Synthetic studies of spiroketal enol ethers: an unexpected oxidation by Martin’s sulfurane

In an attempt to synthesize a spiroketal enol ether natural product, we found that treatment of alcohol 5 with Martin’s sulfurane did not give the anticipated olefin, but instead afforded ketone 15 through an unprecedented oxidation.     

Synthesis of racemic nitramine, isonitramine and sibirine

Condensation of enol ether 6 with methyl vinyl ketone led easily to ketoaldehyde 7 whose cyclisation afforded the azaspiranic enone 8, a key intermediate for the synthesis of the title alkaloids.     

Synthesis of new tropinone derivatives by palladium-catalyzed couplings of 8-azabicyclo[3.2.1]oct-2-enyl nonaflates

Whereas tropinone derived nonaflate 3 was no suitable precursor for Heck-reactions, the related carbamate 7 was an excellent substrate for palladium-catalyzed processes. Nonaflate 7 was either isolated in excellent yield by LDA treatment of ketone 5 followed by trapping with NfF (nonafluorobutanesulfonyl fluoride) or generated in situ by fluoride-catalyzed reaction of silyl enol ether 6 with NfF. The desired 1,3-diene 8 was prepared by conventional Heck-reaction of nonaflate 7 with methyl acrylate in almost quantitative yield. Alternatively, the one-pot nonaflation-Heck protocol starting from silyl enol ether 6 provided 8 in good yield. The couplings of acrylonitrile or phenyl vinyl sulfone were also performed with in situ generated 7 and they afforded the expected 1,3-dienes 9 and 10 in good yields. The Sonogashira-reaction with phenylacetylene also started from silyl enol ether 6 and provided enyne 11 via 7 in good yield. A Diels-Alder reaction of 1,3-diene 8 with N-phenyl maleimide at 100 °C furnished tetracyclic adduct 12 in good yield, with excellent diastereofacial selectivity, but with low endo-exo-selectivity. Nonaflate 14 was easily obtained from the corresponding unsaturated bicyclic ketone 13. It behaved differently in an attempted Heck-reaction and mainly led to fragmentation products 15 and 16, whereas the expected 1,3-diene 17 was formed only as minor component. However, 14 could successfully be used in a Sonogashira-reaction with phenylacetylene to afford compound 18. These transformations demonstrate the great potential of tropinone derived alkenyl nonaflates for diversity oriented syntheses of interesting compounds containing an 8-azabicyclo[3.2.1]octane scaffold.     

Gold and platinum catalyzed cascade reaction of propargyl acetates bearing terminal alkynes or methyl ketones

A gold (III)-catalyzed cascade reaction of propargyl acetates bearing an extra terminal alkyne (1) afforded γ-keto esters 3 and lactones 4. These products should be generated through allenyl ketone intermediate B via a 1,2-acyloxy cyclization/fragmentation/cycloisomerization/hydrolysis sequence. On the other hand, the cascade reaction of α-acetoxy ketones bearing terminal alkynes 5 afforded lactone 6 via allenyl ketone intermediate A. This reaction involves a [3,3]-sigmatropic acyloxy rearrangement/cycloisomerization/hydrolysis sequence.     

Unexpected formation of new photochromic compounds derived from 3,3-diphenyl-3H-naphtho[2,1-b]pyran-1-one

Two new unexpected photochromic compounds were obtained from naphtho[2,1-b]pyran-1-one 1. The reaction of this ketone with the silyl enol ether methyl trimethylsilyl dimethylketene acetal, catalyzed by TiCl₄, afforded the photochromic dihydronaphtho[2,1-b]pyranone 2. The Reformatsky reaction of ketone 1 with ethyl bromoacetate led to the formation of the expected alcohol that under acid treatment gave, unexpectedly, the novel photochromic benzocoumarin 6. UV irradiation compounds 2 and 6 in solution provided thermally stable photoproducts that returned to the initial uncoloured forms under visible irradiation. The photochromic behaviour of these compounds and the structures of the photoproducts formed in these reactions were characterized by 1D and 2D NMR.     

