Addition of silyloxydienes to 2,6-dibromo-1,4-benzoquinone: an approach to highly oxygenated bromonaphthoquinones for the synthesis of thysanone

The synthesis of tetraoxygenated bromonaphthoquinones 6a, 6b, 6c, 6d, key intermediates for a synthesis of the 3C protease inhibitor, thysanone, were investigated. Addition of 1-methoxy-1,3-bis(trimethylsilyloxy)-1,3-butadiene 8 to 2,6-dibromo-1,4-benzoquinone 10 in benzene afforded a mixture of naphthoquinone 6a, arising from Diels-Alder addition followed by aromatisation, and Michael adduct 12. The Michael adduct 12 predominated when THF was used as solvent whereas 6a predominated when benzene was used. Naphthoquinone 6a underwent benzylation to naphthoquinone 6c. Addition of 1,1-dimethoxy-3-trimethylsilyloxy-1,3-butadiene 9 to 2,6-dibromo-1,4-benzoquinone 10 followed by benzylation failed to afford the desired bromonaphthoquinone 6d yet methylation did afford naphthoquinone 6b. Bromonaphthoquinone 6d was finally prepared from naphthol 18, obtained from addition of diene 9 to 1,4-benzoquinone 17, followed by ortho-bromination and oxidation. Attempted Sakurai allylation of bromonaphthoquinone 6d afforded naphthodihydrofuran 21. A similar observation was observed for 2-carbomethoxy-1,4-naphthoquinone 22 that also underwent Sakurai allylation to afford naphthodihydrofuran 23. The structure of Michael adduct 12 was confirmed by X-ray crystallography.     

Asymmetric synthesis of Goniothalesdiol A from (R)-2,3-O-cyclohexylidine glyceraldehyde

Goniothalesdiol A 1 has been synthesized from (R)-2,3-O-cyclohexylidine glyceraldehyde with high stereoselectivity and 22% overall yield in 11 simple steps. The key features of the synthetic strategy include the stereocontrolled allylation of (R)-2,3-O-cyclohexylidine glyceraldehydes; the cross-metathesis with a Grubbs’s second generation catalyst, and the intramolecular base-catalyzed oxy-Michael addition for the formation of the tetrahydropyran ring.     

Stereoselective intramolecular cycloadditions of homochiral N-alkenoyl aryl azides

Starting from the commercially available (S)-1-phenylethylamine and l-alanine benzylester, we synthesised the homochiral N-alkenoyl aryl azides 2a–2d. The intramolecular cycloaddition of unsubstituted 2a and 2b gave enantiopure 3,3a-dihydro-1,2,3-triazolo[1,5-a][1,4]benzodiazepine-4(6H)-ones 3a, 3b, 4a and 4b, while phenyl-substituted 2c and 2d gave enantiopure 1,1a-dihydro-2H-azirino[2,1-c][1,4]benzodiazepine-4(6H)-ones 5c, 5d, 6c and 6d.     

Concise and practical route to tri- and tetra-hydroxy seven-membered iminocyclitols as glycosidase inhibitors from d-(+)-glucurono-γ-lactone

An efficient and short total synthesis of tetrahydroxy-1c and trihydroxy-azepane 1d is reported in 72% and 57% overall yields, respectively, from d-(+)-glucurono-γ-lactone. Thus, d-glucuronolactone 2 on acetonide protection, DIBAL-H reduction and one-pot intermolecular reductive amination followed by -NCbz protection afforded 6-(N-benzyl-N-benzyloxycarbonyl) amino-6-deoxy-1,2-O-isopropylidene-α-d-gluco-1,4-furanose 5a. 1,2-Acetonide hydrolysis in 5a and Pd-mediated intramolecular reductive aminocyclization afforded tetrahydroxyazepane 1c. An analogous pathway with 5-deoxy-1,2-O-isopropylidene-α-d-glucurono-6,3-lactone 3b gave trihydroxy-azepane 1d. Glycosidase inhibitory activity of 1c/1d was studied and 1d was found to be potent inhibitor of α-mannosidase and β-galactosidase.     

