Синтез, антиоксидантна та антибактеріальна активність флуороалкілзаміщених тіазолідинонів та тіазинанонів, що містять амінофосфонатний або амінокарбоксилатний фрагмент

2-R-2-RF-4-оxo-thiazolidines, thiazinanes, and bezothiazinanes incorporating a fragment of aminophosphonic or aminocarboxylic acid and a fluoroalkyl group at C-2 atom of the heterocycle have been prepared by cyclocondensation of the corresponding iminophosphonates or iminocarboxylates, RFCH(R)=NH [R = (EtO)2P(O), COOMe, RF = CF3, CHF2], with mercaptoacetic, 3-mercaptopropionic or thiosalicylic acid. The primary screening of the compounds on the antioxidant and antibacterial activity has been carried out. The antioxidant activity has been determined by the method based on auto-oxidation of adrenaline; the antibacterial activity has been investigated by the method of double serial dilution with the use of Hottinger broth. The compounds investigated show only an insignificant antioxidant effect and the low activity towards the strains of such bacteria as E. coli, Ps. aeroginosa, B. subtilis and St. aureus. Compounds bearing diethoxyphosphonyl or methoxycarbonyl group at C-2 atom of a five- or six-member heterocycle show the similar activity in general. For 2-fluoroalkyl substituted 4-thiazolidinon- or 4-bezothiazinanones a considerable growth of the culture biomass has been revealed, and it can find application for growth stimulation of producers of biologically active compounds. Compounds incorporating the thiazinanones or bezothiazinanones fragment reveal the prooxidant effect, and it can become a basis for manifestation of the antineoplastic or antimicrobic activity.Циклоконденсацией фторалкилзамещенных иминофосфонатов и иминокарбоксилатов, RFCH(R)=NH [R = (EtO)2P(O), COOMe, RF = CF3, CHF2], с тиогликолевой, 3-меркаптопропионовой или тиосалициловой кислотой синтезированы 2-R-2-RF-4-оксо-тиазолидины, тиазинаны и бензотиазинаны, содержащие фрагмент аминофосфоновой или аминокарбоновой кислоты и фторалкильную группу возле С-2 атома гетероцикла. Проведен первичный скрининг соединений на антиоксидантную и антибактериальную активность. Антиоксидантную активность определяли методом, базирующимся на аутоокислении адреналина, а антибактериальную – методом двукратных серийных разбавлений с использованием бульона Хоттингера. Изученные соединения проявляют только незначительный антиоксидантный эффект и являются малоактивными в отношении исследованных штаммов бактерий E. coli, Ps. aeroginosa, B. subtilis и St. aureus. Соединения с диэтоксифосфонильной или метоксикарбонильной группой возле С-2 атома пяти- или шестичленного гетероцикла в общем проявляют близкую активность. Для 2-фторалкилзамещенных 4-тиазолидинон- или 4-бензотиазинанон фосфонатов выявлен значительный прирост биомассы культур в сравнении с контролем, что может найти применение для стимулирования роста продуцентов биологически активных соединений. Соединения с фрагментом тиазинанона или бензотиазинанона проявляют прооксидантный эффект, что может стать основой для проявления противоопухолевой и противомикробной активности.Циклоконденсацією флуороалкілзаміщених імінофосфонатів та імінокарбоксилатів, RFCH(R)=NH [R = (EtO)2P(O), COOMe, RF = CF3, CHF2], з тіогліколевою, 3-меркаптопропіоновою або тіосаліциловою кислотою синтезовано 2-R-2-RF-4-оксо-тіазолідини, тіазинани та бензотіазинани, що містять фрагмент амінофосфонової або амінокарбонової кислоти та флуороалкільну групу біля С-2 атома гетероциклу. Проведено первинний скринінг сполук на антиоксидантну та антибактеріальну активність. Антиоксидантну активність визначали методом, що базується на аутоокисненні адреналіну, а антибактеріальну – методом двократних серійних розведень з використанням бульйону Хоттингера. Вивчені сполуки проявляють тільки незначний антиоксидантний ефект та є малоактивними по відношенню до досліджених штамів бактерій E. coli, Ps. aeroginosa, B. subtilis та St. aureus. Сполуки з діетоксифосфонільною або метоксикарбонільною групою біля С-2 атома п’яти- або шестичленного гетероциклу загалом проявляють подібну активність. Для 2-флуороалкілзаміщених 4-тіазолідинон- або 4-бензотіазинанон фосфонатів виявлено значний приріст біомаси культур порівняно з контролем, що може знайти застосування для стимулювання росту продуцентів біологічно активних сполук. Сполуки з фрагментом тіазинанону або бензотіазинанону проявляють прооксидантний ефект, що може стати основою для прояву протипухлинної та антимікробної активності

The Stereodivergent Formation of 2,6-cis and 2,6-trans-Tetrahydropyrans: Experimental and Computational Investigation of the Mechanism of a Thioester Oxy-Michael Cyclization

