336 results on '"James E. Thomson"'
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2. Microgrewiapine C: Asymmetric Synthesis, Spectroscopic Data, and Configuration Assignment
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Stephen G. Davies, Ai M. Fletcher, Paul M. Roberts, Cameron E. Taylor, and James E. Thomson
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Pharmacology ,Alkaloids ,Complementary and alternative medicine ,Molecular Structure ,Piperidines ,Organic Chemistry ,Drug Discovery ,Pharmaceutical Science ,Molecular Medicine ,Stereoisomerism ,Malvaceae ,Analytical Chemistry - Abstract
The first asymmetric synthesis of microgrewiapine C, a piperidine alkaloid isolated from
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- 2022
3. SuperQuat chiral auxiliaries: design, synthesis, and utility
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Paul M. Roberts, Stephen G. Davies, Ai M. Fletcher, and James E. Thomson
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Geminal ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,010402 general chemistry ,01 natural sciences ,Biochemistry ,Combinatorial chemistry ,Carbonyl group ,0104 chemical sciences ,chemistry.chemical_compound ,Design synthesis ,Nucleophile ,Physical and Theoretical Chemistry ,Selectivity - Abstract
The SuperQuat (4-substituted 5,5-dimethyloxazolidine-2-one) family of chiral auxiliaries was first developed by us in the 1990s to address the shortcomings of the Evans (4-substituted oxazolidin-2-one) family of chiral auxiliaries. The incorporation of geminal dimethyl substitution at C(5) has two effects: (i) it induces a conformational bias on an adjacent, otherwise conformationally labile C(4)-substituent so that it projects towards the N-acyl fragment, thus offering superior diastereofacial selectivity in a range of transformations; and (ii) it hinders nucleophilic attack at the endocyclic carbonyl group, facilitating recovery and recyclability of the auxiliary, with enhanced cleavage properties. This review summarises the development and some of the most common uses of the SuperQuat family of chiral auxiliaries, particularly in the synthesis of natural products or other targets having bioloigcal interest. Where possible, comparisons with the performances of the corresponding Evans auxiliaries are presented.
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- 2019
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4. Mutual kinetic resolution: probing enantiorecognition phenomena and screening for kinetic resolution with racemic reagents
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Stephen G. Davies, Ai M. Fletcher, Paul M. Roberts, and James E. Thomson
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Molecular Structure ,Chemistry ,Organic Chemistry ,Stereoisomerism ,Biochemistry ,Kinetic resolution ,chemistry.chemical_compound ,Kinetics ,Computational chemistry ,Reagent ,Organic synthesis ,Indicators and Reagents ,Physical and Theoretical Chemistry ,Organic Chemicals - Abstract
Enantiorecognition between a racemic reagent and a racemic substrate can be a valuable process in organic synthesis. This review highlights representative examples of this phenomenon and the use of mutual kinetic resolution as a method for screening of kinetic and/or parallel kinetic resolutions.
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- 2021
5. Stereoselective Ammonium-Directed Epoxidation in the Asymmetric Syntheses of Dihydroconduramines (–)-A-2, (–)-B-2, (–)-C-3 and (+)-F-3
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Stephen G. Davies, Ai M. Fletcher, James E. Thomson, Paul M. Roberts, and Solange Da Silva Pinto
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010405 organic chemistry ,Chemistry ,Organic Chemistry ,Enantioselective synthesis ,Regioselectivity ,010402 general chemistry ,01 natural sciences ,Medicinal chemistry ,Catalysis ,0104 chemical sciences ,chemistry.chemical_compound ,Enantiopure drug ,Stereospecificity ,Moiety ,Stereoselectivity ,Triol ,Chemoselectivity - Abstract
Epoxidation of racemic trans -2-(N, N -dibenzylamino)cyclohex-3-en-1-ol, upon treatment with Cl 3 CCO 2 H then m -CPBA, proceeded with poor diastereoselectivity (ca. 60:40 dr), whilst epoxidation of racemic trans -2-(N -benzylamino)cyclohex-3-en-1-ol under the same conditions proceeded with high diastereoselectivity ( > 95:5 dr) and was followed by completely regioselective and stereospecific ring-opening in situ to give, after methanolysis of the intermediate trichloroacetate ester, (1 RS,2 SR,3 SR,4 SR)-2-(N -benzylamino)cyclohexane-1,3,4-triol. Use of aq HBF 4 as the acid protecting agent gave the amino triol directly. The differing diastereoselectivities of these epoxidation reactions may be due to a predilection towards formation of an intramolecular hydrogen-bond in the former substrate disrupting the ability of the in situ formed ammonium moiety to act as a directing group for the incoming oxidant; the presence of two potential hydrogen-bond donors (i.e., two N-H bonds) in the latter substrate circumvents this limitation. With the criterion for a highly diastereoselective (ammonium-directed) epoxidation in this system established, a synthesis of enantiopure trans -2-(N -benzylamino)cyclohex-3-en-1-ol ( > 99% ee) was developed and the ammonium-directed epoxidation was then employed as a key synthetic step to facilitate the asymmetric syntheses of enantiopure dihydroconduramines (-)-A-2, (-)-B-2, (-)-C-3 and (+)-F-3 ( > 98% ee in each case) from 1,3-cyclohexadiene.
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- 2017
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6. Solid state conformations of α,β-unsaturated hydroxamates derived from the ‘chiral Weinreb amide’ auxiliary ( S )- N -1-(1′-naphthyl)ethyl- O - tert -butylhydroxylamine
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Stephen G. Davies, Paul M. Roberts, Jingda Yin, James A. Lee, and James E. Thomson
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Addition reaction ,Lithium amide ,010405 organic chemistry ,Stereochemistry ,Organic Chemistry ,Solid-state ,chemistry.chemical_element ,010402 general chemistry ,01 natural sciences ,Nitrogen ,Catalysis ,0104 chemical sciences ,Inorganic Chemistry ,chemistry.chemical_compound ,chemistry ,Reagent ,Amide ,Ethyl group ,Physical and Theoretical Chemistry ,Conjugate - Abstract
α,β-Unsaturated hydroxamates derived from the ‘chiral Weinreb amide’ auxiliary (S)-N-1-(1'-naphthyl)ethyl-O-tert-butylhydroxylamine consistently adopt a defined conformation and undergo highly diastereoselective conjugate addition reactions with lithium amide reagents. The configuration of the N-1-(1'-naphthyl)ethyl group dictates the position of the O-tert-butyl group and also the configuration adopted by the pyramidal nitrogen atom via a ‘chiral relay’ effect. Conjugate addition of lithium amide reagents to these substrates proceeds on the face opposite to both the O-tert-butyl group and nitrogen lone-pair with high levels of diastereoselectivity.Dedicated to the memory of Professor Howard D. Flack (1943–2017).
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- 2017
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7. Probing Competitive and Co-operative Hydroxyl and Ammonium Hydrogen-Bonding Directed Epoxidations
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James A. Lee, Alice M. R. Kennett, Ai M. Fletcher, Marta Brambilla, Paul M. Roberts, James E. Thomson, Stephen G. Davies, Méabh B. Brennan, Kristína Csatayová, and Angela J. Russell
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Co operative ,chemistry.chemical_compound ,010405 organic chemistry ,Chemistry ,Stereochemistry ,Hydrogen bond ,Organic Chemistry ,Moiety ,Ammonium ,010402 general chemistry ,Ring (chemistry) ,01 natural sciences ,0104 chemical sciences - Abstract
The diastereoselectivities and rates of epoxidation (upon treatment with Cl3CCO2H then m-CPBA) of a range of cis- and trans-4-aminocycloalk-2-en-1-ol derivatives (containing five-, six-, and seven-membered rings) have been investigated. In all cases where the two potential directing groups can promote epoxidation on opposite faces of the ring scaffold, evidence of competitive epoxidation pathways, promoted by hydrogen-bonding to either the in situ formed ammonium moiety or the hydroxyl group, was observed. In contrast to the relative directing group abilities already established for the six-membered ring system (NHBn ≫ OH > NBn2), an N,N-dibenzylammonium moiety appeared more proficient than a hydroxyl group at directing the stereochemical course of the epoxidation reaction in a five- or seven-membered system. In the former case, this was rationalized by the drive to minimize torsional strain in the transition state being coupled with assistance from hydrogen-bonding to the ammonium moiety. In the latter case, this was ascribed to the steric bulk of the ammonium moiety disfavoring conformations in which hydrogen-bonding to the hydroxyl group results in direction of the epoxidation to the syn face. In cases where the two potential directing groups can promote epoxidation on the same face of the ring scaffold, an enhancement of epoxidation diastereoselectivity was not observed, while introduction of a second, allylic heteroatom to the substrate results in diminishment of the rate of epoxidation in all cases. Presumably, reduction of the nucleophilicity of the olefin by the second, inductively electron-withdrawing heteroatom is the dominant factor, and any assistance to the epoxidation reaction by the potential to form hydrogen-bonds to two directing groups rather than one is clearly unable to overwhelm it.
