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Synthesis of substrates for aldolase-catalyzed reactions: A comparison of methods for the synthesis of substituted phenylacetaldehydes
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry. (Widersten)ORCID iD: 0000-0003-4603-4540
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry. (Widersten)
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.ORCID iD: 0000-0002-0675-7675
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.ORCID iD: 0000-0002-4205-6040
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2018 (English)In: Synlett: Accounts and Rapid Communications in Synthetic Organic Chemistry, ISSN 0936-5214, E-ISSN 1437-2096, Vol. 29, no 9, p. 1187-1190Article in journal (Refereed) Published
Abstract [en]

Methods for the synthesis of phenylacetaldehydes (oxidation, one-carbon chain extension) were compared by using the synthesis of 4-methoxyphenylacetaldehyde as a model example. Oxidations of 4-methoxyphenylethanol with activated DMSO (Swern oxidation) or manganese dioxide gave unsatisfactory results; whereas oxidation with 2-iodoxybenzoic add (IBX) produced 4-methoxyphenylacetaldehyde in reasonable (75%) yield. However, Wittig-type one-carbon chain extension with methoxymethylene-triphenylphosphine followed by hydrolysis gave an excellent (81% overall) yield of 4-methoxyphenylacetaldehyde from 4-methoxybenzaldehyde (a cheap starting material). This approach was subsequently used to synthesise a set of 10 substituted phenylacetaldehydes in good to excellent yields.

Place, publisher, year, edition, pages
2018. Vol. 29, no 9, p. 1187-1190
National Category
Organic Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-342939DOI: 10.1055/s-0036-1591963ISI: 000432738600011OAI: oai:DiVA.org:uu-342939DiVA, id: diva2:1185340
Funder
Stiftelsen Olle Engkvist ByggmästareAvailable from: 2018-02-23 Created: 2018-02-23 Last updated: 2018-10-11Bibliographically approved
In thesis
1. Carboligation using the aldol reaction: A comparison of stereoselectivity and methods
Open this publication in new window or tab >>Carboligation using the aldol reaction: A comparison of stereoselectivity and methods
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The research summarized in this thesis focuses on synthesizing aldehyde and aldol compounds as substrates and products for the enzyme D-fructose-6-aldolase (FSA). Aldolases are important enzymes for the formation of carbon-carbon bonds in nature. In biological systems, aldol reactions, both cleavage and formation play central roles in sugar metabolism. Aldolases exhibit high degrees of stereoselectivity and can steer the product configurations to a given enantiomeric and diastereomeric form. To become truly useful synthetic tools, the substrate scope of these enzymes needs to become broadened.

In the first project, phenylacetaldehyde derivatives were synthesized for the use as test substrates for E. coli FSA. Different methods were discussed to prepare phenylacetaldehyde derivatives, the addition of a one carbon unit to benzaldehyde derivatives using a homologation reaction was successful and was proven efficient and non-sensitive to the moisture. The analogues were prepared through two steps with 75-80 % yields for both meta- and para-substituted compounds.

The second project focuses on synthesizing aldol compound using FSA enzymes, both wild type and mutated variants selected from library screening, the assay has been successfully used to identify a hit with 10-fold improvement in an R134V/S166G variant. This enzyme produces one out of four possible stereoisomers.

The third project focuses on the synthesis of a range of aldol compounds using two different approaches reductive cross-coupling of aldehydes by SmI2 or by organocatalysts using cinchonine. Phenylacetaldehydes were reacted with hydroxy-, dihydroxyacetone and hydroxyacetophenone in presence of cinchonine, the reaction was successful with hydroxyacetophenone in moderate yields and 60-99 % de ratio. On the other hand, the aldehydes reacting with methyl- and phenylglyoxal in the presence of SmI2 resulted in moderate yields and without stereoselectivity.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. p. 50
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1730
Keywords
aldol reaction, cinchonine, FSA enzyme, homologation reactions, phenylacetaldehyde derivatives, samarium diiodide.
National Category
Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-362866 (URN)978-91-513-0472-4 (ISBN)
Public defence
2018-11-30, BMC C2:301, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Note

degree of doctor of philosophy (science and teknology)

Available from: 2018-11-07 Created: 2018-10-11 Last updated: 2018-11-19

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Al-Smadi, DerarEnugala, Thilak ReddyNorberg, ThomasKihlberg, JanWidersten, Mikael

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