- Stereoselective synthesis of β-alkylated α-amino acids via palladium-catalyzed alkylation of unactivated methylene C(sp3)-H Bonds with Primary Alkyl Halides
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We report a new set of reactions based on the Pd-catalyzed alkylation of methylene C(sp3)-H bonds of aliphatic quinolyl carboxamides with α-haloacetate and methyl iodide and applications in the stereoselective synthesis of various β-alkylated α-amino acids. These reactions represent the first generally applicable method for the catalytic alkylation of unconstrained and unactivated methylene C-H bonds with high synthetic relevance. When applied with simple isotope-enriched reagents, they also provide a convenient and powerful means to site-selectively incorporate isotopes into the carbon scaffolds of amino acid compounds.
- Zhang, Shu-Yu,Li, Qiong,He, Gang,Nack, William A.,Chen, Gong
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supporting information
p. 12135 - 12141
(2013/09/02)
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- Design and synthesis of prolylcarboxypeptidase (PrCP) inhibitors to validate PrCP as a potential target for obesity
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Prolylcarboxypeptidase (PrCP) is a serine protease that may have a role in metabolism regulation. A class of reversible, potent, and selective PrCP inhibitors was developed starting from a mechanism based design for inhibiting this serine protease. Compound 8o inhibits human and mouse PrCP at IC 50 values of 1 and 2 nM and is not active (IC50 > 25 μM) against a panel of closely related proteases. It has lower serum binding than its close analogues and is bioavailable in mouse. Subchronic dosing of 8o in PrCP-/- and WT mice at 100 mg/kg for 5 days resulted in a 5% reduction in body weight in WT mice and a 1% reduction in PrCP KO mice.
- Zhou, Changyou,Garcia-Calvo, Margareta,Pinto, Shirly,Lombardo, Matthew,Feng, Zhe,Bender, Kate,Pryor, Kellyann D.,Bhatt, Urmi R.,Chabin, Renee M.,Geissler, Wayne M.,Shen, Zhu,Tong, Xinchun,Zhang, Zhoupeng,Wong, Kenny K.,Roy, Ranabir Sinha,Chapman, Kevin T.,Yang, Lihu,Xiong, Yusheng
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experimental part
p. 7251 - 7263
(2010/12/25)
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- A Versatile Chemo-Enzymatic Route to Enantiomerically Pure β-Branched α-Amino Acids
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A series of diastereoisomers of β-methyl-β-phenylalanine analogues 1a?f have been prepared in enantiomerically pure form using a combination of chemo- and biocatalysis. Starting from l-threonine methyl ester 2, a range of β,β-disubstituted didehydroamino
- Roff, Geoffrey J.,Lloyd, Richard C.,Turner, Nicholas J.
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p. 4098 - 4099
(2007/10/03)
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- An efficient and stereodivergent synthesis of threo- and erythro-β-methylphenylalanine. Resolution of each racemic pair by semipreparative HPLC
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threo and erythro diastereoisomers of the constrained amino acid (βMe)Phe can be obtained separately on a multigram scale through a three-step synthesis from the corresponding Z and E isomers of 2-phenyl-4(α-phenylethylidene)-5(4H)-oxazolone. The 5(4H)-ox
- Alías, Miriam,López, María Pilar,Cativiela, Carlos
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p. 885 - 891
(2007/10/03)
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- Catalytic asymmetric hydrogenation of α-(acetamido)acrylates using TRAP trans-chelating chiral bisphosphine ligands: Remarkable effects of ligand P-substituent and hydrogen pressure on enantioselectivity
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The catalytic asymmetric hydrogenation of α-(acetamido)acrylates was carded out with the rhodium complexes prepared from [Rh(cod)2]BF4 and trans-chelating chiral bisphosphine ligands, (S,S)-2,2'-bis[(R)-1-(dialkylphosphino)ethyl]-1,1
- Kuwano,Sawamura,Ito
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p. 2571 - 2578
(2007/10/03)
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- SB-203207 and SB-203208, two novel isoleucyl tRNA synthetase inhibitors from a Streptomyces sp. I. Fermentation, isolation and properties
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Two novel inhibitors of isoleucyl tRNA synthetase designated SB-203207 and SB-203208 have been detected in the culture of a new Streptomyces species. The fermentation, isolation and some properties of the inhibitors are described.
