Project description:The recent promising applications of deuterium-labeled pharmaceutical compounds have led to an urgent need for the efficient synthetic methodologies that site-specifically incorporate a deuterium atom into bioactive molecules. Nevertheless, precisely building a deuterium-containing stereogenic center, which meets the requirement for optimizing the absorption, distribution, metabolism, excretion and toxicity (ADMET) properties of chiral drug candidates, remains a significant challenge in organic synthesis. Herein, a catalytic asymmetric strategy combining H/D exchange (H/D-Ex) and azomethine ylide-involved 1,3-dipolar cycloaddition (1,3-DC) was developed for the construction of biologically important enantioenriched α-deuterated pyrrolidine derivatives in good yields with excellent stereoselectivities and uniformly high levels of deuterium incorporation. Directly converting glycine-derived aldimine esters into the deuterated counterparts with D2O via Cu(i)-catalyzed H/D-Ex, and the subsequent thermodynamically/kinetically favored cleavage of the α-C-H bond rather than the α-C-D bond to generate the key N-metallated α-deuterated azomethine ylide species for the ensuing 1,3-DC are crucial to the success of α-deuterated chiral pyrrolidine synthesis. The current protocol exhibits remarkable features, such as readily available substrates, inexpensive and safe deuterium source, mild reaction conditions, and easy manipulation. Notably, the synthetic utility of a reversed 1,3-DC/[H/D-Ex] protocol has been demonstrated by catalytic asymmetric synthesis of deuterium-labelled MDM2 antagonist idasanutlin (RG7388) with high deuterium incorporation.
Project description:A mild, versatile organophotoredox protocol has been developed for the preparation of diverse, enantioenriched α-deuterated α-amino acids. Distinct from the well-established two-electron transformations, this radical-based strategy offers the unrivaled capacity of the convergent unification of readily accessible feedstock carboxylic acids and a chiral methyleneoxazolidinone fragment and the simultaneous highly diastereo-, chemo-, and regioselective incorporation of deuterium. Furthermore, the approach has addressed the long-standing challenge of the installation of sterically demanding side chains into α-amino acids.
Project description:O-(1-Carboxy-1-alkyloxycarbonyl) hydroxamates were found to spontaneously decarboxylate in aqueous neutral buffer to form O-(2-hydroxyalkylcarbonyl) hydroxamates. While the former molecules do not react rapidly with serine β-lactamases, the latter are quite good substrates of representative class A and C, but not D, enzymes, and particularly of a class C enzyme. The enzymes catalyze hydrolysis of these compounds to a mixture of the α-hydroxy acid and hydroxamate. Analogous compounds containing aryloxy leaving groups rather that hydroxamates are also substrates. Structure-activity experiments showed that the α-hydroxyl group was required for any substantial substrate activity. Although both d- and l-α-hydroxy acid derivatives were substrates, the former were preferred. The response of the class C activity to pH and to alternative nucleophiles (methanol and d-phenylalanine) suggested that the same active site functional groups participated in catalysis as for classical substrates. Molecular modeling was employed to explore how the α-hydroxy group might interact with the class C β-lactamase active site. Incorporation of the α-hydroxyalkyl moiety into novel inhibitors will be of considerable interest.
Project description:A precursor-directed approach to access N-hydroxyalkyl phenylbenzoisoquinolindiones (PBIQs) has been developed. Incubation of plant material of Xiphidium caeruleum with hydroxylamines of various chain lengths (C2 , C4 , C6 , C8 , C10 and C12 ) resulted in 11 new 5-hydroxy- and 5-methoxy PBIQs with different N-hydroxyalkyl side chain lengths. The antiproliferative effect and the cytotoxicity against HUVEC, K-562, and HeLa cell lines of 26 previously reported PBIQs and the 11 newly synthesized N-hydroxyalkyl PBIQs was determined for the first time. The results revealed that introducing long-chain N-aliphatic amine moieties improved the antiproliferative effect and cytotoxicity of PBIQs when compared to derivatives with N-amino acids as side chains.
