Development of versatile cis- and trans-dicarbon-substituted chiral cyclopropane units: synthesis of (1S,2R)- and (1R,2R)-2-aminomethyl-1-(1H-imidazol-4-yl)cyclopropanes and their enantiomers as conformationally restricted analogues of histamine

The cyclopropane ring can be used effectively in restricting the conformation of biologically active compounds to improve activity and also to investigate bioactive conformations. We designed (1S,2R)- and (1R,2R)-2-aminomethyl-1-(1H-imidazol-4-yl)cyclopropanes (1 and 2, respectively) and their enantiomers (ent-1 and ent-2) as conformationally restricted analogues of histamine. The four types of chiral cyclopropanes bearing two differentially functionalized carbon substituents in a cis or trans relationship on a cyclopropane ring, (1S,2R)-2-(tert-butyldiphenylsilyloxy)methyl-1-formylcyclopropane (7) and (1R,2R)-2-(tert-butyldiphenylsilyloxy)methyl-1-formylcyclopropane (8) and their enantiomers (ent-7 and ent-8), were developed as the key intermediates for synthesizing 1, 2, ent-1, and ent-2. The reaction between (R)-epichlorohydrin [(R)-12] and phenylsulfonylacetonitrile (13a) in the presence of NaOEt in EtOH followed by treatment with acid gave the chiral cyclopropane lactone 11a with 98% ee in 82% yield. Compound 11a was converted into both the cis- and trans-chiral cyclopropane units 7 and 8, respectively, via reductive desulfonylation with Mg/MeOH as the key step. The corresponding enantiomers, the cis-substituted ent-7 and the trans-substituted ent-8, were also prepared starting from (S)-epichlorohydrin [(S)-12]. The four conformationally restricted target histamine analogues 1, 2, ent-1, and ent-2 were successfully synthesized from 7, 8, ent-7, and ent-8, respectively. The chiral cyclopropane units 7, 8, ent-7, and ent-8 should be useful as versatile intermediates for synthesizing various compounds having an asymmetric cyclopropane structure.     

Construction of a cis-cyclopropane via reductive radical decarboxylation. Enantioselective synthesis of cis- and trans-1-arylpiperazyl-2-phenylcyclopropanes designed as antidopaminergic agents

(1S,2S)-, (1S,2R)-, and (1R,2S)-1-(2,4-Dimethylphenyl)piperazyl-2-phenylcyclopropane (2a, 3, and ent-3, respectively), which were designed as conformationally restricted analogues of haloperidol (1), a clinically effective antipsychotic agent, were synthesized from chiral epichlorohydrins using the Barton reductive radical decarboxylation as the key step. (1S,2R)-1-(tert-Butyldiphenylsilyloxy)methyl-2-carboxy-2-phenylcyclopropane (5), which was prepared from (S)-epichlorohydrin ((S)-7), was converted into its N-hydroxypyridine-2-thione ester 12, the substrate for the reductive radical decarboxylation. When 12 was treated with TMS3SiH in the presence of Et3B or AIBN, the decarboxylation and subsequent hydride attack on the cyclopropyl radical intermediate from the side opposite to the bulky silyloxymethyl moiety occurred, resulting in selective formation of the corresponding reductive decarboxylation product 4-cis with the cis-cyclopropane structure. From 4-cis, the cis-cyclopropane-type target compound 3 was readily synthesized. Starting from (R)-epichlorohydrin ((R)-7), ent-3 was similarly synthesized. Epimerization of the cyclopropanecarboxamide ent-16-cis, a synthetic intermediate for ent-3, on treatment with a base prepared from Bu2Mg and i-Pr2NH in THF occurred effectively to give the corresponding trans isomer 16-trans, which was converted into 2a with the trans-cyclopropane structure.     

