Asymmetric addition of n-butyllithium to aldehydes: new insights into the reactivity and enantioselectivity of the chiral amino ether accelerated reaction

Granander, Johan; Sott, Richard; Hilmersson, Göran

doi:10.1016/s0040-4020(02)00378-2

Cited by 45 publications

(26 citation statements)

References 36 publications

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“…2.1 was unsatisfactory in terms of yields, a modified synthesis was planned in which the sulfanyl residue is introduced at the end by a Mitsunobu reaction. The synthesis started from oxazolidinone ()-15, which was obtained from l-phenylalanine in two steps [18] [19]. Treatment of ()-15 with BuLi and 3-phenylpropanoyl chloride afforded ()-16 (Scheme 3) [20].…”

mentioning

confidence: 99%

Second‐Generation Inhibitors for the Metalloprotease Neprilysin Based on Bicyclic Heteroaromatic Scaffolds: Synthesis, Biological Activity, and X‐Ray Crystal‐Structure Analysis

Sahli

Frank

Schweizer

et al. 2005

Helvetica Chimica Acta

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A new class of nonpeptidic inhibitors of the Zn II -dependent metalloprotease neprilysin with IC 50 values in the nanomolar activity range (0.034 ± 0.30 mm) were developed based on structure-based de novo design (Figs. 1 and 2). The inhibitors feature benzimidazole and imidazo [4,5-c]pyridine moieties as central scaffolds to undergo H-bonding to Asn542 and Arg717 and to engage in favorable p-p stacking interactions with the imidazole ring of His711. The platform is decorated with a thiol vector to coordinate to the Zn II ion and an aryl residue to occupy the hydrophobic S1' pocket, but lack a substituent for binding in the S2' pocket, which remains closed by the side chains of Phe106 and Arg110 when not occupied. The enantioselective syntheses of the active compounds ()-1, ()-2, ()-25, and ()-26 were accomplished using Evans auxiliaries (Schemes 2, 4, and 5). The inhibitors ()-2 and ()-26 with an imidazo[4,5-c]pyridine core are ca. 8 times more active than those with a benzimidazole core (()-1 and ()-25) ( Table 1). The predicted binding mode was established by X-ray analysis of the complex of neprilysin with ()-2 at 2.25-resolution (Fig. 4 and Table 2). The ligand coordinates with its sulfanyl residue to the Zn II ion, and the benzyl residue occupies the S1' pocket. The 1H-imidazole moiety of the central scaffold forms the required H-bonds to the side chains of Asn542 and Arg717. The heterobicyclic platform additionally undergoes p-p stacking with the side chain of His711 as well as edge-to-face-type interactions with the side chain of Trp693. According to the X-ray analysis, the substantial advantage in biological activity of the imidazopyridine inhibitors over the benzimidazole ligands arises from favorable interactions of the pyridine N-atom in the former with the side chain of Arg102. Unexpectedly, replacement of the phenyl group pointing into the deep S1' pocket by a biphenyl group does not enhance the binding affinity for this class of inhibitors.1. Introduction. ± In the preceding paper [1], we described a new class of inhibitors of the metalloprotease neprilysin with a central 1H-imidazole platform, featuring IC 50 values (IC 50 : concentration of inhibitor at which 50% V max is observed) in the low micromolar range. The de novo design of these compounds was based on the X-ray crystal structure of NEP complexed with phosphoramidon (Protein Data Bank (PDB) file name 1DMT) [2]. For the design of the second-generation inhibitors, we reverted to an unpublished X-ray crystal structure [3] of NEP complexed with the inhibitor thiorphan [4]. During the analysis, we carefully compared the active sites of the two

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mentioning

confidence: 99%

Second‐Generation Inhibitors for the Metalloprotease Neprilysin Based on Bicyclic Heteroaromatic Scaffolds: Synthesis, Biological Activity, and X‐Ray Crystal‐Structure Analysis

