy- and 8-hydroxy-9, 10-dimethoxybenzo [a] quinolizidine skeletons (types 1 and 2) have now become possible through generally applicable routes starting from 3-acetylpyridine (5). The routes involve the mercuric acetate-edetic acid oxidation of the 3-acetylpiperidine derivatives 9a, b or the alkaline ferricyanide oxidation of the quaternary salts (26a, b and 27a, b) of 3-acetylpyridine equivalents, Wolff-Kishner reduction of the acetyl group or reductive desulfurization of the thioketal group, sulfenylation-dehydrosulfenylation of the lactams 12a, b, Michael reaction of the α, β-unsaturated lactams 15a, b, and de-ethoxycarbonylation of the Michael adducts 16a, b as the main operations.

ChemInform Abstract: SYNTHESIS OF (3N)CYCLOPHANES AND RELATED COMPOUNDS BY ALKYLATION OF TOSYLMETHYL ISOCYANIDE WITH BIS(BROMOMETHYL)BENZENES

AbstractDurch Alkylierung von Tosylmethylisocyanid (II) mit Bis‐brommethyl‐benzolen (I) unter den Bedingungen der Phasentransfer‐Katalyse werden die Verbindungen (III) und weiter die Cyclophane (IV)‐(IX) erhalten.

ChemInform Abstract: SYNTHESIS AND PHARMACOLOGICAL ACTIVITY OF 6‐ARYL‐2‐AZABICYCLO(4.2.1)NONANES

A series of 6-phenyl-, 6-(m-methoxyphenyl)-, and 6-(m-hydroxyphenyl)-2-azabicyclo[4.2.1]nonanes was synthesized by a sequence involving alkylation of an appropriate 2-arylcyclopentanone with an aminoalkyl substituent. Subsequent ring closure at the other alpha position on the cyclopentanone ring and Wolff-Kishner reduction afforded the title compound. Several derivatives of these materials showed activity in an antinociceptive assay comparable to codeine. Most analogues were either inactive or toxic.

Synthesis of (3n)cyclophanes and related compounds by alkylation of tosylmethyl isocyanide with bis(bromomethyl)benzenes.

Bis (2-isocyano-2-tosylethyl) benzenes (12a, 12b, and 12c), synthesized by the reaction of tosylmethyl isocyanide (7) with bis (bromomethyl) benzenes (11a, 11b, and 11c) in 2 : 1 molar ratio, reacted again with 11a, 11b, and 11c under phase-transfer conditions to form 2, 11-diisocyano-2, 11-ditosyl[32]cyclophanes of ortho, meta, and para types (14, 15, and 17), 2, 11, 20-triisocyano-2, 11, 20-tritosyl[33]paracyclophane (19), and 2, 11, 20, 29-tetratosyl[34]cyclophanes of meta and para types (16 and 18). [32]Metacyclophane (1), [33]paracyclophane (31), and [34]meta- and paracyclophanes (32 and 33) could be obtained by hydrolysis and Wolff-Kishner reduction of the above intermediates (15, 16, 18, and 19). Hydrolysis of 2, 11-diisocyano-2, 11-ditosyl[32]orthocyclophane (14) yielded 5, 6, 11, 12-tetrahydro-dibenz[b, g]-azulen-5-one (30) instead of the corresponding ketone (26). Structural properties of the prepared cyclophanes (15, 17, 21, 23, 24, 31, and 33) are described on the basis of the proton magnetic resonance (PMR) spectra.

Synthesis and pharmacological activity of 6-aryl-2-azabicyclo[4.2.1]nonanes.

A series of 6-phenyl-, 6-(m-methoxyphenyl)-, and 6-(m-hydroxyphenyl)-2-azabicyclo[4.2.1]nonanes was synthesized by a sequence involving alkylation of an appropriate 2-arylcyclopentanone with an aminoalkyl substituent. Subsequent ring closure at the other alpha position on the cyclopentanone ring and Wolff-Kishner reduction afforded the title compound. Several derivatives of these materials showed activity in an antinociceptive assay comparable to codeine. Most analogues were either inactive or toxic.

