Oligonucleosides with a Nucleobase‐Including Backbone,Part 3, Synthesis of Acetyleno‐Linked Adenosine Dimers

The adenosine‐derived dimers 14a – d and 15b – d have been prepared by coupling the protected 8‐iodoadenosines 3 and 13 with the C(5′)‐ethynylated adenosine derivatives 5 , 6 , 11 , and 12 (Scheme 4). Similarly, the 5′‐epimeric dimer 16 was prepared by coupling 3 with the alkyne 8 (Scheme 5). The propargylic alcohol 4 was transformed into the N‐benzoylated alkyne 5 and into the amine 6 , while the epimeric alcohol 7 was converted to the epimeric amine 8 and the 5′‐deoxy analogues 11 and 12 (Scheme 3). Cross‐coupling of the iodoadenosine 13 with the alkyne 5 to 14a was optimised; it is influenced by the N‐benzoyl and the Et₃SiO group of the alkyne, but hardly by the N‐benzoyl group of the 8‐iodoadenosine. The alkyne is most reactive when it is O‐silylated, but not N‐benzoylated. Cross‐coupling of the 5′‐deoxyalkynes proceeded more slowly. The dimers 14a – d , 15b – d , and 16 were obtained in good yields (Table 2). Deprotection of 14d and 16 led to 18 and 20 , respectively (Scheme 5). The diols 17 and 19 and the hexols 18 and 20 prefer the syn‐conformation in (D₆)DMSO, completely for unit II and ≥80% for unit I; they exhibit partially persistent intramolecular O(5′)−H⋅⋅⋅N(3) H‐bonds. The persistence increases from 18% (unit I of 19 ), 32% (unit II of 17 and 19 ), 45% (unit I of 17 ), 52% (unit II of 18 and 20 ), and 55% (unit I of 20 ) to 82% (unit I of 18 ).     

Oligonucleosides with a Nucleobase‐Including Backbone,Part 2, Synthesis and Structure Determination of Adenosine‐Derived Monomers

The synthesis and structure determination of adenosine‐derived monomeric building blocks for new oligonucleosides are described. Addition of Me₃Si‐acetylide to the aldehyde derived from the known partially protected adenosine 1 led to the epimeric propargylic alcohols 2 and 3 , which were oxidised to the same ketone 4 , while silylation and deprotection led to 7 and 9 (Scheme 1). Introduction of an I substituent at C(8) of the propargylic silyl ethers 10 and 11 was not satisfactory. The protected adenosine 12 was, therefore, transformed in high yield into the 8‐chloro derivative 13 by deprotonation and treatment with PhSO₂Cl; the iodide 15 was obtained in a similar way (Scheme 2). The 8‐Cl and the 8‐I derivatives 13 and 15 were transformed into the propargylic alcohols 17 , 18 , 25 , and 26 , respectively (Scheme 3). The propargylic derivatives 2 , 10 , 17 , 19 , 23 , 25 , and 27 were correlated, and their (5′R) configuration was determined on the basis of NOEs of the anhydro nucleoside 19 ; similarly, correlation of 3 , 11 , 18 , 20 , 24 , 26 , and 28 , and NOE's of 20 evidenced their (5′S)‐configuration.     

Regioselective Synthesis of the 5,6‐Dihydro‐4H‐furo[2,3‐c]pyrrol‐4‐one Skeleton: A New Class of Compounds

We hereby report the first preparation of the 5,6‐dihydro‐4H‐furo[2,3‐c]pyrrol‐4‐one ( 3 ) and its derivatives starting from methyl 3‐(methoxycarbonyl)furan‐2‐acetate ( 8 ). The ester functionality connected to the methylene group was regiospecifically converted to the desired monohydrazide 9 . Conversion of 9 into the acyl azide 10 followed by Curtius rearrangement gave the corresponding isocyanate derivative 11 (Scheme 2). Reaction of 11 with different nucleophiles produced urethane and urea derivatives (Scheme 3). Intramolecular cyclization reactions provided the target compounds (Scheme 5). Removal of the amine‐protecting group formed the title compound 3 .     

