RESUMO
A new strategy focusing on the last-stage asymmetric assembly of the ring D, which inherently possesses the densest part of stereogenic centers and functional groups in the A/B/C/D ring system of (-)-cephalotaxine, has been developed, in which a novel Rh-catalyzed asymmetric (2 + 3) annulation of tertiary enamides with enoldiazoacetates is designed and explored for enantioselective construction of the crucial cyclopentane ring D bearing a unique spirocyclic aza-quaternary stereocenter. Based on the expeditious access of chiral functionalized building block with the tetracyclic A/B/C/D ring system, a concise enantioselective total synthesis of (-)-cephalotaxine starting from readily available homopiperonyl alcohol has been achieved in nine steps with only two column chromatography purifications. Following the tactical introduction of the Meinwald rearrangement, enantioselective divergent syntheses of (-)-cephalotine B with an additional C3-O-C11 oxo-bridged bond (14 steps), (-)-fortuneicyclidin B with an unprecedented C3-C10 bond (14 steps), and its 2-epimer (-)-fortuneicyclidin A (16 steps) have been also accomplished for the first time.
RESUMO
A unified strategy toward asymmetric divergent syntheses of nine C8-ethano-bridged diterpenoids A1-A9 (candol A, powerol, sicanadiol, epi-candol A, atisirene, ent-atisan-16α-ol, 4-decarboxy-4-methyl-GA12, trachinol, and ent-beyerane) has been developed based on late-stage transformations of common synthons having ent-kaurane and ent-trachylobane cores. The expeditious assembly of crucial advanced ent-kaurane- and ent-trachylobane-type building blocks is strategically explored through a regioselective and diastereoselective Fe-mediated hydrogen atom transfer (HAT) 6-exo-trig cyclization of the alkene/enone and 3-exo-trig cyclization of the alkene/ketone, showing the multi-reactivity of densely functionalized polycyclic substrates with πCâC and πCâO systems in HAT-initiated reactions. Following the rapid construction of five major structural skeletons (ent-kaurane-, ent-atisane-, ent-beyerane-, ent-trachylobane-, and ent-gibberellane-type), nine C8-ethano-bridged diterpenoids A1-A9 could be accessed in the longest linear 8 to 11 steps starting from readily available chiral γ-cyclogeraniol 1 and known chiral γ-substituted cyclohexenone 2, in which enantioselective total syntheses of candol A (A1, 8 steps), powerol (A2, 9 steps), sicanadiol (A3, 10 steps), epi-candol A (A4, 8 steps), ent-atisan-16α-ol (A6, 11 steps), and trachinol (A8, 10 steps) are achieved for the first time.
Assuntos
Diterpenos do Tipo Caurano , DiterpenosRESUMO
A new hypervalent-iodine(III)-mediated tandem reaction involving oxidative dearomatization and inâ situ aziridination of phenolic amines is described, providing a mild and effective method for the assembly of structurally interesting and synthetically useful aziridines. Importantly, the densely functionalized aziridines resulting from this unprecedented tandem reaction offer a platform for expeditious access to architecturally diverse aza-heterocycles through transformations initiated by selective ring-opening of aziridines.
RESUMO
Palladium-catalyzed asymmetric [4+5] annulation of ortho-quinone methides (o-QMs) with substituted vinylethylene carbonates (VECs) is described for the first time, giving a novel enantioselective approach to chiral nine-membered benzoheterocycles. Based on this designed [4+5] annulation, an unprecedented silica gel-promoted tandem rearrangement reaction featuring a unique asymmetric aromatic Claisen rearrangement is explored at room temperature, offering a new method for asymmetric construction of all-carbon quaternary stereocenters embedded in chiral functionalized homoallylic alcohols.
RESUMO
Lycopodium alkaloids with structural diversity and biological significance have been stimulating an increasing interest in the synthetic and medicinal communities, in which inspiration and exploration of their related biogenetic relationship generally constitute one of the major concerns. Driven by the plausible biogenetic entry to lycojaponicumin D as the first member of Lycopodium alkaloids having a structurally unusual C3-C13-linked scaffold, a new connection with lycodoline has been proposed and discovered on the basis of the design of an unprecedented bioinspired tandem fragmentation/Mannich reaction. Initiated by expeditious assembly of bridgehead heterofunctionalization in the [3.3.1] bicyclic system of lycodoline, a novel tandem palladium-mediated oxidative dehydrogenation/hetero-Michael reaction has been developed for the strain-driven formation of the C-heteroatom bond, leading to a new approach to conformationally rigid bridgehead heteroquaternary carbons. The present unified strategy provides a scenario for the divergent total syntheses of nine natural Lycopodium alkaloids and four unnatural C12 epimers, wherein (±)-lycojaponicumin D and six lycodoline-type alkaloids have been synthetically achieved for the first time.
