- A Scaffold-Diversity Synthesis of Biologically Intriguing Cyclic Sulfonamides
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A “branching–folding” synthetic strategy that affords a range of diverse cyclic benzo-sulfonamide scaffolds is presented. Whereas different annulation reactions on common ketimine substrates build the branching phase of the scaffold synthesis, a common hydrogenative ring-expansion method, facilitated by an increase of the ring-strain during the branching phase, led to sulfonamides bearing medium-sized rings in a folding pathway. Cell painting assay was successfully employed to identify tubulin targeting sulfonamides as novel mitotic inhibitors.
- Zimmermann, Stefan,Akbarzadeh, Mohammad,Otte, Felix,Strohmann, Carsten,Sankar, Muthukumar Gomathi,Ziegler, Slava,Pahl, Axel,Sievers, Sonja,Kumar, Kamal
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supporting information
p. 15498 - 15503
(2019/11/16)
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- Metal-Free Multicomponent Reaction for Synthesis of 4,5-Disubstituted 1,2,3-(NH)-Triazoles
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A metal-free domino reaction was developed for efficient synthesis of 4,5-disubstituted 1,2,3-(NH)-triazoles by sequentially coupling sulfur salts with aldehydes and sodium azide. In the presence of L-proline, olefinic sulfur salt intermediates rather than epoxides are formed in situ via the coupling of sulfur salts with aldehydes and cyclize with azide ion. This process features mild conditions, high efficiency, commercially available starting materials, and wide substrate scope. (Figure presented.).
- Wu, Guang-Long,Wu, Qin-Pei
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supporting information
p. 1949 - 1953
(2018/04/05)
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- Stereoselective Cyclopropanation of (-)-Levoglucosenone Derivatives Using Sulfonium and Sulfoxonium Ylides
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The synthesis of tri- and tetrasubstituted cyclopropanes from 3-aryl-substituted levoglucosenones (LGO) has been developed. In contrast to the unstabilised ylide dimethylsulfonium methylide which gives epoxides from LGO via 1,2-addition, we have found that the soft nucleophile dimethylsulfoxonium methylide affords cyclopropanes in moderate yields from LGO and in excellent yields and stereoselectivity with 3-aryl LGO derivatives. The use of 1,1,3,3-tetramethylguanidine as base in DMSO to generate the ylide provided the best yields and shortest reaction times. Ester stabilised sulfonium ylides could also be used to generate tetrasubstituted cyclopropane derivatives. One of the products was converted into a cyclopropyl lactone via Baeyer-Villiger oxidation to demonstrate the utility of applying cyclopropanation chemistry to LGO. Georg Thieme Verlag Stuttgart.New York.
- Ledingham, Edward T.,Merritt, Christopher J.,Sumby, Christopher J.,Taylor, Michelle K.,Greatrex, Ben W.
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supporting information
p. 2652 - 2662
(2017/06/13)
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- Diversity-oriented synthesis of cyclopropyl peptides from Ugi-derived dehydroalanines
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A three-step synthesis of cyclopropyl peptides is reported. The protocol involves a consecutive Ugi-4CR/elimination reaction to prepare dehydroalanines followed by a Corey-Chaykovsky cyclopropanation reaction. Peptide-like molecules that resemble some pharmacologically active compounds with a variety of substituents in the cyclopropane ring were prepared. When (2-ethoxy-2-oxoethyl) dimethyl sulfonium ylide was used the reaction exclusively gives the cis-diastereoisomer cyclopropanes in good yields from readily prepared starting materials. A collection of 26 highly substituted cyclopropyl peptides were obtained.
- Contreras-Cruz, David A.,Sánchez-Carmona, Miguel A.,Vengoechea-Gómez, Fabio A.,Pe?a-Ortíz, Daniel,Miranda, Luis D.