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- 2017
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8. Structural Revision of the Hancock Alkaloid (−)-Galipeine
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Paul M. Roberts, Ian T. T. Houlsby, Stephen G. Davies, Ai M. Fletcher, and James E. Thomson
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Models, Molecular ,Molecular Structure ,010405 organic chemistry ,Stereochemistry ,Alkaloid ,Organic Chemistry ,Stereoisomerism ,Carbon-13 NMR ,Crystallography, X-Ray ,010402 general chemistry ,01 natural sciences ,0104 chemical sciences ,chemistry.chemical_compound ,Alkaloids ,chemistry ,Quinolines ,Structural isomer ,Specific rotation - Abstract
The 1H and 13C NMR data of synthetic samples of (S)-N(1)-methyl-2-[2'-(3″-hydroxy-4″-methoxyphenyl)ethyl]-1,2,3,4-tetrahydroquinoline, the originally proposed structure of the Hancock alkaloid (-)-galipeine, do not match those of the natural product. Herein, the preparation of the regioisomer (S)-N(1)-methyl-2-[2'-(3″-methoxy-4″-hydroxyphenyl)ethyl]-1,2,3,4-tetrahydroquinoline is reported, the 1H and 13C NMR data of which are in excellent agreement with those of (-)-galipeine. Comparison of specific rotation data enables assignment of the absolute (S)-configuration of the alkaloid, and together, these data engender the structural revision of (-)-galipeine to (S)-N(1)-methyl-2-[2'-(3″-methoxy-4″-hydroxyphenyl)ethyl]-1,2,3,4-tetrahydroquinoline.
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- 2017
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9. (−)-Pseudodistomin E: First Asymmetric Synthesis and Absolute Configuration Assignment
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Stephen G. Davies, David Zimmer, Paul M. Roberts, James E. Thomson, and Ai M. Fletcher
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chemistry.chemical_classification ,010405 organic chemistry ,Stereochemistry ,Carboxylic acid ,Organic Chemistry ,Enantioselective synthesis ,Absolute configuration ,010402 general chemistry ,01 natural sciences ,Biochemistry ,0104 chemical sciences ,Stereocenter ,chemistry.chemical_compound ,chemistry ,Reagent ,Amide ,Physical and Theoretical Chemistry ,Derivative (chemistry) ,Conjugate - Abstract
(-)-Pseudodistomin E has been prepared for the first time, allowing its structure and absolute configuration to be confirmed. The established conjugate addition of lithium (S)-N-allyl-N-(α-methyl-p-methoxybenzyl)amide to methyl (E,E)-hepta-2,5-dienoate generated the C(2)-stereocenter, and iodolactonisation of a derivative generated the remaining two stereogenic centers. Ensuing iodide displacement was achieved using a tethering strategy, to introduce the nitrogen atom to C(5). Decarboxylative coupling of a carboxylic acid with a dialkylzinc reagent completed construction of the tridecadienyl chain.
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- 2017
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10. Asymmetric syntheses of fagomine and its stereoisomers
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Paul M. Roberts, Stephen G. Davies, Ai M. Fletcher, and James E. Thomson
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chemistry.chemical_compound ,chemistry ,010405 organic chemistry ,Stereochemistry ,Organic Chemistry ,Drug Discovery ,Iminosugar ,Piperidine ,010402 general chemistry ,01 natural sciences ,Biochemistry ,0104 chemical sciences - Abstract
d -Fagomine (1,2,5-trideoxy-1,5-imino-d-arabino-hexitol), a naturally occurring polyhydroxylated piperidine (iminosugar), and its stereoisomers display important biological activities such as glycosidase inhibition. This review delineates both de novo asymmetric and enantiospecific syntheses of fagomine and its stereoisomers.
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- 2019
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11. The asymmetric synthesis of (S,S)-methylphenidate hydrochloride via ring-opening of an enantiopure aziridinium intermediate with phenylmagnesium bromide
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James E. Thomson, Stephen G. Davies, Paul M. Roberts, Matthew E. Peters, and Ai M. Fletcher
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010405 organic chemistry ,Chemistry ,Hydrochloride ,Organic Chemistry ,Enantioselective synthesis ,Regioselectivity ,Phenylmagnesium bromide ,Alkylation ,010402 general chemistry ,Methanesulfonic anhydride ,01 natural sciences ,Biochemistry ,Medicinal chemistry ,0104 chemical sciences ,chemistry.chemical_compound ,Enantiopure drug ,Drug Discovery ,Piperidine - Abstract
The key step in our synthetic strategy towards (S,S)-methylphenidate hydrochloride employs the ring-opening of an in situ formed aziridinium intermediate. Treatment of an α-hydroxy-β-amino ester with methanesulfonic anhydride promoted aziridinium formation and the subsequent addition of phenylmagnesium bromide resulted in stereospecific and regioselective ring-opening to give the corresponding α-phenyl-β-amino ester with overall retention of configuration. Subsequent functional group manipulation followed by N-deprotection and cyclisation generated the piperidine ring within the target compound, and transesterification gave (S,S)-methylphenidate hydrochloride, in only 8 steps from 1,5-pentanediol, in 15% overall yield. These results demonstrate the synthetic utility of enantiopure aziridinium intermediates as substrates for the generation of stereodefined C–C bonds, and crucially this methodology provides access to α-substituted-β-amino ester substrates that are not accessible via enolate alkylation chemistry. The strategy reported herein is potentially applicable to all possible stereoisomers of methylphenidate as well as differentially substituted analogues.
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- 2019
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12. Synthesis of (-)-Conduramine A1, (-)-Conduramine A2 and (-)-Conduramine E2 in Six Steps from Cyclohexa-1,4-diene
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James E. Thomson, Solange Da Silva Pinto, Stephen G. Davies, Ai M. Fletcher, and Paul M. Roberts
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chemistry.chemical_compound ,Enantiopure drug ,Diene ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,Organic chemistry ,Physical and Theoretical Chemistry ,010402 general chemistry ,01 natural sciences ,Biochemistry ,0104 chemical sciences - Abstract
A method to enable the synthesis of conduramines and theirN-substituted derivatives (enantiopure or racemic form) in six steps (five steps forN-substituted derivatives) from cyclohexa-1,4-diene is reported. Key features of this reaction sequence include a preparation of benzene oxide that is amenable to multigram scale, and its efficient ring-opening upon treatment with a primary amine. Epoxidation of the resultant amino alcohols (40% aq HBF4thenm-CPBA) is accompanied by hydrolytic ring-opening in situ to give the correspondingN-substituted conduramine derivatives directly. These may undergo subsequentN-deprotection to give the parent conduramines, as demonstrated by the preparation of enantiopure (−)-conduramine A1, (−)-conduramine A2, and (−)-conduramine E2 (the latter two for the first time). The selectivity of the epoxidation reaction is proposed to be the result of competitive ammonium-directed and hydroxyl-directed epoxidation processes, followed by either direct (SN2-type) or conjugate (SN2′-type) ring-openings of the intermediate epoxides.
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- 2019
13. N-acetylcolchinol methyl ether (a natural product); suhailamine (a phantom natural product)
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Ai M. Fletcher, Stephen G. Davies, Angus Yeung, Paul M. Roberts, and James E. Thomson
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Pharmacology ,Natural product ,010405 organic chemistry ,Stereochemistry ,Organic Chemistry ,Pharmaceutical Science ,Ether ,01 natural sciences ,Colchicum decaisnei ,Imaging phantom ,0104 chemical sciences ,Analytical Chemistry ,010404 medicinal & biomolecular chemistry ,chemistry.chemical_compound ,Complementary and alternative medicine ,chemistry ,Drug Discovery ,Molecular Medicine ,N-acetylcolchinol - Abstract
The reported characterization data for the allocolchicinoid alkaloid suhailamine, isolated fromColchicum decaisneiand known to have an erroneous structure, have been reanalyzed. This analysis has led to the current proposal that suhailamine has the same structure asN-acetylcolchinol methyl ether (NCME), an assertion that is supported by comparison with previously reported data for NCME. Suhailamine is therefore a phantom natural product, while NCME represents a naturally occurring allocolchicinoid rather than a purely synthetic entity.
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- 2019
14. The Hancock alkaloids angustureine, cuspareine, galipinine, and galipeine: A review of their isolation, synthesis, and spectroscopic data
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Ai M. Fletcher, Stephen G. Davies, Paul M. Roberts, and James E. Thomson
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Galipinine ,Cuspareine ,Stereochemistry ,Chemistry ,Organic Chemistry ,Angustureine ,Total synthesis ,Physical and Theoretical Chemistry ,Isolation (microbiology) - Abstract
A review of the isolation, reported methods for the synthesis (up to the end of 2018), and spectroscopic data of angustureine, cuspareine, galipinine, and galipeine, members of the Hancock family of alkaloids based upon a 2‐substituted N(1)‐methyl‐1,2–3,4‐tetrahydroisolquinoline scaffold, is presented.
