Synthesis and Structure of Carbonyliron Complexes of Allenecarboxylates and Allenic Lactones

On irradiation in the presence of Fe(CO)₅, the allenecarboxylates 1 afforded binuclear carbonyliron complexex 6 (Scheme 3), whereas the allenic lactone 7 under similar conditions gave a mixture of one binuclear and two mononuclear carbonyliron complexes ( 9 , 8 , and 10 ; Scheme 4). The structure of the complexes has been elucidated by X-ray crystallography. The structure of the binuclear complex 9 corresponds to that of 6 , while 8 has been shown to be a 1,3-butadiene(tricabonyl)iron complex. The unique structure of the 10 represents a new type of allenic complex. A stepwise formation of the complexes via intermediate allene(tetracarbonyl) iron complexes type 11 and 13 is suggested. Treatment of the binuclear complex 6b with FeCl₃ led to the formation of the free ligand and a mixture of mononuclear complexes 13 and 14 (Scheme 5). On heating, the 1,3-diene complex 8 yielded the free ligand 15 , the prouduct of a (1,3) H shift in the allene 7 ; the complex 10 on the other hand liberates 7 on treatment with ethylenetracarbonitrile (TCNE) (Scheme 6).     

Glyconothio-O-lactones Part II. Cycloaddition to Dienes,Diazomethane, and Carbenoids

The addition of dienes, diazomethane, and carbenoids to the manno- and ribo-configurated thio-γ-O-lactones 1 and 2 was investigated. Thus, 1 (Scheme 1) reacted with 2,3-dimethylbutadiene (→ 4 , 73%), cyclopentadiene (→ 5a/b 1:1, 70%), cyclohexa- 1,3-diene (→ 9a/b 2:3, 92%), and the electron-rich butadiene 6 (→ 7a/b 3:1, 82%). Wheras 5a/b was separated by flash chromatography, 7a/b was desilylated leading to the thiapyranone 8 . Selective hydrolysis of one isopropylidene group of 9a/b and flash chromatography gave 10a and 10b . The structures of the adducts were elucidated by X-ray analysis ( 4 ), by NOE experiments ( 4 , 5a , 5b , 7a/b , 10a , and 10b ), and on the basis of a homoallylic coupling ( 7a/b ). The additions occurred selectively from the ‘exo’ -side of 1 . Only a weak preference for the ‘endo’-adducts was observed. Hydrogenation of 9a/b with Raney-Ni (EtOH, room temperature) gave the thiabicyclo [2.2.2]octane 11 . Under harsher conditions (dioxane, 110°), 9a/b was reduced to the cyclohexyl ß-D C-glycoside 12 which was deprotected to 13 . X-Ray analysis of 13 proved that the desulfuration occurred with inversion of the anomeric configuration. The regioselective addition of the dihydropyridine 14 to 1 (Scheme 2) and the methanolysis of the crude adduct 15 gave the lactams 16a (32%) and 16b (38%). Desilylation of 15 with Bu₄NF · 3H₂O, however, gave the unsaturated piperidinedione 17 (92%) which was deprotected to the tetrol 18 (65%). Similarly, 2 was transformed via 19 (62%) into the triol 20 (74%). The cycloaddition of 1 with CH₂N₂ (Scheme 3) gave a 35:65 mixture of the 2,5-dihydro- 1,3,4-triazole 21 and the crystalline 4,5-dihydro 1,2,3-triazole 22 . Treatment of 21 and 22 with base gave the hydroxytriazoles 23 and 24 , respectively. The structure of 24 was established by X-ray analysis. The triazole mixture 21/22 was separated by prep. HPLC at 5°. At room temperature, 21 already decomposed (half-life 21.6 h) leading in CDCI₃ solution to a complex mixture (containing ca. 20–25% of the spirothiirane 27 and ca. 7–10% of its anomer) and in MeOH solution exclusively to the O,O,S-ortholactone 26 . Crystals of 22 proved be stable at 105°. Upon heating in petroleum ether at 100°, 22 was transformed into a ca. 1:1 mixture of 27 and the enol ether 28 . The reaction of 1 with ethyl diazoacetate (Scheme 4) in the presence of Rh₂(OAc)₄. 2H₂O gave the unsaturated esters 29 (33%) and 30 (26%), whereas the analogous reaction with diethyl diazomalonate afforded the spirothiirane 31 (68%) and the enol ether 32 (29%). Complete transformation of 31 into 32 was achieved by the treatment with P(NEt₂)₃. Similary, 33 (69%) was prepared from 2 .     

