Synthesis Of Thienamycin Research Articles

Continuous production of thienamycin in immobilized cell systems

A novel 2-L bubble column was used to study the continuous, immobilized cell production of thienamycin. Cells of Streptomyces cattleya were immobilized by culturing them in an appropriate growth medium containing 60/80 mesh celite particles. The dilution rate used during the continuous growth phase was 0.2 h(-1). This growth phase was terminated upon the development of heavy cell films (100-500 mum thickness), and the medium was replaced with an appropriate thienamycin production medium. The system was then operated in a batch mode until thienamycin production began. At that time, continuous feeding of the production medium was initiated and the influence of medium composition and dilution rate on CO(2), NH(4), biomass, and thienamycin production investigated. With synthetic production medium, a doubling of the dilution rate from 0.05 to 0.10 h(-1) resulted in a doubling of the thienamycin volumetric productivity. Rates of CO(2) and NH(4) production increased by ca. factors of three and two, respectively. The rate of PO(4) utilization also doubled. When the dilution rate was decreased to 0.05 h(-1), the rates of CO(2) production and PO(4) utilization quickly decreased (i.e., within 3 h). The rates of NH(4) and thienamycin production also decreased but more slowly (i.e., ca. 100 h after the decrease in dilution rate). With complex production medium, the rates of CO(2) production and PO(4) utilization appeared to be a direct function of dilution rate at the dilution rates tested. Thienamycin production in this case was not a function of dilution rate. Comparing the synthetic medium with the complex medium at either dilution rate, the volumetric rate of thienamycin production was higher in the system being fed complex medium. However, the specific activity (units thienamycin/g cell/h) observed with complex medium was lower than that observed with synthetic medium. The higher volumetric productivity observed with complex medium was the result of a high cell loading. The above observations will be discussed in terms of control of thienamycin synthesis and film thickness effects.

ChemInform Abstract: A Synthesis of a Versatile Intermediate Leading to Thienamycin Analogs.

AbstractDas ausgehend von Thr (I) erhältliche Derivat (IVa) wird [über die Stufe (IVb)] in das Azetidinon (Va) übergeführt, das zu den Derivaten (Vb)‐(Vd) umgesetzt wird.

ChemInform Abstract: Stereo‐ and Enantio‐Controlled Synthesis of Chiral Intermediates for the Total Synthesis of Thienamycin and Related β‐Lactam Antibiotics fromh 3‐Hydroxybutyrates.

AbstractStereo‐ and Enantio‐Controlled Synthesis of Chiral Intermediates for the Total Synthesis of Thienamycin and Related β‐Lactam Antibiotics fromh 3‐Hydroxybutyrates.

ChemInform Abstract: An Improved Entry to a Key Intermediate for Thienamycin Synthesis from Methyl (R)‐3‐Hydroxybutanoate via Direct Epimerization at C‐3 on 2‐Azetidinone Rings.

AbstractDas β‐Lactam ′(I) läßt sich nach O‐Silylierung mit Trimethylsilyltriflat (II) zum Silylenolether (III) umsetzen, der zum β‐Lactam (IV) mit umgekehrter Konfiguration hydrolysiert werden kann.

A stereocontrolled synthesis of thienamycin from 6-aminopenicillanic acid

A stereocontrolled synthesis of thienamycin from 6-aminopenicillanic acid

Simple and condensed β-lactams. Part 7. Side chain extensions of some azetidin-2-one derivatives, and the formation of melillo's lactone, a strategic intermediate in the total synthesis of thienamycin, from 3-acetyl-1-benzyl-4-cyanomethylazetidin-2-one

