57253-30-2

A study of the deoxyhalogenation of allylic and propargylic alcohols with tetramethyl-α-halo-enamines is reported. Primary allylic and primary and secondary propargylic alcohols gave the corresponding halides in high yields. Secondary allylic and propargylic alcohols yielded the corresponding secondary halides but the reaction also produced some rearranged primary halides (I > Br > Cl). The reactions with tertiary allylic and tertiary propargylic alcohols gave several products and was therefore of little synthetic value. However, the addition of triethylamine to the reaction mixture or the use of lithium alkoxide instead of alcohol brought about a major change of the course of the reaction which led to amides carrying an allyl or an allenyl group at C2. This was shown to result from a Claisen-Eschenmoser rearrangement of an intermediate α-allyloxy- or propargyloxy-enamine.

The dauc-8-en-11-ol synthase from Streptomyces venezuelae was investigated for its catalytic activity towards alternative terpene precursors, specifically designed to enable new cyclisation pathways. Exchange of aromatic amino acid residues at the enzyme surface by site-directed mutagenesis led to a 4-fold increase of the yield in preparative scale incubations, which likely results from an increased enzyme stability instead of improved enzyme kinetics.

Alkyne aminopalladation reactions starting from tosylamides are reported. The emerging vinylic Pd species are converted either in an intramolecular Heck reaction with olefinic units or in an intermolecular Suzuki reaction by using boronic acids exhibiting broad functional group tolerance. Tetra(hetero)substituted tosylated enamines are obtained in a simple one-pot process.

The enantioselective total synthesis of nesteretal A was achieved in 15 steps via biomimetic cascade hemiacetalizations at the final key step. Other key features of the total synthesis include Sharpless asymmetric dihydroxylation, diastereoselective 1,2-addition, Pd-catalyzed ene-type cyclization, and stereoselective epoxidation to construct a complex structure containing multiple quaternary carbons.

Starting from diverse alkene-tethered aryl iodides and O-benzoyl-hydroxylamines, the enantioselective reductive cross-electrophilic 1,2-carboamination of unactivated alkenes was achieved using a chiral pyrox/nickel complex as the catalyst. This mild, modular, and practical protocol provides rapid access to a variety of β-chiral amines with an enantioenriched aryl-substituted quaternary carbon center in good yields and with excellent enantioselectivities. This process reveals a complementary regioselectivity when compared to Pd and Cu catalysis.

We have developed an asymmetric aza-Wacker-type cyclization of N-Ts hydrazine-tethered tetrasubstituted olefins, affording optically active pyrazolines bearing chiral tetrasubstituted carbon stereocenters. This reaction is tolerant to a broad range of substrates under mild reaction conditions, giving the desired chiral products with high enantioselectivities. Generation of two vicinal stereocenters on the C=C double bonds was also achieved with high selectivities, a process which has been rarely studied for Wacker-type reactions. A mechanistic study revealed that this aza-Wacker-type cyclization undergoes a syn-aminopalladation process. It was also found that for substrates bearing two linear alkyl substituents on the outer carbon atom of the olefin, both of which are larger than a methyl group, the alkyl substituent that is cis to the intranucleophilic group participates more readily in β-hydride elimination. When one of the two alkyl substituents on the outer carbon atom of the olefin is a methyl group, β-hydride elimination proceeds selectively at the methylene side, thus both diastereomers can be prepared via switching the configuration of the olefin. Furthermore, the product can be converted to a pharmaceutical compound in high yields over three steps.

The invention discloses a method for preparing pentazocine intermediates, and belongs to the field of medicine synthesis. The method includes synthesizing chiral intermediates by the aid of simple synthesis processes; carrying out addition and hydrogenation debenzylation to obtain key intermediates (-)-(2S, [2a, 6a, 11S])-1, 2, 3, 4, 5, 6-hexahydrogen-cis-6, 11-dimethyl-2, 6-methylene-3-benzo azocines-8-alcohol. The method has the advantages that the method is low in cost and high in yield and includes simple processes, and the chiral purity of the pentazocine intermediates which are productsprepared by the aid of the method can reach 98%.

The development of a general catalytic system for the palladium-catalyzed carbocyclization of unactivated alkyl bromides with alkenes is described. This approach uses a commercially available bisphosphine ligand and avoids the use of carbon monoxide atmosphere present in prior studies involving alkyl iodides. Detailed mechanistic studies of the transformation are performed, which are consistent with auto-tandem catalysis involving atom-transfer radical cyclization followed by catalytic dehydrohalogenation. These studies also suggest that reactions involving alkyl iodides may proceed through a metal-initiated, rather than metal-catalyzed, radical chain process.

Aza-Heck cyclizations initiated by oxidative addition of Pd0-catalysts into the N?O bond of N-(pentafluoro-benzoyloxy)sulfonamides are described. These studies, which encompass only the second class of aza-Heck reaction developed to date, provide direct access to diverse N-heterocyclic ring systems.

