Knoevenagel condensation of 2-carbethoxycyclohexanone and malononitrile: Synthesis of 4-cyano-3-ethoxy-1-hydroxy-5,6,7,8-tetrahydroisoquinoline,an isomer of the abnormal product

The structure of the abnormal product 1a formed in the Knoevenagel condensation of 2-carbethoxycyclohexanone and malononitrile has been further confirmed. Oxidation of the tetrahydroisoquinoline 3b using Na₂Cr₂O-AcOH-H₂SO₄ gave the keto isoquinoline 3d and the isoquinoline-1-carboxylic acid 5a. The acid chloride of 5a was condensed with diethyl ethoxymagnesiomalonate to afford after decarbethoxylation the methyl ketone 5d which on Baeyer-Villiger oxidation gave a mixture of the acetate 1g and the title compound 1b. The unambiguous synthesis of 1b confirms the structure assigned earlier to the title compound also formed during the partial hydrolysis of the diethoxy compound 1c. Condensation of 2-acetylcyclohexane-1,3-dione with malononitrile gave the quinoline derivative 4c which on ethylation yielded the ketoquinoline 4d. The present studies have confirmed that the quinoline compound 4a is also formed in the condensation of 2-acetylcyclohexanone and cyanoacetamide.     

Yonarolide A,an unprecedented furanobutenolide-containing norcembranoid derivative formed by photoinduced intramolecular [2+2] cycloaddition

Eight polycyclic furanobutenolide-containing norcembrane diterpenoids featuring C19 frameworks (1–8) were rapidly recognized and isolated from the Hainan soft coral Sinularia sp. by the HSQC-based small molecule accurate recognition technology. Yonarolide A (1a), featuring an unprecedented 5/6/4/4/7 pentacyclic ring skeleton, was surprisingly obtained as a transformed product by leaving compound 1 under indoor natural light, and was further proved to be a [2 + 2] cycloaddition product of 1 by photochemical reaction. The absolute stereochemistry of 1a and the three known norcembrane diterpenoids 1, 4, and 7 were determined by using X-ray diffraction (XRD) analyses. Further, with the aid of XRD analysis, the structure of scabrolide B (2), which was previously reported of possessing 5/6/7 tricyclic skeleton, was firmly revised as 2a with the rare inelegane skeleton featured by the highly oxygenated 5/7/6 tricyclic carbocycle.     

Functionalized enamines—XV: Reactivity patterns of carbene addition to morpholine enamine of 1-β-acetoxy-6-oxo-8a-methyl-Δ4a(5)-octalin

Carbenes3a-e add to the α-side of the first double bond of dienamine2 (title compound) to give 1 : 1 adducts4a-e, Chlorofluorocarbene3e gives, in addition, ketone7, corresponding to β-addition at the second double bond of2, and a 2 : 1 adduct8. The reaction of2 with dichlorocarbene3a yields, besides4a, novel ring-expansion products5 and6 corresponding to addition of two moles of3a. Ethoxycarbonylcarbene3f reacts with the dienamine (2) to give isomeric esters9 and10a,b. The structure assignments and the mechanism of formation of the reaction products are discussed.     

Diels-Alder cycloaddition of 2-azadienes to methyl 2-(2,6-dichlorophenyl)-2H-azirine-3-carboxylate in the synthesis of methyl 4-oxo-1,3-diazabicyclo[4.1.0]heptane-6-carboxylates

A number of fused 4-oxo-1,3-diazabicyclo[4.1.0]heptane-6-carboxylates, a new type of compound, have been obtained by Diels-Alder cycloaddition between nucleophilic 2-azadienes and an electrophilic 2H-azirine. The reactions are completely endo- and regioselective, the azirine being added by its less hindered face to the diene. There are two isomers 7 and 8 formed from dienes 1 due either to isomerization of the cycloadducts 7 and 8 or by isomerization of the CN bond of the diene during the reaction. The isomer 10 is formed from diene 2e, and a single diastereoisomer structure 4a-i is formed from dienes 11. Some pyrimidones 8a, 7c/8c, 7e, 10, 11d have been hydrolyzed leading to functionalised aziridines 12, 13 and 15.     