Regioselective intramolecular ring closure of 2-amino-6-bromo-2,6-dideoxyhexono-1,4-lactones to 5- or 6-membered iminuronic acid analogues: synthesis of 1-deoxymannojirimycin and 2,5-dideoxy-2,5-imino-D-glucitol

1-Deoxymannojirimycin (8c) was synthesised from 2-amino-6-bromo-2,6-dideoxy-D-mannono-1,4-lactone (7) by intramolecular direct displacement of the C-6 bromine employing non-aqueous base treatment followed by reduction of the intermediate methyl ester. Likewise, using aqueous base at pH 12, ring closure took place by 5-exo attack on the 5,6-epoxide leading to 2,5-dideoxy-2,5-imino-L-gulonic acid (9b), which was reduced to 2,5-dideoxy-2,5-imino-D-glucitol (9b). The method was further applied to 2-amino-6-bromo-2,6-dideoxy-D-galacto- as well as D-talo-1,4-lactones (14 and 15). However, only the corresponding six-membered ring 1,5-iminuronic acid mimetics, namely (2R,3R,4S,5R)-3,4,5-trihydroxypipecolic acid (2,6-dideoxy-2,6-imino-D-galactonic acid, 16) and (2S,3R,4S,5R)-3,4,5-trihydroxypipecolic acid (2,6-dideoxy-2,6-imino-D-talonic acid, 17), were obtained. The corresponding enantiomers, L-galacto- as well as L-talo-2-amino-6-bromo-2,6-dideoxy-1,4-lactones ent-14 and ent-15, reacted accordingly to give the D-galacto- and L-altro-1,5-iminuronic acid mimetics, (2S,3S,4R,5S)-3,4,5-trihydroxypipecolic acid (2,6-dideoxy-2,6-imino-L-galactonic acid, ent-16) and (2R,3S,4R,5S)-3,4,5-trihydroxypipecolic acids (2,6-dideoxy-2,6-imino-L-talonic acid, ent-17), respectively.     

Streamlined, asymmetric synthesis of 8,4'-oxyneolignans

Highly direct, modular syntheses of several natural 8,4'-oxyneolignans [(-)-1, (+)-1, (-)-2, and (-)-3] and some related variants [(-)-26, (+)-26, (+)-27, and (-)-28] are reported. Utilizing (S)- or (R)-methyl lactate as the chiral sources, two complementary syn- or anti-oriented routes were designed, encompassing nine and five steps, which were carried out to deliver the targets in an enantiomerically pure form. The embodiment of the two independent aryl and aryloxy moieties onto the lactate frame was performed according to a diversity-oriented protocol from the common precursors, aldehydes 6 and ent-6 for the syn-oriented routes and mesyl esters 19 and ent-19 for the anti-oriented routes. These syntheses set the stage for the generation of a wide and diverse repertoire of 8,4'-oxyneolignan compounds and the broad biological interrogation of its members.     

New, efficient synthesis of oseltamivir phosphate (Tamiflu) via enzymatic desymmetrization of a meso-1,3-cyclohexanedicarboxylic acid diester

A new, enantioselective synthesis of the influenza neuraminidase inhibitor prodrug oseltamivir phosphate 1 (Tamiflu) and its enantiomer ent-1 starting from cheap, commercially available 2,6-dimethoxyphenol 10 is described. The main features of this approach comprise the cis-hydrogenation of 5-(1-ethyl-propoxy)-4,6-dimethoxy-isophthalic acid diethyl ester (6a) and the desymmetrization of the resultant all-cis meso-diesters 7a and 7b, respectively. Enzymatic hydrolysis of the meso-diester 7b with pig liver esterase afforded the (S)-monoacid 8b, which was converted into cyclohexenol 17 via a Curtius degradation and a base-catalyzed decarboxylative elimination of the Boc-protected oxazolidinone 14. Introduction of the second amino function via S(N)2 substitution of the corresponding triflate 18 with NaN3 followed by azide reduction, N-acetylation, and Boc-deprotection gave oseltamivir phosphate 1 in a total of 10 steps and an overall yield of approximately 30%. The enantiomer ent-1 was similarly obtained via an enzymatic desymmetrization of meso-diester 7a with Aspergillus oryzae lipase, providing the (R)-monoacid ent-8a.     

