- An Iridium(I) N-Heterocyclic Carbene Complex Catalyzes Asymmetric Intramolecular Allylic Amination Reactions
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A chiral iridium(I) N-heterocyclic carbene complex was reported for the first time as the catalyst in the highly enantioselective intramolecular allylic amination reaction. The current method provides facile access to biologically important enantioenriched indolopiperazinones and piperazinones in good yields (74–91 %) and excellent enantioselectivities (92–99 % ee). Preliminary mechanistic investigations reveal that the C?H activation occurs at the position ortho to the N-aryl group of the ligand.
- Ye, Ke-Yin,Cheng, Qiang,Zhuo, Chun-Xiang,Dai, Li-Xin,You, Shu-Li
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- Iron-Catalyzed Diastereoselective Synthesis of Unnatural Chiral Amino Acid Derivatives
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An iron-catalyzed diastereoselective synthesis of unnatural chiral (S)-α-amino acids with γ-quaternary carbon centers has been developed. The protocol uses inexpensive iron salt as the catalyst, readily available 2-phthaloyl acrylamide and alkenes as the starting materials, and phenylsilane as the reductant, and the reactions were performed well in mixed solvent of 1,2-dichloroethane and ethylene glycol at room temperature. The method shows some advantages including simple and wide substrates, mild conditions, high diastereoselectivity, and easy workup procedures.
- Zhang, Hao,Li, Haifang,Yang, Haijun,Fu, Hua
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- Highly Selective Asymmetric Acetate Aldol Reactions of an N-Acetyl Thiazolidinethione Reagent
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(Equation presented) A highly diastereoselective acetate aldol reaction that uses a tert-leucine-derived thiazolidinethione auxiliary and dichlorophenylborane has been developed. The reaction proceeds in excellent yields and with high diastereoselectivities (drs range from 9.5:1 to >100:1).
- Zhang, Yingchao,Phillips, Andrew J.,Sammakia, Tarek
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- Novel 1,3,2-diazaphospholidines with pseudodipeptide substituents
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Chiral 1,3,2-diazaphospholidine with pseudodipeptide substituents was prepared. This asymmetric inducer provided up to 84% ee in the Pd-catalyzed asymmetric allylic alkylation of (E)-1,3-diphenylallyl acetate with dimethyl malonate, and up to 53% ee in the Rh-catalyzed asymmetric hydrogenation of (Z)-methyl 2-acetamido-3-phenylacrylate.
- Chuchelkin,Gavrilov,Firsin,Zimarev,Novikov,Maksimova,Shiryaev,Zheglov,Tafeenko,Chernyshev,Gavrilov
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- A scalable synthesis of the (S)-4-(tert-butyl)-2-(pyridin-2-yl)-4,5- dihydrooxazole ((S)-t-BuPyOx) ligand
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An efficient method for the synthesis of the (S)-4-(tert-butyl)-2-(pyridin- 2-yl)-4,5-dihydrooxazole ((S)-t-BuPyOx) ligand has been developed. Inconsistent yields and tedious purification in known routes to (S)-t-BuPyOx suggested the need for an efficient, dependable, and scalable synthetic route. Furthermore, a route suitable for the synthesis of PyOx derivatives is desirable. Herein, we describe the development of a three-step route from inexpensive and commercially available picolinic acid. This short procedure is amenable to multi-gram scale synthesis and provides the target ligand in 64% overall yield.
- Shimizu, Hideki,Holder, Jeffrey C.,Stoltz, Brian M.
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- Asymmetric hetero-Diels-Alder Reaction of trans-1-Methoxy-3-trimethylsilyloxy-buta-1,3-diene Catalyzed by Zinc Complexes
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Asymmetric hetero-Diels-Alder reactions of Danishefsky's diene and glyoxylate/pyruvate esters catalyzed by readily available zinc triflate complex with BOX ligand afforded the corresponding adduct which upon treatment with trifluoroacetic acid furnished the hetero-Diels-Alder product in 91 % enantiomeric excess and 87 % isolated yield. This reaction was applied to the concise synthesis of six-membered ulosonic acid C-glycoside.
- Buda, Szymon,Mlynarski, Jacek,Stefaniak, Matylda
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- Acetylene - Dicobaltcarbonyl complexes with chiral phosphinooxazoline ligands: Synthesis, structural characterization, and application to enantioselective intermolecular Pauson-Khand reactions
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The reaction of the phenylacetylene - dicobalthexacarbonyl complex (2) with the 4-R-2-(2-diphenylphosphinophenyl)oxazolines 1 (R = Ph) and 4 (R = CH2CH2SCH3) leads to the selective formation of the chelated complexes 3 and 5, respectively. On the other hand, the tert-butyl-substituted phosphinooxazoline 6 acts as a monodentate ligand, and its reaction with several 1-alkyne-derived complexes (2,7 - 10) affords readily separable mixtures of the diastereomer nonchelated complexes 11a,b - 15a,b. The interconversion rate between diastereomeric pairs is dependent on the steric bulk of the alkyne substituent, and neither 3 nor 5 epimerize at room temperature. The structures of both kinds of complexes have been ascertained by a combination of spectroscopical (IR, NMR), X-ray diffraction, and chiroptical methods; this has allowed the development of a practical procedure for the establishment of the absolute configuration of the chiral alkyne - dicobaltcarbonyl complexes obtained by the selective substitution of a carbon monoxide on one of the diastereotopic cobalt atoms. The intermolecular Pauson - Khand reaction of the chelated complexes 3 and 5 with norbornadiene respectively affords the (+) and (-) enantiomers of expected enone adduct 25, but in low enantiomeric excesses. Contrary to that, the tertiary amine N-oxide-promoted intermolecular Pauson - Khand reactions of nonchelated complexes 11a,b - 13a,b give the corresponding norbornadiene- or norbornene-derived adducts both in high yields (85-99%) and enantioselectivities (93-97% enantiomeric excess), in what constitutes a substantial improvement over preexisting procedures for this reaction. The possibility of achieving chiral induction in the Pauson - Khand reaction of symmetrical alkynes (via the corresponding dicobaltpentacarbonyl complexes with ligand 6) has been demonstrated for the first time. An enantioselectivity mnemonic rule and a mechanistic model that explains the observed asymmetric sense of induction have been developed, and have been found to be in agreement with the results of model semiempirical molecular orbital calculations.
