This paper describes the selective syntheses of two cis-isomer enriched cyclopentanone fragrances: (Z)-3-(2-oxopropyl)-2-(pent-2-en-1-yl)cyclopentanone (4 steps, 62% overall yield, 67% cis) and Magnolione® (5 steps, 60% overall yield, 55% cis). In addition, the asymmetric synthesis of (3aR,7aS)-5-methyl-2,3,3a,4,7,7a-hexahydro-1H-inden-1-one as well as (3a'R,7a'S)-5'-methyl-2',3',3a',4',7',7a'-hexahydrospiro[[1,3]dioxolane-2,1'-indene]) has been realized by an efficient kinetic resolution, which enables the selective synthesis of the 2S,3R-isomer-enriched 3 and 4.
cyclopentanone fragrances; jasmonoids; magnolione; cis-selective synthesis; kinetic resolution
A tunable microwave-assisted protocol for the synthesis of two biologically relevant families of heterocycles has been designed. Via a simple switch of reaction conditions, the same starting materials can be engaged in either an improved synthesis of the dihydrotriazine scaffold or a novel, first-in-class MCR to render the challenging 5-aminoimidazole nucleus in a single step. An additional first in class MCR is also reported utilizing guanidines to afford 2,5-aminoimidazoles.
Imidazole; Multicomponent Reaction; Strecker; Trimethylsilylcyanide
Oxa-Pictet-Spengler cyclization and microwave-assisted C-H arylation have been implemented as key steps in the synthesis of new isochroman heterocycles containing a 4,5,6a,7-tetrahydrodibenzo[de,g]chromene motif. These isochromans may be easily transformed to phenanthrene alkaloids via acidic cleavage of the isochroman ring and standard synthetic manipulations thereafter. The route described is attractive in that it provides access to two biologically interesting scaffolds in simple and high yielding synthetic steps.
C-H activation; Direct arylation; Oxa-Pictet-Spengler; Phenanthrene; Isochroman
To gain access to prenylated hexahydroxanthenes, tandem cascade cyclization-electrophilic aromatic substitution reactions have been studied on substrates bearing allylic and propargylic substituents. Both BF3·OEt2 and TMSOTf can be used to initiate this reaction sequence, resulting in different ratios of the C-2 and C-6 substitution products. Even though allylic transposition is observed in some cases, the results of a crossover experiment are consistent with an intramolecular reaction sequence. Taken together, these studies now allow preparation of either the C-2 or C-6 prenylated hexahydroxanthene products.
Cationic; Cyclization; Electrophilic aromatic substitution; Prenylation; Tandem reactions
Progress toward the cyclobutane core of bielshowskysin is reported. The core was thought to arise from a cyclopropane intermediate via a furan-mediated cyclopropane fragmentation, followed by a 1,4-Michael addition. The synthesis of the cyclopropane intermediate utilizes a Suzuki coupling reaction, an esterification with 2-diazoacetoacetic acid, and a copper catalyzed cyclopropanation. An alcohol intermediate within the synthetic route was obtained in high enantiopurity via a highly selective palladium(II)-catalyzed oxidative kinetic resolution (OKR).
Bielschowskysin; palladium; transesterification; synthesis
Chromenes, isochromenes, and benzoxathioles react with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone to form stable aromatic cations that react with a range of nucleophiles. These oxidative fragment coupling reactions provide rapid access to structurally diverse heterocycles. Conducting the reactions in the presence of a chiral Brønsted acid results in the formation of an asymmetric ion pair that can provide enantiomerically enriched products in a rare example of a stereoselective process resulting from the generation of a chiral electrophile through oxidative carbon–hydrogen bond cleavage.
oxidation; fragment coupling; heterocycles; chiral counterions; enantioselectivity
Gadolinium-containing phosphonate-coated gold nanoparticles were prepared and then non-covalently coated with an amphiphilic fluorous monomer. The monomer spontaneously self-assembles into a non-covalent monolayer shell around the particle. The binding of the shell utilizes a guanidinium-phosphonate interaction analogous to the one exploited by the Wender molecular transporter system. Particle-shell binding was characterized by a 27% decrease in 19F T1 of the fluorous shell upon exposure to the paramagnetic gadolinium in the particle and a corresponding increase in hydrodynamic diameter from 3 nm to 4 nm. Interestingly, a much smaller modulation of 19F T1 is observed when the shell monomer is treated with a phosphonate-free particle. By contrast, the phosphonate-free particle is a much more relaxive 1H T1 agent for water. Together, these observations show that the fluoroalkylguanidinium shell binds selectively to the phosphonate-covered particle. The system’s relaxivity and selectivity give it potential for use in 19F based nanotheranostic agents.
