Synthesis of Unnatural/Nonproteinogenic α‐Amino Acids

Ager, David J.

doi:10.1002/9783527631766.ch12

Cited by 20 publications

(16 citation statements)

References 162 publications

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“…This general boost in activity at lower temperature is valuable because it not only facilitates process development but also enables future exploration of substrates that might be unstable in water at elevated temperature. The mutations, however, did not engender general tolerance for 4-substitution since the enzyme showed negligible activity with 4-nitroindole (2). Surprisingly, activity with 5-nitroindole (3) decreased dramatically, even though Tm2F3 had originally been evolved for activity with this substrate.…”

Section: ■ Resultsmentioning

confidence: 98%

“…As a result, synthetic routes to ncAAs typically require multiple steps, most of which use organic solvents. 2,3 One of the most direct routes to ncAAs is to add a nucleophile to the β-position of a serine-derived lactone 4–6 or aziridine 7,8 (Figure 1a), but this approach has certain drawbacks, such as the need to pre-synthesize the water-sensitive electrophilic reactants.…”

Section: Introductionmentioning

confidence: 99%

“…However, ncAAs are challenging synthetic targets since they possess at minimum two reactive functional groups (the amine and carboxylic acid) and typically have at least one stereocenter. As a result, synthetic routes to ncAAs typically require multiple steps, most of which use organic solvents. , One of the most direct routes to ncAAs is to add a nucleophile to the β-position of a serine-derived lactone − or aziridine , (Figure a), but this approach has certain drawbacks, such as the need to presynthesize the water-sensitive electrophilic reactants.…”

Section: Introductionmentioning

confidence: 99%

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Improved Synthesis of 4-Cyanotryptophan and Other Tryptophan Analogues in Aqueous Solvent Using Variants of TrpB from Thermotoga maritima

et al. 2018

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The use of enzymes has become increasingly widespread in synthesis as chemists strive to reduce their reliance on organic solvents in favor of more environmentally benign aqueous media. With this in mind, we previously endeavored to engineer the tryptophan synthase β-subunit (TrpB) for production of noncanonical amino acids that had previously been synthesized through multistep routes involving water-sensitive reagents. This enzymatic platform proved effective for the synthesis of analogues of the amino acid tryptophan (Trp), which are frequently used in pharmaceutical synthesis as well as chemical biology. However, certain valuable compounds, such as the blue fluorescent amino acid 4-cyanotryptophan (4-CN-Trp), could only be made in low yield, even at elevated temperature (75 °C). Here, we describe the engineering of TrpB from Thermotoga maritima that improved synthesis of 4-CN-Trp from 24% to 78% yield. Remarkably, although the final enzyme maintains high thermostability ( T = 93 °C), its temperature profile is shifted such that high reactivity is observed at ∼37 °C (76% yield), creating the possibility for in vivo 4-CN-Trp production. The improvements are not specific to 4-CN-Trp; a boost in activity at lower temperature is also demonstrated for other Trp analogues.

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Section: ■ Resultsmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Improved Synthesis of 4-Cyanotryptophan and Other Tryptophan Analogues in Aqueous Solvent Using Variants of TrpB from Thermotoga maritima

et al. 2018

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“…Chemical synthesis can access numerous ncAAs by employing intermediates such as serine-derived lactones, hydantoins, or aziridines (Scheme 4, blue). 19,20 A significant benefit of chemical synthesis approaches is their broad applicability, allowing a variety of ncAAs to be produced from a single synthetic pipeline. Limitations are also apparent: chemical synthesis can be labor-intensive, utilize hazardous reagents and produce significant waste products, or generate racemic products that require further purification.…”

Section: Methods For Ncaa Productionmentioning

confidence: 99%

Engineering enzymes for noncanonical amino acid synthesis

2018

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The standard proteinogenic amino acids grant access to a myriad of chemistries that harmonize to create life. Outside of these twenty canonical protein building blocks are countless noncanonical amino acids (ncAAs), either found in nature or created by man. Interest in ncAAs has grown as research has unveiled their importance as precursors to natural products and pharmaceuticals, biological probes, and more. Despite their broad applications, synthesis of ncAAs remains a challenge, as poor stereoselectivity and low functional-group compatibility stymie effective preparative routes. The use of enzymes has emerged as a versatile approach to prepare ncAAs, and nature’s enzymes can be engineered to synthesize ncAAs more efficiently and expand the amino acid alphabet. In this tutorial review, we briefly outline different enzyme engineering strategies and then discuss examples where engineering has generated new ‘ncAA synthases’ for efficient, environmentally benign production of a wide and growing collection of valuable ncAAs.

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“…The constant development in these areas requires facile and reliable access to modified α-amino acids beyond the naturally occurring selection, meaning that the development of new methods for the enantioselective synthesis of unnatural α-amino acids is of great interest [5]. One synthetic strategy involves the direct stereoselective α-alkylation of amino acid ester derivatives [6]. Catalytic methods for this transformation include enantioselective transition metal catalysis or phase transfer organocatalysis, which have been used to incorporate α-aryl, α-allyl or α-alkyl substituents [7].…”

Section: Introductionmentioning

confidence: 99%

Exploring the Scope of Tandem Palladium and Isothiourea Relay Catalysis for the Synthesis of α-Amino Acid Derivatives

et al. 2020

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The scope and limitations of a tandem N-allylation/[2,3]-rearrangement protocol are investigated through the incorporation of a variety of functional groups within an allylic phosphate precursor. This method uses readily accessible N,N-dimethylglycine aryl esters and functionalized allylic phosphates, forming quaternary ammonium salts in situ in the presence of a palladium catalyst. Subsequent enantioselective [2,3]-sigmatropic rearrangement, promoted by the chiral isothiourea tetramisole, generates α-amino acid derivatives with two contiguous stereocenters. The incorporation of electron-withdrawing ester and amide groups gave the best results, furnishing the desired products in moderate to good yields (29–70%), with low diastereocontrol (typically 60:40 dr) but high enantioselectivity (up to 90:10 er). These results indicate that substrate–catalyst interactions in the proposed transition state are sensitive to the substitution pattern of the substrates.

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Synthesis of Unnatural/Nonproteinogenic α‐Amino Acids

Cited by 20 publications

References 162 publications

Improved Synthesis of 4-Cyanotryptophan and Other Tryptophan Analogues in Aqueous Solvent Using Variants of TrpB from Thermotoga maritima

Improved Synthesis of 4-Cyanotryptophan and Other Tryptophan Analogues in Aqueous Solvent Using Variants of TrpB from Thermotoga maritima

Engineering enzymes for noncanonical amino acid synthesis

Exploring the Scope of Tandem Palladium and Isothiourea Relay Catalysis for the Synthesis of α-Amino Acid Derivatives

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