Amphidinolide Y, a novel 17-membered macrolide from dinoflagellate Amphidinium sp.: plausible biogenetic precursor of amphidinolide X

A novel cytotoxic 17-membered macrolide, amphidinolide Y (1), has been isolated from a marine dinoflagellate Amphidinium sp., and it was elucidated to exist as a 9:1 equilibrium mixture of 6-keto- and 6(9)-hemiacetal forms (1a and 1b, respectively) on the basis of 2D NMR data and chemical means. The feeding experiments with (13)C-labeled acetates suggested that amphidinolide Y (1) may be a biogenetic precursor of 16-membered macrodiolide, amphidinolide X (2).     

Total syntheses of amphidinolide X and Y

Concise total syntheses of the cytotoxic marine natural products amphidinolide X (1) and amphidinolide Y (2) as well as of the nonnatural analogue 19-epi-amphidinolide X (47) are described. A pivotal step of the highly convergent routes to these structurally rather unusual secondary metabolites consists of a syn-selective formation of allenol 17 by an iron-catalyzed ring opening reaction of the enantioenriched propargyl epoxide 16 (derived from a Sharpless epoxidation) with a Grignard reagent. Allenol 17 was then cyclized with the aid of Ag(I) to give dihydrofuran 19 containing the (R)-configured tetrasubstituted sp3 chiral center at C.19, which was further elaborated into tetrahydrofuran 25 representing the common heterocyclic motif of 1 and 2. The aliphatic chain of amphidinolide X featuring an anti-configured stereodiad at C.10 and C.11 was generated by a palladium-catalyzed, Et2Zn-promoted addition of the enantiopure propargyl mesylate 29 to the functionalized aldehyde 28. The preparation of the corresponding C.1-C.12 segment of amphidinolide Y relies on asymmetric hydrogenation of an alpha-ketoester, a diastereoselective boron aldol reaction, and a chelate-controlled addition of MeMgBr in combination with suitable oxidation state management for the elaboration of the tertiary acyloin motif. Importantly, the end games of both total syntheses follow similar blueprints, involving key fragment coupling processes via the "9-MeO-9-BBN" variant of the alkyl-Suzuki reaction and final Yamaguchi esterifications to forge the 16-membered macrodiolide ring of amphidinolide X and the 17-membered macrolide frame of amphidinolide Y, respectively. This methodological convergence ensures high efficiency and an excellent overall economy of steps for the entire synthesis campaign.     

The Carbonyl Group as Homoconjugated Electron-Releasing Substituent. Regioselective electrophilic additions at bicyclo[2.2.1]hept-5-en-2-one,bicyclo[2.2.2]oct-5-en-2-one,and derivatives