Assuntos
Alcaloides/síntese química , Lycopodium/química , Alcaloides/química , Cristalografia por Raios X , Ciclização , Modelos Moleculares , Estrutura Molecular , EstereoisomerismoRESUMO
The first total syntheses of Lycopodium alkaloids palhinine A, palhinine D, and their C3-epimers have been divergently achieved through the use of a connective transform to access a pivotal hexacyclic isoxazolidine precursor. A microwave-assisted regio- and stereoselective intramolecular nitrone-alkene cycloaddition was tactically orchestrated as a key step to install the crucial 10-oxa-1-azabicyclo[5.2.1]decane moiety embedded in the conformationally rigid isotwistane framework, demonstrating the feasibility of constructing the highly strained medium-sized ring by introduction of an oxygen bridging linker to relieve the transannular strain in the polycyclic scaffold. Subsequent N-O bond cleavage provided the synthetically challenging nine-membered azonane ring system bearing the requisite C3 hydroxyl group. Late-stage transformations featuring a chemo- and stereoselective reduction of the pentacyclic ß-diketone secured the availability of our target molecules.
Assuntos
Alcaloides/síntese química , Alcaloides/química , Estrutura MolecularRESUMO
A novel enantioselective [4 + 2] annulation of the allenoates having a unique positive ortho-effect with in situ generated ortho-quinone methides has been developed under the catalysis of Cinchona alkaloid. This chiral amine-catalyzed reaction provides an alternative route to asymmetric catalytic construction of synthetically interesting, highly functionalized chiral chromans in good to excellent enantioselectivities (up to 97% ee).
RESUMO
A novel strategy based on phase transfer catalysis for the diastereoselective and enantioselective direct assembly of unsymmetric ß,ß-diaryl-α-amino acid esters via 1,6-conjugate addition of para-quinone methides and glycine derivatives is described. This protocol also provides an alternative route to the synthetically interesting functionalized chiral tetrahydroisoquinoline and its analogues.
RESUMO
A novel DBU-mediated stereoselective spirocyclopropanation of para-quinone methides with sulfonium salts has been developed on the basis of the mode involving a 1,6-conjugate addition/intramolecular dearomatizing cyclization cascade. This reaction provides a mild and effective method for the assembly of synthetically and structurally interesting spirocyclopropanyl para-dienones. The feasibility for the enantioselective access to such functionalized para-dienones has also been explored by using the axially chiral sulfonium salt. Importantly, the regioselective ring openings of the related spirocyclopropanyl para-dienones have been achieved divergently.
RESUMO
An unprecedented asymmetric catalytic tandem aminolysis/aza-Michael addition reaction of spirocyclic para-dienoneimides has been designed and developed through organocatalytic enantioselective desymmetrization. A unified strategy based on this key tandem methodology has been divergently explored for the asymmetric total synthesis of two natural Apocynaceae alkaloids, (+)-deethylibophyllidine and (+)-limaspermidine. The present studies not only enrich the tandem reaction design concerning the asymmetric catalytic assembly of a chiral all-carbon quaternary stereocenter contained in the densely functionalized hydrocarbazole synthons but also manifest the potential for the application of the asymmetric catalysis based on the para-dienone chemistry in asymmetric synthesis of natural products.
Assuntos
Apocynaceae/química , Produtos Biológicos/síntese química , Alcaloides Indólicos/síntese química , Produtos Biológicos/química , Carbazóis/síntese química , Carbazóis/química , Catálise , Alcaloides Indólicos/química , Modelos Moleculares , EstereoisomerismoRESUMO
Triacylamines with Cs symmetry have been explored in asymmetric organocatalysis, leading to the development of a novel catalytic enantioselective desymmetrization of prochiral triacylamines by methanolysis under the catalysis of chiral pseudopeptidic guanidine-guanidinium salt having a weakly coordinating anion. This organocatalytic methodology provides an effective approach to the synthetically useful chiral imide-esters with a 1,5-dicarbonyl moiety, and its synthetic potential has been manifested in the asymmetric synthesis of two GABA analogue drugs, (R)-Baclofen·HCl and (S)-Pregabalin.
Assuntos
Baclofeno , Ésteres , Catálise , Guanidina , Imidas , Pregabalina , EstereoisomerismoRESUMO
The unique reactivity of indolyl-substituted p-QMs as a new type of two-carbon synthon has been explored for the first time in a novel iron(III)-catalyzed tandem annulation. This (2+2) annulation/retro-4π electrocyclization/imino-Nazarov cyclization cascade reaction is characterized by an unusual structural reconstruction of indolyl-substituted p-QMs, leading to an expeditious assembly of synthetically important functionalized cyclopenta[b]indoles.