Tele-substitutions en serie anthracenique—II : Extension de la substitution par l'ionphénate à divers bromo-9 anthracènes méso-alkylés

A competition between normal substitution and tele-substitution is observed with 9-bromoanthracenes bearing in the opposite meso position an ethyl, 1b, or a benzyl group 1d. When treated with potassium phenoxide in HMPT these bromides afford mixtures of 9-alkyl-10-phenoxy-anthracenes 2 and 9-(α(phenoxyalkyl) anthracenes 3. On the other hand 9-bromo-10 isopropylanthracene 1c is quite unreactive and 9-bromo-d10-methoxymethylanthracene 1e leads essentially to anthraldehyde 7.     

Domino routes to substituted benzoindolizines: tandem reorganization of 1,3-dipolar cycloadducts of nitrones with allenic esters/ketones and alternative cycloaddition-palladium catalyzed cyclization pathway

Reactions of C-(4-oxo-4H[1]benzopyran-3-yl)-N-phenyl nitrones (7) with allenic esters (8a-c) and allenic ketones (18a-d) furnish benzoindolizines (9a-k, 19a-d) in good yields. The formation of benzoindolizines is postulated to involve regioselective addition of 1,3-dipole to C2-C3 π bond of allenic esters/ketones followed by domino transformation of the cycloadducts, which involve an intramolecular aza Diels-Alder reaction in the intermediate C. DFT calculations of various parameters for diene and dienophile components in the proposed intermediate C have revealed that conformational constraints imposed by the alkyl groups (R=Me, Et) favor intramolecular aza-Diels-Alder cycloaddition. An alternative domino route to benzoindolizines (9a,d,g) involving sequential one-pot cycloaddition of azadienes (22a-c) with silyl-enol ether (23) followed by palladium(0)-catalyzed Heck coupling reaction has also been developed. Both these approaches represent novel domino routes for the synthesis of benzoindolizines.     

Observation of the primary Zr–C insertion products in the reaction of the (butadiene)zirconocene/B(C6F5)3-betaine Ziegler catalyst system with reactive alkynes

The (conjugated diene) group 4 metallocenes 1a–d (diene=butadiene, isoprene; metallocene=Cp₂Zr, Cp₂Hf, MeCp₂Zr) add B(C₆F₅)₃ to yield the metallacyclic M⋯F–C bridged metallocene–borate–betaine complexes 3a–d. These add one equivalent of acetylene to give the chiral metallacyclic insertion products 5a–d that can be described as either intramolecular ion-pair type complexes involving interaction of the negatively polarized terminal –CHCH–CH₂–[B] group of the resulting σ-ligand system with the positively polarized metallocene moiety of the dipolar betaine product or η²-internal alkene metallocene complexes, respectively, as it is revealed by a comparison with the related acyclic THF-addition products 10 and 12. Propyne inserts unselectively into the terminal Zr–C bond of the complexes 3a–c. In each case a 1:1 mixture of the regioisomers 6a–c (methyl at C2) and 7a–c (methyl group at C1) is obtained.     

A convenient synthesis of benzofuro[3,2-c]isoquinolines and naphtho[1′,2′:4,5]furo[3,2-c]isoquinolines

A convenient method for the preparation of benzofuro[3,2-c]isoquinoline derivatives is described. The condensation reaction of methyl 2-(chloromethyl)-benzoate with substituted salicylonitriles 7a-c and intramolecular cyclization of the resulting substituted methyl 2-[(2-cyanobenzyl)oxy]benzoates 10a-c using potassium tert-butoxide results in the substituted benzofuro[3,2-c]isoquinolin-5(6H)-ones 1a-c. The same sequence of reactions starting from 2-(chloromethyl)benzonitrile and compounds 7a-c gave substituted 5-aminobenzofuro[3,2-c]isoquinolines 13a-c. In addition, this method is useful for the synthesis of other heterocycles. For example, using 1-cyano-2-naphthol 16, instead of the salicylonitriles 7a-c, gives naphtho[1′,2′:4,5]furo[3,2-c]isoquinolines.     

