- Method for synthesizing chiral lactam through tandem reductive amination
-
The invention belongs to the technical field of chemical synthesis preparation, and particularly relates to a method for synthesizing chiral lactam through tandem reductive amination, which successfully realizes ruthenium-catalyzed asymmetric reductive amination/cyclization tandem reaction to efficiently construct chiral lactam by using substrates of keto acid and keto ester.
- -
-
Paragraph 0082-0088; 0092
(2021/02/10)
-
- Direct Synthesis of Chiral NH Lactams via Ru-Catalyzed Asymmetric Reductive Amination/Cyclization Cascade of Keto Acids/Esters
-
Lactams with a stereogenic center adjacent to the N atom have existed in many medicinal agents and bioactive alkaloids. Herein we report a broadly applicable synthesis of enantioenriched NH lactams through a one-pot asymmetric reductive amination/cyclization sequence of easily available keto acids/esters. Such cascade processes alleviate the demand for protecting group manipulations as well as intermediate purification. This strategy is capable of constructing enantioenriched lactams and benzo-lactams of a five-, six-, or seven-membered ring in generally high yield and with excellent enantioselectivities (up to 97% ee). Scalable and concise syntheses of key drug intermediates have further displayed the importance of this methodology.
- Shi, Yongjie,Tan, Xuefeng,Gao, Shuang,Zhang, Yao,Wang, Jingxin,Zhang, Xumu,Yin, Qin
-
supporting information
p. 2707 - 2713
(2020/03/30)
-
- Non- C2-Symmetric Chiral-at-Ruthenium Catalyst for Highly Efficient Enantioselective Intramolecular C(sp3)-H Amidation
-
A new class of chiral ruthenium catalysts is introduced in which ruthenium is cyclometalated by two 7-methyl-1,7-phenanthrolinium heterocycles, resulting in chelating pyridylidene remote N-heterocyclic carbene ligands (rNHCs). The overall chirality results from a stereogenic metal center featuring either a or Δabsolute configuration. This work features the importance of the relative metal-centered stereochemistry. Only the non-C2-symmetric chiral-at-ruthenium complexes display unprecedented catalytic activity for the intramolecular C(sp3)-H amidation of 1,4,2-dioxazol-5-ones to provide chiral -lactams with up to 99:1 er and catalyst loadings down to 0.005 mol % (up to 11 ?200 TON), while the C2-symmetric diastereomer favors an undesired Curtius-type rearrangement. DFT calculations elucidate the origins of the superior C-H amidation reactivity displayed by the non-C2-symmetric catalysts compared to related C2-symmetric counterparts.
- Zhou, Zijun,Chen, Shuming,Hong, Yubiao,Winterling, Erik,Tan, Yuqi,Hemming, Marcel,Harms, Klaus,Houk,Meggers, Eric
-
p. 19048 - 19057
(2019/12/04)
-
- RETRACTED ARTICLE: Site-selective enzymatic C-H amidation for synthesis of diverse lactams
-
A major challenge in carbon?hydrogen (C?H) bond functionalization is to have the catalyst control precisely where a reaction takes place. In this study, we report engineered cytochrome P450 enzymes that perform unprecedented enantioselective C?H amidation reactions and control the site selectivity to divergently construct b-, g-, and d-lactams, completely overruling the inherent reactivities of the C?H bonds. The enzymes, expressed in Escherichia coli cells, accomplish this abiological carbon?nitrogen bond formation via reactive iron-bound carbonyl nitrenes generated from nature-inspired acyl-protected hydroxamate precursors. This transformation is exceptionally efficient (up to 1,020,000 total turnovers) and selective (up to 25:1 regioselectivity and 97%, please refer to compound 2v enantiomeric excess), and can be performed easily on preparative scale.
- Cho, Inha,Jia, Zhi-Jun,Arnold, Frances H.
-
p. 575 - 578
(2019/06/07)
-
- Iridium-Catalyzed Enantioselective C(sp3)-H Amidation Controlled by Attractive Noncovalent Interactions
-
While remarkable progress has been made over the past decade, new design strategies for chiral catalysts in enantioselective C(sp3)-H functionalization reactions are still highly desirable. In particular, the ability to use attractive noncovalent interactions for rate acceleration and enantiocontrol would significantly expand the current arsenal for asymmetric metal catalysis. Herein, we report the development of a highly enantioselective Ir(III)-catalyzed intramolecular C(sp3)-H amidation reaction of dioxazolone substrates for synthesis of optically enriched γ-lactams using a newly designed α-amino-acid-based chiral ligand. This Ir-catalyzed reaction proceeds with excellent efficiency and with outstanding enantioselectivity for both activated and unactivated alkyl C(sp3)-H bonds under very mild conditions. It offers the first general route for asymmetric synthesis of γ-alkyl γ-lactams. Water was found to be a unique cosolvent to achieve excellent enantioselectivity for γ-aryl lactam production. Mechanistic studies revealed that the ligands form a well-defined groove-type chiral pocket around the Ir center. The hydrophobic effect of this pocket allows facile stereocontrolled binding of substrates in polar or aqueous media. Instead of capitalizing on steric repulsions as in the conventional approaches, this new Ir catalyst operates through an unprecedented enantiocontrol mechanism for intramolecular nitrenoid C-H insertion featuring multiple attractive noncovalent interactions.