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- 2019
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15. Comparison of Aerobic and Anaerobic Incubation Conditions for Optimal Recovery of Salmonella
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J. O. Reagan, James E. Thomson, Nelson A. Cox, and J. S. Bailey
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Salmonella ,Enrichment broth ,Recovery rate ,medicine ,Anaerobic incubation ,Biology ,medicine.disease_cause ,Microbiology ,Incubation ,Aerobic incubation ,Food Science - Abstract
Effects of aerobic and anaerobic incubation of selenite-cystine and TT enrichment broth incubated at 37 and 34°C on the growth of Salmonella were determined. Pure cultures of four serotypes of Salmonella were enumerated at 0, 4, 8 and 24 h of incubation and no significant differences related to incubation conditions were found. The effect of microflora other than Salmonella , in pure and mixed cultures and from chicken and feed samples, on the recovery rate of Salmonella after incubation in enrichment media was evaluated and no significant effects were found; however, aerobic incubation usually gave higher Salmonella counts. Greater recovery of Salmonella was obtained by incubating selective plating media aerobically rather than anaerobically. Aerobic incubation of liquid enrichment media and differential plating media is therefore recommended for optimal recovery of Salmonella .
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- 2019
16. Identification of Enterobacteriaceae in Foods with the AutoMicrobic System
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Daniel Y. C. Fung, James E. Thomson, Nelson A. Cox, and J. S. Bailey
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Salmonella ,business.industry ,medicine ,Food science ,Biology ,medicine.disease_cause ,business ,biology.organism_classification ,Microbiology ,Enterobacteriaceae ,Food Science ,Biotechnology - Abstract
Stock cultures (136) and fresh isolates (163) of Enterobacteriaceae from ground beef, processed chickens, frozen pot pies and commercial poultry feeds were identified to species with the AutoMicrobic System (AMS). All stock cultures and fresh isolates were also concurrently tested with two other identification systems (Micro-ID and API), previously evaluated and proven accurate for identification of Enterobacteriaceae . The AMS correctly identified to species 135/136 (99.3%) of the stock cultures and 160/163 (98.2%) of the fresh isolates. All Salmonella cultures tested (74) were correctly identified by AMS.
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- 2019
17. Identification of Enterobacteriaceae from Foods with the Spectrum-10
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M. Van Wart, Nelson A. Cox, J. S. Bailey, and James E. Thomson
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biology ,Food science ,biology.organism_classification ,Microbiology ,Enterobacteriaceae ,Food Science ,Identification system - Abstract
Spectrum-10, a newly developed miniaturized identification system, was analyzed for its ability to accurately and rapidly identify members of the Enterobacteriaceae family. This study, conducted at two separate laboratories, tested freshly isolated organisms from raw and frozen foods (180) and stock cultures (144). For comparison purposes, the Micro-ID and API-20E identification systems were concurrently inoculated with the test organisms. In comparison to the Micro-ID and the API-20E systems, the Spectrum-10 identified 95 to 96% of the stock cultures to genus and species, whereas 93% of the fresh isolates were identified to genus and 82% to species.
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- 2019
18. Survival of Salmonella in Dry Food and Feed
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O. W. Charles, J. V. Shutze, B. J. Juven, James E. Thomson, Nelson A. Cox, and J. S. Bailey
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Salmonella montevideo ,Salmonella ,Animal science ,Inoculation ,medicine ,Salmonella Heidelberg ,Biology ,medicine.disease_cause ,Microbiology ,Meat and bone meal ,Food Science - Abstract
The survival of Salmonella Montevideo and Salmonella heidelberg in dry milk, cocoa powder, poultry feed, and meat and bone meal was studied at three water activities (aw) in the range of 0.4 to 0.75. S. montevideo was more resistant to the various dry environments than S. heidelberg . Salmonellae were enumerated immediately after inoculation, after 2 d, and after 1, 3, 7 and 14 wk. Survival was greater at aw of 0.43 and 0.52 than at 0.75 aw. Based on these findings and due to the marked differences in survival observed in the different products equilibrated at a specific aw value, it is concluded that the survival of salmonellae in a dry product cannot be predicted on the basis of the aw alone.
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- 2019
19. Selecting a Miniaturized System for Identification of Enterobacteriaceae
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Nelson A. Cox, J. S. Bailey, M. C. Goldschmidt, James E. Thomson, and Daniel Y. C. Fung
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Identification (information) ,Biology ,Microbiology ,Food Science ,Reliability engineering - Abstract
The most commonly used commercial diagnostic kits for identification of Enterobacteriaceae are API, Enteric-Tek, Enterotube II, Micro-ID, Minitek and Spectrum-10. The accuracy of identification by all systems does not vary significantly, and falls within the acceptable range. Therefore, a bacteriologist who is considering the use of these products should evaluate factors other than accuracy when making a choice. Twenty-three professional microbiologists who had previous experience with these systems listed advantages and disadvantages of each system, and evaluated the conventional procedure for identification. The comments were summarized and presented in tabular form. The current cost per isolate of each system and the cost of the identification manual, reagents and incidental costs were also determined. These data provide the potential user with comparative information on price, shelf-life, versatility, time required for inoculation, incubation and manipulation after incubation, possible difficulties in determining positive and negative reactions, and potential safety factors for laboratory personnel.
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- 2019
20. Effect of Reduced Processing on Recovery of Foodborne Pathogens from Hot-Boned Broiler Meat and Skin
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James E. Thomson, H. S. Lillard, and D. Hamm
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Salmonella ,business.industry ,animal diseases ,digestive, oral, and skin physiology ,technology, industry, and agriculture ,Broiler ,food and beverages ,Clostridium perfringens ,medicine.disease_cause ,Microbiology ,fluids and secretions ,Medicine ,Food science ,business ,Food Science - Abstract
Recovery of pathogens from breast meat, thigh meat and skin from scalded, defeathered but uneviscerated broiler carcasses with and without spray washing was compared to recovery from breast meat, thigh meat and skin from fully processed, chilled carcasses (controls). The incidence of coagulase-positive staphylococci was not significantly different on meat and skin from both uneviscerated carcasses with and without a spray washing compared to meat and skin from fully processed carcasses. The incidence of Clostridium perfringens was not significantly different on skin, breast and thigh meat for any of the sampling sources except that incidence on meat from control breasts was lower than on breast meat from uneviscerated carcasses without spray-washing; and incidence on meat from control thighs was lower than on meat from spray-washed, uneviscerated carcasses. Salmonella incidence was higher on both breast and thigh meat from fully processed control carcasses than from uneviscerated unwashed carcasses. When uneviscerated carcasses were spray-washed after defeathering, the incidence of Salmonella was not significantly different on breast meat, and significantly lower on thigh meat than on these meats from fully processed control carcasses. Skin from fully processed control carcasses had a higher incidence of Salmonella than did skin from uneviscerated, unwashed carcasses, but not skin from uneviscerated, spray-washed carcasses. Reducing the number of stages of processing significantly reduced the incidence of Salmonella but not of coagulase-positive staphylococci or Clostridium perfringens .
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- 2019
21. Comparison of Sampling Methods for Escherichia coli and Total Aerobic Counts on Broiler Carcasses
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James E. Thomson and Huda S. Lillard
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business.industry ,animal diseases ,digestive, oral, and skin physiology ,technology, industry, and agriculture ,Broiler ,food and beverages ,Sampling (statistics) ,Biology ,medicine.disease_cause ,Microbiology ,Biotechnology ,medicine ,Food science ,business ,Escherichia coli ,Food Science - Abstract
Significantly higher Escherichia coli and total aerobic counts were obtained from broiler carcasses when 20 g of excised breast skin were blended in peptone solution than when either whole carcasses or 20 g of excised breast skin were rinsed in peptone solution for sampling.
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- 2019
22. Comparison of Micro-ID and Minitek-Serology Systems for Rapid Identification of Salmonella
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Nelson A. Cox, J. S. Bailey, and James E. Thomson
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Rapid identification ,Salmonella ,medicine ,Biology ,medicine.disease_cause ,Microbiology ,Food Science ,Identification system ,Serology - Abstract
A 4-h biochemical identification system (Micro-ID) and a rapid confirmation 24-h biochemical and serological procedure (RC) involving the Minitek system were compared for accuracy of Salmonella identification. Of 144 known Salmonella stock cultures, RC correctly classified all, and Micro-ID correctly classified 141. Both systems correctly classified all the Salmonella isolates obtained from four artificially inoculated broiler carcasses. When 113 suspect- Salmonella isolates from naturally contaminated samples were examined, RC correctly classified all, and Micro-ID correctly classified all except one.
