Highly stereoselective and stereodivergent synthesis of four types of THF cores in acetogenins using a C4-chiral building block

[reaction: see text] Four stereoisomers of the THF cores, synthetic intermediates of acetogenins, have been synthesized with high diastereoselectivity by asymmetric alkynylation and subsequent stereodivergent THF ring formation. The asymmetric alkynylation of alpha-oxyaldehyde with (S)-3-butyne-1,2-diol derivatives (C4-unit) gave good yields of syn and anti adducts with >97:3 dr and 94:6 dr, respectively. These adducts were converted into the four types of THF compounds via one-pot THF formation or via intramolecular Williamson synthesis.     

Stereodivergent and reiterative synthesis of bistetrahydrofuran ring cores of annonaceous acetogenins

Eight diastereoisomers of the bistetrahydrofuran ring cores of annonaceous acetogenins have been synthesized by asymmetric alkynylation of alpha-tetrahydrofuranic aldehydes and stereodivergent one-pot tetrahydrofuran (THF) ring formation. In all cases, the asymmetric alkynylation proceeded with very high diastereoselectivity to give eight kinds of optically pure THF cores. We also describe a comparison of the (1)H and (13)C NMR spectral data of the eight isomers and give full details of the THF ring construction.     

Systematic synthesis of Bis-THF ring cores in annonaceous acetogenins

Systematic synthesis of bis-THF ring cores, synthetic intermediates of adjacent bis-THF annonaceous acetogenins, has been achieved by asymmetric alkynylation and subsequent stereodivergent THF ring formation. The asymmetric alkynylation of alpha-tetrahydrofuranic aldehyde with (S)-3-butyne-1,2-diol derivatives gave good yields of erythro- and threo-adducts with very high diastereoselectivity. These adducts were converted into four types of bis-THF cores via two kinds of one-pot THF ring formation. [reaction: see text]     

Two New Bis-tetrahydrofuran Ring Annonaceous Acetogenins from the Roots of Uvaria calamistrata

Althoughourresearchrevealedthatnarumicin-IIanddesacetyluvaricinwerethetwomajorbioactivebis-THFringacetogeninsintherootsofUvariacalamistralaHance,twonewbis-THFringannonaceousacetogeninswithmild-activitiesnamedcalamistrinsF(l)andG(2)hadalsobeenisolated.TheacetogeninsweretraceconstituentsintheplantandstructurallyhadthecharacteristicsofOH-flankedTHFringfromC-l8toC-25andathirdOHgroupatC-5.lwasisolatedaswaxysolid.TheFABMSoflgave[MH1 peakatm/:623,which,combiningwithelementalanaIysis,sugge…     

Muricatin A和Muricatin B刺果番荔枝中的两个新番荔枝内酯

从刺果番荔枝(Annonamuricata)的种子分离得到两个新成分,此两成分及其衍生化物经光谱分析,鉴定为两个新番荔枝肉酯,命名为MuricatinA和MuricatinB。它们属无THF环番荔枝内酯。     

Convergent synthesis of stereoisomers of THF ring moiety of acetogenin thiophene analogue and their antiproliferative activities against human cancer cell lines

The convergent synthesis of thiophene-3-carboxamide analogues of annonaceous acetogenins was accomplished through the asymmetric alkynylation of a 2-formyl THF ring fragment with an alkyne having a thiophene ring as the key step. Eight stereoisomers of the THF ring moiety were synthesized by this convergent route and their antiproliferative activities against 39 human cancer cell lines were evaluated. It was revealed that derivatives having the threo configuration between C17–C18 positions showed more potent activities than the corresponding erythro ones.     

Effect of stereochemistry of Δlac-acetogenins on the inhibition of mitochondrial complex I (NADH-ubiquinone oxidoreductase)

Δlac-Acetogenins are a new type of inhibitors of bovine heart mitochondrial complex I (NADH-ubiquinone oxidoreductase). We synthesized a series of Δlac-acetogenins in which the stereochemistry around the hydroxylated tetrahydrofuran (THF) ring moiety was systematically modified, and examined their inhibitory effect on complex I. The present results revealed that the inhibitory effects of the bis-THF ring analogs are much more potent than those of the mono-THF ring analogs and that the stereochemistry around the bis-THF ring moiety significantly influences the inhibitory effect. The profiles of the structure-activity relationship observed for Δlac-acetogenins were entirely different from those for natural-type acetogenins.     