Total Synthesis of Murrayanine Involving 4,5‐Dimethyleneoxazolidin‐2‐ones and a Palladium(0)‐Catalyzed Diaryl Insertion

A new total synthesis of the natural carbazole murrayanine ( 1 ) was developed by using the 4,5‐dimethyleneoxazolidin‐2‐one 12 as starting material. The latter underwent a highly regioselective Diels–Alder cycloaddition with acrylaldehyde (=prop‐2‐enal; 13 ) to give adduct 14 (Scheme 3). Conversion of this adduct into diarylamine derivative 9 was carried out via hydrolysis and methylation (Scheme 4). Differing from our previous synthesis, in which such a diarylamine derivative was transformed into 1 by a Pd^II‐stoichiometric cyclization, this new approach comprised an improved cyclization through a more efficient Pd⁰‐catalyzed intramolecular diaryl coupling which was applied to 9 , thus obtaining the natural carbazole 1 in a higher overall yield.     

The chemistry of the highly reactive 2,6‐bis(bromomethyl)‐4‐pyrone

Under basic conditions 2,6‐bis(bromomethyl)‐4‐pyrone 8 reacts with tetraethylene glycol to yield the unexpected macrocycle 9 , which is related to the antibiotic Kjellmanianone 10 . We propose that this ring transformation proceeds via the cyclopropyl intermediate d (Scheme 2), which undergoes a ring opening reaction comparable to the Favorskii rearrangement. Also, 8 reacts with methanol/sodium methoxide to yield the 3(2H)‐furanone derivative 11 , the formation of which is suggested to proceed via the intermediate k with a carbenium‐oxonium‐ion subunit (Scheme 3). The structure of the 3(2H)‐furanone derivative was confirmed by X‐ray analysis.     

Oligonucleosides with a Nucleobase‐Including Backbone,Part 1, Concept,Force‐Field Calculations,and Synthesis of Uridine‐Derived Monomers and Dimers

A new type of oligonucleosides has been devised to investigate the potential of oligonucleosides with a nucleobase‐including backbone to form homo‐ and/or heteroduplexes (cf. Fig. 2). It is characterised by ethynyl‐linkages between C(5′) and C(6) of uridine, and between C(5′) and C(8) of adenosine. Force‐field calculations and Maruzen model studies suggest that such oligonucleosides form autonomous pairing systems and hybridize with RNA. We describe the syntheses of uridine‐derived monomers, suitable for the construction of oligomers, and of a dimer. Treatment of uridine‐5′‐carbaldehyde ( 2 ) with triethylsilyl acetylide gave the diastereoisomeric propargylic alcohols 6 and 7 (1 : 2, 80%; Scheme 1). Their configuration at C(5′) was determined on the basis of NOE experiments and X‐ray crystal‐structure analysis. Iodination at C(6) of the (R)‐configured alcohol 7 by treatment with lithium diisopropylamide (LDA) and N‐iodosuccinimide (NIS) gave the iodide 17 (62%), which was silylated at O−C(5′) to yield 18 (89%; Scheme 2). C‐Desilylation of 7 with NaOH in MeOH/H₂O led to the alkyne 10 (98%); O‐silylation of 10 at O−C(5′) gave 16 (84%). Cross‐coupling of 18 and 16 yielded 63% of the dimer 19 , which was C‐desilylated to 20 in 63% yield. Cross‐coupling of 10 and the 6‐iodouridine 13 (70%), followed by treatment of the resulting dimer 14 with HF and HCl in MeCN/H₂O, gave the deprotected dimer 15 (73%).     

Selenium‐Containing Heterocycles from Isoselenocyanates: Synthesis of 1H‐5‐Selena‐1,3,6‐triazaaceanthrylene Derivatives

The reaction of aryl isoselenocyanates 8 with methyl 3‐amino‐4‐chloro‐1‐ethylpyrrolo[3,2‐c]quinoline‐2‐carboxylate ( 6 ) in boiling pyridine leads to tetracyclic selenaheterocycles of type 9 in high yield (Scheme 3). A reaction mechanism via an intermediate selenoureido derivative A and cyclization via nucleophilic substitution of Cl by Se is proposed (Schemes 3 and 5). The reaction of 6 with 4‐bromophenyl isothiocyanate yields the analogous thiaheterocycle 12 (Scheme 4). The molecular structures of 9c and 12 have been established by X‐ray crystallography.     