In CHCl₃, CH₃CN, or AcOH, benzeneselenenyl chloride (PhSeCl), bromide (PhSeBr), and acetate (PhSeOAc), 2-nitrobenzenesulfenyl chloride (NO₂C₆H₄SCl), and 2,4-dinitrobenzenesulfenyl chloride ((NO₂)₂C₆H₃SCl) added to bicyclo[2.2.1]hept-5-en-2-one ( 5 ) in an. anti fashion with complete stereo- and regioselectivity, giving adducts 20–24 in which the chloride, bromide, or acetoxy substituent (X) occupies the endo position at C(6) and the Se- or S-substituent (E) the exo position at C(5), The addition 5 + (NO₂)₂C₆H₃SCl→ 24 was accompanied by the formation of (1RS, 2RS)-2-(2,4-dinitrophenylthio)cyclopent-3-ene-l-acetic acid ( 25 ). The latter was the major product in AcOH containing LiClO₄. The additions of PhSeCl and PhSeBr to bicyclo[2.2.2]oct-5-en-2-one ( 6 ) were less stereoselective (proportion of exo vs. endo mode of electrophilic attack was ca. 3:1) but highly regioselective gazing adducts 27/28 and 29/30 , respectively, the regioselectivity being the same as that of the electrophilic additions of 5 . The reaction of PhSeCl with a 4:1 mixture of 2-exo-chloro- and 2-endo-chlorobicyclo[2.2.1]hept-5-ene-2-carbonitriles ( 12 ) was slower than addition 5 + PhSeCl; it gave adducts 31/32 (4:1) in which the PhSe moiety occupies the exo position at C(6) and the Cl atom the endo position at C(5). The addition of PhSeCl to 2-chlorobicyclo[2.2.1]oct-5-ene-2-carbonitriles ( 13 ) was very slow and gave adducts with the same regioselectivity as 12 + PhSeCl, but opposite with that of reactions of the corresponding enones 5 and 6 . PhSeX (X = Cl, Br, OAc) added to 2-cyanobicyclo[2.2.1]hept-5-en-2-yl acetates ( 14 ) with the same regioselectivity as 12 + PhSeCl. The additions of PhSeCl, PhSeBr, NO₂C₆H₄SCl, and (NO₂)₂C₆H₃SCl to 2-(bicyclo[2.2.1]hept-5-en-2-ylidene)propanedinitrile ( 49 ) were not regioselective, showing that a dicyanomethylidene function is not like a carbonyl function when homoconjugated with a π system. The results are in agreement with predictions based on MO calculations suggesting that a carbonyl group homoconjugated with an electron-deficient centre can behave as an electron-donating, remote substituent because of favourable n(CO)?σC(1), C(2)?p(C(6) hyperconjugative interaction.     

Alkene carbosulphenylation and carboselenylation: The use of allyltrimethylsilane and o-silylated enolates.

Allyltrimethylsilane, as well as O-silylated enolates, can be alkylated by the PhSCl adducts of alkenes and vinyl ethers (1, X=SPh); the PhSeCl analogues (1, X=SePh), however, are less useful for alkylation purposes due to competing nucleophilic attack at selenium.     

Asymmetric synthesis of a diastereomer of the structure proposed for amphidinolide A and the determination of its absolute configuration

An asymmetric synthesis of a diastereomer (2) of the structure (1) proposed for amphidinolide A, a cytotoxic macrolide from the cultured dinoflagellate Amphidinium sp., has been accomplished. The absolute configuration of amphidinolide A was established as 3 from comparison of NMR data, HPLC analysis, and [α]_D values of amphidinolide A, and comparison with the synthetic diastereomers 2 and 3, the latter of which was synthesized previously by Trost's group.     

Biodegradable network elastomeric polyesters from multifunctional aromatic carboxylic acids and poly(ϵ‐caprolactone) diols

Novel biodegradable network polyesters were prepared from multifunctional aromatic carboxylic acids [trimesic acid (Y), pyromellic acid (X), and mellic acid (Y_M)] and poly(?‐caprolactone) (PCL) diols with molecular weights of 530, 1250, and 2000. Prepolymers prepared by a melt polycondensation method were cast from dimethylformamide solutions and postpolymerized at 220 °C for various times to form a network. The resultant films were transparent, flexible, and insoluble in organic solvents. The network polyesters obtained were characterized by infrared absorption spectra, wide‐angle X‐ray diffraction analysis, density measurements, differential scanning calorimetry, thermomechanical analysis, and tensile testing. Some network polyester films, including YPCL_1250, XPCL₁₂₅₀, and Y_MPCL₂₀₀₀, showed elastomeric properties with high ultimate elongation and low tensile modulus. The enzymatic degradation was measured by the weight loss of the network polyester films in a buffer solution with Rhizopus delemar lipase at 37 °C. The degree and rate of degradation increased with the increasing molecular weight of the PCL diols, but they decreased in the order of YPCL > XPCL > Y_MPCL because of the increase in the crosslinking densities of the network films. The degraded products after enzymatic degradation showed that the ester linkage of the PCL component and the aromatic ester linkage between Y and PCL diols were hydrolyzed. © 2002 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 40: 4523–4529, 2002     