Studies on the constituents of Broussonetia species VIII. Four new pyrrolidine alkaloids, broussonetines R, S, T, and V and a new pyrroline alkaloid, broussonetine U, from Broussonetia kazinoki Sieb

Four new pyrrolidine alkaloids, broussonetines R, S, T, and V and a new pyrroline alkaloid, broussonetine U were isolated from the branches of Broussonetia kazinoki SIEB. (Moraceae) in low yield. Broussonetines R, S and T were formulated as (2R,3R,4R,5R)-2-hydroxymethyl-3,4-dihydroxy-5-[(1R)-1-hydroxy-3-[6-(4-hydroxybutyl)-cyclohexy-2-on-1(6)-enyllpropyl] pyrrolidine (1), (2R,3R,4R,5R)-2-hydroxymethyl-3,4-dihydroxy-5-[(1R,10S)-1,10,13-trihydroxytridecyl] pyrrolidine (2), (2R,3R,4R,5R)-2-hydroxymethyl-3,4-dihydroxy-5-[(1R,5S)-1,5, 13-trihydroxy-10-oxo-tridecyl] pyrrolidine (3). And broussonetines U and V were proposed to be (2S,3S,4S)-2-hydroxymethyl-3, 4-dihydroxy-5-(9-oxo-13-hydroxytridecyl)-5-pyrroline (4), (2R,3S,4R,5R)-2-hydroxymethyl-3,4-dihydroxy-5-[(E)-9-oxo-13-hydroxy-3-tridecenyl] pyrrolidine (5), respectively, by spectroscopic and chemical methods.     

Design, synthesis, and 1,3-dipolar cycloaddition of (5R)- [and (5S)]-5,6-dihydro-5-phenyl-2H-1,4-oxazin-2-one N-oxides as chiral (E)-geometry-fixed alpha-alkoxycarbonylnitrones

Optically pure (5R)- [and (5S)]-5,6-dihydro-5-phenyl-2H-1, 4-oxazin-2-one N-oxides [(5R)- and (5S)-2] were designed as chiral (E)-geometry-fixed alpha-alkoxycarbonylnitrones 1. The nitrones (5R)- and (5S)-2 were synthesized by three-step oxidation of (R)- and (S)-phenylglycinols [(R)- and (S)-3], condensation of the resulting (R)- and (S)-2-hydroxylamino-2-phenylethanols [(R)- and (S)-5] with glyoxylic acid, and cyclization of the intermediary nitrones (R)- and (S)-6b. The nitrone (5R)-2reacted with olefins 7-14 under mild conditions to afford the corresponding cycloadducts 15-22 as the main products via the least sterically demanding exo modes. Cycloadduct 30 obtained from (5S)-2 and cyclopentadiene was effectively elaborated to (1S,4S, 5R)-4-benzyloxycarbonylamino-2-oxabicyclo[3.3.0]oct-7-en-3-one (28), the key synthetic intermediate of carbocyclic polyoxin C.     

Five new nortropane alkaloids and six new amino acids from the fruit of Morus alba LINNE growing in Turkey

Investigation of the constituents of the fruits of Morus alba LINNE (Moraceae) afforded five new nortropane alkaloids (1-5) along with nor-psi-tropine (6) and six new amino acids, morusimic acids A-F (7-12). The structures of the new compounds were determined to be 2alpha,3beta-dihydroxynortropane (1), 2beta,3beta-dihydroxynortropane (2), 2alpha,3beta,6exo-trihydroxynortropane (3), 2alpha,3beta,4alpha-rihydroxynortropane (4), 3beta,6exo-dihydroxynortropane (5), (3R)-3-hydroxy-12-[(1S,4S)-4-[(1S)-1-hydroxyethyl]-pyrrolidin-1-yll-dodecanoic acid-3-O-beta-D-glucopyranoside (7), (3R)-3-hydroxy-12-[(1S,4S)-4-[(1S)-1-hydroxyethyl]-pyrrolidin-1-yll-dodecanoic acid (8), (3R)-3-hydroxy-12-1(1R,4R,5S)-4-hydroxy-5-methyl-piperidin-1-yll-dodecanoic acid-3-O-beta-D-glucopyranoside (9), (3R)-3-hydroxy-12-[(1R,4R,5S)-4-hydroxy-5-methyl-piperidin-1-yll-dodecanoic acid (10), (3R)-3-hydroxy-12-[(1R,4R,5S)-4-hydroxy-5-hydroxymethyl-piperidin-1-yl]-dodecanoic acid-3-O-beta-D-glucopyranoside (11), and (3R)-3-hydroxy-12-[(1R,4S,5S)-4-hydroxy-5-methyl-piperidin-1-yl]-dodecanoic acid (12) on the basis of spectral and chemical data.     

