Total synthesis of (+)-piericidin A1 and (−)-piericidin B1

The convergent syntheses of (+)-piericidin A₁ 1 and (?)-piericidin B₁ 2 have been achieved based on classical Julia-Lythgoe olefination between 4-hydroxy-5,6-dimethoxy-3-methyl-2-[5-oxo-3-methyl-pent-(2E)-enyl]-pyridine 3 corresponding to the left half of the final molecule, and chiral phenyl sulfones, (4R,5R)-2,4,6-trimethyl-5-methoxy-1-phenylsulfonyl-octa-(2E,6E)-diene 20 and (4R,5R)-5-tert-butyldimethylsiloxy-2,4,6-trimethyl-1-phenylsulfonyl-octa-(2E,6E)-diene 33, corresponding to the right halves. The construction of the two stereogenic centers in the right half of piericidins was achieved based on lipase-catalyzed hydrolysis of methyl (2,3)-anti-3-acetoxy-2,4-dimethyl-hex-(4E)-enoate (±)-22.     

Heck arylations of pent-4-enoates or allylmalonate using a palladium/tetraphosphine catalyst

The Heck reaction of aryl halides with functionalised alk-1-enes should be a powerful method for the synthesis of functionalised (E)-1-arylalk-1-ene derivatives. The major problem of this reaction is the palladium-catalysed migration of the carbon-carbon double bond along the alkyl chain when there are no substituents on the C3 carbon of the alk-1-enes. We observed that for the arylation of ethyl pent-4-enoate, ethyl 2-methylpent-4-enoate or dimethyl allylmalonate this migration could be partially or completely controlled using appropriate reaction conditions. The ramification on the alkyl chain and the substituents on the aryl halide have also an important influence on this migration. Moreover, the cis,cis,cis-1,2,3,4-tetrakis(diphenylphosphinomethyl)cyclopentane/1/2[PdCl(C₃H₅)]₂ system catalyses this reaction with a wide range of aryl bromides using very high ratio substrate/catalyst in good yields.     

Total syntheses of (+)-spiculoic acid A and (+)-zyggomphic acid, new marine natural products of polyketide origin

The total syntheses of both natural (+)-spiculoic acid A and (+)-zyggomphic acid, new cytotoxic marine natural products of polyketide origin, have been accomplished for the first time. These syntheses were achieved by the highly stereoselective and high-yielding intramolecular Diels-Alder reaction of a functionalized (E,E,E)-2,7,9-dodecanal derivative to construct the core tetrahydroindan-2-one skeleton. A stereocongener of (+)-spiculoic acid A, i.e., the (2R,5S,6R)-isomer, was also synthesized. The details of these total syntheses are described.     

Synthesis of the trichloroacetamide derivative of enantio-iso-ADDA methyl ester

The divergent syntheses of the trichloroacetamide derivatives of (2S,3R,8R,9R,4E,6E)-3-amino-9-methoxy-2,6,8-trimethyl-10-phenyl-decadenoic acid (enantio-iso-ADDA), and (2R,3R,8R,9R,4E,6E)-3-amino-9-methoxy-2,6,8-trimethyl-10-phenyl-decadenoic acid (enantio-ADDA), have been achieved. Our approach takes advantage of highly efficient non-aldol aldol, palladium catalysed aza-Claisen and cross-metathesis methodologies.     

Synthesis of aromatic tetracyclic tin compounds by template and transmetallation reactions: Alkyl vs aryl migration from tin to nitrogen

The syntheses of [bis(3,5-di-tert-butyl-2-hydroxy-2-phenyl)amine]diphenyltin (1) and [bis(3,5-di-tert-butyl-2-hydroxy-2-phenyl)amine]dichloro-phenyl-stannate (2) by template reactions using 3,5-di-tert-butylcatechol, aqueous ammonia and SnPh₂Cl₂ are reported. We also report the syntheses of compounds 2, [bis(3,5-di-tert-butyl-2-hydroxy-2-phenyl)amine]trichloro-stannate (4), [bis(3,5-di-tert-butyl-2-hydroxy-2-phenyl)methylamine]chloro-methyltin (5), and [bis(3,5-di-tert-butyl-2-hydroxy-2-phenyl)-n-butylamine]n-butyl-chlorotin (6) and [bis(3,5-di-tert-butyl-2-hydroxy-2-phenyl)amine]n-butyl-dichloro-stannate (7), performed by transmetallation reactions of the octahedral zinc coordination compound Zn[3,5-di-tert-butyl-1,2-quinone-(3,5-di-tert-butyl-2-hydroxy-1-phenyl)imine]₂ (3) with SnPhCl₃ or SnPh₂Cl₂, SnCl₄, SnMe₂Cl₂, Sn(nBu)₂Cl₂ and Sn(nBu)Cl₃, respectively. The X-ray diffraction structures of compounds 1, 2, 4 and 6 are reported. The transmetallation reactions with Sn(alkyl)₂Cl₂ afforded pentacoordinated tin compounds, where an alkyl group migrated from tin to nitrogen, while similar reactions with Sn-Ph compounds did not present any phenyl group migration.     