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- 2019
23. Minitek Inoculum Broth for Testing Indole Production by Enterobacteriaceae
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James E. Thomson, Nelson A. Cox, and J. S. Bailey
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Indole test ,biology ,equipment and supplies ,biology.organism_classification ,Microbiology ,Enterobacteriaceae ,Food Science - Abstract
With 73 members of the Enterobacteriaceae family, detection of indole production with Minitek inoculum broth (MIB) correlated more closely with the results of the conventional method than did detection with the Minitek H2S/indole disk.
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- 2019
24. Microcosamine A, Microgrewiapine A and Microgrewiapine B: three homochiral alkaloids?
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Ai M. Fletcher, Cameron E. Taylor, Stephen G. Davies, James E. Thomson, and Paul M. Roberts
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010405 organic chemistry ,Stereochemistry ,Chemistry ,Organic Chemistry ,Enantioselective synthesis ,Absolute configuration ,010402 general chemistry ,01 natural sciences ,Biochemistry ,Reductive amination ,0104 chemical sciences ,Stereocenter ,chemistry.chemical_compound ,Amide ,Drug Discovery ,Proton NMR ,Specific rotation ,Piperidine - Abstract
An asymmetric synthesis of microcosamine A, microgrewiapine A and microgrewiapine B (Microcos paniculata alkaloids) is reported. Conjugate addition of lithium (S)-N-benzyl-N-(α-methylbenzyl)amide to tert-butyl crotonate followed by enolate oxidation generates the C(2) and C(3) stereogenic centres of the targets, with subsequent diastereoselective intramolecular reductive amination being used to form the piperidine ring, simultaneously producing the C(6) stereogenic centre. 1H NMR 3J coupling constant and nOe analyses allow unambiguous assignment of relative configuration of the alkaloids. Comparison of specific rotation data for microcosamine A and microgrewiapine B is consistent with both possessing the absolute (2S,3R,6S)-configuration. For microgrewiapine A, conflicting data regarding the absolute configuration are revealed: in the isolation study a Mosher’s analysis concludes a (2S,3R,6S)-configuration, but comparison of specific rotation data suggests a (2R,3S,6R)-configuration. Thus it is promulgated it is imprudent to suggest the absolute configuration of this natural product; its re-isolation is required for resolution of this problem.
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- 2021
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25. Microconine [N-methyl-2-methyl-3-methoxy-6-(deca-l’,3′,5′-trienyl)piperidine, an alkaloid from Microcos paniculata]: Synthesis, stereochemistry and spectroscopic data
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Paul M. Roberts, Cameron E. Taylor, Ai M. Fletcher, James E. Thomson, and Stephen G. Davies
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biology ,Stereochemistry ,Organic Chemistry ,Enantioselective synthesis ,biology.organism_classification ,Biochemistry ,Reductive amination ,Stereocenter ,Microcos paniculata ,chemistry.chemical_compound ,Enantiopure drug ,chemistry ,Amide ,Drug Discovery ,Specific rotation ,Piperidine - Abstract
Unambiguously corrected 1H NMR data for the originally isolated sample of microconine [N-methyl-2-methyl-3-methoxy-6-(deca-l’,3′,5′-trienyl)piperidine], an alkaloid found in Microcos paniculata, are reported. The asymmetric synthesis of the (2S,3R,6S)- and (2S,3S,6S)-stereoisomeric forms [epimeric at C(3)] of this compound allows the unambiguous assignment of the relative 2,3-cis-3,6-cis-configuration of the natural product. The synthesis uses the conjugate addition of enantiopure lithium (S)-N-benzyl-N-(α-methylbenzyl)amide to tert-butyl crotonate and ensuing enolate oxidation with (+)-camphorsulfonyloxaziridine to generate the requisite C(2) and C(3) stereogenic centres found within the target. After elaboration, an intramolecular reductive amination was used to form the piperidine ring, with concomitant formation of the C(6) stereogenic centre. Comparison of specific rotation data is consistent with the alkaloid having the absolute (2R,3R,6R)-configuration.
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- 2021
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26. Pyrrolizidines, indolizidines and quinolizidines via a double reductive cyclisation protocol: concise asymmetric syntheses of (+)-trachelanthamidine, (+)-tashiromine and (+)-epilupinine
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David Zimmer, Stephen G. Davies, James E. Thomson, Ai M. Fletcher, Marta Brambilla, and Paul M. Roberts
- Subjects
Indolizidines ,Quinolizidine ,010405 organic chemistry ,Chemistry ,Stereochemistry ,Organic Chemistry ,Enantioselective synthesis ,Indolizidine ,010402 general chemistry ,01 natural sciences ,Biochemistry ,Quinolizidines ,0104 chemical sciences ,chemistry.chemical_compound ,Amide ,Drug Discovery ,Pyrrolizidine ,Hydroxymethyl - Abstract
The asymmetric syntheses of pyrrolizidine, indolizidine and quinolizidine alkaloids have been achieved using the diastereoselective conjugate addition of lithium (R)-N-benzyl-N-(α-methylbenzyl)amide to α-alkenyl-α,β-unsaturated esters followed by diastereoselective protonation of the resultant enolates as the key stereodefining steps. The azabicyclic scaffolds were then efficiently constructed upon sequential oxidative cleavage of the olefinic units within the resultant β-amino esters and hydrogenolytic N-debenzylation of the corresponding dialdehydes, which occurs with concomitant double reductive cyclisation. Subsequent reduction of the ester moieties with LiAlH4 gave (+)-trachelanthamidine, (+)-tashiromine, (1S,8aR)-1-(hydroxymethyl)octahydroindolizine and (+)-epilupinine in 4.9, 4.1, 3.0 and 5.9% overall yield, respectively, in only six steps from commercially available starting materials.
- Published
- 2016
- Full Text
- View/download PDF
27. Asymmetric Syntheses of (−)-ADMJ and (+)-ADANJ: 2-Deoxy-2-amino Analogues of (−)-1-Deoxymannojirimycin and (+)-1-Deoxyallonojirimycin
- Author
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Stephen G. Davies, Aude L.A. Figuccia, Ai M. Fletcher Paul, James E. Thomson, and M. Roberts
- Subjects
chemistry.chemical_classification ,Carbamate ,010405 organic chemistry ,Stereochemistry ,medicine.medical_treatment ,Organic Chemistry ,Diastereomer ,010402 general chemistry ,01 natural sciences ,Aldehyde ,0104 chemical sciences ,chemistry.chemical_compound ,Enantiopure drug ,chemistry ,Bromide ,Yield (chemistry) ,Intramolecular force ,medicine ,Moiety - Abstract
The asymmetric syntheses of (–)-ADMJ and (+)-ADANJ, the 2-deoxy-2-amino analogues of (–)-1-deoxymannojirimycin and (+)-1-deoxyallonojirimycin, are described herein. Methodology for the ring-closing iodoamination of bishomoallylic amines followed by in situ ring-expansion (via intramolecular ring-opening of the corresponding aziridinium intermediates with a tethered carbamate moiety) to give oxazolidin-2-ones was initially optimised on a model system. Subsequent application of this methodology to two enantiopure bishomoallylic amines (which were produced via aminohydroxylation of an α,β-unsaturated ester, partial reduction and reaction of the corresponding aldehyde with vinylmagnesium bromide) also proceeded with concomitant N-debenzylation to afford the corresponding diastereoisomerically pure (>99:1 dr) oxazolidin-2-ones. Subsequent deprotection of these enantiopure templates gave (–)-ADMJ and (+)-ADANJ as single diastereoisomers in 16 and 24% overall yield, respectively.
- Published
- 2016
- Full Text
- View/download PDF
28. Strategies for the construction of morphinan alkaloid AB-rings: regioselective Friedel-Crafts-type cyclisations of γ-aryl-β-benzoylamido acids with asymmetrically substituted γ-aryl rings
- Author
-
Stephen G. Davies, Paul M. Roberts, Andrew Smith, Euan C. Goddard, Jonathan M. Withey, James E. Thomson, and Angela J. Russell
- Subjects
Morphinan ,010405 organic chemistry ,Stereochemistry ,Aryl ,Alkaloid ,Organic Chemistry ,Regioselectivity ,010402 general chemistry ,Ring (chemistry) ,01 natural sciences ,Catalysis ,0104 chemical sciences ,Inorganic Chemistry ,chemistry.chemical_compound ,chemistry ,Lewis acids and bases ,Physical and Theoretical Chemistry ,Friedel–Crafts reaction ,Morphinan alkaloids - Abstract
The regioselectivity of the Friedel-Crafts-type cyclisation of a range of γ-aryl-β-benzoylamido acids, bearing oxy substituents at the C(3)- and C(4)-positions of the γ-aryl ring, has been investigated. In all of the cases examined (with 3,4-dimethoxy, 3,4-methylenedioxy and 3-hydroxy-4-methoxy substituents) the Lewis acid promoted cyclisation proceeds with exclusive regioselectivity for attack at the C(6)-position rather than at the C(2)-position, and furnishes the corresponding N - and O -protected 3-amino-6,7-dihydroxy-1-tetralone derivatives. This inherent regioselectivity can be overturned by the regioselective introduction of chlorine as a blocking group for the C(6)-position; subsequent Lewis acid promoted cyclisation then proceeds with exclusive regioselectivity for attack at the C(2)-position to deliver the corresponding N - and O -protected 3-amino-5-chloro-7,8-dihydroxy-1-tetralone derivative. These complementary cyclisation protocols represent useful methods for the preparation of these benzo-fused carbocyclic ring systems, which are the functionalised AB-rings of a range of morphinan alkaloids.