Synthesis of bicyclo[2.2.2]oct-5-en-2-ones via a tandem intermolecular Michael addition intramolecular aldol process (a bridged Robinson annulation)

A novel one-pot synthesis of the several bicyclo[2.2.2]oct-5-en-2-ones 19 has been developed in which a cyclic or acyclic ketone 18 is reacted with a cyclic enone 6 in the presence of strong acid to give the bicyclic enone product 19. Alternatively, the intermediate diketone 21 can be prepared separately and subjected to the reaction conditions to give the bicyclic enones 19 in good yields.     

Synthesis of BCD tricyclic analogues of the novel cardiac glycoside rhodexin A

A concise synthesis of novel cardiac glycoside analogues of rhodexin A, 14 and 24, having the BCD tricyclic system is described. The key constructive step is an inverse-electron demand Diels-Alder reaction of the silyl enol ether 4 and the 2-acetyldiene, 7 and 15.     

Synthesis of the spiroketal fragment of bistramide A via an exocyclic enol ether

An efficient synthesis of the spirocyclic fragment 1 of bistramides is reported. An olefination reaction of lactone 4 with sulfone 5 gave the enol ether 3, which upon cyclization in acidic media provided the spiroketal ring system. This compound was then converted into the C19-C36 fragment of the bistramides via successive Julia-Kocienski and Horner-Emmons olefinations.     

Synthesis of exo enol ether-cyclic ketal isomers of substituted furanmethanol structures related to marine furanocembranoids

Oxidations of the 2-alkenylfurans 8a and 8b, using peroxy reagents, lead to the dienedione 9 and the furan epoxide 10, respectively. Treatment of the epoxide 10 with p-TSA in MeOH produces the enol ether cyclic ketal 12, which is rapidly isomerised to the furanmethanol ether 15, isolated in 80% yield. By contrast, when the propanol-substituted furan epoxide 23 was kept in CDCl₃ containing traces of HCl for 2 h, a 3:2 mixture of Z- and E-isomers of the enol ether spiro ketals 25a and 25b was produced in >92% yield; after 24 h this mixture of isomers underwent dehydration leading to the corresponding enol ether triene 26 (70%). When a solution of the dienedione 9 in H₂O-THF containing p-TSA was stirred at 25 °C for 20 h, the tertiary alcohol 27 was produced which, after a further 20 h was converted into the furan vicinal diol 29. Likewise, when the ‘cembranoid’ dienedione 31 was treated with p-TSA-H₂O, the hydroxymethyl-substituted furanobutenolide 33 was produced in 40% yield. It is probable that the enol ether cyclic hemiketals 28 and 32/34, which are related to 12 and 25, and also to the naturally occurring cembranoids 1 and 2 found in corals, are transient intermediates in the conversions leading to 29 and 33 from 9 and 31, respectively.     

Synthesis of a regioisomeric analogue of the 3C-protease inhibitor thysanone via a Hauser annulation strategy

Hauser annulation of 3-cyano-5,7-dimethoxy-(3H)-isobenzofuran-1-one 4 with ethyl acrylate as a method to access activated naphthoquinone 3, a key intermediate for the synthesis of thysanone 1, proved unreliable. In contrast to this, Hauser annulation of regioisomeric 3-cyano-4,6-dimethoxy-(3H)-isobenzofuran-1-one 13 with ethyl acrylate proceeded readily affording ethyl 5,7-dimethoxy-1,4-naphthoquinone 12, after oxidation of the initial dihydroxynaphthalene 16. Allylation of naphthoquinone 12 followed by reductive methylation and Wacker oxidation afforded ketone 11 that underwent CBS reduction to (2′S)-alcohol 19 followed by cyclisation to lactone 20. Reduction of the lactone followed by oxidative demethylation afforded (1S,3S)-6,8-dimethoxy-1-hydroxy-3-methylpyrano[2,3-c]-1,4-naphthoquinone 22, a regioisomeric analogue of the 3C-protease inhibitor thysanone 1.     