Crotylation of (R)-2,3-O-cyclohexylideneglyceraldehyde: a simple synthesis of (+)-trans-oak lactone

Crotylations of (R)-2,3-cyclohexylideneglyceraldehyde (1) were utilized in a simple synthesis of trans-oak lactone (I), a representative example of chiral β,γ-disubstituted-γ-butyrolactones. In this endeavor, crotylations of 1 in THF mediated with four low valent metals were studied. All these reactions took place efficiently producing 2 in good yields but with varied stereoselectivities. Each reaction produced the corresponding secondary alcohol adduct 2b and 2c predominantly with diastereoisomer 2a only in trace amounts. Among these four reactions, only Sn-mediated addition yielded 2b as the major products. Later, 2c was converted into 2d through oxidation-reduction. Finally, 2c was transformed into trans-oak lactone I in a few steps. Following this route, 2a, 2b, and 2d would produce other stereoisomers of oak lactone.     

Activation and transfer of oxygen—XII : Alkoxy adducts derived from 1,3,10-trimethylalloxazinium (1,3-dimethylflavinium) cations

Monoalkoxy adducts, derived from an alloxazinium cation and an alcohol in the presence of a base, are readily converted into dialkoxy adducts. Two types of dialkoxy adducts are formed. In the reaction with a monohydric alcohol C₄ is preferred for the second intermolecular nucleophilic attack to give the 4,10a-dialkoxy adduct, which rearranges into a hexahydroimidazo[4,5-b]quinoxalme derivative 5c. In the reaction with a dihydric alcohol C_4a, is the second reaction site in an intramolecular nucleophilic ringclosure to give a 4a,10a-dialkoxy adduct 6c which can be isolated as such. Both types of dialkoxy adducts can be reconverted into the alloxazinium cation.The structures of the dialkoxy adducts give every reason to reject the conclusion in the literature that C_9a is the primary addition site.Starting from 5c several reactions have been effected: (a) conversions into tetra- and di-hydroimidazo[4,5-b]quinoxalinium cations 7 and 9 and ring opening of 9 into a ureido-dihydroquinoxaline 10 (Scheme 4); (b) a rearrangement of a transient hexahydroimidazo[4,5-b]quinoxaline 5d into spirohydantoin 4 and a rearrangement of cation 7 into the alloxazinium cation 1 (Scheme 5); (c) preparation of acetylated tetra- and hexa-hydroimidazo[4,5-b]quinoxalines 11 and 12. Conversions of cation 11 into 9 and 1 and conversions of 12 into a benzimidazolinium cation 14 (Schemes 6 and 7). Degradation of 14 affords 1,2-dimethylbenzimidazole (15, Scheme 6).     

Simple and condensed β-lactams-I : The application of diketene in β-lactam synthesis. The synthesis and functional group manipulations of diethyl 3-acetyl-4-oxoazetidine-2,2-dicarboxylates

Acylation of the N-substituted diethyl aminomalonates 3a–3d with diketene furnished the ring tautomers 6a–6d of the expected acetoacetyl derivatives 5. By treatment with iodine and sodium ethoxide compounds 6a–6d are smoothly converted into the β-lactam derivatives 2a–2d. Deethoxycarbonylation of the ethylene ketals 7a–7d of the latter furnishes mixtures of the corresponding diastereomeric monoesters 8 and10. The ethoxycarbonyl groups of the trans esters 8 are more reactive than those of the cis isomers 10. This permits, under appropriate conditions, selective alkaline hydrolysis and NaBH₄ reduction of the trans esters 8 in the presence of the cis esters 10. Reduction of the cis ester 10c under more forceful conditions furnishes the trans hydroxymethyl derivative 11c.     

