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Al-Smadi, D., Enugala, T. R., Kessler, V., Mhasal, A. R., Kamerlin, S. C., Kihlberg, J., . . . Widersten, M. (2019). Chemical and Biochemical Approaches for the Synthesis of Substituted Dihydroxybutanones and Di-, and Tri-Hydroxypentanones. Journal of Organic Chemistry, 84(11), 6982-6991
Open this publication in new window or tab >>Chemical and Biochemical Approaches for the Synthesis of Substituted Dihydroxybutanones and Di-, and Tri-Hydroxypentanones
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2019 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 84, no 11, p. 6982-6991Article in journal (Refereed) Published
Abstract [en]

Polyhydroxylated compounds are building blocks for the synthesis of carbohydrates and other natural products. Their synthesis is mainly achieved by different synthetic versions of aldol-coupling reactions, catalyzed either by organocatalysts, enzymes or metal-organic catalysts. We have investigated the formation of 1,4-substituted 2,3-dihydroxybutan-1-one derivatives from para- and meta-substituted phenylacetaldehydes by three distinctly different strategies. The first involved a direct aldol reaction with hydroxyacetone, dihydroxyacetone or 2-hydroxyacetophenone, catalyzed by the cinchona derivative cinchonine. The second was reductive cross-coupling with methyl or phenyl glyoxal promoted by SmI2 resulting in either 5-substituted 3,4-dihydroxypentan-2-ones or 1,4 bis-phenyl substituted butanones, respectively. Finally, in the third case, aldolase catalysis was employed for synthesis of the corresponding 1,3,4-trihydroxylated pentan-2-one derivatives. The organocatalytic route with cinchonine generated distereomerically enriched syn products (de = 60−99 %), with moderate enantiomeric excesses (ee = 43−56%), but did not produce aldols with either hydroxyacetone or dihydroxyacetone as donor ketones. The SmI2-promoted reductive cross-coupling generated product mixtures with diastereomeric and enantiomeric ratios close to unity. This route allowed for the production of both 1-methyl- and 1-phenylsubstituted 2,3-dihydroxybutanones, at yields between 40−60%. Finally, the biocatalytic approach resulted in enantiopure syn (3R,4S) 1,3,4-trihydroxypentan-2-ones.

National Category
Organic Chemistry
Research subject
Chemistry with specialization in Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-383068 (URN)10.1021/acs.joc.9b00742 (DOI)000471212000043 ()
Available from: 2019-05-08 Created: 2019-05-08 Last updated: 2019-07-05Bibliographically approved
Al-Smadi, D. (2018). Carboligation using the aldol reaction: A comparison of stereoselectivity and methods. (Doctoral dissertation). Uppsala: Acta Universitatis Upsaliensis
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: 2018-11-30
Ma, H., Engel, S., Enugala, T. R., Al-Smadi, D. & Widersten, M. (2018). New Stereoselective Biocatalysts for Carboligation and Retro-Aldol Cleavage Reactions Derived from D-Fructose 6-Phosphate Aldolase. Biochemistry, 57(40), 5877-5885
Open this publication in new window or tab >>New Stereoselective Biocatalysts for Carboligation and Retro-Aldol Cleavage Reactions Derived from D-Fructose 6-Phosphate Aldolase
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2018 (English)In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 57, no 40, p. 5877-5885Article in journal (Refereed) Published
Abstract [en]

D-Fructose 6-phosphate aldolase (FSA) catalyzes the asymmetric cross-aldol addition of phenylacetaldehyde and hydroxyacetone. We conducted structure guided saturation mutagenesis of noncatalytic active-site residues to produce new FSA variants, with the goal of widening the substrate scope of the wild-type enzyme toward a range of para- and meta-substituted arylated aldehydes. After a single generation of mutagenesis and selection, enzymes with diverse substrate selectivity scopes were identified. The kinetic parameters and stereoselectivities for a subset of enzyme/substrate combinations were determined for the reactions in both the aldol addition and cleavage reaction directions. The achieved collection of new aldolase enzymes provides new tools for controlled asymmetric synthesis of substituted aldols.

National Category
Biochemistry and Molecular Biology
Research subject
Biochemistry
Identifiers
urn:nbn:se:uu:diva-360283 (URN)10.1021/acs.biochem.8b00814 (DOI)000447238100012 ()30204427 (PubMedID)
Funder
Stiftelsen Olle Engkvist ByggmästareCarl Tryggers foundation
Available from: 2018-09-11 Created: 2018-09-11 Last updated: 2018-12-10Bibliographically approved
Al-Smadi, D., Enugala, T. R., Norberg, T., Kihlberg, J. & Widersten, M. (2018). Synthesis of substrates for aldolase-catalyzed reactions: A comparison of methods for the synthesis of substituted phenylacetaldehydes. Synlett: Accounts and Rapid Communications in Synthetic Organic Chemistry, 29(9), 1187-1190
Open this publication in new window or tab >>Synthesis of substrates for aldolase-catalyzed reactions: A comparison of methods for the synthesis of substituted phenylacetaldehydes
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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.

National Category
Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-342939 (URN)10.1055/s-0036-1591963 (DOI)000432738600011 ()
Funder
Stiftelsen Olle Engkvist Byggmästare
Available from: 2018-02-23 Created: 2018-02-23 Last updated: 2018-10-11Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-4603-4540

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