Asymmetric Synthesis of Pipecolic Acid and Derivatives

Cant, Alastair A.; Sutherland, Andrew

doi:10.1055/s-0031-1289767

Cited by 26 publications

(3 citation statements)

References 68 publications

(88 reference statements)

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“…Moreover, the biosynthetic approaches allow for the use of the low-cost l-Lysine as a starting material, thus increasing the value of the final drug. [3] Typically, l-PA synthesis has been performed using chemical methods that involve harsh conditions and hazardous reagents, mainly due to the difficulty of obtaining optically pure l-PA. [4][5][6] In the last fifty years, several multi-step syntheses including protection-deprotection steps and using organic solvents yielded ~45 % of Pipecolic Acid starting from l-Lysine. [7][8][9] In 2021, a highly selective method has been developed by starting with Oppolzer chiral sultam and yielding 81 % of Pipecolic Acid.…”

Section: Introductionmentioning

confidence: 99%

“…Typically, l ‐PA synthesis has been performed using chemical methods that involve harsh conditions and hazardous reagents, mainly due to the difficulty of obtaining optically pure l ‐PA [4–6] . In the last fifty years, several multi‐step syntheses including protection‐deprotection steps and using organic solvents yielded ∼45 % of Pipecolic Acid starting from l ‐Lysine [7–9] .…”

Section: Introductionmentioning

confidence: 99%

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Biocatalytic Synthesis of l‐Pipecolic Acid by a Lysine Cyclodeaminase: Batch and Flow Reactors

Stalder,

Benítez‐Mateos,

Paradisi

2024

ChemCatChem

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L‐Pipecolic Acid (L‐PA) is a valuable building block for the synthesis of pharmaceuticals such as anesthetics and immunosuppressants. Thus, more efficient and greener strategies are desired for its production. Herein, we have applied a previously engineered variant of the Lysine Cyclodeaminase from Streptomyces pristinaespiralis (e‐SpLCD) for the bioconversion of L‐Lysine into L‐PA. The reaction can be performed by the free e‐SpLCD reaching full conversion to 50 mM L‐PA. From a biotechnological perspective, the process scale‐up has been trialed in a SpinChem® reactor, albeit with lower conversion yields. To further enhance the biocatalyst stability, we present a detailed study of the e‐SpLCD immobilization on microparticles. This enabled the integration of the immobilized biocatalyst into a packed‐bed reactor for the continuous flow synthesis of L‐PA. The full conversion was achieved in 90 min, maintaining also high operational stability. Remarkably, the addition of exogenous cofactor was not needed for the flow reaction, although the long‐term operational stability was improved by the addition of NAD+.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Biocatalytic Synthesis of l‐Pipecolic Acid by a Lysine Cyclodeaminase: Batch and Flow Reactors

Stalder,

Benítez‐Mateos,

Paradisi

2024

ChemCatChem

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“… 12 Subsequently, these compounds were found to be excellent synthetic intermediates for a range of applications. Intramolecular conjugate addition reactions allowed the stereoselective synthesis of pipecolic acids, 13 , 14 while cycloaddition processes led to the preparation of fluorescent unnatural α-amino acids. 15 To further explore the synthetic utility of enone-derived α-amino acids and inspired by the work of the Roberts and Walsh groups, 10 , 11 we proposed that these could undergo stereoselective reduction to give the corresponding allylic alcohol ( Scheme 1 c).…”

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confidence: 99%

Stereoselective Synthesis of meso- and l,l-Diaminopimelic Acids from Enone-Derived α-Amino Acids

Songsri,

McErlain,

Sutherland

2024

J. Org. Chem.

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The stereoselective synthesis of meso-diaminopimelic acid (meso-DAP), the key cross-linking amino acid of the peptidoglycan cell wall layer in Gram-negative bacteria, and its biological precursor, l,l-DAP, is described. The key step involved stereoselective reduction of a common enone-derived amino acid by substrate- or reagent-based control. Overman rearrangement of the resulting allylic alcohols, concurrent alkene hydrogenation and trichloroacetamide reduction, and subsequent ruthenium-catalyzed arene oxidation completed the synthesis of each stereoisomer. The synthetic utility of this approach was demonstrated with the efficient preparation of an l,l-DAP-derived dipeptide.

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Catalytic Asymmetric Aza‐Diels‐Alder Reaction: Pivotal Milestones and Recent Applications to Synthesis of Nitrogen‐Containing Heterocycles

2021

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In this review, the pivotal achievements and recent advances in catalytic asymmetric aza‐DAR reported up to 2020 are retrospectively considered and their potency for enantioselective synthesis of useful chiral piperidine, quinoline, pyridazine, oxazine and oxadiazine derivatives and fused compounds of higher molecular complexity bearing these pharmacology‐relevant heterocyclic scaffolds is demonstrated. The reported data are systematized according both to key electron transfer modes (normal or invers electron demand reactions) and to main types of attainable heterocyclic products. Of significant attention are an analysis of activation strategies (complexation, enamine or enolate formation, H‐bonding, etc.) applicable to reactions with particular types of dienes and dienophiles and identification of plausible reaction pathways (either concerted or stepwise) over stereoselective cyclization processes. The review contains 310 references and 122 synthetic schemes.

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Asymmetric Synthesis of Pipecolic Acid and Derivatives

Cited by 26 publications

References 68 publications

Biocatalytic Synthesis of l‐Pipecolic Acid by a Lysine Cyclodeaminase: Batch and Flow Reactors

Biocatalytic Synthesis of l‐Pipecolic Acid by a Lysine Cyclodeaminase: Batch and Flow Reactors

Stereoselective Synthesis of meso- and l,l-Diaminopimelic Acids from Enone-Derived α-Amino Acids

Catalytic Asymmetric Aza‐Diels‐Alder Reaction: Pivotal Milestones and Recent Applications to Synthesis of Nitrogen‐Containing Heterocycles

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