Synthesis of 1‐Methyl‐6,10‐diphenylheptalene Derivatives

The reduction of heptalene diester 1 with diisobutylaluminium hydride (DIBAH) in THF gave a mixture of heptalene‐1,2‐dimethanol 2a and its double‐bond‐shift (DBS) isomer 2b (Scheme 3). Both products can be isolated by column chromatography on silica gel. The subsequent chlorination of 2a or 2b with PCl₅ in CH₂Cl₂ led to a mixture of 1,2‐bis(chloromethyl)heptalene 3a and its DBS isomer 3b . After a prolonged chromatographic separation, both products 3a and 3b were obtained in pure form. They crystallized smoothly from hexane/Et₂O 7 : 1 at low temperature, and their structures were determined by X‐ray crystal‐structure analysis (Figs. 1 and 2). The nucleophilic exchange of the Cl substituents of 3a or 3b by diphenylphosphino groups was easily achieved with excess of (diphenylphospino)lithium (=lithium diphenylphosphanide) in THF at 0° (Scheme 4). However, the purification of 4a / 4b was very difficult since these bis‐phosphines decomposed on column chromatography on silica gel and were converted mostly by oxidation by air to bis(phosphine oxides) 5a and 5b . Both 5a and 5b were also obtained in pure form by reaction of 3a or 3b with (diphenylphosphinyl)lithium (=lithium oxidodiphenylphospanide) in THF, followed by column chromatography on silica gel with Et₂O. Carboxaldehydes 7a and 7b were synthesized by a disproportionation reaction of the dimethanol mixture 2a / 2b with catalytic amounts of TsOH. The subsequent decarbonylation of both carboxaldehydes with tris(triphenylphosphine)rhodium(1+) chloride yielded heptalene 8 in a quantitative yield. The reaction of a thermal‐equilibrium mixture 3a / 3b with the borane adduct of (diphenylphosphino)lithium in THF at 0° gave 6a and 6b in yields of 5 and 15%, respectively (Scheme 4). However, heating 6a or 6b in the presence of 1,4‐diazabicyclo[2.2.2]octane (DABCO) in toluene, generated both bis‐phosphine 4a and its DBS isomer 4b which could not be separated. The attempt at a conversion of 3a or 3b into bis‐phosphines 4a or 4b by treatment with t‐BuLi and Ph₂PCl also failed completely. Thus, we returned to investigate the antipodes of the dimethanols 2a, 2b , and of 8 that can be separated on an HPLC Chiralcel‐OD column. The CD spectra of optically pure (M)‐ and (P)‐configurated heptalenes 2a, 2b , and 8 were measured (Figs. 4, 5, and 9).     

Thermal Reaction of Azulenes with Dimethyl Acetylenedicarboxylate in Supercritical Carbon Dioxide

1,3,4,6,8-Pentamethylazulene ( 9 ), when heated at 100° in supercritical CO₂ at 150 bar in the presence of 4 equiv. of dimethyl acetylenedicarboxylate (ADM), led to the formation of 16% of a 1:1 mixture of dimethyl 3,5,6,8,10-pentamethylheptalene-1,2-dicarboxylate 12a ) and its double-bond-shifted isomer 12b as well as 4% of the corresponding azulene-1,2-dicarboxylate 13 (Scheme 4). The formation of the [1 + 2] adduct 11 (cf. Scheme 2) was not observed. Similarly, benz[a]azulene ( 25 ) yielded in supercritical CO₂ (150°/170 bar) in the presence of 4 equiv. of ADM dimethyl benzo[d]heptalene-6,7-dicarboxylate ( 29 ; 30%) and dimethyl benzo[a]cyclopent[cd]azulene-1,2-dicarboxylate ( 28 ; 22%; Scheme 5). The reaction of 5,9-diphenylbenz[a]azulene ( 26 ) and ADM in supercritical CO₂ (100°/150 bar) gave the corresponding benzo[d]heptalene-6,7-dicarboxylate 31 (22%) and dimethyl 5,9-diphenyl-4b,10-etheno-10H-benz[a]azulene-11,12-dicarboxylate( 30 ; 25%; Scheme 5).     