- Wang, Hao,Park, Yoonsu,Bai, Ziqian,Chang, Sukbok,He, Gang,Chen, Gong
-
supporting information
p. 7194 - 7201
(2019/05/10)
-
- Ruthenium(II)-Catalyzed Enantioselective γ-Lactams Formation by Intramolecular C-H Amidation of 1,4,2-Dioxazol-5-ones
-
We report the Ru-catalyzed enantioselective annulation of 1,4,2-dioxazol-5-ones to furnish γ-lactams in up to 97% yield and 98% ee via intramolecular carbonylnitrene C - H insertion. By employing chiral diphenylethylene diamine (dpen) as ligands bearing electron-withdrawing arylsulfonyl substituents, the reactions occur with remarkable chemo- and enantioselectivities; the competing Curtius-type rearrangement was largely suppressed. Enantioselective nitrene insertion to allylic/propargylic C - H bonds was also achieved with remarkable tolerance to the C=C and C=C bonds.
- Xing, Qi,Chan, Chun-Ming,Yeung, Yiu-Wai,Yu, Wing-Yiu
-
supporting information
p. 3849 - 3853
(2019/04/25)
-
- Amino acid chiral ligand containing bidentate coordination group, chiral catalyst, and corresponding preparation methods and applications thereof
-
The present invention relates to an amino acid chiral ligand containing a bidentate coordination group, a chiral catalyst, and corresponding preparation methods and applications thereof. The chiral ligand is prepared from a cheap and easily available amino acid, and the development of the chiral ligand can improve the diversity of the chiral ligand. The chiral Ir (III) catalyst is simply and efficiently prepared from the chiral ligand only through a one-step reaction. The chiral Ir (III) catalyst is characterized in that a bidentate guiding group is introduced to an amino acid framework to change the original coordination mode of the amino acid and Ir in order to enhance the chiral control ability of the amino acid to the Ir(III) catalyst. The chiral Ir(III) catalyst is designed and synthesized for the first time, and the selectivity reaches up to 99% ee when the catalyst is successfully applied to the high-efficiency asymmetric synthesis of chiral gamma-cyclolactam, so the catalyst has superior stereo control ability.
- -
-
Paragraph 0121-0125
(2019/10/02)
-
- Ruthenium(II)-Catalyzed Enantioselective ?-Lactams Formation by Intramolecular C-H Amidation of 1,4,2-Dioxazol-5-Ones
-
We report the Ru-Catalyzed enantioselective annulation of 1,4,2-Dioxazol-5-Ones to furnish ?-Lactams in up to 97% yield and 98% ee via intramolecular carbonylnitrene C-H insertion. By employing chiral diphenylethylene diamine (dpen) as ligands bearing electron-Withdrawing arylsulfonyl substituents, the reactions occur with remarkable chemo- A nd enantioselectivities; the competing Curtius-Type rearrangement was largely suppressed. Enantioselective nitrene insertion to allylic/propargylic C-H bonds was also achieved with remarkable tolerance to the Ca?C and Ca‰iC bonds.
- Xing, Qi,Chan, Chun-Ming,Yeung, Yiu-Wai,Yu, Wing-Yiu
-
-
- Conversion of γ- and δ-Keto Esters into Optically Active Lactams. Transaminases in Cascade Processes
-
A one-pot two-step enzymatic strategy has been designed for the production of optically active γ- and δ-lactams in aqueous medium under mild conditions. The approach is based on the biotransamination of ethyl or methyl keto esters bearing different alkyl or aryl substitution patterns at α-position to the ketone functionality. In this manner, the keto esters were transformed into the corresponding amino esters with excellent conversions, which underwent spontaneous cyclisation in the reaction medium without addition of external reagents. Depending on the transaminase selectivity, both lactam enantiomers can be obtained, so initial enzyme screenings were performed using commercially available and made in house enzymes. Reaction conditions were optimised focusing on the substrate concentration, temperature and ratio of amine donor vs acceptor. Thus, ten γ- and δ-lactams were obtained in good to high isolated yields (70–90%) and excellent selectivities (94–99%) after one or two days at 30 or 45 °C. (Figure presented.).
