Chemoenzymatic methods for the enantioselective preparation of sesquiterpenoid natural products from aromatic precursors

Banwell, Martin G.; Edwards, Alison J.; Harfoot, Gwion J.; Jolliffe, Katrina A.; McLeod, Malcolm D.; McRae, Kenneth J.; Stewart, Scott G.; Vögtle, Markus

doi:10.1351/pac200375020223

Cited by 91 publications

(11 citation statements)

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“…The synthesis and physicochemical properties of these compounds will be described in detail elsewhere. 2 Briefly, the synthesis involved the biotransformation of iodobenzene using the genetically engineered microorganism Escherichia coli JM109 (pDTG601), which overexpresses toluene dioxygenase, to yield the corresponding iodinated cis-1,2-dihydrocatechol as starting material (30,31). A suitably protected epoxy derivative of this starting material was then reacted with the relevant 1,-diaminoalkane or -arene to give, after appropriate deprotection and de-iodination, the polyhydroxylated precursor to compounds of the general type 1 (Fig.…”

Section: Synthesis and Structural Properties Of Hs Mimetics-mentioning

confidence: 99%

Use of Sulfated Linked Cyclitols as Heparan Sulfate Mimetics to Probe the Heparin/Heparan Sulfate Binding Specificity of Proteins

Freeman¹,

Liu

Banwell

et al. 2005

Journal of Biological Chemistry

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Heparin and heparan sulfate (HS) are structurally diverse glycosaminoglycans (GAG) that are known to interact, via unique structural motifs, with a wide range of functionally distinct proteins and modulate their biological activity. To define the GAG motifs that interact with proteins, we assessed the ability of 15 totally synthetic HS mimetics to interact with 10 functionally diverse proteins that bind heparin/HS. The HS mimetics consisted of cyclitol-based pseudo-sugars coupled by linkers of variable chain length, flexibility, orientation, and hydrophobicity, with variations in sulfation also being introduced into some molecules. Three of the proteins tested, namely hepatocyte growth factor, eotaxin, and elastase, failed to interact with any of the sulfated linked cyclitols. In contrast, each of the remaining seven proteins tested exhibited a unique reactivity pattern with the panel of HS mimetics, with tetrameric cyclitols linked by different length alkyl chains being particularly informative. Thus, compounds with short alkyl spacers (2-3 carbon atoms) effectively blocked the interaction of fibroblast growth factor-1 (FGF-1) and lipoprotein lipase with heparin/HS, whereas longer chain spacers (7-10 carbon atoms) were required for optimal inhibition of FGF-2 and vascular endothelial growth factor binding. This effect was most pronounced with the chemokine, interleukin-8, where alkyl-linked tetrameric cyclitols were essentially inactive unless a spacer of >7 carbon atoms was used. The heparin-inhibitable enzymes heparanase and cathepsin G also displayed characteristic inhibition patterns, cathepsin G interacting promiscuously with most of the sulfated cyclitols but heparanase activity being inhibited most effectively by HS mimetics that structurally resemble a sulfated pentasaccharide. These data indicate that a simple panel of HS mimetics can be used to probe the HS binding specificity of proteins, with the position of anionic groups in the HS mimetics being critical. Heparan sulfate (HS)1 is a glycosaminoglycan that is ubiquitously expressed as a proteoglycan on cell surfaces and throughout the extracellular matrix (ECM) in most multicellular animals (1-5). The polysaccharide is composed of alternating glucuronic acid and N-acetylglucosamine units, which, during biosynthesis, are subjected to a range of modifications such as O-sulfation at various positions, N-deacetylation, and Nsulfation of N-acetylglucosamine residues as well as C-5 epimerization of glucuronic acid to iduronic acid. Theoretically up to 48 different disaccharides could occur in HS due to these modifications, although so far only 23 have been identified (2). Nevertheless, as a result of the presence of these different disaccharides, HS chains exhibit remarkable structural heterogeneity. Such diversity is further enhanced by the considerable variation in chain length of the glycosaminoglycan. Heparin, a glycosaminoglycan with a much more restricted cellular distribution than HS, is structurally closely related to HS but has ϳ80% of its disacc...

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Section: Synthesis and Structural Properties Of Hs Mimetics-mentioning

confidence: 99%

Use of Sulfated Linked Cyclitols as Heparan Sulfate Mimetics to Probe the Heparin/Heparan Sulfate Binding Specificity of Proteins

Freeman¹,

Liu

Banwell

et al. 2005

Journal of Biological Chemistry

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“…The absolute stereochemistry in 7 is incorporated via microbial dihydroxylation of phenethyl acetate 8 in the whole-cell fermentation with toluene dioxygenase, overexpressed in E. coli JM109(pDTG601A) [32]. The enzymatically derived arene cis -dihydrodiols such as 7 have found widespread use in enantioselective synthesis of natural products [33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51].…”

Section: Resultsmentioning

confidence: 99%

Chemoenzymatic Total Synthesis of (+)-10-Keto-Oxycodone from Phenethyl Acetate

2019

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The total synthesis of (+)-10-keto-oxycodone was attained from phenethyl acetate in a stereoselective manner. Absolute stereochemistry was established via enzymatic dihydroxylation of phenethyl acetate with the recombinant strain JM109 (pDTG601A) that furnished the corresponding cis-cyclohexadienediol whose configuration corresponds to the absolute stereochemistry of the ring C of (+)-10-keto-oxycodone. Intramolecular Heck reaction was utilized to establish the quaternary carbon at C-13, along with the dibenzodihydrofuran functionality. The C-14 hydroxyl and C-10 ketone were installed via SmI2-mediated radical cyclization, and oxidation of a benzylic alcohol (obtained from an intermediate nitrate azide), respectively. The synthesis of (+)-10-keto-oxycodone was completed in a total of 14 operations (21 steps) and an overall yield of ~2%. Experimental and spectral data are provided for key intermediates and new compounds.

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“…70,71 The synthesis began with the chemoenzymatic dihydroxylation of bromobenzene (107) with recombinant E. coli JM109(pDTG601) to provide diol 108 as a single enantiomer. 72,73 Protection of the diol moiety as an acetonide followed by regioselective aziridination furnished compound 109. 74,75 Dehalogenation of vinylbromide 109 with tributyltin hydride afforded allyl aziridine 110 in 76% yield.…”

Section: Aziridine-based Bicyclic Cyclitolsmentioning

confidence: 99%

Conformationally constrained fused bicyclic iminosugars: synthetic challenges and opportunities

Hensienne¹,

Hazelard²,

Compain³

2019

Arkivoc

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Chemoenzymatic methods for the enantioselective preparation of sesquiterpenoid natural products from aromatic precursors

Cited by 91 publications

References 1 publication

Use of Sulfated Linked Cyclitols as Heparan Sulfate Mimetics to Probe the Heparin/Heparan Sulfate Binding Specificity of Proteins

Use of Sulfated Linked Cyclitols as Heparan Sulfate Mimetics to Probe the Heparin/Heparan Sulfate Binding Specificity of Proteins

Chemoenzymatic Total Synthesis of (+)-10-Keto-Oxycodone from Phenethyl Acetate

Conformationally constrained fused bicyclic iminosugars: synthetic challenges and opportunities

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