Asymmetric Synthesis of α,α-Disubstituted Amino Acids by Cycloaddition of (<i>E</i>)-Ketonitrones with Vinyl Ethers

Zhang, Xiaofei; Cividino, Pascale; Poisson, Jean‐François; Shpak‐Kraievskyi, Pavlo; Laurent, Mathieu Y.; Martel, Arnaud; Dujardin, Gilles; Py, Sandrine

doi:10.1021/ol500483t

Cited by 29 publications

(18 citation statements)

References 63 publications

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“…3a). DMAD facilitates in situ generation of nitrone 36,37 10 and provides reactive functionalities to build new ring systems in SD phase, as well as to elaborate scaffolds later in SE phase. Figure 3 depicts building of SD phase in a de novo branching cascades approach from primary substrates (indicated by blue arrows), as well as from 11 (indicated by red arrows).…”

Section: Resultsmentioning

confidence: 99%

De novo branching cascades for structural and functional diversity in small molecules

et al. 2015

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The limited structural diversity that a compound library represents severely restrains the discovery of bioactive small molecules for medicinal chemistry and chemical biology research, and thus calls for developing new divergent synthetic approaches to structurally diverse and complex scaffolds. Here we present a de novo branching cascades approach wherein simple primary substrates follow different cascade reactions to create various distinct molecular frameworks in a scaffold diversity phase. Later, the scaffold elaboration phase introduces further complexity to the scaffolds by creating a number of chiral centres and incorporating new hetero-or carbocyclic rings. Thus, employing N-phenyl hydroxylamine, dimethyl acetylenedicarboxylate and allene ester as primary substrates, a compound collection of sixty one molecules representing seventeen different scaffolds is built up that delivers a potent tubulin inhibitor, as well as inhibitors of the Hedgehog signalling pathway. This work highlights the immense potential of cascade reactions to deliver compound libraries enriched in structural and functional diversity.

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Section: Resultsmentioning

confidence: 99%

De novo branching cascades for structural and functional diversity in small molecules

et al. 2015

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“…The latter revealed to be a key intermediate to access pseudodipeptides containing an acyclic α,α-disubstituted amino acid, through ester 4 (Pg = COCF 3 ). 15 During this work, we found an interesting chemodivergence of the SmI 2 -promoted reductive opening of N-acylated derivatives of isoxazolidine 2, yielding selectively either ester 4 (Pg = COCF 3 ) or aldehyde 3 (Pg = COCH 3 ). We eventually realized that enantiopure isoxazolidine 2 could be exploited to access α,α-disubstituted amino acids of opposite absolute configuration through selective manipulation of the three different carbonyl groups in compounds 3 or 4.…”

Section: Introductionmentioning

confidence: 83%

δ-Valerolactamic Quaternary Amino Acid Derivatives: Enantiodivergent Synthesis and Evidence for Stereodifferentiated β-Turn-Inducing Properties

et al. 2021

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Enantiopure (R) and (S) cyclic α,α-disubstituted amino acid derivatives displaying a δ-valerolactam side chain were prepared from a common isoxazolidine precursor. The (R)configured δ-valerolactam 11 was converted into diastereoisomeric pseudopeptides to investigate its ability to induce secondary structures in peptidomimetics. Conformational studies of these pseudopeptides were carried out in the solid state (X-ray diffraction), in solution (NMR analyses) and in silico (computer-aided conformational analysis), which demonstrated that such quaternary amino acid induce β-turn conformations stable enough to be retained in polar media (DMSO).Incorporation of this new type of α,α-disubstituted amino acid into a representative pseudopeptidic sequence by N-then C-elongation, and N-debenzylation are also described herein and could serve for the synthesis of various structured peptidomimetics.

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“…Chemicals and solvents were purchased from commercial suppliers and used as received unless stated otherwise [Sigma Aldrich: potassium carbonate (99%), anisole (99%); LiAlH 4 (1 M in diethyl ether), trifluoroacetic acid (99%), Boc-L-phenylalanine methyl ester (98%), L-phenylalanine methyl ester hydrochloride (98%), Amberlyst A21 (4.6 eq./kg dry weight); BLDpharm: Boc-4-iodo-D-phenylalanine (98%); Fluorochem: O,N-dimethylhydroxylamine hydrochloride (98%), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (99%), ethyl(hydroxyimino)cyanoacetate (98%), (carbethoxyethylidene)triphenylphosphorane (94%), succinic anhydride (99%); Carl Roth: triethylamine (99.5%), hydrochloric acid (37%); Oxchem: phenylboronic acid (95%); ACROS organics: diisopropylethylamine (98%); ChemLab: acetonitrile (HPLC grade)]. According to a reported literature procedure [69], L-phenylalanine methyl ester hydrochloride was neutralized by addition of sodium carbonate in water and extraction of the aqueous phase with ethyl acetate yielded free L-phenylalanine methyl ester. Analytical thin layer chromatography was performed on pre-coated aluminium plates (Merck, silica gel 60, F 254 ) and spots were visualized with UV light (254 nm) or potassium permanganate stain.…”

Section: General Informationmentioning

confidence: 99%

Development of a multistep reaction cascade for the synthesis of a sacubitril precursor in continuous flow

et al. 2019

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The active pharmaceutical ingredient sacubitril acts as a neprilysin inhibitor in the body and is administered to patients suffering from high blood pressure and chronic heart failure. In this paper, we report the development of a three-step setup for the synthesis of an advanced sacubitril precursor in continuous flow. The key transformation of our cascade is a Suzuki-Miyaura coupling facilitated by a heterogeneous palladium catalyst. Its implementation in a packed-bed reactor and the application of continuous flow methodologies allow intensification of the cross-coupling reaction compared to batch processing. The subsequent steps for the synthesis of the target molecule involve Boc-deprotection as well as N-succinylation, which have been optimized using the statistical "Design of Experiments" (DoE) approach. In this way, the individual as well as interactive effects of selected parameters on the output of the reactions could be investigated very efficiently. The consecutive performance of the three reaction steps using an integrated setup enabled the synthesis of a late-stage sacubitril precursor in continuous flow with 81% overall yield. Keywords Continuous flow chemistry. Heterogeneous catalysis. Multistep reaction cascade. Palladium. Sacubitril Highlights • Development of a multistep setup for the integrated synthesis of a latestage sacubitril precursor in continuous flow. • Intensification of Suzuki coupling in continuous flow employing a heterogeneous palladium catalyst implemented in a packed-bed reactor. • Optimization of Boc-deprotection as well as N-amidation using the "Design of Experiments" approach.

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Asymmetric Synthesis of α,α-Disubstituted Amino Acids by Cycloaddition of (E)-Ketonitrones with Vinyl Ethers

Cited by 29 publications

References 63 publications

De novo branching cascades for structural and functional diversity in small molecules

De novo branching cascades for structural and functional diversity in small molecules

δ-Valerolactamic Quaternary Amino Acid Derivatives: Enantiodivergent Synthesis and Evidence for Stereodifferentiated β-Turn-Inducing Properties

Development of a multistep reaction cascade for the synthesis of a sacubitril precursor in continuous flow

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