Pheromone synthesis. Part 249: Syntheses of methyl (R,E)-2,4,5-tetradecatrienoate and methyl (2E,4Z)-2,4-decadienoate,the pheromone components of the male dried bean beetle,Acanthoscelides obtectus (Say)

The enantiomers of methyl (E)-2,4,5-tetradecatrienoate (1), a component of the male pheromone of Acanthoscelides obtectus, were synthesized from the enantiomers of 1-undecyn-3-ol (6), which were obtained via asymmetric acetylation of (±)-1-trimethylsilyl-1-undecyn-3-ol (4) with vinyl acetate as catalyzed by lipase PS (Amano). The ortho ester Claisen rearrangement of 6 with triethyl orthoacetate was the key-step to generate the chiral allenic system. A new synthesis of (±)-1 was also executed starting from (±)-6. Three different syntheses of methyl (2E,4Z)-2,4-decadienoate (2), another component of the male pheromone of A. obtectus, were achieved by means of either palladium-catalyzed Heck reaction or a Claisen and an Al₂O₃ catalyzed thermal rearrangements.     

Temperature dependence of the volumetric properties of some alkoxypropanols + n-alkanol mixtures

The excess molar volumes V_m^E for binary liquid mixtures containing dipropylene glycol monomethyl ether or dipropylene glycol monobutyl ether and methanol, 1-propanol, 1-pentanol and 1-heptanol have been measured as a function of composition using a continuous dilution dilatometer at T=(288.15, 298.15, and 308.15) K and atmospheric pressure over the whole concentration range. The excess volume results allowed the following mixing quantities to be reported in all range of concentrations or at equimolar concentrations: α, volume expansivity; (∂V_m^E/∂T)_p; (∂H^E/∂P)_T at T=298.15 K. The obtained results have been compared at T=298.15 K with the calculated values by using the Flory theory of liquid mixtures. The theory predicts the α, and α^E values rather well, while the calculated values of (∂V_m^E/∂T)_p and (∂H^E/∂P)_T show general variation with the alkyl chain length of the alkoxypropanols. The results are discussed in terms of order or disorder creation.     

Chemoenzymatic syntheses of N-trifluoroacetyl-l-daunosamine,N-trifluoroacetyl-l-acosamine,N-benzoyl-d-acosamine,and N-benzoyl-d-ristosamine from an achiral precursor,methyl sorbate

A conjugated addition of benzylamine to methyl (4R,5S)-4,5-(isopropylidenedioxy)-(2E)-hexenoate 8a followed by lactonization under acidic condition proceeds to the formal total syntheses of l-daunosamine 4 and l-acosamine 2. On the other hand, direct conjugated addition of benzylamine to methyl (4S,5S)-4,5-epoxy-(2E)-hexenoate 5 and the subsequent intramolecular nucleophilic attack by the ester carbonyl group on the epoxy ring of the substrates leads to the formal total syntheses of d-acosamine 2 and d-ristosamine 1.     

Organometallische komplexverbindungen: VIII. Einfluss von achiralen substituenten auf die optische induktion bei der metallinduzierten synthese von 3-methyl-E-4-hexen-2-on

Bis(μ-methyl-1,3-dimethyl-η³-allylnickel) which has been modified by P ligands with a chiral substituent reacts with carbon monoxide under the formation of optically active 3-methyl-E-4-hexen-2-on. The investigated P ligands (PR^★R₂) have one chiral substituent (R^★ = 1R,3R,4S-(?)-menthyl) and the other substituents have been varied by taking the same alkyl or alkoxy groups (R = Me, Et, i-Pr, OMe, OEt, O-i-Pr). It has been found that the extent and the direction of optical induction depends on the concentration of the P-ligand and the kind of the achiral substituents at phosphorus.     