A general approach to (5S,6R)-6-alkyl-5-benzyloxy-2-piperidinones: application to the asymmetric syntheses of neurokinin substance P receptor antagonist (-)-L-733,061 and (-)-deoxocassine

A general approach to (5S,6R)-6-alkyl-5-benzyloxy-2-piperidinones based on the regio- and diastereoselective reductive alkylation of (S)-3-benzyloxyglutarimide 7 is described. This method opens an entrance to chiral nonracemic substituted 3-piperidinols. The versatility of the method is illustrated by the asymmetric syntheses of neurokinin substance P receptor antagonist L-733,061 (ent-1), (-)-deoxocassine (4), and an inhibitor of HIV proteases (5a).     

Nitrosylated iron-thiolate-sulfinate complexes with {Fe(NO)}6/7 electronic cores: relevance to the transformation between the active and inactive NO-bound forms of iron-containing nitrile hydratases

The five-coordinated iron-thiolate nitrosyl complexes [(NO)Fe(S,S-C6H3R)2]- (R = H (1), m-CH3 (2)), [(NO)Fe(S,S-C6H2-3,6-Cl2)2]- (3), [(NO)Fe(S,S-C6H3R)2]2- (R = H (10), m-CH3 (11)), and [(NO)Fe(S,S-C6H2-3,6-Cl2)2]2- (12) have been isolated and structurally characterized. Sulfur oxygenation of iron-thiolate nitrosyl complexes 1-3 containing the {Fe(NO)}6 core was triggered by O2 to yield the S-bonded monosulfinate iron species [(NO)Fe(S,SO2-C6H3R)(S,S-C6H3R)]- (R = H (4), m-CH3 (5)) and [(NO)Fe(S,SO2-C6H2-3,6-Cl2)(S,S-C6H2-3,6-Cl2)]2(2-) (6), respectively. In contrast, attack of O2 on the {Fe(NO)}7 complex 10 led to the formation of complex 1 accompanied by the minor products, [Fe(S,S-C6H4)2]2(2-) and [NO3]- (yield 9%). Reduction of complexes 4-6 by [EtS]- in CH3CN-THF yielded [(NO)Fe(S,SO2-C6H3R)(S,S-C6H3R)]2- (R = H (7), m-CH3 (8)) and [(NO)Fe(S,SO2-C6H2-3,6-Cl2)(S,S-C6H2-3,6-Cl2)]2- (9) along with (EtS)2 identified by 1H NMR. Compared to complex 10, complexes 7-9 with the less electron-donating sulfinate ligand coordinated to the {Fe(NO)}7 core were oxidized by O2 to yield complexes 4-6. Obviously, the electronic perturbation of the {Fe(NO)}7 core caused by the coordinated sulfinate in complexes 7-9 may serve to regulate the reactivity of complexes 7-9 toward O2. The iron-sulfinate nitrosyl species with the {Fe(NO)}6/7 core exhibit the photolabilization of sulfur-bound [O] moiety. Complexes 1-4-7-10 (or 2-5-8-11 and 3-6-9-12) are interconvertible under sulfur oxygenation, redox processes, and photolysis, respectively.     

