Ring C closure as key step in the synthesis of steroids

Sarabèr, Florence C.E.; Groot, Aede de

doi:10.1016/j.tet.2006.03.027

Cited by 29 publications

(6 citation statements)

References 151 publications

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“…* Semisynthesis-where a readily available steroid is used as the starting material and through functional group manipulation, and redox strategies, the desired target compound can be accessed, [15][16][17][18][19][20] * De novo or total synthesis-where the tetracyclic structure is constructed from simpler building blocks, through CÀ C bond-forming and ring construction reactions. Due to the difficulty in selectively oxidising CÀ H bonds in these complex structures, a common approach to steroid synthesis is by using ring-forming reactions with the oxygen functionality already in the desired position.…”

Section: Synthesis Of Oxygenated Steroidsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“… Semisynthesis‐ where a readily available steroid is used as the starting material and through functional group manipulation, and redox strategies, the desired target compound can be accessed, [15–20] De novo or total synthesis‐ where the tetracyclic structure is constructed from simpler building blocks, through C−C bond‐forming and ring construction reactions. …”

Section: Introductionmentioning

confidence: 99%

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Selective Hydroxylation of C(sp³)−H Bonds in Steroids

Abas

Blencowe

Brookfield

et al. 2023

Chemistry A European J

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Steroids are highly prevalent structures in small‐molecule therapeutics, with the level of oxidation being key to their biological activity and physicochemical properties. These C(sp3)‐rich tetracycles contain many stereocentres, which are important for creating specific vectors and protein binding orientations. Therefore, the ability to hydroxylate steroids with a high degree of regio‐, chemo‐ and stereoselectivity is essential for researchers working in this field. This review will cover three main methods for the hydroxylation of steroidal C(sp3)−H bonds: biocatalysis, metal‐catalysed C−H hydroxylation and organic oxidants, such as dioxiranes and oxaziridines.

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Section: Synthesis Of Oxygenated Steroidsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Selective Hydroxylation of C(sp³)−H Bonds in Steroids

Abas

Blencowe

Brookfield

et al. 2023

Chemistry A European J

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“…3 While seeming to therefore represent a mature area of medicinal science that has thrived due to advances in organic chemistry, we believe that exploration in this area remains quite constrained due to inherent limitations associated with compound synthesis: (1) semisynthesis is effective for broad exploration of only the natural enantiomeric series, 4 and (2) despite the myriad of approaches to de novo synthesis of steroids, highly efficient and flexible routes remain scarce. 5 This perspective has fueled our curiosity in exploring this area of chemical science, and has recently led to the establishment of a new convergent strategy for the asymmetric synthesis of partially aromatic steroids. 6 As illustrated in Figure 1, the approach features a metallacycle-mediated annulative cross-coupling reaction ( 1 + 2 → 3 ), regioselective cyclopropanation ( 3 → 4 ) and a new acid-mediated vinylcyclopropane rearrangement cascade ( 4 → 5 ).…”

mentioning

confidence: 99%

“…In particular, compositions of matter that would well be recognized as steroidal in nature have been remarkably successful in the clinic as treatments for a wide range of medical issues, and this broad class of molecules is understood to be the most well-studied and successful class of natural product inspired pharmaceuticals . While seeming to therefore represent a mature area of medicinal science that has thrived due to advances in organic chemistry, we believe that exploration in this area remains quite constrained due to inherent limitations associated with compound synthesis: (1) semisynthesis is effective for broad exploration of only the natural enantiomeric series, and (2) despite the myriad of approaches to de novo synthesis of steroids, highly efficient and flexible routes remain scarce . This perspective has fueled our curiosity in exploring this area of chemical science and has recently led to the establishment of a new convergent strategy for the asymmetric synthesis of partially aromatic steroids .…”

mentioning

confidence: 99%

Synthesis and Discovery of Estra-1,3,5(10),6,8-pentaene-2,16α-diol

Wai

Anesini

et al. 2018

Org. Lett.

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A metallacycle-centered approach to the assembly of partially aromatic synthetic steroids was investigated as a means to prepare a boutique collection of unique steroidal agents. The synthesis and discovery of estra-1,3,5(10),6,8-pentaene-2,16α-diol (VII) is described, along with structure-activity relationships related to its cytotoxic properties. Overall, VII was found to have a GI = 0.2 μg/mL (∼800 nM) in MDA-MB-231 human breast cancer cells, be an efficacious estrogen receptor agonist with potency for ERβ > ERα (ERβ EC = 21 nM), possess selective affinity to the cdc-2-like kinase CLK4 (K = 350 nM), and be phenotypically related to paclitaxel by an unbiased panel assessment.