Practical and robust method for stereoselective preparations of ketene silyl (thio)acetal derivatives and NaOH-catalyzed crossed-Claisen condensation between ketene silyl acetals and methyl esters

We developed an efficient, practical, and robust method for stereoselective preparations of (Z)-ketene trimethylsilyl (TMS) thioacetals from thioesters and alkyl (1Z)- or (1Z,3E)-1,3-bis(TMS)dienol ethers from alkyl β-ketoesters. The former preparation was performed by convenient procedure (LDA-TMSCl, 0-5 °C, 2.5 h), while the latter preparation involved convenient method A (2NaHMDS-2TMSCl) and cost-effective method B (NaH, NaHMDS-2TMSCl). The first catalytic NaOH-catalyzed crossed-Claisen condensation between ketene silyl acetals and methyl esters proceeded successfully to give a variety of α-monomethyl β-ketoesters and inaccessible α,α-disubstituted β-ketoesters. For further extension, a couple of Claisen-aldol tandem reactions of the obtained β-ketoester analogues utilizing TiCl₄ and TiCl₄-Bu₃N reagents smoothly proceeded with good to excellent stereoselectivity.     

TiCl4-mediated olefination of aldehydes with acetic acid and alkyl acetates: a stereoselective approach to (E)-α,β-unsaturated carboxylic acids and esters

A new method has been developed for the preparation of α,β-unsaturated carboxylic acids and corresponding esters with (E)-stereoselectivity via the TiCl₄-mediated olefination of aldehydes. The method, which uses readily available acetic acid or its alkyl esters as active methylene partners, is more flexible and complementary to conventional routes in the preparation of (E)-cinnamic acid derivatives.     

Conformational space of tetrakis(2-naphthalenyl)ethene: a naphthologous AIE luminogen

The AIE luminogen tetrakis(2-naphthalenyl)ethene (2-NA ₄ E) was synthesized by Barton’s double extrusion diazo-thione coupling method from 2,2′-dinaphthyl thioketone and 2,2′-(diazomethylene)bisnaphthylene in 77 % yield. The structure of 2-NA ₄ E was confirmed by its ¹H NMR and ¹³C NMR spectra with full assignments. 2-NA ₄ E and its parent tetraphenylethene (Ph ₄ E) have been subjected to a comprehensive computational DFT study, in search of their conformational spaces. Seven conformers and two transition states of 2-NA ₄ E have been located. Four conformers and one transition state of Ph ₄ E have been located. The conformers of 2-NA ₄ E and Ph ₄ E are not overcrowded, as indicated by the contact distances in the fjord and cove regions. The relative free energies (ΔG ₂₉₈) of the six most stable conformers of 2-NA ₄ E are in the narrow range of 2.3 kJ/mol; they make comparable contributions (12–29 %) to the equilibrium mixture. The energy barriers for the diastereomerization D ₂-Z,Z,Z,Z $ \rightleftharpoons $ ? D ₂-E,E,E,E via the transition state C ₁-Z,E,E,Z and for the enantiomerization C ₂-Z,Z,E,E $ \rightleftharpoons $ ? C ₂-E,E,Z,Z via the transition state C _i -Z,E,Z,E are only 29.8 and 29.0 kJ/mol, respectively, indicating very rapid rates of diastereomerization and enantiomerization at room temperature. The values of naphthalenyl torsion angles and ethenic twist angles in 2-NA ₄ E are almost identical to those in the parent Ph ₄ E. The previously proposed “bulkiness” of the naphthalenyl substituents and the validity of the restriction of naphthalenyl rotation are challenged. The analysis of the AIE effect in 2-NA ₄ E should take into account the intermolecular homochiral and heterochiral interactions between the conformers.     

Steric structure of alkyl 2-aryl(hetaryl)hydrazono-3-fluoroalkyl-3-oxopropionates

Steric structure of fluorinated 2-arylhydrazono-3-oxo esters was studied by ¹H, ¹⁹F, and ¹³C NMR spectroscopy and X-ray analysis. It was found that these compounds in the crystalline state and in solutions in acetone-d ₆, DMSO-d ₆, and CDCl₃ exist as Z isomers with the ester fragment involved in intramolecular hydrogen bond with the hydrazone NH proton. Exceptions are alkyl 2-arylhydrazono-4,4-difluoro-3-oxobutanoates which exist in acetone-d ₆ as mixtures of Z and E isomers, the former prevailing. Unlike fluorinated analogs, ethyl 2-(4-methylphenyl)hydrazono-3-oxobutanoate in crystal has the structure of E isomer in which intramolecular hydrogen bond is formed between the NH proton and acetyl carbonyl group. The same compound in acetone-d ₆, DMSO-d ₆, and CDCl₃ gives rise to a mixture of Z and E isomers, the latter prevailing.     

