Determination of the Relative and Absolute Stereochemistry of Fostriecin (CI-920)

Boger, Dale L.; Hikota, Masataka; Lewis, Bryan M.

doi:10.1021/jo962166h

Cited by 66 publications

(59 citation statements)

References 21 publications

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“…The relative configurations of C4-C6 and C9-C11 of cytostatin were assigned as syn at C4/C5 and C9/C10 and as anti at C5/C6 and C10/C11 by the research groups of Waldmann and Boger by comparison of key features of the 1 H NMR spectra of cytostatin with those of relevant models. [2,3] This approach lowered the number of structure candidates down to four, namely: 1 ss, 1 rs, 1 sr, and 1 rr.[4]Based on an analogy to fostriecin 2 [5] and related compounds (which share three stereocenters with 1), the research groups of Waldmann and Boger independently synthesized (4S,5S,6S,9S,10S,11S)-1 (hereafter called 1 ss), and concluded, by comparison of spectroscopic, physical, and biological properties, that this was the natural product.We have recently commented on the logic of proof and disproof of stereostructures by comparison of synthetic and natural samples.[6] If two or more stereoisomers of a natural product can reasonably be expected to have substantially identical spectra, then a rigorous assignment of the structure should include proof that the candidate isomer matches the natural product and, more importantly, proof that the other isomers do not. Acetogenins, such as the murisolins have very remote groups of stereocenters (10 or more methylene groups apart), so it can be expected that diastereomers might exhibit substantially identical spectra.…”

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confidence: 99%

Confirmation of the Stereostructure of (+)‐Cytostatin by Fluorous Mixture Synthesis of Four Candidate Stereoisomers

et al. 2008

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Dedicated to Professor Yoshito Kishi on the occasion of his 70th birthdayCytostatin (1) is a potent and selective inhibitor of protein phosphatase 2A that was isolated from the cultured broth of Streptomyces sp. by Ishizuka and co-workers (Scheme 1).[1] It inhibits lung metastasis of melanoma cells in mice and displays potent cytotoxic activity toward leukemia cell lines (inhibitory concentration; IC 50 = 42-65 nm). Ishizuka and coworkers assigned the two-dimensional structure (constitution) of cytostatin (1) by analysis of 1D and 2D NMR spectra. The relative configurations of C4-C6 and C9-C11 of cytostatin were assigned as syn at C4/C5 and C9/C10 and as anti at C5/C6 and C10/C11 by the research groups of Waldmann and Boger by comparison of key features of the 1 H NMR spectra of cytostatin with those of relevant models. [2,3] This approach lowered the number of structure candidates down to four, namely: 1 ss, 1 rs, 1 sr, and 1 rr.[4]Based on an analogy to fostriecin 2 [5] and related compounds (which share three stereocenters with 1), the research groups of Waldmann and Boger independently synthesized (4S,5S,6S,9S,10S,11S)-1 (hereafter called 1 ss), and concluded, by comparison of spectroscopic, physical, and biological properties, that this was the natural product.We have recently commented on the logic of proof and disproof of stereostructures by comparison of synthetic and natural samples.[6] If two or more stereoisomers of a natural product can reasonably be expected to have substantially identical spectra, then a rigorous assignment of the structure should include proof that the candidate isomer matches the natural product and, more importantly, proof that the other isomers do not. Acetogenins, such as the murisolins have very remote groups of stereocenters (10 or more methylene groups apart), so it can be expected that diastereomers might exhibit substantially identical spectra.[6] In contrast, the two groups of stereocenters in cytostatin (1) are only insulated by an ethylene group. Will enantiomers 1 ss and 1 rr have different spectra from their diastereomers 1 rs and 1 sr? To answer this question, and thereby to prove which three isomers were not cytostatin, we undertook the fluorous mixture synthesis [7,8] of all four isomers of 1.The fluorous mixture synthesis (FMS) strategy to make the four isomers of cytostatin is briefly outlined in Scheme 2. Late introduction of the triene is dictated by its chemical instability, so we followed the strategy of Bialy and Waldmann [2d] by planning to prepare four individual vinyl iodides 3 by coupling with alkenyl stannane 4.These four isomers are made over several steps from a single four-compound mixture of fluorous-tagged quasiisomers M-5 [9] ("quasi" because the compounds have different fluorous tags and are not true isomers [10] ). In turn, M-5 is made by coupling between fluorous-tagged quasiracemic aldehydes M-6 with quasiracemic keto phosphonates M-7 by a Horner-Wadsworth-Emmons (HWE) reaction.From the FMS standpoint, the configurations of the stereocenters ...

