Synthesis of Cinacalcet congeners

Wang, Xin; Chen, Ying; Crockett, Richard; Briones, Jorge; Yan, Tony Q.; Orihuela, Carlos J.; Zhi, Ben; Ng, John S.

doi:10.1016/j.tetlet.2004.09.063

Cited by 11 publications

(10 citation statements)

References 6 publications

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“…).As part of a program aimed at developing new organocatalysts for asymmetric organic transformations, we recently observed that the pyrrolidine sulfonamide 1 serves as an efficient catalyst for a-aminoxylation and Mannich-type reactions. [11,12] These processes take place with exceptionally high levels of enantio-and/or diastereoselectivity. Moreover, the catalyst also shows high activity for a-sulfenylation reactions of aldehydes and ketones.…”

mentioning

confidence: 99%

Direct, Highly Enantioselective Pyrrolidine Sulfonamide Catalyzed Michael Addition of Aldehydes to Nitrostyrenes

Wang

2005

Angew Chem Int Ed

347

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Dedicated to Professor Victor J. Hruby on the occasion of his 65th birthdayThe Michael addition reaction is without question one of the most general and versatile methods for formation of CÀC bonds in organic synthesis.[1] Thus, it is not surprising that the development of enantioselective catalytic protocols for this cornerstone reaction has received much attention.[2] Efforts aimed at achieving asymmetric versions of the process by using chiral organocatalysts have been explored intensively in recent years.[3] l-Proline and other pyrrolidine-based catalytic systems for asymmetric Michael reactions have been described, but only moderate enantioselectivities are typically observed. [4,5] As a result, the design and development of new and efficient chiral organocatalysts to achieve high levels of enantio-and/or diastereoselectivity in Michael conjugate additions remain a major challenge in synthetic organic chemistry. [6][7][8][9] Recently, Kotsuki and his co-workers described a chiral pyrrolidine-pyridine catalyst that promoted highly enantio-and diastereoselective Michael addition reactions of ketones with nitrostyrenes.[10] However, poor enantioselectivity (ca. 22 % ee) resulted when an aldehyde was used as the substrate. Herein, we describe the chiral pyrrolidine sulfonamide 1, which catalyzes the Michael conjugate additions of aldehydes to nitrostyrenes with high levels of enantio-(89-99 % ee) and diastereoselectivity (! 20:1 d.r.).As part of a program aimed at developing new organocatalysts for asymmetric organic transformations, we recently observed that the pyrrolidine sulfonamide 1 serves as an efficient catalyst for a-aminoxylation and Mannich-type reactions. [11,12] These processes take place with exceptionally high levels of enantio-and/or diastereoselectivity. Moreover, the catalyst also shows high activity for a-sulfenylation reactions of aldehydes and ketones.[13] Based on these observations, we envisioned that the (S)-pyrrolidine sulfonamide 1 would react with an aldehyde to form a chiral enamine, which could serve as a Michael donor in reactions with nitroolefins. In addition, a model inspection suggested that the process would take place by the preferential enamine addition to the less hindered Si face of the nitroolefin [Eq. (1)]. Consequently, high levels of enantio-and/or diastereoselectivity are expected. In addition, the bifunctional nature of catalyst 1, which possesses an acidic sulfonamide [14] and a basic pyrrolidine group, could be expected to lead to high catalytic activities even in the absence of an acidic additive. Herein, we describe the results of the studies using 1 to promote highly enantio-and diastereoselective Michael addition reactions.The reaction of isobutyraldehyde with trans-b-nitrostyrene in the presence of the pyrrolidine sulfonamide 1 (20 mol %) in various solvents at room temperature was investigated initially. As evident in Table 1, the reaction yields varied significantly in the solvents tested. In general, the reaction proceeded more rapidly in polar solvents. For...