Transformation of Amino Acids into Nonracemic 1‐(Heteroaryl)ethanamines by the Enamino Ketone Methodology

N‐Protected L ‐phenylalanines 1a,b were transformed, via the corresponding Weinreb amides 2 and ethynyl ketones 3 , into chiral enamino ketones 4 (Scheme 1). Similarly, L ‐threonine 6 was transformed in four steps into the enamino ketone 10 . Cyclocondensations of 4 and 10 with pyrazolamines 11 , benzenecarboximidamide ( 12 ), and hydrazine derivatives 18 afforded N‐protected 1‐heteroaryl‐2‐phenylethanamines 15a – e, 16, 17 , and 21a – k and 1‐heteroaryl‐1‐aminopropan‐2‐ols 23a,b in good yields (Schemes 2 and 3). Finally, deprotection by catalytic hydrogenation furnished free amines 22a – g and 24a,b (Scheme 3).     

A Simple One‐Pot Synthesis of N‐Alkyl‐2,5‐diaryl‐1,3‐dioxol‐4‐amines

An efficient procedure for the synthesis of N‐alkyl‐2,5‐diaryl‐1,3‐dioxol‐4‐amines 3 via a one‐pot reaction of aromatic aldehydes 2 and alkyl isocyanides 1 at room temperature in good yields is described (Scheme 1, Table).     

Oligonucleotide Analogues with a Nucleobase‐Including Backbone:, Part 6, 2‐Deoxy‐D‐erythrose‐Derived Phosphoramidites: Synthesis and Incorporation into 14‐Mer DNA Strands

Two modified DNA 14‐mers have been prepared, containing either a 2‐deoxy‐D ‐erythrose‐derived adenosine analogue carrying a C(8)−CH₂O group (deA*), or a 2‐deoxy‐D ‐erythrose‐derived uridine analogue, possessing a C(6)−CH₂O group (deU*). These nucleosides are linked via a phosphinato group between O−C(3′) (deA* and deU*) and O−C(5′) of one neighbouring nucleotide, and between C(8)−CH₂O (deA*), or C(6)−CH₂O (deU*) and O−C(3′) of the second neighbour. N⁶‐Benzoyl‐9‐(β‐D ‐erythrofuranosyl)adenine ( 3 ) and 1‐(β‐D ‐erythrofuranosyl)uracil ( 4 ) were prepared from D ‐glucose, deoxygenated at C(2′), and converted into the required phosphoramidites 1 and 2 . The modified tetradecamers 31 and 32 were prepared by solid‐phase synthesis. Pairing studies show a decrease in the melting temperature of 7 to 8 degrees for the duplexes 31 ⋅ 30 and 32 ⋅ 29 , as compared to the unmodified DNA duplex 29 ⋅ 30 . A comparison with the pairing properties of tetradecamers similarly incorporating deoxyribose‐ instead of the deoxyerythrose‐derived nucleotides evidences that the CH₂OH substituent at C(4′) has no significant effect on the pairing.     

Selenium‐Containing Heterocycles from Isoselenocyanates: Synthesis of 1,3‐Selenazoles from N‐Phenylimidoyl Isoselenocyanates

