Use of the Wolff Rearrangement of Diazo Ketones from Amino Acids as a synthetic method for the formation of oligonucleo-peptides: A novel approach to chimeric biomolecules

Photolysis and Ag-benzoate-catalyzed decomposition of the diazo ketones 2 and 4 derived from Z-Ala-OH and Z-Ala-Ala-OH in the presence of oligonucleotide derivatives bearing at the 5′-terminus an NH₂ instead of the OH group, or an aminohexyl phosphate group lead to Z-protected 3-aminobutanoyl and to Z-Ala-β-HAla derivatives, respectively (conjugates 12 , 13 , and 17 - 23 , Schemes 3-5), In solution, this amide-forming acylation reaction could be realized only with oligomers containing up to 8 unprotected nucleotide building blocks (Schemes 3 and 4). With the analogous polymer-bound and protected oligonucleotide derivatives as amino nucleophiles, excellent yields were obtained with all chain lengths tested (up to 15mer Scheme 5), The products were purified by reversed-phase HPLC and characterized by MALDI-TOF mass spectrometry (Figs. 2–4, Table 2) and by capillary gel electrophoresis (Fig.2).     

Reaktionen von 3-(Dimethylamino)-2H-azirinen mit 1,3-Benzoxazol-2(3H)-thion

Reaction of 3-(Dimethylamino)-2H-azirines with 1,3-Benzoxazole-2(3H)-thione The reaction of 3-(dimethylamino)-2H-azirines 2 with 1,3-benzoxazole-2(3H)-thione ( 5 ), which can be considered as NH-acidic heterocycle (pK_aca. 7.3), in MeCN at room temperature, leads to 3-(2-hydroxyphenyl)-2-thiohydantoins 6 and thiourea derivatives of type 7 (Scheme 2). A reaction mechanism for the formation of the products via the crucial zwitterionic intermediate A ′ is suggested. This intermediate was trapped by methylation with Mel and hydrolysis to give 9 (Scheme 4). Under normal reaction conditions, A ′ undergoes a ring opening to B which is hydrolyzed during workup to yield 6 or rearranges to give the thiourea 7. A reasonable intermediate of the latter transformation is the isothiocyanate E (Scheme 3) which also could be trapped by morpholine. In i-PrOH at 55–65° 2a and 5 react to yield a mixture of 6a , 2-(isopropylthio)-1,3-benzoxazole ( 12 ), and the thioamide 13 (Scheme 5). A mechanism for the surprising alkylation of 5 via the intermediate 2-amino-2-alkoxyaziridine F is proposed. Again via an aziridine, e.g. H ( Scheme 6 ), the formation of 13 can be explained.     

Ringöffnungen von sterisch gehinderten spirocyclischen 2, 5-Dihydro-1, 3, 4-thiadiazolen mit cycloaliphatischen,sekundären Aminen

Ring Opening of Sterically Crowded Spirocyclic 2, 5-Dihydro-l, 3, 4-thiadiazoles by Cycloaliphatic Secondary Amines At room temperature, the spirocyclic 2, 5-dihydro-l, 3, 4-thiadiazole 3 reacted with cyclic secondary amines 6 via ring opening to give N-alkylidene-hydrazones of type 7 (Scheme 2). A reaction mechanism via a base-catalyzed transformation of the dihydrothiadiazole ring to the corresponding thiolate 19 and the intermediate thioaldehyde 21 is proposed in Scheme 6. An analogous reaction occurred with the mixture of the dispiro compounds 4/5 and morpholine ( 6a ) or azetidine ( 6d ), leading to a mixture of isomeric dihydrazones 8 and 9 (Scheme 3). The structure of the symmetrical isomer 8a was established by X-ray crystallography. In addition to 8a and 9a , the thiirane lOa (Scheme 3) was isolated as a minor product.     