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confidence: 99%

Direct, Highly Enantioselective Pyrrolidine Sulfonamide Catalyzed Michael Addition of Aldehydes to Nitrostyrenes

Wang

2005

Angew Chem Int Ed

347

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“…Thiel and coworkers reported that the dihydronaphthalene related substance 2, recognized as congeners by Wang et al [6] before, was formed when the amide was reduced by NaBH 4 in the presence of Lewis acid. [3] Initially, we planned to synthesize the substance 2 shown in Scheme 3, but during our preparation the substance 2 was obtained with the purity of 87.49% by HPLC.…”

Section: Resultsmentioning

confidence: 99%

“…The ketone 9 was reduced to the alcohol 10 by NaBH 4 in 94% yield. The alcohol 10 was chlorinated using 5 equiv of thionyl chloride in anhydrous dichloromethane to give the compound 11 in 72% yield, which was further reacted with 3-(3-(trifluoromethyl)phenyl) propan-1-amine 5 [6] in the presence of potassium carbonate and a catalytic amount of potassium iodide. The crude product was salified and purified by recrystallization in acetonitrile to get 2 with satisfactory purity of 95.26% by HPLC.…”

Section: Resultsmentioning

confidence: 99%

Efficient Synthesis of Substances Related to Cinacalcet Hydrochloride via Heck Coupling

Fan

et al. 2014

Synthetic Communications

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Efficient synthetic methods to process substances related to cinacalcet hydrochloride 1, generated during the preparation, were described. The compounds were identified as [1-(7,8-dihydro-naphthalen-1-yl)-ethyl]-[3-(3-trifluoromethyl-phenyl)-propyl]-amine hydrochloride 2,[1-(5,6,7,8-tetrahydro-naphthalen-1-yl)-ethyl]-[3-(3-trifluoromethyl-phenyl)-propyl]-amine hydrochloride 3 and [1-(naphthalen-2-yl)-ethyl]-[3-(3-trifluoromethylphenyl)-propyl]-amine hydrochloride 4. All were prepared from commercially available materials in several linear steps and characterized by their respective spectral data.

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“…To demonstrate the utility of this one-pot sequence, this method was applied to the synthesis of cinacalcet, [43][44][45][46][47] a clinically used calcimimetic agent (e.g., Sensipar, Mimpara). The synthesis would feature the N-alkylation of (R)naphthylethylamine [(R)-2b] with alcohol 4 (see Scheme 4).…”

Section: Resultsmentioning

confidence: 99%

“…It is worth noting that under these conditions, the alkylation of poor nucleophilic amines such as hexamethyldisilazane, tosylamine, and benzyl carbamate could not be achieved. To demonstrate the utility of this one-pot sequence, this method was applied to the synthesis of cinacalcet, [43][44][45][46][47] a clinically used calcimimetic agent (e.g., Sensipar, Mimpara). The synthesis would feature the N-alkylation of (R)naphthylethylamine [(R)-2b] with alcohol 4 (see Scheme 4).…”

Section: Resultsmentioning

confidence: 99%

Synthesis of Amines from Alcohols in a Nonepimerizing One‐Pot Sequence – Synthesis of Bioactive Compounds: Cinacalcet and Dexoxadrol

et al. 2012

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A general, mild, and chemoselective one‐pot oxidation/imine‐iminium formation/nucleophilic addition sequence allowing the N‐alkylation of amines by alcohols is described. This metal‐free, one‐pot sequence produced a wide variety of amines in good yields and diastereoselectivities, without the epimerization of the enantioenriched amines or alcohols involved in the process. This method was applied to the syntheses of the biologically active compounds cinacalcet and dexoxadrol.

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Synthesis of Cinacalcet congeners

Cited by 11 publications

References 6 publications

Direct, Highly Enantioselective Pyrrolidine Sulfonamide Catalyzed Michael Addition of Aldehydes to Nitrostyrenes

Direct, Highly Enantioselective Pyrrolidine Sulfonamide Catalyzed Michael Addition of Aldehydes to Nitrostyrenes

Efficient Synthesis of Substances Related to Cinacalcet Hydrochloride via Heck Coupling

Synthesis of Amines from Alcohols in a Nonepimerizing One‐Pot Sequence – Synthesis of Bioactive Compounds: Cinacalcet and Dexoxadrol

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