- Castro, Jaume,Moyano, Albert,Pericas, Miquel A.,Riera, Antoni,Alvarez-Larena, Angel,Piniella, Joan F.
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- Chiral auxiliary control of tacticity in free radical polymerization
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Chiral oxazolidine acrylamides undergo stereocontrolled free radical polymerization. Remarkably high degrees of tacticity have been demonstrated in the polymerization of acrylamides with these chiral auxiliaries that are derived from valine, phenylglycine, and tert-leucine. The polyacrylamides formed in these polymerizations can be converted to poly(acrylic acid), P(AA), and poly(methyl acrylate), P(MA), by hydrolysis and esterification. Tacticities as high as 92% have been measured for P(AA) and P(MA) resulting from these reactions. NMR studies of the microstructure of the polymers formed using chiral auxiliaries to control the stereochemistry of the reaction showed that the distribution of stereochemical sequences could be predicted by a statistical analysis based upon the mechanism of stereoselection. Specifically, these studies confirm that the stereocontrol is the result of facial selectivity in the addition of the monomer to the growing polymer radical. This face selectivity is thought to be the result of steric hindrance to approach of the monomer to one face of the radical caused by the chiral auxiliary. Further NMR studies were used to propose an analysis of the stereochemistry of P(MA) at the hexad level. Using HETCOR techniques, eight of the twenty hexads were conclusively identified, and a further six were narrowed to two possible choices.
- Porter, Ned A.,Allen, Timothy R.,Breyer, Robert A.
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- Synthesis of chiral polydentate ligands and the use of their titanium complexes as pre-catalysts for the asymmetric trimethylsilylcyanation of benzaldehyde
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A number of polydentate ligands based on enantiomerically pure binaphthol have been synthesized. The ligand complexes with titanium isopropoxide were used as catalysts for the asymmetric addition of trimethylsilyl cyanide to benzaldehyde. A fragment with axial chirality is responsible for the configuration of O-trimethylsilyl cyanohydrin product. In the case of the optimum ligand based on (R)-binaphthol and (S)-leucinol, an enantiomeric excess of 86% and quantitative yield were achieved in 4 h.
- Belokon,Chusov,Skrupskaya,Bor'Kin,Yashkina,Lyssenko,Il'In,Strelkova,Timofeeva,Peregudov,North
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- Total Synthesis of the Alleged Structure of Crenarchaeol Enables Structure Revision**
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Crenarchaeol is a glycerol dialkyl glycerol tetraether lipid produced exclusively in Archaea of the phylum Thaumarchaeota. This membrane-spanning lipid is undoubtedly the structurally most sophisticated of all known archaeal lipids and an iconic molecule in organic geochemistry. The 66-membered macrocycle possesses a unique chemical structure featuring 22 mostly remote stereocenters, and a cyclohexane ring connected by a single bond to a cyclopentane ring. Herein we report the first total synthesis of the proposed structure of crenarchaeol. Comparison with natural crenarchaeol allowed us to propose a revised structure of crenarchaeol, wherein one of the 22 stereocenters is inverted.
- Cunha, Ana V.,Havenith, Remco W. A.,Holzheimer, Mira,Minnaard, Adriaan J.,Schouten, Stefan,Sinninghe Damsté, Jaap S.
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supporting information
p. 17504 - 17513
(2021/07/06)
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- N-1 BRANCHED ALKYL ETHER SUBSTITUTED IMIDAZO[4,5-C]QUINOLINE COMPOUNDS, COMPOSITIONS, AND METHODS
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Imidazo[4,5-c]quinoline compounds having a substituent that is attached at the N-1 position by a branched group, single enantiomers of the compounds, pharmaceutical compositions containing the compounds, and methods of making the compounds are disclosed. Methods of use of the compounds as immune response modifiers, for inducing cytokine biosynthesis in humans and animals, and in the treatment of diseases including infectious and neoplastic diseases are also disclosed.
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(2020/06/19)
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- N-1 BRANCHED ALKYL SUBSTITUTED IMIDAZO[4,5-C]QUINOLINE COMPOUNDS, COMPOSITIONS, AND METHODS
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Imidazo[4,5-c]quinoline compounds having a substituent that is attached at the N-1 position by a branched group, single enantiomers of the compounds, pharmaceutical compositions containing the compounds, and methods of making the compounds are disclosed. Methods of use of the compounds as immune response modifiers, for inducing (or inhibiting) cytokine biosynthesis in humans and animals, and in the treatment of diseases including infectious and neoplastic diseases are also disclosed.