Synthesis of l,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acids and homologous pyridine and azepine analogues thereof

Several syntheses of the previously unknown 1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid and various 5- and 6-substituted derivatives thereof have been devised. Some of these processes have been extended to the heretofore unreported 5,6,7,8-tetrahydropyrrolo[1,2-a]pyridine-8-carboxylic acid and 5,6,7,8-tetrahydro-9H-pyrrolo[1,2-a]azepine-9-carboxylic acid derivatives.Two new processes were developed for the conversion of pyrroles into the corresponding pyrrol-2-acetic acid esters. Both processes were based on the use of the readily available ethoxalylpyrrole derivatives as the starting material. One sequence involved saponification of the α-keto ester, followed by Wolff–Kishner reduction of the crude α-keto acid salt and subsequent esterification of the acetic acid derivative thus produced. The second synthesis commenced with reduction of the 2-ethoxalpyrrole with sodium borohydride to the α-hydroxy ester, which was further reduced to the acetic acid ester with an equimolar mixture of triphenylphosphine and triphenylphosphine diiodide.

A Facile Synthesis of 2, 15-Hexadecanedione using Alkyl Sulfone

2, 15-Hexadecanedione (5), a key intermediate for the synthesis of dl-muscone, was prepared from alkyl sulfone. The Claisen condensation of 1, 6-bis (p-toluenesulfonyl) hexane (1) and ethyl 4, 4- (ethylenedioxy) valerate afforded 2, 2, 15, 15-bis (ethylenedioxy) -6, 11-bis (p-toluenesulfonyl) -5, 12-hexadecanedione (2) in quantitative yield. The reductive elimination of the sulfonyl groups, the Wolff-Kishner reduction, and hydrolysis of the diacetal gave 2, 15-hexadecanedione (5) in good yield.

Terpenoid chemistry. XXV. The absolute configuration of ( - )-ngaione, ( - )-epingaione and related substances

The absolute configuration of (-)-ngaione has been confirmed as (2'S,5'R)-4-methyl-1-(5'-methyl-2',3',4',5'-tetrahydro[2',3''-bifuran]-5'-yl)pentan-2-one as was proposed by Hegarty, Kelly, Park and Sutherland in 1970, by converting it into (–)-ngaiane, (2S,5S)-5-methyl-5-(4''-methylpentyl)-2,3,4,5-tetrahydro[2,3'-bifuran], which is shown to resist ring opening by nucleophiles. Further confirmation was obtained by the ozonolysis of (–)-ngaiane to (–)-(4R)-4,8-dimethylnonan-4-olide comparable in molecular rotation with (–)-(4S)-4-methylhexan-4-olide which has been correlated with (–)-(R)-linalool. Wolff-Kishner reduction of the hydrazone or semicarbazone of (–)-ngaione yields mainly an E,Z(1S,4ξ)-1-(furan-3'-yl)-4,8-dimethylnon-5-en-1-ol with some ngaiane. Being (+)-ngaione, ipomeamarone does not have the absolute configuration assigned by Kubota, Nakajima and Matsuura in 1964. The name ipomeamarone is redundant, implies an incorrect stereochemistry and should be abandoned.

ChemInform Abstract: SYNTHESIS AND ABSOLUTE CONFIGURATION OF (‐)‐D3‐TRITWISTANE, (‐)‐(1S,3S,6S,7S,10S,12S)PENTACYCLO(8.4.0.02,7.03,12.06,11)TETRADECANE

AbstractDie partielle Hydrolyse des syn‐Diacetoxy‐Cz‐bis‐methanotwistans (I) liefert das Diastereomerengemisch der Hydroxyacetate (II) und (III), die nach Oxidation, Ringerweiterung mit Diazornethan (IV) und Wolff‐Kishner‐Reduktion das C2‐Methanoditwistanol (V) ergeben.

