Guiding Transient Peptide Assemblies with Structural Elements Embedded in Abiotic Phosphate Fuels.

Despite great progress in the construction of non-equilibrium systems, most approaches do not consider the structure of the fuel as a critical element to control the processes. Herein, we show that the amino acid side chains (A, F, Nal) in the structure of abiotic phosphates can direct assembly and reactivity during transient structure formation. The fuels bind covalently to substrates and subsequently influence the structures in the assembly process. We focus on the ways in which the phosphate esters guide structure formation and how structures and reactivity cross regulate when constructing assemblies. Through the chemical functionalization of energy-rich aminoacyl phosphate esters, we are able to control the yield of esters and thioesters upon adding dipeptides containing tyrosine or cysteine residues. The structural elements around the phosphate esters guide the lifetime of the structures formed and their supramolecular assemblies. These properties can be further influenced by the peptide sequence of substrates, incorporating anionic, aliphatic and aromatic residues. Furthermore, we illustrate that oligomerization of esters can be initiated from a single aminoacyl phosphate ester incorporating a tyrosine residue (Y). These findings suggest that activated amino acids with varying reactivity and energy contents can pave the way for designing and fabricating structured fuels.

Spontaneous and Selective Peptide Elongation in Water Driven by Aminoacyl Phosphate Esters and Phase Changes.

Nature chose phosphates to activate amino acids, where reactive intermediates and complex machinery drive the construction of polyamides. Outside of biology, the pathways and mechanisms that allow spontaneous and selective peptide elongation in aqueous abiotic systems remain unclear. Herein we work to uncover those pathways by following the systems chemistry of aminoacyl phosphate esters, synthetic counterparts of aminoacyl adenylates. The phosphate esters act as solubility tags, making hydrophobic amino acids and their oligomers soluble in water and enabling selective elongation and different pathways to emerge. Thus, oligomers up to dodecamers were synthesized in one flask and on the minute time scale, where consecutive additions activated autonomous phase changes. Depending on the pathway, the resulting phases initially carry nonpolar peptides and amphiphilic oligomers containing phosphate esters. During elongation and phosphate release, shorter oligomers dominate in solution, while the aggregated phase favors the presence of longer oligomers due to their self-assembly propensity. Furthermore we demonstrated that the solution phases can be isolated and act as a new environment for continuous elongation, by adding various phosphate esters. These findings suggest that the systems chemistry of aminoacyl phosphate esters can activate a selection mechanism for peptide bond formation by merging aqueous synthesis and self-assembly.

Annulation of Enals with Carbamoylpropiolates via NHC-Catalyzed Enolate Pathway: Access to Functionalized Maleimides/Iso-maleimides and Synthesis of Aspergillus FH-X-213.

Herein we report the N-heterocyclic carbene (NHC)-catalyzed [3 + 2] annulation of α,ß-unsaturated aldehydes with carbamoylpropiolates via an unusual enolate pathway leading to the construction of highly functionalized maleimides or isomaleimides. The electronic effect imposed by the alkyl/aryl group present on the amide nitrogen of carbamoylpropiolates plays a crucial role in the selective formation of these important five-membered heterocyclic building blocks. The developed protocol is mild and tolerates a wide range of substituents on both substrates. The application of this protocol in the synthesis of the antibacterial natural product Aspergillus FH-X-213 has also been demonstrated.

Construction of unique SCF3-containing building blocks via allylic alkylation of Morita-Baylis-Hillman adducts.

Lewis base-catalyzed allylic alkylation of Morita-Baylis-Hillman adducts with α-SCF3 ketones has been demonstrated. The developed strategy provides efficient access to a series of highly functionalized scaffolds featuring trifluoromethanesufinyl motif on a stereogenic carbon.

Stereoselective construction of deoxy-cruciferane alkaloids by NHC-catalyzed intramolecular annulation of homoenolate with quinazolinone.

Chiral N-heterocyclic carbene (NHC)-catalyzed intramolecular [3 + 2] annulation of enals with an unactivated imine moiety of quinazolinone via formal homoenolate cycloaddition has been demonstrated. It is an excellent approach for stereoselective syntheses of deoxy-cruciferane alkaloids comprising a biologically important pyrroloindoline scaffold. Notably, this is the first report on the NHC-catalyzed asymmetric intramolecular homoenolate annulation with cyclic N-acyl amidine.