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(2020/12/29)
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- HEPATITIS B VIRUS SURFACE ANTIGEN INHIBITOR
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Disclosed in the present invention is a new 11-oxo-7,11-dihydro-6h-benzo-[f]pyrido[1,2-d][1,4]azepine oxepin-10-carboxylic acid derivative serving as a hepatitis B virus surface antigen inhibitor. Specifically disclosed are a compound represented by formula (V) or a pharmaceutically acceptable salt thereof, and applications of the compound represented by formula (V) or the pharmaceutically acceptable salt thereof and a pharmaceutical composition thereof in the treatment of viral hepatitis B.
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Paragraph 0151; 0152; 0153; 0292
(2020/04/21)
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- Enantioselective Synthesis of Chiral Vicinal Amino Alcohols Using Amine Dehydrogenases
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Chiral vicinal amino alcohols are an important motif found in many biologically active molecules. In this study, biocatalytic reductive amination of α-hydroxy ketones with ammonia was investigated using engineered amine dehydrogenases (AmDHs) derived from the leucine amino acid dehydrogenase (AADH) from Lysinibacillus fusiformis. The AmDHs thus identified enabled the synthesis of (S)-configured vicinal amino alcohols from the corresponding α-hydroxy ketones in up to 99% conversions and >99% ee. One of the AmDH variants was used to prepare a key intermediate for the antituberculosis pharmaceutical ethambutol.
- Chen, Fei-Fei,Cosgrove, Sebastian C.,Birmingham, William R.,Mangas-Sanchez, Juan,Citoler, Joan,Thompson, Matthew P.,Zheng, Gao-Wei,Xu, Jian-He,Turner, Nicholas J.
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p. 11813 - 11818
(2019/12/02)
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- Enantioselective Synthesis of N-Benzylic Heterocycles: A Nickel and Photoredox Dual Catalysis Approach
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Reported herein is a dual nickel- and photoredox-catalyzed modular approach for the preparation of enantioenriched N-benzylic heterocycles. α-Heterocyclic carboxylic acids, easily obtainable from common commercial material, are reported as suitable substrates for a decarboxylative strategy in conjunction with a chiral pyridine-oxazoline (PyOx) ligand, providing quick access to enantioenriched drug-like products. The presence of a directing group on the heterocyclic moiety is shown to be beneficial, affording improved stereoselectivity in a number of cases.
- Pezzetta, Cristofer,Bonifazi, Davide,Davidson, Robert W. M.
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supporting information
p. 8957 - 8961
(2019/11/11)
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- Development of C2-Symmetric Chiral Bifunctional Triamines: Synthesis and Application in Asymmetric Organocatalysis
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The synthesis and application of a newly designed C2-symmetric chiral bifunctional triamine family (C2-CBT) is reported. These enantiopure chiral triamine scaffolds can be accessed in multigram amounts from simple amino acids while avoiding chromatographic purification. As a proof of principle, C2-CBT has been studied in the aldol reaction of cyclic ketones with isatins, with the target tertiary alcohols being formed in a highly efficient manner. Catalyst recovery by simple extraction techniques and subsequent reuse has been performed.
- Ca?ellas, Santiago,Alonso, Pedro,Pericàs, Miquel à.
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supporting information
p. 4806 - 4810
(2018/08/24)
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- Synthesis and Cytotoxicity Evaluation of C4- and C5-Modified Analogues of the α,β-Unsaturated Lactone of Pironetin
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Pironetin is a natural product with potent antiproliferative activity that forms a covalent adduct with α-tubulin via conjugate addition into the natural product's α,β-unsaturated lactone. Although pironetin's α,β-unsaturated lactone is involved in its binding to tubulin, the structure–activity relationship at different positions of the lactone have not been thoroughly evaluated. For a systematic evaluation of the structure–activity relationships at the C4 and C5 positions of the α,β-unsaturated lactone of pironetin, twelve analogues of the natural product were prepared by total synthesis. Modifying the stereochemistry at the C4 and/or C5 positions of the α,β-unsaturated lactone of pironetin resulted in loss of antiproliferative activity in OVCAR5 ovarian cancer cells. While changing the C4 ethyl substituent with groups such as methyl, propyl, cyclopropyl, and isobutyl were tolerated, groups with larger steric properties such as an isopropyl and benzyl groups were not.
- Huang, David S.,Wong, Henry L.,Georg, Gunda I.
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supporting information
p. 520 - 528
(2017/04/10)
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- Synthesis of Chiral Bicyclic Guanidinium Salts using Di(imidazole-1-yl)methanimine
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A detailed account of the synthesis of chiral bicyclic guanidinium salts is presented. This work represents the first systematic investigation of an approach toward the challenging target molecules via a key guanylation step employing di(imidazole-1-yl)methanimine (6) followed by a two-fold cyclization, which resulted in guanidinium salts 8 and 10. Factors governing the regioselectivity of the final cyclization step are discussed based on further data obtained in the course of the attempted syntheses of two additional bicyclic guanidinium salts.
