Synthesis of tricyclic analogues of methyllycaconitine using ring closing metathesis to append a B ring to an AE azabicyclic fragment

The synthesis of several ABE tricyclic analogues of the alkaloid methyllycaconitine 1 is reported. The analogues contain two key pharmacophores: a homocholine motif formed from a tertiary N-ethyl amine in a 3-azabicyclo[3.3.1]nonane ring system and a 2-(3-methyl-2,5-dioxopyrrolidin-1-ly)benzoate ester 4. The synthesis of the ABE tricyclic analogues of MLA 1 began with selective allylation at C-3 of 3 to produce allyl beta-keto ester 4. Double Mannich reaction of 4 with ethylamine and formaldehyde produced bicyclic amine 5 The C-9 ketone of bicyclic amine 5 was selectively reduced to form bicyclic alcohols 6 and 7 which were subsequently allylated to form dienes 8 and 9. Ring closing metathesis of dienes 8 and 9 afforded tricyclic ethers 11 and 12, respectively, the C-8 ester of which was reduced to a hydroxymethyl group to form ABE tricyclic analogues 13 and 14. Addition of allylmagnesium bromide to the C-9 ketone of 20 afforded dienes 21 and 22, which underwent ring closing metathesis to form tricyclic esters 23 and 24, respectively. Reduction of the C-8 ethyl ester of 23 and 24 to a hydroxymethyl group afforded diols 25 and 26 respectively. The 2-(3-methyl-2,5-dioxopyrrolin-1-ly)benzoate ester was introduced by conversion of alcohols 13, 14, 25 and 26, to the anthranilate esters 16, 17, 27 and 28 using N-(trifluoroacetyl)anthranilic acid 15 followed by fusion with methylsuccinic anhydride to afford the substituted anthranilates 18, 19, 29 and 30 containing the key 2-(3-methyl-2,5-dioxopyrrolidin-1-ly)benzoate ester pharmacophore.     

Synthesis and biological evaluation of conformationally restricted σ(1) receptor ligands with 7,9-diazabicyclo[4.2.2]decane scaffold

The key step in the synthesis of the 7,9-diazabicyclo[4.2.2]decane system was a modified Dieckmann condensation of piperazinebutyrate 11, which makes use of trapping the first cyclized intermediate with TMS-Cl. Reduction of the bicyclic ketone 14 with LiBH(4) at -90 °C provided diastereoselectively (>99?:?1) the syn-configured alcohol 15a, which was converted into the final alcohol and ethers 16a-g. The configuration at the 2-position was established by X-ray structure analysis of methyl and ethyl ethers 15b and 15c. In contrast to bicyclic systems with a three-carbon bridge, inversion of the configuration at the 2-position of the alcohol 15a failed to give the inverted alcohol 19a. However, an unselective reduction of the ketone 24 with L-Selectride led to the diastereomeric alcohols 16a and 25a in the ratio 36?:?64. LiAlH(4) reduction of the tosylate 20 and the alkene 18 yielded the diazabicyclo-decane 26 and -decene 27 without further substituents at the four-carbon bridge. The σ(1) and σ(2) receptor affinities were investigated in receptor binding studies with radioligands. All test compounds showed a lower σ(1) affinity than the corresponding bicyclic derivatives with a three-membered bridge. The reduced σ(1) receptor affinity is attributed to the larger four-membered bridge. This hypothesis is supported by the alkene 27, which represents the most potent σ(1) ligand of this series (K(i) = 7.5 nM). In the alkene 27 the size and flexibility of the bridge is considerably reduced by the double bond. The methyl ether 25b and the unsubstituted derivatives 26 and 27 revealed moderate inhibition of the growth of the human tumor cell lines A-427, 5637 and MCF-7. Again, these compounds are less potent than the analogues with a three-membered bridge. The IC(50)-value of the most potent σ(1) ligand 27 against the small cell lung cancer cell line A-427 (IC(50) = 10 μM) should be emphasized, since this cell line is particularly sensitive to homologues with a three-carbon bridge.     

Desymmetrization of meso-hydrobenzoin using chiral, nucleophilic phosphine catalysts

The desymmetrization of meso-hydrobenzoin is described using chiral phosphine catalysts 8b-d and 9-11. The best enantioselectivity at room temperature was obtained with the newly synthesized phospholane 8c and benzoic anhydride, but the reaction is very slow. Much faster reactions, but somewhat lower enantioselectivities were observed using the bicyclic phosphine catalyst 9. To obtain product 5a with >90% ee required conditions where the ee is upgraded due to the formation of the dibenzoate 6a. Among the new phospholane catalysts, 8b has the best selectivity in the kinetic resolution of benzylic alcohols, but not at the level observed previously with catalyst 11.     

