Prostaglandins and congeners. 28. Synthesis of 2-(.omega.-carbalkoxyalkyl)cyclopent-2-en-1-ones, intermediates for prostaglandin syntheses

Bernady, Karel F.; Poletto, John F.; Nocera, Joseph; Mirando, P.; Schaub, Robert E.; Weiss, Martin J.

doi:10.1021/jo01311a032

Cited by 38 publications

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“…Direct formation of the cis -decalin 20 has previously been achieved through the sequential addition of MeMgCl and chlorobutylmagnesium bromide38 to oxonitrile 21 (Scheme 6). 39 Mechanistic experiments performed prior to finding the electrophile-dependent alkylations of C -magnesiated nitriles, implied that the intermediate dimagnesiated nitrile 27 , generated immediately following the axial conjugate addition, was particularly reactive and cyclized to 20 faster than a chair-to-chair conformational inversion ( 27 → 26 ) 29.…”

Section: Resultsmentioning

confidence: 99%

Metalated nitriles: stereodivergent cation-controlled cyclizations

et al. 2008

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Stereodivergent cyclizations of γ-hydroxy cyclohexanecarbonitriles are controlled simply through judicious choice of cation in the alkylmetal base. Deprotonating a series of cyclic γ-hydroxy nitriles with i-PrMgBr generates C-magnesiated nitriles that cyclize under stereoelectronic control to cisfused hydrindanes, decalins, and bicyclo [5.4.0] undecanes. An analogous deprotonation with BuLi triggers cyclization to trans-fused hydrindanes, decalins, and bicyclo [5.4.0] undecanes consistent with a sterically controlled electrophilic attack on an equatorial nitrile anion. Using cations to control the geometry of metalated nitriles provides a versatile, stereodivergent cyclization to cis-and transhydrindanes, decalins, and [5. 4. 0] undecanes, and reveals the key geometric requirements for intramolecular S N 2 and S N 2′ displacements. IntroductionMetalated nitriles are nucleophilic chameleons, readily adapting to the local environment by adopting different structures. 2 X-ray crystallographic analyses of metalated nitriles 3 show two main structural classes: N-metalated nitriles in which the metal coordinates to the nitrile nitrogen, 4 and C-metalated nitriles 5 in which the metal is bound to the formally anionic carbon (Figure 1, 1 and 2, respectively). Crystallographically derived bond lengths for N-and Cmetalated nitriles reveal only a slight weakening of the C≡N triple bond (1.15-1.20 Å), relative to the C≡N bond length of neutral nitriles (1.14 Å), 6 indicative of a predominant inductive stabilization 7 of the negative electron density. Consistent with the inductive stabilization are short C-CN bonds 8 stemming from an electrostatic contraction between the formal anion and the powerful electron-withdrawing nitrile group. 9 Moderating the ligand or metal environment exerts a pronounced influence on the site of coordination in metalated nitriles. The solid-state N-and C-palladated nitriles 1 and 2 10 differ rather modestly in their structural features, essentially in the nature of the phosphine ligand, but exhibit completely different coordination modes to the same nitrile! 7 Li NMR reveals basically the same structural trends for metalated nitriles in solution; a preference for N-or C-metalation that depends intimately on ligand and solvent, 11 and minimal delocalization of the anion into the carbon-nitrogen triple bond. 9 Differences in the site of metal coordination relay into different reactivity modes for N-and C-metalated nitriles. For example, reductive elimination from the N-palladated nitrile 1 is ten Correspondence to: Fraser F. Fleming. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers th...

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Section: Resultsmentioning

confidence: 99%

Metalated nitriles: stereodivergent cation-controlled cyclizations

et al. 2008

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“…Condensation of 3-O-benzyl-protected 2-ethylestrone 35 with diethyl oxalate in the presence of alkoxide has been reported in the literature, and the subsequent formation of pyrazole E-ring systems using hydrazine monohydrate is well known. [58] Thus, 36 was condensed with hydrazine monohydrate in ethanol at room temperature to give a hydrated cyclic product, and addition of p-toluenesulfonic acid monohydrate followed by heating for 5 min gave the desired pyrazole 37 in good yield. The remaining deprotection and sulfamoylation reactions were slightly more problematic, as the debenzylation of 37 with Pd/C (5 % wt.)…”

Section: Chemistrymentioning

confidence: 99%

Focused Libraries of 16‐Substituted Estrone Derivatives and Modified E‐Ring Steroids: Inhibitors of 17ß‐Hydroxysteroid Dehydrogenase Type 1