The origins of the stereodivergence in the thioester oxy-Michael cyclization for the formation of 4-hydroxy-2,6-cis- or 2,6-trans-substituted tetrahydropyran rings under different conditions was investigated both computationally and experimentally. Synthetic studies showed that the 4-hydroxyl group was essential for stereodivergence. When the 4-hydroxyl group was present, TBAF-mediated conditions gave the 2,6-trans-tetrahydropyran and trifluoroacetic acid-mediated conditions gave the 2,6-cis-tetrahydropyran. This stereodivergence vanished when the hydroxyl group was removed or protected. Computational studies revealed that: (i) the trifluoroacetic acid catalysed formation of 2,6-cis-tetrahydropyrans was mediated by a trifluoroacetate-hydroxonium bridge and proceeded via a chair-like transition state; (ii) the TBAF-mediated formation of 2,6-trans-tetrahydropyrans proceeded via a boat-like transition state, where the 4-hydroxyl group formed a crucial hydrogen bond to the cyclizing alkoxide; (iii) both reactions are under kinetic control. The utility of this stereodivergent approach for the formation of 4-hydroxy-2,6-substituted tetrahydropyran rings has been demonstrated by the total syntheses of the anti-osteoporotic natural products diospongin A and

Studies of Catalyst-Controlled Regioselective Acetalization and Its Application to Single-Pot Synthesis of Differentially Protected Saccharides.

This article describes the studies on regioselective acetal protection of monosaccharide-based diols using chiral phos-phoric acids (CPAs) and their immobilized polymeric variants, (R)-Ad-TRIP-PS and (S)-SPINOL-PS as the catalysts. These catalyst-controlled regioselective acetalizations were found to proceed with high regioselectivities (up to >25:1 rr) on various D-glucose, D-galactose, D-mannose and L-fucose derived 1,2-diols, and could be carried in a re-giodivergent fashion depending on the choice of the chiral catalyst. The polymeric catalysts were conveniently recy-cled and reused multiple times for gram scale functionalizations with catalytic loading as low as 0.1 mol%, and their performance was often found to be superior to the performance of their monomeric variants. These regioselective CPA-catalyzed acetalizations were successfully combined with common hydroxyl group functionalizations as single-pot telescoped procedures to produce 34 regioisomerically pure differentially protected mono- and disaccharide de-rivatives. To further demonstrate the utility of the polymeric catalysts, the same batch of (R)-Ad-TRIP-PS catalyst was recycled and reused to accomplish single-pot gram-scale syntheses of 6 differentially protected D-glucose derivatives. The subsequent exploration of the reaction mechanism using NMR studies of deuterated and nondeuterated sub-strates revealed that low-temperature acetalizations happen via syn-addition mechanism, and that the reaction regi-oselectivity exhibits strong dependence on the temperature. The computational studies indicate complex tempera-ture-dependent interplay of two reaction mechanisms, one involving an anomeric phosphate intermediate and an-other via concerted asynchronous formation of acetal that results in syn-addition products. The computational models also explain the steric factors responsible for the observed C2-selectivities and are consistent with experimentally observed selectivity trends

Concise Enantioselective Synthesis of Oxygenated Steroids via Sequential Copper(II)-Catalyzed Michael Addition/Intramolecular Aldol Cyclization Reactions

A new scalable enantioselective approach to functionalized oxygenated steroids is described. This strategy is based on chiral bis­(oxazoline) copper­(II) complex-catalyzed enantioselective and diastereoselective Michael reactions of cyclic ketoesters and enones to install vicinal quaternary and tertiary stereocenters. In addition, the utility of copper­(II) salts as highly active catalysts for the Michael reactions of traditionally unreactive β,β′-enones and substituted β,β′-ketoesters that results in unprecedented Michael adducts containing vicinal all-carbon quaternary centers is also demonstrated. The Michael adducts subsequently undergo base-promoted diastereoselective aldol cascade reactions resulting in the natural or unnatural steroid skeletons. The experimental and computational studies suggest that the torsional strain effects arising from the presence of the Δ⁵-unsaturation are key controlling elements for the formation of the natural cardenolide scaffold. The described method enables expedient generation of polycyclic molecules including modified steroidal scaffolds as well as challenging-to-synthesize Hajos–Parrish and Wieland–Miescher ketones

Studies of the Mechanism and Origins of Enantioselectivity for the Chiral Phosphoric Acid-Catalyzed Stereoselective Spiroketalization Reactions

Mechanistic and computational studies were conducted to elucidate the mechanism and the origins of enantiocontrol for asymmetric chiral phosphoric acid-catalyzed spiroketalization reactions. These studies were designed to differentiate between the S_N1-like, S_N2-like, and covalent phosphate intermediate-based mechanisms. The chiral phosphoric acid-catalyzed spiroketalization of deuterium-labeled cyclic enol ethers revealed a highly diastereoselective syn-selective protonation/nucleophile addition, thus ruling out long-lived oxocarbenium intermediates. Hammett analysis of the reaction kinetics revealed positive charge accumulation in the transition state (ρ = −2.9). A new computational reaction exploration method along with dynamics simulations supported an asynchronous concerted mechanism with a relatively short-lived polar transition state (average lifetime = 519 ± 240 fs), which is consistent with the observed inverse secondary kinetic isotope effect of 0.85. On the basis of these studies, a transition state model explaining the observed stereochemical outcome has been proposed. This model predicts the enantioselective formation of the observed enantiomer of the product with 92% ee, which matches the experimentally observed value