- Stefanska, Anna L.,Cassels, Robert,Ready, Sarah J.,Warr, Stephen R.
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p. 357 - 363
(2007/10/03)
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- Aza-Darzens asymmetric synthesis of N-(p-toluenesulfinyl)aziridine 2- carboxylate esters from sulfinimines (N-sulfinyl imines)
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The one-step aza-Darzens reaction of sulfinimines 2 with lithium α- bromoenolates readily affords diversely substituted cis and trans N- sulfinylaziridine 2-carboxylate esters 3 and 7 in good yield and excellent diastereoselectivity. Higher yields, but lower de's, result when a mixture of the α-bromo ester and 2 are treated with base. The N-sulfinyl group is transformed, nearly quantitatively, without ring opening, into the N-tosyl activating group by oxidation with m-CPBA. Selective removal of the N- sulfinyl group in aziridines 3a and 3h with TFA/H2O affords 1H-aziridines 21 which are difficult to prepared by other means. However, C(3) activated azirines such as 3b undergo ring-opening under these conditions. Alternatively, the N-sulfinyl group, even in C(3)-activated aziridines, was selectively and efficiently removed by treatment of the aziridine with 2 equiv of MeMgBr.
- Davis, Franklin A.,Liu, Hu,Zhou, Ping,Fang, Tianan,Reddy, G. Venkat,Zhang, Yulian
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p. 7559 - 7567
(2007/10/03)
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- A new strategy for the synthesis of four individual isomers of β-methylphenylalanine
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The application of an allylic strain effect in boron enolates and asymmetric Michael-like addition/electrophilic bromination reactions is reported for the asymmetric synthesis of the individual isomers of unusual constrained amino acids. For β-substituted
- Lung,Li,Lou,Hruby
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- Development of a Model for the δ Opioid Receptor Pharmacophore. 2. Conformationally Restricted Phe3 Replacements in the Cyclic δ Receptor Selective Tetrapeptide Tyr-cOH (JOM-13)
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The in vitro pharmacological properties and conformational features of analogs of the δ opioid receptor selective tetrapeptide Tyr-cOH (JOM-13) in which the Phe3 residue was replaced by each of the four stereoisomers of β-methylphenylalanine (β-MePhe) were investigated.Both analogs in which the α carbon of the Phe3 replacement has L-stereochemistry display high affinity for δ receptors with the (2S,3S)-MePhe3 analog exhibiting approximately 8-fold higher affinity than the (2S,3R)-MePhe3 diastereomer.Surprisingly, one analog with D-stereochemistry in residue 3, the (2R,3R)-MePhe3 analog, also display high affinity for the δ receptor and is extraordinarily selective for this receptor.All analogs were agonists in the mouse vas deferens (MVD) and guinea pig ileum (GPI) smooth muscle bioassays, displaying MVD and GPI potencies consistent with their δ and μ opioid receptor affinities, respectively.The use of β-MePhe as a replacement for Phe3 was based upon the desire to reduce the conformational flexibility of the Phe3 side chain by imposing a steric rotational constraint in the form of the β-methyl substituent and to thus deduce the residue 3 side chain orientation in the δ receptor-bound conformation from the correlation between δ receptor binding affinities and conformational preferences.Molecular mechanics computations revealed, however, that the conformational constraints imposed by the β-methyl group in the (2S,3S)-MePhe3 and (2S,3R)-MePhe3 analogs were too modest to allow unequivocal determination of δ receptor-bound residue 3 side chain conformation.However, analysis of the high-affinity (2R,3R)-MePhe3 analog revealed a strong preference for a single side chain conformer (χ1 ca 60 deg).Low-energy conformers of this analog could only be effectively superimposed with low-energy conformers of the parent peptide in which the Phe3 side chain conformation was limited to χ1 ca -60 deg.This observation eliminates the last remaining uncertainty regarding conformational features of the pharmacophore elements in the δ receptor-bound state, allowing the proposal of a complete model.