- Mourelle-Insua, ángela,Zampieri, Luiz Arthur,Lavandera, Iván,Gotor-Fernández, Vicente
-
supporting information
p. 686 - 695
(2018/02/21)
-
- TRICYCLIC MODULATORS OF TNF SIGNALING
-
The invention provides tricyclic heterocyclic compounds, pharmaceutically acceptable salts, prodrugs, biologically active metabolites, stereoisomers and isomers thereof wherein the variables are defined herein. The compounds of the invention may be useful for treating immunological and oncological conditions.
- -
-
Page/Page column 153
(2016/11/02)
-
- A chiral 2-phenyl pyrrolidine synthetic method
-
The invention discloses a synthetic method of chiral 2-phenylpyrrolidine. The synthetic method comprises the following steps: (1) butoxycarbonyl protective reaction: carrying out reaction on chiral 2-amino-phenylacetic acid and di-tert-butyl dicarbonate to obtain chiral 2-( butoxycarbonyl amino)-2-phenylacetic acid; (2) condensation and reduction reaction: carrying out condensation on the chiral 2-(butoxycarbonyl amino)-2-phenylacetic acid and 2, 2-dimethyl-1, 3-dioxane-4, 6-dione, and carrying out reduction by virtue of sodium borohydride to obtain chiral 2-(2, 2-dimethyl-4, 6-dicarbonyl-1, 3-dioxane-5-yl)-1-phenyl ethyl tert-butyl carbamate; (3) de-protection and heating ring closure reaction: carrying out de-protection and heating ring closure reaction on the chiral 2-(2, 2-dimethyl-4, 6-dicarbonyl-1, 3-dioxane-5-yl)-1-phenyl ethyl tert-butyl carbamate to obtain chiral 5-phenylpyrrolidine-2-ketone; and (4) reduction reaction: reducing the chiral 5-phenylpyrrolidine-2-ketone by virtue of lithium aluminium hydride to obtain the chiral 2-phenylpyrrolidine. The synthetic method is simple in operation, high in yield and cheap and easily acquired in raw materials and is suitable for industrial production.
- -
-
Paragraph 0045; 0046
(2017/02/02)
-
- FUSED TRICYCLIC BENZIMIDAZOLES DERIVATIVES AS MODULATORS OF TNF ACTIVITY
-
A series of tricyclic benzimidazole derivatives, in particular dihydro-1H- imidazo [1,2-a]benzimidazo le, dihydro-1H-pyrrolo [1,2-a]benzimidazo le, dihydro-1H- pyrazino[1,2-a]benzimidazole, dihydro-1H-[1,4]oxazino[4,3-a]benzimidazole and dihydrothiazolo[3,4-a]benzimidazolem, and analogues thereof, being potent modulators of human TNFa activity, are accordingly of benefit in the treatment and/or prevention of various human ailments, including autoimmune and inflammatory disorders; neurological and neurodegenerative disorders; pain and nociceptive disorders; cardiovascular disorders; metabolic disorders; ocular disorders; and oncological disorders.
- -
-
Page/Page column 119
(2015/06/25)
-
- Gold-catalyzed oxidative cyclization of chiral homopropargyl amides: Synthesis of enantioenriched γ-lactams
-
A gold-catalyzed tandem cycloisomerization/oxidation of homopropargyl amides has been developed, which provides ready access to synthetically useful chiral γ-lactams with excellent ee by combining the chiral tert-butylsulfinimine chemistry and gold cataly
- Shu, Chao,Liu, Meng-Qi,Wang, Shan-Shan,Li, Long,Ye, Long-Wu
-
p. 3292 - 3299
(2013/06/27)
-
- Synthesis of γ-, δ-, and ε-lactams by asymmetric transfer hydrogenation of N-(tert-butylsulfinyl)iminoesters
-
Highly enantiomerically enriched γ- and δ-lactams have been prepared by a simple and very efficient procedure that involves the asymmetric transfer hydrogenation of N-(tert-butylsulfinyl)iminoesters followed by desulfinylation of the nitrogen atom and spo
- Guijarro, David,Pablo, Oscar,Yus, Miguel
-
p. 3647 - 3654
(2013/05/22)
-
- Studies on pyrrolidinones. On the synthesis of 5-aryl-2-pyrrolidones
-
The optimization of the synthesis of 5-aryl-2-pyrrolidinones from decarbonylation of pyroglutamic acid in Eaton's reagent in the presence of aromatic derivatives is described. Four synthesized compounds were evaluated for their antiproliferative activity in the NCI-60 cancer cell lines panel.
- Ghinet, Alina,Rigo, Benoit,Gautret, Philippe
-
p. 1065 - 1072
(2013/09/23)
-
- Tandem ring-opening decarboxylation of cyclopropane hemimalonates with sodium azide: A short route to γ-aminobutyric acid esters
-
Cyclopropane hemimalonates, when treated with sodium azide, undergo a tandem ring-opening decarboxylation to produce γ-azidobutyric acids in good yields. These adducts were hydrogenated to form γ-aminobutyric acid (GABA) methyl esters.