A concise synthesis of Ni-didecarboxysirohydrochlorin hexamethylester—a model compound for key intermediates in heme d1 and heme biosynthesis

An efficient synthesis of Ni-didecarboxysirohydrochlorin hexamethylester rac-13 was achieved by Barton olefination starting from a readily available dioxo-isobacteriochlorin rac-9. The synthetic route should open a general facile access to this type of naturally occurring hydroporphyrins. Isobacteriochlorins 3–6 are key intermediates in heme d₁ and heme biosynthesis of sulfate reducing and denitrifying bacteria as well as in archaebacteria.     

Synthesis and rearrangement of cycloalkyl[1,2-e]oxazolo[3,2-a]pyrimidin-8/9-ones: an access to cycloalkyl[1,2-d]oxazolo[3,2-a]pyrimidin-5-ones

2-Substituted-4a-hydroxy-9H-cycloalkyl[1,2-e]oxazolo[3,2-a]pyrimidin-9-ones 2a-c were synthesized by an one-step cyclocondensation from the 5-substituted-2-amino-2-oxazolines 1a-c with ethyl 2-oxocyclohexanecarboxylate in ethanol at room temperature, and easily dehydrated to provide 2-substituted-9H-cycloalkyl[1,2-e]oxazolo[3,2-a]pyrimidin-9-ones 3. In refluxing xylene, the reaction conducted with various ethyl 2-oxocycloalkanecarboxylates led to the two isomeric 2-substituted-8/9H-cycloalkyl[1,2-e]oxazolo[3,2-a]pyrimidin-8/9-ones 3 and 2-substituted-5H-cycloalkyl[1,2-d]oxazolo[3,2-a]pyrimidin-5-ones 4. The structure of some compounds was unambiguously established using X-ray crystallography. According to results from the DSC analysis of compound 2a, formation of the thermodynamically stable pyrimidinones 4 could be related to an intramolecular rearrangement of kinetically controlled pyrimidinones 3.     

Stereochemie von α,ω-Diphenyl-alkan-α,ω-diolen

Reduction (both catalytically and with complex hydrides) of the diphenyl diketones1 (a, b, c andd withn=0, 2, 3 and 4) was investigated mainly with regard to the diastereomeric ratio of the diols2. For2 a and2 b exact results were obtained by NMR spectroscopy (without or with shift reagents) of the diol mixture (2 a) or after stereoselective cyclization to the cyclic ethers (3 b). AlsoGC andLLC were employed for the analysis of2 a (GC of the trimethylsilyl derivatives) and for the ethers3, resp. (GC for3 a and3 d;LLC for3 b and3 c). The reduction of1 a, 1 b (and in part1 c) proceeds with high stereoselectivity; themeso-diol preponderates in the case of2 a, therac.-diol for2 b and2 c; with increasingn the diastereomeric ratio approaches the statistical ratio of 1∶1. Preparations of the stereoisomeric diols (2 b, c andd via acetylenic precursors) and of the cyclic diphenyl ethers (by stereoselective cyclization and/or chromatographic separation;3 c and3 d for the first time) as well as the determination of their configurations are described. The latter was achieved by NMR and for the ethers3 also by hydrogenation of the corresponding heteroaromatics.     

Microwave assisted synthesis of 3-benzazepin-2-ones as building blocks for 2,3-disubstituted tetrahydro-3-benzazepines

Microwave assisted condensation of primary amines with keto acids 1a–c provided directly 3,4-disubstituted 1,3-dihydro-3-benzazepin-2-ones 2. Whereas small amine size, such as NH₃ afforded high yields of secondary lactams 2a, 2d, and 2g, primary amines with larger substituents in α-position led to lower yields of 2 or even to regioisomeric indanone derivatives 4. However, subsequent alkylation of 2a, 2d, and 2g with various alkyl halides provided the corresponding N-substituted 3-benzazepin-2-ones 2 in good yields. Hydrogenation of 2 followed by BH₃ reduction led to 3-benzazepines 9. 3-Benzyl-2-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (9c) reveals high σ₁ affinity and selectivity over σ₂ and NMDA receptors.     

