Stereocontrolled synthesis of functionalized 1-azaspirans : Efficient synthesis of perhydrohistrionicotoxin

A formal total synthesis of perhydrohistrionicotoxin (H₁₂-HTX) is described based on a stereocontrolled α-acyliminium ion-olefin cyclisation. In the key step of the synthesis three asymmetric C atoms (C₆ C₇ and C₈) are introduced in a single operation leading to the formation of the spiro formate ester 15. Compound 15 is converted to the spirothiolactam alcohol 17, a known precursor of H₁₂-HTX.The versatility of the synthetic approach is further demonstrated by the stereocontrolled syntheses of other functionalized 1-azaspirans, viz the 6-Endo-Trig products 20 and 24 and the 5-Exo-Trig products 26 and 28. The formation of the latter two compounds is remarkable with respect to the mechanism.¹³C NMR data of a series of 1-azaspirans are provided, which inter alia show the existence of a conformational equilibrium in 1-azaspiro alcohol 16,Mass spectral criteria are used for assignment 5-Exo-or 6-Endo-cyclisation products.     

Stereocontrolled spirocyclic bislactams derived from pyroglutamic acid

The synthesis of rigid spirocyclic bislactams derived from pyroglutamic acid has been established.     

Phosphine-catalyzed synthesis of highly functionalized coumarins

2-Styrenyl allenoates are converted into cyclopentene-fused dihydrocoumarins through phosphine-catalyzed regio- and diastereoselective [3 + 2] cycloadditions. Remarkably, changing the solvent from THF to benzene promotes the conversion of the 2-(2-nitrostyrenyl) allenoate into a tricyclic nitronate through a previously undocumented mode of phosphine catalysis. This nitronate was subjected to efficient face-, regio-, and exo-selective 1,3-dipolar cycloadditions to provide tetracyclic coumarin derivatives.     

Facile synthesis of highly functionalized ethyltrifluoroborates

Organotrifluoroborates are generating increased interest because of their ease of preparation and purification and indefinite shelf life. Herein we report the preparation of organotrifluoroborates bearing functional groups that can be manipulated at different stages of the synthetic route, exploiting the inertness of their carbon-boron bonds. The alkylation of 2,2-dicyanoethyltrifluoroborate with a variety of electrophiles and of (EWG)2CH2 with potassium iodomethyltrifluoroborate resulted in di- and trisubstituted ethyltrifluoroborates in good to excellent yields.     

Stereocontrolled 1,3-phosphatyloxy and 1,3-halogen migration relay toward highly functionalized 1,3-dienes

A double migratory cascade reaction of α-halogen-substituted propargylic phosphates to produce highly functionalized 1,3-dienes has been developed. This transformation features 1,3-phosphatyloxy group migration followed by 1,3-shifts of bromine and chlorine as well as the unprecedented 1,3-migration of iodine. The reaction is stereodivergent: (Z)-1,3-dienes are formed in the presence of a copper catalyst, whereas gold-catalyzed reactions exhibit inverted stereoselectivity, producing the corresponding E products.     

Efficient synthesis of highly functionalized cyclic aminimides

[reaction: see text]. Simple condensation reactions of various alpha,beta-epoxy or alpha,beta-aziridinyl methyl esters with 1,1-dialkyl hydrazines provided cyclic aminimides (1,1-dialkyl-3-oxopyrazolidines) with a heteroatom substituent at the 4-position in good yields. The reaction proceeds smoothly, without any coreagent, providing the product as an easily isolable precipitate. The reaction is expected to be a good candidate for combinatorial synthesis of a highly functionalized five-membered ring scaffold. The scope and limitations of this reaction were investigated by varying the substituents R(1)-R(5).     

Stereocontrolled synthesis of functionalized cis-cyclopentapyrazolidines by 1,3-dipolar cycloaddition reactions of azomethine imines

The reaction of alkene-tethered alpha-ketocarboxylic acid derivatives with monosubstituted hydrazines allows highly substituted cis-cyclopentapyrazolidine ring systems to be constructed rapidly. Successful cyclocondensations are realized under thermal reaction conditions; in some cases, protic or Lewis acids accelerate these reactions. alpha-Methoxy-alpha,beta-unsaturated esters are suitable alkene components, as are alkenes having either electron-withdrawing or electron-donating substituents at the terminal alkene carbon. alpha-Ketoesters, alpha-ketoamides, and alpha-ketothioesters can be employed. Various hydrazines substituted with N-acyl, N-carboalkoxy, or N-carbamothioyl protecting groups are tolerated in these transformations. The rate of intramolecular cycloaddition is found to reflect not only the reactivity and equilibrium concentration of the azomethine imine intermediate, but, also in some cases, the rate at which hydrazone stereoisomers interconvert under the reaction conditions.     