- Turo?kin, Aleksej,Honeker, Roman,Raven, William,Selig, Philipp
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p. 4516 - 4529
(2016/07/06)
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- Design, Synthesis, Fungicidal Activity, and Unexpected Docking Model of the First Chiral Boscalid Analogues Containing Oxazolines
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Chirality greatly influences the biological and pharmacological properties of a pesticide and will contribute to unnecessary environmental loading and undesired ecological impact. No structure and activity relationship (SAR) of enantiopure succinate dehydrogenase inhibitors (SDHIs) was documented during the structure optimization of boscalids. On the basis of commercial SDHIs, oxazoline natural products, and versatile oxazoline ligands in organic synthesis, the first effort was devoted to explore the chiral SDHIs and the preliminary mechanism thereof. Fine-tuning furnished chiral nicotinamides 4ag as a more promising fungicidal candidate against Rhizoctonia solani, Botrytis cinerea, and Sclerotinia sclerotiorum, with EC50 values of 0.58, 0.42, and 2.10 mg/L, respectively. In vivo bioassay and molecular docking were investigated to explore the potential in practical application and plausible novelty in action mechanism, respectively. The unexpected molecular docking model showed the different chiral effects on the binding site with the amino acid residues. This chiral nicotinamide also featured easy synthesis and cost-efficacy. It will provide a powerful complement to the commercial SDHI fungicides with the introduction of chirality.
- Li, Shengkun,Li, Dangdang,Xiao, Taifeng,Zhang, Shasha,Song, Zehua,Ma, Hongyu
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p. 8927 - 8934
(2016/12/07)
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- Simple primary β-amino alcohol catalyzed enantioselective Diels-Alder reaction of 3-hydroxy-2-pyridones
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The simple primary β-amino alcohol catalyzed Diels-Alder reaction of 3-hydroxy-2-pyridones as dienes with N-substituted maleimides to provide the highly substituted optically active isoquinuclidines as a single diastereomers in excellent enantioselectivities (up to 98%) with excellent chemical yields (up to 95%) was demonstrated. A range of simple β-amino alcohols were synthesized from the corresponding inexpensive amino acids and their catalytic activity was examined for this reaction.
- Takahashi, Toshihisa,Subba Reddy,Kohari, Yoshihito,Seki, Chigusa,Furuyama, Taniyuki,Kobayashi, Nagao,Okuyama, Yuko,Kwon, Eunsang,Uwai, Koji,Tokiwa, Michio,Takeshita, Mitsuhiro,Nakano, Hiroto
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p. 5771 - 5776
(2016/12/03)
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- Synthesis of Air- and Moisture-Stable, Storable Chiral Oxorhenium Complexes and Their Application as Catalysts for the Enantioselective Imine Reduction
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Air-/moisture-stable, crystalline, and storable chiral salicyloxazoline based oxorhenium(V) complexes have been synthesized and their catalytic application for the asymmetric reduction of ketimines using hydrosilane as hydride source is disclosed. A broad substrate scope, high yields, and excellent enantioselectivities (up to 99 %) are attained. Furthermore, the syntheses of enantiopure α-amino esters, γ- and δ-lactams, and isoindolinones have also been carried out using this methodology. Finally, the method has been applied to synthetic targets of pharmaceutical relevance, such as R-(+)-salsolidine and R-(+)-crispine A.
- Das, Braja Gopal,Nallagonda, Rajender,Dey, Dhananjay,Ghorai, Prasanta
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supporting information
p. 12601 - 12605
(2015/09/01)
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- Highly enantioselective Michael addition of diethyl malonate to chalcones catalyzed by cinchona alkaloids-derivatived bifunctional tertiary amine-thioureas bearing multiple hydrogen-bonding donors
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Chalcones are still challenge substrates in Michael reactions, and only limited success has been achieved. This work describes a highly enantioselective Michael addition of diethyl malonate with chalcones catalyzed by cinchona alkaloids-derivatived bifunctional tertiary amine-thioureas bearing multiple hydrogen-bonding donors.
- Liu, Yulong,Wang, Xie,Wang, Xiaoyun,He, Wei
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supporting information
p. 3163 - 3166
(2014/05/06)
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- Enantio- and diastereoselective palladium catalysed arylative and vinylative allene carbocyclisation cascades
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The enantioselective synthesis of heavily decorated spirolactams has been accomplished via an arylative or vinylative allene carbocyclisation cascade. Mediated by silver phosphate, a range of allene-linked pro-nucleophiles and aryl or vinyl iodides were reacted in the presence of catalytic Pd(OAc)2 and chiral bis(oxazoline) ligands to afford the spirolactam products in good yields and high enantio- and diastereoselectivities. The Royal Society of Chemistry 2013.
- Li, Meiling,Hawkins, Alison,Barber, David M.,Bultinck, Patrick,Herrebout, Wouter,Dixon, Darren J.