Synthese von Trifluoromethyl-substituierten Schwefel-Heterocyclen unter Verwendung von 3,3,3-Trifluorobrenztraubensäure-Derivaten

Synthesis of Trifluoromethyl-Substituted Sulfur Heterocycles Using 3,3,3-Trifluoropyruvic-Acid Derivatives The reaction of methyl 3,3,3-trifluoropyruvate ( 1 ) with 2,5-dihydro-1,3,4-thiadiazoles 4a, b in benzene at 45° yielded the corresponding methyl 5-(trifluoromethyl)-1,3-oxathiolane-5-carboxylates 5a, b (Scheme 1) via a regioselective 1,3-dipolar cycloaddition of an intermediate ‘thiocarbonyl ylide’ of type 3 . With methyl pyruvate, 4a reacted similarly to give 6 in good yield. Methyl 2-diazo-3,3,3-trifluoropropanoate ( 2 ) and thiobenzophenone ( 7a ) in toluene underwent a reaction at 50°; the only product detected in the reaction mixture was thiirane 8a (Scheme 2). With the less reactive thiocarbonyl compounds 9H-xanthene-9-thione ( 7b ) and 9H-thioxanthene-9-thione ( 7c ) as well as with 1,3-thiazole-5(4H)-thione 12 , diazo compound 2 reacted only in the presence of catalytic amounts of Rh₂(OAc)₄. In the cases of 7a and 7b , thiiranes 8b and 8c , respectively, were the sole products (Scheme 3). The crystal struture of 8c has been established by X-ray crystallography (Fig.). In the reaction with 12 , desulfurization of the primarily formed thiirane 14 gave the methyl 3,3,3-trifluoro-2-(4,5-dihydro-1,3-thiazol-5-ylidene)propanoates (E)-and (Z)- 15 (Scheme 4). A mechanism of the Rh-catalyzed reaction via a carbene addition to the thiocarbonyl S-atom is proposed in Scheme 5.     

Synthese eines 1,2-trans-konfigurierten, äquatorialen Glycosyl-phosphonat-Analogen von D-myo-Inositol-1,4,5-trisphosphat

Synthesis of a 1,2-trans-Configurated, Equatorial Glycosylphosphonate Analogue of D -myo-Inositol 1,4,5-Trisphosphate The diphosphonate analogue 3 of D -myo-inositol 1,4,5-trisphosphate ( 1 ), a 1,2-trans-configurated, equatorial glycosylphosphonate, was synthesized and characterized as its hexasodium salt 3a . In a first approach, the silylated galactal 4 (Scheme 1) was transformed into the oxirane 5 and hence, by treatment with Me₃SiP(OMe)₂, into a mixture of the glycosylphosphonate 6 and its silyl ether 7 . This mixture was desilylated and then treated with acetone and FeCl₃ to yield 8 and 9 (64 and 22%, resp., from 4 ). In a second approach, the acetates 11/12 (Scheme 2) were treated with P(OMe)₃/Me₃SiOTf in MeCN to afford the anomeric glycosylphosphonates 16/17 (1:1, 60%), while the trichloroacetimidate 10 gave mostly the αD -anomer 16 . The αD -anomer 20 was obtained from 12 and P(OPh)₃. The highest yield of a β-D phosphonate was realized by treating 12 with the cyclic phosphite 15 (→ 18/19 , 40% each). The β-D -phosphonate 17 was debenzylated (→ 21 ) and protected to give 8 . Transformation of 8 into the bromide 22 (43%) proved difficult due to the facile demethylation of thephosphonate, and was best followed by treatment of the crude product with CH₂N₂ and 2,2-dimethoxyporpane. Phosphorylation of 22 yielded 41% of the (dimethoxyphosphoryl)phosphate 23 . The conditions of the Arbuzov reaction slowly converted the bromide 23 into the bis(phosphoryl)phosphate 24 (69%), which was then deprotected. The resulting 3 was purified via the ammonium salt and transformed into 3a (72%).     

Carbonyliron Complexes of Allenic Acids,Esters, Amides,and Imides

On irradiation in the presence of Fe(CO)₅, the allenic amides and imides showed a similar course of complexation to that of esters and lactones, respectively, e.g. the amides of type 10 led to diiron complexes of type 11 (Scheme 3), whereas the imide 12 yielded a mixture of a dinuclear and two mononuclear complexes ( 13–15 , Scheme 4). The racemic ester 6 also gave mononuclear ( 7a , 7b , and 9 ) and dinuclear complexes (8 a and 8b ; Scheme 2). In case of the allenic acid 4 , only complexation of type 5 was observed (Scheme 1).     