Chiral recognition ability of alpha-cyclodextrin with regard to some monoterpenoids under gas-liquid chromatographic conditions

Gas-liquid chromatography was applied to investigate the mechanism of alpha-cyclodextrin (alpha-CD) complexation processes with some chiral monoterpenoids differing from each other in chemical properties and structure. They were chosen from hydrocarbons, alcohols, aldehydes and ketones of acyclic, monocyclic and bicyclic structure. The relationships between the retention factor, k, of a guest solute (G) and alpha-CD concentration were studied. The obtained data enabled the stoichiometry, the stability of individual complexes and the separation factor of enantiomers to be determined. It was found that almost all the investigated monoterpenoids, apart from the acyclic ones, form inclusion complexes with alpha-CD. Straight-line relations (r vs. [alpha-CD]) were observed for monocyclic alcohols and pulegone, without any trace of enantioselectivity. This behaviour indicates that the 1:1 stoichiometry of the G-CD complexes does not lead to chiral recognition. Parabolic relations arising from 1:2 stoichiometry were found for limonene, alpha-phellandrene, some monocycylic ketones and all the investigated bicyclic terpenoids. It appeared that only the second step of complexation displayed marked enantioselectivity. However, a loss of efficiency resulting from slower equilibration is then noticeable. Attempts are made to rationalize the chromatographic results with respect to the structure of the investigated compounds.     

The mass spectra of 1,2,4-triazines and related compounds

The mass spectra of monocyclic 1,2,4-triazines and 1,2,4-triazines fused to a pyrazole ring through a bridgehead nitrogen have been investigated: fragmentation pathways were elucidated by the use of metastable ions and high resolution mass measurements. The spectra of the monocyclic 1,2,4-triazines indicate that loss of nitrogen from the molecular ions is a relatively unimportant feature. The decomposition modes of the bicyclic pyrazolo[3,2-c]-as-triazines are sensitive to the nature of the substituent in the triazine ring.     

Chiral Thiazolidine-2-Thione Derived Iminium Salts as Reagents for Kinetic Resolution

Abstract

There are currently few simple reagent systems available which can effect efficient kinetic resolution of racemic compounds. We report here a series of chiral bicyclic iminium salts, which can resolve racemic secondary alcohols to give both the unreacted alcohol and the sulphide resulting from reaction in moderate enantiomeric excess.     

Kinetic resolutions of azomethine imines via copper-catalyzed [3 + 2] cycloadditions

An effective method has been developed for the kinetic resolution of racemic azomethine imines via [3 + 2] cycloadditions with alkynes catalyzed by a chiral copper complex. Efficient kinetic resolution is observed for a variety of N1 and C5 substituents on the dipole, thereby furnishing a wide array of useful enantioenriched azomethine imines, which can readily be transformed into monocyclic and bicyclic pyrazolidinones.     

Photochemische Reaktionen. 83. Mitteilung. Verbindungen der 3,4-Dihydrojonon-Reihe als Modelle zur Photochemie γ, δ- bzw. δ, ϵ-ungesättigter Ketone und Aldehyde

Compounds of the 3,4-dihydro-ionone series as models for the photochemistry of γ, δ- and δ,?- unsaturated ketones and aldehydes . The photochemistry of γ, δ- and δ,?-unsaturated carbonyl compounds of the dihydro-ionone series has been studied, with special attention to the investigation of oxetane formation versus hydrogen abstraction. UV.-irradiation of the dihydro-β-ionone compounds with structure A ( 1 , 7 , 14 , 18 , 24 , 29 ) led to isomeric ethers with structures B ( 2 , 8 , 15 , 19 , 25 , 30 ), C ( 3 , 9 , 16 , 20 , 26 , 31 ) and D ( 4 , 21 , 27 ), isomeric bicyclic alcohols with structure E ( 5 , 10 , 17 , 22 , 28 ), and photoreduction products with structure F ( 6 , 11 , 12 , 13 ). Photolysis of dihydro-γ-ionone ( 32 ) gave a complex mixture containing fragmentation product 35 , hydrocarbon 36 , β-ambrinol ( 34 ), oxetane 33 , as well as dihydro-β-ionone ( 1 ) and three of its photoproducts ( 2 , 3 , 5 ). The dihydro-α-ionone compounds 37 and 40 gave mixtures of fragmentation products and the oxetanes 38 and 41 . Irradiation of the side-chain homologues 42 and 45 yielded 43 , which photo-cyclizes to 44 . In contrast, 3 , 4 -dihydro-3′,4′-dehydro-β-ionone ( 46 ) gave merely the isomeric open-chain triene-ketone 47 . The structures assigned to the ethers 2 , 3 , 33 , 38 and to the alcohols 5 , 10 , 13 could be confirmed by chemical reactions and mutual interconversions. The structure of the ether 21 had to be established by X-ray analysis, details of which are described. A novel intramolecular hydrogen transfer is involved in formation of ethers B . The photocyclization A → D probably proceeds by addition of the carbonyl-C atom to the double bond ( A → h ), followed by methyl (1 → 2)-shift ( h → i ). Process A → h may also be involved in formation of compounds of type C and E .     

