Recent Developments in the Synthesis of Chiral Compounds with Quaternary Centers by Organocatalytic Cascade Reactions

Quaternary carbon stereocenters are present in a wide variety of organic compounds and drug molecules. Highly enantioselective construction of such quaternary carbon stereocenters has received considerable attention owing to the great challenges in their syntheses. With the development of asymmetric organocatalytic cascade reactions, several efficient methods for the construction of optically pure compounds with quaternary carbon centers have been developed. This focused review highlights the asymmetric synthesis of chiral compounds with quaternary centers through organocatalytic cascade reactions.Cascades of quaternary centers: Quaternary carbon stereocenters are present in a wide variety of organic compounds and drug molecules. Construction of such stereocenters is challenging. This focused review highlights the synthesis methods of chiral compounds with quaternary centers by organocatalytic cascade reactions.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/137475/1/ajoc201500486.pd

Efficient splicing correction by PNA conjugation to an R6-Penetratin delivery peptide

Sequence-specific interference with the nuclear pre-mRNA splicing machinery has received increased attention as an analytical tool and for development of therapeutics. It requires sequence-specific and high affinity binding of RNaseH-incompetent DNA mimics to pre-mRNA. Peptide nucleic acids (PNA) or phosphoramidate morpholino oligonucleotides (PMO) are particularly suited as steric block oligonucleotides in this respect. However, splicing correction by PNA or PMO conjugated to cell penetrating peptides (CPP), such as Tat or Penetratin, has required high concentrations (5–10 μM) of such conjugates, unless an endosomolytic agent was added to increase escape from endocytic vesicles. We have focused on the modification of existing CPPs to search for peptides able to deliver more efficiently splice correcting PNA or PMO to the nucleus in the absence of endosomolytic agents. We describe here R6-Penetratin (in which arginine-residues were added to the N-terminus of Penetratin) as the most active of all CPPs tested so far in a splicing correction assay in which masking of a cryptic splice site allows expression of a luciferase reporter gene. Efficient and sequence-specific correction occurs at 1 μM concentration of the R6Pen–PNA705 conjugate as monitored by luciferase luminescence and by RT-PCR. Some aspects of the R6Pen–PNA705 structure–function relationship have also been evaluated

A versatile method for the preparation of conjugates of peptides with DNA/PNA/analog by employing chemo-selective click reaction in water

The specific 1,3 dipolar Hüisgen cycloaddition reaction known as ‘click-reaction’ between azide and alkyne groups is employed for the synthesis of peptide–oligonucleotide conjugates. The peptide nucleic acids (PNA)/DNA and peptides may be appended either by azide or alkyne groups. The cycloaddition reaction between the azide and alkyne appended substrates allows the synthesis of the desired conjugates in high purity and yields irrespective of the sequence and functional groups on either of the two substrates. The versatile approach could also be employed to generate the conjugates of peptides with thioacetamido nucleic acid (TANA) analog. The click reaction is catalyzed by Cu (I) in either water or in organic medium. In water, ∼3-fold excess of the peptide-alkyne/azide drives the reaction to completion in 2 h with no side products

Regioselective Electrophilic Fluorination of Rationally Designed Imidazole Derivatives

We report the regioselective and direct functionalization of rationally designed imidazole derivatives through electrophilic fluorination with <i>N</i>-fluorobenzenesulfonimide enabled via in situ deprotonation with lithium 2,2,6,6-tetramethylpiperidine. Aided by a controlled protecting group switch, we were able to effectively target both the reactive 5- as well as the difficult to target 4-position of these molecules, leading to a series of fluorinated polysubstituted imidazoles in gram scale

Asymmetric Construction of Spirocyclopentenebenzofuranone Core Structures via Highly Selective Phosphine-Catalyzed [3 + 2] Cycloaddition Reactions

An efficient organocatalytic asymmetric [3 + 2] cycloaddition reaction between 3-substituted methylenebenzofuranone derivatives and diverse Morita–Baylis–Hillman carbonates to provide complex polysubstituted spirocyclopentenebenzofuranone scaffolds in a single step is reported. C2-symmetric phospholanes were efficient nucleophilic catalysts of this transformation under mild conditions, providing reaction products comprised of three consecutive stereocenters, including one all-carbon center, with excellent enantioselectivity