Chemical Synthesis of the Cardiotonic Steroid Glycosides and Related Natural Products

Heasley, Brian

doi:10.1002/chem.201103733

Cited by 84 publications

(49 citation statements)

References 178 publications

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“…A previous synthesis of ouabagenin by Deslongchamps, while an elegant accomplishment, proceeded in 41 steps from Hajos-Parrish ketone in 0.21% overall yield and relied on a relay synthesis from degradation of authentic ouabain (17). In addition, several synthetic studies on this molecule have been disclosed (18). …”

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confidence: 99%

Strategic Redox Relay Enables A Scalable Synthesis of Ouabagenin, A Bioactive Cardenolide

Renata

Zhou

Baran

2013

Science

167

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Here we report a scalable route to the polyhydroxylated steroid ouabagenin with an unusual spin on the age-old practice of steroid semi-synthesis. The incorporation of both redox and stereochemical relays during the design of this synthesis resulted in efficient access to more than 500 mg of a key precursor towards ouabagenin–and ultimately ouabagenin itself–and the discovery of innovative methods for C–H and C–C activation and C–O bond hemolysis. Given the medicinal relevance of the cardenolides in the treatment of congestive heart failure, a variety of ouabagenin analogs could potentially be generated from the key intermediate as a means of addressing the narrow therapeutic index of these molecules.

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confidence: 99%

Strategic Redox Relay Enables A Scalable Synthesis of Ouabagenin, A Bioactive Cardenolide

Renata

Zhou

Baran

2013

Science

167

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“…[5] Accordingly, their potential use in oncology has been investigated. Numerous laboratories have reported synthetic studies on these natural products, [7,8] which has culminated in the successful total syntheses of ouabain by the Deslongchamps group and ouabagenin, its aglycon, by Baran. [6] Cardenolides and bufadienolides share a characteristic steroid-like framework that is distinct from conventional androstane/pregnane-type steroids in that they have cis A/B and C/D ring junctions, a tertiary 14b-hydroxyl group, and a 17b-unsaturated lactone.…”

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confidence: 99%

A Convergent Total Synthesis of 19‐Hydroxysarmentogenin

et al. 2013

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Crossopetalum gaumeri (Loes.), a medical plant among the Yucatec Mayan community, contains various highly cytotoxic natural products, including 19-hydroxysarmentogenin-3b-Ob-6-deoxyguloside (Figure 1). [1] This compound belongs to a family of cardenolides and bufadienolides, which are Scheme 2. Reagents and conditions: a) toluene, reflux; HCl (1 m), THF, RT, 78 %; b) LiAlH 4 , Et 2 O, À78 8C to RT; c) MnO 2 , CH 2 Cl 2 , RT, 66 % (2 steps); d) Ac 2 O, Et 3 N, CH 2 Cl 2 , RT, 99 %; e) OsO 4 , NaIO 4 , 2,6lutidine, H 2 O, dioxane, RT, 94 %; f) m-CPBA, CH 2 Cl 2 , RT, 67 %; g) K 2 CO 3 , MeOH, RT, 92 %; h) TBSOTf, 2,6-lutidine, CH 2 Cl 2 , RT; i) PPTS, H 2 O, MeOH, 0 8C, 99 % (2 steps); j) DIBAL-H, CH 2 Cl 2 , À78 8C, 63 %; k) TBSOTf, 2,6-lutidine, CH 2 Cl 2 , RT, 96 %; l) O 3 , CH 2 Cl 2 , À78 8C; Ph 3 P, RT, 80 %; m) A, LDA, THF, RT, 71 % (E/Z = 1:1.2); n) TBAF, THF, 60 8C; o) Ac 2 O, pyridine, DMAP, RT, 84 % (2 steps). DIBAL-H = diisobutylaluminum hydride, DMAP = N,N-dimethyl-4-amino pyridine, LDA = lithium diisopropylamide, m-CPBA = meta-chloroperoxybenzoic acid, PPTS = pyridinium p-toluenesulfonate, TBAF = tetra-n-butylammonium fluoride, TBS = tert-butyldimethylsilyl. AngewandteChemie 5301

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“…The pharmaceutical availability of cardenolides has depended upon their natural sources because of difficulties associated with their chemical syntheses [68]. Even more surprising is that the biosynthetic pathways for these diverse cardenolides have not been completely worked out, and there are numerous outstanding questions about their biosynthesis and accumulation.…”

Section: Resultsmentioning

confidence: 99%

Medicinal Plants: A Public Resource for Metabolomics and Hypothesis Development

et al. 2012

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Specialized compounds from photosynthetic organisms serve as rich resources for drug development. From aspirin to atropine, plant-derived natural products have had a profound impact on human health. Technological advances provide new opportunities to access these natural products in a metabolic context. Here, we describe a database and platform for storing, visualizing and statistically analyzing metabolomics data from fourteen medicinal plant species. The metabolomes and associated transcriptomes (RNAseq) for each plant species, gathered from up to twenty tissue/organ samples that have experienced varied growth conditions and developmental histories, were analyzed in parallel. Three case studies illustrate different ways that the data can be integrally used to generate testable hypotheses concerning the biochemistry, phylogeny and natural product diversity of medicinal plants. Deep metabolomics analysis of Camptotheca acuminata exemplifies how such data can be used to inform metabolic understanding of natural product chemical diversity and begin to formulate hypotheses about their biogenesis. Metabolomics data from Prunella vulgaris, a species that contains a wide range ofantioxidant, antiviral, tumoricidal and anti-inflammatory constituents, provide a case study of obtaining biosystematic and developmental fingerprint information from metabolite accumulation data in a little studied species. Digitalis purpurea, well known as a source of cardiac glycosides, is used to illustrate how integrating metabolomics and transcriptomics data can lead to identification of candidate genes encoding biosynthetic enzymes in the cardiac glycoside pathway. Medicinal Plant Metabolomics Resource (MPM) [1] provides a framework for generating experimentally testable hypotheses about the metabolic networks that lead to the generation of specialized compounds, identifying genes that control their biosynthesis and establishing a basis for modeling metabolism in less studied species. The database is publicly available and can be used by researchers in medicine and plant biology.

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Chemical Synthesis of the Cardiotonic Steroid Glycosides and Related Natural Products

Cited by 84 publications

References 178 publications

Strategic Redox Relay Enables A Scalable Synthesis of Ouabagenin, A Bioactive Cardenolide

Strategic Redox Relay Enables A Scalable Synthesis of Ouabagenin, A Bioactive Cardenolide

A Convergent Total Synthesis of 19‐Hydroxysarmentogenin

Medicinal Plants: A Public Resource for Metabolomics and Hypothesis Development

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