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supporting information
p. 6146 - 6156
(2017/09/29)
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- Oxoindole derivative containing ternary spiro and synthetic method of oxoindole derivative
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The invention discloses an oxoindole derivative containing ternary spiro. Four different isatin derivatives are respectively reacted with sulfur ylide so as to synthesize a three-membered ring product, the structural formulas of the sulfur ylide structure, isatin derivatives and three-membered ring product are respectively as shown in the specification; the four isatin derivatives are respectively as follows: R1 is methyl, R2 is ethyoxyl; R1 is methoxy group, R2 is methoxy group; R1 is chlorine, and R2 is ethyoxyl; R1 is methoxy group, R2 is ethyoxyl. The oxoindole derivative has the advantages that the three-membered cyclization reaction carried out between the sulfur ylide and the isatin derivatives is involved in the invention, and has the advantages of short reaction time, high yield and high selectivity.
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Paragraph 0021; 0023; 0025
(2017/08/29)
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- Synthesis of fullerene C60monoadducts. Cyclopropanation of C60with sulfonium ylides
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3′H-Cyclopropa[1,9](C60-Ih)[5,6]fullerene-3′-carboxylic acid can be synthesized in a good yield by cyclopropanation of fullerene C60with 2-(dimethyl-λ4-sulfanylidene)acetates provided that the ester residue is readily hydrolyzable in acid medium.
- Nikolaev,Davidovich,Piotrovskii
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p. 1050 - 1053
(2016/09/04)
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- Development of multikilogram continuous flow cyclopropanation of N -benzylmaleimide through kinetic analysis
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A convenient and high-yielding method for the synthesis of trans-(dioxo)-azabicyclo-[3.1.0]-hexane carboxylate, a key intermediate of complex molecules, is presented using a flow cyclopropanation process. From a detailed kinetic study, it is demonstrated that the reaction concentration, addition time of reagents, and initial mixing temperature are the critical parameters to minimize formation of byproducts and to get high reaction yield. Using a modular tubular flow reactor, the trans/cis-(dioxo)-azabicyclo-[3.1.0]-hexane carboxylate was obtained in 92% yield and isomerized under basic conditions to produce the trans-isomer in greater than 99% diastereomeric excess. Using this approach, the reaction yield was significantly increased compared to the batch process, and the robustness and reproducibility of this flow process was demonstrated for the synthesis of this key intermediate on a multikilogram scale.
- Buono, Frederic G.,Eriksson, Magnus C.,Yang, Bing-Shiou,Kapadia, Suresh R.,Lee, Heewon,Brazzillo, Jason,Lorenz, Jon C.,Nummy, Laurence,Busacca, Carl A.,Yee, Nathan,Senanayake, Chris
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p. 1527 - 1534
(2015/02/19)
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- PROCESS FOR THE SYNTHESIS OF SUBSTITUTED PYRAZOLES
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A process for the preparation of 4,5-di- and 2,4,5-trisubstituted pyrazole 3-carboxylates from 3-acyloxirane-2-carboxylates and hydrazine compounds.
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Page/Page column 9
(2010/05/13)
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- Synthesis of α-sulfanyl-β-amino acid derivatives by using nanocrystalline magnesium oxide
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The Mannich-type reaction between alkyl, aryl and heterocyclic aldimines and sulfonium salts for the synthesis of α-sulfanyl-β-amino acid derivatives by using nanocrystalline magnesium oxide (NAP-MgO) is described. These products are obtained in moderate to high yields with moderate diastereoselectivities. The configuration of ethyl-3-{[(4-methylphenyl)sulfonyl] amino}-2-(methylsulfanyl)-3-(4-nitrophenyl)propanoate (major isomer) has been confirmed by X-ray diffraction technique to be anti, and consistent with the assignment based on 1H NMR spectroscopy. These α-sulfanyl- β-amino acid derivatives are important building blocks for pharmaceuticals with potent biological activity.
- Kantam, M. Lakshmi,Mahendar, Koosam,Sreedhar, Bojja,Choudary, Boyapati. M.,Bhargava, Suresh K.,Priver, Steven H.