Hammett equation and generalized Pauling's electronegativity equation

Substituent interaction energy (SIE) was defined as the energy change of the isodesmic reaction X-spacer-Y + H-spacer-H --> X-spacer-H + H-spacer-Y. It was found that this SIE followed a simple equation, SIE(X,Y) = -ksigma(X)sigma(Y), where k was a constant dependent on the system and sigma was a certain scale of electronic substituent constant. It was demonstrated that the equation was applicable to disubstituted bicyclo[2.2.2]octanes, benzenes, ethylenes, butadienes, and hexatrienes. It was also demonstrated that Hammett's equation was a derivative form of the above equation. Furthermore, it was found that when spacer = nil the above equation was mathematically the same as Pauling's electronegativity equation. Thus it was shown that Hammett's equation was a derivative form of the generalized Pauling's electronegativity equation and that a generalized Pauling's electronegativity equation could be utilized for diverse X-spacer-Y systems. In addition, the total electronic substituent effects were successfully separated into field/inductive and resonance effects in the equation SIE(X,Y) = -k(1)F(X)F(Y) - k(2)R(X)R(Y) - k(3)(F(X)R(Y) + R(X)F(Y)). The existence of the cross term (i.e., F(X)R(Y) and R(X)F(Y)) suggested that the field/inductive effect was not orthogonal to the resonance effect because the field/inductive effect from one substituent interacted with the resonance effect from the other. Further studies on multi-substituted systems suggested that the electronic substituent effects should be pairwise and additive. Hence, the SIE in a multi-substituted system could be described using the equation SIE(X1, X2, ..., Xn) = Sigma(n-1)(i=1)Sigma(n)(j=i+1)k(ij)sigma(X)isigma(X)j.     

Biosynthetic study of amphidinolide W

The biosynthetic origins of amphidinolide W (1) were investigated on the basis of (13)C-NMR data of 13C-enriched samples obtained by feeding experiments with [1-13C], [2-13C], and [1,2-13C2] sodium acetate in cultures of a strain Y-42 of the dinoflagellate Amphidinium sp. These incorporation patterns suggested that 1 was generated from a hexaketide chain, two acetate units, four isolated C1 units from C-2 of acetates, and four branched C1 units from C-2 of acetates. The acetate-incorporation patterns for C-1-C-2-(C-21) and C-8-C-18-(C-23, C-24) of 1 corresponded well to those for C-1-C-2-(C-27) and C-5-C-15-(C-28, C-29) of amphidinolide H (2) isolated from this strain.     

Amphidinolide X,a novel 16-membered macrodiolide from dinoflagellate Amphidinium sp

A novel cytotoxic 16-membered macrodiolide, amphidinolide X (1), has been isolated from a marine dinoflagellate Amphidinium sp. (strain Y-42). The gross structure of 1 was elucidated on the basis of spectroscopic data including one-bond and long-range (13)C-(13)C correlations. The relative and absolute stereochemistries were determined by combined analyses of NOESY data and (1)H-(1)H and (1)H-(13)C coupling constants of 1 and NMR data of the degradation products. Amphidinolide X (1) is the first macrodiolide consisting of polyketide-derived diacid and diol units from natural sources. The biosynthetic origins of 1 were investigated by means of feeding experiments with (13)C-labeled acetates.     

Amphidinolides H2-H5, G2, and G3, new cytotoxic 26- and 27-membered macrolides from dinoflagellate Amphidinium sp

Six new macrolides, amphidinolides H2 (5), H3 (6), H4 (7), H5 (8), G2 (9), and G3 (10), have been isolated from a marine dinoflagellate Amphidinium sp. (strain Y-42). Cytotoxicity of five derivatives (11-15) of amphidinolide H (1) in addition to 10 amphidinolides (1-10) containing amphidinolides H (1), G (2), B (3), and D (4) was examined, and it was found that the presence of an allyl epoxide, an S-cis-diene moiety, and the ketone at C-20 was important for the cytotoxicity of amphidinolide H (1)-type macrolides.     

