Total Synthesis of a CD-Ring: Side-Chain Building Block for Preparing 17-<i>epi</i>-Calcitriol Derivatives from the Hajos–Parrish Dione

Michalak, Karol; Wicha, J.

doi:10.1021/jo201083w

Cited by 12 publications

(3 citation statements)

References 38 publications

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“…As a typical feature of steroids, aplykurodinones contain a lipophilic side chain with the stereocenter at C13 connected to the core. [7] As part of our current program of natural product synthesis, we were interested in the development of an oxidative process to expand the potential of the Hajos-Parrish methodology to the synthesis of chiral hydrindenediones with quaternary carbon stereo-centers. [3] The continued interest in steroids [4] is highlighted by a recent total synthesis of rac-1 by Danishefsky and coworkers, who employed an elegant strategy featuring an ionic Diels-Alder reaction to form the racemic hyndrindane core.…”

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confidence: 99%

“…On the other hand, this class of molecules features a cis hydrindane moiety (C7-C8 configuration), a structural framework that is also found in pavidolide B (3). [7] As part of our current program of natural product synthesis, we were interested in the development of an oxidative process to expand the potential of the Hajos-Parrish methodology to the synthesis of chiral hydrindenediones with quaternary carbon stereo-centers. [5] "Hajos-Parrish-type" ketones [6] are versatile scaffolds for the formation of complex target molecules, as they are often available in enantioenriched form.…”

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Formal Enantioselective Synthesis of Aplykurodinone‐1

Peixoto¹,

Jean²,

Maddaluno³

et al. 2013

Angew Chem Int Ed

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Aplykurodinone-1 (1) is a degraded sterol that can be isolated from the skin of Syphonota geographica, a mollusc that belongs to the Aplysiidae family (Scheme 1). [1] While the biological profile of this molecule remains unknown to date, the closely related aplykurodinone-B (2) exhibits mild cytotoxic activities. [2] Noteworthy, the structure of 1 features six contiguous stereocenters, including a stereogenic quaternary center, embedded in an intriguing hydroindenone system. As a typical feature of steroids, aplykurodinones contain a lipophilic side chain with the stereocenter at C13 connected to the core. On the other hand, this class of molecules features a cis hydrindane moiety (C7-C8 configuration), a structural framework that is also found in pavidolide B (3). [3] The continued interest in steroids [4] is highlighted by a recent total synthesis of rac-1 by Danishefsky and coworkers, who employed an elegant strategy featuring an ionic Diels-Alder reaction to form the racemic hyndrindane core. [5] "Hajos-Parrish-type" ketones [6] are versatile scaffolds for the formation of complex target molecules, as they are often available in enantioenriched form. [7] As part of our current program of natural product synthesis, we were interested in the development of an oxidative process to expand the potential of the Hajos-Parrish methodology to the synthesis of chiral hydrindenediones with quaternary carbon stereo-centers. [8] Herein, we report the successful implementation of this strategy, resulting in the concise formal enantioselective synthesis of 1.The structure of 1 inspired a synthetic approach in which the formation of the quaternary carbon center C7 is pivotal to the stereoselective assembly of the complete skeleton (Scheme 2). In accordance with this plan, we envisaged the preparation of 7 by Michael coupling of 4 and 5, followed by the enantioselective Robinson annulation of adduct 6. Next, oxidation of 7 at C9 followed by the formal deoxygenation at C11 was planned in order to access 8. A chemoselective reduction of the olefin would lead to the stereocenters at C8 and C3 in 9. Our assumptions were that the cis relationship at C8-C7 could be thermodynamically favored, while the trans relationship at C8-C3 could be changed by epimerization. Then, chemo-and diastereoselective reduction of 9 followed by oxidative lactonization would lead to the known tricyclic system 10. Overall, the stereocenter at C7 of 7 would control the formation of the three other stereogenic centers.To evaluate this strategy, rac-7 was produced on a multigram scale from readily available 4 and 5. [9] In order to perform the formal deoxygenation of 7, the reduction of the ketone moiety at C11 was followed by the mesylation of the resulting hydroxy group to facilitate the elimination step (Scheme 3). Regarding the oxidation of C9, we anticipated that a dienolate formed in the presence of bases such as 1, 8diazabicyclo[5.4.0]undec-7-ene (DBU) would steer the regioselectivity of the process. As it is compatible with this base, molecular oxyg...

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confidence: 99%

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confidence: 99%

Formal Enantioselective Synthesis of Aplykurodinone‐1

Peixoto¹,

Jean²,

Maddaluno³

et al. 2013

Angew Chem Int Ed

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“…Michalak and Wicha reported stereoselective alkylation of des-AB 17- epi -steroid, used for the synthesis of 17- epi -calcitriol derivatives. Cyclopropane carboxylic ester 178 was reduced with lithium in liquid ammonia–THF in the presence of tert -butanol, followed by oxidation with Jones reagent and treatment with diazomethane, afforded ester 179 .…”

Section: Methods For Stereoselective Generation Of C-20(h) Stereogeni...mentioning

confidence: 99%