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supporting information
p. 5265 - 5267
(2013/06/27)
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- Modular bifunctional chiral thioureas as versatile organocatalysts for highly enantioselective aza-Henry reaction and michael addition
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A series of new modular bifunctional chiral thiourea organocatalysts were synthesized from natural Cinchona alkaloids and amino acids, and their performance in the aza-Henry reaction of nitroalkanes to imines, the Michael addition of acetylacetone to nitroolefins and the Michael addition of acetone to nitroolefins was investigated. Under the mild conditions, the important building blocks β-nitro amines and γ-nitro carbonyl compounds could be obtained in good yields (up to 95%) with excellent enantioselectivities (up to 99% ee) and diastereoselectivity (up to 17:1). Copyright
- Li, Hua,Zhang, Xu,Shi, Xin,Ji, Nan,He, Wei,Zhang, Shengyong,Zhang, Bangle
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p. 2264 - 2274
(2012/11/06)
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- Cr/Ni-catalyzed vinylation of aldehydes: A mechanistic study on the catalytic roles of nickel and chromium
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The roles of nickel and chromium catalysts in the coupling reaction of vinyl halides and aldehydes, the so-called Nozaki-Hiyama-Kishi (NHK) reaction, have been studied by UV/Vis spectroscopy, electrochemical, and spectroelectrochemical methods. Electrochemical studies revealed that nickel plays the central role in activating the vinyl halide by reductive cleavage, to form a rapidly decomposing vinyl-Ni species. The latter can, however, be stabilized in the presence of the Cr complex. The redox behavior of the Ni complexes in the presence of vinyl halide demonstrated that the vinyl halide activation results from interaction with a one-electron reduced nickel species [formally NiI], not necessarily with a Ni0 species. It was furthermore shown by UV/Vis spectroscopy and spectroelectrochemical methods that low-valent nickel [Ni0] results from the interaction of the NiII catalyst with CrCl2. It takes two to tango! The initial stages of the Cr/Ni-catalyzed vinylation of aldehydes (the Nozaki-Hiyama-Kishi reaction) were analyzed by electrochemical methods. The role of low-valent nickel in the C-halogen(Hal) cleavage of the vinyl halide was established, as well as the generation of the former from NiII and CrII. Copyright
- Harnying, Wacharee,Kaiser, Andre,Klein, Axel,Berkessel, Albrecht
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experimental part
p. 4765 - 4773
(2011/06/19)
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- Expanded scope for the iridium-catalyzed asymmetric isomerization of primary allylic alcohols using readily accessible second-generation catalysts
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A second generation of chiral (P,N)-iridium catalysts - readily accessible from inexpensive l-serine - displays expanded scope for the asymmetric isomerization of primary allylic alcohols.
- Mantilli, Luca,Mazet, Clement
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supporting information; scheme or table
p. 445 - 447
(2010/04/04)
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- Simply air: Vanadium-catalyzed oxidative kinetic resolution of methyl o-chloromandelate by ambient air
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Vanadium-catalyzed oxidative kinetic resolution (OKR) of methyl o-chloromandelate 2a, key intermediate of the well-known oral antiplatelet agent (S)-clopidogrel, was achieved by ambient air for the first time. The air oxidation system, which was composed of vanadium and tridentate Schiff base ligands derived from amino alcohols and salicylaldehyde derivatives, afforded an efficient and economic approach to the target intermediate with high enantioselectivities (>99% ee).
- Yin, Lu,Jia, Xian,Li, Xing Shu,Chan, Albert S.C.
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body text
p. 774 - 777
(2011/11/12)
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- Design of a genetic algorithm for the simulated evolution of a library of asymmetric transfer hydrogenation catalysts
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A library of catalysts was designed for asymmetric-hydrogen transfer to acetophenone. At first, the whole library was submitted to evaluation using high-throughput experiments (HTE). The catalysts were listed in ascending order, with respect to their performance, and best catalysts were identified. In the second step, various simulated evolution experiments, based on a genetic algorithm, were applied to this library. A small part of the library, called the mother generation (GO), thus evolved from generation to generation. The goal was to use our collection of HTE data to adjust the parameters of the genetic algorithm, in order to obtain a maximum of the best catalysts within a minimal number of gen-erations. It was namely found that simulated evolution's results depended on the selection of GO and that a random GO should be preferred. We also demonstrated that it was possible to get 5 to 6 of the ten best catalysts while investigating only 10% of the library. Moreover, we developed a double algorithm making this result still achievable if the evolution started with one of the worst GO.
- Vriamont, Nicolas,Govaerts, Bernadette,Grenouillet, Pierre,De Bellefon, Claude,Oliant, Olivier
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supporting information; scheme or table
p. 6267 - 6278
(2010/01/19)
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- (S)-N-(5-Chlorothiophene-2-sulfonyl)-β,β-diethylalaninol a Notch-1-sparing γ-secretase inhibitor
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Accumulation of beta-amyloid (Aβ), produced by the proteolytic cleavage of amyloid precursor protein (APP) by β- and γ-secretase, is widely believed to be associated with Alzheimer's disease (AD). Research around the high-throughput screening hit (S)-4-chlorophenylsulfonyl isoleucinol led to the identification of the Notch-1-sparing (9.5-fold) γ-secretase inhibitor (S)-N-(5-chlorothiophene-2-sulfonyl)-β,β-diethylalaninol 7.b.2 (Aβ 40/42 EC50 = 28 nM), which is efficacious in reduction of Aβ production in vivo.
