6-Strand to Stable 10/12 Helix Conformational Switch by Incorporating Flexible ß-hGly in the Homooligomers of Camphor Derived ß-Amino Acid: NMR and X-Ray Crystallographic Evidence.

Rational design of unnatural amino acid building blocks capable of stabilizing predictable secondary structures similar to protein fragments is pivotal for foldamer chemistry/catalysis. Here, we introduce novel ß-amino acid building blocks: [1S,2R,4R]exoCDA and [1S,2S,4R]endoCDA, derived from the abundantly available R(+)-camphor, which is traditionally known for its medicinal value. Further, we demonstrate that the homooligomers of exoCDA adopt 6-strand conformation, which switches to a robust 10/12-helix simply by inserting flexible ß-hGly spacer at alternate positions (1 : 1 ß-hGly/exoCDA heterooligomers), as evident by DFT-calculations, solution-state NMR spectroscopy and X-ray crystallography. To the best of our knowledge, this is the first example of crystalline-state structure of left-handed 10/12-mixed helix, that is free from the conventional approach of employing ß-amino acids of either alternate chirality or alternate ß2/ß3 substitutions, to access the 10/12-helix. The results also show that the homooligomers of heterochiral exoCDA don't adopt helical fold, instead exhibit banana-shaped strands, whereas the homodimers of the other diastereomer endoCDA, nucleate 8-membered turns. Furthermore, the homo-exoCDA and hetero-[ß-hGly-exoCDA] oligomers are found to exhibit self-association properties with distinct morphological features. Overall, the results offer new possibilties of constructing discrete stable secondary and tertiary structures based on CDAs, which can accommodate flexible residues with desired side-chain substitutions.

Synthesis of cis-fused cyclopentenone-pyrrolidine scaffolds via sequential aza-Piancatelli and Conia-ene type reactions in one pot.

A novel one-pot protocol that enables sequential execution of an aza-Piancatelli rearrangement and a Conia-ene type reaction has been developed under Lewis acid catalysis. Here, a combination of B(C6F5)3 and Cu(OTf)2, triethylamine, and triphenylphosphine yielded a wide range of cis-fused cyclopentenone-pyrrolidine scaffolds in one pot with good yields and diastereoselectivity.

Metal-free functionalization of tyrosine residues in short peptides and study of the morphological alterations.

An efficient functionalization of tyrosine residues in phenolic regions is achieved under metal-free conditions. The strategy involves the conversion of a tyrosine residue to 4-amino phenylalanine or 4-amino-3-methoxy phenylalanine in short peptides through a controlled oxidative dearomatization. This transformation is achieved in one pot with good yields and excellent regioselectivity. Consequently, the self-assembly of the peptide compounds has been studied at the nanoscopic level before and after functionalization. The results suggest that the peptide derivatives comprising amide groups promote intermolecular H-bonding interactions and the difference in -OH and -NH2 functional groups is found to be responsible for the morphological changes. Morphological transitions from 1D nanowires to 2D nanosheets were observed during functional group modification.

Decarboxylative [3 + 2] cycloaddition of propargyl cyclic carbonates with C,O-bis(nucleophile)s to access dihydrofuro[3,2-c]coumarins and dihydronaphtho[1,2-b]furans with quaternary center.

The development of efficient and straightforward strategies for obtaining chiral complex molecules from readily available starting materials is of great value in drug discovery. The stereodivergent synthesis of heterocycles bearing quaternary centers remains a challenge due to inherent steric issues. Herein, we report an enantioselective copper-catalyzed decarboxylative [3 + 2] cycloaddition of propargyl cyclic carbonates/carbamates with 4-hydroxycoumarins to afford a wide range of dihydrofuro[3,2-c]coumarins in excellent yields and enantioselectivity. The strategy has been successfully applied to other C,O-bisnucleophiles, such as α-naphthols, to obtain dihydronaphtho[1,2-b]furans with good yields.

Rh-Catalyzed Twofold Conjugate Addition of 2-Arylimidazo[1,2-a]pyridines to p-Quinols To Access Bridged Scaffolds with Three Contiguous Stereocenters.

A Rh(III)-catalyzed annulation of 2-arylimidazo[1,2-a]pyridines with p-quinols has been realized, leading to bridged heterocycles with three contiguous stereocenters via a twofold conjugate addition. The cascade reaction is diastereoselective and proceeds through a sequential Rh-catalyzed ortho C(sp2)-H functionalization of the aryl group of imidazo[1,2-a]pyridine with p-quinol followed by an intramolecular conjugate addition to provide a series of diverse, novel bridged heterocycles.