- Mosberg, Henry I.,Omnaas, John R.,Lomize, Andrei,Heyl, Deborah L.,Nordan, Ian,et al.
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p. 4384 - 4391
(2007/10/02)
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- Exploration for Large-scale Stereoselective Synthesis of Unusual Amino Acids by using 4-Phenyoxazolidin-2-one as a New Chiral Resolution Reagent
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Individual isomers of β-branched α-amino acids have been stereoselectively and asymmetrically synthesized in high yield by a new method which uses 4-phenyloxazolidin-2-one as a novel chiral resolution reagent acting simultaneously as the auxiliary.
- Li, Guigen,Patel, Dinesh,Hruby, Victor J.
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p. 3057 - 3060
(2007/10/02)
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- Asymmetric synthesis of unusual amino acids: An efficient synthesis of optically pure isomers of β-methylphenylalanine
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Substitution of the diastereotopic β-hydrogens of many α-amino acids provides an approach to the three dimensional topographic control of peptide structure. Asymmetric synthesis of the desired amino acids is needed to facilitate these studies. All four in
- Dharanipragada,VanHulle,Bannister,Bear,Kennedy,Hruby
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p. 4733 - 4748
(2007/10/02)
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- Potent Angiotensin II Antagonists with Non-β-branched Aminoacids in Position 5
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Amino acids with lipophilic side chains that contain more than one functional group on the β-carbon, i.e. a β-branched hydrocarbon moiety, are required in position 5 of angiotensin II (AII) analogue with potent agonist activity.This requirement for agonis
- Samanen, J.,Narindray, D.,Cash, T.,Brandeis, E.,Adams, W.,et al.
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p. 466 - 472
(2007/10/02)
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- ASYMMETRIC SYNTHESIS OF UNUSUAL AMINO ACIDS: SYNTHESIS OF OPTICALLY PURE ISOMERS OF β-METHYLPHENYLALANINE
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All the four individual isomers of β-methylphenylalanine have been synthesized in very high optical purities by utilizing in part the chiral imide enolate bromination methodology of Evans and co-workers.
- Dharanipragada, Ramalinga,Nicolas, Ernesto,Toth, Geza,Hruby, Victor J.
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p. 6841 - 6844
(2007/10/02)
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- Stereoselective Alkylation of Arenes with Threonine Trifluoromethanesulfonates
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N-Phthaloylthreonine and -allothreonine methyl esters 3 react with trifluoromethanesulfonic anhydride / pyridine in dichloromethane to give threonine and allothreonine, respectively, trifluoromethanesulfonates 4 in quantitative yields.Arenes can be alkyla
- Effenberger, Franz,Weber, Thomas
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p. 421 - 430
(2007/10/02)
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- RESOLUTION AND USE IN α-AMINO ACID SYNTHESIS OF IMIDAZOLIDINONE GLYCINE DERIVATIVES
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The imidazolidinones (rac.-1 and rac.-2) obtained from pivalaldehyde and glycine amides are resolved efficiently by crystallization of diastereomeric ammonium salts with chiral acids (mandelates and a gulonate respectively).The free bases are acylated under Schotten-Baumann conditions to give enantiomerically pure 1-Bz-, 1-BOC-, 1-Z- or 1-formyl-2-t-butyl-3-methyl- or -3-benzyl-4-imidazolidinones.Diastereoselective alkylation of the 3-methyl derivatives (BMI) with a variety of electrophiles (LDA/THF -70 to +25 degC) gives trans-disubstituted imidazolidinones exclusively (3-22).Some of these are hydrolyzed by a procedure employing excess acidic ion exchange resin to give enantiomerically pure (R)- or (S)-amino acids.The procedure is compared with other methods of generating chiral glycine enolates.
- Fitzi, Robert,Seebach, Dieter
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p. 5277 - 5292
(2007/10/02)
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