Solid-Phase Synthesis of Amino- and Carboxyl-Functionalized Unnatural α-Amino Acid Amides

Scott, William L.; Zhou, Ziniu; Martynow, Jacek; O’Donnell, Martin J.

doi:10.1021/ol901279v

Cited by 16 publications

(11 citation statements)

References 12 publications

(15 reference statements)

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“…43 In collaboration with colleague Bill Scott, the solution-phase synthesis of unnatural amino acids (Schemes 1, 2, 3, 5-9, 11, 12) and dipeptides (Scheme 13) was adapted (see Scheme 22 for bases used in solid-phase chemistry) and extended to permit the solid-phase synthesis of a large number of amino acids derivatives, peptidomimetics and unnatural peptides. [45][46][47][48][49] Access to these structures is essential to the success of the Distributed Drug Discovery (D3) program, which seeks to educate global students while they do research synthesizing molecules for the M A N U S C R I P T…”

Section: Selective Alkylation Of Dipeptides By Ptcmentioning

confidence: 99%

Benzophenone Schiff bases of glycine derivatives: Versatile starting materials for the synthesis of amino acids and their derivatives

O’Donnell

2019

Tetrahedron

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This review focuses on the introduction and early development, in solution, of phase-transfer catalyzed (PTC) reactions to afford racemic or enantioenriched natural and unnatural amino acids. To form monosubstituted amino acids alkylation reactions are performed on the benzophenone Schiff base of glycine. For α,α-disubstituted amino acids the activated intermediate is an aldimine derivative of the monosubstituted amino acid. Enantioenriched products are produced by organocatalysis using derivatives of Cinchona alkaloids as the phasetransfer catalyst. Selectivity for monoalkylatation and lack of product racemization depend on the acidities of the glycine imines, and dialkylated products are formed from aldimine esters of monoalkyl amino acids. The racemic and catalytic enantioselective reactions of a cationic glycine equivalent with organoboranes, organometallics and malonate anion are discussed as are other reactions of these versatile Schiff bases derivatives. Keywords Amino Acid Synthesis Unnatural Amino Acids Phase-Transfer Catalysis (PTC) Asymmetric Synthesis Benzophenone Schiff Bases Imines of Amino Acid Derivatives Organocatalysis Racemic and Stereoselective Reactions Glycine and Other Amino Acid Anion Equivalents Glycine Cation Equivalents Contents 10 9. Synthesis of α-methyl histidine by two complementary routes 11 10. PTC mono-or dialkylation with potassium carbonate 12 11. Intra-and intermolecular PTC dialkylations of a glycine equivalent 12 12. Acidities (pKa) of imine derivatives of glycine: Insights into alkylations 13 ___________________________________________________________________ This is the author's manuscript of the article published in final edited form as: O'Donnell, M. J. (2019). Benzophenone Schiff bases of glycine derivatives: Versatile starting materials for the synthesis of amino acids and their derivatives. Tetrahedron.

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Section: Selective Alkylation Of Dipeptides By Ptcmentioning

confidence: 99%

Benzophenone Schiff bases of glycine derivatives: Versatile starting materials for the synthesis of amino acids and their derivatives

O’Donnell

2019

Tetrahedron

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“…Products for this 11-step synthesis were obtained in moderate overall yields ( Table 1 ). Structure 2d , which incorporates a stable, protected phosphotyrosine analog [ 6 ], gives a particular example of the interesting types of molecules available by this route.…”

Section: Resultsmentioning

confidence: 99%

“…4-(4-Formyl-3,5-dimethoxyphenoxy)butyric acid (BAL linker), Fmoc-Gly-OH ( N -Fmoc-glycine), and HBTU (2-(1 H -benzotriazole-1-yl)-1,1,3,3-tetramethylaminium hexafluorophosphate) were purchased from NovaBiochem. Diethyl [(4-α-bromomethyl)phenyldifluoromethyl]phosphonate [ 6 ] and O - tert -butyldiphenylsilyl-3-aminopropanol hydrochloride [ 13 ] were prepared according to literature procedures. Solution and solid-phase organic transformations and resin washes were carried out at ambient temperature, unless indicated otherwise.…”

Section: Methodsmentioning

confidence: 99%

“…The Distributed Drug Discovery (D3) project seeks to simultaneously educate and innovate while searching for drug leads for neglected diseases [ 1 , 2 , 3 , 4 , 5 , 6 ]. Central to this effort is the availability of simple, inexpensive and reproducible synthetic procedures providing access to large numbers of biomimetic molecules.…”

Section: Introductionmentioning

confidence: 99%

“…Compounds 1 can be readily synthesized on solid-phase using BAL type resins and naturally occurring amino acids [ 9 , 10 ]. For more extensive sets of derivatives, unnatural amino acid side chains R 1 can be introduced during the course of the solid-phase synthesis utilizing the recently described chemistry outlined in Scheme 1 [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

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Solid-Phase Synthetic Route to Multiple Derivatives of a Fundamental Peptide Unit

et al. 2010

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Amino acids are Nature’s combinatorial building blocks. When substituted on both the amino and carboxyl sides they become the basic scaffold present in all peptides and proteins. We report a solid-phase synthetic route to large combinatorial variations of this fundamental scaffold, extending the variety of substituted biomimetic molecules available to successfully implement the Distributed Drug Discovery (D3) project. In a single solid-phase sequence, compatible with basic amine substituents, three-point variation is performed at the amino acid α-carbon and the amino and carboxyl functionalities.

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Recent Advances in Synthesis of Difluoromethylene Phosphonates for Biological Applications

et al. 2021

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For almost 40 years, difluoromethylene phosphonates have proven to be versatile molecular tools in biochemical studies owing to their close resemblance to naturally occurring phosphates and phosphonates. As bioisosteric, non‐hydrolyzable analogs of these essential molecules, difluoromethylene phosphonates can target the critical parts of the cellular machinery and therefore exhibit a diverse spectrum of biological activity. In the past ten years, there have appeared many new methods for the synthesis of difluoromethylene phosphonates. Most notably, photoredox catalysis has firmly entered the field, while cross‐coupling and nucleophilic strategies have met considerable elaboration and refinement, entirely in accord with the current trends in synthetic organic chemistry. Herein, we introduce difluoromethylene phosphonates as a distinct, high‐tech subclass of synthetic phosphonates resulting from the research efforts on the cross‐section of organophosphorus, organofluorine, and bioorganic chemistry. We then proceed to the discussion of general methods for the preparation of difluoromethylene phosphonates, comprehensively reviewing reactions developed in the past 15 years while providing the context of earlier works where appropriate. Finally, we present selected examples of molecules with high biological activity, their biological targets, and the synthetic steps employed for their preparation.

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Solid-Phase Synthesis of Amino- and Carboxyl-Functionalized Unnatural α-Amino Acid Amides

Cited by 16 publications

References 12 publications

Benzophenone Schiff bases of glycine derivatives: Versatile starting materials for the synthesis of amino acids and their derivatives

Benzophenone Schiff bases of glycine derivatives: Versatile starting materials for the synthesis of amino acids and their derivatives

Solid-Phase Synthetic Route to Multiple Derivatives of a Fundamental Peptide Unit

Recent Advances in Synthesis of Difluoromethylene Phosphonates for Biological Applications

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