- Published
- 2016
- Full Text
- View/download PDF
29. Trading N and O. Part 3: Synthesis of 1,2,3,4-tetrahydroisoquinolines from α-hydroxy-β-amino esters
- Author
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Matthew S. Kennedy, Paul M. Roberts, Stephen G. Davies, Aileen B. Frost, James E. Thomson, and Ai M. Fletcher
- Subjects
Amino esters ,010405 organic chemistry ,Stereochemistry ,Aryl ,Organic Chemistry ,Diastereomer ,Enantioselective synthesis ,Regioselectivity ,010402 general chemistry ,01 natural sciences ,Biochemistry ,0104 chemical sciences ,Carbenium ion ,chemistry.chemical_compound ,Enantiopure drug ,chemistry ,Drug Discovery ,Moiety - Abstract
All rights reserved.A range of enantiopure 1,2,3,4-tetrahydroisoquinolines have been prepared directly from α-hydroxy-β-amino esters. Activation of the α-hydroxy group upon treatment with Tf2O and 2,6-di-tert-butyl-4-methylpyridine promotes aziridinium formation, which is then followed by rupture of the C(3)-N bond and Friedel-Crafts alkylation-type cyclisation of an N-benzyl moiety onto the resultant benzylic carbenium ion. The nature of the N-protecting group was varied and it was found that superior yields were obtained for reactions employing two benzylic groups. In the cases where two different N-benzyl groups were used, the regioselectivity resulting from competitive cyclisation of either N-benzyl group was addressed by the introduction of a p-trifluoromethyl group on one of the N-benzyl moieties, which retarded the rate of cyclisation via this electron poor aryl ring. This methodology was employed in the asymmetric synthesis of a range of enantiopure 1,2,3,4-tetrahydroisoquinolines, which were isolated in good yields as single diastereoisomers.
- Published
- 2016
- Full Text
- View/download PDF
30. The asymmetric synthesis of enantiopure C(5)-substituted transpentacins via diastereoselective conjugate additions to a β′-amino-α,β-unsaturated ester
- Author
-
Paul M. Roberts, Charlotte M. Zammit, Ai M. Fletcher, Stephen G. Davies, and James E. Thomson
- Subjects
chemistry.chemical_classification ,Lithium amide ,010405 organic chemistry ,Stereochemistry ,Organic Chemistry ,Diastereomer ,Enantioselective synthesis ,010402 general chemistry ,01 natural sciences ,Catalysis ,0104 chemical sciences ,Inorganic Chemistry ,chemistry.chemical_compound ,Enantiopure drug ,chemistry ,Reagent ,Hydroxymethyl ,Physical and Theoretical Chemistry ,Alkyl ,Conjugate - Abstract
The asymmetric synthesis of a range of 1,2-anti-1,5-syn-transpentacins, bearing either alkyl, phenyl or hydroxymethyl substituents at the C(5)-position, has been achieved using the diastereoselective conjugate additions of Grignard reagents to an enantiopure β′-amino-α,β-unsaturated ester as the key step. In addition, the doubly diastereoselective conjugate addition of an enantiopure lithium amide reagent to the β′-amino-α,β-unsaturated ester provided access to the corresponding β,β′-diamino ester, which was subsequently converted to both (S,S)-(2,5-diaminocyclopent-1-yl)methanol and (S,S)-2,5-diaminocyclopentane-1-carboxylic acid. In each case, the final enantiopure products were obtained as single diastereoisomers (>99:1 dr) in good yields over five steps or fewer from commercially available starting materials.
- Published
- 2016
- Full Text
- View/download PDF
31. Asymmetric syntheses of the methyl 3-deoxy-3-amino-glycosides of d-glycero-l-gulo-heptose, d-glycero-d-galacto-heptose, d-glycero-l-allo-heptose and d-glycero-d-allo-heptose
- Author
-
Paul M. Roberts, Marta Brambilla, James A. Lee, Stephen G. Davies, Ai M. Fletcher, James E. Thomson, Michael A. Waul, and Wilfred T. Diment
- Subjects
chemistry.chemical_classification ,010405 organic chemistry ,Chemistry ,Stereochemistry ,Organic Chemistry ,Glycoside ,Heptose ,010402 general chemistry ,01 natural sciences ,Catalysis ,0104 chemical sciences ,Inorganic Chemistry ,chemistry.chemical_compound ,Amide ,Physical and Theoretical Chemistry ,Conjugate - Abstract
The methyl glycosides of 3-deoxy-3-amino- d - glycero - l - gulo -heptose, 3-deoxy-3-amino- d - glycero - d - galacto -heptose, 3-deoxy-3-amino- d - glycero - l - allo -heptose and 3-deoxy-3-amino- d - glycero - d - allo -heptose were prepared from the corresponding d -aldopentoses via a seven step synthetic sequence. The doubly diastereoselective conjugate additions of the requisite antipode of lithium N -benzyl- N -(α-methylbenzyl)amide to four diastereoisomeric d -aldopentose-derived α,β-unsaturated esters and in situ enolate oxidation with the requisite antipode of camphorsulfonyloxaziridine (CSO) were used as the key, stereodefining steps. Sequential protection of the C(2)-hydroxyl group within the resultant α-hydroxy-β-amino esters and partial reduction of the ester functionality furnished the corresponding β-amino aldehydes. Subsequent N- and O-deprotection gave the target compounds (as the corresponding methyl pyranosides and/or methyl furanosides) in good yields and high diastereoisomeric purity.
- Published
- 2016
- Full Text
- View/download PDF
32. Rapid stereoselective syntheses of heteroarene-fused azacycles via diastereoselective conjugate addition of heteroaryl substituted lithium amides
- Author
-
Paul M. Roberts, Katherine E. Holder, Stephen G. Davies, David Zimmer, Ai M. Fletcher, and James E. Thomson
- Subjects
Pharmacology ,chemistry ,Organic Chemistry ,chemistry.chemical_element ,Lithium ,Stereoselectivity ,Combinatorial chemistry ,Analytical Chemistry ,Conjugate - Abstract
Conjugate addition of heteroaryl substituted lithium amides to a range of α,β-unsaturated esters followed by in situ enolate oxidation with (–)-(camphorsulfonyl)oxaziridine gave the corresponding α-hydroxy-β-amino esters. Subsequent Friedel-Crafts type cyclisation of these α-hydroxy-β-amino esters gave a range of heteroarene-fused azacycles in good yields and high diastereoselectivities.
- Published
- 2018
33. The Hancock Alkaloids (-)-Cuspareine, (-)-Galipinine, (-)-Galipeine, and (-)-Angustureine: Asymmetric Syntheses and Corrected
- Author
-
Stephen G, Davies, Ai M, Fletcher, Ian T T, Houlsby, Paul M, Roberts, James E, Thomson, and David, Zimmer
- Subjects
Alkaloids ,Magnetic Resonance Spectroscopy ,Molecular Structure ,Quinolines - Abstract
The asymmetric syntheses of all members of the Hancock alkaloid family based upon a 2-substituted N-methyl-1,2,3,4-tetrahydroquinoline core are delineated. The conjugate addition of enantiopure lithium N-benzyl- N-(α-methyl- p-methoxybenzyl)amide to 5-( o-bromophenyl)- N-methoxy- N-methylpent-2-enamide is used to generate the requisite C-2 stereogenic center of the targets, while an intramolecular Buchwald-Hartwig coupling is used to form the 1,2,3,4-tetrahydroquinoline ring. Late-stage diversification completes construction of the C-2 side chains. Thus, (-)-cuspareine, (-)-galipinine, (-)-galipeine, and (-)-angustureine were prepared in overall yields of 30%, 28%, 15%, and 39%, respectively, in nine steps from commercially available 3-( o-bromophenyl)propanoic acid in all cases. Unambiguously corrected
- Published
- 2018
34. The Hancock alkaloids (-)-cuspareine, (-)-galipinine, (-)-galipeine, and (-)-angustureine: asymmetric syntheses and corrected 1H and 13C NMR data
- Author
-
Ian T. T. Houlsby, David Zimmer, Ai M. Fletcher, Stephen G. Davies, Paul M. Roberts, and James E. Thomson
- Subjects
Pharmacology ,010405 organic chemistry ,Stereochemistry ,Chemistry ,Organic Chemistry ,Pharmaceutical Science ,Nuclear magnetic resonance spectroscopy ,Carbon-13 NMR ,010402 general chemistry ,01 natural sciences ,0104 chemical sciences ,Analytical Chemistry ,Stereocenter ,chemistry.chemical_compound ,Enantiopure drug ,Propanoic acid ,Complementary and alternative medicine ,Amide ,Intramolecular force ,Drug Discovery ,Side chain ,Molecular Medicine - Abstract
The asymmetric syntheses of all members of the Hancock alkaloid family based upon a 2-substituted N-methyl-1,2,3,4-tetrahydroquinoline core are delineated. The conjugate addition of enantiopure lithium N-benzyl- N-(α-methyl- p-methoxybenzyl)amide to 5-( o-bromophenyl)- N-methoxy- N-methylpent-2-enamide is used to generate the requisite C-2 stereogenic center of the targets, while an intramolecular Buchwald-Hartwig coupling is used to form the 1,2,3,4-tetrahydroquinoline ring. Late-stage diversification completes construction of the C-2 side chains. Thus, (-)-cuspareine, (-)-galipinine, (-)-galipeine, and (-)-angustureine were prepared in overall yields of 30%, 28%, 15%, and 39%, respectively, in nine steps from commercially available 3-( o-bromophenyl)propanoic acid in all cases. Unambiguously corrected 1H and 13C NMR data for the originally isolated samples of (-)-cuspareine, (-)-galipinine, and (-)-angustureine are also reported, representing a valuable reference resource for these popular synthetic targets.