- Cole, Derek C.,Stock, Joseph R.,Kreft, Anthony F.,Antane, Madelene,Aschmies, Suzan H.,Atchison, Kevin P.,Casebier, David S.,Comery, Thomas A.,Diamantidis, George,Ellingboe, John W.,Harrison, Boyd L.,Hu, Yun,Jin, Mei,Kubrak, Dennis M.,Lu, Peimin,Mann, Charles W.,Martone, Robert L.,Moore, William J.,Oganesian, Aram,Riddell, David R.,Sonnenberg-Reines, June,Sun, Shaiu-Ching,Wagner, Erik,Wang, Zheng,Woller, Kevin R.,Xu, Zheng,Zhou, Hua,Jacobsen, J. Steven
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scheme or table
p. 926 - 929
(2009/09/06)
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- Pd(II)/tBu-quinolineoxazoline: An Air-Stable and modular chiral catalyst system for enantioselective oxidative cascade cyclization
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[Chemical Equation Presented] An air-stable and structurally tunable chiral tBu-quinolineoxazoline/Pd(II) catalyst system has been developed for the enantioselective oxidative cascade cyclization of a variety of disubstituted olefinic substrates, with the apparent advantages of good yields and excellent enantioselectivities (up to 98% ee) and diastereoselectivities (dr >24:1). A transition-state model has also been proposed to account for the excellent stereocontrol.
- He, Wei,Yip, Kai-Tai,Zhu, Nian-Yong,Yang, Dan
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supporting information; scheme or table
p. 5626 - 5628
(2010/03/02)
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- Stereoselective synthesis of 2,4,5-trisubstituted piperidines by carbonyl ene and Prins cyclisations
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An approach to 2,4,5-trisubstituted piperidines is reported, in which the key step is the Prins or carbonyl ene cyclisation of aldehydes of the type 1. Prins cyclisation catalysed by concentrated hydrochloric acid in CH 2Cl2 at -78 °C afforded good yields of two of the four possible diastereomeric piperidines, with the 4,5-cis product 7 predominating in a diastereomeric ratio of up to 94: 6. The diastereoselectivity of the cyclisation decreased as the 2-substituent increased in size, becoming unselective for very bulky 2-substituents. In contrast, cyclisation catalysed by MeAlCl2 in CH2Cl2 or CHCl3 at temperatures of between 20-60 °C, favoured the 4,5-trans diastereomer 8, in a diastereomeric ratio of up to 99: 1. The low-temperature cyclisations catalysed by HCl proceed under kinetic control via a mechanism involving the development of significant carbocationic character, in which the 4,5-cis cation is more stable than the 4,5-trans cation as a result of overlap with the neighbouring oxygen. The cyclisations catalysed by MeAlCl2 proceed under thermodynamic control, affording the product in which both the 4- and 5-substituents are equatorial.
- Cariou, Claire A.M.,Kariuki, Benson M.,Snaith, John S.
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supporting information; experimental part
p. 3337 - 3348
(2009/02/05)
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- Enantioselective synthesis of the C8-C20 segment of curvicollide C
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The enantioselective synthesis of the C8-C20 fragment of curvicollide C has been accomplished. A catalytic asymmetric Claisen rearrangement (CAC), a diastereoselective methyl cupration of an alkynoate, and a Julia-Kocienski olefination served as key C/C-connecting transformations.
- Koerner, Marleen,Hiersemann, Martin
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p. 4979 - 4982
(2008/03/28)
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- METHOD FOR PRODUCING OPTICALLY ACTIVE CYCLOALKYLIDENE BISOXAZOLINE COMPOUND AND INTERMEDIATE THEREOF
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It is provided to an optically active cycloalkylidenebisamidoalcohol compound represented by the formula (3): wherein R1 represents a C1-6 alkyl group, an optionally substituted phenyl group, an optionally substituted aralkyl group or a hydrogen atom, or two R1s, which are bonded to the same carbon atom, are bonded to form a ring together with the carbon atom to which they are bonded, R2 represents a C1-6 alkyl group, an optionally substituted aralkyl group or an optionally substituted phenyl group and * represents an asymmetric center, a method for producing it and a method for producing an optically active cycloalkylidenebisoxazoline compound represented by the formula (4): wherein R1, R2 and * are as defined above, using thereof.
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(2008/06/13)
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- METHOD FOR PRODUCING OPTICALLY ACTIVE BISAMIDO ALCOHOL COMPOUND
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It is provided that a method for producing an optically active bisamidoalcohol compound represented by the formula (3): wherein R1 represents a C1-6 alkyl group, an optionally substituted phenyl group, an optionally substituted aralkyl group or a hydrogen atom, or two R1s, which are bonded to the same carbon atom, are bonded to form a ring together with the carbon atom to which they are bonded, R2 represents a C1-6 alkyl group, an optionally substituted phenyl group, a 1-naphthyl group, a 2-naphthyl group or an optionally substituted aralkyl group, R3 and R4 are the same or different, and each represents a hydrogen atom or C1-3 alkyl group, m represents an integer of 0 to 2, and * represents an asymmetric center, which comprises reacting an optically active aminoalcohol compound represented by the formula (1): wherein R1, R2 and * are as defined above, with a diester compound represented by the formula (2): wherein R3, R4 and m are as defined above and R5 represents a C1-3 alkyl group, in the presence of a lithium compound.
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Page/Page column 11
(2008/06/13)
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- Chiral auxiliaries as docking/protecting groups in biohydroxylation: (S)-specific hydroxylation of enantiopure tert-butyl-substituted spirooxazolidines derived from cyclopentanone
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An enantiopure tert-butyl-substituted derivative of cyclopentanone, which is a vital member of the chiral docking/ protecting group series, is employed, for the first time, to stereoselectively (90% de) introduce an (S)-configured hydroxyl group onto an unactivated carbon atom present in the cyclopentane ring using the fungus Beauveria bassiana ATCC 7159. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005.