The reaction of N‐phenylbenzamides 5 with excess SOCl₂ under reflux gave N‐phenylbenzimidoyl chlorides 6 , which, on treatment with KSeCN in acetone, yielded imidoyl isoselenocyanates of type 2 . These products, obtained in almost quantitative yield, were stable in the crystalline state. They were transformed into selenourea derivatives 7 by the reaction with NH₃, or primary or secondary amines. In acetone at room temperature, 7 reacted with activated bromomethylene compounds such as 2‐bromoacetates, acetamides, and acetonitriles, as well as phenacyl bromides and 4‐cyanobenzyl bromide to to give 1,3‐selenazol‐2‐amines of type 9 (Scheme 2). A reaction mechanism via alkylation of the Se‐atom of 7 , followed by ring closure and elimination of aniline, is most likely (cf. Scheme 7). In the case of selenourea derivatives 7d and 7l with an unsubstituted NH₂ group, an alternative ring closure via elimination of H₂O led to 1,3‐selenazoles 10a and 10b , respectively (Schemes 4 and 7). On treatment with NaOH, ethyl 1,3‐selenazole‐5‐carboxylates 9l and 9s were saponified and decarboxylated to give the corresponding 5‐unsubstituted 1,3‐selenazoles 12a and 12b (Scheme 6). The molecular structures of selenourea 7f and the 1,3‐selenazoles 9c and 9d have been established by X‐ray crystallography (Figs. 1 and 3).     

Derivatives from Isoselenocyanates: Synthesis of 2‐Phenyl‐6H‐[5,1,3]benzoselenadiazocine

The reaction of N‐phenylbenzimidoyl isoselenocyanates 8 with primary and secondary amines in acetone at room temperature, followed by treatment with a base, led to 6H‐[5,1,3]benzoselenadiazocine derivatives of type 10 (Scheme 3). An analogous cyclization was observed when 8a and 8b were reacted with the Na salt of diethyl malonate in EtOH at room temperature, which yielded the eight‐membered selenaheterocycles 11 (Scheme 5). The molecular structures of some of the products, as well as that of a sulfur analogue, have been established by X‐ray crystallography (Figs. 1–4). The isoselenocyanates 8 have been prepared from N‐(2‐methylphenyl)benzamides 5 in a three‐step procedure via the corresponding imidoyl chlorides 6 , side‐chain chlorination to give 7 , and treatment with KSeCN (Scheme 2).     

7‐Halogenated 7‐Deazapurine 2′‐Deoxyribonucleosides Related to 2′‐Deoxyadenosine, 2′‐Deoxyxanthosine,and 2′‐Deoxyisoguanosine: Syntheses and Properties

A series of 7‐fluorinated 7‐deazapurine 2′‐deoxyribonucleosides related to 2′‐deoxyadenosine, 2′‐deoxyxanthosine, and 2′‐deoxyisoguanosine as well as intermediates 4b – 7b, 8, 9b, 10b , and 17b were synthesized. The 7‐fluoro substituent was introduced in 2,6‐dichloro‐7‐deaza‐9H‐purine ( 11a ) with Selectfluor (Scheme 1). Apart from 2,6‐dichloro‐7‐fluoro‐7‐deaza‐9H‐purine ( 11b ), the 7‐chloro compound 11c was formed as by‐product. The mixture 11b / 11c was used for the glycosylation reaction; the separation of the 7‐fluoro from the 7‐chloro compound was performed on the level of the unprotected nucleosides. Other halogen substituents were introduced with N‐halogenosuccinimides ( 11a → 11c – 11e ). Nucleobase‐anion glycosylation afforded the nucleoside intermediates 13a – 13e (Scheme 2). The 7‐fluoro‐ and the 7‐chloro‐7‐deaza‐2′‐deoxyxanthosines, 5b and 5c , respectively, were obtained from the corresponding MeO compounds 17b and 17c , or 18 (Scheme 6). The 2′‐deoxyisoguanosine derivative 4b was prepared from 2‐chloro‐7‐fluoro‐7‐deaza‐2′‐deoxyadenosine 6b via a photochemically induced nucleophilic displacement reaction (Scheme 5). The pK_a values of the halogenated nucleosides were determined (Table 3). ¹³C‐NMR Chemical‐shift dependencies of C(7), C(5), and C(8) were related to the electronegativity of the 7‐halogen substituents (Fig. 3). In aqueous solution, 7‐halogenated 2′‐deoxyribonucleosides show an approximately 70% S population (Fig. 2 and Table 1).     