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Pentacyclic Compounds by Samarium Diiodide‐Induced Cascade Cyclizations of Naphthyl‐Substituted 1,3‐Diones

Wefelscheid

Reißig

2008

Adv Synth Catal

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Treatment of naphthyl-substituted cyclopentane-1,3-diones with the samarium diiodidehexamethylphosphoramide (HMPA) complex in the presence of tert-butyl alcohol provided the expected tetracyclic diols with steroid-like structures. Surprisingly, reactions without the proton source led to the efficient formation of a new pentacyclic diol. In this case the toxic additive HMPA could be substituted by a combination of lithium bromide (in situ generation of samarium dibromide) and N,N-dimethylimidazolidone. The styrene-like alkene moiety of this product was used to prepare an ensemble of highly substituted pentacyclic steroid-like compounds.Keywords: electron transfer; ketyl-aryl coupling; polycycles; radical reactions; samarium diiodide; steroids In earlier communications we have reported that garyl ketones undergo novel samarium diiodide-induced cyclizations leading to synthetically useful hexahydronaphthalene derivatives.[1] The closely related reaction of simple cyclic g-naphthyl-substituted ketones furnished tetracyclic compounds with steroidlike constitution, but "unnatural" cis/cis annulation of rings B/C/D.[2] Here we describe our experiments with cyclic 1,3-diones as precursors for the crucial samarium ketyls, [3] which were performed to generate steroid analogous products with additional functionality in ring D.The required naphthyl-substituted 1,3-diketones were prepared by a straightforward four-step synthesis following the Torgov approach to steroids as exemplified for compound 5 (Scheme 1).[4] Dione 3 was obtained by addition of vinylmagnesium bromide to tetralone 1 followed by a Pd-catalyzed allylic alkylation.[4d] Oxidation of 3 with DDQ [4e] and subsequent reduction [5] of the alkene moiety furnished dione 5 in 35 % overall yield. Analogously, 6 and 13 were prepared from the corresponding precursors. Cyclopentane-1,3-dione derivative 5 was treated with an excess of samarium diiodide in the presence of HMPA [6] and tert-butyl alcohol and provided the expected diols 7a/7b in yields varying between 67-74 %. The ratio of diastereomers 7a/7b strongly depends on the amount of the proton source (Table 1, entries 1-4). Standard conditions (8 equivs.) led to an unselective reaction (entry 1), whilst use of only 1 equiv. of tert-butyl alcohol (entry 4) induced a highly diastereoselective formation of tetracyclic diol 7a.[7] The relative configurations of 7a and 7b were unequivocally proven by X-ray analyses.[8] The conversion of cyclohexane-1,3-dione derivative 6 into tetracyclic diol 8 is rather slow and even after a reaction time of two days 25 % of 6 was recovered (entry 5). We assume a mechanism for these cyclizations as proposed before, [2] but here a subsequent stereoselective reduction of the remaining cycloalkanone carbonyl group by the excess of samarium diiodide generates the second hydroxy group. This step affords products 7 and 8 with trans-arranged hydroxy groups. However, the protonation at the carbon adjacent to the benzene ring proceeds with varying stereoselectivity, being strongly d...

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Ring C closure as key step in the synthesis of steroids

Cited by 29 publications

References 151 publications

Selective Hydroxylation of C(sp³)−H Bonds in Steroids

Selective Hydroxylation of C(sp³)−H Bonds in Steroids

Synthesis and Discovery of Estra-1,3,5(10),6,8-pentaene-2,16α-diol

Pentacyclic Compounds by Samarium Diiodide‐Induced Cascade Cyclizations of Naphthyl‐Substituted 1,3‐Diones

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Ring C closure as key step in the synthesis of steroids

Cited by 29 publications

References 151 publications

Selective Hydroxylation of C(sp3)−H Bonds in Steroids

Selective Hydroxylation of C(sp3)−H Bonds in Steroids

Synthesis and Discovery of Estra-1,3,5(10),6,8-pentaene-2,16α-diol

Pentacyclic Compounds by Samarium Diiodide‐Induced Cascade Cyclizations of Naphthyl‐Substituted 1,3‐Diones

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Selective Hydroxylation of C(sp³)−H Bonds in Steroids

Selective Hydroxylation of C(sp³)−H Bonds in Steroids