Formation and sigmatropic rearrangement of PhCOC(NO2)CH2 cycloadducts of 1,3-cyclohexadiene: a theoretical study

Competing cycloaddition pathways for the reaction of 2-nitro-1-phenyl-2-propen-1-one with 1,3-cyclohexadiene were investigated employing computational methods. A bifurcating pathway was found for formation of nitroketone 3 and nitronic ester 5. A second bifurcating pathway was found for the formation of nitroketone 4 and enol ether 6. Sigmatropic rearrangements of two cycloadducts, nitronic ester 5 and enol ether 6, were also studied computationally. The reaction pathways were mapped using the B3-LYP/6-311G(d) method and relative energies for species 3-6 were calculated at the same level. Solution-phase corrections were performed by the PCM method. The calculations for both bifurcating cycloaddition pathways indicate kinetic control with similar rate-determining activation energies. The nitroketone 3 is more stable than nitronic ester 5 by 5.3 kcal/mol and nitroketone 4 is more stable than enol ether 6 by 3.9 kcal/mol, consistent with the observed direction of sigmatropic rearrangement.     

Synthesis of the tetracyclic core of the bisabosquals

HCl-catalyzed deprotection and cyclization of 8b provided tricycle 9b cleanly. Epoxidation of 9b afforded tetracycle 13 with the wrong stereochemistry at the tertiary alcohol. Selective elimination of the tertiary alcohol to give the exocyclic methylene compound, alkene cleavage to form the ketone with OsO₄ and NaIO₄, and addition of MeMgBr to the ketone from the least hindered face gave tertiary alcohol 16 with the tetracyclic core of bisabosqual A (1).     

Selective sulfonylation of 4-C-hydroxymethyl-β-l-threo-pento-1,4-furanose: synthesis of bicyclic diazasugars

Hydroxymethylation of α-d-xylo-pentodialdose 6 using excess formaldehyde and sodium hydroxide in THF-water (one pot aldol and crossed Cannizzaro reactions) followed by hydrogenolysis of C3-O-benzyl group afforded triol 8. The regio-selective α- and β-sulfonylation of hydroxymethyl groups in 8 afforded 9a (α-sulfonylation) and 14 (β-sulfonylation) in good yield. The cleavage of the 1,2-acetonide functionality, individually in 9a and 14, followed by reaction with 1,3-diaminopropane gave in situ formation of sugar aminals, that undergo concomitant nucleophilic displacement of the sulfonyloxy group by amino functionality to give hitherto unknown bicyclic diazasugars 4 and 5, respectively, with a hydroxymethyl substituent at C-7.     

Methylene-2-ethynylcyclopropanes: synthesis and biological activity of (Z)- and (E)-9-{[2-ethynyl-2-(hydroxymethyl)cyclopropylidene]methyl}adenine and -guanine

Synthesis of methylene-2-ethynylcyclopropane analogues of nucleosides 12a, 12b, 13a, and 13b is described. Ethyl methylenecyclopropane carboxylate 14 was hydroxymethylated to give alcohol 15, which was reduced to diol 16. Selective protection with tert-butyldimethylsilyl group gave derivative 17, which was oxidized to aldehyde 18. Wittig reaction with CBr₄ gave dibromoalkene 19. Elimination of both bromine atoms afforded methylene-2-ethynylcyclopropane 20. Bromoselenenylation using N-bromosuccinimide and diphenyldiselenide gave intermediate 21. Alkylation of adenine and 2-amino-6-chloropurine with 21 provided the Z,E-isomeric mixtures 22a and 22c. Oxidation afforded selenoxides 23a and 23c. Mild thermolysis furnished methylenecyclopropanes Z-24a, E-24a, and 24c. Deprotection and separation of Z,E-isomers gave adenine analogues 12a and 13a, and 2-amino-6-chloropurine intermediates 12c and 13c. Hydrolytic dechlorination of 12c and 13c afforded guanine analogues 12b and 13b. Adenine Z-isomer 12a inhibits replication of Epstein-Barr virus through its cytotoxicity. The E-isomer 13a is a substrate for adenosine deaminase.     