Novel Organocatalytic Activation of Unmodified Morita–Baylis–Hillman Alcohols for the Synthesis of Bicyclic α‐Alkylidene‐Ketones

The organocatalytic activation of Morita–Baylis–Hillman alcohols via H‐bonding‐iminium‐ion formation is demonstrated for the first time. This activation strategy enables the Morita‐Baylis–Hillman alcohols to undergo a formal S_N2′ reaction. In combination with the well‐established enamine reactivity, this creates a new reactivity pattern. The application of this new activation mode for the synthesis of bicyclic α‐alkylidene‐ketones is demonstrated. The developed reaction sequence proceeds efficiently affording nature‐inspired target products with four contiguous stereogenic centers in a highly stereoselective manner.     

Synthesis of enantiomerically pure 1,2-diamine derivatives of 7-azabicyclo[2.2.1]heptane. New leads as glycosidase inhibitors and rigid scaffolds for the preparation of peptide analogues

Enantiomerically pure alcohols (-)- and (+)-7-tert-butoxycarbonyl-6-endo-p-toluenesulfonyl-7-azabicyclo[2.2.1]hept-2-en-5-endo-ol ((-)-11 and (+)-11) have been obtained from the Diels-Alder adduct of N-(tert-butoxycarbonyl)pyrroel and 2-bromo-1-p-toluenesulfonylacetylene, including a resolution method. These two alcohols were converted into (+)- and (-)-5-exo-amino-7-(tert-butoxycarbonyl)-2,3-exo-isopropylidenedioxy-7-azabicyclo[2.2.1]heptane ((+)-18 and (-)-18) and (+)- and (-)-5-endo-amino-7-(tert-butoxycarbonyl)-2,3-exo-isopropylidenedioxy-7-azabicyclo[2.2.1]heptane ((+)-19 and (-)-19) after adequate functionalization and desulfonylation steps. The corresponding conformationally constrained bicyclic 1,2-diamines (+)-4, (-)-4, (+/-)-5, (+/-)-6, (+)-7, and (-)-7 were obtained from the protected precursors 18 and 19 and evaluated as glycosidase inhibitors. Diamines (+)-4, (-)-4, (+)-6, and (-)-6 can be seen as new nonpeptide molecular scaffolds for the design of peptide analogues.     

Syntheses of monocyclic and bicyclic 2,4(1H,3H)-pyrimidinediones and their serotonin 2 antagonist activities

New serotonine 2 (5-HT2) antagonists with a monocyclic or bicyclic 2,4(1H,3H)-pyrimidinedione have been prepared and their activities evaluated. In a series of monocyclic compounds, 1-substituted 5-phenyl-2,4(1H,3H)-pyrimidinedione 14 showed potent in vitro activity, and the corresponding 3-substituted 5-phenyl and 6-phenyl derivatives 3, 8 and 20a also showed moderate activity. In the bicyclic compounds, 3-substituted 5,6,7,8-tetrahydro-2,4(1H,3H)-quinazolinedione 33 exhibited the most potent activity among the compounds prepared in this paper. The in vivo antagonist activity of 33 was comparable to that of ketanserin, a typical peripheral 5-HT2 antagonist.     

Oxydation ausgewählter δ,ϵ- und ϵ,ξ-ungesättigter Alkohole mit Blei(IV)-acetat

The lead tetraacetate (LTA) oxidation of dihydro-γ-jonol ( 2 ) gives the new bicyclic ether 4 in high yield. On the other hand, LTA oxidation of the alcohols 8, 14, 20 , results in the formation of complex mixtures of oxidation products, from which the spiro compounds 10, 16, 22 , the bicyclic ethers 11, 12, 17, 18, 23 , and the carbonyl compounds 13, 19 have been isolated.     

