Synthesis of L-.alpha.-methyldopa from asymmetric intermediates

Reinhold, Donald F.; Firestone, Raymond A.; Gaines, Walter A.; Chemerda, J. M.; Sletzinger, M.

doi:10.1021/jo01267a059

Cited by 39 publications

(16 citation statements)

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“…Another frequently used ␣-hydrogen-␣-amino acid is L-tert-leucine, which is used as a building block for a variety of antiviral (e.g., anti-human immunodeficiency virus), antiarthritis, and anticancer drugs under development and as a chiral auxiliary in chemical asymmetric synthesis (5,10). Besides ␣-hydrogen-␣-amino acids, ␣,␣-disubstituted ␣-amino acids also constitute a group of compounds of increasing importance, as exemplified by the use of L-␣-methyl-3,4-dihydroxyphenylalanine (L-␣-methyldopa) as an antihypertensive drug (34,42), ␣-methylvaline as an intermediate for the herbicide Arsenal and related herbicides (47,49), and L-␣-methylphenylglycine as a building block for the new fungicide fenamidone (27).…”

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confidence: 99%

l-Selective Amidase with Extremely Broad Substrate Specificity fromOchrobactrum anthropiNCIMB 40321

Sonke¹,

Ernste²,

Tandler³

et al. 2005

Appl Environ Microbiol

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An industrially attractive L-specific amidase was purified to homogeneity from Ochrobactrum anthropi NCIMB 40321 wild-type cells. The purified amidase displayed maximum initial activity between pH 6 and 8.5 and was fully stable for at least 1 h up to 60°C. The purified enzyme was strongly inhibited by the metal-chelating compounds EDTA and 1,10-phenanthroline. The activity of the EDTA-treated enzyme could be restored by the addition of Zn 2؉ (to 80%), Mn 2؉ (to 400%), and Mg 2؉ (to 560%). Serine and cysteine protease inhibitors did not influence the purified amidase. This enzyme displayed activity toward a broad range of substrates consisting of ␣-hydrogen-and (bulky) ␣,␣-disubstituted ␣-amino acid amides, ␣-hydroxy acid amides, and ␣-N-hydroxyamino acid amides. In all cases, only the L-enantiomer was hydrolyzed, resulting in E values of more than 150. Simple aliphatic amides, ␤-amino and ␤-hydroxy acid amides, and dipeptides were not converted. The gene encoding this L-amidase was cloned via reverse genetics. It encodes a polypeptide of 314 amino acids with a calculated molecular weight of 33,870. Since the native enzyme has a molecular mass of about 66 kDa, it most likely has a homodimeric structure. The deduced amino acid sequence showed homology to a few other stereoselective amidases and the acetamidase/ formamidase family of proteins (Pfam FmdA_AmdA). Subcloning of the gene in expression vector pTrc99A enabled efficient heterologous expression in Escherichia coli. Altogether, this amidase has a unique set of properties for application in the fine-chemicals industry.Enantiomerically pure ␣-amino acids, both natural and unnatural, form an important class of chiral building blocks for the pharmaceutical and agrochemical industries. Examples of important ␣-hydrogen-␣-amino acids are D-phenylglycine (DPhg) and D-p-hydroxyphenylglycine, which are produced as side chains for the manufacture of semisynthetic ␤-lactam antibiotics such as ampicillin, amoxicillin, and cephalexin (14, 53), and D-valine, an intermediate for the pyrethroid insecticide fluvalinate (28). Another frequently used ␣-hydrogen-␣-amino acid is L-tert-leucine, which is used as a building block for a variety of antiviral (e.g., anti-human immunodeficiency virus), antiarthritis, and anticancer drugs under development and as a chiral auxiliary in chemical asymmetric synthesis (5, 10). Besides ␣-hydrogen-␣-amino acids, ␣,␣-disubstituted ␣-amino acids also constitute a group of compounds of increasing importance, as exemplified by the use of L-␣-methyl-3,4-dihydroxyphenylalanine (L-␣-methyldopa) as an antihypertensive drug (34, 42), ␣-methylvaline as an intermediate for the herbicide Arsenal and related herbicides (47, 49), and L-␣-methylphenylglycine as a building block for the new fungicide fenamidone (27).Enantiomerically pure ␣-amino acids can be produced on a commercial scale by a number of different processes, both chemical and enzymatic. Biocatalytic processes that have been commercialized include the acylase process operated by Degussa (8) a...

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confidence: 99%

l-Selective Amidase with Extremely Broad Substrate Specificity fromOchrobactrum anthropiNCIMB 40321

Sonke¹,

Ernste²,

Tandler³

et al. 2005

Appl Environ Microbiol

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“…Our company was well versed in dealing with complex synthetic problems, with significant expertise in the development of enantiopure drugs, as evidenced by the remarkable manufacturing route to enantiopure Aldomet developed in the early 1960's. [20][21][22] However, the scale, stereochemical challenges and accelerated development pace of the Crixavan project was a significant challenge to the chemists tasked with accessing numerous potential intermediates in enantiopure form, and endeavoring to assemble these fragments according to several different synthetic schemes. 23 Influenced by these events, we launched an initiative to explore the emerging field of laboratory automation and robotics to speed and streamline the development of these challenging, complex drug candidates.…”

Section: Pharmaceutical Process Research At the Dawn Of The New Millementioning

confidence: 99%

High throughput analysis enables high throughput experimentation in pharmaceutical process research

Welch

2019

React. Chem. Eng.

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“…The three non-natural amino acids are building blocks of a precursor for BILN 2061 (64), a novel NS3 protease inhibitor with antiviral activity in humans [159]. Besides a-H-a-amino acids, a,a-disubstituted a-amino acids also constitute a group of compounds of increasing importance, as exemplified by the use of L-a-methyl-3,4-dihydroxyphenylalanine (L-a-methylDOPA) (65) as antihypertensive drug [160,161], a-methylvaline (66) as an intermediate for the herbicide Arsenal (67) and related herbicides [162,163], and L-a-methylphenylglycine (68) as a building block for the new fungicide fenamidone (69) [164].…”

Section: -56mentioning

confidence: 99%