Project description:α-Hydroxyalkyl-hydroperoxides (α-HHs), from the addition of water to Criegee intermediates in the ozonolysis of olefins, are reactive components of organic aerosols. Assessing the fate of α-HHs in such media requires information on the rates and products of their reactions in aqueous organic matrixes. This information, however, is unavailable due to the lack of analytical techniques for the detection and identification of labile α-HHs. Here, we report the mass spectrometric detection (as Cl- adducts) of the α-HH produced in the ozonolysis of a C15 diolefin in water (W):acetonitrile (AN) mixtures of variable composition containing inert NaCl. α-HH decays into a gem-diol + H2O2 within τ1/e ≈ 52 min in 50% (v:v) water, but persists longer than a day in ≤10% water mixtures. The strong nonlinear dependence of τ1/e on solvent composition reveals that water content is a major factor controlling the fate of α-HHs in atmospheric particles. It also suggests that α-HH decomposes while embedded in WnANm clusters rather than randomly dissolved in molecularly homogeneous W:AN mixtures.
Project description:Disclosed here is a catalytic asymmetric azidation reaction for the efficient synthesis of α-azido ketones bearing a labile tertiary stereocenter. With a superb chiral squaramide catalyst, a mild asymmetric formal H-N3 insertion of α-carbonyl sulfoxonium ylides proceeded with excellent efficiency and enantioselectivity. This organocatalytic process not only complements the previous α-azidation approaches for the formation of quaternary stereocenters and mostly for 1,3-dicarbonyl compounds, but also has advantages over the well-known metal-catalyzed asymmetric carbene insertion chemistry using α-diazocarbonyl compounds. Detailed mechanistic studies via control reactions and NMR studies provided important insights into the reaction pathway, which features reversible protonation and dynamic kinetic resolution. The curiosity in mechanism also led to the development of a simplified alternative protocol with a cheaper HN3 source.
Project description:Protected 4-hydroxycyclopentenones (4-HCPs) constitute an important class of intermediates in chemical synthesis. A route to this class of compound has been developed. Key steps include Noyori reduction (which establishes the stereochemistry of the product), ring-closing metathesis, and simple functional group conversions to provide a set of substituted 4-HCPs in either enantiomeric form.
Project description:A straightforward approach toward enantioenriched α-substituted α,β-unsaturated δ-lactams is described. Although a considerable number of approches toward α,β-unsaturated δ-lactams have been reported, there are relatively few examples of enantioenriched α,δ-disubstituted α,β-unsaturated δ-lactams formation. The δ-stereocenter was formed by addition of allylmagnesium bromide to an N-tert-butylsulfinyl imine. The α,β-unsaturated δ-lactam was furnished by ring-closing metathesis. Although Baylis-Hillman chemistry failed on this cyclic compound, introduction of the hydroxyethyl group prior to ring-closing metathesis was successful. A Baylis-Hillman reaction was used to introduce the substituent at the α-position of the α,β-unsaturated lactam.
Project description:The enantioselective addition of anilines to azoalkenes was accomplished through the use of a chiral phosphoric acid catalyst. The resulting α-arylamino hydrazones were obtained in good yields and excellent enantioselectivities and provide access to enantioenriched α-arylamino ketones. A serendipitous kinetic resolution of racemic α-arylamino hydrazones is also described.
Project description:Radical cyclizations (Bu(3)SnH, Et(3)B/air, rt) of racemic alpha-halo-ortho-alkenyl anilides provide 3,4-dihydroquinolin-2-ones in high yield. Cyclizations of enantioenriched precursors occur in similarly high yields and with transfer of axial chirality to the new stereocenter of the products with exceptionally high fidelity (often >95%). Single and tandem cyclizations of alpha-halo-ortho-alkenyl anilides bearing an additional substituent on the alpha-carbon occur with high chirality transfer and high diastereoselectivity. Straightforward models are proposed to interpret both the chirality transfer and diastereoselectivity aspects. These first examples of an approach for axial chiral transfer from a reactive species in the amide to an acceptor suggest broad potential for extension both within and beyond radical reactions.