Showing papers by "Tomas Hudlicky published in 2009"
TL;DR: This tutorial review provides a survey of syntheses in which an enzyme step contributed to generating downstream molecular complexity in the target, and provides a guide to the types of enzymatic transformations suitable for incorporation into synthetic schemes.
Abstract: This tutorial review provides a survey of syntheses in which an enzymatic step contributed to generating downstream molecular complexity in the target. The first part provides a guide to the types of enzymatic transformations suitable for incorporation into synthetic schemes. The principles of symmetry, especially the concept of “latent symmetry”, which are often used to simplify enantiodivergent design of targets, are discussed next. The examples are discussed in the order of a degree of experimental difficulty associated with the execution of a particular biological technique. Lipase resolutions and desymmetrizations are discussed first followed by more advanced protocols involving oxidoreductase enzymes and ending with examples of syntheses that employ pathway engineering and directed evolution of proteins. Future prospects of biocatalytic methods as means of efficient preparation of target compounds are indicated. The authors hope that the review will serve to convince those synthetic chemists reluctant to use biological methods to include enzymatic procedures in their design.
189 citations
TL;DR: This account is a tribute to Professor David Gibson in recognition of his discovery of enzymatic dihydroxylation of aromatic compounds four decades ago, which greatly contributed to advancing biocatalysis as a disciplinewith major impact on synthesis of optically pure compounds.
Abstract: This account is a tribute to Professor David Gibson in recognitionof his discovery of enzymatic dihydroxylation of aromatic compoundsfour decades ago. Here are highlighted some of the milestones inmicrobiology, biochemistry, molecular biology, and synthetic organicchemistry connected with this unique reaction. Gibson’sdiscovery greatly contributed to advancing biocatalysis as a disciplinewith major impact on synthesis of optically pure compounds. Personalrecollections of several chemists who have embraced this technologyin their own work, along with the authors’ recollectionsof the early days of research involving the CIS-dihydrodiols,are provided as Notes at the end of the article. 1 Introduction: History of Biocatalysis 2 The Discovery of Enzymatic Dihydroxylation 3 Processing of Arenes by Oxidoreductase Enzymes 4 Considerations of the Mechanism 5 Diversity of Metabolites 6 CIS-Dihydrodiols as SyntheticIntermediates: Analysis of Reactivity and Symmetry Options 7 Historically Important Milestones in Applications to Synthesis 8 Outlook 9 Notes
172 citations
TL;DR: The formal synthesis of oseltamivir is achieved in ten steps and incorporates a unique translocation of the olefin with concomitant elimination of the C2 hydroxy group (see scheme).
Abstract: A short chemoenzymatic formal synthesis of oseltamivir from ethyl benzoate has been achieved. The key steps involve a toluene dioxygenase-mediated dihydroxylation, hetero-Diels-Alder cycloaddition, and generation of C4 acetamido functionality. The formal synthesis of oseltamivir is achieved in ten steps and incorporates a unique translocation of the olefin with concomitant elimination of the C2 hydroxy group (see scheme).
83 citations
TL;DR: The hetero-Diels-Alder reaction of this diol with an acyl nitroso dienophile yielded regio- and stereoselectively a bicyclic oxazine, which upon reduction provided a useful derivative of amino shikimate that can be exploited in an approach to oseltamivir (Tamiflu) and other amino cyclitols.
Abstract: A series of benzoate esters (methyl, ethyl, n-Pr, i-Pr, n-Bu, t-Bu, allyl, and propargyl) were subjected to enzymatic dihydroxylation by E. coli JM 109(pDTG 601) strain in a whole-cell fermentation. The cis-cyclohexadienediols were obtained in yields of ∼1g/L except for n-propyl- and i-propyl benzoate which were found to be poor substrates. n-Butyl and t-butyl benzoates were not oxidized at all. The absolute stereochemistry for all metabolites was determined by comparison with a standard prepared from (1S-cis)-3-bromo-3,5-cyclohexadiene-1,2-diol, whose absolute configuration is well established. The free diols were found to be quite stable compared to other cis-dihydrodiols of this type, however, their acetonides underwent a dimerizationvia a regio- and stereoselective Diels–Alder cycloaddition. The diol derived from ethyl benzoate was subjected to a stereo- and regioselective inverse electron demand Diels–Alder cycloadditions with several dienophiles. The new adducts were completely characterized. The hetero-Diels–Alder reaction of this diol with an acyl nitroso dienophile yielded regio- and stereoselectively a bicyclic oxazine, which upon reduction provided a useful derivative of amino shikimate that can be exploited in an approach to oseltamivir (Tamiflu) and other amino cyclitols. The diol was also converted to carba-α-L-galactopyranose to demonstrate its potential utility as a source of pseudo sugars. Experimental and spectral data are provided for all new compounds.
36 citations
TL;DR: In this article, a regioselective opening of 1,2-epoxycyclohex-3-ene with a chiral-auxiliary version of the Burgess reagent was used to provide a diastereomeric pair of cis-fused cyclic sulfamidates, which were transformed to trans-amino benzoates with ammonium benzoate and converted to (−)-2 and (+)-2 by oxidative cleavage and reductive amination.
35 citations
TL;DR: In this paper, a Density functional theory (DFT) study for the interaction of the achiral version of the Burgess reagent with oxiranes is included along with an explanation of the lack of asymmetric induction observed in reactions conducted in a catalytic mode with C2-symmetric catalysts.
17 citations
TL;DR: A one-pot procedure for the conversion of thebaine to hydrocodone was achieved by employing palladium catalysis in aqueous medium and this procedure was found to be comparable to the two-step protocol which employs diimide reduction of the baine followed by acid-catalyzed hydrolysis of the resulting 8,14-dihydrothebaine.
Abstract: The ethylene glycol ketal of neopinone was prepared in a one-pot procedure by the reaction of thebaine with ethylene glyocol in the presence of p-toluenesulfonic acid. The ketal is also an intermediate in the conversion of thebaine to hydrocodone with ethylene glycol and Pd(OAc)(2), followed by hydrogenation. Additionally, a one-pot procedure for the conversion of thebaine to hydrocodone was achieved by employing palladium catalysis in aqueous medium. Palladium serves a dual purpose in this transformation, first for the activation of the dienol ether of thebaine and second as a hydrogenation catalyst. This procedure was found to be comparable to the two-step protocol which employs diimide reduction of thebaine followed by acid-catalyzed hydrolysis of the resulting 8,14-dihydrothebaine to hydrocodone. Experimental and spectral data are provided for all compounds.
10 citations
9 citations
Patent•
17 Dec 2009
TL;DR: The present application relates to novel C-1 substituted analogues of pancratistatin and 7-dexoypancratistinatin of Formula (I), pharmaceutical compositions thereof and the use of said compounds of Formula(I) in the treatment of cancer as mentioned in this paper.
Abstract: The present application relates to novel C-1 substituted analogues of pancratistatin and 7-dexoypancratistatin of Formula (I), pharmaceutical compositions thereof and the use of said compounds of Formula (I) in the treatment of cancer The application also relates to processes for the preparation of said compound of Formula (I) and intermediates thereof.
1 citations