(+)-Sorangicin A: evolution of a viable synthetic strategy

An effective, asymmetric total synthesis of the antibiotic (+)-sorangicin A (1) has been achieved. Central to this venture was the development of first- and second-generation syntheses of the signature dioxabicyclo[3.2.1]octane core, the first featuring chemo- and stereoselective epoxide ring openings facilitated by a Co₂(CO)₆-alkyne complex, the second involving a KHMDS-promoted epoxide ring formation/opening cascade. Additional highlights include effective construction of the dihydro- and tetrahydropyran ring systems, respectively, via a stereoselective conjugate addition/α-oxygenation protocol and a thioketalization/hydrostannane reduction sequence. Late-stage achievements entailed two Julia-Kociénski olefinations to unite three advanced fragments with high E-stereoselectivity, followed by a modified Stille protocol to introduce the Z,Z,E trienoate moiety, thereby completing the carbon skeleton. Mukaiyama macrolactonization, followed by carefully orchestrated Lewis and protic acid-promoted deprotections that suppressed isomerization and/or destruction of the sensitive (Z,Z,E)-trienoate linkage completed the first, and to date only, total synthesis of (+)-sorangicin A (1).     

Stereoisomerism in the series of isoindole-based quaternary salts

Steric structure of quaternary ammonium salts of the 3-[alkyl(aryl)amino]-1-[alkyl(aryl)iminio]-1H-isoindole series was studied by ¹H NMR spectroscopy and X-ray analysis. The examined salts are characterized by E,E configuration of substituents with respect to the exocyclic C-N bonds, and the presence of ortho- and meta-substituents in the benzene rings on the nitrogen atoms gives rise to atropisomers. Sterically hindered N-(2,4,6-trimethylphenyl) derivative was found to exist as Z,Z isomer which undergoes irreversible thermal isomerization into the more stable E,E isomer through intermediate Z,E structure. The reactions of 1,1,3-trichloro-1H-isoindole with secondary aromatic amines having an electron-withdrawing substituent in the ortho position in the presence of organic bases (triethylamine, N,N-dimethylbenzylamine) are accompanied by decomposition of the latter and formation of unsymmetrically substituted salts of the 3-[alkyl(aryl)amino]-1-(dialkyliminio)-1H-isoindole series, which contain both arylamine residue and dialkylamino group and are also characterized by atropisomerism.     

Alkoxy substituted (E,E)-3,6-bis(styryl)pyridazine—a photosensitive mesogen for liquid crystals

(E,E)-3,6-Bis(styryl)pyridazines (3a-t) bearing 2, 4 or 6 alkoxy chains were prepared by applying the Siegrist reaction of 3,6-dimethylpyridazine (13) and the corresponding azomethines 10a-t. The transversal dipole moment of these calamitic compounds effects an extremely high tendency for self-organization in thermotropic LC phases (N, S_A, S_B, S_C, S_E, S_I/F, and Cub). The conjugated core structure represents moreover a chromophore with a high photosensitivity for (E,E)?(E,Z) isomerization reactions: this property makes the compounds interesting for optical imaging and switching techniques.     

Synthesis of Hydrodipyrrins Tailored for Reactivity at the 1- and 9-Positions

A collection of 33 hydrodipyrrins (9 targets, 21 intermediates, and 3 byproducts) has been prepared. The hydrodipyrrins (dihydrodipyrrins, tetrahydrodipyrrins, and hexahydrodipyrrins) contain a pyrrole ring and a geminal-dimethyl substituted 1-pyrroline (or pyrrolidine) ring. The α-substituents on the pyrrole ring (H, Br, CHO) and pyrroline ring (H, CH₃, CH(OR)₂, OMe, SMe) provide different reactivity combinations (Nu⁻, E⁺) and 0, 1, or 2 carbon atoms (which can give rise to the bridging meso-carbons in hydroporphyrins). Straightforward access to various hydrodipyrrins should facilitate development of syntheses of diverse hydroporphyrins.     

Facile synthesis of 2,4-dienals via an arsonium salt and its application to some natural products

2,4-Dienals were synthesized conveniently by using a new formylenylolefination method. The aldehydes were reacted with formylallyltriphenylarsonium bromide ( 2 ) in Et₂O THF H₂O (9 : 1 : 0.05) in the presence of K₂CO₃ at room temperature to give (2E,4E)-and (2E,4Z)-dienals, in favor of the former. They could be easily separated by chromatography, and the latter, in CH₂Cl₂, could be converted to the former on treatment with a catalytic amount of iodine in daylight. The configurations of the (E,E) products have been conveniently identified by ¹H NMR determined in C₆D₆. The syntheses of two natural products, navenone A and Otanthus maritima amide, by this method are also reported in detail.