An enantioselective and modular platform for C4'-modified nucleoside analogue synthesis enabled by intramolecular trans-acetalizations.

C4'-modified nucleoside analogues continue to attract global attention for their use in antiviral drug development and oligonucleotide-based therapeutics. However, current approaches to C4'-modified nucleoside analogues still involve lengthy (9-16 steps), non-modular routes that are unamenable to library synthesis. Towards addressing the challenges associated with their syntheses, we report a modular 5-step process to a diverse collection of C4'-modified nucleoside analogues through a sequence of intramolecular trans-acetalizations of readily assembled polyhydroxylated frameworks.

Hydroalkynylative cyclization of 1,6-enynes with terminal alkynes.

A rhodium-catalyzed highly regio- and enantioselective hydroalkynylation, generating -hydrobenzofuranone-tethered enynes has been developed. The reaction proceeds with a selective head-to-head insertion and symmetry breaking Michael addition cascade. One product was produced from tens of possible isomers through precise control of chemo-, regio-, and stereoselectivities using a single rhodium catalyst.

Divergent synthesis of chiral cyclic azides via asymmetric cycloaddition reactions of vinyl azides.

Vinyl azides, bearing conjugated azide and alkene functional groups, have been recognized as versatile building blocks in organic synthesis. In general vinyl azides act as 3-atom (CCN) synthons through the fast release of molecular nitrogen and have been extensively utilized in the construction of structurally diverse N-heterocycles. Keeping the azide moiety intact in organic transformations to synthesis chiral azides is an important but challenging task.

Diastereoselective Synthesis of Polysubstituted Spirocyclopenta[ c]furans by Gold-Catalyzed Cascade Reaction.

With the synergistic activation of alkynyl alcohols and alkynyl enones by a single gold catalyst, diverse multisubstituted spirocyclopenta[ c]furans were synthesized in good to excellent yields under mild conditions. Three rings were constructed efficiently in one pot from easily available acyclic starting materials.

Copper-Catalyzed Oxidative Trifunctionalization of Olefins: An Access to Functionalized β-Keto Thiosulfones.

Aerobic oxidative trifunctionalization of olefins for the synthesis of functionalized β-keto thiosulfones has been described. The transformation proceeds through molecular oxygen activation under copper catalysis and forms the two new C-S bonds in a single operation using mild conditions. A novel Cu-catalyzed sulfonyl radical addition/oxidation/funtionalization relay mechanism was proposed for the discovered reaction.

Pd-Catalyzed Isocyanide Assisted Reductive Cyclization of 1-(2-Hydroxyphenyl)-propargyl Alcohols for 2-Alkyl/Benzyl Benzofurans and Their Useful Oxidative Derivatization.

An unusual Pd-catalyzed isocyanide assisted 5-exo-dig reductive cyclization of 1-(2-hydroxyphenyl)-propargyl alcohols is achieved for 2-alkyl/benzyl benzofurans. The reaction features a high substrate scope, insensitivity to air, and excellent product yielding. Further, a direct metal-free C-H functionalization (azidation, alkoxylation, and hydroxylation) and selective oxidative cleavage of thus synthesized 2-benzylfurans are described for azido-, alkoxy-, hydroxyl-, amide-, and tetrazolyl adducts.

Iodo Meyer-Schuster rearrangement of 3-alkoxy-2-yn-1-ols for β-mono (exclusively Z-selective)-/disubstituted α-iodo-α,β-unsaturated esters.

We herein present the iodo Meyer-Schuster rearrangement of 3-alkoxypropargyl alcohols for α-iodo-α,β-unsaturated esters using iodine or NIS in dichloromethane at ambient temperature. Substrates prepared from both aldehydes and ketones are found to be equally good feedstock for the reaction to produce β-mono- and -disubstituted products. Irrespective of the substitution, substrates prepared from aldehydes gave Z-isomers exclusively.

Palladium-catalyzed tandem intramolecular oxy/amino-palladation/isocyanide insertion: synthesis of α-benzofuranyl/indolylacetamides.

A novel palladium-catalyzed approach to 2-benzofuranyl/indolylacetamides from 1-(o-hydroxy/aminophenyl)propargylic alcohols and isocyanides is described. The reaction proceeds through a cascade that includes oxy/aminopalladation, isocyanide insertion, and 1,4-hydroxyl migration. No oxidant or ligand is needed to promote the cascade, and the reactions are carried out under mild conditions to afford the products through high functional tolerance.

Synthesis of substituted 3-iodocoumarins and 3-iodobutenolides via electrophilic iodocyclization of ethoxyalkyne diols.

A convenient and general synthesis of various 4-substituted 3-iodocoumarins and 4,5-disubstituted 3-iodobutenolides is described via an exclusive 6-endo-dig iodocyclization of 3-ethoxy-1-(2-alkoxyphenyl)-2-yn-1-ols and 5-endo-dig iodocyclization of 1-alkoxy-4-ethoxy-3-yn-1,2-diols, respectively. The reaction is carried out under very mild conditions using I2 in CH2Cl2 or toluene at room temperature. Oxygens in OMe and OMOM groups were used as efficient nucleophiles for this intramolecular cyclization to obtain the products in good to excellent yields.

Tandem aldehyde-alkyne-amine coupling/cycloisomerization: A new synthesis of coumarins.

Cu-catalyzed A(3) coupling of ethoxyacetylene, pyrrolidine and salicylaldehydes led to a concomitant cycloisomerization followed by hydrolysis of the resultant vinyl ether to afford coumarins in a cascade process. The reaction proceeded through exclusive 6-endo-dig cyclization and is compatible with halo and keto groups giving coumarins in good to moderate yields.

A new synthesis of γ-butyrolactones via AuCl(3)- or Hg(II)-catalyzed intramolecular hydroalkoxylation of 4-bromo-3-yn-1-ols.

An efficient conversion of 4-bromo-3-yn-1-ols to γ-butyrolactones via AuCl(3)-catalyzed electrophilic cyclization (hydroxyl-assisted regioselective hydration) in wet toluene is described. Various secondary and tertiary alcohols including benzylic systems were found to be equally reactive with moderate to excellent yields obtained in all cases.