Toward the synthesis of cobyric acid. Enantioselective syntheses of completely differentiated ring D synthons.
ABSTRACT: Alkyne acids 11 were prepared in an enantioselective fashion from allylic ester derivatives 18 or 20 by Ireland-Claisen rearrangement, followed by Si-assisted elimination of HBr. The title compounds are attractive ring D synthons for an ongoing synthesis of cobyric acid.
Project description:Allylic cyclopropenecarboxylates undergo ring expansion reactions to give 2-allyloxyfuran intermediates, which subsequently rearrange to ?(?,?) butenolides via a Claisen rearrangement or to the corresponding ?(?,?) butenolides via further Cope rearrangement. Also described are methods for chirality transfer in the rearrangement of nonracemic allylic esters.
Project description:A concise synthesis of homocitric acid lactone was developed to accommodate systematic placement of carbon isotopes (specifically (13)C) for detailed studies of this cofactor. This new route uses a chiral allylic alcohol, available in multigram quantities from enzymatic resolution, as a starting material, which transposes asymmetry through an Ireland-Claisen rearrangement.
Project description:For the first time, the concept of supramolecular synthons was applied to giant rigid superspheres based on pentaphosphaferrocene [Cp<sup>R</sup>Fe(?<sup>5</sup>-P<sub>5</sub>)] (R = Me, Et) and Cu(I) halides, which reach 2.1-3.0 nm in diameter. Two supramolecular synthons, ?-? and ?-?, are discovered based on halogen···Cp<sup>R</sup> and Cp*···Cp* specific interactions, respectively. The geometry of the synthons is reproducible in a series of crystal structures of various supramolecules. The ?-? synthon alone is realized more frequently for Br-containing superspheres. A combination of the ?-? and ?-? synthons is more typical for Cl-containing supramolecules. Each supramolecule can bear up to nine synthons to give mostly 2D and 3D architectures.
Project description:Radiotracers labelled with short-lived fluorine-18 (t(1/2) = 109.7 min) are keenly sought for biomedical imaging with positron emission tomography (PET). The radiotracers are mostly required at high specific radioactivities, necessitating their radiosyntheses from cyclotron-produced no-carrier-added [(18)F]fluoride ion. PET radiotracers encompass wide structural diversity and molecular weight. Hence, diverse (18)F-labeling methodology is needed to accomplish the required radiosyntheses in a simple and rapid manner. A useful strategy is to introduce nucleophilic [(18)F]fluoride ion first into a labeling synthon that may then be applied to label the target radiotracer. Here, we show that various functionalized [(18)F]fluoroarenes may be rapidly synthesized as labeling synthons through single-step reactions of appropriate diaryliodonium salts with [(18)F]fluoride ion. Decay-corrected radiochemical yields (RCYs) varied with position of functional group, choice of electron-rich aryl ring in the diaryliodonium salt, and choice of anion. Under best conditions, (18)F-labeled fluorobenzaldehydes, fluorobenzyl halides, fluorobenzoic acid esters and fluorophenyl ketones were obtained selectively in 40-73%, 20-55%, 46-89% and 81-98% RCYs, respectively. This versatile straightforward methodology will enhance the scope for producing structurally complex, yet useful, PET radiotracers.
Project description:The regioselective synthesis of 3,5-disubstituted isoxazoles was achieved through the 1,3-dipolar cycloaddition of nitrile oxides with 1,1-disubstituted bromoalkenes. The substituted bromoalkenes function as alkyne synthons which were used to construct 5,5-disubstituted bromoisoxazoline intermediates that aromatize to the analogous isoxazoles through the loss of HBr.
Project description:The successful application of dihydropyrido[1,2-a]indolone (DHPI) substrates in Pd-catalyzed asymmetric allylic alkylation chemistry facilitates rapid access to multiple alkaloid frameworks in an enantioselective fashion. Strategic bromination at the indole C3 position greatly improved the allylic alkylation chemistry and enabled a highly efficient Negishi cross-coupling downstream. The first catalytic enantioselective total synthesis of (-)-goniomitine, along with divergent formal syntheses of (+)-aspidospermidine and (-)-quebrachamine, are reported herein.