The Transformation of Jervine into 18-Functional D-Homo-C-norsteroids. IV. The Transformation of Jervine into (20R)-18,20β-Epoxy-3β-hydroxy-17β-ethyletiojervan-18-one 3-Acetate via (20R)-18,20β-Epoxy-3β-hydroxy-12α,17β-ethyletiojervan-11-one 3-Acetate

Abstract Catalytic hydrogenation of (22S,25S)-N-acetyl-3β,23β-dihydroxyveratra-5,13(17)-dien-11-one 3-acetate over rhodium-platinum catalyst in acetic acid gave (22S,25S)-N-acetyl-3β,23β-dihydroxyveratranin-11 -one 3-acetate (2) in ca 70% yield, together with two minor products. Irradiation of 2 in benzene containing mercury(II) oxide and iodine gave 20-formyl-3β-hydroxy-12α,17β-ethyletiojervan-11-one 3-acetate (5) in 43% yield, accompanied by the 17-epimer of (22S,23R,25S)-N-acetyl-3β-hydroxy-5α-jervanin-11-one 3-acetate (4%). Aldehyde 5 was transformed into 3β-hydroxy-12α,17β-ethyletiojervane-11,20-dione 3-acetate (15) (79% yield) by photo- or coppercatalysed oxygenation of the corresponding enamine. Reduction of 15 with sodium borohydride gave 3β,20β-dihydroxy-12α,17β-ethyletiojervan-11-one 3-acetate (17) as a major product (69%), together with the 20-epimer. The hypoiodite reaction of 17 gave 18,20β-epoxy-3β-hydroxy-17β-ethyl-12α-etiojervan-11-one 3-acetate (19) in 92% yield. Hydrolysis of 19 resulted in the isomerization of the C/D ring junction to give 18,20β-epoxy-3β-hydroxy-17β-ethyletiojervan-11 -one (20), the first 18-functional C/D trans D-homo-C-norsteroid ever prepared. Wolff-Kishner reduction of 20 gave the corresponding 11-deoxo compound; its acetylation followed by oxidation yielded 18,20β-epoxy-3β-hydroxy-17β-ethyletiojervan-18-one 3-acetate. The 11-oxo function of 19 can be reduced quite easily with lithium aluminum hydride to give the corresponding 11β-ol.

Synthesis of 5-p-hydroxybenzyl-5,6-dihydro-2-naphthol, (±)-sequirin D

A high-yield six-step synthesis of sequirin D (1a), a naturally occurring norlignan, is described. Michael addition of deoxyanisoin (2) to acrylonitrile gives a ketonitrile (3), which on Wolff–Kishner reduction is reduced and hyrolysed in situ to 4,5-bis-p-methoxyphenylpentanoic acid (4). Cyclodehydration of (4) with polyphosphoric acid, followed by borohydride reduction and dehydration furnishes di-O-methylsequirin D (1b) which affords on demethylation sequirin D (1a) in an overall yield from (2) of 60%. The key synthon (4) has also been prepared by three other routes.

Highly stereocontrolled synthesis of [3.3.3] propellane sesquiterpenes. ( ± )-Modhephene and (±)-epimodhephene

Stereospecific total synthesis of (±)-modhephene ( 2) and (±)-epimodhephene ( 3) are reported. Conjugate addition of 1-trimethylsilyl-1-butyn-4-yl cuprate (BF 3-etherate catalysis) to bicyclic ketone 6, fluoride ion-promoted deblocking of the terminal acetylene, and ene reaction, gave tricyclic enone 11. Sequential Wittig methylenation, regiocontrolled epoxidation, and Lewis acid catalyzed isomerization afforded ketone 14 whose double bond relocation and Wolff-Kishner reduction led exclusively to 2. In a still shorter route to 3, 3-butenyl cuprate addition to 6 was utilized to gain access to 7. Thermolysis of this intermediate, methylenation, and double bond isomerization were found to deliver pure 3 successfully.

SYNTHESIS AND ABSOLUTE CONFIGURATION OF (−)-D3-TRITWISTANE, (−)-(1S,3S,6S,7S,10S,12S)PENTACYCLO[8.4.0.02,7.03,12.06,11]TETRADECANE

Abstract Diazomethane ring expansion of 12-acetoxy-C2-bismethanotwistan-8-one (11) followed by the Wolff–Kishner reduction and the Jones oxidation gave C2-methanoditwistan-4-one (14) whose incubation with Rhodotorula rubra afforded the (−)-enantiomer 16, which was converted into (−)-(1S,3S,6S,7S,10S,12S)-D3,-tritwistane (7).