The oxoazetidinecarboxylic acids (2a) and (2b) and the homologous acid (8b) were converted by treatment of their chlorides with ethyl diazoacetate into the diazo esters (4a, b), and (10b), respectively. Irradiation of the diazo ester (4b) afforded the diethyl and ethyl hydrogen malonates (17) and (18), respectively. Attempted thermal decarboxylation of the latter resulted in profound degradation to give a mixture of the isomeric compounds (19a, b). NaBH4 reduction at –78 °C of the diazo ester (4d) gave mixtures of the diastereoisomers of the diazo esters (4e) and (20). The (hydroxymethyl)-azetidinone (6b) was converted via the aldehyde (5b) and the nitroethyl derivative (22) into the acetals (23) and (25). Attempts to convert the nitrile (7a) into either the acid (8a) or the ester (9a) in acceptable yields, failed. The nitriles (7g) and (7e)[obtained in two steps from the nitrites (7c) and (7b), respectively] were converted by refluxing hydrochloric acid into Melillo's lactone (28)(the key intermediate of a practical synthesis of the carbapenem antibiotic thienamycin) and its N-unsubstituted analogue (30), respectively.

Diastereoselective aldol reactions of β-silylenolates: a formal synthesis of thienamycin

The lithium enolate (1) of benzyl β-phenyldimethylsilylbutanoate reacts with β-phenyldimethylsilylpropionaldehyde (2) to give, with high diastereoselectivity, the aldol product (3), which is converted into the β-lactam (7), a known precursor of thienamycin.

A formal synthesis of (±)-thienamycin

An α-silylethylidene-β-lactam is generated via chlorosulphonyl isocyanate (CSI) addition to a silylated allenyl sulphide and converted into a key intermediate for the synthesis of thienamycin.

A formal total synthesis of thienamycin from 4-propargyl-2-azetidinone.

A mild and efficient method for the conversion of propiolic esters to β-keto esters was developed. Initially, propiolic esters were converted to β-phenylthio-α, β-unsaturated esters, which were treated with N-bromoacetamide in an aqueous solvent followed by reductive debromination with an aqueous solution of sodium sulfite, affording β-keto esters in good yields. Using this new method, a formal total synthesis of (±)-thienamycin from 4-propargyl-2-azetidinone was accomplished.

A Synthesis of a Versatile Intermediate Leading to Thienamycin Analogs

Abstract l-Threonine was converted to a versatile azetidinone derivative stereospecifically in 3 steps. This azetidinone was further transformed to (3S,4R)-3-[(R)-1-hydroxyethyl]-1-(4-methoxybenzyl)-4-[(phenylthio)-carbonylmethyl]-2-azetidinone (S-Phenyl thioester), a key intermediate for the synthesis of thienamycin and it’s biologically active analogs. Since the thiol part of this S-phenyl thioester can be exchanged easily with other complex or useful thiols under mild conditions, important S-thioester precursors for the production of carbapenem analogs were obtained in high yield.

Reverse transsulfuration and its relationship to thienamycin biosynthesis in Streptomyces cattleya.

Cystathionine gamma-lyase (EC 4.4.1.1) was purified from Streptomyces cattleya, an actinomycete which produces the unusual beta-lactam antibiotic thienamycin. The enzyme displays broad substrate specificity and is similar to gamma-lyases purified from other microorganisms. That the gamma-lyase functions in vivo to provide cysteine for antibiotic synthesis was shown by two types of experiments. First, cystathionine and methionine, as well as cysteine itself, are efficiently utilized by S. cattleya for thienamycin biosynthesis. Second, propargylglycine, a mechanism-based inactivator of cystathionine gamma-lyase in vitro, inhibits the synthesis of thienamycin in vivo. This inhibition can be substantially reversed by providing the cells with another source of cysteine, such as cystine.

A FACILE, STEREOCONTROLLED ENTRY TO KEY INTERMEDIATES FOR THIENAMYCIN SYNTHESIS FROM ETHYL (S)-3-HYDROXYBUTANOATE

Abstract A new synthetic approach to optically active key intermediates for thienamycin synthesis is described which involves the highly stereocontrolled transformation of the 2-azetidinone obtained via the condensation of ethyl (S)-3-hydroxybutanoate with the N-silylimine of trimethylsilylpropynal.

