Total Synthesis of (+)-Geldanamycin and (−)-o-Quinogeldanamycin with Use of Asymmetric Anti- and Syn-Glycolate Aldol Reactions

Andrus, Merritt B.; Meredith, Erik; Simmons, Bryon; Sekhar, B. B. V. Soma; Hicken, Erik J.

doi:10.1021/ol0267432

Cited by 66 publications

(28 citation statements)

References 25 publications

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“…98 Six years later, the Panek laboratory also completed its total synthesis in only 20 linear steps and 2% overall yield. 99 Biosynthetic production would later provide large quantities of geldanamycin and expedite the synthesis of multiple semi-synthetic analogues, with most modifications occurring at the C17 quinone position.…”

Section: Conformationally-restricted Analogues Of Polyketide Naturmentioning

confidence: 99%

Conformation–activity relationships of polyketide natural products

2015

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Polyketides represent an important class of secondary metabolites that interact with biological targets connected to a variety of disease-associated pathways. Remarkably, nature’s assembly lines, polyketide synthases, manufacture these privileged structures through a combinatorial mixture of just a few structural units. This review highlights the role of these structural elements in shaping a polyketide’s conformational preferences, the use of computer-based molecular modeling and solution NMR studies in the identification of low-energy conformers, and the importance of conformational analogues in probing the bound conformation. In particular, this review covers several examples wherein conformational analysis complements classic structure-activity relationships in the design of biologically active natural product analogues.

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Section: Conformationally-restricted Analogues Of Polyketide Naturmentioning

confidence: 99%

Conformation–activity relationships of polyketide natural products

2015

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“…However, the configuration of the stereocenter that is generated is retained in the end product and corresponds to that of the (R)-diketide. [16] A mutant strain of S. hygroscopicus var. geldanus, K390-76-1, in which the AHBA synthesis genes of the geldanamycin pathway had been deleted and replaced by the neomycin resistance gene, was used.…”

Section: Introductionmentioning

confidence: 99%

Determination of the Cryptic Stereochemistry of the First PKS Chain‐Extension Step in Ansamitocin Biosynthesis by Actinosynnema pretiosum

et al. 2006

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The biosynthesis of the antitumor antibiotic, ansamitocin, involves the assembly of a linear octaketide on the ansamitocin (asm) polyketide synthase (PKS), which is then cyclized to proansamitocin and further modified to the final product. In the first chain-extension step on the asm PKS, a stereocenter is generated which is then obliterated in a subsequent double-bond migration. The cryptic configuration at this stereocenter was determined by first synthesizing the two enantiomers of the intermediate diketide as their N-acetylcysteamine (SNAC) thioesters. These were then used to demonstrate that only the R enantiomer complements a 3-amino-5-hydroxybenzoic acid (AHBA) deficient mutant of Actinosynnema pretiosum to restore ansamitocin formation. The low efficiency of complementation by the diketide, compared to AHBA, is due to inefficient loading onto the PKS and not the inhibition of the enzyme. A presumed next chain-extension intermediate-the triketide with an unrearranged double bond-was also synthesized as its SNAC ester, but did not complement the AHBA(-) mutant.

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“…The first total synthesis of herbimycin was reported by Nakata and co-workers in 1991 [91]. However, the total synthesis of GDA was not available until 2003, when Andrus and co-workers reported a procedure that afforded the natural product as a 1:10 mixture with (−)- o -quinogeldanamycin in low yield [92]. This result was due primarily to problematic oxidation of the trimethoxy precursor to the paraquinone.…”

Section: Natural Product Inhibitors Of Hsp90mentioning

confidence: 99%