A copper-promoted tandem reaction of a variety of azobenzenes and allyl bromides via N=N bond cleavage to regioselectively construct quinoline derivatives has been developed. The azobenzenes act as not only construction units but also an oxidant for quinoline formation.

We report efficient Pd-catalyzed cyclizations of oxime esters with 1,1-disubstituted alkenes as the basis of a general entry to α,α-disubstituted pyrrolidine derivatives. We also demonstrate that catalytic asymmetric variants of this chemistry are feasible by employing a suitable chiral ligand. The Royal Society of Chemistry 2013.

A base mediated isomerisation-allylation protocol of 1,3-disubstituted propenols has been established. The use of diaryl and aryl-silyl substrates is reported alongside the use of substituted allyl bromides. Mechanistic experiments have also been conducted to elucidate the reaction pathway. The Royal Society of Chemistry 2013.

The total synthesis of the 2-pyrone natural products nectriapyrone, aplysiopsenes A-C, ent-aplysiopsene D, phomapyrones A and D, and of 8,9-dehydroxylarone were achieved by Wittig olefination starting with vermopyrone. Infectopyrone was synthesized by Horner-Wadsworth-Emmons reaction starting with phomapyrone D. Racemic phomapyrone C methyl ether was obtained by hydrogenation of nectriapyrone. The total syntheses were achieved starting from commercially available 3,5-heptanedione and led to the desired natural products in 18-46% over 5-6 steps, whereupon all five-step syntheses were carried out with a single chromatographic workup. The total synthesis of infectopyrone, aplysiopsenes A-D, of phomapyrones A and D, and of 8,9-dehydroxylarone were achieved for the first time, giving unambiguous proof for the proposed structures of these natural products.

The in situ preparation of chiral amido alkyl ate yttrium complexes from an array of chiral N-benzyl-like-substituted binaphthyldiamines is reported. These chiral heteroleptic complexes are shown to be efficient catalysts for the enantioselective intramolecular hydroamination of primary amines tethered to sterically demanding alkenes at high reaction temperatures. Fine tuning of their chiral environment allowed up to 77% ee to be reached for the cyclization of aminoalkenes bearing 1,2-dialkyl-substituted carbon-carbon double bonds. These chiral complexes also demonstrate the ability to promote the cyclization of amine-tethered trisubstituted alkenes in up to 55% ee, as the first report of the formation of enantioenriched quaternary centers by an hydroamination reaction.

(Chemical Equation Presented) The synthesis of the C10-C32 core structure of spirangien A is reported. The pivotal aldol coupling between both key intermediates provides a synthetic challenge in the synthesis of this complex natural product.

(Chemical Equation Presented) Against nuclear export! Immunofluorescence assays indicate that anguinomycin C is a potent inhibitor of protein export from the nucleus. Key features in the total synthesis of this antitumor natural product include a Cr-catal

The synthesis of the C23-C32 fragment of spirangien A is reported using Evans' alkylation, Evans-Metternich aldol reaction and a substrate controlled stereoselective reduction.

A coordinatively unsaturated ruthenium complex catalyzed the formation of a carbon-carbon bond between two judiciously chosen alkene and alkyne partners in good yield, and in a chemo- and regioselective fashion, despite the significant degree of unsaturation of the substrates. The resulting 1,4-diene forms the backbone of the cytotoxic marine natural product amphidinolide P. The alkene partner was rapidly assembled from (R)-glycidyl tosylate, which served as a linchpin in a one-flask, sequential three-components coupling process using vinyllithium and a vinyl cyanocuprate. The synthesis of the alkyne partner made use of an unusual anti-selective addition under chelation-control conditions of an allyltin reagent derived from tiglic acid. In addition, a remarkably E-selective E2 process using the azodicarboxylate-triphenylphosphine system is featured. Also featured is the first example of the use of a β-lactone as a thermodynamic spring to effect macrolactonization. The oxetanone ring was thus used as a productive protecting group that increased the overall efficiency of this total synthesis. This work was also an opportunity to further probe the scope of the ruthenium-catalyzed alkene-alkyne coupling, in particular using enynes, and studies using various functionalized substrates are described.

A three-step synthesis of vinylglycine 1 has been developed using a readily available starting material (but-3-enenitrile 2), based on the Neber rearrangement of the corresponding N-chloroimidate, and using cheap, convenient reagents.Also described is a convenient optical resolution of the N-tert-butoxycarbonyl derivative by papain-catalysed enantioselective esterifucation in a two-phase system.From the optically active amino acid, related amino acids obtained via epoxidation, dihydroxylation and cyclopropanation have been prepared.The related β,γ-unsaturated amino acids (E)-2-aminopent-3-enoic acid 20 and (E)-2-amino-3-methylpent-3-enoic acid 22 have been synthesised using the same approach.