Darstellung und thermolyse von hexakis(perfluororganylthio/seleno)ethanen

Thiocarbonylcompounds such as 1a, 1b, 1c, 1d, 1e and 1f were prepared and irradiated with UV- light in hexane solution. The products obtained in this photolyses are 3a, 3b and 3c. Only 3c dissociates in the temperature range 140-190° reversible to 2c. The others, 3a and 3b, decompose yielding bis(trifluoromethyl)diselenide, 6b and 6d, without forming the corresponding methyl radical 2a and 2b. This was proved by spin-trapping experiments utilizing phenyl-t-butylnitrone. Attempts to prepare 3e were unsuccessful but led to the new compounds 7a, 7b, 7c, 1,1,1-tris(trifluoromethylseleno)ethan (7d) and, surprisingly, 9. Physical and spectroscopic data of the newly prepared substances are provided.     

Stereoselective total synthesis of the (Z)-isomer of a novel phytotoxic nonenolide from Phomopsis sp. HCCB03520 and its C-6 epimer

The (Z)-isomer of a phytotoxic nonenolide, (6S,7R,9R)-6,7-dihydroxy-9-propylnon-4-eno-9-lactone isolated from Phomopsis sp. HCCB03520 and its C-6 epimer have been synthesized through a common route starting from butyraldehyde. The synthesis involves enantioselective Maruoka allylation, Sharpless asymmetric epoxidation and intramolecular ring closing metathesis as the important steps.     

Formal syntheses of (−)- and (+)-aphanorphine from (2S,4R)-4-hydroxyproline

We describe the efficient formal syntheses of both natural (−)-aphanorphine and unnatural (+)-aphanorphine from the same commercially available amino acid, (2S,4R)-4-hydroxyproline. The tricyclic framework was constructed by intramolecular Friedel-Crafts reaction. (1R,4S)-1-Methyl-8-methoxy-3-(4-toluenesulfonyl)-2,3,4,5-tetrahydro-1,4-methano-3-benzazepine (8) was synthesized in six steps from sulfonamide 3; (−)-aphanorphine methyl ether 24 was obtained in seven steps from lactone 10. Intramolecular etherification of 18 proceeded with excellent stereoselectivity in the presence of BF₃·OEt₂, which has paved an efficient synthetic route to a series of medicinally attractive heterocycles.     

Preparation and reactivity of macrocyclic dienynes

(1E,5E)-Cyclopentadeca-1,5-dien-3-yne (1c), which represents the first macrocyclic 1,5-dien-3-yne, can be obtained by thermal- or butyllithium-induced fragmentation of the corresponding 1,2,3-selenadiazole 8. The (E,E)-dienyne functionality causes a geometrical strain E_g, which enhances the reactivity in addition (1c→12,13) and cycloaddition (1c→10) reactions and lowers the isomerization barrier to the unstrained (E,Z)-configuration 1d (E_g = 0). A slow process 1c→1d occurs even at ambient temperatures within several weeks.     

Quinolizidines—IV: Total syntheses of (±)-ankorine and (±)-11-methoxyprotoemetinol

The first total synthesis of ankorine (4), an Alangium lamarckii alkaloid, has been accomplished in the form of a recemic modification by means of an initial condensation of 2-benzyloxy-3,4-dimethoxyphenacyl bromide with the lactim ether 6, derived from ethyl (±)-trans-5-ethyl-2-oxo-4-piperidineacetate (5), and succeeding steps proceeding through the intemediates 7a, 8a, 9a, 10a (X=Cl), 11a, and 12a. A parallel synthetic route starting with 3,4,5-trimethoxyphenacyl bromide and 6 gave (±)-11-methoxyprotoemetinol (12c) via the intermediates 7c, 8c, 9c, 10c (X =I,ClO₄), and 11c. The trimethyl ether 12c did not match the O-Me derivative (type 12e) of natural ankorine. Thus, the formula 4 defines the structure and relative stereochemistry of ankorine.