Understand the Specific Regio- and Enantioselectivity of Fluostatin Conjugation in the Post-Biosynthesis

Abstract

Fluostatins, benzofluorene-containing aromatic polyketides in the atypical angucycline family, conjugate into dimeric and even trimeric compounds in the post-biosynthesis. The formation of the C–C bond involves a non-enzymatic stereospecific coupling reaction. In this work, the unusual regio- and enantioselectivities were rationalized by density functional theory calculations with the M06-2X (SMD, water)/6–311 + G(d,p)//6–31G(d) method. These DFT calculations reproduce the lowest energy C1-(R)-C10′-(S) coupling pathway observed in a nonenzymatic reaction. Bonding of the reactive carbon atoms (C1 and C10′) of the two reactant molecules maximizes the HOMO–LUMO interactions and Fukui function involving the highest occupied molecular orbital (HOMO) of nucleophile p-QM and lowest unoccupied molecular orbital (LUMO) of electrophile FST2− anion. In particular, the significant π–π stacking interactions of the low-energy pre-reaction state are retained in the lowest energy pathway for C–C coupling. The distortion/interaction–activation strain analysis indicates that the transition state (TScp-I) of the lowest energy pathway involves the highest stabilizing interactions and small distortion among all possible C–C coupling reactions. One of the two chiral centers generated in this step is lost upon aromatization of the phenol ring in the final difluostatin products. Thus, the π–π stacking interactions between the fluostatin 6-5-6 aromatic ring system play a critical role in the stereoselectivity of the nonenzymatic fluostatin conjugation.

Design of High-Barrier and Environmentally Degradable FDCA-Based Copolyesters: Experimental and Theoretical Investigation

“…To understand the degradation mechanisms of PNDF, we built a hydrolytic model of PNDF under neutral conditions based on the low-energy conformers. Density functional theory (DFT) calculations and subsequent Fukui function (FF) analysis were performed to illustrate the reactivity and regio-selectivity of PNDF during hydrolysis. , In the current study, the Fukui indices f + showed the tendency of carbonyl carbon atoms to be attacked by electrophiles. The f + values represent the reducibility of carbonyl carbon atoms according to their nucleophilic attack ability.…”

Domination of H-Bond Interactions in the Solvent-Triggering Gelation Process

“…48−51 The H-bond binding energy (E HB ) was obtained by subtracting the dimer energy from the monomer energy (eq 6) and could be split into electrostatic action (E elst ), dispersion action (E dis ), induction (E ind ), and exchange mutual exclusion (E exch ). 48,49,52 The solvation free energy (dissolution energy) was calculated by using the SPE in the solvent model to subtract that calculated in the vacuum phase (standard state, 298 K, 1 atm) (eq 7). The Multifunctional Wavefunction Analyser (Multiwfn 3.8) 53 explored by Beijing Keyin combined with Visual Molecular Dynamics (VMD1.9.4)…”

Flavin-enabled reductive and oxidative epoxide ring opening reactions

“…The benzofluorene core of the kinamycins and lomaiviticins is further decorated with a diazo group endowing these compounds with potent antitumor activities that has attracted considerable attention 29 , 30 . The atypical angucyclines are often characterized by a highly oxygenated A-ring that can undergo further modifications such as acylation, epoxidation, glycosylation, and dimerization leading to significant structural diversity 18 , 21 , 27 , 31 , 32 . The α/β hydroxylases Alp1U and Lom6 were recently reported to catalyze stereoselective epoxide hydrolysis reactions during the biosynthesis of kinamycins and lomaiviticin 23 .…”