The Claisen rearrangement of precursors bearing a stereogenic centre adjacent to carbon 1 of the pericyclic nucleus has been investigated in the sulfur series.Dithioesters having a methyl and various alkyl or alkenyls groups on the β-carbon were deprotonated by LDA.The resulting enethiolates were allylated on sulfur to give S-allyl ketenedithioacetals.The thio-Claisen transposition of the latter compounds was achieved either at room temperature or at 101 deg C to afford good yield of allylated dithioesters.Diastereomeric selectivities up to 95:5 have been observed.These results have been explained by a steric effect and correlated to allylic strain values.

The trimethylsilyl enolate 9 of (1'R,2'S)-N-methylephedrine propionate was condensed with tiglic aldehyde to afford the (1'R,2'S,2S,3R)-ester 10 with high stereoselectivity; conversion into the aldehyde 12 was effected without epimerization, and the seque

As an extension of the work carried out on the conjugate addition reactions of lithiated 3-alkylallylic sulfoxides, phosphine oxides, and phosphonates to cyclic enones, the effects of placing methyl groups at C2, at C2 and C3, and at C1 and C3 of the allyl system and of placing the allyl system within a five-membered ring are examined.From the lithiated 2-methallyl and (E)-2-methylbut-2-enyl ("tiglyl") sulfoxides, mixtures of diastereomeric (E)- and (Z)-vinilyc sulfoxides resulting from conjugate addition to cyclopentenone are obtained.The proportion of Z diastereomers formed increases with the reaction temperature.In contrast, lithiated (Z)-2-methylbut-2-enyl ("angelyl") sulfoxides and the tiglyl and angelyl phosphine oxides undergo highly diastereoselective conjugate addition to give (E)-vinylic products.Lithiated 1,3-dimethylbut-2-enyl sulfoxides undergo stereoconvergent reactions in that the starting sulfoxides, as mixtures of diastereomers, are converted into vinylic sulfoxides, which are obtained as single diastereomers.The individual diastereomers of tert-butyl cyclopentenyl sulfoxide upon lithiation undergo conjugate addition with cyclopentenone to give the same vinylic sulfoxide.A sulfenate ester also results from carbonyl addition.The structures of the diastereomers have been established by high-field (1)H NMR spectoscopy, by chemical correlation, and in two cases by X-ray crystallographic studies.The destabilizing influence of the methyl groups on the normal "trans-fused chair-chair"-like extended transition state causing access to "cis-fused boat-boat"-like, "cis-fused chair-chair"-like, and "trans-fused boat-chair"-like transition states involving planar lithiated reagents provides a rationale for the results.The temperature dependence of some of these reactions, and simple quenching experiments in which the individual lithiated diasteromers of the cyclopentenyl sulfoxide are converted into a single diasteromer, provide evidence for planar lithiated sulfoxides.

4-Toluenesulphonyl iodide reacts thermally at alkylsulphone.Spiro- and bicyclo-alkyl compounds are also formed with other free radical precursors.The reactions are believed to take place through a chain mechanism in which cobaloxime(II), present adventitiously or formed by partial homolysis of the substrate, abstracts iodine from the toluenesulphonyl iodide to give the toluenesulphonyl radical, which attacks the organic ligand of the cobaloxime, preferably at the terminal olefinic carbon, thereby displacing cobaloxime(II) and giving the observed organic product.

Several 1-cyano-2(trichloroethyl)cyclopropanes have been synthesised by a sequence of reactions involving homolytic displacement of cobaloxime(II) from allylcobaloxime(III) complexes by bromocyanomethyl radicals and homolytic displacement of cobaloxime(II) from but-3-enylcobaloxime(III) complexes by trichloromethyl radicals: the latter complexes being formed from the 1-bromo-1-cyanobut-3-enes formed in the reactions of the allylcobaloxime(III) complexes.In cases where the but-3-enylcobaloxime(III) complex could not be synthesised, alternative routes to 1-cyano-2-(trichloroethyl)cyclopropanes have been demonstrated, including the homolytic displacement of bromine atoms from 1-bromo-1-cyanobut-3-enes by trichloromethyl radicals.

Aliphatic acids containing an isoprenoid 1,5-diene moiety are prepared in high yields by the selective gamma alkylation of α,β-unsaturated acids with allylic electrophiles. The gamma-regioselectivity of the alkylation is controlled by the use of the dicopper(I) dienolates prepared from the α,β-unsaturated acids. The method offers a particularly facile means for synthesizing isoprenoid 1,5-diene natural products such as farnesoic acid by alkylation of senecioic acid with geranyl bromide; geranoic acid by alkylation of senecioic acid with 3,3-dimethallyl bromide; and dl-lanceol by alkylation of tiglic acid with an allylic bromide derived from dl-limonene. Such products find use in the synthesis of insect pheremones, insect juvenile hormones, and components of perfumes.