Theranostic; Gold nanoparticle; Surfaces; Relaxivity; Fluorine
2-Amino-1,4-dihydropyrimidines were reacted with bis-electrophiles to produce novel fused bi-pyrimidine, pyrimido-aminotriazine, and pyrimido-sulfonamide scaffolds. In addition, a quinazoline library was constructed using a guanidine Atwal-Biginelli reaction with 1-(quinazolin-2-yl)guanidines. The product heterocycles have novel constitutions with high nitrogen atom counts and represent valuable additions to screening libraries for the discovery of new modulators of biological targets.
Guanidines; Pyrimidines; Quinazolines; Atwal-Biginelli reaction; Screening library
Macrocyclic peptidomimetics are valuable in research and serve as lead compounds in drug discovery efforts. New methods to prepare such structures are of considerable interest. In this pilot study, we show that an organic template harboring a latent cinnamyl cation participates in novel Friedel-Crafts macrocyclization reactions with tryptophan. Upon joining the template to Trp-Trp-Tyr, a single operation efficiently generates eight unique macrocycles. Each has been isolated and thoroughly characterized. Product distribution as a function of Brønsted and/or Lewis acidic conditions was explored, and outcomes were compared to rearrangements induced within a corresponding tyrosine-linked cyclic ether. The solution structure of a new macrocyclic pyrroloindoline was solved using a combination of two-dimensional NMR methods and molecular mechanics simulations. Template-induced structural diversification of peptide sequences harboring aromatic residues has potential to create myriad macrocycles that target surfaces involved in protein-protein interactions.
Peptidomimetic; Macrocycle; Friedel-Crafts; Diversity; NMR solution structure
An efficient method is described for the synthesis of N-(2-aminophenyl)-2-hydroxyethylamines via a copper catalyzed N-selective arylation of β-amino alcohols with iodoanilines. The corresponding coupling products are useful intermediates for the synthesis of a variety of N-2-hydroxyethyl-substituted benzimidazoles, benzimidazolones, and iminobenzimidazoles. We found that 2-iodoaniline only arylates certain amino alcohols but not amines lacking a hydroxyl group. We also demonstrate the arylation of sterically demanding β-amino alcohols, such as ephedrine and prolinol with aryl iodides at room temperature.
Cross-coupling; Copper catalysis; Arylation; Amino Alcohol; Iodoaniline; Benzimidazole
Ether transfer methodology is capable of stereoselectively generating 1,3-diol mono- and diethers in good yield. Surprisingly, allylic and benzylic substrates provide none of the desired products when exposed to previously optimized conditions of iodine monochloride. Herein, second-generation activation conditions for ether transfer have been developed that circumvents undesired side reactions for these substrates. The application of this chemistry to the enantioselective synthesis of diospongins A and B has now been accomplished.
Ether transfer; Diospongin; Antiosteoporotic activity; Radical cyclization
The enantiodivergent hydroboration reactions of racemic allenylsilane (±)-4 with (dIpc)2BH and subsequent crotylboration of achiral aldehydes with the product crotylborane (S)-E-5 at −78 °C provide (E)-δ-silyl-anti-homoallylic alcohols 6 in 71–89% yield and with 93–96% ee. Intriguingly, mismatched double asymmetric crotylboration reactions of enantioenriched chiral aldehydes 20 with (S)-E-5 proceed under Curtin–Hammett control to give anti-β-hydroxylcrotylsilanes 24 as the only products.
Enantiodivergent hydroboration; Mismatched double asymmetric; crotylboration; Curtin–Hammett control
A formal synthesis of didehydrostemofoline and isodidehydrostemofoline has been accomplished by preparing an intermediate in the Overman synthesis of these alkaloids from commercially available 2-deoxy-D-ribose. The work presented in this account chronicles the evolution of our explorations to identify the optimal steric and electronic control elements necessary to generate the tricyclic core structure of these alkaloids in a single operation from an acyclic precursor. The key step in the synthesis is a novel dipolar cycloaddition cascade sequence that is initiated by cyclization of a rhodium-derived carbene onto the nitrogen atom of a proximal imine group to generate an azomethine ylide that then undergoes spontaneous cyclization via dipolar cycloaddition. The synthesis features several other interesting reactions, including a Boord elimination to prepare a chiral allylic alcohol, a highly diastereoselective Hirama-Itô cyclization, and a useful modification of the Barton decarboxylation protocol.