Synthese und Reaktionen 8-gliedriger Heterocyclen aus 3-Dimethylamino-2,2-dimethyl-2H-azirin und Saccharin bzw. Phthalimid

Synthesis and Reactions of 8-membered Heterocycles from 3-Dimethylamino-2,2-dimethyl-2H-azirine and Saccharin or Phthalimide 3-Dimethylamino-2,2-dimethyl-2H-azirine ( 1 ) reacts at 0-20° with the NH-acidic compounds saccharin ( 2 ) and phthalimide ( 8 ) to give the 8-membered heterocycles 3-dimethylamino-4,4-dimethyl-5,6-dihydro-4 H-1,2,5-benzothiadiazocin-6-one-1,1-dioxide ( 3a ) and 4-dimethylamino-3,3-dimethyl-1,2,3,6-tetrahydro-2,5-benzodiazocin-1,6-dione ( 9 ), respectively. The structure of 3a has been established by X-ray (chap. 2). A possible mechanism for the formation of 3a and 9 is given in Schemes 1 and 4. Reduction of 3a with sodium borohydride yields the 2-sulfamoylbenzamide derivative 4 (Scheme 2); in methanolic solution 3a undergoes a rearrangement to give the methyl 2-sulfamoyl-benzoate 5 . The mechanism for this reaction as suggested in Scheme 2 involves a ring contraction/ring opening sequence. Again a ring contraction is postulated to explain the formation of the 4H-imidazole derivative 7 during thermolysis of 3a at 180° (Scheme 3). The 2,5-benzodiazocine derivative 9 rearranges in alcoholic solvents to 2-(5′-dimethylamino-4′,4′-dimethyl-4′H-imidazol-2′-yl) benzoates ( 10 , 11 ), in water to the corresponding benzoic acid 12 , and in alcoholic solutions containing dimethylamine or pyrrolidine to the benzamides 13 and 14 , respectively (Scheme 5). The reaction with amines takes place only in very polar solvents like alcohols or formamide, but not in acetonitrile. Possible mechanisms of these rearrangements are given in Scheme 5. Sodium borohydride reduction of 9 in 2-propanol yields 2-(5′-dimethylamino-4′,4′-dimethyl-4′H-imidazol-2′-yl)benzyl alcohol ( 15 , Scheme 6) which is easily converted to the O-acetate 16 . Hydrolysis of 15 with 3N HCl at 50° leads to an imidazolinone derivative 17a or 17b , whereas hydrolysis with 1N NaOH yields a mixture of phthalide ( 18 ) and 2-hydroxymethyl-benzoic acid ( 19 , Scheme 6). The zwitterionic compound 20 (Scheme 7) results from the hydrolysis of the phthalimide-adduct 9 or the esters 11 and 12 . Interestingly, compound 9 is thermally converted to the amide 13 and N-(1′-carbamoyl-1′-methylethyl)phthalimide ( 21 , Scheme 7) whose structure has been established by an independent synthesis starting with phthalic anhydride and 2-amino-isobutyric acid. However, the reaction mechanism is not clear at this stage.     

1-Substituted 1,3-Dihydroisothianaphthen-2,2-dioxides: Preparation and Use as ortho-Quinodimethane Precursors in Intramolecular Cycloadditions. Preliminary communication

1,3-Dihydroisothianaphthen-2,2-dioxide (1) was readily converted to the 1-substituted sulfones 3 by deprotonation and subsequent electrophilic attack (Scheme 3 and Table). The appropriate 1-alkenyl- and 1-alkenoyl-sulfones 3 on heating at 213° to 240° underwent SO₂-extrusion to give, via the non-isolated (E)-quinodimethanes II (Scheme 1), polycyclic products such as 4, 6 and 7 in good yields (Schemes 4 and 5). On the other hand, thermolysis of the 1-alkenoyl-1-thioether sulfones 9 furnished mainly the isochromenes 10 (Scheme 6).     

Umwandlung von 6-Methylen-tricyclo[3.2.1.02,7]oct-3-en-8-onen mit Ameisensäure in kernmethylierte Phenylessigsäuren