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experimental part
p. 5042 - 5052
(2010/08/20)
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- Preparation of chiral cyclopropanes with a carbohydrate fragment from levoglucosenone
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Levoglucosenone (a chiral α,β-unsaturated ketone derivative of cellulose) underwent stereoselective cyclopropanation with sulfonium ylides to form chiral trisubstituted cyclopropanes annulated with the carbohydrate moiety in high yields.
- Samet, Alexander V.,Shestopalov, Anatolly M.,Lutov, Dmitriy N.,Rodinovskaya, Lyudmila A.,Shestopalov, Alexander A.,Semenov, Victor V.
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p. 1986 - 1989
(2008/02/13)
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- Asymmetric sulfonium ylide mediated cyclopropanation: Stereocontrolled synthesis of (+)-LY354740
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The reaction of ester-stabilized sulfonium ylides with cyclopentenone to give (+)-5 ((1S,5R,6S)-ethyl 2-oxobicyclo[3.1.0]hexane-6-carboxylate), an important precursor to the pharmacologically important compound (+)-LY354740, has been studied using chiral sulfides operating in both catalytic (sulfide, Cu(acac)2, ethyl diazoacetate. 60°C) and stoichiometric modes (sulfonium salt, base, room temperature). It was found that the reaction conditions employed had a major influence over both diastereo- and enantio-selectivity. Under catalytic conditions, good enantioselectivity with low diastereoselectivity was observed, but under stoichiometric conditions low enantioselectivity with high diastereoselectivity was observed. When the stoichiometric reactions were conducted at high dilution, diastereoselectivity was reduced. This indicated that base-mediated betaine equilibration was occurring (which is slow relative to ring closure at high dilution). Based on this model, conditions for achieving high enantioselectivity were established as follows: use of a preformed ylide, absence of base, hindered ester (to reduce ylide-mediated betaine equilibration), and low concentration. Under these conditions high enantioselectivity (95% ee) was achieved, albeit with low diastereocontrol. Our model for selectivity has been applied to other sulfonium ylide mediated cyclopropanation reactions and successfully accounts for the diastereoselectivity observed in all such reported reactions to date.
- Aggarwal, Varinder K.,Grange, Emma
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p. 568 - 575
(2008/09/21)
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- Process development of (1S,2S,5R,6S)-spiro[bicyclo[3.1.0]hexane-2′, 5′-dioxo-2,4′-imidazolidine]-6-carboxylic acid, (R)-α- methylbenzenemethanamine salt (LSN344309)
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Process development and a pilot-plant process for the synthesis of 4 and its resolution to obtain (1S,2S,5R,6S)-spiro[bicyclo[3.1.0]hexane-2′, 5′-dioxo-2,4′-imidazolidine]-6-carboxylic acid, (R)-α- methylbenzenemethanamine salt (5) are described. Starting from the inexpensive raw 2-cyclopenten-1-one and sulfur ylide 1 the racemic bicyclo keto ester 2 was synthesized. Reaction of 2 with potassium cyanide and ammonium carbonate under Buecherer-Berg's reaction conditions affords racemic 3 in 80% yield. Hydrolysis of 3 followed by the resolution with (R)-(+)-α- methylbenzylamine gave 4 in excellent yield and purity under optimized conditions. The improvement of the original discovery process to accommodate safety and environmental requirements for scale-up in manufacturing facilities is also discussed.
- Rasmy, Ossama M.,Vaid, Radhe K.,Semo, Michael J.,Chelius, Erik C.,Robey, Roger L.,Alt, Charles A.,Rhodes, Gary A.,Vicenzi, Jeffery T.
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- Cycloalkyl substituted polyamines for cancer therapy and methods of synthesis therefor
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Conformationally restricted polyamine compounds useful in treatment of cancer and other diseases marked by abnormal cell proliferation are disclosed. Improved methods of synthesizing such compounds are also disclosed. In one method of the invention, a carbene-bearing or carbene equivalent-bearing compound is reacted with the double bond of an alkene compound to form a cyclopropyl ring as the first step in the synthesis.