Cytotoxic diterpenoids from Vietnamese medicinal plant Croton tonkinensis GAGNEP

Six new ent-kaurane-type diterpenoids were isolated from the leaves of the endemic Vietnamese medicinal plant Croton tonkinensis GAGNEP. (Euphorbiaceae) together with three known ent-11alpha-acetoxy-7beta,14alpha-dihydroxykaur-16-en-15-one (1), ent-kaur-16-en-15-one 18-oic acid (5) and ent-18-hydroxykaur-16-ene (7). Their structures were determined by spectroscopic analyses to be ent-7beta-acetoxy-11alpha-hydroxykaur-16-en-15-one (2), ent-18-acetoxy-11alpha-hydroxykaur-16-en-15-one (3), ent-11alpha-acetoxykaur-16-en-18-oic acid (4), ent-15alpha,18-dihydroxykaur-16-ene (6), ent-11alpha,18-diacetoxy-7beta-hydroxykaur-16-en-15-one (8), and ent-(16S)-1alpha,14alpha-diacetoxy-7beta-hydroxy-17-methoxykauran-15-one (14). ent-Kaurane-type diterpenoids from Croton tonkinensis 2-4, 6, and 9-13, were tested for toxicity in the brine shrimp lethality assay. Compounds 9, 10, and 12 demonstrated significant activity, compounds 2, 3, 6, and 11 showed weak activity, and compounds 4 and 13 were inactive.     

Chiral bridged aminotroponiminate complexes of the lanthanides

The enantiomerically pure bridged aminotroponimines, S,S- and R,R-H2{(iPrATI)2diph}, in which two amino-isopropyl-troponimine moieties are linked by 1,2-diamino-1,2-diphenylethane, were deprotonated with nBuLi to give the corresponding dilithium salts [{Li(THF)}2{(S,S)-(iPrATI)2diph)}] (1a) and [{Li(THF)}2{(R,R)-(iPrATI)2diph)}] (1b). The potassium salts [{K(THF)2}2{(S,S)-(iPrATI)2diph}] (2a) and [{K(THF)2}2{(R,R)-(iPrATI)2diph}] (2b) were obtained by a deprotonation reaction with KH. Transmetallation of 2a and 2b with anhydrous lanthanide trichlorides led to [(S,S)-{(iPrATI)2diph}LnCl(THF)] (Ln = Ho (3a), Er (4a)) and [(R,R)-{(iPrATI)2diph}LnCl(THF)] (Ln = Ho (3b), Er (4b), Yb (5b)), respectively. The corresponding Yb complex [(S,S)-{(iPrATI)2diph}YbCl(THF)] (5a) was obtained by treatment of 1a with YbCl3 at elevated temperature. Performing the same reaction at room temperature results in the metallate complex [(S,S)-{(iPrATI)2diph}YbCl2][Li(THF)4] (6). Reaction of NaC5H5 with afforded [(S,S)-{(iPrATI)2diph}Yb(eta5-C5H5)(THF)] (7). The structures of 1a, 3a, 4a, 5a, 5b, 6, and 7 were confirmed by single crystal X-ray diffraction in the solid-state.     

Diastereoselective hydroxylation of 6-substituted piperidin-2-ones. An efficient synthesis of (2S,5R)-5-hydroxylysine and related alpha-amino acids