In a preceding communication [5] it was shown that 1, 5-dimethyl-6-methylene-tricyclo[3.2.1.0^2,7]oct-3-en-8-one ( 2 ) and related tricyclic ketones are converted by strong acids (CF₃COOH, FSO₃H) into polymethylated tropylium salts with loss of carbon monoxide, e.g. the 1, 2, 4-trimethyltropylium ion 4 from 2 (Scheme 1). Under the influence of neat formic acid at 20°, 2 gives rise to ring-methylated phenylacetic acids, i.e. 2, 4, 5-trimethylphenylacetic acid ( 5 , main product) as well as smaller amounts of 2, 4, 6-and 2, 3, 5-trimethylphenylacetic acids ( 6, 7 resp.; Scheme 2). –On rearrangement of 2 in HCOOD, ca. 2 D-atoms are incorporated (formula d₂-5) into the 2, 4, 5-trimethylphenylacetic acid. The tricyclic 15 , containing 3 methyl groups, gives 2, 3, 5, 6-tetramethylphenylacetic acid ( 11 ; Scheme 4) with formic acid; the isomeric tricyclic 16 , 2, 3, 4, 5-tetramethylphenylacetic acid ( 12 ; Scheme 5). From 1, 2, 4, 5-tetramethyl-6-methylene-tricyclo[3.2.1.0^2,7]oct-3-en-8-one ( 17 ) one obtains pentamethylphenylacetic acid ( 14 ; Scheme 6). Similarly from 18 , a phenylacetic acid derivative, most probably 4-ethyl-2, 5-dimethyl-phenylacetic acid ( 19 ; Scheme 17), has been obtained. –In no case was the formation of α-phenylpropionic acid derivatives observed, not even from the tricyclic 23 containing six methyl groups. From the tricyclic ketone 2 in 70% formic acid a trimethyl-cyclohepta-2, 4, 6-triene-1-carboxyclic acid with partial formula 24 , besides 2, 4, 5-trimethylphenylacetic acid ( 5 ), is formed. 24 remained practically unchanged on standing in neat formic acid and thus does not represent an intermediate product arising by the rearrangement of 2 in that solvent. On standing in methanolic sulfuric acid, tricyclic 2 furnishes the two stereioisomeric methanol-addition products Z- 26 and E- 26 (Scheme 10); these are converted into the phenylacetic acids 5 , 6 and 7 by neat formic acid. The conversion of 2 and related compounds into ring-polymethylated phenylacetic acids, represents a novel and rather complicated reaction. In our opinion the reaction paths represented in Schemes 12 and 18 are responsible for the conversion of 2 into the trimethylphenylacetic acids, compound 40 representing a key intermediate. Analogous reaction paths can be assumed for the other tricyclic ketone transformations. The use of shift reagents in the NMR. spectroscopy and the high-resolution gas-chromatography of the corresponding methyl esters proved particularly important for the analysis of the reaction mixtures. The majority of the polymethylated phenylacetic acids were independently synthesised by means of the Willgerodt-Kindler reaction (chap. 3.2.), whose course is strongly influenced by methyl groups in the ortho-positions of the acetophenone derivatives employed.     

Diazo-Transfer Reaction with Diphenyl Phosphorazidate

Diphenyl phosphorazidate (DPPA) was used as the azide source in a one-pot synthesis of 2,2-disubstituted 3-amino-2H-azirines 1 (Scheme 1). The reaction with lithium enolates of amides of type 2 , bearing two substituents at C(2), proceeded smoothly in THF at 0°; keteniminium azides C and azidoenamines D are likely intermediates. Under analogous reaction conditions, DPPA and amides of type 3 with only one substituent at C(2) gave 2-diazoamides 5 in fair-to-good yield (Scheme 2). The corresponding 2-diazo derivatives 6–8 were formed in low yield by treatment of the lithium enolates of N,N-dimethyl-2-phenylacetamide, methyl 2-phenylacetate, and benzyl phenyl ketone, respectively, with DPPA. Thermolysis of 2-diazo-N-methyl-N-phenylcarboxamides 5a and 5b yielded 3-substituted 1,3-dihydro-N-methyl-2H-indol-2-ones 9a and 9b , respectively (Scheme 3). The diazo compounds 5–8 reacted with 1,3-thiazole-5 (4H)-thiones 10 and thiobenzophenone ( 13 ) to give 6-oxa-1,9-dithia-3-azaspiro[4.4]nona-2,7-dienes 11 (Scheme 4) and thiirane-2-carboxylic acid derivatives 14 (Scheme 5), respectively. In analogy to previously described reactions, a mechanism via 1,3-dipolar cycloaddition, leading to 2,5-dihydro-1,3,4-thiadiazoles, and elimination of N₂ to give the ‘thiocarbonyl ylides’ of type H or K is proposed. These dipolar intermediates with a conjugated C?O group then undergo either a 1,5-dipolar electrocyclization to give spirohetrocycles 11 or a 1,3-dipolar electrocyclization to thiiranes 14 .     