Synthesis of nonadjacently linked tetrahydrofurans: an iodoetherification and olefin metathesis approach

[reaction: see text] A convergent approach to the synthesis of the bis-tetrahydrofuran (THF) components of the nonadjacently linked THF-containing acetogenins is illustrated in the synthesis of 2, a potential intermediate for the antitumor agent bullatanocin (squamostatin C). The plan centers on the olefin cross-metathesis of THF allylic alcohol derivatives 3 and 4 as the key segment coupling step and the assembly of 3 and 4 through the iodoetherification of 1,2-O-isopropylidene-5-alkene precursors.     

Synthesis of 1-arylmethyl-2-(2-cyanoethyl)aziridines and their rearrangement into novel 2-(aminomethyl)cyclopropanecarbonitriles

1-Arylmethyl-2-(bromomethyl)aziridines were transformed into novel 2-(2-cyanoethyl)aziridines upon treatment with alpha-lithiated trimethylsilylacetonitrile in THF in an efficient and straightforward approach. The latter aziridines underwent ring opening by reaction with benzyl bromide in acetonitrile, affording 5-amino-4-bromopentanenitriles through a regiospecific ring opening of intermediate aziridinium salts by bromide. Further elaboration of these gamma-bromonitriles resulted in the synthesis of novel 2-[N,N-bis(arylmethyl)aminomethyl]cyclopropanecarbonitriles in high yields by means of a 1,3-cyclization protocol upon treatment with KOtBu in THF.     

Dinitrogen coordination and cleavage promoted by a vanadium complex of a sigma,pi,sigma-donor ligand

The deprotonation of the tripyrrole MeTPH(2) [MeTPH(2) = 2,5-[(2-pyrrolyl)(C(6)H(5))2C](2)(MeNC(4)H(2))], containing one N-methylated pyrrolyl ring, was carried out with 2 equiv of KH. The corresponding dipotassium salt reacted with VCl(3)(THF)(3) to afford the complex [(MeTP)VCl(THF)].THF (1). While the two lateral pyrrolide rings are sigma-bonded, the central one is perpendicularly oriented in a sort of pi-fashion. However, the bond distances clearly indicated that only the quaternized N atom is forming a bonding contact. Subsequent reduction of 1 with Na yielded the corresponding divalent complex [(MeTP)V(THF)].(C(7)H(8))(0.5) (2) where the central N-methylated ring adopted a more regular pi-orientation. When treated with a strong Lewis acid (AlMe(3)), THF was extracted from the vanadium coordination sphere, forming the dinuclear dinitrogen complex [(MeTP)V(mu-N(2))](2).(C(7)H(8))(2.9) (3). Reduction of 3 with potassium graphite gave cleavage of dinitrogen, affording the mixed-valent nitride-bridged complex [(MeTP)V(mu-N)](2).(THF) (4).     

Multimetallic synergic sedation of a labile sodium atrane: synthesis and characterization of a tetranuclear sodium atrane cation complex

A series of sodium and aluminum atrane complexes of Na(3)L(THF)(5) (1), [AlLMe][Na(4)L(THF)(6)] (2), AlL(THF) (3), AlNaLMe(THF)(2) (4), and AlNaLOBn(THF)(2) (5), wherein L = tris(2-oxy-4,6-di-tert-butyl-benzyl)amine, were synthesized and characterized by NMR, X-ray crystallography, and elemental analysis. The trinuclear sodium atrane complex of Na(3)L(THF)(5) (1) is labile at room temperature; however, the tetranuclear sodium atrane cation in complex 2 can be stabilized by a multimetallic synergetic effect due to a firm interaction ring of -[Na-O-benzene](3)-. Complex 2 is also the first example of a sodatrane and alumatrane ion-paired complex in which both the cationic and anionic moieties contain an atrane ligand.     