The synthesis of (2S,5R)-5-hydroxy-6-oxo-1,2-piperidinedicarboxylates (5) and related (3S,6R)-3-hydroxy-6-alkyl-2-oxo-1-piperidinecarboxylates has been developed. The approach is based on the asymmetric hydroxylation of enolates generated from the corresponding N-protected-6-substituted piperidin-2-ones. The utility of 5a as a precursor in the synthesis of (2S,5R)-5-hydroxylysine (1), an amino acid unique to collagen and collagen-like proteins, has also been demonstrated. (2S)-6-oxo-1,2-piperidinedicarboxylates (6) required for hydroxylation studies were prepared in 38-74% yield, starting from conveniently protected aspartic acid as inexpensive chiral adduct. Hydroxylation of 6 to 5 proceeds in high yield and excellent diastereoselectivity by treatment of their Li-enolate with (+)-camphorsulfonyloxaziridine at -78 degrees C. Ring opening of di-tert-butyl (2S,5R)-6-oxo-1,2-piperidinedicarboxylate ((5R)-5a) under reductive conditions afforded the corresponding 1,2-diol (17) in 91%, which was further transformed to (2S,5R)-5-hydroxylysine in four steps (84%). 17 is also a versatile intermediate in the preparation of tert-butyl (2S,5R)-2-[(tert-butoxycarbonyl)amino]-5-hydroxy-6-iodohexanoate (3) and tert-butyl (2S)-2-[(tert-butoxycarbonyl)amino]-4-[(2R)-oxiranyl]butanoate (4), two amino acid derivatives used in the total synthesis of the bone collagen cross-link (+)-pyridinoline (2a).     

Biooxidation of (+)-catechin and (-)-epicatechin into 3,4-dihydroxyflavan derivatives by the endophytic fungus Diaporthe sp. isolated from a tea plant

The microbial transformation of (+)-catechin (1) and (-)-epicatechin (2) by endophytic fungi isolated from a tea plant was investigated. It was found that the endophytic filamentous fungus Diaporthe sp. transformed them (1, 2) into the 3,4-cis-dihydroxyflavan derivatives, (+)-(2R,3S,4S)-3,4,5,7,3',4'-hexahydroxyflavan (3) and (-)-(2R,3R,4R)-3,4,5,7,3',4'-hexahydroxyflavan (7), respectively, whereas (-)-catechin (ent-1) and (+)-epicatechin (ent-2) with a 2S-phenyl group resisted the biooxidation.     

Atmospheric pressure chemical ionization multi-stage mass spectrometry in the characterization of stereoisomeric synthons of cyclopropane amino acids

The mass spectrometric behaviour of (1S,2R)-, (1R,2R)-, (1R,2S)- and (1S,2S)-2-[(S)-2,2-dimethyl-1, 3-dioxolan-4-yl]-1-spiro-?4'[2'-phenyl-5'(4'H)-oxazolone]? cyclopropane (2) and (1S,2R)-, (1R,2R)-, (1R,2S)- and (1S, 2S)-methyl-1-benzamido-2-[(S)-2,2-dimethyl-1, 3-dioxolan-4-yl]cyclopropanecarboxylate (3) was studied under atmospheric pressure ionization conditions and by multi-stage mass spectrometric (MS(n)) experiments performed with an ion trap. Interestingly, by using methanol as solvent, compounds 2 lead to [M + H + CH(3)OH](+) ions which, as proved by collisional experiments, exhibit the same structure of the corresponding compound 3. MS/MS of [MH](+) ions allows a clear characterization of the different stereoisomers, which give rise to specific fragmentation pathways, rationalized with respect to the structure of the neutral molecules.     

Iron-molybdenum charge-transfer hybrids containing organometallic and inorganic fragments bridged by aryldiazenido ligands in a mu-eta(6):eta(1) coordination mode: syntheses, characterization, X-ray structures, electrochemistry, and theoretical investigation