Bromohydrin reactions of Grieco’s bicyclic lactone

The bromohydrin reaction in Grieco’s bicyclic lactone 1 was reinvestigated. Two regioisomeric bromohydrins were obtained (2 and 8), and their configurations were unambiguously determined by X-ray diffraction analyses.     

Formal synthesis of (±)-udoteatrial hydrate

The formal synthesis of antimicrobial diterpene udoteatrial hydrate (1) is described in nine steps. Diol 6 used as starting material. The key intermediate 4 was obtained from bicyclic ketone 5 via the key Norrish type I reaction.     

Syntheses and regiochemistry of enol addition to 9-phenyl-9H-xanthen-9-ol

Regioselective C-C bond formation of 9-phenyl-9H-xanthen-9-ol 1 with various enolizable ketones I-X in an acidic (HBr) medium, obtained by the reaction of 1,1′-(ethane-1,2-diyl)dipyridinium bistribromide (EDPBT) with ketone is observed. Except for ketone, 4-methyl-pentan-2-one VII in all other cases examined the attack to xanthenyl carbocation is from the thermodynamically stable enolizable side of the unsymmetrical ketones. In the case of 3-methyl-butan-2-one VIII the equilibrium is in favor of the more stable enolizable ketone, which has large steric factor, hence no reaction was observed during its addition to alcohol 1.     

Efficient and scalable synthesis of thiazole fused benzazepine as a D2 partial agonist

The development of an efficient and scalable synthetic route to prepare the selective D2 partial agonist (1) is described here. Regioselective nitration of tetrahydrobenzazepine 2, followed by reductive amination, hydrogenation, and oxidative cyclization afforded 1 in good yield, without the need of column chromatography.     

The synthesis of 2,4-dienyl fluoroalkyl ketones by a tandem three-stage sequence of propargyl 2-fluoroalkylvinyl ether formation, Claisen rearrangement, and allene-to-conjugated diene isomerization

A tandem three stages process to a series of trifluoromethyl and halodifluoromethyl 2,4-unsaturated ketones 4a-c is described. This process started with the preparation of 2-fluoroalkyl substituted propargyl vinyl ether 3a-d by treatment of a mixture of individual ethyl α-per(poly)fluoroalkyl acetates 1a-d and propargyl alcohol 2 in CH₂Cl₂ with the mixed base (Na₂CO₃/TEA) at ambient temperature. When heated in toluene at 80°C, these ethers readily underwent a tandem propargyl-allenyl Claisen rearrangement and isomerization of the resultant 3,4-dienone to give 2,4-unsaturated fluoroalkyl ketones 4a-c (Z/E mixture). The reaction of ethyl α-per(poly)fluoroalkyl acetate 1 with 1-phenyl propargyl alcohol 5 in refluxing CH₂Cl₂ in the presence of the mixed base (Na₂CO₃/TEA) directly afforded the corresponding unsaturated fluoroalkyl ketone 6a-c in one pot. In the presence of NaH, the reaction of ethyl 3-halo-3-fluoroalkylacrylates 8a-b with 1,1-dimethyl propargyl alcohol 9 at −50°C to 0°C also gave the unsaturated fluoroalkyl ketones 10a-b in one pot. The difluorovinyl propargyl ether 11 produced by reduction of 2-bromodifluoromethyl substituted propargyl vinyl ether 3b rearranged in hot benzene to give the corresponding allene 12 bearing a gem-difluoromethylene group in the middle of the aliphatic chain.     

Protonation and rearrangement of the tricyclo[4.2.2.2]dodeca-3,7,9,11-tetraene scaffold

The biplanemers 2a,b contain enol ether substructures, which permit facile protonations of the π electron system. The subsequent ether cleavage is characterized by rearrangements of the polycyclic scaffold of the carbenium ions or the electroneutral primary products. Apart from the expected products 3a and 5a, a series of unexpected ketones and diketones (4a′, 9b, 10b, 11b, and 12b) were obtained.