Reaction of Hydroxymethyl- and Alkyl-Substituted Azulenes with Manganese Dioxide

It is shown that the 2-(hydroxymethyl)-1-methylazulenes 6 are being oxidized by activated MnO₂ in CH₂Cl₂ at room temperature to the corresponding azulene-1,2-dicarbaldehydes 7 (Scheme 2). Extension of the MnO₂ oxidation reaction to 1-methyl- and/or 3-methyl-substituted azulenes led to the formation of the corresponding azulene-1-carbaldehydes in excellent yields (Scheme 3). The reaction of unsymmetrically substituted 1,3-dimethyl-azulenes (cf. 15 in Scheme 4) with MnO₂ shows only little chemoselectivity. However, the observed ratio of the formed constitutionally isometric azulene-1-carbaldehydes is in agreement with the size of the orbital coefficients in the HOMO of the azulenes. The reaction of guaiazulene ( 18 ) with MnO₂ in dioxane/H₂O at room temperature gave mainly the expected carbaldehyde 19 . However, it was accompanied by the azulene-diones 20 and 21 (Scheme 5). The precursor of the demethylated compound 20 is the carbaldehyde 19 . Similarly, the MnO₂ reaction of 7-isopropyl-4-methyalazulene ( 22 ) as well as of 4,6,8-trimethylazulene ( 24 ) led to the formation of a mixture of the corresponding azulene-1,5-diones and azulene-1,7-diones 20 / 23 and 25 / 26 , respectively, in decent yields (Schemes 6 and 7). No MnO₂ reaction was observed with 5,7-dimethylazulene.     

First Examples of Reactions of Azole N-Oxides with Thioketones: A Novel Type of Sulfur-Transfer Reaction

The reactions of 1,4,5-trisubstituted imidazole 3-oxides 1a – k with cyclobutanethiones 5a , b in CHCl₃ at room temperature give imidazole-2(3H)-thiones 9a – k in high yield. The second product formed in this reaction is 2,2,4,4-tetramethylcyclobutane-1,3-dione ( 6a ; Scheme 2). Similar reactions occur with 1 and adamantanethione ( 5c ) as thiocarbonyl compound, as well as with 1,2,4-triazole-4-oxide derivative 10 and 5a (Scheme 3). A reaction mechanism by a two-step formation of the formal cycloadduct of type 7 via zwitterion 16 is proposed in Scheme 5. Spontaneous decomposition of 7 yields the products of this novel sulfur-transfer reaction. The starting imidazole 3-oxides are conveniently prepared by heating a mixture of 1,3,5-trisubstituted hexahydro-1,3,5-triazines 3 and α-(hydroxyimino) ketones 2 in EtOH (cf. Scheme 1). As demonstrated in the case of 9d , a `one-pot' procedure allows the preparation of 9 without isolation of the imidazole 3-oxides 1 . The reaction of 1c with thioketene 12 leads to a mixture of four products (Scheme 4). The minor products, 9c and the ketene 15 , result from an analogous sulfur-transfer reaction (Path a in Scheme 5), whereas the parent imidazole 14 and thiiranone 13 are the products of an oxygen-transfer reaction (Path b in Scheme 5).     

Totalsynthese von (–)-Norgestrel

Total-Synthesis of (–)-Norgestrel (–)-Norgestrel ( 1a ) or (–)-norethindrone ( 1b ), two active progestational ingredients of currently used contraceptives have been synthesized stereoselectively. Compound 1a has been obtained starting from m-cresol methyl ether, dimethyl malonate, and (E)-1,4-dibromo-2-butene. The steroid skeleton has been constructed using an intramolecular Diels-Alder reaction of an o-quinodimethane derivative preceeded by a photo-enolization of an appropriate methyl-substituted acetophenone derivative. Chirality has been introduced at an early stage during an S_cN′ reaction (cf. Scheme 1). Compound 1b has been obtained similarly using a previously reported mixture of the enantiomerically pure constitutional isomers 18b / 19b (cf. Scheme 3).     

A Novel Route for the Synthesis of Deoxy Fluoro Sugars and Nucleosides

The reaction of (diethylamino)sulfur trifluoride (DAST) with methyl 5-O-benzoyl-β-D -xylofuranoside ( 1 ) followed by column chromatography afforded the riboside 2 (62%) and the ribo-epoxide 3 (18%) (Scheme 1). Under similar reaction conditions, the α-D -anomer 4 gave the riboside 5 and the difluoride 6 in 60 and 9% yield, respectively. Treatment of the β-D -xyloside 10 with DAST gave, after chromatographic purification, the riboside 11 as the principal product (48%; Scheme 2). These results suggest that the C(3)−O−SF₂NEt₂ derivatives were initially formed in the case of the xylosides studied. The distinctive feature of the reaction of DAST with the β-D -arabinoside 12 consists in the formation of a 3- or 5-benzylideneoxoniumyl-substituted intermediate on one of the consecutive transformations, which finally give rise to the inversion of the configuration at C(3) affording the xylosides 17 (18%) and 18 (55%); the lyxoside 14 was also isolated from the reaction mixture in a yield of 25% (Scheme 3). In the presence of the non-participating 5-O-trityl group, i.e., from the reaction products of 21 with DAST, the compounds 23 and 24 were isolated in 16 and 52% yield, respectively (Scheme 4). It may be thus reasonable to conclude that, in the case of the β-D -arabinosides 12 and 21 , the principal route of the reaction is the formation of the intermediate C(2)−O−SF₂NEt₂ derivative. Unlike 21 , the α-D -arabinoside 26 was converted to the lyxo-epoxide 25 (53%) and the lyxoside 27 (14%), which implies the intermediate formation of the C(3)−O−SF₂NEt₂ derivative (Scheme 5).     