Co-catalyzed autoxidation of alkene in the presence of silane. The effect of the structure of silanes on the efficiency of the reaction and on the product distribution

A systematic investigation of the structural effect of silanes on the Co-catalyzed reductive oxygenation of alkene in the presence of silane (Mukaiyama-Isayama reaction) showed that the efficiency of the reaction decreases with the increase of the steric bulk of the silanes. A similar trend was observed for the metal-exchange reaction between Co(III)-alkylperoxo complex and silane, too. The peroxidation of (S)-limonene, followed by deprotection of the derived silyl peroxides, provides a mixture of the corresponding monocyclic hydroperoxide 24 and the bicyclic one 25, the ratio being a marked function of the steric bulk of silanes.     

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.     

Ab initio calculation of carbon clusters. II. Relative stabilities of fullerene and nonfullerene C24

Chemical stabilities of six low-energy isomers of C24 derived from global-minimum search are investigated. The six isomers include one classical fullerene (isomer 1) whose cage is composed of only five- and six-membered rings (56-MRs), three nonclassical fullerene structures whose cages contain at least one four-membered ring (4-MR), one plate, and one monocyclic ring. Chemical and electronic properties of the six C24 isomers are calculated based on a density-functional theory method (hybrid PBE1PBE functional and cc-pVTZ basis set). The properties include the nucleus-independent chemical shifts (NICS), singlet-triplet splitting, electron affinity, ionization potential, and gap between the highest occupied molecular orbital and the lowest unoccupied molecular orbital (HOMO-LUMO) gap. The calculation suggests that the neutral isomer 2, a nonclassical fullerene with two 4-MRs, may be more chemically stable than the classical fullerene (isomer 1). Analyses of molecular orbital NICS show that the incorporations of 4-MRs into the cage considerably reduce paratropic contributions from HOMO, HOMO-1, and HOMO-2, which are mainly responsible for the sign change in NICS from positive for isomer 1 (42) to negative (-19) for isomer 2, although C24 clusters satisfy neither 4N+2 nor 2(N+1)2 aromaticity rule. Anion photoelectron spectra of four cage isomers, one plate, one monocyclic ring, and one tadpole isomer, as well as three bicyclic ring isomers are calculated. The simulated photoelectron spectra of mono- and bicyclic rings (with C1 symmetry) appear to match the measured HOMO-LUMO gap (between the first and second band in the experimental spectra) [S. Yang et al., Chem. Phys. Lett. 144, 431 (1988)]. Nevertheless, the nonclassical fullerene isomers 3 and 4 apparently also match the measured vertical detachment energy (2.90 eV) reasonably well. These results suggest possible coexistence of nonclassical fullerene isomers with the mono- and bicyclic ring isomers of C24(-) under the experimental conditions.     

Étude de réactions photochimiques—XXIV: Réactions intramoléculaires de type ionique des alcools allyliques et homo-allyliques: Une approche vers l'étude conformationnelle des cholestènes-4 et cholestènes-5 excités

The C₅C₆ double bond of triplet-excited homoallylic alcohols 1, 5, 8, 10 and 13 is deactivated by protonation. Three secondary intramolecular processes follow: (a) addition to yield the oxetans 2, 6, 9, 11, 14; (b) fragmentation (followed by photocycloaddition which gives the oxetans 3, 12, 15); (c) isomérisation (Δ⁵ → Δ⁴). The C₄C₅ double bond of excited allylic alcohols 4, 16, 18, 20 and 7 is deactivated in the same way but only one secondary process is observed: fragmentation (followed by photocycloaddition giving rise to the oxetans 3, 12, 17, 19 and 21). Reactions in both homoallylic and allylic series have the same carbonium ion as intermediate. The triplet-excited homoallylic series have a conformation different from the triplet excited allylic series. The particular reactivity of each series is assigned to the conformational difference.     

Oxiranylmethyl-Fragmentierung zur Bildung von Cyclopentadecan-1,5-dion-Derivaten. Eine Musconsynthese

