Process Development of the Synthetic Route to R116301

Michel, Guillaume; Cuypers, Jef; Dingenen, Jul

doi:10.1021/op700086d

Cited by 16 publications

(7 citation statements)

References 21 publications

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“…The oxazolidinones 25 were formed with reasonable diastereoselectivity (dr 80:20) and good enantioselectivity (er 87:13 for major isomer, as determined by 1 H NMR spectroscopy with the Pirkle solvating agent). A similar (but racemic) procedure has been conducted on a 4‐substituted N ‐Boc‐piperidine as part of a synthesis of an NK 1 antagonist 18…”

Section: Resultsmentioning

confidence: 99%

²H NMR Studies on Two‐Homopolypeptide Lyotropic Enantiodiscriminating Mesophases: Experimental Quantification of Solute–Fiber Affinities

Lesot

Lafon

Aroulanda

et al. 2008

Chemistry A European J

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The analytical potential and enantioselective properties of lyotropic mesophases made by mixing two chemically different chiral polypeptides are described. Here we examine the case of a mixture of poly-gamma-benzyl-L-glutamate (PBLG) and poly-epsilon-carbobenzyloxy-L-lysine (PCBLL). We demonstrate that 2H NMR spectroscopy on these chiral oriented mixtures can discriminate both enantiomers and enantiotopic directions in prochiral molecules. Moreover, in such systems, degree of enantiodiscrimination, resolution, and sensitivity can be conjointly optimized by changing the relative proportion of the two polypeptides. Therefore, these new enantiodiscriminating media provide a favorable alternative to single-polypeptide mesophases with respect to stereochemical applications. At a more fundamental level, the present work points out that solute distribution in the vicinity of each polypeptide partly governs the degree of enantiodiscrimination and NMR relaxation rates. To this end, the experimental trends of solute NMR observables (Delta nu Q, T1) versus the fraction of peptide units of each polymer were analyzed by using a "mean-field" model derived from that proposed for mixtures of thermotropic nematic solvents, and based on the separation of intermolecular interactions between the solute and both polypeptides. This approach allows the relative solute-fiber affinities in these lyotropic systems to be determined. To identify the factors controlling solute-polypeptide affinities, we investigated various solutes (polar/apolar, rigid/flexible, achiral/prochiral/chiral molecules) using 2H NMR at natural abundance or on isotopically enriched solutes.

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Section: Resultsmentioning

confidence: 99%

²H NMR Studies on Two‐Homopolypeptide Lyotropic Enantiodiscriminating Mesophases: Experimental Quantification of Solute–Fiber Affinities

Lesot

Lafon

Aroulanda

et al. 2008

Chemistry A European J

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“…A similar (but racemic) procedure has been conducted on a 4-substituted N-Boc-piperidine as part of a synthesis of an NK 1 antagonist. [18] In 2008, we reported that the organolithium derived from deprotonation of N-Boc-piperidine with sBuLi and TMEDA could be converted to its organozinc derivative and used in Negishi-type coupling reactions with aryl bromides to give 2-arylpiperidines. [19] To our disappointment, this procedure was unsuccessful using the DTR method.…”

Section: Full Papermentioning

confidence: 99%

Asymmetric Substitutions of 2‐Lithiated N‐Boc‐piperidine and N‐Boc‐azepine by Dynamic Resolution

Coldham

Raimbault

Whittaker

et al. 2010

Chemistry A European J

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Proton abstraction of N-tert-butoxycarbonyl-piperidine (N-Boc-piperidine) with sBuLi and TMEDA provides a racemic organolithium that can be resolved using a chiral ligand. The enantiomeric organolithiums can interconvert so that a dynamic resolution occurs. Two mechanisms for promoting enantioselectivity in the products are possible. Slow addition of an electrophile such as trimethylsilyl chloride allows dynamic resolution under kinetic control (DKR). This process occurs with high enantioselectivity and is successful by catalysis with substoichiometric chiral ligand (catalytic dynamic kinetic resolution). Alternatively, the two enantiomers of this organolithium can be resolved under thermodynamic control with good enantioselectivity (dynamic thermodynamic resolution, DTR). The best ligands found are based on chiral diamino-alkoxides. Using DTR, a variety of electrophiles can be used to provide an asymmetric synthesis of enantiomerically enriched 2-substituted piperidines, including (after Boc deprotection) the alkaloid (+)-beta-conhydrine. The chemistry was extended, albeit with lower yields, to the corresponding 2-substituted seven-membered azepine ring derivatives.