- Published
- 2018
35. Asymmetric synthesis of d-fagomine and its diastereoisomers
- Author
-
Stephen G. Davies, Matthew S. Kennedy, Ai M. Fletcher, Paul M. Roberts, and James E. Thomson
- Subjects
Lithium amide ,010405 organic chemistry ,Stereochemistry ,Organic Chemistry ,Enantioselective synthesis ,Diastereomer ,010402 general chemistry ,01 natural sciences ,Biochemistry ,0104 chemical sciences ,chemistry.chemical_compound ,Enantiopure drug ,Aldol reaction ,chemistry ,Drug Discovery ,Conjugate - Abstract
A divergent strategy for the asymmetric syntheses of d -fagomine and three of its diastereoisomers has been developed. The diastereoselective conjugate addition of an enantiopure lithium amide to an α,β-unsaturated ester was used as the key step to install the correct configuration required for the C(5)-stereogenic centre within the targets. In situ enolate oxidation generated the corresponding anti-α-hydroxy-β-amino ester, which possessed the correct configuration required for the C(4)-stereogenic centre within both d -fagomine and d -3-epi-fagomine. Subsequent epimerisation of this key anti-α-hydroxy-β-amino ester upon oxidation and diastereoselective reduction gave the corresponding syn-α-hydroxy-β-amino ester, which possessed the correct configuration required for the C(4)-stereogenic centre within both d -4-epi-fagomine and d -5-epi-fagomine. Elaboration of both α-hydroxy-β-amino esters upon reduction to the corresponding aldehydes followed by aldol reaction generated the requisite C(3)-stereogenic centres within the target compounds, then cyclisation and deprotection gave the enantiopure iminosugars in good overall yields, as single diastereoisomers (>99:1 dr).
- Published
- 2018
36. Asymmetric synthesis of secondary benzylic alcohols via arene chromium tricarbonyl complexes
- Author
-
M. Rute G. da Costa, M. João M. Curto, James E. Thomson, Stephen G. Davies, and Fátima C. Teixeira
- Subjects
chemistry.chemical_classification ,Chiral auxiliary ,010405 organic chemistry ,Aryl ,Organic Chemistry ,Enantioselective synthesis ,chemistry.chemical_element ,Organic chemistry ,Asymmetric synthesis ,010402 general chemistry ,Hydroxylamines ,01 natural sciences ,Biochemistry ,Aldehyde ,Medicinal chemistry ,Catalysis ,0104 chemical sciences ,chemistry.chemical_compound ,Chromium ,Hydroxylamine ,Enantiopure drug ,chemistry ,Reagent ,Drug Discovery - Abstract
Submitted by Paula Candeias (paula.candeias@lneg.pt) on 2019-01-29T17:52:50Z No. of bitstreams: 1 Tetrahedron_Vol.74_5965-5973.pdf: 203363 bytes, checksum: c19a796719b55e32806c8a762122afd7 (MD5) Approved for entry into archive by Paula Candeias (paula.candeias@lneg.pt) on 2019-01-29T17:53:33Z (GMT) No. of bitstreams: 1 Tetrahedron_Vol.74_5965-5973.pdf: 203363 bytes, checksum: c19a796719b55e32806c8a762122afd7 (MD5) Made available in DSpace on 2019-01-29T17:53:33Z (GMT). No. of bitstreams: 1 Tetrahedron_Vol.74_5965-5973.pdf: 203363 bytes, checksum: c19a796719b55e32806c8a762122afd7 (MD5) Previous issue date: 2018 info:eu-repo/semantics/publishedVersion
- Published
- 2018
37. Diastereoselective ammonium-directed epoxidation in the asymmetric syntheses of dihydroconduramines (+)-C-2, (−)-C-2, (+)-D-2, (+)-E-2, (+)-F-2, and (−)-F-2
- Author
-
Ai M. Fletcher, Stephen G. Davies, Paul M. Roberts, James E. Thomson, and Solange Da Silva Pinto
- Subjects
010405 organic chemistry ,Chemistry ,Stereochemistry ,Organic Chemistry ,Substrate (chemistry) ,010402 general chemistry ,01 natural sciences ,0104 chemical sciences ,Stereocenter ,chemistry.chemical_compound ,Enantiopure drug ,Ammonium ,Enantiomer ,Selectivity - Abstract
Epoxidations (40% aq HBF4 then m-CPBA) of racemic cis-2-(N-benzylamino)cyclohex-3-en-1-ol and racemic cis-2-(N,N-dibenzylamino)cyclohex-3-en-1-ol proceed with very high levels of diastereoselectivity (>95:5 dr). The latter is in direct contrast to the epoxidation of the corresponding trans-diastereoisomer (which proceeds with essentially no selectivity), showing that the relative configuration of the substrate dramatically influences the diastereoselectivity in these instances. Meanwhile, epoxidations of enantiopure (1R,2S,αR)-2-[(N-α-methylbenzyl)amino]cyclohex-3-en-1-ol and (1S,2R,αR)-2-[(N-α-methylbenzyl)amino]cyclohex-3-en-1-ol [surrogates for the enantiomers of cis-2-(N-benzylamino)cyclohex-3-en-1-ol] proceed with complete diastereoselectivity (>95:5 dr) under the same conditions, showing that neither the presence of the α-methyl group nor the relative configuration of the α-methylbenzyl stereocenter have an effect upon the established level of diastereoslectivity in these cases. In contrast, epoxidations of enantiopure (1R,2S,αR)-2-[N-benzyl-N-(α-methylbenzyl)amino]cyclohex-3-en-1-ol and (1S,2R,αR)-2-[N-benzyl-N-(α-methylbenzyl)amino]cyclohex-3-en-1-ol [surrogates for the enantiomers of cis-2-(N,N-dibenzylamino)cyclohex-3-en-1-ol] proceed with lower diastereoselectivity (∼70:30 dr). Thus, the presence of the α-methyl group has a detrimental effect on the established level of diastereoselectivity in these cases (although again the relative configuration of the α-methylbenzyl stereocenter is unimportant). The diastereoselective epoxidation pathway is used to enable the asymmetric syntheses of six hitherto unknown, enantiopure dihydroconduramines (+)-C-2, (−)-C-2, (+)-D-2, (+)-E-2, (+)-F-2, and (−)-F-2 (>99% ee in each case).
- Published
- 2018
38. Asymmetric syntheses of (2R,3S)-3-hydroxyproline and (2S,3S)-3-hydroxyproline
- Author
-
Paul M. Roberts, Ai M. Fletcher, Stephen G. Davies, Sean M. Linsdall, and James E. Thomson
- Subjects
Stereospecificity ,010405 organic chemistry ,Stereochemistry ,Chemistry ,Yield (chemistry) ,Organic Chemistry ,Diastereomer ,3-hydroxyproline ,Physical and Theoretical Chemistry ,010402 general chemistry ,01 natural sciences ,Biochemistry ,0104 chemical sciences - Abstract
Two synthetic routes have been developed for the asymmetric syntheses of (2 R,3 S)- and (2 S,3 S)-3-hydroxyproline. The key synthetic step in each of these strategies is the conversion of protected α,δ-dihydroxy-β-amino esters (either 2,3- anti- or 2,3- syn-configured) into β,δ-dihydroxy-α-amino esters (protected forms thereof), via the intermediacy of the corresponding aziridinium ions. The products of these stereospecific rearrangements were then cyclized and deprotected to afford (2 R,3 S)-3-hydroxyproline and (2 S,3 S)-3-hydroxyproline as single diastereoisomers (99:1 dr) in26% overall yield.