A SYNTHETIC APPROACH TO (+)-THIENAMYCIN FROM METHYL (R)-3-HYDROXYBUTANOATE. A NEW ENTRY TO (3R, 4R)-3-[(R)-1-HYDROXYETHYL]-4-ACETOXY-2-AZETIDINONE

Abstract A new entry to the O-silylated form of the title azetidinone, a well-established key intermediate for thienamycin synthesis, is described which relies on the stereocontrolled transformation of the 2-azetidinone obtained via the condensation of methyl (R)-3-hydroxybutanoate with the N-silylimine of trimethylsilylpropynal.

An improved entry to a key intermediate for thienamycin synthesis from methyl ( [formula omitted])-3-hydroxybutanoate via direct epimerization at C-3 on 2-azetidinone rings

An improved entry to a key thienamycin intermediate is described which relies upon the direct epimerization at C-3 of the 3-(1-hydroxyethyl)-2-azetidinone derivatives readily obtained from methyl ( R )-3-hydroxybutanoate.

Alternative preparation of methyl 3-amino-2,3,6-trideoxy-α- d- arabino-hexopyranoside and chiral intermediates for the synthesis of thienamycin

Alternative preparation of methyl 3-amino-2,3,6-trideoxy-α- d- arabino-hexopyranoside and chiral intermediates for the synthesis of thienamycin

Synthesis of Thienamycin and 2-Alkylthiomethyl-carbapenam (2-Homo-thienamycin) Analogues from 6-Aminopenicillanic Acid

Synthesis of Thienamycin and 2-Alkylthiomethyl-carbapenam (2-Homo-thienamycin) Analogues from 6-Aminopenicillanic Acid

Stereospecific synthesis of chiral precursors of thienamycin from L-Threonine

L-Threonine was transformed, stereospecifically, to a versatile β-lactam ( 5a) in 3 steps. This β-lactam was further converted to a key intermediate ( 25) for the synthesis of thienamycin and its biologically active analogues. Furthermore, the compound 5a was changed to iodides ( 18 and 23), cyanides ( 19 and 24), chloromethylketone ( 26) and aldehydes ( 30 and 31) which appear to have a latent potential as precursors for the syntheses of the carbapenems.

ChemInform Abstract: TOTAL SYNTHESIS OF THIENAMYCIN: A NEW APPROACH FROM ASPARTIC ACID

Chemischer InformationsdienstVolume 13, Issue 41 Natural Products ChemInform Abstract: TOTAL SYNTHESIS OF THIENAMYCIN: A NEW APPROACH FROM ASPARTIC ACID P. J. REIDER, P. J. REIDERSearch for more papers by this authorE. J. J. GRABOWSKI, E. J. J. GRABOWSKISearch for more papers by this author P. J. REIDER, P. J. REIDERSearch for more papers by this authorE. J. J. GRABOWSKI, E. J. J. GRABOWSKISearch for more papers by this author First published: October 12, 1982 https://doi.org/10.1002/chin.198241340Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume13, Issue41October 12, 1982 RelatedInformation

Further studies on the synthesis of thienamycin: a facile and stereoselective synthesis of a bicyclic .beta.-keto ester by 1,3-dipolar cycloaddition

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTFurther studies on the synthesis of thienamycin: a facile and stereoselective synthesis of a bicyclic .beta.-keto ester by 1,3-dipolar cycloadditionTetsuji Kametani, Shyh Pyng Huang, Atsushi Nakayama, and Toshio HondaCite this: J. Org. Chem. 1982, 47, 12, 2328–2331Publication Date (Print):June 1, 1982Publication History Published online1 May 2002Published inissue 1 June 1982https://doi.org/10.1021/jo00133a019RIGHTS & PERMISSIONSArticle Views258Altmetric-Citations46LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (509 KB) Get e-Alerts Get e-Alerts

Total synthesis of thienamycin: a new approach from aspartic acid

A practical stereospecific synthesis of thienamycin 1 has been achieved. Key steps include a lead tetracetate oxidative decarboxylation and subsequent insertion of a four carbon diazo containing unit into a 3-acetoxy-2-azetidinene.