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“…This difficulty has been noted by others, and has unfortunately been the cause of abandonment of many Ti-based procedures for large scale applications. [17] When first scaling up the present reaction, the filtration required an unacceptable time (several hours to days) to complete, thus rendering the process impractical for large scale. Numerous variations of the aqueous solution used for quenching, order of addition, and filtration medium led to no improvement in filtration rate.…”

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confidence: 99%

Direct Titanium‐Mediated Conversion of Ketones into Enamides with Ammonia and Acetic Anhydride

et al. 2012

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N-Acyl enamides are useful compounds in organic synthesis. In the realm of catalytic asymmetric hydrogenation, they are among the most exhaustively studied class of substrates, and provide access to valuable chiral amine building blocks. [1] These substrates have also demonstrated broad utility in catalytic asymmetric CÀC bond forming processes such as aza-ene, [2] Michael, [3] Friedel-Crafts, [4] cycloaddition, [5] and arylation [6] reactions. Despite the extensive applications of Nacyl enamides, their preparation remains challenging. The direct condensation of acetamide with ketones, while attractive in its simplicity, proceeds either in low yields or not at all for the majority of ketone substrates.[7] The Pd-catalyzed cross-coupling of vinyl electrophiles with amides [8] and the Heck reaction of N-vinylacetamide with aryl halides [9] often require additional steps for preparation of coupling precursors and employ a costly transition metal catalyst.[10] The addition of alkyl magnesium or alkyl lithium reagents to nitriles followed by trapping with Ac 2 O or AcCl has limited functional-group tolerance [11] and requires low reaction temperatures.[12] By far the most commonly employed procedure is the two-step conversion of ketones through ketoximes (Scheme 1). [13] This reaction was first described in 1975 by Barton and coworkers. After a first step of oxime formation, the ketoxime was then treated with Ac 2 O and either pyridine at reflux, Cr(OAc) 2 , or Ti(OAc) 3 for reductive acylation.[13] Subsequently, numerous alternative reducing agents were developed.[14] The most commonly employed reductant is Fe powder, which was first demonstrated by Barton and Zard in 1985 [14a] and subsequently developed by Burk and Zhang in 1998. [14b,c] From a large scale perspective, the use of highenergy hydroxylamine, generating a high-energy oxime intermediate, and reducing the oxime at high temperatures present safety concerns. In addition, the workup of the Fe process is often tedious, requiring filtration of large amounts of inorganic salts. While several alternatives to Fe metal have emerged recently, these still rely on the same overall two-step process through a ketoxime.[14d-g] Our own requirements for large-scale synthesis of N-acetyl enamides for asymmetric hydrogenation prompted us to develop a more direct and process-friendly alternative in which hydroxylamine is replaced with ammonia. Herein we describe a direct, redoxfree synthesis of enamides from ketones, ammonia, and Ac 2 O mediated by Ti(OiPr) 4 . In addition, we introduce the use of edte (N,N,N',N'-tetrakis(2-hydroxyethyl)ethylenediamine) to effect water solubilization of the Ti and allow a simple extractive workup.Our strategy for enamide synthesis was based on condensation of a ketone with ammonia to give an N-unsubstituted imine or enamine, followed by N-acetylation on addition of Ac 2 O. The imine formation presented a challenge due to the volatility of ammonia, which excluded the common method for imine formation by azeotropic distillation for remo...

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Process Development of the Synthetic Route to R116301

Cited by 16 publications

References 21 publications

²H NMR Studies on Two‐Homopolypeptide Lyotropic Enantiodiscriminating Mesophases: Experimental Quantification of Solute–Fiber Affinities

²H NMR Studies on Two‐Homopolypeptide Lyotropic Enantiodiscriminating Mesophases: Experimental Quantification of Solute–Fiber Affinities

Asymmetric Substitutions of 2‐Lithiated N‐Boc‐piperidine and N‐Boc‐azepine by Dynamic Resolution

Direct Titanium‐Mediated Conversion of Ketones into Enamides with Ammonia and Acetic Anhydride

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Process Development of the Synthetic Route to R116301

Cited by 16 publications

References 21 publications

2H NMR Studies on Two‐Homopolypeptide Lyotropic Enantiodiscriminating Mesophases: Experimental Quantification of Solute–Fiber Affinities

2H NMR Studies on Two‐Homopolypeptide Lyotropic Enantiodiscriminating Mesophases: Experimental Quantification of Solute–Fiber Affinities

Asymmetric Substitutions of 2‐Lithiated N‐Boc‐piperidine and N‐Boc‐azepine by Dynamic Resolution

Direct Titanium‐Mediated Conversion of Ketones into Enamides with Ammonia and Acetic Anhydride

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²H NMR Studies on Two‐Homopolypeptide Lyotropic Enantiodiscriminating Mesophases: Experimental Quantification of Solute–Fiber Affinities

²H NMR Studies on Two‐Homopolypeptide Lyotropic Enantiodiscriminating Mesophases: Experimental Quantification of Solute–Fiber Affinities