The Decomposition of cis-Fused Cyclopenteno-1,2,4-Trioxanes induced by Ferrous Salts and some oxophilic reagents

Two cis-fused cyclopenteno-1,2,4-trioxanes, 1a and 1b , were subjected to Zn in AcOH or FeCl₂ · 4H₂O in MeCN. In the first case, the main course was deoxygenation to give cyclopentanone ( 18 ) and the 1,4-diphenyl- or 1,4-bis(4-fluorophenyl)cyclopent-3-ene-1,2-diol 10 (Scheme 5). In the second case, isomerization chiefly occurred resulting in the formation of a dimer 9 of the respective 3,5-diaryl-5-hydroxycyclopent-2-enyl 5-hydroxypentanoates 8 (Scheme 3).     

Tandem Hydroformylation/Reductive Amination of 3‐Allyl‐2‐methylquinazolin‐4(3H)‐one

The 3‐allyl‐2‐methylquinazolin‐4(3H)‐one ( 1 ), a model functionalized terminal olefin, was submitted to hydroformylation and reductive amination under optimized reaction conditions. The catalytic carbonylation of 1 in the presence of Rh catalysts complexed with phosphorus ligands under different reaction conditions afforded a mixture of 2‐methyl‐4‐oxoquinazoline‐3(4H)‐butanal ( 2 ) and α,2‐dimethyl‐4‐oxoquinazoline‐3(4H)‐propanal ( 3 ) as products of ‘linear’ and ‘branched’ hydroformylation, respectively (Scheme 2). The hydroaminomethylation of quinazolinone 1 with arylhydrazine derivatives gave the expected mixture of [(arylhydrazinyl)alkyl]quinazolinones 5 and 6 , besides a small amount of 2 and 3 (Scheme 3). The tandem hydroformylation/reductive amination reaction of 1 with different amines gave the quinazolinone derivatives 7 – 10 . Compound 10 was used to prepare the chalcones 11a and 11b and pyrazoloquinazolinones 12a and 12b (Scheme 4).     

Glyconothio-O-lactones. Part I. Preparation and reactions with nucleophiles

Furanoid and pyranoid glyconothio-O-lactones were prepared by photolysis of S-phenacyl thioglycosides or by thermolysis of S-glycosyl thiosulfinates, which gave better results than the thionation of glyconolactones with Lawesson's reagent. Thermolysis of the thiosulfinates obtained from the dimannofuranosyl disulfide 7 or the manofuranosyl methly disulfide 8 (Scheme 2) gave low yields of the thio-O-lactone 2 . However, photolysis of the S-phenacyl thioglycoside 6 obtained by in situ alkylation of the thiolato anion derived from 5 led in 78–89% to 2 . Similarly, the dithiocarbonate 10 was transformed, via 11a , into the ribo-thio-O-lactone 12 (79%). Thermolysis of the peracetylated thiosulfinates 14 (Scheme 3) led to the intermediate thio-O-lactone 15 , which underwent facile β-elimination of AcOH (→ 16 , 75%) during chromatography. The perbenzylated S-glucopyranosyl dithiocarbonate 18 (Scheme 4) was transformed either into the S-phenacyl thioglucoside 19 or into a mixture of the anomeric methyl disulfides 21a/b . Whereas the photolysis of 19 led in moderate yield to 2-deoxy-thio-O-lactone 20 , oxidation of 21b and thermolysis of resulting thiosulfinates gave the thio-O-lactone 4 (79%), which was transformed into 20 (36%) upon photolysis. The pyranoid manno-thio-O-lactone 26 was prepared in the same way and in good yields from 22 via the dithiocarbonate 24b and the disulfide 25 . The ring conformations of the δ-thio-O-lactones, flattened ⁴C₁ for 15 and 4 and B_2,5 for 26 , are similar to the ones of the O-analogous oxo-glyconolactones. The reaction of 2 (Scheme 5) with MeLi and then with MeI gave the thioglycoside 27 (29%) and the dimeric thio-O-lactone 29 (47%). The analogous treatment of 2 with lithium dimethylcuprate (LiCuMe₂) and MeI led to a 4:1 mixture (47%) of 31 and 27 . The structure of 2 was proven by an X-ray analysis, and the configuration at C(6) and C(5) of 29 was deduced from NOE experiments. Substitution of MeI by CD₃I led to the CD₃S analogues of 27 , 29 , and 31 , i.e. 28 , 30 , and 32 , respectively, evidencing carbophilic addition and ‘exo’-attack on 2 by MeLi and the enethiolato anion derived from 2 . The preferred ‘endo’-attack of LiCuMe₂ is rationalized by postulating a single-electron transfer and a diastereoselective pyramidalization of the intermediate radical anion.     