Quinones and quinone methides—V: Further rearrangements of the dimer from 5-methoxy-2-(4-methoxyphenylmethyl)-1,4-benzoquinone

In strongly acid solutions the dimer 3 dissociates to the quinone 1 and quinone methide 2 which recombine with elimination of p-methoxybenzyl alcohol to form the xanthylium salt 9a. With zinc and acetic acid 3 yields isormeric meso- and dl-ethylenediquinol derivatives 14a. Sodium borohydride reduction of 3 yields an alcoholic quinol 5a which rapidly reoxidizes to the spiro-tetrahydrofuran derivative 24a. Possible mechanisms which may be involved in the formation of these rearranged products are discussed.     

Quinones and quinone methides—IV: Dimerization reactions of 2-phenylmethyl-5-methoxy-1,4-benzoquinones

Base catalyzed dimerization of 2-(4-methoxyphenylmethyl)-5-methoxy-1,4-benzoquinone 6 yields as the chief product an unusual tetrahydroxanthen derivative 7a. The structure of 7a suggests that it is formed by combination of two molecules of the ortho-quinone methide tautomer of 6. Rearrangement of 7a yields the dihydro-oxepin derivative 15 and the indanspirocyclohexene derivatives 17 and 18a, all of which are formed as minor products in the dimerization of 6. In contrast to 6 related 2-(1-phenylethyl)-1,4-benzoquinones do not dimerize in basic media.     

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.     

Functionalized enamines—XV: Reactivity patterns of carbene addition to morpholine enamine of 1-β-acetoxy-6-oxo-8a-methyl-Δ-octalin

Carbenes3a-e add to the α-side of the first double bond of dienamine2 (title compound) to give 1 : 1 adducts4a-e, Chlorofluorocarbene3e gives, in addition, ketone7, corresponding to β-addition at the second double bond of2, and a 2 : 1 adduct8. The reaction of2 with dichlorocarbene3a yields, besides4a, novel ring-expansion products5 and6 corresponding to addition of two moles of3a. Ethoxycarbonylcarbene3f reacts with the dienamine (2) to give isomeric esters9 and10a,b. The structure assignments and the mechanism of formation of the reaction products are discussed.     

Natural product synthesis from (8aR)- and (8aS)-bicyclofarnesols: synthesis of (+)-wiedendiol A, (+)-norsesterterpene diene ester and (−)-subersic acid

Both enantiomers (8aR)-7 and (8aS)-7 of bicyclofarnesol were synthesized from the enzymatic resolution products (1R,4aR,8aR)-1,2,3,4,4a,5,6,7,8,8a-decahydro-5,5,8a-trimethyl-2-oxo-trans-naphthalene-1-methanol-2-ethylene acetal (8aR)-5 (98% ee) and acetate of (1S,4aS,8aS)-1,2,3,4,4a,5,6,7,8,8a-decahydro-5,5,8a-trimethyl-2-oxo-trans-naphthalene-1-methanol-2-ethylene acetal (8aS)-6 (>99% ee), respectively. The formal synthesis of (+)-wiedendiol 1 was achieved via a coupling reaction of an ate complex derived from 1,2,4-trimethoxybenzene with allyl bromide (8aS)-8 derived from (8aS)-7. The total synthesis of (+)-norsesterterpene diene ester 2 was achieved, based on the synthesis of (13E,10S)-α,β-unsaturated aldehyde 12, derived from (8aS)-7, followed by the selective construction of the (3E,5E)-diene moiety including a C(2)-stereogenic centre in (+)-2. The total synthesis of (−)-subersic acid 3 was carried out based on a Stille coupling between allyl trifluoroacetate congener 25c, derived from (8aR)-7, corresponding to the diterpene part, and aryl stannane congener 26 in the presence of Pd catalyst and CuI as an additive.     

Metabromation du dimethyl-2,6 phenol et de son ether methylique en milieu superacide

In SbF₅-HF, reaction of bromine with 2,6-dimethylphenol gives the meta bromo compound 1b which is further halogenated to 3,4-dibromo-2,6-dimethylphenol 1c. In the same conditions ether 2a yields successively 2b and 2d. Meta bromination of compounds 1a,2a,2b implies electrophilic attack on the O-protonated substrate, whereas reaction of the neutral phenol 1b leads to the p-bromoderivative 1c. All products are obtained in excellent yields (> 85%).     