Vicker¹,

Lawrence²,

Allan³

et al. 2006

ChemMedChem

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17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1), an oxidoreductase which has a preferential reductive activity using NADPH as cofactor, converts estrone to estradiol and is expressed in many steroidogenic tissues including breast and in malignant breast cells. As estradiol stimulates the growth and development of hormone-dependent breast cancer, inhibition of the final step of its synthesis is an attractive target for the treatment of this disease. The parallel synthesis of novel focused libraries of 16-substituted estrone derivatives and modified E-ring pyrazole steroids as new potent 17beta-HSD1 inhibitors is described. Substituted 3-O-sulfamoylated estrone derivatives were used as templates and were immobilised on 2-chlorotrityl chloride resin to give resin-bound scaffolds with a multi-detachable linker. Novel focused libraries of 16-substituted estrone derivatives and new modified E-ring steroids were assembled from these immobilised templates using solid-phase organic synthesis and solution-phase methodologies. Among the derivatives synthesised, the most potent 17beta-HSD1 inhibitors were 25 and 26 with IC50 values in T-47D human breast cancer cells of 27 and 165 nm, respectively. Parallel synthesis resulting in a library of C5'-linked amides from the pyrazole E-ring led to the identification of 62 with an IC50 value of 700 nM. These potent inhibitors of 17beta-HSD1 have a 2-ethyl substituent which will decrease their estrogenic potential. Several novel 17beta-HSD1 inhibitors emerged from these libraries and these provide direction for further template exploration in this area. A new efficient diastereoselective synthesis of 25 has also been developed to facilitate supply for in vivo evaluation, and an X-ray crystal structure of this inhibitor is presented.

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“…Adding BuMgCl or BuLi to benzaldehyde affords metal alkoxides 15a that are readily transformed into the secondary benzylic chloride 2k upon exposure to 2.5 equivalents of NbCl 5 . An analogous addition of the chlorine-containing Grignard reagent 16 48 efficiently provides the dichloride 2l indicating that NbCl 5 tolerates additional chlorination in the substrate (Scheme 5). …”

Section: Resultsmentioning

confidence: 99%

Allylic and Allenic Halide Synthesis via NbCl₅- and NbBr₅-Mediated Alkoxide Rearrangements

2009

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Addition of NbCl 5 , or NbBr 5 , to a series of magnesium, lithium, or potassium allylic or propargylic alkoxides directly provides allylic or allenic halides. Halogenation formally occurs through a metallahalo-[3,3] rearrangement although concerted, ionic, and direct displacement mechanisms appear to operate competitively. Transposition of the olefin is equally effective for allylic alkoxides prepared by nucleophilic addition, deprotonation, or reduction. Experimentally, the niobium pentahalide halogenations are rapid, afford essentially pure E-allylic or allenic halides after extraction, and are applicable to a range of aliphatic and aromatic alcohols, aldehydes, and ketones.

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Prostaglandins and congeners. 28. Synthesis of 2-(.omega.-carbalkoxyalkyl)cyclopent-2-en-1-ones, intermediates for prostaglandin syntheses

Cited by 38 publications

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Metalated nitriles: stereodivergent cation-controlled cyclizations

Metalated nitriles: stereodivergent cation-controlled cyclizations

Focused Libraries of 16‐Substituted Estrone Derivatives and Modified E‐Ring Steroids: Inhibitors of 17ß‐Hydroxysteroid Dehydrogenase Type 1

Allylic and Allenic Halide Synthesis via NbCl₅- and NbBr₅-Mediated Alkoxide Rearrangements

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Prostaglandins and congeners. 28. Synthesis of 2-(.omega.-carbalkoxyalkyl)cyclopent-2-en-1-ones, intermediates for prostaglandin syntheses

Cited by 38 publications

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Metalated nitriles: stereodivergent cation-controlled cyclizations

Metalated nitriles: stereodivergent cation-controlled cyclizations

Focused Libraries of 16‐Substituted Estrone Derivatives and Modified E‐Ring Steroids: Inhibitors of 17ß‐Hydroxysteroid Dehydrogenase Type 1

Allylic and Allenic Halide Synthesis via NbCl5- and NbBr5-Mediated Alkoxide Rearrangements

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Allylic and Allenic Halide Synthesis via NbCl₅- and NbBr₅-Mediated Alkoxide Rearrangements