‘Three-Component Reaction’ with aromatic thioketones,phenyl azide,and dimethyl fumarate

The reaction of thiobenzophenone (= diphenylmethanethione; 8a ) or 9H-fluorene-9-thione ( 8b ) and methyl fumarate ( 9 ) in excess PhN₃ at 80° yields a mixture of diastereoisomeric thiiranes 10 and 11 (Scheme 1). A mechanism involving the initial formation of 1-phenyl-4, 5-dihydro-1H-1, 2, 3-triazole-4, 5-dicarboxylate 12 by 1, 3-dipolar cycloaddition of PhN₃ and 9 is proposed in Scheme 2. The diazo compound 13 , which is in equilibrium with 12 , undergoes a further 1, 3-dipolar cycloaddition with thioketones 8 to give 2, 5-dihydro-1, 3, 4-thiadiazoles 14 . Elimination of N₂ yields the thiocarbonyl ylide 15 which cyclizes to the corresponding thiirane. Desulfurization of the thiiranes 10 and 11 with hexamethylphosphorous triamide leads to the olefinic compounds 16 (Scheme 3). The crystal structures of 10a , 11a , and 16b were determined.     

Benzo[a]heptalenes from Heptaleno[1,2‐c]furans. Part 2

It is shown in this ‘Part 2’ that heptaleno[1,2‐c]furans 1 react thermally in a Diels–Alder‐type [4+2] cycloaddition at the furan ring with vinylene carbonate (VC), phenylsulfonylallene (PSA), α‐(acetyloxy)acrylonitrile (AAN), and (1Z)‐1,2‐bis(phenylsulfonyl)ethene (ZSE) to yield the corresponding 1,4‐epoxybenzo[d]heptalenes (cf. Schemes 1, 5, 6, and 8). The thermal reaction of 1a and 1b with VC at 130° and 150°, respectively, leads mainly to the 2,3‐endo‐cyclocarbonates 2,3‐endo‐ 2a and ‐ 2b and in minor amounts to the 2,3‐exo‐cyclocarbonates 2,3‐exo‐ 2a and ‐ 2b . In some cases, the (P*)‐ and (M*)‐configured epimers were isolated and characterized (Scheme 1). Base‐catalyzed cleavage of 2,3‐endo‐ 2 gave the corresponding 2,3‐diols 3 , which were further transformed via reductive cleavage of their dimesylates 4 into the benzo[a]heptalenes 5a and 5b , respectively (Scheme 2). In another reaction sequence, the 2,3‐diols 3 were converted into their cyclic carbonothioates 6 , which on treatment with (EtO)₃P gave the deoxygenated 1,4‐dihydro‐1,4‐epoxybenzo[d]heptalenes 7 . These were rearranged by acid catalysis into the benzo[a]heptalen‐4‐ols 8a and 8b , respectively (Scheme 2). Cyclocarbonate 2,3‐endo‐ 2b reacted with lithium diisopropylamide (LDA) at ?70° under regioselective ring opening to the 3‐hydroxy‐substituted benzo[d]heptalen‐2‐yl carbamate 2,3‐endo‐ 9b (Scheme 3). The latter was O‐methylated to 2,3‐endo‐(P*)‐ 10b . The further way, to get finally the benzo[a]heptalene 13b with MeO groups in 1,2,3‐position, could not be realized due to the fact that we found no way to cleave the carbamate group of 2,3‐endo‐(P*)‐ 10b without touching its 1,4‐epoxy bridge (Scheme 3). The reaction of 1a with PSA in toluene at 120° was successful, in a way that we found regioisomeric as well as epimeric cycloadducts (Scheme 5). Unfortunately, the attempts to rearrange the products under strong‐base catalysis as it had been shown successfully with other furan–PSA adducts were unsuccessful (Scheme 4). The thermal cycloaddition reaction of 1a and 1b with AAN yielded again regioisomeric and epimeric adducts, which could easily be transformed into the corresponding 2‐ and 3‐oxo products (Scheme 6). Only the latter ones could be rearranged with Ac₂O/H₂SO₄ into the corresponding benzo[a]heptalene‐3,4‐diol diacetates 20a and 20b , respectively, or with trimethylsilyl trifluoromethanesulfonate (TfOSiMe₃/Et₃N), followed by treatment with NH₄Cl/H₂O, into the corresponding benzo[a]heptalen‐3,4‐diols 21a and 21b (Scheme 7). The thermal cycloaddition reaction of 1 with ZSE in toluene gave the cycloadducts 2,3‐exo‐ 22a and ‐ 22b as well as 2‐exo,3‐endo‐ 22c in high yields (Scheme 8). All three adducts eliminated, by treatment with base, benzenesulfinic acid and yielded the corresponding 3‐(phenylsulfonyl)‐1,4‐epoxybenzo[d]heptalenes 25 . The latter turned out to be excellent Michael acceptors for H₂O₂ in basic media (Scheme 9). The Michael adducts lost H₂O on treatment with Ac₂O in pyridine and gave the 3‐(phenylsulfonyl)benzo[d]heptalen‐2‐ones 28a and 3‐exo‐ 28b , respectively. Rearrangement of these compounds in the presence of Ac₂O/AcONa lead to the formation of the corresponding 3‐(phenylsulfonyl)benzo[a]heptalene‐1,2‐diol diacetates 30a and 30b , which on treatment with MeONa/MeI gave the corresponding MeO‐substituted compounds 31a and 31b . The reductive elimination of the PhSO₂ group led finally to the 1,2‐dimethoxybenzo[a]heptalenes 32a and 32b . Deprotonation experiments of 32a with t‐BuLi/N,N,N′,N′‐tetramethylethane‐1,2‐diamine (tmeda) and quenching with D₂O showed that the most acid C? H bond is H? C(3) (Scheme 9). Some of the new structures were established by X‐ray crystal‐diffraction analyses (cf. Figs. 1, 3, 4, and 5). Moreover, nine of the new benzo[a]heptalenes were resolved on an anal. Chiralcel OD‐H column, and their CD spectra were measured (cf. Figs. 8 and 9). As a result, the 1,2‐dimethoxybenzo[a]heptalenes 32a and 32b showed unexpectedly new Cotton‐effect bands just below 300 nm, which were assigned to chiral exciton coupling between the heptalene and benzo part of the structurally highly twisted compounds. The PhSO₂‐substituted benzo[a]heptalenes 30b and 31b showed, in addition, a further pair of Cotton‐effect bands in the range of 275–245 nm, due to chiral exciton coupling of the benzo[a]heptalene chromophore and the phenylsulfonyl chromophore (cf. Fig. 10).     