Eine neue Aminoazirin-Reaktion. Bildung von 3,6-Dihydropyrazin-2(1H)-onen

A New Aminoazirine Reaction. Formation of 3,6-Dihydropyrazin-2(1H)-ones The reaction of 3-(dimethylamino)-2H-azirines 1 and 2-(trifluoromethyl)-1,3-oxazol-5(2H)-ones 5 in MeCN or THF at 50–80° leads to 5-(dimethylamino)-3,6-dihydropyrazin-2(1H)-ones 6 (Scheme 3). Reaction mechanisms for the formation of 6 are discussed: either the oxazolones 5 react as CH-acidic heterocycles with 1 (Scheme 4), or the azirines 1 undergo a nucleophilic attack onto the carbonyl group of 5 (Scheme 6). The reaction via intermediate formation of N-(trifluoroacetyl)dipeptide amide 8 (Scheme 5) is excluded.     

Claisen-Umlagerung von 2-Propinyl-(3-pyridyl)-und Allyl-(3-pyridyl)äthern

Claisen Rearrangement of 2-Propinyl (3-Pyridyl) and Allyl (3-Pyridyl) Ethers

1 Verbindungen vom Typ 1 werden mit Ausnahme von 17 und 25 als Äther benannt. Der systematische Name von 1 ist: 3-(2-Propinyl)oxy-pyridin.

2-Propinyl (3-pyridyl) ether ( 1 ), synthesized from the corresponding 3-pyridinol, was heated in DMF or decane at 208° in a sealed tube. In this way the furopyridines 2 and 3 were formed, and furthermore the pyranopyridine 4 if decane was used as solvent (Scheme 1). The same reactions took place with (2-methyl-3-pyridyl) 2-propinyl ether ( 14 ). In DMF only 15 , and in decane 16 as well as 15 were formed (Scheme 3). The rearrangement of the pyridine derivative 17 , which is substituted in both O-positions to the ether moiety, gave in both DMF and decane the diastereoisomeric tetracyclic compounds 18 and 19 . The same kind of reaction took place with 25 (Scheme 4). In the thermolysis of the allyl 3-pyridyl ether ( 27 ) cyclization was observed, too. The isolated product has the structure of the dihydrofuropyridine 28 (Scheme 6). The substituted allyl 3-pyridyl ether 30 reacted in the same way to the dihydrofuropyridine 31 (Scheme 6).     

Stickstoffhaltige Dieisen-hexacarbonyl-Komplexe aus 3-Phenyl-2H-azirinen

Nitrogen-containing diiron-hexacarbonyl complexes from 3-phenyl-2H-azirines Reaction of 2,2-dimethyl-3-phenyl-2H-azirine ( 1 ) with diiron-enneacarbonyl yields as an insertion product, and in addition to other products, the diiron-hexacarbonyl complex 2 (Scheme 1), whose structure was derived from spectral data, in particular ¹³C-NMR.-data (Table 1). With trimethylamine oxide in benzene, 2 is converted into the urea derivative 3 , and yields with cerium (IV) ammonium nitrate the nitrate 4 (Scheme 1). The analogous complexes 6 and 9 have been obtained by irradiation of 1-phenyl-vinyl azide ( 5 ) and ironpentacarbonyl (Scheme 1) and from vinyl isocyanate ( 8 ) and diiron-enneacarbonyl at 40° (Scheme 2), respectively. The azirine 1 , an acetylenic compound and diiron-enneacarbonyl in benzene react to give complexes of type 10 as the main product (Scheme 3). The structure of complex 10 has been established by X-ray single crystals analysis. On the ¹³C-NMR. time scale the carbonyl groups of compound 10 show a fluxional behaviour: below ?50° the CO-groups of one of the two Fe(CO)₃-groups undergo intranuclear exchange, above ?50° the CO-groups of both Fe(CO)₃-groups undergo intranuclear exchange. Tentative reaction mechanisms for the formation of the complexes of type 2 and 10 are formulated in Schemes 5, 6 and 7.     

Photocyclisierungen von 1, 1'-Polymethylen-di-2-pyridonen. 46. Mitteilung über Photoreaktionen

Photocyclization of 1, 1′-Polymethylene-di-2-pyridones . Benzophenone sensitized irradiation of the four dipyridones 1-4 gave the internal photocyclization products 6 (64%, Scheme 4), 7 (60%, Scheme 5), 8 (Scheme 6), and 11 (26%, Scheme 7), respectively. The decamethylene compound 5 yielded only polymeric material. The primary [2+2] photoproduct 8 from dipyridone 3 (Scheme 6) is relatively unstable. Further irradiation or heating to 65° induced a Cope rearrangement to give compound 9 which, on heating to 137°, was converted into the isomeric compound 10 . This product, as well as the other photoproducts mentioned, are rearranged back to their respective starting materials upon direct irradiation with 254 nm light or by heating to higher temperatures. The various possibilities for cycloadditions of pyridones are discussed as well as the possible factors which are responsible for the highly regioselective photoreactions of the dipyridones 1–4 .     

