Asymmetric Synthesis of Active Pharmaceutical Ingredients

Farina, Vittorio; Reeves, Jonathan T.; Senanayake, Chris H.; Song, Jinhua J.

doi:10.1021/cr040700c

Cited by 512 publications

(242 citation statements)

References 283 publications

(344 reference statements)

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“…Three strategies are presently used for the preparation of enantiomerically pure compounds,o ne of them being the chiral pool synthesis, where chiral natural products are used as buildingb locks for the synthesis of complex molecules. [1] The other two strategies include resolution of racemates [2] and asymmetrics ynthesis, where in the latter case chiral reagents or catalysts are used. [3] Although asymmetrics ynthesis based on catalysis (asymmetric catalysis) is av ery powerful method for obtaining enantiomerically pure compounds, the most commonm ethod used in chemical industry for obtaining such compounds is still by resolution.…”

mentioning

confidence: 99%

Heterogeneous Acid‐Catalyzed Racemization of Tertiary Alcohols

Görbe

Lihammar

Bäckvall

2017

Chemistry A European J

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Tertiary alcohols are important structural motifs in natural productsa nd building blocks in organic synthesis buto nly few methods are known for their enantioselective preparation. Chiral resolution is one of these approaches that leaves one enantiomer (50 %o ft he material) unaffected. An attractive method to increase the efficiency of those resolutions is to racemizet he unaffected enantiomer.I nt he present work, we have developed a practical racemization protocol for tertiary alcohols. Five different acidic resin materials were tested. The Dowex 50WX8 was the resin of choice since it was capable of racemizing tertiary alcohols withouta ny byproductf ormation. Suitable solvents and ab iphasic system were investigated, andt he optimized system was capable of racemizing differently substituted tertiarya lcohols.The stereoselective synthesis of organic moleculesi so fahigh demandi nt he pharmaceutical anda grochemical industry. Three strategies are presently used for the preparation of enantiomerically pure compounds,o ne of them being the chiral pool synthesis, where chiral natural products are used as buildingb locks for the synthesis of complex molecules. [1] The other two strategies include resolution of racemates [2] and asymmetrics ynthesis, where in the latter case chiral reagents or catalysts are used. [3] Although asymmetrics ynthesis based on catalysis (asymmetric catalysis) is av ery powerful method for obtaining enantiomerically pure compounds, the most commonm ethod used in chemical industry for obtaining such compounds is still by resolution. In ar esolution, which could be crystallization, chiral chromatography,o rk inetic resolution, two enantiomers are separated and the desired enantiomer is collected. The drawback of the resolution strategy is that only 50 %o ft he material is used, and the unwanted enantiomer is discarded. As olutiono ft his problem is to racemize the unwanted enantiomer and to recirculate the racemic mixture, which increases efficiency.T herefore, there is ah igh demand of efficient racemizationm ethods in industrial applications.Racemizationc an be achieved by av ariety of techniques: thermalr acemization, enzyme-catalyzed racemization, racemization via meso-intermediates, racemization by nucleophilic substitution, racemizationb yr adicala nd redox reactions, photochemical racemization, and acid-or base-catalyzed racemization. [4] The most common racemization catalysts for secondary alcohols are transition-metal-based hydrogen-transfer catalysts, which racemize the alcoholi nadehydrogenation-hydrogenation (oxidation-reduction) pathway. [5] When such ar acemization catalyst is combinedw ith ak inetic resolution catalyst (e.g. an enzyme)aso called "dynamic kinetic resolution" (DKR) can be achieved. [6] Te rtiary alcohols and their esters are important compounds, which are found in anumber of natural products. [7] These compounds are also important buildingb locks in synthetic chemistry. [8] The synthesis of optically pure tertiary alcohols is still a challengin...

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mentioning

confidence: 99%

Heterogeneous Acid‐Catalyzed Racemization of Tertiary Alcohols

Görbe

Lihammar

Bäckvall

2017

Chemistry A European J

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“…[2,3] sigmatropic rearrangement and ring-closing metathesis. RCM of the corresponding diene gave 63, which was used as precursor for a formal total synthesis of (±)-perhydrohistrionicotoxin 5.…”

Section: Ring-closing Metathesismentioning

confidence: 99%

Modular Asymmetric Synthesis of Functionalized Azaspirocycles Based on the Sulfoximine Auxiliary

et al. 2007

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A modular asymmetric synthesis of the functionalized azaspirocycles 6 (m = 2, n = 1), 7 (m = 1, n = 2), 8 (m = n = 2), 12, 20, and 24 from the cyclic allylic sulfoximines 1 is described. The synthetic strategy is based on the stereoselective construction of the carbocycle 4 containing the amino-substituted tertiary C atom from 1 followed by the generation of the azaspirocycle. Three different routes have been followed for the synthesis of the heterocyclic ring: N,C-dianion cycloalkylation, ring-closing metathesis, and N-acyl iminium ion formation.

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“…[1] In this respect, the enantioselective reduction of prochiral ketones has acquired greater importance, since the resulting enantioenriched secondary alcohols are key intermediates for the preparation of a large number of biologically active compounds. [2] Asymmetric transfer hydrogenation (ATH) has proven to be an efficient, mild and versatile method for this particular transformation, in which the use of molecular hydrogen or highly reactive hydride reagents can be avoided. [3] Nowadays, most transfer hydrogenations are performed using transition metal complexes, mainly based on ruthenium, rhodium or iridium.…”

Section: Introductionmentioning

confidence: 99%

Modular Furanoside Pseudodipeptides and Thioamides, Readily Available Ligand Libraries for Metal‐Catalyzed Transfer Hydrogenation Reactions: Scope and Limitations

et al. 2012

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Two new highly modular carbohydratebased, pseudodipeptide and thioamide ligand libraries have been synthesized for the rhodium-and ruthenium-catalyzed asymmetric transfer hydrogenation (ATH) of prochiral ketones. These series of ligands can be prepared efficiently from easily accessible d-xylose and d-glucose. The ligand libraries contain two main ligand structures (pseudodipeptide and thioamide) that have been designed by making systematic modifications to one of the most successful ligand families developed for the ATH. As well as studying the effect of these two ligand structures on the catalytic performance, we also evaluated the effect of modifying several of the ligand parameters. We found that the effectiveness of the ligands at transferring the chiral information in the product can be tuned by correctly choosing the ligand components (ligand structure and ligand parameters). Excellent enantioselectivities (ees up to 99%) were therefore obtained in both enantiomers of the alcohol products using a wide range of substrates.

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Asymmetric Synthesis of Active Pharmaceutical Ingredients

Cited by 512 publications

References 283 publications

Heterogeneous Acid‐Catalyzed Racemization of Tertiary Alcohols

Heterogeneous Acid‐Catalyzed Racemization of Tertiary Alcohols

Modular Asymmetric Synthesis of Functionalized Azaspirocycles Based on the Sulfoximine Auxiliary

Modular Furanoside Pseudodipeptides and Thioamides, Readily Available Ligand Libraries for Metal‐Catalyzed Transfer Hydrogenation Reactions: Scope and Limitations

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