- Muenzer, Dieter F.,Griengl, Herfried,Moumtzi, Alexandra,Saf, Robert,Terzani, Tullio,De Raadt, Anna
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p. 793 - 796
(2007/10/03)
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- Enantioselective synthesis of α-substituted ketones by asymmetric addition of chiral zinc enamides to 1-alkenes
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A zinc enamide of a chiral imine derived from a ketone and (S)-valinol or (S)-t-leucinol undergoes addition to 1-alkene to generate a γ-zincioimine intermediate, which reacts with a carbon electrophile to give upon hydrolysis an optically active α-substituted ketone in good yield. The stereoselectivity of the addition reaction may reach 99% for the reaction of a cyclohexanone imine with ethylene. Copyright
- Nakamura, Masaharu,Hatakeyama, Takuji,Hara, Kenji,Nakamura, Eiichi
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p. 6362 - 6363
(2007/10/03)
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- Experimental determination of the absolute enantioselectivity of an antibody-catalyzed Diels-Alder reaction and theoretical explorations of the origins of stereoselectivity
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The exo and endo Diels-Alder adducts of p-methoxycarbonylbenzyl trans-1,3-butadiene-1-carbamate and N,N-dimethylacrylamide have been synthesized, and the absolute configurations of resolved enantiomers have been determined. On the basis of this information, the absolute enantioselectivities of the Diels-Alder reaction catalyzed by antibodies 13G5 and 4D5 as well as other catalytic antibodies elicited in the same immunizations have been established. The effects of different arrangements of catalytic residues on the structure and energetics of the possible Diels-Alder transition states were modeled quantum mechanically at the B3LYP/6-311++G**//B3LYP/6-31+G** level of theory. Flexible docking of these enantiomeric transition states in the antibody active site followed by molecular dynamics on the resulting complexes provided a prediction of the transition -state binding modes and an explanation of the origin of the observed enantioselectivity of antibody 13G5.
- Cannizzaro, Carina E.,Ashley, Jon A.,Janda,Houk
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p. 2489 - 2506
(2007/10/03)
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- Asymmetric synthesis of protected 1,2-amino alcohols using tert-butanesulfinyl aldimines and ketimines
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tert-Butanesulfinyl aldimines and ketimines bearing an α-benzyloxy or α-silyloxy substituent serve as precursors in the synthesis of protected 1,2-amino alcohols in high yields and diastereoselectivities. General protocols are described for the addition of unbranched alkyl, branched alkyl, and aryl organometallic reagents to N-sulfinyl aldimines 1 and 2 and ketimines 5 and 6. Furthermore, the selective N- or O-deprotection of sulfinamide products 3, 4, 7, and 8 is described, enabling further synthetic transformations of the reaction products.
- Tang,Volkman,Ellman
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p. 8772 - 8778
(2007/10/03)
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- A general synthesis of enantiopure 1,2-aminoalcohols via chiral morpholinones
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Eleven optically active 1,2-aminoalcohols 20a-i and 26b-c were prepared from D-phenylglycine via cyclic imines 7b-i (or enamine 7a). The key step of the strategy is the diastereoselective reduction of chiral oxazinones 7a-i.
- Segat-Dioury, Fabienne,Lingibé, Olivier,Graffe, Bernadette,Sacquet, Marie-Claude,Lhommet, Gérard
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p. 233 - 248
(2007/10/03)
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- Versatile chiral bidentate ligands derived from α-amino acids: Synthetic applications and mechanistic considerations in the palladium- mediated asymmetric allylic substitutions
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A new class of chiral amidine-phosphine hybrid ligands 7a,b, which are readily accessible from the corresponding α-amino acids, were developed. A versatility for construction of new ligands is desirable, by which a variety of reactions and substrates become applicable. Indeed, a variety of modifications, such as exchange reactions to other amino groups in the amidine skeleton and the production of other types of ligands, are possible using the precursor compounds of 7a. Thus, novel chiral ligands 7c,d, 8, 11, and 13, which provide sterically and electronically different chiral circumstances, were prepared and used for the palladium-mediated asymmetric allylic substitutions of both acyclic and cyclic compounds. In these reactions, high levels of asymmetric induction were achieved for both substrates. A marked advancement of reactivity and enantioselectivity in palladium-catalyzed asymmetric allylations of 1,3-diphenylpropen-2-yl pivalate 14a was attained by examination of electronic substituent effects in a new series of chiral P-N and S-N hybrid ligands 8 and 11. Mechanistic views concerning the enantiodiscriminating step were demonstrated, in which a good correlation between a novel Pr/Mr concept and the absolute configuration of allylation products are discussed for the prediction of enantioselecting direction. The use of ketene silyl acetals as nucleophiles was investigated and compared with the corresponding harder anionic carbon nucleophiles. The former nucleophiles afforded higher enantioselectivity in asymmetric allylic transformations of 14a.
- Saitoh, Akihito,Achiwa, Kazuo,Tanaka, Kiyoshi,Morimoto, Toshiaki
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p. 4227 - 4240
(2007/10/03)
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- Synthesis of 1,2-aminoalcohols by Ti(IV)-catalyzed photohydroxymethylation of chiral aldimines
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The N-(α-phenylethyl) alkylated aldimines 3a-c are conveniently hydroxymethylated with moderate diastereoselectivities by means of irradiation in methanolic solution in the presence of titanium(IV)chloride.
