Enantiospecific Synthesis of Analogues of the Diketide Intermediate of the Erythromycin Polyketide Synthase (PKS)

Harris, Robert G.; Cutter, Annabel L.; Weissman, Kira J.; Hanefeld, Ulf; Timoney, Máire C.; Staunton, James

doi:10.1039/a800584b

Cited by 19 publications

(25 citation statements)

References 6 publications

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“…[39] (2S,3R)-3-Hydroxy-2-methylbutanoic Acid (2S,3R)-13 C NMR data were in accordance with those reported in the literature. [39] (R)-()-4-Ethyl-2-oxazolidinone (R)-19 …”

Section: Full Paperssupporting

confidence: 92%

“…This time, the racemic oxazolidinone 12 was acylated using butyryl chloride to obtain the Nbutanoyloxazolidinone 14. This underwent the diastereoselective aldol reaction with acetaldehyde in the presence of TiCl 4 /(À)-sparteine/NMP to afford the racsyn-15 in 59% yield and 95% de, according to 1 H NMR [39] and chiral HPLC analysis (Scheme 15). Enzymatic resolution of the enantiomers of aldol adduct 15 via transesterification catalysed by Candida antarctica lipase type B in n-hexane, afforded the acylated aldol adduct 16 and the non-acylated aldol adduct 15 with 50% conversion and >99% enantiomeric excess of the product after 20 hours (Scheme 16).…”

Section: Racemic Auxiliaries: Applications To Asymmetric Synthesismentioning

confidence: 99%

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New Routes to Chiral Evans Auxiliaries by Enzymatic Desymmetrisation and Resolution Strategies

Neri

Williams

2003

Adv Synth Catal

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This paper describes how enantiomerically enriched Evans auxiliaries can be successfully prepared by either an enzymatic desymmetrisation strategy or an asymmetric synthesis using racemic auxiliaries and an enzymatic resolution. Desymmetrisation of N-Boc-protected serinol has been achieved in good yield and high enantiomeric excess using porcine pancreas lipase. This has been exploited in different ways to prepare enantiomerically enriched (4R)-and (4S)-substituted 2-oxazolidinones. In another approach to asymmetric synthesis, starting from a racemic Evans auxiliary, by means of a diastereoselective aldol reaction coupled with a lipase-catalysed resolution, we achieved the preparation of enantiomerically enriched b-hydroxy acids and enantiomerically enriched 2-oxazolidinones.

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“…[39] (2S,3R)-3-Hydroxy-2-methylbutanoic Acid (2S,3R)-13 C NMR data were in accordance with those reported in the literature. [39] (R)-()-4-Ethyl-2-oxazolidinone (R)-19 …”

Section: Full Paperssupporting

confidence: 92%

Section: Racemic Auxiliaries: Applications To Asymmetric Synthesismentioning

confidence: 99%

New Routes to Chiral Evans Auxiliaries by Enzymatic Desymmetrisation and Resolution Strategies

Neri

Williams

2003

Adv Synth Catal

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“…NDK-CoA and EDK-CoA were synthesized, as described previously 11 , 12 , 13 . Ellman's reagent was used to precisely quantify the concentration of each stock solution.…”

Section: Methodsmentioning

confidence: 99%

Recognition of acyl carrier proteins by ketoreductases in assembly line polyketide synthases

2016

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Ketoreductases (KRs) are the most widespread tailoring domains found in individual modules of assembly line polyketide synthases (PKSs), and are responsible for controlling the configurations of both the α-methyl and β-hydroxyl stereogenic centers in the growing polyketide chain. Because they recognize substrates that are covalently bound to acyl carrier proteins (ACPs) within the same PKS module, we sought to quantify the extent to which protein-protein recognition contributes to the turnover of these oxidoreductive enzymes using stand-alone domains from the 6-deoxyerythronolide B synthase (DEBS). Reduced 2-methyl-3-hydroxyacyl-ACP substrates derived from two enantiomeric acyl chains and four distinct ACP domains were synthesized and presented to four distinct KR domains. Two KRs, from DEBS modules 2 and 5, displayed little preference for oxidation of substrates tethered to their cognate ACP domains over those attached to the other ACP domains tested. In contrast, the KR from DEBS module 1 showed a ca. 10-50-fold preference for substrate attached to its native ACP domain, whereas the KR from DEBS module 6 actually displayed a ca. 10-fold preference for the ACP from DEBS module 5. Our findings suggest that recognition of the ACP by a KR domain is unlikely to affect the rate of native assembly line polyketide biosynthesis. In some cases, however, unfavorable KR-ACP interactions may suppress the rate of substrate processing when KR domains are swapped to construct hybrid PKS modules.

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“…The conditions for off‐loading and analysis of the β‐OH diketide were optimized on a model system as follows. A sample (2 nmol) of β‐OH diketide‐SNAC (prepared as described previously [48]) was dissolved in 400 m m potassium phosphate buffer (pH 7.4). Then, 2 μL of hydrazine was added to a total volume of 25 μL.…”

Section: Methodsmentioning

confidence: 99%

The changing patterns of covalent active site occupancy during catalysis on a modular polyketide synthase multienzyme revealed by ion‐trap mass spectrometry

2009

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A catalytically competent, homodimeric diketide synthase comprising the first extension module of the erythromycin polyketide synthase was analysed using MS, after limited proteolysis to release functional domains, to determine the pattern of covalent attachment of substrates and intermediates to active sites during catalysis. Using the natural substrates, the acyltransferase and acylcarrier protein of the loading module were found to be heavily loaded with propionyl starter groups, while the ketosynthase was fully propionylated. The acylcarrier protein of the extension module was partly occupied by the product diketide, and the adjacent chain‐releasing thioesterase domain was vacant, implying that the rate‐ limiting step is transfer of the diketide from the acylcarrier protein to the thioesterase domain. The data suggest an attractive model for preventing iterative chain extension by efficient repriming of the ketosynthase domain after condensation. Use of the alternative starter unit valeryl‐CoA produced an altered pattern, in which a significant proportion of the extension acylcarrier protein was loaded with methylmalonate, not diketide, consistent with the condensation step having become an additional slow step. Strikingly, when NADPH was omitted, the extension acylcarrier protein contained methylmalonate and none of the expected keto diketide, in contrast to results obtained previously by mixing individual recombinant domains, showing the importance of also studying intact modules. The detailed patterns of loading of the extension acylcarrier protein (of which there are two in the homodimer) also provided the first evidence for simultaneous loading of both acylcarrier proteins and for the coordination of timing between the two active centres for chain extension.

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Enantiospecific Synthesis of Analogues of the Diketide Intermediate of the Erythromycin Polyketide Synthase (PKS)

Cited by 19 publications

References 6 publications

New Routes to Chiral Evans Auxiliaries by Enzymatic Desymmetrisation and Resolution Strategies

New Routes to Chiral Evans Auxiliaries by Enzymatic Desymmetrisation and Resolution Strategies

Recognition of acyl carrier proteins by ketoreductases in assembly line polyketide synthases

The changing patterns of covalent active site occupancy during catalysis on a modular polyketide synthase multienzyme revealed by ion‐trap mass spectrometry

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