4-Methoxy- and 4-cyano-substituted lithium aryloxides: electronic effects of substituents on aggregation

The para-substituted lithium aryloxides [{4-NC-C6H4OLi.(Pyr)2}2.Pyr] 1a, [{4-NC-C6H4OLi.(THF)2}2] 1b, [{4-MeO-C6H4OLi.Pyr}4] 2a, [4-MeO-C6H4OLi.(THF)n] 2b, [{4-NC-2,6-(t-Bu)2-C6H2OLi.(Pyr)2}infinity] 3a, [{4-NC-2,6-(t-Bu)2-C6H2OLi.(THF)2}infinity] 3b, [{4-MeO-2,6-(t-Bu)2-C6H2OLi.Pyr}2.(Pyr)2] 4a, and [4-MeO-2,6-(t-Bu)2-C6H2OLi.(THF)n] 4b were prepared by the direct deprotonation of the corresponding phenol with an alkyllithium base (BuLi or MeLi) in the appropriate solvent, either pyridine or THF. All compounds were characterized by 1H and 13C NMR spectroscopy, and the crystal structures of 1a, 1b, 2a, 3a, 3b and 4a were elucidated. The cyano derivatives 1a and 1b adopt discrete tetrasolvated Li2O2 ring dimers whereas the methoxy analogue 2a crystallizes as a tetrasolvated molecular tetramer with a pseudo cubic Li4O4 core. The sterically encumbered cyano derivatives 3a and 3b form isostructural 1D polymeric chains of monomers via bridging of the phenolate ligands through Li...NC and Li-O contacts. In comparison, the crystal structure of the methoxy counterpart 4a is a disolvated molecular Li2O2 ring dimer. Solution NMR spectroscopic studies of 1-4 in d5-pyridine and d8-THF indicate that the methoxy complexes are more highly aggregated than the cyano derivatives, consistent with the solid-state studies. Ab initio molecular orbital calculations at the HF/6-31G* level of theory indicate that the origin of the aggregation state variations between the cyano and methoxy complexes is due to electronic effects.     

Flexibility in the coordination chemistry of the 2,3-dimethylindolide ligand with potassium,yttrium, and samarium

The coordination chemistry of the 2,3-dimethylindolide anion (DMI), (Me(2)C(8)H(4)N)(-), with potassium, yttrium, and samarium ions is described. In the potassium salt [K(DMI)(THF)](n), 1, prepared from Me(2)C(8)H(4)NH and KH in THF, the dimethylindole anion binds and bridges potassium ions in three different binding modes, namely eta(1), eta(3), and eta(5), to form a two-dimensional extended structure. In the dimethoxyethane (DME) adduct [K(DMI)(DME)(2)](2), 2, prepared by crystallizing a sample of 1 from DME, DMI exists as a mu-eta(1):eta(1) ligand. Compound 1 reacts with SmI(2)(THF)(4) in THF to form the distorted octahedral complex trans-(DMI)(2)Sm(THF)(4), 3, in which the dimethyindolide anions are bound in the eta(1) mode to samarium. Reaction of 2,3-dimethylindole with Y(CH(2)SiMe(3))(3)(THF)(2) afforded the amide complex (DMI)(3)Y(THF)(2), 4, in which the dimethylindolide anions are also bound in the eta(1) mode to yttrium. Compound 1 also reacts with (C(5)Me(5))(2)LnCl(2)K(THF)(2) (Ln = Sm, Y) to form unsolvated amide complexes (C(5)Me(5))(2)Ln(DMI) (Ln = Sm, 5; Y, 6), in which DMI attaches primarily through nitrogen, although the edge of the arene ring is oriented toward the metals at long distances.     

Novel Annonaceous acetogenins from Graviola (Annona muricata) fruits with strong anti-proliferative activity

Five bioactive Annonaceous acetogenins, including three new compounds, annonamuricins A (1), B (2), and C (3), one registered but no spectral data reported compounds, annonamuricin D (4), and one known compound annonacin (5) were isolated from Graviola fruit (Annona muricata) and further determined through bioassay-guided fractionation. All five compounds are C35 Anonnonaceous acetogenins with a mono-tetrahydrofuran ring and four hydroxyls. Their structures were elucidated using spectral methods as well as chemical modification after isolation via chromatographic techniques and HPLC purification. These acetogenins demonstrated potent anti-proliferative activities against human prostate cancer PC-3 cells.     