Wittig homologation of 2-(chloromethyl)-2H-chromen-2-ol derivatives: a new facile synthesis of substituted 2,3-dihydrobenzoxepine-4-carboxylates

Wittig homologation of 2-(chloromethyl)-2H-chromen-2-ol derivatives 2a–t with (ethoxycarbonylmethylene)triphenylphosphorane provided the 2-oxoethylidene-2,3-dihydrobenzoxepine-4-carboxy-lates 3a–t with Z (cis) selectivity. Various basic catalysts were studied for the reaction of 2-(chloromethyl)-2H-chromen-2-ol 2a with the combination of Wittig reagent to provide compound 3b. The reaction of 2-(chloromethyl)-2H-chromen-2-ol 2a with other Wittig reagents, such as methylene(triphenylene)phosphorane and (1-ethoxycarbonylethylidene)triphenylphosphorane provided ketone derivative 4a rather 2-oxoethylidene derivative 3b. The ketone derivative 4a was reacted with Wittig reagent (ethoxycarbonylmethylene)triphenylphosphorane to give 2,3-dihydrobenzoxepine-4-carboxylate 3b. The present approach is novel, straight forward and being reported for the first time.     

Enantiopure erythro- and threo-1-aryl-1-[2-pyrrolidyl]-methanols: synthesis from l-proline

Enantiopure (1R,2S)-erythro- and (1S,2S)-threo-isomers of four new aryl-pyrrolidyl alcohols 5aH, 5aMe, 5bH and 5bMe have been obtained in five steps from (−)-(S)-proline and fully characterized. The oxidation of alcohol 8 into aldehyde 9 was the most difficult step and racemization occurs during Swern oxidation but this difficulty can be overcome by using SO₃/pyridine as oxidant. Diastereomer I of the protected amino alcohol 10a crystallized and was shown to be the (1R,2S)-erythro-isomer (e-10a-I) using X-ray crystallography. Therefore the (1R,2S)-erythro structure was assigned to all compounds obtained from e-10a-I, and, as a consequence, the (1S,2S)-threo structure was assigned to diastereomers II.     

Indenone chemistry—II : Synthesis and reactions of 2,3-dimethylene-6-methoxyindanone

Debromination of the dibromoindenone 5 affords the title compound 8, which dimerizes immediately via a Diels-Alder reaction to the dimers 7a and 7b. The diene 8 can be trapped with cyclopentadiene affording the exo -adduct 9a and the endo -adduct 9b. The norbornene double bond in the adduct 9a can be selectively oxidized to the cis-exo-dial 10.     

An efficient synthesis of (7S,10R)-2-bromo-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole: application in the preparation and structural confirmation of a potent 5-HT6 antagonist

(7S,10R)-5-Methyl-2-((3-(trifluoromethyl)phenyl)sulfonyl)-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole 1a is a potent 5-HT₆ antagonist (h5-HT₆ K_i = 1.5 nM) which is derived from an epiminocyclohept[b]indole scaffold. In order to synthesize 1a on a multi-gram scale to support advanced biological testing, an efficient chiral resolution of the intermediate tert-butyl 2-bromo-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-11-carboxylate 2 was developed. After derivatizing 2 with (1R)-(?)-menthyl chloroformate it was found that a single diastereomer 7a could be isolated by selective precipitation from n-hexane. The absolute stereochemistry of 7a was determined by X-ray crystallography and the structure was confirmed as (7S,10R)-tert-butyl 2-bromo-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-11-carboxylate. Removal of the chiral auxiliary under basic conditions afforded intermediate 2a in >99% enantiomeric purity and with 80% yield based on recovery from the racemic compound 2. Intermediate 2a was used successfully to synthesize 5-HT₆ antagonist 1a on a multi-gram scale.     

Absolute configuration assignment of 3-indolylacetate esters

Herein we describe a straightforward method for the determination of the absolute configuration of 3-indolyl(bromo)acetate 7, 3-indolyl(alkoxy)acetates 8a–f and 3-indolyl(amino)acetate 8g, based on ¹H NMR spectral analysis. The conformational preferences for two diastereomeric esters were calculated by DFT, which matched very well with the experimental results. X-ray diffraction analysis allowed us to validate the methodology, and independent absolute configuration evidence was obtained by vibrational circular dichroism.     

Key intermediates in the synthesis of enantiopure antagonists at NMDA receptors: a structural study

The two diastereomeric amino acid derivatives 8 (3aS,5R,6aS)-5-tert-butoxycarbonylamino-4,5,6,6a-tetrahydro-3aH-cyclopenta[d]isoxazole-3,5-dicarboxylic acid diethyl ester, its epimer 9 (3aS,5S,6aS), and carboxylic acid 10 obtained by hydrolysis of 9, which are intermediates in the synthesis of novel NMDA receptor antagonists 6 and 7 (Fig. 1), have been characterized by X-ray studies at 293 K for 8 and 10, and at 100 K for 9. The configuration of the carbon binding the 5-tert-butoxycarbonylamino moiety (BOC) determines the different molecular complexity: the chain structure for 8, dimeric for 9, and chain dimers for 10. The pharmacophoric parameters in compound 8 (from which the active 7 is derived) are comparable with those observed for NMDA receptor antagonism, while 9 and 10 do not present the structural features, which match these pharmacophoric characteristics.     