- Published
- 2018
39. Trading N and O. Part 4: Asymmetric synthesis of syn-β-substituted-α-amino acids
- Author
-
Catherine J. Greenaway, James E. Thomson, Matthew S. Kennedy, Stephen G. Davies, Christoph Mayer, Ai M. Fletcher, and Paul M. Roberts
- Subjects
chemistry.chemical_classification ,010405 organic chemistry ,Stereochemistry ,Organic Chemistry ,Substituent ,Enantioselective synthesis ,Diastereomer ,Leaving group ,Regioselectivity ,010402 general chemistry ,01 natural sciences ,Biochemistry ,0104 chemical sciences ,Amino acid ,chemistry.chemical_compound ,Enantiopure drug ,chemistry ,Drug Discovery ,Moiety ,heterocyclic compounds - Abstract
A total of nine enantiopure syn-β-substituted-α-amino acids have been synthesised, comprising both syn-β-hydroxy-α-amino acids and syn-β-fluoro-α-amino acids. The key step in the synthetic strategy towards these syn-β-substituted-α-amino acids involves a stereospecific rearrangement, which proceeds via the intermediacy of the corresponding aziridinium ions. The requisite enantiopure syn-α-hydroxy-β-amino esters were prepared via asymmetric aminohydroxylation of the corresponding α,β-unsaturated esters followed by epimerisation of the resultant anti-α-hydroxy-β-amino esters at the C(2)-position. Subsequent activation of the α-hydroxy moiety as a leaving group followed by displacement by the β-amino substituent gave the corresponding aziridinium species. Regioselective in situ ring-opening of the aziridinium intermediates with either water or fluoride gave the corresponding syn-β-hydroxy-α-amino ester or syn-β-fluoro-α-amino ester, respectively, and N-deprotection and ester hydrolysis afforded the target syn-β-substituted-α-amino acids as single diastereoisomers in good overall yield.
- Published
- 2018
40. Asymmetric syntheses of polysubstituted homoprolines and homoprolinols
- Author
-
Stephen G. Davies, Haewon Song, J. Gair Ford, Paul M. Roberts, Benjamin G. Saward, Ai M. Fletcher, Aude L.A. Figuccia, Kristína Csatayová, James A. Lee, and James E. Thomson
- Subjects
Chemistry ,Stereochemistry ,Organic Chemistry ,Diastereomer ,Enantioselective synthesis ,Metathesis ,Biochemistry ,chemistry.chemical_compound ,Gulonic acid ,Enantiopure drug ,Drug Discovery ,Organic chemistry ,Hydroamination ,Sorbic acid - Abstract
Complementary protocols for the diastereoselective syn- and anti-dihydroxylations of enantiopure dihydropyrrole scaffolds were used as the key steps in the asymmetric syntheses of several polysubstituted homoprolines and homoprolinols. The requisite dihydropyrroles were prepared in three steps from commercially available sorbic acid via either hydroamination or aminohydroxylation of the corresponding tert-butyl ester, followed by ring-closing metathesis. Subsequent olefinic oxidation and deprotection gave access to the corresponding enantiopure homoprolines [(2S,3S,4R)-dihydroxyhomoproline, (2S,3R,4R)-dihydroxyhomoproline and (S,S,S)-3-amino-4-hydroxy-homoproline], enantiopure α-hydroxy-homoprolines [3,6-dideoxy-3,6-imino- d -allonic acid and 3,6-dideoxy-3,6-imino- d -gulonic acid] and enantiopure homoprolinols [1,4-dideoxy-1,4-imino- l -allitol and (S,S,S)-3-amino-4-hydroxyhomoprolinol] as single diastereoisomers in good overall yields.
- Published
- 2015
- Full Text
- View/download PDF
41. Syntheses of (R)-sitagliptin
- Author
-
James E. Thomson, Ai M. Fletcher, and Stephen G. Davies
- Subjects
Inorganic Chemistry ,Stereospecificity ,Chemistry ,Stereochemistry ,Sitagliptin ,Organic Chemistry ,medicine ,Stereoselectivity ,Physical and Theoretical Chemistry ,Combinatorial chemistry ,Catalysis ,medicine.drug - Abstract
In the last 10 years, since Merck’s discovery and development of (R)-sitagliptin phosphate as a treatment for type 2 diabetes, numerous efforts towards efficient synthesis of (R)-sitagliptin have been reported. In this review, several total syntheses of (R)-sitagliptin are described, highlighting the key stereoselective and stereospecific strategies employed.
- Published
- 2015
- Full Text
- View/download PDF
42. Diastereoselective conjugate additions to alkoxycarbene cations of the iron chiral auxiliary [(η 5 -C 5 H 5 )Fe(CO)(PPh 3 ) C(OMe)CH CHR] +
- Author
-
Stephen G. Davies, Robert J.C. Easton, Mario E. C. Polywka, James E. Thomson, and Jeffrey Mckenna
- Subjects
Chiral auxiliary ,Stereochemistry ,Organic Chemistry ,Protonation ,Biochemistry ,Medicinal chemistry ,Inorganic Chemistry ,chemistry.chemical_compound ,Nucleophile ,chemistry ,Reagent ,Materials Chemistry ,Physical and Theoretical Chemistry ,Demethylation ,Conjugate - Abstract
The conjugate additions of alkyllithium reagents to alkoxycarbene cations of the iron chiral auxiliary [(η5-C5H5)Fe(CO)(PPh3) C(OMe)CH CHR]+ proceeded with moderate to excellent diastereoselectivity. The resultant methoxyvinyl complexes were transformed into the corresponding iron acyl complexes following a sequence of protonation and demethylation. The overall transformation yields iron acyl complexes of opposite relative configuration to those which result from the conjugate addition of the same nucleophile to the corresponding α,β-unsaturated iron acyl complex.
- Published
- 2015
- Full Text
- View/download PDF
43. Concise total asymmetric syntheses of (−)-fagomine, two of its epimers, and two seven-membered ring congeners
- Author
-
Stephen G. Davies, Ai M. Fletcher, David J. Klauber, James E. Thomson, Paul M. Roberts, J. Gair Ford, and Kristína Csatayová
- Subjects
chemistry.chemical_compound ,Enantiopure drug ,Stereochemistry ,Chemistry ,Organic Chemistry ,Drug Discovery ,Enantioselective synthesis ,Diastereomer ,Organic chemistry ,Epimer ,Ring (chemistry) ,Sorbic acid ,Biochemistry - Abstract
Diastereoselective syn- and anti-dihydroxylations of enantiopure tetrahydropyridine and tetrahydroazepine scaffolds have been used in total asymmetric syntheses of the polyhydroxylated azacycles (−)-fagomine, (−)-3-epi-fagomine, (−)-5-epi-fagomine and two related polyhydroxylated azepanes. In each case, the target compounds were isolated as single diastereoisomers (>99:1 dr) in fewer than eight steps from the commercially available starting materials, sorbic acid and the requisite α-methylbenzylamine.
- Published
- 2015
- Full Text
- View/download PDF
44. Synthesis and Crystal Structures of 2-Azido-4-aminocyclohexane-1,3-diols
- Author
-
Stephen G. Davies, James A. Lee, Amber L. Thompson, James E. Thomson, and Méabh B. Brennan
- Subjects
chemistry.chemical_compound ,Crystallography ,Chemistry ,Hydrogen bond ,Epoxide ,Regioselectivity ,Orthorhombic crystal system ,General Chemistry ,Crystal structure ,Triclinic crystal system ,Condensed Matter Physics ,Organometallic chemistry ,Monoclinic crystal system - Abstract
2-Azido-4-aminocyclohexane-1,3-diols 12, 14 and 16 were synthesised and their crystal structures were studied by X-ray diffraction. Compound 12 crystallizes in the monoclinic space group P2 1 /n with cell parameters of a = 13.7059(2) A, b = 10.8861(2) A, c = 13.8675(3) A, β = 117.2365(10)°, V = 1839.67(6) A3 and Z = 4. Compound 14 crystallizes in the orthorhombic space group Pcab with cell parameters of a = 9.9508(1) A, b = 10.9839(2) A, c = 24.7035(4) A, V = 2700.06(7) A3 and Z = 8. Compound 16 crystallizes in the triclinic space group $$\text{P}\bar{\it{1}}$$ with cell parameters of a = 10.9511(3) A, b = 11.3148(3) A, c = 15.9545(5) A, α = 86.3487(11)°, β = 87.4723(11)°, γ = 89.3398(10)°, V = 1970.91(10) A3 and Z = 4. All three structures were characterised by arrays of hydrogen bonding interactions and these crystallographic studies also revealed their conformations, which gave valuable information into the regioselectivity of epoxide ring-opening during their formation. Three 2-azido-4-aminocyclohexane-1,3-diols 12, 14 and 16 were synthesised and their crystal structures were studied by X-ray diffraction. All three structures were characterised by arrays of hydrogen bonding interactions and these crystallographic studies also revealed valuable conformational data which was used to rationalise the regioselectivity of epoxide ring-opening during their formation.