Biosynthetic study of amphidinolide B

The biosynthetic origins of amphidinoide B (1) were investigated on the basis of 13C-NMR data of 13C-enriched samples obtained by feeding experiments with [1-(13)C], [2-(13)C], and [1,2-(13)C2] sodium acetates in cultures of a dinoflagellate Amphidinium sp. These incorporation patterns suggested that 1 was generated from three successive polyketide chains, an isolated C1 unit from C-2 of acetates, six branched C1 units from C-2 of acetates, and an "m-m" and an "m-m-m" unit derived only from C-2 of acetates. The labeling patterns of amphidinolide B (1) were different from those of amphidinolide H (2), a 26-membered macrolide closely related to 1.     

Selenium catalyzed conversion of vinyl halides into α-alkoxy acetals

The reaction of vinyl halides with phenylselenenyl chloride in alcohols affords α-alkoxy acetals and diphenyl diselenide which can be oxidized to PhSe cations by nitrate or persulfate anions. The reaction can be carried out with catalytic amounts of PhSeCl or PhSeSePh. The reaction proceeds through the formation of the methoxyselenenylation product which then suffers solvolysis. Under controlled conditions, the 1-phenyl-1-methoxy-2-bromo-2-phenylselenenyl ethane was isolated from the reaction of β-bromostyrene and PhSeCl in methanol. Several deselenenylation reactions of this α-halogenoselenide are reported.     

Synthesis of 1,2-Difunctionalized 1,3-Butadienes through a Sequence of Sigmatropic Rearrangements

Just by the introduction of isomerizable groups and successive [3,3] or [2,3] rearrangements, the diols 1 can be transformed into the new synthetic building blocks 2 . The conversion often proceeds with high stereoselectivity or even stereospecificity, and in some cases in a one-pot reaction. X, Y=NHCOCCl₃, N₃, P(O)Ph₂, 4-SO₂C₆H₄Me, S(O)Ar, SCOR.     

Chiral direction and interconnection of helical three-connected networks in metal-organic frameworks

The control of the interpenetration and chirality of a family of metal-organic frameworks is discussed. These systems contain two- (A) and four-fold (B) interpenetration of helical three-connected networks generated by binding the 1,3,5-benzenetricarboxylate (btc) ligand to a metal center. These frameworks have the general formula Ni(3)(btc)(2)X(m)Y(n).solvent (where X = pyridine or 4-picoline, Y = ethylene glycol, 1,2-propanediol, 1,4-butanediol, meso-2,3-butanediol, 1,2,6-hexanetriol, glycerol). The structural and chemical effects of modifying the alcohol and aromatic amine ligands bound to the metal center include controlling the thermal stability and the degree of interpenetration. Covalent linking of the four interpenetrating networks in the A family and the switching of diol binding from mono- to bidentate are demonstrated. Recognition of chiral diols by the hand of the network helices is investigated by binding an alcohol ligand with two chiral centers of opposite sense to the same helix. This reveals the subtle nature of the helix-ligand interaction.     

Total synthesis of amphidinolide X

A concise total synthesis of the cytotoxic marine natural product amphidinolide X (1) is described. A key step of the highly convergent route to this structurally rather unusual macrodiolide derivative consists of a newly developed, highly syn selective formation of allenol 6 by an iron-catalyzed ring opening reaction of the enantioenriched propargyl epoxide 5 (derived from a Sharpless epoxidation) with a Grignard reagent. Allenol 6 was then cyclized with the aid of Ag(I) to give dihydrofuran 7 containing the (R)-configured quarternary sp3 chiral center at C19 of the target. The anti-configured chiral centers at C10 and C11 were formed by the palladium-catalyzed, Et2Zn-promoted addition of propargyl mesylate 12 to the functionalized aldehyde 11. The key fragment coupling at the C13-C14 bond was achieved by the "9-MeO-9-BBN" variant of the alkyl-Suzuki reaction. Finally, the 16-membered macrodiolide ring was formed by a Yamaguchi esterification/lactonization strategy.     