Total synthesis; Dipolar cycloaddition; Azomethine ylide; Stemofoline alkaloids; Cascade reaction
Chiral oxygenated molecules are pervasive in natural products and medicinal agents; however, their chemical syntheses often necessitate numerous, wasteful steps involving functional group and oxidation state manipulations. Herein a strategy for synthesizing a readily diversifiable class of chiral building blocks, allylic alcohols, through sequential asymmetric C—H activation/resolution is evaluated against the state-of-the-art. The C—H oxidation routes’ capacity to strategically introduce oxygen into a sequence and thereby minimize non-productive manipulations is demonstrated to effect significant decreases in overall step-count and increases in yield and synthetic flexibility.
C–H oxidation; Allylic oxidation; Allylic alcohols; Enantioselective; Palladium; Sulfoxide
LUMO-lowering organocatalysis has been extended to promote the conjugate addition of S-alkyl and -pyrrolyl silylketene acetals to α,β-unsaturated aldehydes, yielding both, syn and anti Mukaiyama–Michael products with high levels of enantioselectivity. This strategy allows for the generation of chemically useful 1,5-dicarbonyl systems and again highlights the utility of organocatalysis.
Mukaiyama–Michael; nantioselective organocatalysis
The synthesis of several sulfates of trichothecene mycotoxins is presented. Deoxynivalenol (DON) and its acetylated derivatives were synthesized from 3-acetyldeoxynivalenol (3ADON) and used as substrate for sulfation in order to reach a series of five different DON-based sulfates as well as T2-toxin-3-sulfate. These substances are suspected to be formed during phase-II metabolism in plants and humans. The sulfation was performed using a sulfuryl imidazolium salt, which was synthesized prior to use. All protected intermediates and final products were characterized via NMR and will serve as reference materials for further investigations in the fields of toxicology and bioanalytics of mycotoxins.
Deoxynivalenol; T2-toxin; Masked mycotoxins; Sulfation; Trichothecenes
Alkylation of 2-mercaptopyridine with 1,2-dibromoethane affords a cyclic dihydrothiazolopyridinium salt that can serve as a precursor of 2-aminopyridines. Its reaction with primary or secondary amines, either neat or in DMSO, under mild conditions gives the title compounds.
aminopyridine; heteroaryl amine; thiazolopyridinium; N-alkyl pyridinium
A virtual library of 54 inositol analog mimics of In(1,4,5)P3 has been docked, scored, and ranked within the binding site of human inositol 1,4,5-trisphosphate 3-kinase A (IP3-3KA). Chemical synthesis of the best scoring structure that also met distance criteria for 3′-OH to -P in Phosphate has been attempted along with the synthesis of (1S,2R,3S,4S)-3-fluoro-2,4-dihydroxycyclohexanecarboxylic acid as an inositol analog, useful for non-invasive visualization and quantitation of IP3-3KA enzymatic activity
A substrate-induced stereocontrol strategy was used to gain access to the tetracyclic core of (-)-lemonomycin. An advanced intermediate was prepared from a known substituted tyrosinol through a 16-step sequence, which involved a Pictet-Spengler reaction, a [3+2] dipolar cycloaddition and an enamide hydrogenation.
(-)-Lemonomycin; Tetrahydroisoquinoline antitumor antibiotics; Pictet-Spengler reaction; [3+2] dipolar cycloaddition
The preparation of an indole appended vinamidinium salt, an indole appended vinylogous amide and an indole appended chloroenal are described. The subsequent regiospecific conversion of these indole containing building blocks to functionalized pyrazoles and pyrroles is detailed.
Vinamidinium salt; Vinylogous amide; Chloroenal; Pyrrole; Pyrazole; Indole
We report the palladium-catalyzed enantioselective cyclization of 1,6-enamidynes to form spirocyclic ring systems. We applied this methodology to the concise synthesis of the skeletal core of the kopsifoline alkaloids.
Palladium catalysis; enantioselective synthesis; electrophilic activation; spirocyclization; natural product synthesis
A full account of synthetic efforts toward a lowly oxidized taxane framework is presented. A non-natural taxane, dubbed “taxadienone”, was synthesized as our first entry into the taxane family of diterpenes. The final synthetic sequence illustrates a seven-step, gram-scale and enantioselective route to this tricyclic compound in 18% overall yield. This product was then modified further to give (+)-taxadiene, the lowest oxidized member of the taxane family of natural products.
Total synthesis; Terpene; Taxane; Taxadiene; Cyclase phase
A catalytic method for the decarboxylative coupling of 2-(azaaryl)carboxylates with aryl halides is described. The decarboxylative cross-coupling presented is mediated by a system catalytic in both palladium and copper without requiring stoichiometric amounts of organometallic reagents or organoboronic acids. This method circumvents additional synthetic steps required to prepare 2-azaaryl organometallics and organoborates as nucleophilic coupling partners, which are prone to protodemetallation and protodeborylation and produce potentially toxic byproducts.
Decarboxylative cross-coupling; (2-azaaryl)carboxylates; Palladium; Copper