Representative members of a new family of covalently bonded charge-transfer molecular hybrids, of general formula [(eta5-C5H5)Fe(mu,eta6:eta1-p-RC6H4NN)Mo(eta2-S2CNEt2)3] +PF6- (R: H, 5+PF6-; Me, 6+PF6-; MeO, 7+PF6-) and [(eta5-C5Me5)Fe(mu,eta6:eta1-C6H5NN)Mo(eta2-S2CNEt2)3]+PF6-, 8+PF6-, have been synthesized by reaction of the corresponding mixed-sandwich organometallic hydrazines [(eta5-C5H5)Fe(eta6-p-RC6H4NHNH2)]+PF6- (R: H, 1+PF6-; Me, 2+PF6-; MeO, 3+PF6-) and [(eta5-C5Me5)Fe(eta6-C6H5NHNH2)]+PF6-, 4+PF6-, with cis-dioxomolybdenum(VI) bis(diethyldithiocarbamato) complex, [MoO2(S2CNEt2)2], in the presence of sodium diethyldithiocarbamato trihydrate, NaSC(=S)NEt2.3H2O, in refluxing methanol. These iron-molybdenum complexes consist of organometallic and inorganic fragments linked each other through a pi-conjugated aryldiazenido bridge coordinated in eta6 and eta1 modes, respectively. These complexes were fully characterized by FT-IR, UV-visible, and 1H NMR spectroscopies and, in the case of complex 7+PF6-, by single-crystal X-ray diffraction analysis. Likewise, the electrochemical and solvatochromic properties were studied by cyclic voltammetry and UV-visible spectroscopy, respectively. The electronic spectra of these hybrids show an absorption band in the 462-489 and 447-470 nm regions in CH2Cl2 and DMSO, respectively, indicating the existence of a charge-transfer transition from the inorganic donor to the organometallic acceptor fragments through the aryldiazenido spacer. A rationalization of the properties of 5+PF6--8+PF6- is provided through DFT calculations on a simplified model of 7+PF6-. Besides the heterodinuclear complexes 5+PF6--8+PF6-, the mononuclear molybdenum diazenido derivatives, [(eta1-p-RC6H4NN)Mo(eta2-S2CNEt2)3] (R: H, 9; Me, 10; MeO, 11), resulting from the decoordination of the [(eta5-C5H5)Fe]+ moiety of complexes 5+PF6--7+PF6-, were also isolated. For comparative studies, the crystalline and molecular structure of complex 10.Et2O was also determined by X-ray diffraction analysis and its electronic structure computed.     

Conformationally constrained dipeptide surrogates with aromatic side-chains: synthesis of 4-aryl indolizidin-9-one amino acids by conjugate addition to a common alpha,omega-diaminoazelate enone intermediate

Four methyl 9-oxo-8-(N-(Boc)-amino)-4-phenyl-1-azabicyclo[4.3.0]nonane carboxylates (11, 4-Ph-I(9)aa-OMe) were synthesized from (2S,8S,5E)-di-tert-butyl-4-oxo-5-ene-2,8-bis[N-(PhF)amino]azelate [(5E)-7, PhF = 9-(9-phenylfluorenyl)] via a seven-step process featuring a conjugate addition/reductive amination/lactam cyclization sequence. Various nucleophiles were used in the conjugate addition reactions on enone (5E)-7 as a general route for making alpha,omega-diaminoazelates possessing different substituents in good yield albeit low diastereoselectivity except in the case of aryl Grignard reagents (9/1 to 15/1 drs). 6-Phenylazelates (6S)-8d and (6R)-8d were separated by chromatography and diastereoselective precipitation and independently transformed into 4-Ph-I(9)aa-OMe. From (6S)-8d, (2S,4R,6R,8S)-4-Ph-I(9)aa-OMe 11 was prepared selectively in 51% yield. Reductive amination of (6R)-8d provided the desired pipecolates 9 along with desamino compound 10, which was minimized by performing the hydrogenation in the presence of ammonium acetate. Subsequent ester exchange, lactam cyclization, and amine protection provided three products (2R,4S,6S,8R)-, (2R,4S,6S,8S)-, and (2S,4S,6R,8S)-4-Ph-I(9)aa-OMe 11 in 10, 6, and 6% yields, respectively, from (6R)-8d. Ester hydrolysis of (2S,4R,6R,8S)-11 furnished 4-phenyl indolizidin-9-one N-(Boc)amino acid 3 as a novel constrained Ala-Phe dipeptide surrogate for studying conformation-activity relationships of biologically active peptides.     

