Biosynthesis and Metabolism of Cyclopropane Rings in Natural Compounds

Wessjohann, Ludger A.; Brandt, Wolfgang; Thiemann, Thies

doi:10.1021/cr0100188

Cited by 575 publications

(314 citation statements)

References 202 publications

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“…44 The cyclopropyl functionality is useful for a variety of synthetic modifications, highlighting the potential for chemo-biosynthetic expansion of the aglycone library. 45 Further biosynthetic elaboration of these new aklanonic acid analogs can be achieved by reconstituting in S. coelicolor CH999 a variety of downstream enzymes such as the fourth ring cyclase (dnrD), the ketoreductase (dnrE), and the glycosyltransferases from the daunorubicin pathway ( Figure 2). 33,46,47 Analogous glycosyltransferases have been identified in the daunorubicin 48 and aclacinomycin A 49 biosynthetic gene clusters.…”

Section: Discussionmentioning

confidence: 99%

Engineered Biosynthesis of Aklanonic Acid Analogues

2005

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Aklanonic acid, an anthraquinone natural product, is a common advanced intermediate in the biosynthesis of several antitumor polyketide antibiotics, including doxorubicin and aclacinomycin A. Intensive semisynthetic and biosynthetic efforts have been directed toward developing improved analogs of these clinically important compounds. The primer unit of such polyfunctional aromatic polyketides is an attractive site for introducing novel chemical functionality, and attempts have been made to modify the primer unit by precursor directed biosynthesis or protein engineering of the polyketide synthase (PKS). We have previously demonstrated the feasibility of engineering bimodular aromatic PKSs capable of synthesizing unnatural hexaketides and octaketides. In this report we extend this ability by preparing analogs of aklanonic acid, a decaketide, and its methyl ester. For example, by recombining the R1128 initiation module with the dodecaketide-specific pradimicin PKS, the isobutyryl primed analog of aklanonic acid (YT296b, 10) and its methyl ester (YT299b, 12) were prepared. In contrast, elongation modules from dodecaketide-specific spore pigment PKSs were unable to interact with the R1128 initiation module. Thus, in addition to revealing a practical route to new anthracycline antibiotics, we also observed a fundamental incompatibility between antibiotic and spore pigment biosynthesis in the actinomycetes bacteria.

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Section: Discussionmentioning

confidence: 99%

Engineered Biosynthesis of Aklanonic Acid Analogues

2005

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“…Because cyclopropyl-substituted heterocycles are of particular interest in medicinal chemistry, [20] we performed further model reactions with dicyclopropyl-substituted oxazole derivative 7 e. The conversion of the acetyl group into a silyl enol ether moiety was achieved in 85 % yield by subjecting oxazole 7 e to a mixture of sodium iodide and tert-butyldimethylsilyl chloride in acetonitrile (Scheme 11). Product 34 should be a very useful precursor for a variety of subsequent reactions that are typical for silyl enol ethers.…”

Section: Resultsmentioning

confidence: 99%

Synthesis of 5‐Acetyloxazoles and 1,2‐Diketones from β‐Alkoxy‐β‐ketoenamides and Their Subsequent Transformations

Lechel

Gerhard

Trawny

et al. 2011

Chemistry A European J

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Lithiated alkoxyallenes, nitriles, and carboxylic acids have been employed as precursors in a three-component reaction leading to highly substituted β-alkoxy-β-ketoenamides. Upon treatment with trifluoroacetic acid, these enamides could be easily cyclized to 5-acetyloxazole derivatives. The synthesis is very flexible with respect to the substitution pattern at C-2 and C-4 of the oxazole core. A mechanistic suggestion for the oxazole formation is presented on the basis of (18)O-labeled compounds and their mass spectrometric analysis. In several cases, 1,2-diketones are formed as side products or even as major components. The acetyl moiety at C-5 of the oxazole derivatives can efficiently be converted into alkenyl or alkynyl moieties, which allows a multitude of subsequent reactions. Condensation reactions of the acetyl group provided the expected oxime or hydrazone. By applying a Fischer reaction, the phenylhydrazone could be transferred into an indole, which emphasizes the potential of 5-acetyloxazoles for the preparation of highly substituted (poly)heterocyclic systems. The alkynyl group at C-2 is prone to addition reactions, providing an enamine with interesting photophysical properties. Sonogashira couplings were performed with 5-alkynyl-substituted oxazoles, furnishing the expected aryl-substituted products. This alkynyl unit was employed for the preparation of a new, star-shaped trisoxazole derivative. The ability of this multivalent compound to form self-assembled monolayers between the basal plane of highly oriented pyrolytic graphite and 1-phenyloctane was demonstrated by scanning tunneling microscopy (STM). The star-shaped compound seems to prefer the C(3)-symmetric arrangement in this two-dimensional crystal. Two 1,2-diketones were smoothly converted into functionalized quinoxaline derivatives.

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“…The cyclopropane and aziridine rings are constitutents in more than 4000 natural isolated and 100 biologically active agents. [78] In addition, they are useful synthetic intermediates or building blocks for the synthesis of natural products and pharmaceuticals, and as templates for the construction of conformationally restricted amino acids and peptides. [79] Since Aggarwal et al [80] pioneered the use of organocatalyst in the enantioselective cyclopropanation reaction in 2001, significant advances have been made in the development of organocatalytic methods.…”

Section: Cycloaddition Reactionsmentioning

confidence: 99%

Asymmetric Synthesis with Silicon‐Based Bulky Amino Organocatalysts

Shi

2010

Adv Synth Catal

218

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Recent years have witnessed an explosive growth in the field of amino organocatalysis, especially in asymmetric enamine and iminium catalysis. Except for the obvious interaction between organocatalyst and substrate, the impact of bulky side group ons stereoselectivity is not as simple as one could imagine. Within the development of bulky sitestereoselective organocatalysts, functional silyl organocatalysts with a bulky silicon group are promising and meet the high standards of modern synthetic methods. This review focuses on the recent advances in the synthetic applications of silicon-based, bulky amino organocatalysts in which catalysts containing an organosilicon moiety or group play a formative role in controlling both the course of the reaction as well as the stereoselectivity.

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Biosynthesis and Metabolism of Cyclopropane Rings in Natural Compounds

Cited by 575 publications

References 202 publications

Engineered Biosynthesis of Aklanonic Acid Analogues

Engineered Biosynthesis of Aklanonic Acid Analogues

Synthesis of 5‐Acetyloxazoles and 1,2‐Diketones from β‐Alkoxy‐β‐ketoenamides and Their Subsequent Transformations

Asymmetric Synthesis with Silicon‐Based Bulky Amino Organocatalysts

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