Herstellung neuer polycyclischer Verbindungen durch intramolekulare Diels-Alder-Reaktionen von Cyclohexa-2,4-dien-1-on-Abkömmlingen

Synthesis of new polycyclic compounds by means of intramolecular Diels-Alder reactions of cyclohexa-2,4-dien-1-one derivatives Thermal rearrangement of mesityl penta-2,4-dienyl ether ( 1 ), consisting of the isomers E (93%) and Z (7%), furnished, besides mesitol, the two mesityl penta-1,3-dienyl ethers 2 (24%) and 3 (3%), and the two tricyclic ketones 4 (4,5%) and 5 (12,5%) (Scheme 1). A probable mechanism for this formation of 2 involves a [1,5]-hydrogen shift in (Z)- 1 . Isomerisation of (E)- 1 to (Z)- 1 at 145° occurs via reversible sigmatropic [3,3]- and [5,5]-rearrangements of (E)- 1 to the cyclohexadienones 38 and 39 respectively (see Chapter A p. 1710, and Scheme 15). Formation of 3 from either (Z)- 1 or 2 is rationalized by a series of pericyclic reactions as outlined in Chapter A and Scheme 16. The tricyclic ketones 4 and 5 are undoubtedly formed by internal Diels-Alder reactions of the 6-pentadienyl-cyclohexa-2,4-dien-1-one 6 (Scheme 2). In fact, at 80° 6 is converted into 4 (5%) and 5 (35%). At 80° the cyclohexadienone derivative 7 furnished the corresponding tricyclic ketones 8 (15%) and 9 (44%) (Scheme 2). 5 and 9 contain a homotwistane skeleton. 8 and 9 are easily prepared by reaction of sodium 2,6-dimethylphenolate with 3-methyl-penta-2,4-dienyl bromide at ambient temperature, followed by heating, and finally separation by cristallization and chromatography. The cyclohexadienones 6 and 7 have mainly (E)-configuration. Here too (E) → (Z) isomerization is a prerequisite for the internal Diels-Alder reaction, and this partly takes place intramolecularly through reversible Claisen and Cope rearrangements (Scheme 17). On the other hand, experiments in the presence of 3,5-d₂-mesitol have shown (Table 1) that intermolecular reactions, involving radicals and/or ions, are also operating (see Chapter B , p. 1712). Two different modi (I and II) exist for intramolecular Diels-Alder reactions (Scheme 18). Whereas only modus I is observed in the cyclization of 5-alkenyl-cyclohexa-l,3-dienes, in that of (2)-cyclohexadienones 6 and 7 (Scheme 2) both modi are operating. Only in modus 11-type transitions is the butadienyl conjugation of the side chain retained, so that modus 11-type addition is preferred (Chapter C p. 1716). Analogously to the synthesis of the tricyclic ketones 4 , 5 , 8 and 9 , the tricyclic ketone 15 (Scheme 4) and the tetracyclic ketone 11 (Scheme 3) are prepared from mesitol, pentenyl bromide and cycloheptadienyl bromide, respectively. From the polycyclic ketones derivatives such as the alcohols 16 , 17 , 18 , 19 , 23 , 24 and 25 (Schemes 9 and 11), policyclic ethers 20 , 21 , 22 and 26 (Scheme 10), epoxides 30 , 32 (Scheme 13), diketones 31 , 33 (Scheme 13) and ether-alcohols 35 and 36 (Scheme 14) have been prepared. Most of these conversions show high stereoselectivity.     