Chemoenzymatic synthesis of enantiomerically pure tricyclic benzomorphan analogues

The key step in the synthesis of enantiomerically pure benzomorphan analogous tricyclic amines 2 is the kinetic resolution of secondary alcohol 7 using the lipase from Pseudomonas fluorescence. The (S)-configured alcohol (S)-7 and the (R)-configured ester (R)-8 were obtained in good yield (40% and 46%, respectively) and excellent enantiomeric excess (99% ee and 98.4% ee, respectively). A diastereoselective oxa-Pictet-Spengler reaction of (S)-7 with ethyl glyoxalate (OHC–CO₂Et) followed by a Dieckmann cyclization provided the tricyclic ring system 11, which allowed the diastereoselective introduction of an amino group at the 6-position. The absolute configuration of alcohol (S)-7 was determined with the tricyclic alcohol 13. The quantum mechanically calculated specific optical rotation of (S,S,S)-configured alcohol 13 is in accordance with the measured specific rotation of the synthesized compound. Moreover, X-ray crystal structure analysis of the synthesized compound, determined with the three-beam interference method, proved the (S,S,S)-configuration of 13. The enantiomerically pure dimethylamine 12 showed moderate affinity toward σ₂ receptors.     

Hydantoins,thiohydantoins, glycocyamidines—36: 1,5,5- and 3,5,5-triphenyl derivatives

In contrast to the α-chloroamides 1a-c which, when reacted with potassium N-cyanoanilide, furnish anomalous substitution products (2a-c), the related nitrile and ester yields normal substitution products (3a and b) under the same conditions. 1,5,5-Triphenylhydantoin (4a) and a series (5a-8a, 13 and 14) of its derivatives have been prepared starting with 3a and b. Acid hydrolysis of 3a yields, in addition to the normal products (4a and 5a) considerable quantities of the rearranged product 4b. An authentic sample of the latter, as well as a series of its derivatives (5b-8b and 11) have been prepared starting with α,α-diphenylglycinonitrile and 2-methylthio-1,4,4-triphenyl-2-imidazolin-5-one (9). When reacted with ammonia and ammonium iodide, 9 gave, in addition to the normal ammonolysis product 7b, the Dimroth rearrangement product 16, as well as 5,5-diphenylglycocyamidine, by apparent dephenylation of 16. The mass spectra of the imidazole derivatives 4–8, a and b, 9, 11, 13 and 14 are discussed.     

Reactions of the 1-halo-7-(2-hydroxyethoxy)cycloheptenes and the 3-halo-4-(2-hydroxyethoxy)bicyclo[3.2.1]oct-2-enes with potassium t-butoxide

Reactions of 1 - bromo - 7 - (2 - hydroxyethoxy)cycloheptene 2 and its chloro analogue 3 with potassium t-butoxide in dimethyl sulphoxide or tetrahydrofuran gave cycloheptatriene and cis - 8,11 - dioxabicyclo[5.4.0]undec - 2 - ene 18 as the major products together with small amounts of the trans-isomer 17,8,11-dioxabicyclo[5.4.0]undec - 1(7) - ene 14, 8,11 - dioxabicyclo[5.4.0] - undec - 1 - ene 19, cyclohept - 2 - enone ethylene ketal 15, cyclohept - 3 - enone ethylene ketal 16, and 1- and 2 - t - butoxycyclohepta - 1,3 - diene 20. Similar reactions of 3 - bromo - and 3 - chloro - 4 - (2 - hydroxyethoxy)bicyclo[3.2.1]oct - 2 - ene 4 and 5 gave 4,7 - dioxatricyclo[7.2.1.0^3,8]dodeca - 2 - ene 26 as the major product together with small amounts of 3,6 - dioxatricyclo[7.2.1.0^2,7]dodeca - 2(7) - ene 27 and bicyclo[3.2.1]oct - 3 - ene - 2 - one ethylene ketal 28. Mechanisms for these transformations are discussed.     

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.