Nucleotides. Part LXXVIII

Several N(‐hydroxyalkyl)‐2,4‐dinitroanilines were transformed into their phosphoramidites (see 5 and 6 in Scheme 1) in view of their use as fluorescence quenchers, and modified 2‐aminobenzamides (see 9, 10, 18 , and 19 in Scheme 1) were applied in model reactions as fluorophors to determine the relative fluorescence quantum yields of the 3′‐Aba and 5′‐Dnp‐3′‐Aba conjugates (Aba=aminobenzamide, Dnp=dinitroaniline). Thymidine was alkylated with N‐(2‐chloroethyl)‐2,4‐dinitroaniline ( 24 ) to give 25 which was further modified to the building blocks 27 and 28 (Scheme 3). The 2‐amino group in 29 was transformed by diazotation into the 2‐fluoroinosine derivative 30 used as starting material for several reactions at the pyrimidine nucleus (→ 31, 33 , and 35 ; Scheme 4). The 3′,5′‐di‐O‐acetyl‐2′‐deoxy‐N²‐[(dimethylamino)methylene]guanosine ( 37 ) was alkylated with methyl and ethyl iodide preferentially at N(1) to 43 and 44 , and similarly reacted N‐(2‐chloroethyl)‐2,4‐dinitroaniline ( 24 ) to 38 and the N‐(2‐iodoethyl)‐N‐methyl analog 50 to 53 (Scheme 5). The 2′‐deoxyguanosine derivative 53 was transformed into 3′,5′‐di‐O‐acetyl‐2‐fluoro‐1‐{2‐[(2,4‐dinitrophenyl)methylamino]ethyl}inosine ( 54 ; Scheme 5) which reacted with 2,2′‐[ethane‐1,2‐diylbis(oxy)]bis[ethanamine] to modify the 2‐position with an amino spacer resulting in 56 (Scheme 6). Attachment of the fluorescein moiety 55 at 56 via a urea linkage led to the doubly labeled 2′‐deoxyguanosine derivative 57 (Scheme 6). Dimethoxytritylation to 58 and further reaction to the 3′‐succinate 59 and 3′‐phosphoramidite 60 afforded the common building blocks for the oligonucleotide synthesis (Scheme 6). Similarly, 30 reacted with N‐(2‐aminoethyl)‐2,4‐dinitroaniline ( 61 ) thus attaching the quencher at the 2‐position to yield 62 (Scheme 7). The amino spacer was again attached at the same site via a urea bridge to form 64 . The labeling of 64 with the fluorescein derivative 55 was straigthforward giving 65 . and dimethoxytritylation to 66 and further phosphitylation to 67 followed known procedures (Scheme 7). Several oligo‐2′‐deoxynucleotides containing the doubly labeled 2′‐deoxyguanosines at various positions of the chain were formed in a DNA synthesizer, and their fluorescence properties and the T_ms in comparison to their parent duplexes were measured (Tables 1–5).     

Amine‐Promoted One‐Pot,Multicomponent Route to Spiro‐Fused‐Pyran Derivatives in Aqueous Media

The primary amine‐promoted synthesis of spiro‐fused‐pyran derivatives via the three‐component reaction of ninhydrin, malononitrile, and cyclic 1,3‐diketo compounds is described. This new methodology affords the title compounds in high yields and short time, and with easy workup without chromatographic purification steps or extraction. All structures were confirmed by IR, ¹H‐ and ¹³C‐NMR spectroscopy, and mass spectroscopy. A plausible mechanism for this type of reaction is proposed (Scheme 2).     

Thermal [2+3]‐Cycloadditions of trans‐1‐Methyl‐2,3‐diphenylaziridine with CS and CC Dipolarophiles: An Unexpected Course with Dimethyl Dicyanofumarate