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confidence: 99%

Confirmation of the Stereostructure of (+)‐Cytostatin by Fluorous Mixture Synthesis of Four Candidate Stereoisomers

et al. 2008

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“…Lit. [5] [a] D 25 ϩ61°(c 0.2, MeOH) [7,8]. PLME was then evaluated for in vitro antifungal activity.…”

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Identification of Phoslactomycin E as a Metabolite Inducing Hyphal Morphological Abnormalities in Aspergillus fumigatus IFO 5840

et al. 2007

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In our survey for antifungal compounds, a fermentation broth of Streptomyces sp. HA81-2 was found to inhibit the in vitro growth of Aspergillus fumigatus IFO 5840 accompanied by hyphal morphological abnormalities. One of the isolated antibiotics was identified as phoslactomycin E based on LC-MS and NMR spectral data. In a preliminary assay using the membrane fractions of A. fumigatus, phoslactomycin E was found to inhibit the activity of 1,3-b glucan synthase.Keywords antifungal activity, phoslactomycin E, Aspergillus fumigatus, hyphal morphological abnormalities, 1,3-b glucan synthase Opportunistic fungal infections are a major cause of serious morbidity and mortality in immunocompromised patients. However, there are few drugs for antifungal chemotherapy of deep-seated mycosis. As both human and fungal cells are eukaryotes, it is difficult to develop antifungal drugs without side effects in human hosts. Current targets are limited to ergosterol, cell wall components, biosynthetic pathways of cell wall and cytosine deaminase [1,2]. Therefore, there is a great need for novel antifungal drugs with new mechanisms of action. Morphological deformation of fungal hyphae is often induced by antifungal drugs [3]. As this phenomenon is specific to fungi, it could be used to screen for selective antifungal antibiotics [4]. In addition, this hyphal deformation is expected to reflect the disruption of cell wall biosynthesis, which is a specific target of antifungal agents. Moreover, investigating the mechanism of antifungal-induced hyphal morphological abnormalities is potentially useful for understanding the morphogenesis of fungal hyphae.In the course of our search for antifungal antibiotics, we found that a fermentation broth of Streptomyces sp. HA81-2 exhibited antifungal activity against Aspergillus fumigatus IFO 5840 accompanied by hyphal abnormalities. The isolated active fraction was identified as phoslactomycin E (PLME) [5] based on LC-MS and NMR spectral data. We herein report the isolation procedures for PLME, its molecular characteristics, and its induction of morphological changes in fungal cells.Active principles were isolated as follows; fermentation broth was filtered, the filtrate was applied on Diaion HP-20 column, and then eluted using an increasing gradient of aq MeOH (10ϳ100%). The 80ϳ90% MeOH fractions were concentrated in vacuo to afford crude extract, which was partitioned between water and CHCl 3 . Purification of

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“…19 The stereochemistry at C5 had been determined by chemical degradation of the natural product by Hokanson and French in 1985. 18 This left the C8, C9, and C11 stereocenters undefined.…”

Section: Fostriecinmentioning

confidence: 99%

“…18 The full stereochemical assignment of fostriecin was determined by Boger, allowing for the assignment of most of the stereocenters of the rest of the family by analogy. 19 …”

Section: Introductionmentioning

confidence: 99%

Synthetic Strategies Employed for the Construction of Fostriecin and Related Natural Products

2016

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Fostriecin and related natural products present a significant challenge for synthetic chemists due to their structural complexity and chemical sensitivity. This review will chronicle the successful efforts of synthetic chemists in the construction of these biologically active molecules. Key carbon–carbon bond forming reactions will be highlighted, as well as the methods used to install the numerous stereocenters present in this class of compounds.

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Determination of the Relative and Absolute Stereochemistry of Fostriecin (CI-920)

Cited by 66 publications

References 21 publications

Confirmation of the Stereostructure of (+)‐Cytostatin by Fluorous Mixture Synthesis of Four Candidate Stereoisomers

Confirmation of the Stereostructure of (+)‐Cytostatin by Fluorous Mixture Synthesis of Four Candidate Stereoisomers

Identification of Phoslactomycin E as a Metabolite Inducing Hyphal Morphological Abnormalities in Aspergillus fumigatus IFO 5840

Synthetic Strategies Employed for the Construction of Fostriecin and Related Natural Products

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