uu.seUppsala universitets publikationer
Ändra sökning
Länk till posten
Permanent länk

Direktlänk
BETA
Publikationer (4 of 4) Visa alla publikationer
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
Öppna denna publikation i ny flik eller fönster >>Chemical and Biochemical Approaches for the Synthesis of Substituted Dihydroxybutanones and Di-, and Tri-Hydroxypentanones
Visa övriga...
2019 (Engelska)Ingår i: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 84, nr 11, s. 6982-6991Artikel i tidskrift (Refereegranskat) 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.

Nationell ämneskategori
Organisk kemi
Forskningsämne
Kemi med inriktning mot organisk kemi
Identifikatorer
urn:nbn:se:uu:diva-383068 (URN)10.1021/acs.joc.9b00742 (DOI)000471212000043 ()
Tillgänglig från: 2019-05-08 Skapad: 2019-05-08 Senast uppdaterad: 2019-07-05Bibliografiskt granskad
Al-Smadi, D. (2018). Carboligation using the aldol reaction: A comparison of stereoselectivity and methods. (Doctoral dissertation). Uppsala: Acta Universitatis Upsaliensis
Öppna denna publikation i ny flik eller fönster >>Carboligation using the aldol reaction: A comparison of stereoselectivity and methods
2018 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2018. s. 50
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1730
Nyckelord
aldol reaction, cinchonine, FSA enzyme, homologation reactions, phenylacetaldehyde derivatives, samarium diiodide.
Nationell ämneskategori
Organisk kemi
Identifikatorer
urn:nbn:se:uu:diva-362866 (URN)978-91-513-0472-4 (ISBN)
Disputation
2018-11-30, BMC C2:301, Husargatan 3, Uppsala, 09:15 (Engelska)
Opponent
Handledare
Anmärkning

degree of doctor of philosophy (science and teknology)

Tillgänglig från: 2018-11-07 Skapad: 2018-10-11 Senast uppdaterad: 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
Öppna denna publikation i ny flik eller fönster >>New Stereoselective Biocatalysts for Carboligation and Retro-Aldol Cleavage Reactions Derived from D-Fructose 6-Phosphate Aldolase
Visa övriga...
2018 (Engelska)Ingår i: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 57, nr 40, s. 5877-5885Artikel i tidskrift (Refereegranskat) 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.

Nationell ämneskategori
Biokemi och molekylärbiologi
Forskningsämne
Biokemi
Identifikatorer
urn:nbn:se:uu:diva-360283 (URN)10.1021/acs.biochem.8b00814 (DOI)000447238100012 ()30204427 (PubMedID)
Forskningsfinansiär
Stiftelsen Olle Engkvist ByggmästareCarl Tryggers stiftelse för vetenskaplig forskning
Tillgänglig från: 2018-09-11 Skapad: 2018-09-11 Senast uppdaterad: 2018-12-10Bibliografiskt granskad
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
Öppna denna publikation i ny flik eller fönster >>Synthesis of substrates for aldolase-catalyzed reactions: A comparison of methods for the synthesis of substituted phenylacetaldehydes
Visa övriga...
2018 (Engelska)Ingår i: Synlett: Accounts and Rapid Communications in Synthetic Organic Chemistry, ISSN 0936-5214, E-ISSN 1437-2096, Vol. 29, nr 9, s. 1187-1190Artikel i tidskrift (Refereegranskat) 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.

Nationell ämneskategori
Organisk kemi
Identifikatorer
urn:nbn:se:uu:diva-342939 (URN)10.1055/s-0036-1591963 (DOI)000432738600011 ()
Forskningsfinansiär
Stiftelsen Olle Engkvist Byggmästare
Tillgänglig från: 2018-02-23 Skapad: 2018-02-23 Senast uppdaterad: 2018-10-11Bibliografiskt granskad
Organisationer
Identifikatorer
ORCID-id: ORCID iD iconorcid.org/0000-0003-4603-4540

Sök vidare i DiVA

Visa alla publikationer