Studies Directed toward Asymmetric Synthesis of Cardioactive Steroids via Anionic Polycyclization

Yang, Zhixiang; Shannon, Dean; Truong, Vouy-Linh; Deslongchamps, Pierre

doi:10.1021/ol027125o

Cited by 38 publications

(19 citation statements)

References 17 publications

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“…The initial steps of the synthesis, drawn from our previous studies on steroid skeleton synthesis,9–11 were successful (Scheme ). Thus, the union of Nazarov substrate 3 10b with freshly prepared cyclohexenone 2 11, 12 in the presence of Cs 2 CO 3 at 0 °C followed by decarboxylation afforded tricycle 4 with an overall yield of 78 %. Reduction of the resulting aldehyde with Li(Et 3 CO) 3 AlH13 and then protection of the alcohol as its PMB ether14 afforded aldol precursor 5 in 74 % yield over two steps The aldol reaction to form the desired tetracycle 6 in 83% yield occurred in the presence of KHMDS.…”

Section: Methodsmentioning

confidence: 98%

Total Synthesis of Ouabagenin and Ouabain

et al. 2008

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Dedicated to Professor Zdenek Valenta on the occasion of his 80th birthdayOuabain (1 a), a cardioactive glycoside isolated from the bark of the African ouabio tree (Acokanthera ouabio) by Arnaud in 1888), [1] has received considerable attention since it was discovered that an ouabain-like compound occurs naturally in mammals and acts as an endogenous digitalis as proposed by Szent-Gyorgyi.[2] After some debate, it was established that the endogenous and plant derived ouabain are in fact identical.[3] Ouabagenin (1 b), the aglycone of ouabain, was isolated for the first time in 1942 by Mannich and Siewert, [4] who proposed a structure for the aglycone, and the structure for ouabain, which was later proven to be correct. [5] Progress towards the construction of these highly oxygenated steroids has been made recently, [6][7][8] but to date no total synthesis has been reported. Our foray into this field was based on a hypothesis that the polyanionic cyclization (double-Michael addition followed by aldol condensation) methodology developed by our research group [9] would allow facile access to an appropriately functionalized tetracyclic intermediate with the desired A/B cis, B/C trans, and C/D cis ring junctions. Our initial studies [9,10] suggested a promising synthetic route towards 14-b-OH steroidal intermediates, and herein we report the completion of the first total synthesis of ouabagenin (1 b) and in turn ouabain (1 a).Our strategy was based on the initial rapid construction of densely functionalized tetracycle D, (Scheme 1), which contains, in principle, the functionalities required for ouabagenin (1 b) and in turn ouabain (1 a). Tetracycle D would be readily available from tricycle C, which in turn could be produced from the condensation of chiral building blocks A and B.The initial steps of the synthesis, drawn from our previous studies on steroid skeleton synthesis, [9][10][11] were successful (Scheme 2). Thus, the union of Nazarov substrate 3[10b] with freshly prepared cyclohexenone 2 [11,12] in the presence of Cs 2 CO 3 at 0 8C followed by decarboxylation afforded tricycle 4 with an overall yield of 78 %. Reduction of the resulting aldehyde with Li(Et 3 CO) 3 AlH [13] and then protection of the alcohol as its PMB ether [14] afforded aldol precursor 5 in 74 % yield over two steps The aldol reaction to form the desired tetracycle 6 in 83% yield occurred in the presence of KHMDS. In order to reduce the ketone at C1 to give the desired b stereochemistry, it was necessary to first deprotect the alcohol at C11, by saponification of the acetate, which assisted the subsequent surprisingly facile reduction of the C1 ketone with NaBH 4 in EtOH at À78 8C to produce 7 with an overall yield of 95 %.Oxidation of PMB ether 7 was carried out in a CH 2 Cl 2 solution, which was rigorously dried with molecular sieves prior to addition of DDQ, to afford orthoester 8 in 84 % yield. [15,16] From orthoester 8, formation of a silyl enol ether using excess TBSOTf and oxidation to the enone with DDQ [17] proceeded smoothly to aff...

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Section: Methodsmentioning

confidence: 98%

Total Synthesis of Ouabagenin and Ouabain

et al. 2008

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“…With these results, we felt necessary to unambiguously assign the absolute configuration of our synthetic (+)- 4 by an independent synthesis route that could use chiral material of well-established absolute configuration. Based on the work of Yamashita, 20 and Deslongchamps, 21 readily available Hajos-Parrish ketone (+)- 6 12 was converted into known aldehyde (+)- 10 in 5 steps and 36% overall yield (Scheme 3). Nucleophilic addition of CH 3 Li in THF delivered the corresponding secondary alcohol as mixture of diastereomers, which converged into methyl ketone (+)- 11 upon oxidation with the Dess-Martin reagent.…”

Section: Resultsmentioning

confidence: 99%

“…Aldehyde (+)- 10 Was prepared in five steps and 36% overall yield from known Hajos-Parrish ketone (+)- 6 12 using the sequence described by Deslongchamps 21 with the following modification: NaBH 4 reduction of the Hajos-Parrish ketone (+)- 6 was carried out using the method of Yamashita and Hirama. 20 Characterization data for (+)- 10 matched those described by Deslongchamps.…”

Section: Methodsmentioning

confidence: 99%

A total synthesis of (−)-hortonone C

et al. 2017

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A total synthesis of the cytotoxic terpenoid hortonone C was accomplished and its absolute stereochemistry confirmed. Intermediate (+)-4 was synthesized using either an asymmetric conjugate addition strategy, or by elaboration of the Hajos-Parrish ketone. Reduction of (+)-4 under dissolving-metal conditions and trapping the enolate intermediate served to control the cis-stereochemistry at the ring fusion and provide a silyl enol ether necessary for ring expansion. Comparison of optical rotation data confirmed that the absolute configuration of natural hortonone C is (6S,7S,10S).

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“…Despite the long history of research in this area, the interest in cardenolides continues. Recently reported work on cardenolides includes the total synthesis of digitoxigenin1,5 and ouabain,6 biosynthesis7 and the search for new, less toxic digitalis‐like compounds with better pharmacological properties for therapeutic use 8. It has recently been reported that cardenolides have a growth inhibitory effect on cancer cell lines9 and show antiproliferative10 and cytotoxic11 activity.…”

Section: Introductionmentioning

confidence: 99%

Cyclobutanone Approach to the Synthesis of Cardenolides

2005

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17β‐(3‐Oxocyclobutyl)androstane, prepared by the thermal [2 + 2] cycloaddition of dichloroketene to 3β‐acetoxypregna‐5,20‐diene, is the key intermediate in the new, efficient synthesis of steroids bearing the 17β‐butenolide fragment that characterizes cardenolides. The six‐step synthesis of 3β‐tert‐butyldimethylsilyloxy‐14α‐carda‐5,20(22)‐dienolide was achieved with a total yield of 32%. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)

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Studies Directed toward Asymmetric Synthesis of Cardioactive Steroids via Anionic Polycyclization

Cited by 38 publications

References 17 publications

Total Synthesis of Ouabagenin and Ouabain

Total Synthesis of Ouabagenin and Ouabain

A total synthesis of (−)-hortonone C

Cyclobutanone Approach to the Synthesis of Cardenolides

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