Assuntos
Indóis , Ferro , Catálise , Ciclização , Indolquinonas , Indóis/químicaRESUMO
Divergent route: a direct C-C bond-forming approach to the key aryl-substituted all-carbon quaternary stereogenic center present in bioactive hydrodibenzofuran alkaloids has been discovered. This approach involves an unprecedented organocatalytic enantioselective Michael addition of α-cyanoketones with acrylates and was used in a novel and divergent synthetic strategy for the title compounds in asymmetric fashion.
Assuntos
Alcaloides/síntese química , Alcaloides de Amaryllidaceae/síntese química , Benzofuranos/química , Galantamina/síntese química , Espermidina/análogos & derivados , Alcaloides/química , Alcaloides de Amaryllidaceae/química , Brassicaceae/química , Carbono/química , Catálise , Ciclização , Galantamina/química , Liliaceae/química , Espermidina/síntese química , Espermidina/química , EstereoisomerismoRESUMO
A novel strategy based on Cu-catalyzed (4+1) cascade annulation of terminal alkynes as one-carbon synthons with 2-(tosylmethyl)anilines has been developed for the expeditious synthesis of 2,3-disubstituted indoles, in which in situ generations of aza-o-quinone methides and alkynyl-copper(I) species are involved. This annulation provides an effective method for the assembly of synthetically and structurally interesting 2,3-disubstituted indoles.
RESUMO
An unprecedented asymmetric catalytic (4 + 2) annulation reaction of aryl-substituted γ-methylidene-δ-valerolactones (GMDVs) with isatin-derived para-quinone methides (p-QMs) has been developed under the catalysis of palladium(0) and (S,S,S)-(-)-Xyl-SKP, offering a new approach for the diastereo- and enantioselective synthesis of chiral cyclohexadienone-fused cyclohexyl spirooxindoles. Significantly, three highly congested contiguous tetrasubstituted carbon atoms embedded in bispirocyclic skeleton, of which two are vicinal quaternary stereogenic centers, are forged in an effective and selective manner (up to 99% yield, up to 95% ee, >20/1 dr). The current reaction represents the first exploration of enantioselective catalytic (4 + 2) annulation forming the six-membered carbocycles in the chemistry of both GMDVs and p-QMs.
RESUMO
A new tandem annulation of p-quinone methides (p-QMs) with ynamides is described. This cascade reaction features a unique combination of (2 + 2) annulation, retro-4π electrocyclization, and imino-Nazarov cyclization, wherein vinyl p-quinone methides (p-VQMs) as one of the key intermediates have been identified chemically. Significantly, an unusual structural reconstruction of p-QMs involving the cleavage of the C5-C6 bond and the late-stage formation of the C4-C6 bond is involved, leading to a methodology development for the construction of functionalized aminoindenes.
RESUMO
A new one-pot procedure for the preparation of aminoenone from chloroalkyl enone and sodium azide was demonstrated. The structure of the presumed triazoline intermediate in this process was confirmed by X-ray analysis for the first time. As the application of this methodology, the synthesis of polycyclic alkaloid hexahydroapoerysopine (1a) was achieved through an efficient synthetic route.
Assuntos
Alcaloides/química , Aminas/química , Nitrogênio/química , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Espectrometria de Massas por Ionização por ElectrosprayRESUMO
An unprecedented umpolung spirocyclopropanation reaction of p-quinone methides and α-keto carbonyls is described. Our umpolung strategy based on 1,6-conjugate addition and intramolecular nucleophilic substitution offers a new method for effective access to a series of highly functionalized spirocyclohexadienonyl cyclopropanes having two vicinal quaternary carbons in ≤98% yield and >20:1 dr. Significantly, cyclic and acyclic topological structures of α-keto carbonyls as 1,1-dipole one-carbon synthons have a distinct influence on the stereochemistry of products, showing a reversal of diastereoselectivity in this P(NMe2)3-mediated umpolung spirocyclopropanation.
RESUMO
A novel asymmetric catalytic (2+3) annulation of p-quinone methides with CN-substituted trimethylenemethane is described under palladium catalysis, providing an alternative approach for the enantioselective construction of highly functionalized chiral spirocyclopentyl p-dienones. Driven by the significant improvement in the reactivity and enantioselectivity, a novel type of non-C2-symmetric phosphoramidite ligand from the chirality-matched combination of (S)-BINOL and sterically demanding amine derived from l-hydroxyproline is evolved and explored for the protocol presented here.
RESUMO
The catalytic enantioselective synthesis of all-carbon quaternary stereogenic centers in spirocyclic diketones has been achieved for the first time by an unprecedented asymmetric vinylogous alpha-ketol rearrangement in which an enantiocontrolled semipinacol-type 1,2-carbon migration was realized using multifunctional cinchona-modified primary amine catalysis.