Syntheses and structures of lanthanide borohydrides supported by a bridged bis(amidinate) ligand and their high activity for controlled polymerization of ε-caprolactone, L-lactide and rac-lactide

Metathesis reaction of LLnCl(THF)(2) [L = (Me(3)SiNC(C(6)H(5))N)(2)(CH(2))(3)] with NaBH(4) in a 1 : 1.5 molar ratio in THF (THF = tetrahydrofuran) at 60 °C afforded the monoborohydride LLn(BH(4))(DME) [Ln = Y (1), Nd (2), Sm(3) and Yb(4)] crystallized from DME solution (DME = dimethoxyethane). Crystal structure analyses revealed 1-4 are monomers, in which each metal is ligated by one L ligand, one η(3)-BH(4) group and one DME molecule in a trigonal bipyramid geometry. Complexes 1-4 were found to be very active single-site initiators for the controlled ring opening polymerization of ε-caprolactone (ε-CL) and L-lactide (L-LA) as judged by relatively narrow molecular weight distributions (M(w)/M(n): 1.34-1.50) and experimental values M(n)(exp) were in good agreement with theoretic values M(n)(theo). The highest activity and the best control over the molecular weight for both monomers were found for the system with 2. These monoborohydride complexes can also initiate the ring opening polymerization of rac-LA to gave heterotactically enriched polyLA with Pr (heterotactic enrichment) values in a range of 0.69-0.85 depending on the lanthanide metals and the most effective heterotactic enrichment (Pr) was found for 1 (Pr = 0.85). Moreover, complex 1 initiated the polymerization of rac-LA in a living fashion.     

Quinone-annonaceous acetogenins: synthesis and complex I inhibition studies of a new class of natural product hybrids

The natural product hybrids quinone-mucocin and quinone- squamocin D were synthesized. In these hybrids, the butenolide unit of the annonaceous acetogenins mucocin and squamocin D is exchanged for the quinone moiety of the natural complex I substrate ubiquinone. For both syntheses, a modular, highly convergent approach was applied. Quinone-mucocin was constructed out of a tetrahydropyran (THP) component 1, a tetrahydrofuran (THF) unit 2, and a quinone precursor 3. A stereoselective, organometallic coupling reaction was chosen for the addition of the THP unit to the rest of the molecule. In the final step, the oxidation to the free quinone was achieved by using cerium(IV) ammonium nitrate (CAN) as the oxidizing agent. Quinone-squamocin D was assembled in a similar manner, from the chiral side chain bromide 16, the central bis-THF core 17, and the quinone precursor 18. Inhibition of complex I (isolated from bovine heart mitochondria) by the quinone acetogenins and several smaller building blocks was examined; quinone mucocin and quinone-squamocin D act as strong inhibitors of complex I. These results and the data from the smaller substructures indicate that other substructures of the acetogenins besides the butenolide group, such as the polyether component and the lipophilic left-hand side chain, are necessary for the strong binding of the acetogenins to complex I.     

Tetrasilacyclobutadiene ((t)Bu(2)MeSi)(4)Si(4): a new ligand for transition-metal complexes

The anionic complex of [tetrakis(di-tert-butylmethylsilyl) tetrasilacyclobutadiene]dicarbonylcobalt, [(R4Si4)Co(CO)2]-.K+ (R = SiMetBu2) 2-.K+, was synthesized by the reaction of tetrasilacyclobutadiene dianion dipotassium salt [R4Si4]2-.2K+ 1 with an excess of CpCo(CO)2 in THF. X-ray analysis of 2-.[K+(diglyme)2(THF)] showed an almost planar Si4 ring of rectangular shape with an in-plane arrangement of the silyl substituents. 2- was also prepared as a free anion with the [K+[2.2.2]cryptand] counterion by complexation with [2.2.2]cryptand and as a dimer {2-.[K+(THF)3]}2 without complexing reagents in THF. Such a tetrasilacyclobutadiene fragment represents a new type of ligand for Co complexes, being the first example of a cyclobutadiene containing only heavier group 14 elements.     