Cyclopentenone Annulation of 2-Oxocycloalkane-1-carbonitriles

Phase-transfer alkylation of the 2-oxocycloalkane-l-carbonitriles 1a and 1b with ethyl 4-bromo-3-methoxy-2-butenoate ( 2 ), followed by deprotection and base-catalyzed cyclization gave the annulated cyclopentenones 5a and 5b , respectively, in high overall yields (Scheme 1). Stereoselective catalytic hydrogenation of 5b followed by de-ethoxycarbonylation afforded 14-oxo-cis-bicyclo[10.3.0]pentadecane-l-carbonitrile ( 7 ). Treatment of 7 with LiN(i-Pr)₂ in THF gave the known synthetic muscone precursor 8 (Scheme 2). The tricyclo[10.4.0.0^1,15]hexadecan-14-one ( 14 ) was prepared from 7 in 5 steps by a reaction sequence proceeding without affecting the chiral centres (Scheme 2). The structure of 14 was established by X-ray structure analysis (Figure).     

Synthesis of a Phosphonic Acid Analogue of N-Acetyl-2,3-didehydro-2-deoxyneuraminic Acid,an Inhibitor of Vibrio cholerae Sialidase

The synthesis of the phospha analogue 10 of DANA ( 2 ) is described. Bromo-hydroxylation of the known 11 (→ 12 and 13 ) followed by treatment of the major bromohydrin 13 with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) gave the oxirane 14 (Scheme 1). Depending on the solvent, TiBr₄ transformed 14 into 16 or into a 15 / 16 mixture. Reductive debromination of 16 (→ 17 ), followed by benzylation provided 18 . Oxidattve decarboxylation (Pb(OAc)₄) of the acid, obtained by saponification of 18 , yielded the anomeric acetates 19 and 20 . While 19 was inert under the conditions of phosphonoylation, the more reactive imidate 22 , obtained together with 23 from 19 / 20 via 21 (Scheme 2), gave a mixture of the phosphonates 24 / 25 and the bicyclic acetal 26 . Debenzylation of 24 / 25 and acetylation led to the acetoxyphosphonates 27 / 28 . Since β-elimination of AcOH from 27 / 28 proved difficult, the bromide 34 was prepared from 27 / 28 by photobromination and subjected to reductive elimination with Zn/Cu (→ 35 ; Scheme 3). This two-step sequence was first investigated using the model compounds 30 and 31 . Transesterification of 35 , followed by deacetylation gave 10 , which is a strong inhibitor of the Vibrio Cholerae sialidase.     