Three new megastigmane glucopyranosides from the Cardamine komarovii

Three new megastigmane glucopyranosides, komaroveside A [(3S,4R,5Z,7E)-3,4-dihydroxy-5,7-megastigmadien-9-one-3-O-β-D-glucopyranoside] (1), komaroveside B [(3S,4S,5S,6R,7E)-5,6-epoxy-3,4-dihydroxy-7-megastigmen-9-one-3-O-β-D-glucopyranoside] (2) and komaroveside C [(3S,4S,5S,6R,7E,9S)-5,6-epoxy-3,4,9-trihydroxy-7-megastigmen-3-O-β-D-glucopyranoside] (3) were isolated, together with eight known compounds, from Cardamine komarovii. The identification of these compounds and the elucidation of their structures were based on 1D- and 2D-NMR spectral data analysis. The isolated compounds were tested for their cytotoxicity against four human tumor cell lines (A549, SK-OV-3, SK-MEL-2, HCT15) in vitro using the sulforhodamine B bioassay.     

Rogiolenyne A,B, and C: The First Branched Marine C15 Acetogenins. Isolation from the Red Seaweed Laurencia microcladia or the Sponge Spongia zimocca of II Rogiolo

It is shown here that the red seaweed Laurencia microcladia, collected off the torrent II Rogiolo, south of Livorno, contains rogiolenyne A (= (?)-(1R*,2S*,3R*,5S*,7S*)-2-(bromomethyl)-5-[(Z)-1-chlorohex-3-en-5-ynyl]-3-ethyl-4,8-dioxabicyclo[5.1.0]octane; (?)- 1 ) while the sponge Spongia zimocca, which grows in the same small area, contains rogiolenyne B (= (?)-(2R*3R*,4R*,5R*,7S*)-3-(bromomethyl)-5-chloro-7-[(Z)-1-chlorohex-3-en-5-ynyl]-2-ethyloxepan-4-ol; (?)- 4a ) and its acetate, rogiolenyne C((?)- 4b ). These structures, which are based on extensive NMR and MS data and on chemical transformation, are the first examples of branched marine C₁₅ acetogenins. Biogenesis of (?)- 1 in L. microcladia is thought to involve C(12) extrusion form a C₁₅ linear tetraen-1-yne precursor via H⁺-induced cyclopropane ring closure, followed by Br⁺-induced cyclopropane ring opening, aided by C–O^? attack (Scheme 2). It is also proposed that transfer of (?)- 1 to S. zimocca is followed by epoxide ring opening by Cl^? to give (?)- 4a and acetylation to give (?)- 4b .     

Diastereoselective reactions at enantiomerically pure, sterically congested cyclohexanes as an entry to wailupemycins A and B: total synthesis of (+)-wailupemycin B

Wailupemycin A (1) and B (2) are polyketide natural products with a highly substituted cyclohexanone core. Three different routes for the syntheses of these compounds were pursued, which commenced from either (R)-(-)-carvone (ent-5) or (S)-(+)-carvone (5). In the first approach it was attempted to construct the skeleton of wailupemycin A from triol 19 (nine steps from ent-5; 19 % yield) by a sequence of diastereoselective epoxidation, nucleophilic ring opening at C-13 and carbonyl addition at C-5. The synthetic plan failed at the stage of the carbonyl addition to aldehyde 27, which had been obtained in seven steps (18 % yield) from triol 19. The second route included an epoxide ring opening at C-13 and a carbonyl addition at C-7 as key steps. It could have led to either wailupemycin A or B depending on the diastereoselectivity of the addition step. Starting from allylic alcohol 30 (six steps from ent-5; 59 % yield) the cyclohexanone 28 was obtained in five steps (54 % yield). Unfortunately, the carbonyl addition failed also in this instance. In the eventually successful third attempt the skeleton of wailupemycin B was built from cyclohexanone 43 (eight steps from 5; 53 % yield) by highly diastereoselective carbonyl addition reactions at C-7 and C-12. The phenyl group at C-14 was introduced at a late stage of the synthetic sequence. Careful protecting group manipulation finally allowed for the total synthesis of (+)-wailupemycin B. The absolute and relative configuration of the natural product was unambiguously confirmed. The total yield of wailupemycin B amounted to 6 % over 23 steps starting from (S)-(+)-carvone (5).