The thermal reaction of trans‐1‐methyl‐2,3‐diphenylaziridine (trans‐ 1a ) with aromatic and cycloaliphatic thioketones 2 in boiling toluene yielded the corresponding cis‐2,4‐diphenyl‐1,3‐thiazolidines cis‐ 4 via conrotatory ring opening of trans‐ 1a and a concerted [2+3]‐cycloaddition of the intermediate (E,E)‐configured azomethine ylide 3a (Scheme 1). The analogous reaction of cis‐ 1a with dimethyl acetylenedicarboxylate ( 5 ) gave dimethyl trans‐2,5‐dihydro‐1‐methyl‐2,5‐diphenylpyrrole‐3,4‐dicarboxylate (trans‐ 6 ) in accord with orbital‐symmetry‐controlled reactions (Scheme 2). On the other hand, the reactions of cis‐ 1a and trans‐ 1a with dimethyl dicyanofumarate ( 7a ), as well as that of cis‐ 1a and dimethyl dicyanomaleate ( 7b ), led to mixtures of the same two stereoisomeric dimethyl 3,4‐dicyano‐1‐methyl‐2,5‐diphenylpyrrolidine‐3,4‐dicarboxylates 8a and 8b (Scheme 3). This result has to be explained via a stepwise reaction mechanism, in which the intermediate zwitterions 11a and 11b equilibrate (Scheme 6). In contrast, cis‐1,2,3‐triphenylaziridine (cis‐ 1b ) and 7a gave only one stereoisomeric pyrrolidine‐3,4‐dicarboxylate 10 , with the configuration expected on the basis of orbital‐symmetry control, i.e., via concerted reaction steps (Scheme 10). The configuration of 8a and 10 , as well as that of a derivative of 8b , were established by X‐ray crystallography.     

Oligonucleosides with a Nucleobase‐Including Backbone. Part 11

A linear and a convergent synthesis of uridine‐derived backbone‐base‐dedifferentiated (backbone including) oligonucleotide analogues were compared. The Sonogashira cross‐coupling of the alkyne 1 and the iodide 2 gave the dimer 4 that was C‐desilylated and again coupled with 2 to give the trimer 6 (Scheme 1). Repeating this linear sequence led to the pentamer 10 . Coupling yields were satisfactory up to formation of the trimer 6 , but decreased for the coupling to higher oligomers. Similarly, coupling of the alkynes 5, 7 , and 9 with the iodouridine 3 gave, in decreasing yields, the trimer 12 , tetramer 13 , and pentamer 14 , respectively. The dimeric iodouracil 20 was synthesized by coupling the alkyne 17 with the iodide 16 to the dimer 18 , followed by iodination at C(6/I) to 19 and O‐silylation (Scheme 2). The iodinated dimer 23 was prepared by iodinating and O‐silylating the known dimer 21 . Coupling of 20 and 23 with the dimer 5 , trimer 7 , and tetramer 9 gave the tetramers 8 and 13 , the pentamers 10 and 14 , and the hexamer 15 , respectively (Scheme 3). The oligomers up to the pentamer 14 were deprotected to provide the trimer 24 , tetramer 25 , and pentamer 26 (Scheme 4). There was no evidence for the heteropairing of the pentamer 26 and rA₇ , nor for the pairing of rU₅ and rA₇, while a UV melting experiment showed the beginning of a sigmoid curve for the interaction of rU₇ with rA₇. Therefore, the pentamer 26 does not pair more strongly with rA₇ than rU₅.     