- Emmett, Michael R.,Grover, Huck K.,Kerr, Michael A.
-
p. 6634 - 6637
(2012/10/08)
-
- Highly stereoselective double (R)-phenylglycinol-induced cyclocondensation reactions of symmetric aryl bis(oxoacids)
-
The double cyclocondensation of symmetric pyridyl bis(oxoacids) 2b and 3b with (R)-phenylglycinol stereoselectively gave access to bis-phenylglycinol- derived oxazolopyrrolidine 9 and oxazolopiperidone 10, respectively. Application of the stereocontrolled
- Amat, Mercedes,Arroniz, Carlos,Molins, Elies,Escolano, Carmen,Bosch, Joan
-
p. 2175 - 2184
(2011/05/08)
-
- Highly diastereoselective and enantioselective preparation of homoallylic amines: Application for the synthesis of β-amino acids and γ-lactams
-
Reactions of N-silyl- and N-aluminoimines with B- allyldiisopinocampheylborane in the presence of methanol, followed by oxidative workup furnished homoallylic amines in good yields and high ee. A 11B NMR spectroscopy study revealed that the reactions do not proceed, even at room temperature, unless a molar equivalent of water or methanol is added. The first reagent-controlled asymmetric crotylboration and alkoxyallylboration of aldimines furnishing β-methyl or βalkoxy homoallylic amines in very high diastereoselectivity and enantioselectivity are reported herein. Crotylboration and alkoxyallylboration of imines proceed only with the "allyl"-boron "ate" complexes, instead of the "allyl"-dialkylboron reagents used with aldehydes. The addition of methanol is necessary for these reactions as well. Application of this methodology for the conversion of representative nitriles to β-amino acids in two steps has been described. Additionally, a procedure for the preparation of chiral δ-amino alcohols and γ-lactams from nitriles is also reported.
- Ramachandran, P. Veeraraghavan,Burghardt, Thomas E.
-
p. 4387 - 4395
(2007/10/03)
-
- Chemical and microsomal oxidation of tertiary amides: Regio- and stereoselective aspects
-
The conformationally restricted tertiary amides N-methyl-2-pyrrolidone 6, N-methyl-2-piperidone 7 and N-methyl-ε-caprolactam 8 were oxidised by 5,10,15,20-tetraphenylporphyrinatoiron(III) chloride/tert-butyl hydroperoxide (TPPFe/ButOOH) and by phenobarbital-induced rat liver microsomes. The products were the N-demethylated lactams together with the analogous N-methylimides and norimides. For the TPPFe/ButOOH reaction ring oxidation is preferred to N-demethylation, paralleling the relative stabilities of the corresponding intermediate carbon-centred radicals as calculated by the AM1 semi-empirical method. In contrast, the microsomal reaction of the N-methyllactams strongly favours N-demethylation, demonstrating that hydrogen atom abstraction from the alkyl group Z to the amide carbonyl oxygen atom is preferred. The chiral tertiary amides N-methyl-N-(1-phenylethyl)benzamide 9 and N-methyl-5-phenyl-2-pyrrolidone 10 were also oxidised by TPPFe/ButOOH and by phenobarbital-induced rat liver microsomes. Using TPPFe/ButOOH, loss of the secondary alkyl group of 9 is preferred by a factor of ca. 6. Similarly, ring oxidation of 10 is favoured over demethylation by a factor of 9. For the microsomal reaction of (R)-9 dealkylation is preferred over demethylation by a factor of 1.7, whereas for (S)-9 demethylation is favoured by a factor of 1.25. For the microsomal reaction of (R)-10 and (S)-10 ring oxidation at the 5-position of the pyrrolidone ring is preferred over demethylation by factors of ca. 4 and 9 for the two isomers, respectively, and the (S)-enantiomer undergoes ring oxidation 2-3 times more readily than the (R)-enantiomer. For both 9 and 10 there is negligible stereochemical influence of the chiral centre upon the N-demethylation reaction. The results show that the stereochemical preference of the microsomal N-dealkylation reaction is modest.
- Iley, Jim,Tolando, Roberto,Constantino, Luis
-
p. 1299 - 1305
(2007/10/03)
-
- Esterase catalysed enantioselective ring closure
-
Porcine liver esterase catalyses the reaction of γ-amino esters in water to give a mixture of the corresponding γ-lactam and the hydrolysis product, deacylation of the acyl enzyme intermediate by ring closure occurs with a high enantioselectivity giving an ee of 90% for the formation of (S)-5-phenyl-2-pyrrolidone from racemic ethyl 4-phenyl-4-aminobutanoate.
- Barker, C. Vivienne,Korn, Stewart R.,Monteith, Michael,Page, Michael I.
-
p. 721 - 722
(2007/10/03)
-