- Griesbeck, Axel G.,Buhr, Stefan,Lex, Johann
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p. 2535 - 2536
(2007/10/03)
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- Chiral quinolinyl-oxazolines as ligands for copper(I)-catalyzed asymmetric cyclopropanation
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Chiral quinolinyl-oxazoline compounds have been synthesized from enantiomerically pure amino alcohols and 8-quinoline-carboxylic acid using a convenient procedure. Asymmetric cyccopropanation of styrene with diazoacetates in the presence of 1 mol% of CuOTf and quinolinyl-oxazolines gave 2-phenylcyclopropane carboxylates in moderate enantiomeric excesses.
- Wu, Xin-Yan,Li, Xiang-Hong,Zhou, Qi-Lin
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p. 4143 - 4150
(2007/10/03)
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- Radical reaction initiated and stereocontrolled by zinc chloride
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The reaction of allyltributyltin with methyl 2-[N-((4S)-4-(1-methylethyl)-2-oxazolidinone-3-carbamoyl)amino]-2-bromoacetate (5 a) was accelerated at -50°C in the presence of AIBN and stopped in the presence of galvinoxyl, indicating that the reaction proceeds through a radical mechanism. The reaction was accelerated dramatically at -78°C in the presence of ZnCl2·OEt2, and the ZnCl2-mediated reaction was stopped in the presence of galvinoxyl. In the presence of 2 equiv ZnCl2·OEt2, the reaction afforded methyl (2R)-2-[N-((4SH-(1-methylethyl)-2-oxazolidinone-3-carbamoyl)amino]-4-pentenoate {6a(R)} with high diastereoselectivity (93:7). Taken together, ZnCl2·OEt2 works as a radical initiator as well as chelating agent.
- Yamamoto, Yoshinori,Onuki, Setsuko,Yumoto, Masatoshi,Asao, Naoki
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p. 765 - 780
(2007/10/03)
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- Method of producing optically active tert-leucinol and its use
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A method of producing optically active tert-leucinol (formula I) of high enantiomeric purity STR1 by converting racemic (RS)-tert-leucinol into a diastereomeric salt pair by reaction with an optically active acid, removing the salt pair from solution by fractionated crystallization and separating therefrom the optically active acid to release the optically active tert-leucinol from the salt. The optically active acid used is an N-acylated tert-leucine of general formula VIII: STR2 in which R can be hydrogen or an alkyl-, arylalkyl- or aryl group with up to 20 C atoms and * signifies a chirality center.
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- Enantioselective allylic oxidation of cycloalkenes by using Cu(II)-tris(oxazoline) complex as a catalyst
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Optically active copper(II)-tris(oxazoline) complex that was synthesized as a model compound of the active site of non-heme oxygenase, was found to catalyze allylic oxidation of cycloalkenes to give the corresponding 2-cycloalkenyl benzoates with moderate to excellent enantioselectivity (up to 93% ee) under die Kharash-Sosnovsky reaction conditions.
- Kawasaki, Ken-Ichi,Katsuki, Tsutomu
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p. 6337 - 6350
(2007/10/03)
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- A new chiral disulfonamide ligand derived from α-amino acid for catalytic enantioselective cyclopropanation
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A new disulfonamide prepared from α-amino acid in five steps catalyzed cyclopropanation of allylic alcohols with Et2Zn and CH2I2 to afford the corresponding cyclopropylmethanols in moderate to good enantioselectivites. In particular, the reaction of cinnamyl alcohol in the presence of a chiral disulfonamide 1k afforded an excellent enantioselectivity (85% ee).
- Imai, Nobuyuki,Sakamoto, Katsumasa,Maeda, Masahiro,Kouge, Kazushi,Yoshizane, Kenji,Nokami, Junzo
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p. 1423 - 1426
(2007/10/03)
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- Synthesis of (R)-tert-Leucinol by Classical Resolution of the Racemic Mixture
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Optically active tert-leucinol is an important building block in asymmetric synthesis.However, the (R) enantiomer particularly has so far remained difficult to obtain, mainly because of the laborious synthesis of the precursor amino acid, (R)-tert-leucine.Here we present a new, classical resolution of racemic tert-leucinol, which allows straightforward preparation of each, but especially the (R) enantiomer, in good yields and high optical purities.The feasibility of the synthesis of useful derivatives is demonstrated by transformation into the corresponding (R)-4-tert-butyl-2-oxazolidinone. - Keywords: amino alcohols; asymmetric syntheses; chiral auxiliaries; enantiomeric resolution
- Drauz, Karlheinz,Jahn, Wilfried,Schwarm, Michael
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p. 538 - 540
(2007/10/03)
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- ASYMMETRIC SYNTHESIS WITH CHIRAL HYDROGENOLYSABLE AMINES: A NEW ROUTE TO ENANTIOPURE ETHANOLAMINES
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Enantiopure ethanolamines have been obtained via diastereoselective reduction of chiral 2,3-dihydro-6H-1,4-oxazin-2-ones.
- Lingibe, Olivier,Graffe, Bernadette,Sacquet, Marie-Claude,Lhommet, Gerard
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p. 1469 - 1472
(2007/10/02)
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