Sahli

Frank

Schweizer

et al. 2005

Helvetica Chimica Acta

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“…The synthesis of the bamino ether 3 has previously been published. [15] Deprotonation of cyclohexene oxide by mixed sodium/lithium-amide complexes: The asymmetric deprotonation reactions were performed by adding nBuLi and/or nBuNa to a solution of the chiral amino ether in Et 2 O or THF at À78 8C. After a few minutes at À78 8C, the solution was equilibrated at 20 8C and the cyclohexene oxide was added.…”

Section: Resultsmentioning

confidence: 99%

“…The synthesis of the chiral b-amino ether (S)-2-isopropylamino-1-methoxy-3-methylbutane (3) has been described previously. [15] (S)-3-(N-tert-Butoxycarbonylamino)-3-phenylpropanenitrile: A mixture of (R)-2-(N-tert-butoxycarbonylamino)-2-phenylethyl tosylate (18.87 g, 45.3 mmol, 1.0 equiv) dissolved in DMF (125 mL) was added to a suspension of finely ground NaCN (6.66 g, 136 mmol, 3.0 equiv) in DMF (125 mL) and the mixture stirred overnight at room temperature. A solution of NaOH (2.0 m, 200 mL) was added and the mixture extracted with dichloromethane (3 100 mL).…”

Section: Methodsmentioning

confidence: 99%

Kinetic and NMR Spectroscopic Studies of Chiral Mixed Sodium/Lithium Amides Used for the Deprotonation of Cyclohexene Oxide

Sott

Granander

Williamson

et al. 2005

Chemistry A European J

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The mixed-metal complex formed from n-butylsodium, n-butyllithium, and a chiral amino ether has been studied by NMR spectroscopy. Three different mixed-metal amides were used as chiral bases for the deprotonation of cyclohexene oxide. The selectivity and initial rate of reaction were compared for sodium-amido ethers, lithium-amido ethers, and mixtures of sodium and lithiumamido ethers in diethyl ether and tetrahydrofuran, respectively. The mixed sodium/lithium amides are more reactive than the single sodium and lithium amides, whereas the stereoselectivities are higher when lithium amides are used. The alkali-metal/gamma-amido ethers exhibit both higher initial reaction rates and stereoselectivities than their beta-amido ether analogues. NMR spectroscopic studies of mixtures of n-butylsodium (nBuNa), n-butyllithium (nBuLi), and the gamma-amino ethers in diethyl ether show the exclusive formation of dimeric mixed-metal amides. In diethyl ether, the lithium atom of the mixed-metal amide is internally coordinated and the sodium atom is exposed to solvent; however, in tetrahydrofuran, both metals are internally coordinated.

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“…However, THF is a stronger Lewis base than DEE, and therefore its ability to coordinate to lithium is considerably better [50,51,81,82]. DEE with two ethyl groups on the oxygen will, upon coordination to lithium, especially in a crowded environment, lose more entropy than the cyclic THF.…”

Section: Solvation Effectsmentioning

confidence: 99%

Computational Perspectives on Organolithiums

Lill

Sten²

2014

Lithium Compounds in Organic Synthesis

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Asymmetric addition of n-butyllithium to aldehydes: new insights into the reactivity and enantioselectivity of the chiral amino ether accelerated reaction

Cited by 45 publications

References 36 publications

Second‐Generation Inhibitors for the Metalloprotease Neprilysin Based on Bicyclic Heteroaromatic Scaffolds: Synthesis, Biological Activity, and X‐Ray Crystal‐Structure Analysis

Second‐Generation Inhibitors for the Metalloprotease Neprilysin Based on Bicyclic Heteroaromatic Scaffolds: Synthesis, Biological Activity, and X‐Ray Crystal‐Structure Analysis

Kinetic and NMR Spectroscopic Studies of Chiral Mixed Sodium/Lithium Amides Used for the Deprotonation of Cyclohexene Oxide

Computational Perspectives on Organolithiums

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