- Published
- 2015
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45. Syntheses of Dihydroconduramines (±)-B-1, (±)-E-1, and (±)-F-1 via Diastereoselective Epoxidation of N-Protected 4-Aminocyclohex-2-en-1-ols
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Kristína Csatayová, William D. Green, Stephen G. Davies, James A. Lee, James E. Thomson, Ai M. Fletcher, Méabh B. Brennan, Paul M. Roberts, and Angela J. Russell
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chemistry.chemical_compound ,chemistry ,Stereochemistry ,Organic Chemistry ,Moiety ,Ammonium - Abstract
Diastereoselective syntheses of dihydroconduramines (±)-B-1, (±)-E-1, and (±)-F-1 have been achieved from N-protected 4-aminocyclohex-2-en-1-ols via two complementary procedures for epoxidation as the key step. Treatment of either trans- or cis-4-N-benzylaminocyclohex-2-en-1-ol with Cl3CCO2H and then m-chloroperoxybenzoic acid (m-CPBA) resulted in initial formation of the corresponding ammonium species, followed by epoxidation on the face syn to the ammonium moiety exclusively; chemoselective N-benzylation then provided either (1RS,2SR,3RS,4RS)- or (1RS,2RS,3SR,4SR)-2,3-epoxy-4-N,N-dibenzylaminocyclohexan-1-ol, respectively. Treatment of either trans- or cis-4-N,N-dibenzylaminocyclohex-2-en-1-ol with m-CPBA resulted in initial formation of the corresponding N-oxide, followed by epoxidation on the face syn to the hydroxyl group exclusively; reduction then provided either (1RS,2RS,3SR,4RS)- or an alternative route to (1RS,2RS,3SR,4SR)-2,3-epoxy-4-N,N-dibenzylaminocyclohexan-1-ol, respectively. In all cases, S(N)2-type ring opening of these epoxides upon treatment with aqueous H2SO4 proceeded by nucleophilic attack with inversion at C(2) preferentially, distal to the in situ formed ammonium moiety. Hydrogenolytic N-deprotection then gave the corresponding dihydroconduramines (±)-B-1, (±)-E-1, and (±)-F-1.
- Published
- 2015
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46. Pinacolatoboron fluoride (pinBF) is an efficient fluoride transfer agent for diastereoselective synthesis of benzylic fluorides
- Author
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Aude L.A. Figuccia, James A. Lee, Ai M. Fletcher, Stephen G. Davies, Paul M. Roberts, Alice M. R. Kennett, Dorus Heijnen, Alexander J. Cresswell, James E. Thomson, and Melloney J. Morris
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Pinacol ,Aryl ,Organic Chemistry ,Epoxide ,Biochemistry ,Medicinal chemistry ,law.invention ,chemistry.chemical_compound ,chemistry ,Transfer agent ,law ,Drug Discovery ,Alkoxy group ,Organic chemistry ,Fluoride ,Walden inversion ,Boron trifluoride - Abstract
The incorporation of alkoxy ligands within a range of alkoxyfluoroboranes and dialkoxyfluoroboranes results in fluoroborane reagents with attenuated Lewis acidity and increased ability to donate fluoride ion(s) when compared to boron trifluoride itself. Pinacolatoboron fluoride (pinBF), prepared in situ from BF3·OEt2 and bis(O-trimethylsilyl)pinacol, has been identified as an efficient fluoride donor which allows highly stereoselective SN1-type epoxide ring-opening (with retention of configuration) of a range of trans-β-methyl-substituted aryl epoxides to give the corresponding syn-fluorohydrins. The substrate scope of this transformation is more broad than the analogous protocol using boron trifluoride alone.
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- 2015
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47. Enantiopure 3-Amino-Substituted 1-Indanones, 1-Tetralones, and 1-Benzosuberones via Friedel–Crafts Cyclisation of ω-Aryl-β-benzamido Acids
- Author
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Stephen G. Davies, James E. Thomson, Euan C. Goddard, Angela J. Russell, and Paul M. Roberts
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chemistry.chemical_compound ,Enantiopure drug ,1-Tetralone ,Chemistry ,Stereochemistry ,Aryl ,Amide ,Organic Chemistry ,Diastereomer ,Ring (chemistry) ,Friedel–Crafts reaction ,Tetralones - Abstract
Conjugate addition of enantiopure lithium ( R )- N -benzyl- N -(α-methylbenzyl)amide to a range of ω-aryl-α,β-unsaturated esters gives the corresponding ω-aryl-β-amino esters as single diastereoisomers in high yields. Friedel–Crafts cyclisation of the pendant carbonyl group onto the ω-aryl ring then gives a range of 3-amino-substituted 1-indanones, 1-tetralones, and 1-benzosuberones, representing an efficient and short protocol for the preparation of these benzo-fused carbocycles in enantiopure form.
- Published
- 2015
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48. Asymmetric Syntheses of Nakinadine D, Nakinadine E, and Nakinadine F: Confirmation of Their Relative (RS,SR)-Configurations and Proposal of Their Absolute (2S,3R)-Configurations
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James E. Thomson, Ai M. Fletcher, Rushabh S. Shah, Stephen G. Davies, and Paul M. Roberts
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Magnetic Resonance Spectroscopy ,Molecular Structure ,Natural materials ,Pyridines ,Chemistry ,Stereochemistry ,Methyl phenylacetate ,Organic Chemistry ,Stereoisomerism ,Carbon-13 NMR ,Computers, Molecular ,chemistry.chemical_compound ,Alkaloids ,Nakinadine F ,Nakinadine E ,Nakinadine D ,Specific rotation - Abstract
The syn- and anti-diastereoisomeric forms of the reported structures of the marine alkaloids nakinadines D-F have been synthesized, for the first time in all cases, via an approach involving asymmetric Mannich-type (imino-aldol) reactions of methyl phenylacetate with N-tert-butylsulfinyl imines as the key steps to control the stereochemistry. Comparison of the (1)H and (13)C NMR spectroscopic data reported for the natural materials with those acquired for these synthetic samples confirms the initially assigned relative (RS,SR)-configurations of these three alkaloids. In the absence of specific rotation (or other diagnostic) data for the natural materials, it is not possible to unambiguously assign their absolute configurations, although given the absolute (2S)-configurations assigned to nakinadines B and C, and the absolute (2S,3R)-configuration previously established for nakinadine A, the data herein uphold our proposal that nakinadines D-F share the absolute (2S,3R)-configuration.
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- 2015
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49. Asymmetric synthesis of N,O-diacetyl-3-epi-xestoaminol C: structure and absolute configuration confirmation of 3-epi-xestoaminol C
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Stephen G. Davies, Kristína Csatayová, Susanna G. Archer, Ai M. Fletcher, James E. Thomson, and Paul M. Roberts
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Natural product ,010405 organic chemistry ,Stereochemistry ,Organic Chemistry ,Enantioselective synthesis ,Absolute configuration ,chemistry.chemical_element ,010402 general chemistry ,01 natural sciences ,Biochemistry ,0104 chemical sciences ,chemistry.chemical_compound ,chemistry ,Yield (chemistry) ,Amide ,Drug Discovery ,Lithium ,Derivative (chemistry) ,Conjugate - Abstract
The asymmetric synthesis of N,O-diacetyl-3-epi-xestoaminol C is reported. The synthesis employs diastereoselective aminohydroxylation of tert-butyl crotonate [conjugate addition of lithium (S)-N-benzyl-N-(α-methylbenzyl)amide, then in situ enolate oxidation with (+)-camphorsulfonyloxaziridine (CSO)] and a diastereoselective reduction protocol as the key stereodefining steps. The synthetic sample of the natural product was isolated as its N,O-diacetyl derivative for ease of purification; this material was prepared in ten steps and 17% overall yield from commercially available tert-butyl crotonate. This synthesis confirms unambiguously both the assigned structure and absolute (S,S)-configuration of the natural product.
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- 2016
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50. The conjugate addition of enantiomerically pure lithium amides as chiral ammonia equivalents part III: 2012-2017
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Stephen G. Davies, Ai M. Fletcher, Paul M. Roberts, and James E. Thomson
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Inorganic Chemistry ,010405 organic chemistry ,Organic Chemistry ,Physical and Theoretical Chemistry ,010402 general chemistry ,01 natural sciences ,Catalysis ,0104 chemical sciences - Abstract
This review covers further applications of the conjugate addition of enantiomerically pure lithium amides as chiral ammonia equivalents in asymmetric synthesis and provides an update since our last review of this area, which was published in 2012.
- Published
- 2017
Catalog
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