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Page/Page column 9-10
(2010/01/31)
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- Excitatory amino acid receptor modulators
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The present invention relates to compounds of the formula ???in which R1 is defined in the specification, and non-toxic metabolically labile esters and amides thereof are useful as modulators of metabotropic glutamate receptor function.
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- Excitatory amino acid receptor antagonists
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Compounds of the formula STR1 in which X represents a bond, S, SO or SO 2 ; and R is as defined in the specification are useful as modulators of metabotropic glutamate receptor function.
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- EXCITATORY AMINOACID RECEPTOR MODULATORS
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Compounds of the formula STR1 in which R 1 and R 2 are as defined in the specification, and non-toxic metabolically labile ester and amides thereof are useful as modulators of metabotropic glutamate receptor function.
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- Preparation of bicyclohexane derivative
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A process for the preparation of (+)-2-amino-bicyclo[3.1.0]-hexane-2-6-dicarboxylic acid, or a pharmaceutically acceptable salt thereof, which comprises hydrolysing (-)-2-spiro-5''-hydantoinbicyclo[3.1.0]hexane-6-carboxylic acid or a salt thereof, and optionally forming a pharmaceutically acceptable salt. Also disclosed are intermediates useful in the process.
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- Preparation of bicyclohexane derivative
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A process for the preparation of (+)-2-amino-bicyclo[3.1.0]-hexane-2-6-dicarboxylic acid, or a pharmaceutically acceptable salt thereof, which comprises hydrolysing (-)-2-spiro-5'-hydantoinbicyclo[3.1.0]hexane-6-carboxylic acid or a salt thereof, and optionally forming a pharmaceutically acceptable salt. Also disclosed are novel intermediates useful in the process.
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- Excitatory amino acid receptor antagonists
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Compounds of the formula ???in which X represents a bond, S, O or NRa; and R is as defined in the specification are useful as modulators of metabotropic glutamate receptor function.
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- Excitatory amino acid receptor antagonists
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Compounds of the formula ???in which X represents a bond, S, SO or SO2; and R is as defined in the specification are useful as modulators of metabotropic glutamate receptor function.
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- Studies on uricosuric diuretics. II. Substituted 7,8-dihydrofuro[2,3-g]-1,2-benzisoxazole-7-carboxylic acids and 7,8-dihydrofuro[2,3-g]benzoxazole-7-carboxylic acids
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A series of substituted 7,8-dihydrofuro[2,3-g]-1,2-benzisoxazole-7-carboxylic acids and 7,8-dihydrofuro[2,3-g]benzoxazole-7-carboxylic acids were synthesized and evaluated for uricosuric and diuretic activities in rats. Many of the benzisoxazole derivatives showed uricosuric and only weak diuretic activities, whereas the benzoxazoles exhibited potent diuretic activities with little affecting urate excretion. Among these compounds, 5-chloro-7,8-dihydro-3-phenylfuro[2,3-g]-1,2-benzisoxazole-7-carboxylic acid (AA-193) was found to be a potent uricosuric agent without diuretic activity and was selected for further development.
- Sato,Dan,Onuma,Tanaka,Aoki,Koga
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p. 1760 - 1772
(2007/10/02)
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- Ester synthesis
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A novel process is described for the preparation of compounds of formula STR1 wherein R2 and R3 are each chloro or bromo; X is carboxyl, nitrile, optionally substituted carbonamide, carbonyl halide or an ester group. Those compounds wherein X is an appropriate ester group --COOB where B is an aryl group such as m-phenoxybenzyl are known insecticides; compounds where X is other than --COOB may be suitably converted thereto. The novel process consists of a series of steps from the corresponding acetyl compound of formula STR2 which comprises halogenation, reduction, esterification and finally elimination reactions.
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