The Allyl Ester as Carboxy-Protecting Group in the Stereoselective Construction of Neuraminic-Acid Glycosides

The application of the allyl-ester moiety as protecting principle for the carboxy group of N-acetylneuraminic acid is described. Peracetylated allyl neuraminate 2 is synthesized by reacting the caesium salt of the acid 1 with allyl bromide. Treatment of 2 with HCl in AcCl or with HF/pyridine gives the corresponding 2-chloro or 2-fluoro derivatives 3 and 4 , respectively (Scheme 1). In the presence of Ag₂CO₃, the 2-chloro carbohydrate 3 reacts with di-O-isopropylidene-protected galactose 5 to give the 2–6 linked disaccharide with the α-D -anomer 6a predominating (α-D /β-D = 6:1; Scheme 2). Upon activation of the 2-fluoro derivative 4 with BF₃ · Et₂O, the β-D -anomer 6b is formed preferentially (α-D /β-D = 1:5). In further glycosylations of 4 with long-chain alcohols, the β-D -anomers are formed exclusively (see 10 and 11 ; Scheme 4). The allyl-ester moiety can be removed selectively and quantitatively from the neuraminyl derivatives and the neuraminyl disaccharides by Pd(0)-catalyzed allyl transfer to morpholine as the accepting nucleophile (see Scheme 5).     

1,5-Dipolare Elektrocyclisierung von Acyl-substituierten ‘Thiocarbonyl-yliden’ zu 1,3-Oxathiolen

1,5-Dipolar Electrocyclization of Acyl-Substituted ‘Thiocarbonyl-ylides’ to 1,3-Oxathioles The reaction of α-diazoketones 15a, b with 4,4-disubstituted 1,3-thiazole-5(4H)-thiones 6 (Scheme 3), adamantanethione ( 17 ), 2,2,4,4-tetramethyl-3-thioxocyclobutanone ( 19 ; Scheme 4), and thiobenzophenone ( 22 ; Scheme 5), respectively, at 50–90° gave the corresponding 1,3-oxathiole derivatives as the sole products in high yields. This reaction opens a convenient access to this type of five-membered heterocycles. The structures of three of the products, namely 16c, 16f , and 20b , were established by X-ray crystallography. The key-step of the proposed reaction mechanism is a 1,5-dipolar electrocyclization of an acyl-substituted ‘thiocarbonyl-ylide’ (cf. Scheme 6). The analogous reaction of 15a, b with 9H-xanthen-9-thione ( 24a ) and 9H-thioxanthen-9-thione ( 24b ) yielded α,β-unsaturated ketones of type 25 (Scheme 5). The structures of 25a and 25c were also established by X-ray crystallography. The formation of 25 proceeds via a 1,3-dipolar electrocyclization to a thiirane intermediate (Scheme 6) and desulfurization. From the reaction of 15a with 24b in THF at 50°, the intermediate 26 (Scheme 5) was isolated. In the crude mixtures of the reactions of 15a with 17 and 19 , a minor product containing a CHO group was observed by IR and NMR spectroscopy. In the case of 19 , this side product could be isolated and was characterized by X-ray crystallography to be 21 (Scheme 4). It was shown that 21 is formed – in relatively low yield – from 20a . Formally, the transformation is an oxidative cleavage of the C?C bond, but the reaction mechanism is still not known.     

Synthese von 3,3-Dimethylperhydro-1,4-diazepin-2,5,7-trionen aus 3-Dimethylamino-2,2-dimethyl-2H-azirin und Malonsäuremonoamiden

Synthesis of 3,3-Dimethylperhydro-1,4-diazepin-2,5,7-triones from 3-Dimethylamino-2,2-dimethyl-2H-azirine and Malonic Acid Monoamides Reaction of the aminoazirine 1 and malonic acid monoamides 5 in CH₃CN yielded triamides of type 6 (Scheme 2), which were transformed to the corresponding phenylthioates 9 by treatment of a solution of 6 and thiophenol in CH₃CN with HCl (Scheme 4). Cyclization of 9 to give the 1,4-diazepin-2,5,7-trione of type 10 was achieved with NaH in toluene at about 90°. It has been shown that 2-oxazolin-5-ones are intermediates in the selective cleavage of the therminal amide function of 6 (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 .     

