Synthesis of the North 1 Unit of the Cephalostatin Family from Hecogenin Acetate<sup>1</sup>

Kim, Seongkon; Sutton, Scott C.; Guo, Cunlan; Lacour, Thomas; Fuchs, P. L.

doi:10.1021/ja9817139

Cited by 55 publications

(35 citation statements)

References 102 publications

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Section: Polyoxygenated Steroids and Derivativesmentioning

confidence: 99%

“…The synthetic pathway started with the transformation of a spiroketal functionality of tigogenin to a keto ester using the method previously described by Micovic et al, and modified by Fushs et al [67]. The keto ester I was then transformed to a trihydroxyl intermediate II by Grignard reagent which, after oxidation, gave compounds 21 and 22.…”

Section: Polyoxygenated Steroids and Derivativesmentioning

confidence: 99%

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Marine Natural Products as Models to Circumvent Multidrug Resistance

et al. 2016

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Multidrug resistance (MDR) to anticancer drugs is a serious health problem that in many cases leads to cancer treatment failure. The ATP binding cassette (ABC) transporter P-glycoprotein (P-gp), which leads to premature efflux of drugs from cancer cells, is often responsible for MDR. On the other hand, a strategy to search for modulators from natural products to overcome MDR had been in place during the last decades. However, Nature limits the amount of some natural products, which has led to the development of synthetic strategies to increase their availability. This review summarizes the research findings on marine natural products and derivatives, mainly alkaloids, polyoxygenated sterols, polyketides, terpenoids, diketopiperazines, and peptides, with P-gp inhibitory activity highlighting the established structure-activity relationships. The synthetic pathways for the total synthesis of the most promising members and analogs are also presented. It is expected that the data gathered during the last decades concerning their synthesis and MDR-inhibiting activities will help medicinal chemists develop potential drug candidates using marine natural products as models which can deliver new ABC transporter inhibitor scaffolds.

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Section: Polyoxygenated Steroids and Derivativesmentioning

confidence: 99%

Section: Polyoxygenated Steroids and Derivativesmentioning

confidence: 99%

Marine Natural Products as Models to Circumvent Multidrug Resistance

et al. 2016

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“…Meanwhile, Fuchs and co-workers reported the first total synthesis of 1 and other cephalostatin members [6][7][8]. Very recently, Shair et al have reported the second total synthesis of 1 using an elegant allylic oxidation method of C-18 [9].…”

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confidence: 99%

Selective transformations of cephalostatin analogues

Nawasreh

2011

Pure and Applied Chemistry

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The highly tumor inhibitory cephalostatins (e.g., cephalostatin 1), a marine natural product isolated from Cephalodiscus gilcristi, have attracted us to synthesize biologically active analogues. The goal of this study is to shed more light on selective desymmetrization of a symmetrical starting analogue through the F-ring opening route applied to certain analogues using different borane complexes. Previously, we have reported a selective opening of the spiroketal in the northern part of an analogue using catechol-borane and D-(N-tosyl) valine-borane complexes. We demonstrate here the possibility of opening the southern part of the same analogue using salicylic acid-borane complex by which extra flexibility is harvested. In contrast, a different reaction type took place when another analogue was treated with 3,4-diaminobenzonitrile-borane complex, which give after H 2 O 2 oxidation, products arising from Δ 14 bond hydration. This led us to conclude that the geometry of both borane complex and substrate govern the regioselectivity of the products. However, the electronic nature of both substrate and borane-complex govern the chemoselectivity.During the 1990s, Winterfeldt's group was busy in the synthesis of symmetrical and asymmetrical analogues [5]. Meanwhile, Fuchs and co-workers reported the first total synthesis of 1 and other cephalostatin members [6][7][8]. Very recently, Shair et al. have reported the second total synthesis of 1 using an elegant allylic oxidation method of C-18 [9]. The work of these groups depends on asymmetrical coupling of the proper steroidal parts to generate a rigid desired synthetic target. Despite the number of synthetic procedures in the literature, the interest in alternative and more convenient procedure for the synthesis of 1 is high. Thus, our philosophy is completely different. Based on desymmetrizing of the gram-scaled symmetrical diketone (2) followed by remote interconversion methods, we build up our strategy aiming at either the synthesis of flexible analogues or perhaps the natural product itself. This strategy enables us to gather a lot of information about the behavior of the active centers in such complicated structures along with building a helpful spectral database. M. M. NAWASREHScheme 1 Different-side spiroketal opening of 3. (i) 16 equiv a, abs THF, 0-7 °C, two weeks; (ii) 10 equiv b, abs THF, 0-2 °C, four weeks. M. M. NAWASREHScheme 2 Regioselective spiroketal opening of 6. (i) 1.5 equiv c, 24 h/0-5 °C; (ii) 10 equiv d/3 days/78 %.Scheme 3 Hydroboration-oxidation of 8 using the complex e. (i) 16 equiv e, abs THF/H 2 O 2 , 0-8 °C.Scheme 4 Regioselective hydration of 11. (i) 5 equiv BH 3 ؒTHF, 0-7 °C.

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“…The North 1 synthesis44 began with the reduction of hecogenin acetate 32 with DIBAL-H followed by acylation to provide rockogenin diacetate (Scheme 22). Rockogenin diacetate was converted into pseudorockogenin triacetate 69 by pyridinium hydrochloride catalyzed reaction with acetic anhydride.…”

Section: Classical First Generation Synthesesmentioning

confidence: 99%