Construction of Octahydro-4H-cyclopenta[b]pyridin-6-one Skeletons using Pot, Atom, and Step Economy (PASE) Synthesis.

Cascade aza-Piancatelli reaction and [3+3]/[4+2] cycloaddition reactions are carried out using the ideality principles of pot, atom, and step economy (PASE) synthesis. The reaction resulted in generation of octahydro-4H-cyclopenta[b]pyridin-6-one scaffolds. Moreover, octahydro-5,7a-epoxycyclopenta[cd]isoindol-4-one frameworks of gracilamine alkaloid and a novel decahydro-1H-dicyclopenta[cd,hi]isoindol-6-one were also realized in good yields with excellent regio- and diastereo-selectivities.

Design principles and functional basis of enantioselectivity of alanyl-tRNA synthetase and a chiral proofreader during protein biosynthesis.

Homochirality of the cellular proteome is attributed to the L-chiral bias of the translation apparatus. The chiral specificity of enzymes was elegantly explained using the 'four-location' model by Koshland two decades ago. In accordance with the model, it was envisaged and noted that some aminoacyl-tRNA synthetases (aaRS) that charge larger amino acids are porous to D-amino acids. However, a recent study showed that alanyl-tRNA synthetase (AlaRS) can mischarge D-alanine and that its editing domain, but not the universally present D-aminoacyl-tRNA deacylase (DTD), is responsible for correcting the chirality-based error. Here, using in vitro and in vivo data coupled with structural analysis, we show that AlaRS catalytic site is a strict D-chiral rejection system and therefore does not activate D-alanine. It obviates the need for AlaRS editing domain to be active against D-Ala-tRNAAla and we show that it is indeed the case as it only corrects L-serine and glycine mischarging. We further provide direct biochemical evidence showing activity of DTD on smaller D-aa-tRNAs that corroborates with the L-chiral rejection mode of action proposed earlier. Overall, while removing anomalies in the fundamental recognition mechanisms, the current study further substantiates how chiral fidelity is perpetuated during protein biosynthesis.

Total synthesis of antiviral drug, nirmatrelvir (PF-07321332).

The emergence and rapid spread of coronavirus disease 2019 (COVID-19), a potentially fatal disease, caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has swiftly led to public health crisis worldwide. Hence vaccines and antiviral therapeutics are an important part of the healthcare response to combat the ongoing threat by COVID-19. Here, we report an efficient synthesis of nirmatrelvir (PF-07321332), an orally active SARS-CoV-2 main protease inhibitor.

Quaternary carbon construction through Piancatelli rearrangement: easy access to spirocyclopentenones.

A new and efficient approach to a series of novel multifunctionalized spirocyclopentenone scaffolds through Piancatelli rearrangement was developed under metal-free conditions. This method has been successfully applied to O-, N- and C-nucleophiles with excellent yields.

Cation Triggered Domino Aza-Piancatelli Rearrangement/Friedel-Crafts Alkylation of Indole-Tethered Furfuyl Alcohols to Access Cycloocta[b]indole Core of Alkaloids.

A domino approach to bridged cycloocta[b]indolone through a cascade of aza-Piancatelli rearrangement/Friedel-Crafts alkylation is developed. This transformation has been realized by reaction of an indole-tethered 2-furylcarbinol and substituted aniline in the presence of a Lewis acid to initiate aza-Piancatelli rearrangement followed by an in situ intramolecular Friedel-Crafts alkylation to access bridged tetracyclic frameworks in one pot.

Mn-catalyzed radical initiated domino transformation of alkynylated cyclohexadienones with TMSN3 and O2 to bicyclic azido alcohols.

An efficient Mn-catalyzed cascade azide radical addition/cyclization/oxygen insertion reaction of alkyne-tethered cyclohexadienones with TMSN3 under mild conditions is reported. This domino reaction presents good diastereoselectivity generating bicyclic azido alcohol scaffolds which can be transformed into useful building blocks in organic synthesis for medicinal chemistry.

Metal Free Domino ß-Azidation/[3 + 2] Cycloaddition Reaction for the Synthesis of 1,2,3-Triazole-Fused Dihydrobenzoxazinones.

A metal free DBU catalyzed synthesis of 1,2,3-triazole-fused dihydrobenzoxazinone derivatives by tandem ß-azidation/[3 + 2] cycloaddition reaction has been developed under mild conditions. The methodological studies offer a broad scope and proceed well with a wide range of alkynylated cyclohexa 2,5-dienones, giving new cis-triazole-fused tricyclic scaffolds.