Reactions of Stable α‐Chlorosulfanyl Chlorides with CS‐Functionalized Compounds

The smooth reaction of 3‐chloro‐3‐(chlorosulfanyl)‐2,2,4,4‐tetramethylcyclobutanone ( 3 ) with 3,4,5‐trisubstituted 2,3‐dihydro‐1H‐imidazole‐2‐thiones 8 and 2‐thiouracil ( 10 ) in CH₂Cl₂/Et₃N at room temperature yielded the corresponding disulfanes 9 and 11 (Scheme 2), respectively, via a nucleophilic substitution of Cl^? of the sulfanyl chloride by the S‐atom of the heterocyclic thione. The analogous reaction of 3‐cyclohexyl‐2,3‐dihydro‐4,5‐diphenyl‐1H‐imidazole‐2‐thione ( 8b ) and 10 with the chlorodisulfanyl derivative 16 led to the corresponding trisulfanes 17 and 18 (Scheme 4), respectively. On the other hand, the reaction of 3 and 4,4‐dimethyl‐2‐phenyl‐1,3‐thiazole‐5(4H)‐thione ( 12 ) in CH₂Cl₂ gave only 4,4‐dimethyl‐2‐phenyl‐1,3‐thiazol‐5(4H)‐one ( 13 ) and the trithioorthoester derivative 14 , a bis‐disulfane, in low yield (Scheme 3). At ?78°, only bis(1‐chloro‐2,2,4,4‐tetramethyl‐3‐oxocyclobutyl)polysulfanes 15 were formed. Even at ?78°, a 1 : 2 mixture of 12 and 16 in CH₂Cl₂ reacted to give 13 and the symmetrical pentasulfane 19 in good yield (Scheme 5). The structures of 11, 14, 17 , and 18 have been established by X‐ray crystallography.     

7‐Oxanorbornane and Norbornane Mimics of a Distorted β‐D‐Mannopyranoside: Synthesis and Evaluation as β‐Mannosidase Inhibitors

The racemic 7‐oxanorbornanyl and norbornanyl aminoalcohols 3, 4, 42, 45 , and 46 were synthesized and tested as snail β‐mannosidase inhibitors. The amino tetraol 3 was obtained from the known sulfonyl acrylate 9 and furan 10 . Esterification provided 11 that underwent an intramolecular Diels–Alder reaction to the 7‐oxanorbornene 12 . Reduction of 12 to 13 , desulfonylation, isopropylidenation, and cis‐dihydroxylation gave 16 . A second isopropylidenation to 17 , followed by debenzylation and a Mitsunobu–Gabriel reaction provided 19 that was deprotected via 20 to 3 . Diels–Alder cycloaddition of furfuryl acetate and maleic anhydride to 21 , followed by alcoholysis of the anhydride, cis‐dihydroxylation, isopropylidenation, and Barton decarboxylation gave the ester 25 . Deacetylation to 26 and a Mitsunobu–Gabriel reaction led to 27 that was transformed into the N‐Boc analogue 29 , reduced to the alcohol 30 , and deprotected to 4 . The 1‐aminonorbornane 5 was obtained from Thiele's Acid 31 . Diels–Alder cycloaddition of the cyclopentadiene obtained by thermolysis of the diester 32 , methanolysis of the resulting anhydride 33 , dihydroxylation, isopropylidenation, Barton decarboxylation, and Curtius degradation led to the benzyl carbamate 39 that was reduced to the alcohol 40 , transformed into the N‐Boc carbamate 41 , and deprotected to 5 . The alcohol 40 was also transformed into the benzylamine 42 , aniline 45 , and hydroxylamine 46 . Snail β‐mannosidase was hardly inhibited by 3, 4, 42, 45 , and 46 . Only the amino triol 5 proved a stronger inhibitor. The inhibition by 5 depends on the pH value (at pH 3.5: K_i = 1900 μM ; at pH 4.5: K_i = 340 μm; at pH 5.5: K_i = 110 μm). The results illustrate the strong dependence of the inhibition by bicyclic mimics upon the precise geometry and orientation of the amino group as determined by the scaffold. It is in keeping with the hypothesis that the reactive conformation imposed by snail β‐mannosidase is close to a ^1,4B/¹S₃.