Intramolecular substitutions of secondary and tertiary alcohols with chirality transfer by an iron(III) catalyst.
ABSTRACT: Optically pure alcohols are abundant in nature and attractive as feedstock for organic synthesis but challenging for further transformation using atom efficient and sustainable methodologies, particularly when there is a desire to conserve the chirality. Usually, substitution of the OH group of stereogenic alcohols with conservation of chirality requires derivatization as part of a complex, stoichiometric procedure. We herein demonstrate that a simple, inexpensive, and environmentally benign iron(III) catalyst promotes the direct intramolecular substitution of enantiomerically enriched secondary and tertiary alcohols with O-, N-, and S-centered nucleophiles to generate valuable 5-membered, 6-membered and aryl-fused 6-membered heterocyclic compounds with chirality transfer and water as the only byproduct. The power of the methodology is demonstrated in the total synthesis of (+)-lentiginosine from D-glucose where iron-catalysis is used in a key step. Adoption of this methodology will contribute towards the transition to sustainable and bio-based processes in the pharmaceutical and agrochemical industries.
Project description:Trisubstituted allenes with a 3-(1'-alkenylidene)-pyrrolidin-2-one motif were successfully deracemized (13 examples, 86-98?% ee) employing visible light (?=420?nm) and a chiral triplet sensitizer as the catalyst (2.5?mol?%). The photocatalyst likely operates by selective recognition of one allene enantiomer via hydrogen bonds and by a triplet-sensitized racemization process. Even a tetrasubstituted allene (45?% ee) and a seven-membered 3-(1'-alkenylidene)-azepan-2-one (62?% ee) could be enantiomerically enriched under the chosen conditions. It was shown that the axial chirality of the allenes can be converted into point chirality by a Diels-Alder (94-97?% ee) or a bromination reaction (91?% ee). Ring opening of the five-membered pyrrolidin-2-one was achieved without significantly compromising the integrity of the chirality axis (92?% ee).
Project description:A strategy of dynamic covalent chemistry within constrained biaryls was developed for the modulation of axial chirality. The ring fusion partners of amide and aldehyde allowed the manipulation of ring/chain equilibrium and chirality transfer within cyclic diastereomeric hemiaminal. Dynamic covalent reactions (DCRs) with alcohols, thiols, and secondary amines further enabled the reversal of chirality relay and thereby regulation of axial chirality. Moreover, a combination of NMR, X-ray, and density functional theory results shed light on the structural basis of chirality transfer, exhibiting modest to excellent diastereoselectivity under thermodynamic control. The critical role of the amide unit in the modulation of axial chirality was also corroborated. Finally, the chiroptical signal was controlled through changing solvents, DCRs, and stimuli-responsive switching of DCRs.
Project description:Gold(I)-catalysed direct allylic etherifications have been successfully carried out with chirality transfer to yield enantioenriched, ?-substituted secondary allylic ethers. Our investigations include a full substrate-scope screen to ascertain substituent effects on the regioselectivity, stereoselectivity and efficiency of chirality transfer, as well as control experiments to elucidate the mechanistic subtleties of the chirality-transfer process. Crucially, addition of molecular sieves was found to be necessary to ensure efficient and general chirality transfer. Computational studies suggest that the efficiency of chirality transfer is linked to the aggregation of the alcohol nucleophile around the reactive ?-bound Au-allylic ether complex. With a single alcohol nucleophile, a high degree of chirality transfer is predicted. However, if three alcohols are present, alternative proton transfer chain mechanisms that erode the efficiency of chirality transfer become competitive.
Project description:The total synthesis of hyacinthacine A2 is reported via a novel transannular hydroamination in which planar chirality of a 5-aza-trans-cyclooctene precursor is transferred to point chirality in the product. Key to the success of this strategy was the development of a method for establishing absolute planar chirality via stereocontrolled photoisomerization of a 5-aza-cis-cyclooctene. This was accomplished by constructing a 5-aza-cis-cyclooctene precursor with a trans-fused acetonide. The improved diastereoselectivity observed upon photoisomerization of this derivative is attributed to the conformational strain of the eight-membered ring in the minor diastereomer.
Project description:Currently, more than 1,200 agrochemicals are listed and many of these are regularly used by farmers to generate the food supply to support the expanding global population. However, resistance to pesticides is an ever more frequently occurring phenomenon, and thus, a continuous supply of novel agrochemicals with high efficiency, selectivity, and low toxicity is required. Moreover, the demand for a more sustainable society, by reducing the risk chemicals pose to human health and by minimizing their environmental footprint, renders the development of novel agrochemicals an ever more challenging undertaking. In the last two decades, fluoro-chemicals have been associated with significant advances in the agrochemical development process. We herein analyze the contribution that organofluorine compounds make to the agrochemical industry. Our database covers 424 fluoro-agrochemicals and is subdivided into several categories including chemotypes, mode of action, heterocycles, and chirality. This in-depth analysis reveals the unique relationship between fluorine and agrochemicals.
Project description:A total synthesis of rhazinilam based on a transannular cyclization strategy is described. Using a Heck reaction, the axial chirality of a halogenated 13-membered lactam can be exploited to create the quaternary chiral stereogenic center in the target molecule with high enantiospecificity.
Project description:Reversible covalent bonding is often used for the creation of novel supramolecular structures, multi-component assemblies and sensing ensembles. Despite the remarkable success of dynamic covalent systems, the reversible binding of a mono-alcohol with high strength is challenging. Here, we show that a strategy of carbonyl activation and hemiaminal ether stabilization can be embodied in a four-component reversible assembly that creates a tetradentate ligand and incorporates secondary alcohols with exceptionally high affinity. Evidence is presented that the intermediate leading to binding and exchange of alcohols is an iminium ion. To demonstrate the use of this assembly process we also explored chirality sensing and enantiomeric excess determinations. An induced twist in the ligand by a chiral mono-ol results in large Cotton effects in the circular dichroism spectra indicative of the handedness of the alcohol. The strategy revealed in this study should prove broadly applicable for the incorporation of alcohols into supramolecular architecture construction.
Project description:A regioselective protocol for the synthesis of substituted allylic chlorides, bromides, and fluorides has been established. Remarkably, the method can be applied to the enantioselective synthesis of challenging chiral allylic chlorides. When the allylic halides are treated with the base triazabicyclodecene as the catalyst, a [1,3]-proton shift takes place, giving the corresponding vinyl halides in excellent yields with excellent Z:E ratios. Furthermore, the [1,3]-proton shift takes place with an outstanding level of chirality transfer from chiral allylic alcohols (?98%) to give chiral trifluoromethylated vinyl chlorides.
Project description:Core-resonant circular dichroism (CD) signals are induced by molecular chirality and vanish for achiral molecules and racemic mixtures. The highly localized nature of core excitations makes them ideal probes of local chirality within molecules. Simulations of the circular dichroism spectra of several molecular families illustrate how these signals vary with the electronic coupling to substitution groups, the distance between the X-ray chromophore and the chiral center, geometry, and chemical structure. Clear insight into the molecular structure is obtained through analysis of the X-ray CD spectra.