ABSTRACT
Fluorine substitution can have a profound impact on molecular conformation. Here, we present a detailed conformational analysis of how the 1,3-difluoropropylene motif (-CHF-CH2-CHF-) determines the conformational profiles of 1,3-difluoropropane, anti- and syn-2,4-difluoropentane, and anti- and syn-3,5-difluoroheptane. It is shown that the 1,3-difluoropropylene motif strongly influences alkane chain conformation, with a significant dependence on the polarity of the medium. The conformational effect of 1,3-fluorination is magnified upon chain extension, which contrasts with vicinal difluorination. Experimental evidence was obtained from NMR analysis, where polynomial complexity scaling simulation algorithms were necessary to enable J-coupling extraction from the strong second-order spectra, particularly for the large 16-spin systems of the difluorinated heptanes. These results improve our understanding of the conformational control toolkit for aliphatic chains, yield simple rules for conformation population analysis, and demonstrate quantum mechanical time-domain NMR simulations for liquid state systems with large numbers of strongly coupled spins.
ABSTRACT
Herein, we report a convenient synthesis of unprecedented aza-diketopiperazines (aza-DKPs). The strategy is based on selective diversification of bicyclic aza-DKP scaffolds by click reaction, N-acylation, and/or N-alkylation. These scaffolds containing either azido or amino groups were obtained by a key Rh(I)-catalyzed hydroformylative cyclohydrocarbonylation reaction of allyl-substituted aza-DKP. The methodology is readily amenable to the parallel synthesis of original aza-DKPs to enlarge the chemical diversity of aza-heterocycles.
ABSTRACT
A rapid and atom economical multicomponent synthesis of complex aza-diketopiperazines (aza-DKPs) driven by Rh(i)-catalyzed hydroformylation of alkenylsemicarbazides is described. Combined with catalytic amounts of acid and the presence of nucleophilic species, this unprecedented multicomponent reaction (MCR) enabled the formation of six bonds and a controlled stereocenter from simple substrates. The efficacy of the strategy was demonstrated with a series of various allyl-substituted semicarbazides and nucleophiles leading to the preparation of 3D-shaped bicyclic aza-DKPs. Moreover, an analysis of their 3D molecular descriptors and "drug-likeness" properties highlights not only their originality in the chemical space of aza-heterocycles but also their great potential for medicinal chemistry.
Subject(s)
Aza Compounds/chemical synthesis , Diketopiperazines/chemical synthesis , Aza Compounds/chemistry , Catalysis , Combinatorial Chemistry Techniques/methods , Diketopiperazines/chemistry , Rhodium/chemistry , Semicarbazides/chemical synthesis , Semicarbazides/chemistry , StereoisomerismABSTRACT
Fluorination is commonly exercised in compound property optimization. However, the influence of fluorination on hydrogen-bond (HB) properties of adjacent functional groups, as well as the HB-accepting capacity of fluorine itself, is still not completely understood. Although the formation of OHâ â â F intramolecular HBs (IMHBs) has been established for conformationally restricted fluorohydrins, such interaction in flexible compounds remained questionable. Herein is demonstrated for the first time-and in contrast to earlier reports-the occurrence of OHâ â â F IMHBs in acyclic saturated γ-fluorohydrins, even for the parent 3-fluoropropan-1-ol. The relative stereochemistry is shown to have a crucial influence on the corresponding (h1) JOHâ â â F values, as illustrated by syn- and anti-4-fluoropentan-2-ol (6.6 and 1.9â Hz). The magnitude of OHâ â â F IMHBs and their strong dependence on the overall molecular conformational profile, fluorination motif, and alkyl substitution level, is rationalized by quantum chemical calculations. For a given alkyl chain, the "rule of shielding" applies to OHâ â â F IMHB energies. Surprisingly, the predicted OHâ â â F IMHB energies are only moderately weaker than these of the corresponding OHâ â â OMe. These results provide new insights of the impact of fluorination of aliphatic alcohols, with attractive perspectives for rational drug design.
ABSTRACT
The N-tosylcarboxamide group can direct the room-temperature palladium-catalyzed C-H alkoxylation and halogenation of substituted arenes in a simple and mild procedure. The room-temperature stoichiometric cyclopalladation of N-tosylbenzamide was first studied, and the ability of the palladacycle to react with oxidants to form C-X and C-O bonds under mild conditions was demonstrated. The reaction conditions were then adapted to promote room-temperature ortho-alkoxylations and ortho-halogenations of N-tosylbenzamides using palladium as catalyst. The scope and limitation of both alkoxylations and halogenations was studied and the subsequent functional transformation of the N-tosylcarboxamide group through nucleophilic additions was evaluated. This methodology offers a simple and mild route to diversely functionalized arenes.
Subject(s)
Palladium/chemistry , Catalysis , Halogenation , Molecular Structure , StereoisomerismABSTRACT
Very high diastereoselectivity can be achieved by 1,3-chelation-controlled allylation of aldehydes that possess a non-chelating α-ether substituent, even if the α-position is a quaternary centre and/or a spiro-epoxide. This reaction was used as a key step in an enantioselective synthesis of the angiogenesis inhibitor luminacinâ D.
Subject(s)
Aldehydes/chemistry , Benzaldehydes/chemistry , Chelating Agents/chemistry , Epoxy Compounds/chemistry , Ether/chemistry , Spiro Compounds/chemistry , Catalysis , StereoisomerismABSTRACT
The N-tosylcarboxamide group offers the possibility of directing the Pd-catalyzed C-H arylation of arenes providing a new entry to biarylcarboxamides. Moreover, its ability to react according to different reaction conditions including intramolecular reactions makes it a pivotal directing group for a divergent synthesis of biaryl-based compounds.