Efficient microwave-assisted synthesis of highly functionalized pyrimidine derivatives

A generally applicable one-pot procedure for the rapid, easy, and diverse asymmetric functionalization of pyrimidines was developed that requires minimum efforts for the purification of the final products. 4-Amino-6-aryl-substituted pyrimidines are prepared in good yields by combined microwave-assisted amination and Suzuki-Miyaura cross-coupling reactions. The acid-mediated amination reaction affords the products as easily separable salts in 30-40 min reaction time.     

Efficient synthesis of highly functionalized vinylogous thiol esters

A series of vinylogous thiol esters 2,3 and 2,6-dioxo-1,2,5,6-tetrahydropyridines (cyclic vinylogous thiol esters) 4 were prepared in high to excellent yields from the tandem reaction of readily available α-alkenoylketene diethylthioacetals 1 and diethyl malonate. A plausible mechanism, which involves a base catalyzed retro-Michael ring opening of cyclohexanenes 2 to give vinylogous thiol ester 3, is disclosed.     

Organocatalytic enantioselective synthesis of highly functionalized polysubstituted pyrrolidines

The organocatalytic conjugate addition of different aldehydes to beta-nitroacrolein dimethyl acetal, generating the corresponding highly functionalized nitroaldehydes in high yields and with high stereoselectivities, has been studied in detail. These transformations have been achieved by using both readily available starting materials in a 1:1 ratio as well as commercially available catalysts at a 10 mol % catalyst loading. Furthermore, a very short and efficient protocol has been devised for the preparation of highly enantioenriched pyrrolidines containing two or three contiguous stereocenters starting from the obtained Michael adducts. 3,4-Disubstituted pyrrolidines have been obtained in a single step by Zn-mediated chemoselective reduction of the nitro group followed by intramolecular reductive amination, and trisubstituted homoproline derivatives have been prepared by means of an olefination reaction and a cascade process involving chemoselective reduction of the nitro group followed by a fully diastereoselective intramolecular aza- Michael reaction.     

An efficient synthesis of highly functionalized chiral lactams

A new method was developed to synthesize highly functionalized lactams via a one pot reductive amination/lactam formation reaction. This methodology is amenable for parallel synthesis and was used to prepare a large number of lactam analogs in a library format with good ee (de) retention.     

Practical synthesis of a highly functionalized thiazole ketone

Compound 1 is a uniquely substituted ketone prepared via addition of a thiazole anion to an aromatic nitrile in good overall yield. An exploration into the generality of the addition of thiazole anions to nitriles allowed us to make a variety of thiazole ketones in good to excellent yields. The non-odorous thiolate-mediated demethylation reaction used in the synthesis of 1 is also presented.     

Stereocontrolled synthesis of fully functionalized D-glucosamine monosaccharides via a domino nitro-Michael/Henry reaction

A diastereoselective domino nitro-Michael/Henry reaction involving a beta-hydroxyaldehyde and a nitroalkene provides direct access to fully functionalized D-glucosamine monosaccharides.     

An efficient synthesis of highly functionalized dinucleotide cap analogs

An efficient synthesis of new cap analogs containing aminoallyl linkers such as m⁷G[5′]pppp[5′]U-aminoallyl and m₂^7,3′OG[5′]pppp[5′]U-aminoallyl is reported. The final cap analog has been isolated with high purity (>99.8%) after ion-exchange column purification.     

Stereocontrolled synthesis of onchidins

[structure: see text] The first total synthesis of a molecule possessing the stereochemistry proposed for onchidin is described. The structure synthesized appears to be different from that of the marine natural product.     

Tricyclic heterocycles as precursors to functionalized spirocyclic oximes

An efficient synthesis of functionalized spirocyclic oximes from tricyclic heterocycles is reported. This novel method accomplishes high diastereoselectivity via an intramolecular 1,3-dipolar cycloaddition with a regenerating Michael linker strategy. Ring opening of the tricyclic N-(trimethylsilyloxy)pyrrolo[3,4-c]isoxazolidine framework was found to be essential for successful N-alkylation of the tertiary amine on the polymer support. β-Elimination of the quaternary salt releases the spirocyclic oximes from the solid support in overall yields of 45–60%.     

Stereocontrolled synthesis of dihydropseudoclovene-B

Aryl participated intramolecular cyclisation of the bromophenol 16 yielded the dienone 17 which was converted into dihydropseudoclovene-B (7) via a stereocontrolled route.