Oligosaccharide Analogues of Polysaccharides Part 25

The ethynylated gluco‐azide 11 was prepared from the dianhydrogalactose 7 by ethynylation, transformation into the dianhydromannose 10 , and opening of the oxirane ring by azide (Scheme 1). The retentive alkynylating ring opening of 11 and of the corresponding amine 12 failed. (2‐Acetamidoglucopyranosyl)acetylenes were, therefore, prepared from the corresponding mannopyranosylacetylenes. Retentive alkynylating ring opening of the partially protected β‐D ‐mannopyranose 15 , possessing a C(3) OH group, gave a 85 : 15 mixture of 16 and the (E)‐enyne 17 . The alkyne 16 was deprotected to the tetrol 18 that was selectively protected and transformed into the C(2) O triflate 20 . Treatment with NaN₃ in DMF afforded a 85 : 15 mixture of the β‐D ‐gluco configured azide 21 and the elimination product 22 . Similarly, the α‐D ‐mannopyranosylacetylene 23 was transformed into the azide 26 . Retentive alkynylating ring opening of the ethynylated anhydromannose 28 gave the expected β‐D ‐mannopyranosyl 1,4‐dialkyne 29 as the main product besides the diol 28 , the triol 31 , and the (E)‐enyne 30 (Scheme 2). This enyne was also obtained from 31 by a stereoselective carboalumination promoted by the cis (axial) HO C(2) group. Deprotection of the dialkynylated mannoside 31 led to 32 , whereas selective silylation, triflation, and azidation gave a 3 : 7 mixture of the 1‐ethynylglucal 35 and the β‐D ‐gluco azide 36 , which was transformed into the diethynylated β‐D ‐GlcNAc analogue 38 . Similarly, the diethynylated α‐D ‐mannopyranoside 39 was transformed into the disilylated α‐D ‐GlcNAc analogue 41 , and further into the diol 42 and the monosilyl ether 43 (Scheme 5). Eglinton coupling of 41 gave the symmetric buta‐1,3‐diyne 44 , which did not undergo any further Eglinton coupling, even under forcing conditions. However, Eglinton coupling of the monosilyl ether 43 and subsequent desilylation gave the C₁‐symmetric cyclotrimer 45 in moderate yields.     

Synthesis of 3‐Aminotropones from N‐Boc‐Protected Furan‐2‐amine (=tert‐Butyl Furan‐2‐ylcarbamate; Boc=(tert‐Butoxy)carbonyl) by Cycloaddition Reactions and Subsequent Rearrangement

The 3‐aminotropones (=3‐aminocyclohepta‐2,4,6‐trien‐1‐ones) 4 were prepared in two steps by i) a [4+3] cycloaddition reaction between a conveniently substituted α,α′‐dihalo ketone 1 and a furan‐2‐amine derivative 2 functionalized at C(2) by a protected amino group (→ 3 ), and ii) a base‐induced molecular rearrangement of the cycloadduct 3 via cleavage of the O‐bridge. A mechanism for the formation of 3‐aminotropones is proposed on the basis of the initial deprotonation of the [(tert‐butoxy)carbonyl]amino (BocNH) group of 3 , followed by O‐bridge opening, an acid–base equilibrium, and finally an alkoxyaluminate elimination to afford the conjugated stable troponoid system (Scheme 7).     

Introduction of Adjacent Oxygen‐Functionalities in Dimethyl Heptalenedicarboxylates

The bromination of dimethyl 8‐methoxy‐1,6,10‐trimethylheptalene‐4,5‐dicarboxylate ( 6 ; Scheme 2) with N‐bromosuccinimide (NBS) in N,N‐dimethylformamide (DMF) leads in acceptable yields to the corresponding 9‐bromoheptalenedicarboxylate 10 (Table 1). Ether cleavage of 6 with chlorotrimethylsilane (Me₃SiCl)/NaI results in the formation of oxoheptalenedicarboxylate 13 in good yield (Scheme 4). The latter can be acetyloxylated to the (acetyloxy)oxoheptalenedicarboxylate 14 with Pb(OAc)₄ in benzene (Scheme 5). Oxo derivative 14 , in turn, can be selectively O‐methylated with dimethyl sulfate (DMS) in acetone to the (acetyloxy)methoxyheptalenedicarboxylates 15 and 15′ (Scheme 6). The AcO group of the latter can be transformed into a benzyl or methyl ether group by treatment with MeONa in DMF, followed by the addition of benzyl bromide or methyl iodide (cf. Scheme 9). Reduction of the ester groups of dimethyl 7,8‐dimethoxy‐5,6,10‐trimethylheptalene‐1,2‐dicarboxylate ( 25′ ) with diisobutylaluminium hydride (DIBAH) in tetrahydrofuran (THF) leads to the formation of the corresponding dimethanol 26′ , which can be cyclized oxidatively (IBX, dimethyl sulfoxide) to 8,9‐dimethoxy‐6,7,11‐trimethylheptaleno[1,2‐c]furan ( 27 ; Scheme 11).