Total synthesis and structural revision of (+)-amphidinolide W

An enantioselective first total syntheis of amphidinolide W (2) and a revision of its C6 absolute stereochemistry (1) are described. Amphidinolide W (1), a 12-membered macrolide isolated from Amphidinium sp., has shown potent antitumor properties against a variety of NCI tumor cell lines. The synthesis is convergent, and four of the five chiral centers were derived through asymmetric synthesis. The synthesis features Sharpless asymmetric dihydroxylation, diastereoselective alkylation, efficient cross metathesis of functionalized substrates, and novel functional group transformations using selective lipase-catalyzed hydrolysis of the primary acetate group. Of particular note, the C6 absolute stereochemistry of amphidinolide W (1) has now been revised through our current synthesis.     

Studies on the highly regio- and stereoselective selenohydroxylation of 1,2-allenylic sulfoxides with PhSeCl

The selenohydroxylation of 1,2-allenyl sulfoxides with PhSeCl in MeCN/H₂O (10/1) afforded E-3-hydroxy-2-phenylseleno-1-alkenyl sulfoxides in good yields and high regio-/stereoselectivities.     

Ruthenium(II) complexes containing the pentadentate SNNNS chelating ligand 2,6–diacetylpyridine bis(4–(p-tolyl)thiosemicarbazone). Synthesis,reactivity and electrochemistry

Ruthenium(II) heptacoordinate complexes containing the pentadentate SNNNS chelating ligand 2,6–diacetylpyridine bis(4–(p-tolyl)thiosemicarbazone) (L1H2) have been prepared. The compounds were of the type Ru(L1H2)X2 [X=Cl (1);Br (2); SCN (3)],[Ru(L1H2)- (Y)Cl]Cl [Y=imidazole (4); pyridine-N-oxide (5)] and [Ru(L1H2)(PPh3)X]Y, [X=Cl (6), (7);Br (8); Y=ClO4/ PF6]. The complexes were characterised by i.r., u.v.–vis. and n.m.r. spectroscopy and their electrochemical behaviour was examined by cyclic voltammetry. They exhibit a reversible to quasi-reversible RuII/RuIII couple in MeCN solution at a glassy carbon working electrode using an Ag/AgCl electrode as the reference. This revised version was published online in June 2006 with corrections to the Cover Date.     

Stereocontrolled total synthesis of amphidinolide X via a silicon-tethered metathesis reaction

Two esterifications and an RCM to create the challenging trisubstituted C12-C13 double bond were required in the total synthesis of amphidinolide X (1) reported here. Assembling the three fragments in this order, no RCM occurred or the process yielded mainly isomer Z. However, generating the E double bond first, by a new variant of a Si-tethered metathesis (using Schrock's catalyst), and carrying out the esterification and macrolactonization steps later, 1 was obtained exclusively.     

Stereocontrolled and convergent total synthesis of amphidinolide T3

Stereocontrolled and convergent total synthesis of amphidinolide T3 has been described. A retrosynthetic scheme was constructed that led to the recognition of readily available and enantiomerically related compounds as starting materials for the total synthesis of amphidinolide T3. Thus, the two key building blocks 6 and 7 were defined as subtargets and synthesized in optically active forms. The C1-C12 fragment 6 was derived from commercially available D-glutamic acid or its synthetically equivalent (R)-5-hydroxymethyltetrahydrofuran-2-one 16 as starting material involving highly diastereoselective asymmetric allylation as a key step. The C13-C21 fragment 7 was efficiently synthesized in high yield through the dithiane coupling of the segment 10 and iodide 11, followed by subsequent deprotection and Petasis olefination. Eventually, assembly of the fragment aldehyde 6 and dithiane 7 along with C-C bond formation, a two-step oxidation-reduction sequence, selective macrolactonization, and functional transformation furnished the convergent total and formal synthesis of amphidinolide T3 and T4, and this approach also provides a flexible and practical synthesis of amphidinolide T macrolides.