Straightforward access to enantioenriched pyrazyl alcohols using chiral organomagnesiates

The clean iodine-metal exchange of iodopyrazine and subsequent enantioselective addition of the intermediate pyrazyl magnesiate to aldehydes using ((R,R)-TADDOLate)Bu₂MgLi₂ is reported. New chiral pyrazylalcohols were obtained in enantiomeric excesses of up to 90%.     

Straightforward access to enantioenriched 2-allylpiperidine: application to the synthesis of alkaloids

An efficient stereocontrolled preparation of (2R,R(S))-2-allyl-(N-tert-butylsulfinyl)piperidine and its enantiomer is detailed. The sequence requires only two synthetic operations with one-column chromatography and is readily scaled up. The versatility of these chiral building blocks was exemplified by the total or formal synthesis of some natural and unnatural alkaloids.     

Enantioselective homoallyl-cyclopropanation of dibenzylideneacetone by modified allylindium halide reagents—rapid access to enantioenriched 1-styryl-norcarene

Dibenzylideneacetone (8) reacts with in situ-generated allylindium halide reagents to yield the product of a homoallyl-cyclopropanation reaction: 2-(3″-butenyl)-1,1-bis[(E)-2′-phenylethenyl]cyclopropane (9), which proceeds via step-wise cleavage of the CO bond and delivery of two allyl fragments from the reagent. A range of enantiomerically enriched ligands have been tested as stoichiometric asymmetric modifiers for this process. Enantiopure compounds such as cinchona alkaloids, ephedra, aminoalcohols and tartaric acid derivatives, which have proven of utility as asymmetric modifiers for the indium-mediated allylation of aldehydes and ketones, were very inefficient in the process 8→9. However, mandelic acid derivatives, in particular mandelates, were found to be of significant potential. The absolute stereochemistry of the cyclopropane 9 has been determined by degradation to 1,1-dicarboxymethyl-2-butylcyclopropane, converging with an independent enantioselective synthesis starting from hexene. Under optimised conditions, viz. using allylindium iodide reagents and working-up with aqueous Na₂SO₃ to avoid iodine-mediated polymerisation, (S)-9 can be generated in 86% yield and with (S)-methyl mandelate as modifier useful enantiopurity (94/6 er) was observed. The cyclopropane product ((S)-9) undergoes RCM using standard conditions to afford a norcarene unit ((1S,6S)-1-(E)-2′-(phenylethenyl)-bicyclo[4.1.0]hept-2-ene) without loss of enantiopurity.     

Practical access to highly enantioenriched quaternary carbon Michael adducts using simple organocatalysts

A three component catalyst system entailing an amino acid (O(t)Bu-L-threonine), a hydrogen bond donor (sulfamide), and an amine base (DMAP) allows α-branched aldehyde addition to nitroalkenes in good to high yield and excellent ee. Importantly, the lowest reported catalyst loading (5.0 mol%) and aldehyde stoichiometry (1.2-2.0 equiv) is demonstrated and in most instances the best current product profile is observed.     

Dynamic kinetic resolution of racemic beta-haloalcohols: direct access to enantioenriched epoxides

The direct chemo-enzymatic DKR of racemic beta-haloalcohols is reported, yielding the corresponding optically active epoxides in a single step. The mutant haloalcohol dehalogenase HheC Cys153Ser Trp249Phe is used for the asymmetric ring closure, whereas racemization of the remaining enantiomer of the haloalcohol is achieved using the new iridacycle 3, one of the most effective racemization catalysts to date for beta-haloalcohols.     

Tertiary aromatic amide for memory of chirality: access to enantioenriched alpha-substituted valine

A new methodology for the asymmetric synthesis of quaternary alpha-substituted amino acids using memory of chirality has been developed. This strategy employs dynamic axial chirality of tertiary aromatic amides to memorize the initial chirality of an alpha-amino acid during the enolization step. Starting from L-valine, an oxazolidin-5-one containing a tertiary aromatic amide was synthesized in one step and then alkylated with various electrophiles with good yield and enantioselectivity (up to 96%). Quaternary products can be obtained enantiomerically pure by recrystallization. One-step deprotection affords enantioenriched (S)-alpha-methyl valine (ee = 94%) or enantiopure (S)-alpha-isopropyl aspartic acid (ee >99%) in only three steps starting from L-valine.     

Zinc mediated straightforward access to diacylpyrroles

In this article, we report the preparation of various 2,4- and 2,5-diacylpyrroles via two zinc-mediated acylation reactions of non-protected pyrroles.     

Catalytic asymmetric cleavage of sp3 C-N bonds for access to highly enantioenriched N-benzylic sulfonamides

In the presence of 10 mol% of a chiral phosphoric acid, a variety of racemic N-benzylic sulfonamides having N-(3-indolyl)methyl groups smoothly undergo kinetic resolution with benzyl thiol at 0 °C or at room temperature and the remaining sulfonamides are recovered in moderate to excellent yields and with excellent ee.     