The Formation of Cyclopentadecane-1,5-dione Derivatives by an Oxiranylmethyl Fragmentation. A Synthesis of Muscone A new method for the preparation of cyclopentadecane-1,5-dione ( 11 ) and its 3-methylderivative 12 , compounds with a musk fragrance, is described. Starting from the readily available bicyclic enones 9 and 10 , the epoxy-p-toluenesulfonate 15 and its methylderivatives 20A and 20B were prepared by reduction with diisobutyl-aluminium hydride or sodium borohydride (to 13 and 18A , 18B ), epoxidation with m-chloroperbenzoic acid (to 14 and 19A , 19B ), followed by tosylation. Heating of 15 and 20A or 20B with calcium carbonate in water/dioxane under reflux caused fragmentation leading to the diketones 11 and 12 in high yields. The same fragmentation also occurred with sodium hydrogencarbonate in dimethylsulfoxide at 160°, but in lower yields. The conversion of 12 into rac-muscone ( 2 ) was accomplished by developing a method for selectively forming the monotosylhydrazone 27 . The latter was reduced with sodium borohydride and the crude alcohol 28 oxidized to 2 . Unexpectedly the pyrolysis of the epoxy-acetate 29 at 350° in a sealed glass tube led to the bicyclic ketone 10 . Treatment of 3-methylcyclopentadecane-1,5-dione ( 12 ) with peracetic acid and boron trifluoride etherate gave the stable crystalline ozonide 33 .     

Synthesis and Biological Activity of 7,8,9‐Trideoxy‐ and 7R DesTHP‐Peloruside A

The stereoselective syntheses of 7,8,9‐trideoxypeloruside A ( 4 ) and a monocyclic peloruside A analogue lacking the entire tetrahydropyran moiety ( 3 ) are described. The syntheses proceeded through the PMB‐ether of an ω‐hydroxy β‐keto aldehyde as a common intermediate which was elaborated into a pair of diastereomeric 1,3‐syn and ‐anti diols by stereoselective Duthaler–Hafner allylations and subsequent 1,3‐syn or anti reduction. One of these isomers was further converted into a tetrahydropyran derivative in a high‐yielding Prins reaction, to provide the precursor for bicyclic analogue 4 . Downstream steps for both syntheses included the substrate‐controlled addition of a vinyl lithium intermediate to an aldehyde, thus connecting the peloruside side chain to C15 (C13) of the macrocyclic core structure in a fully stereoselective fashion. In the case of monocyclic 3 macrocyclization was based on ring‐closing olefin metathesis (RCM), while bicyclic 4 was cyclized through Yamaguchi‐type macrolactonization. The macrolactonization step was surprisingly difficult and was accompanied by extensive cyclic dimer formation. Peloruside A analogues 3 and 4 inhibited the proliferation of human cancer cell lines in vitro with micromolar and sub‐micromolar IC₅₀ values, respectively. The higher potency of 4 highlights the importance of the bicyclic core structure of peloruside A for nM biological activity.     

Selective conversion of the oximes of pinocamphone and isopinocamphone into bicyclic lactams

A method is proposed for the selective conversion of oximes of terpene ketones of the pinane (2,6,6-trimethylbicyclo[3.1.1]heptane) series into the corresponding bicyclic lactams which consists in the action on these oximes of sulfuric acid in a weak nucleophile — a nitrile. The fact that the interaction takes place through the stage of formation of N-acylamidines — products of the nucleophilic stabilization of the intermediate carbocations — permits the rearrangement of the latter and the formation of monocyclic products to be avoided, which makes it possible to obtain in good yields bicyclic lactams, the synthesis of which by other methods is problematical.Institute of Physical Organic Chemistry, Belarus Academy of Sciences, Minsk. Translated from Khimiya Prirodnykh Soedinenii, No. 3, pp. 365–369, May–June, 1993.     

Electrophilic fluorination of pyroglutamic acid derivatives: application of substrate-dependent reactivity and diastereoselectivity to the synthesis of optically active 4-fluoroglutamic acids.

Electrophilic fluorination of enantiomerically pure 2-pyrrolidinones (4) derived from (L)-glutamic acid has been investigated as a method for the synthesis of single stereoisomers of 4-fluorinated glutamic acids. Reaction of the lactam enolate derived from 9 with NFSi results in a completely diastereoselective monofluorination reaction to yield the monocyclic trans-substituted alpha-fluoro lactam product 21. Unfortunately, a decreased kinetic acidity in 21 and other structurally related monofluorinated products renders them resistant to a second fluorination. In contrast, the bicyclic lactam 12 is readily difluorinated under the standard conditions described to yield the alpha,alpha-difluoro lactam 24. The difference in reactivity between the two types of related lactams is attributed mainly to the presence or lack of a steric interaction between the base used for deprotonation and the protecting group present in the pyrrolidinone substrates. This conclusion was reached based on analysis of the X-ray crystal structure of 21, molecular modeling, and experimental evidence. The key intermediates 21 and 24 are converted to (2S,4R)-4-fluoroglutamic acid and (2S)-4,4-difluoroglutamic acid, respectively.