Transformation of trans-4-aryl-3-chloro-1-(2-chloroethyl)azetidin-2-ones into 3-aryl-2-(ethylamino)propan-1-ols via intermediate 1-(1-aryl-2-chloro-3-hydroxypropyl)aziridines and trans-2-aryl-3-(hydroxymethyl)aziridines

trans-4-Aryl-3-chloro-1-(2-chloroethyl)azetidin-2-ones, prepared through cyclocondensation of chloroketene and the appropriate imines in a diastereoselective way, were unexpectedly transformed into 3-aryl-2-(ethylamino)propan-1-ols using LiAlH(4) in THF under reflux. A stepwise analysis showed that the initially formed 1-(1-aryl-2-chloro-3-hydroxypropyl)aziridines were converted into trans-2-aryl-3-(hydroxymethyl)aziridines, most probably via N-spiro bis-aziridinium intermediates, which were subsequently prone to undergo ring opening by LiAlH(4) to afford 3-aryl-2-(ethylamino)propan-1-ols.     

Diastereoselective ring expansion of beta-lactams toward gamma-lactams via N-acyliminium intermediates

[reaction: see text] The diastereoselective synthesis of highly functionalized gamma-lactams starting from 4-(1-bromoalkyl)-2-azetidinones via N-acyliminium intermediates is described. The carbenium ions, formed by dissociation of bromide from 4-(1-bromoalkyl)-2-azetidinones in polar medium, are converted via a ring expansion toward N-acyliminium ions, which are susceptible to attack of oxygen, nitrogen, and carbon nucleophiles. In this way, a variety of 5-hydroxy-, 5-alkoxy, 5-cyano-, 5-allylamino- and 5-azido-4,4-dimethyl-2-pyrrolidinones were synthesized. It was found that dehydrobromination of 4-(1-bromoalkyl)-2-azetidinones constituted an important side reaction when the title reactions were carried out in DMSO. When THF was used as a solvent, generally no dehydrobromination was observed, implying that higher yields of gamma-lactams were obtained in THF compared to reactions performed in DMSO. Also substituents of the 4-(1-bromoalkyl)-2-azetidinones play an important role concerning the obtained diastereoselectivity and the degree of dehydrobromination.     

N-tert-Butoxy-1-aminopyrenyl Radicals. Isolation,Electronic Structure,and Magnetic Characterization

N-tert-Butoxy-2,7-di-tert-butyl-1-pyrenylaminyl (4), N-tert-butoxy-2-tert-butyl-1-pyrenylaminyl (5), and N-tert-butoxy-7-tert-butyl-1-pyrenylaminyl (6) free radicals were generated by the reaction of the lithium amides of the corresponding 1-aminopyrenes with tert-butyl peroxybenzoate in THF at -78 degrees C. Although 6 could not be isolated due to the gradual decomposition in solution, 4 and 5 were quite persistent and could be isolated as monomeric radical crystals. The X-ray crystallographic analyses for the isolated free radicals were successfully carried out, indicating that the N and O atoms are almost coplanar with the pyrene ring. The ESR spectra of 4 and 5 were very complex due to the presence of many magnetically unequivalent protons. Therefore, the proton hyperfine coupling (hfc) constants were determined by (1)H ENDOR/TRIPLE resonance spectroscopy. To assign the hfc constants for the pyrene ring protons, a partially deuterated radical, 4-d(4), was prepared and the ENDOR and ESR spectra were measured. To discuss the spin density distribution for 4 and 5 ab initio molecular orbital calculations were performed by the DFT UBecke 3LYP method, using the STO 6-31G basis set. Magnetic susceptibility measurements were carried out for 4 and 5 with a SQUID magnetometer. For 4 a weak antiferromagnetic interaction was observed, and for 5 a very strong antiferromagnetic interaction was observed. The antiferromagnetic interactions were explained by their crystal structures.