1,3-Dipole mit zentralem S-Atom aus der Umsetzung von Aziden mit Thiocarbonyl-Verbindungen: Eine unerwartete MeS-Wanderung im Abfangprodukt eines ‘Thiocarbonyl-aminids’ mit Dithiobenzoesäure-methylester

1,3-Dipoles with a Central S-Atom from the Reaction of Azides and Thiocarbonyl Compounds: An Unexpected MeS Migration in the Trapping Product of a ‘Thiocarbonyl-aminide’ with Methyl Dithiobenzoate Reaction of PhN₃ with O-methyl thiobenzoate ( 11a ) and thioacetate ( 11c ) as well as with the dithio esters 11b,d at 80° yields the corresponding imidates and thioimidates 12 (Scheme 3). The formation of 12 is rationalized by a 1,3-dipolar cycloaddition of the azide and the C?S group followed by successive elimination of N₂ and S. In the three-component reaction of 11b , PhN₃, and the sterically crowded thioketone 1a , 1,2,4-trithiolane 13a and 1,4,2-dithiazolidine 3a are formed in addition to 12b (Scheme 4). The heterocycles 13a and 3a are trapping products of 1a and ‘thiocarbonyl-thiolate’ 5a and ‘thiocarbonyl-aminide’ 2a (Ar?Ph), respectively (Scheme 6). These 1,3-dipoles are formed as reactive intermediates. Surprisingly, in the presence of catalytic amounts of acids, the major product is the (methyldithio)cyclobutyl thioimidate of type 14 (Scheme 5), formed by an acid-catalyzed MeS migration in dithiazolidine 17 . A reaction mechanism is proposed in Scheme 7.     

A Novel Synthetic Approach to (±)‐Desoxynoreseroline

(±)‐Desoxynoreseroline ( 3 ), the basic ring structure of the pharmacologically active alkaloid physostigmine ( 1 ), was synthesized starting from 3‐allyl‐1,3‐dimethyloxindole ( 9 ). The latter was prepared from the corresponding 2H‐azirin‐3‐amine 6 by a BF₃‐catalyzed ring enlargement via an amidinium intermediate 7 (Scheme 1). An alternative synthesis of 9 was also carried out by the reaction of N‐methylaniline with 2‐bromopropanoyl bromide ( 12 ), followed by intramolecular Friedel–Crafts alkylation of the formed anilide 13 to give Julian's oxindole 11 . Further alkylation of 11 with allyl bromide in the presence of LDA gave 9 in an excellent yield (Scheme 3). Ozonolysis of 9 , followed by mild reduction with (EtO)₃P, gave the aldehyde 14 , whose structure was chemically established by the transformation to the corresponding acetal 15 (Scheme 4). Condensation of 14 with hydroxylamine and hydrazine derivatives, respectively, gave the corresponding imine derivatives 16a – 16d as a mixture of syn‐ and anti‐isomers. Reduction of this mixture with LiAlH₄ proceeded by loss of ROH or RNH₂ to give racemic 3 (Scheme 5).     

Fulven-Dimere: Synthese,Strukturbeweis and thermisches Verhalten

Fulvene-Dieters: Synthesis, Structure Elucidation and Thermal Behaviour In contrast to earlier assumptions, thermal reaction of pure fulvene ( 1a ), 6-methylfulvene ( lb ) and 6, 6-dimethylfuivene ( 1c ) at 227deg; gives oligomeric mixtures consisting mainly of the endo-[4 + 2]-eycloaddition products 2a , 2b and 2c . Thermal reactivity of the fulvenes decreases strongly in the series 1a > 1b > 1c . While the dimers 2b and 2c equilibrate very easily in solution above room temperature with 1b and 1c , respectively, 2a equilibrates with the isomer 5a (? 1, 6-Dimethyliden3a α, 3bβ, 6a α, 6bβ-tetrahydro-1-H), 6 H-bi (cyclopentadienylen). This surprising rearrangement envolves a formal 1,3-shift of the 1, 2-dihydrofulvene-unit of 2a (s. Scheme 4).     

Synthesis of the macrocyclic spermidine alkaloids oncinotine, neooncinotine, isooncinotine and pseudoonicotine in racemic forms (author's transl)]

Synthesis of the Macrocyclic Spermidine Alkaloids Oncinotine, Neooncinotine, Isooncinotine and Pseudooncinotine in Racemic Forms . The four isomeric spermidine alkaloids (Scheme 1) mentioned in the title were synthesized as follows: Reaction of the piperidine derivative 5 and the bromide 6 led to the intermediate 13 which was converted to (±)-oncinotine (±- 1 ) and (±)-pseudooncinotine (±- 4 ) (Scheme 3). The analogous reaction of 5 and the isomeric bromid 7 gave the intermediate 22 from which (±)-neooncinotine (±- 2 ) and (±)-isooncinotine (±- 3 ) were synthesized (Scheme 4). The overall yields were found to be between 22 (±- 1 ) and 54% (±- 3 ).