ChemInform Abstract: SYNTHESIS OF BRIDGED 2‐PHENYLCYCLOHEXYLAMINES AS POTENTIAL ANALGETICS

AbstractAusgehend von den cyclischen Ketonen (I) erhält man über die entsprechenden Enamine (III) mit Acrylchlorid (IV) die bicyclischen Diketone (V).

Synthesis of 2,5-Dehydrohomoadamantane (Tetracyclo[5.3.1.02,5.03,9]undecane) from 2,4-Dehydrohomoadamantane (Tetracyclo[5,3.1.03,5.04,9]undecane)

Abstract A reaction of 2,4-dehydrohomoadamantane with NBS in AcOH followed by LiAlH4 reduction and subsequent CrO3–pyridine complex oxidation gave endo-2-bromohomoadamantan-4-one (9) in good yield. A treatment of 9 with t-BuOK in t-BuOH followed by Wolff-Kishner reduction furnished 2,5-dehydrohomoadamantane.

Asymmetric synthesis of an optically active trans doubly bridged ethylene, (–)-(R)-D2-bicyclo[8.8.0]octadec-1(10)-ene

U.v. irradiation of the cis bicyclic αβ-unsaturated ketone (5) in diethyl Lg-(+)-tartrate afforded a 1 : 7 mixture of the cis(5) and the trans ketone (6) enriched in the (–)-enantiomer; Wolff–Kishner reduction of (6) yielded (–)-D2-bicyclo[8.8.0]octadec-1(10)-ene (7)(optical purity 0·5–1·0%) with the (R)- configuration.

The Transformation of Jervine into 18-Functional C-Nor-D-homosteroids

Abstract N,O-Diacetyldeoxojervine, obtained by the Wolff-Kishner reduction of jervine followed by acetylation, has been catalytically hydrogenated to (22S,25S)-N,3-O-diacetyl-5α-veratranine-3β,3β-diol. Irradiation in benzene containing mercury(II) oxide and iodine afforded 20-formyl-17β-ethyl-12α-etiojervan-3β-ol 3-acetate which was converted into 17β-ethyl-3β-hydroxy-12α-etiojervan-20-one 3-acetate by dye-sensitized photo-oxygenation of the corresponding morpholine enamine. Reduction to 17β-ethyl-12α-etiojervane-3β,20β-diol 3-acetate with sodium borohydride followed by irradiation in benzene in the presence of mercury(II) oxide and iodine afforded an 18-functional C-nor-D-homosteroid, (20R)-18,20-epoxy-17β-ethyl-12α-etiojervane-3β,20β-diol. The configuration of the methyl group on the tetrahydrofuran ring has been shown to be α on the basis of the NMR spectrum, confirming a previous assignment.

Synthesis of bridged 2-phenylcyclohexylamines as potential analgetics.

9-Amino-1-(m-hydroxyphenyl) bicyclo [3. 3. 1] nonanes (Va) and their seven-membered homologs (Vb) were synthesized as potential analgetic agents. Condensation of acryloyl chloride with the morpholine enamine of the cyclohexanone (1a) gave the diketone (4a). Ketalization of 4a followed by Wolff-Kishner reduction gave the 9-oxo derivative (11), which was converted to the 9-amino derivative (16) via the oxime (12). Condensation of acryloyl chloride and the morpholine enamine of the cycloheptanone (1b) gave the imminium salt (3b). Reaction of 3b with NH2OH occurred regiospecifically to give the 9-oxo-10-oxime (19). The oxime (19) was ultimately converted to the 10-amino derivative (27) via the amino-alcohol (21). LiAlH4 reduction of the 10-endo-ethoxycarbamoyl derivative (25) and its 9-hydroxy derivative (23) anomalously gave epimeric mixtures of the 10-methylamino derivatives. From the primary amines 16 and 27, various N-substituted derivatives were prepared for pharmacological evaluation. None showed significant activity.