Chiral phosphoric acid-catalyzed enantioselective three-component Povarov reaction using cyclic enethioureas as dienophiles: stereocontrolled access to enantioenriched hexahydropyrroloquinolines

Three become one: Phosphoric acid-catalyzed enantioselective three-component Povarov reactions of aldehydes, anilines, and endocyclic enethioureas have been developed (see scheme). This process afforded hexahydropyrroloquinolines in high yields with excellent diastereo- and enantioselectivities. The presence of the thiourea functionality is crucial for the enantioselectivity of the reaction.     

Synthesis of enantioenriched triarylmethanes by stereospecific cross-coupling reactions

Coupling with inversion: Chiral diarylmethanol derivatives undergo a stereospecific nickel-catalyzed cross-coupling reaction with aryl Grignard reagents (see scheme). The reaction proceeds with inversion of configuration and high enantiospecificity. The method has been applied to the asymmetric synthesis of a triarylmethane-based anti-cancer compound.     

Energy-independent intracellular gene delivery mediated by polymeric biomimetics of cell-penetrating peptides

Efficient gene transfer into mammalian cells mediated by small molecular amphiphile-polymer conjugates, bile acid-polyethylenimine (BA-PEI), is demonstrated, opening an efficient transport route for genetic materials across the cell membrane. This process occurs without the aid of endocytosis or other energy-consuming processes, thus mimicking macromolecular transduction by cell-penetrating peptides. The exposure of a hydrophilic face of the amphiphilic BA moiety on the surface of BA-PEI/DNA complex that mediates direct contact of the BA molecules to the cell surface seems to play an important role in the endocytosis- and energy-independent internalization process. The new modality of the polymeric biomimetics can be applied to enhanced delivery of macromolecular therapeutics.     

Synthetic approach to natural products by Claisen rearrangement of glyceraldehyde derivatives

For the purpose of organic syntheses of some corynanthe-type indole alkaloids, sesquiterpenes, and steroids, optically active intermediates cyclopentanone 3-allylalcohol, α-methylene-γ-butylo lactones andtrans-hydrindanone-propionic acid, were synthesized from (R)- and (S)-isopropylideneglyceraldehyde derived fromD-mannitol andLascorbic acid, respectively, utilizing Claisen rearrangement as a key reaction. Actually total syntheses of natural alkaloids, (-)-antirhine, (+)-dihydroantirhine and (-) dihydrocorynantheol were accomplished.     

A simple and easy access to 3-N-alkyl-5-vinyloxazolidinones mediated by palladium-phosphine catalysts

A new entry for the synthesis of 3-alkyl substituted 5-vinyloxazolidin-2-one derivatives 2 from cis-2-butenylene-1,4-dicarbonate 1 and primary amines mediated by palladium-phosphine catalysts is described. The scope and limitation, a plausible mechanism, and an asymmetric version of the reaction are also discussed.     

Direct Prebiotic Pathway to DNA Nucleosides

It is assumed that RNA played a key role in the origin of life, and the transition to more complex but more stable DNA for continuous information storage and replication requires the development of a ribonucleotide reductase to obtain the deoxyribonucleotides from ribonucleotides. This step, as well as an alternative path from abiotic molecules to DNA‐based life is completely unknown. Shown here is the formation of deoxyribonucleosides under relevant prebiotic conditions in water in high regio‐ and stereoselectivity, from all canonical purine and pyrimidine bases, by condensation with acetaldehyde and sugar‐forming precursors. Thus, a continuous path to deoxyribonucleosides, starting from simple, prebiotically available molecules has been discovered. Furthermore, the deoxyapionucleosides (DApiNA) were identified as a potential DNA progenitor. The results suggest that the DNA world evolved much earlier than previously assumed.     

Tandem Staudinger-azaWittig mediated ring expansion: rapid access to new isofagomine-tetrahydroxyazepane hybrids

New seven-membered iminosugars with potent and selective inhibition towards glycosidases have been prepared as 1-N-iminosugar homologues via a tandem Staudinger-azaWittig mediated ring expansion.     

Promotion of Henry reactions using Cu(OTf)2 and a sterically hindered Schiff base: access to enantioenriched β-hydroxynitroalkanes

The steric and electronic properties of chiral Schiff base ligands derived from cinchona alkaloids were evaluated in asymmetric Henry reactions. Amongst these, the sterically hindered ligand 2 showed outstanding catalytic efficiency in the Cu(II) catalyzed asymmetric addition of nitroalkanes to a variety of aldehydes to afford the desired adducts in high yields (up to 97%) with excellent enantioselectivities (up to 99% ee) and moderate to good diastereoselectivities (up to 84:16 dr).     

A biocatalytic route to enantioenriched, sulfanyl aldol products

The aldol products derived from sulfur- or selenium containing acceptors were prepared by kinetic resolution in the presence of antibody 84G3 with enantiomeric excesses ranging from 56 to 70%. Much higher level of enantioselectivity was obtained (enantiomeric excesses all superior to 96%) for sulfanyl aldol products derived from thiomethoxyacetone with three different acceptors.