Project description:Enantioselective Pd-catalyzed allylic alkylations of dihydropyrido[1,2-a]indolone (DHPI) substrates were used to construct the C20-quaternary stereocenters of multiple monoterpene indole alkaloids. Stereodivergent Pictet-Spengler and Bischler-Napieralski cyclization/reduction cascades furnish the cis- and trans-fused azadecalin subunits present in Aspidosperma and Kopsia alkaloids, respectively, en?route to highly efficient syntheses of (+)-limaspermidine and (+)-kopsihainanine?A.
Project description:Bridged bicyclic tertiary allylic amines aza-norbornene 1 and isoquinuclidene 2 add to isocyanates, isothiocyanates, and in situ-generated carbodiimides to form zwitterionic intermediates that undergo 1,3-diaza-Claisen rearrangements to afford highly substituted ureas, thioureas, and guanidines, respectively. Aza-norbornene 1 is significantly more reactive toward 1,3-diaza-Claisen rearrangements than isoquinuclidene 2. This reactivity difference is most likely due to the inherent ring strain in the aza-bicyclo[2.2.1]heptene ring system of aza-norbornene 1. The most apparent reactivity trend of the heterocumulenes is that the most electron-deficient heterocumulenes are more reactive toward 1,3-diaza-Claisen rearrangements. The introduction of a new stereocenter ?- to the nucleophilic nitrogen in aza-norbornene 1 and isoquinuclidine 2 decreases the reactivity toward 1,3-diaza-Claisen rearrangements, while the exodiastereomers 3b and 4b are less reactive than the corresponding endodiastereomers 3a and 4a. Isocyanates that bear an electron-withdrawing group react with allylic amines 1-3b to afford mixtures of ureas and isoureas; however, with excess isocyanate and heat, thermodynamic equilibration is possible affording ureas. Inspired by this observation, a one-pot reaction of isocyanates with amines 1, 2, and 3b followed by BF3·OEt2-catalyzed isomerization of the urea/isourea mixture was developed that affords the corresponding ureas in excellent yields.
Project description:The design of novel supramolecular synthons for functional groups relevant to drugs is an essential prerequisite for applying crystal engineering in the development of novel pharmaceutical cocrystals. It has been convincingly shown over the past decade that molecular level control and modulation can influence the physicochemical properties of drug cocrystals. Whereas considerable advances have been reported on the design of cocrystals for carboxylic acids and carboxamide functional groups, the sulfonamide group, which is a cornerstone of sulfa drugs, is relatively unexplored for reproducible heterosynthon-directed crystal engineering. The occurrence of synthons and isostructurality in sulfonamide-lactam cocrystals (SO2NH2?CONH hydrogen bonding) is analyzed to define a strategy for amide-type GRAS (generally recognized as safe) coformers with sulfonamides. Three types of supramolecular synthons are identified for the N-H donor of sulfonamide hydrogen bonding to the C=O acceptor of amide. Synthon 1: catemer synthon C 2 (1)(4) chain motif, synthon 2: dimer-cyclic ring synthon R 2 (2)(8)R 4 (2)(8) motifs, and synthon 3: dimer-catemer synthon of R 2 (2)(8)C 1 (1)(4)D notation. These heterosynthons of the cocrystals observed in this study are compared with the N-H?O dimer R 2 (2)(8) ring and C(4) chain motifs of the individual sulfonamide structures. The X-ray crystal structures of sulfonamide-lactam cocrystals exhibit interesting isostructurality trends with the same synthon being present. One-dimensional, two-dimensional and three-dimensional isostructurality in crystal structures is associated with isosynthons and due to their recurrence, novel heterosynthons for sulfonamide cocrystals are added to the crystal engineer's toolkit. With the predominance of sulfa drugs in medicine, these new synthons provide rational strategies for the design of binary and potentially ternary cocrystals of sulfonamides.
Project description:Organozinc, -magnesium, and -lithium nucleophiles initiate a Brook/Ireland-Claisen rearrangement sequence of allylic silyl glyoxylates resulting in the formation of gamma,delta-unsaturated alpha-silyloxy acids.