Development of methodology for the synthesis of 4-arylflavan-3-ol lactones
| dc.contributor.advisor | Bezuidenhoudt, B. C. B. | |
| dc.contributor.advisor | Steenkamp, J. A. | |
| dc.contributor.advisor | Kamara, B. I. | |
| dc.contributor.author | Van Tonder, Bernadette | |
| dc.date.accessioned | 2016-01-12T11:43:07Z | |
| dc.date.available | 2016-01-12T11:43:07Z | |
| dc.date.issued | 2008-05 | |
| dc.description.abstract | English: The phenolic content of the heartwood of Peltophorum africanum (African wattle) and Burkea africanum (Red syringa) proved to contain a variety of compounds including the novel 4-arylflavan-3-ol lactones, 6-(3,4-dihydroxyphenyl)-6,6a,8,12b-tetrahydroisochromeno[ 3,4-c]chromene-3,8,10,11,12-pentaol and 6-(3,4,5-tri-hydroxylphenyl)- 6,6a,8,12b-tetrahydroisochromeno[3,4-c]chromene-3,8,10,11,12-pentaol respectively. Several attempts at the synthesis of these compounds to give final proof of the structure including the stereochemistry at the three chiral centres, failed due to the fact that the nucleophilicity of the pyrogallol ring of the gallic acid analogue (both protected and fee phenolic) is reduced to such an extent by the presence of the carbonyl group that it cannot effectively react with a C-4 electrophile generated on the flavan-3-ol starting material. In addition it became evident that the starting materials and products are sensitive to more drastic acid and basic reaction conditions to the extent that no desired products could be isolated from the attempted coupling of gallic acid analogues to C-4 functionalised flavan-3-ols. In order to alleviate these problems, it was envisaged to utilize a nucleophile without the carbonyl attached to it, thus changing the substrate to a pyrogallol entity containing a 1- hydroxypropyl - or allyl substituent. After coupling at C-4 of the flavan-3-ol the required carbonyl could then be introduced by consecutive water elimination and isomerization (1-hydroxylpropyl substituent) or isomerization (allyl substituent) followed by ozonolysis (with non-reductive work-up) and subsequent esterification. Since the starting materials for the synthetic strategy were not available commercially, both the flavan-3,4-diol and 1-(3’,4’,5’-trimethoxyphenyl)propan-1-ol had to be synthesized. While the phenylpropan-1-ol analogue was obtained in 64 % yield through utilisation of a Grignard reaction between 3,4,5-trimethoxybenzaldehyde and ethylmagnesium bromide, the required 3’,4’,7-trimethoxyflavan-3,4-diol became available through synthesis and subsequent manipulation of the appropriate chalcone. Thus trans-2’- ethoxymethoxy-3,4,4’-trimethoxychalcone, obtained by standard Claisen-Schmidt condensation of 2-ethoxymethoxy-4-methoxyacetophenone and 3,4- dimethoxybenzaldehyde, was epoxidized with dimethyldioxirane to give the chalcone epoxide in 98 % yield. Deprotection and cyclization to the dihydroflavonol were accomplished in 67.5 % overall yield via treatment of the chalcone epoxide with benzylmercaptan and tin(iv)chloride, followed by reaction of the subsequent -hydroxy- -benzylmercaptodihydrochalcone with silver tetrafluoroborate. Altough the syn- and anti-isomers of the mercaptodihydrochalcone were observed, both of these isomers led to only the 2,3-trans-dihydroflavonol. Finally, NaBH4 reduction of the dihydroflavonol gave the flavan-3,4-diol 70 % yield. Since the starting materials for - and products from the coupling reaction are known to be acid/base sensitive, it was decided to functionalise the flavan-3,4-diol through a mercaptan leaving unit that could be activated by thiophilic Lewis acid in order to induce coupling with the pyrogallol moiety. Silver tetrafluoroborate catalysed model reactions between 4-benzylmercaptochroman and the aromatic nucleophiles, resorcinol and methylated pyrogallol, gave the 4-arylchromans in 62 and 72% yield respectively. When the nucleophile was changed to 1-(3’,4’,5’-trimethoxyphenyl)propan-1-ol or the dehydrated version, 1-(3’,4’,5’-trimethoxy-phenyl)-1-propene, however, no couple could be detected. Since no apparent change in nucleophilicity could be identified as the cause of the reaction not giving any product, the failure can probably be ascribed to steric congestion brought about by the methoxy- and allyl - or propyl groups adjacent to the required point of reaction. As it is known from literature that radicals play an important role in the in vivo synthesis of many natural products, a biomimetic approach towards the synthesis of the 4- arylflavan-3-ol lactones was considered as next alternative. It was therefore envisaged that generation of a phenolic radical at C-2 of the pyrogallol ring of a flav-3-ene 3-gallate ester moiety could result in the formation of the desired lactone. Thus tetra-O-methyl catechin was converted into the 3-keto compound by mild IBX (2-iodoxybenzoic acid) oxidation in 61 % yield. Treatment of the catechin derivative with LDA followed by quenching of the enolate with t-butyldiphenylchlorosilane led to 3-tertbutyldiphneylsilyloxy- 3’,4’,5,7-tetramethoxyflav-3-ene in 84 % yield; thus proving that the double bond was indeed in the right position (between C-3 and C-4 and not C-2 and C-3) for the lactone to be formed. With the position of the double bond established, the enolization reaction was repeated with 2-bromobenzoyl chloride as model electrophile and the enol ester obtained in 22 % yield. In this instance, however, the desired enol ester was accompanied by the 2,3-unsaturated isomer (43 %). With all the uncertainties round the oxidation and enol formation sorted out, the final step in this strategy for the synthesis of the target lactones can now attempted with confidence. AIBN initiated radical cyclization of 3-O-(3”,4”,5”-trimethoxybenzoyl)-3’,4’,7-trimethoxyflav-3-ene and 3-O-(3”,4”,5”-trimethoxybenzoyl)-3’,4’,5’,7-tetramethoxyflav-3-ene will, however, receive attention in a subsequent PhD study. | en_ZA |
| dc.description.abstract | Afrikaans: Hoewel ‘n groot verskeidenheid fenoliese verbindings reeds oor die jare uit die kernhout van Peltophorum africanum (“African wattle”) en Burkea africanum (Rooisering) geïsoleer is, is twee nuwe unieke 4-arielflavan-3-ol laktone, naamlik 6- (3,4-dihidroksielfeniel)-6,6a,8,12b-tetrahidroisochromeno[3,4-c]chromeen- 3,8,10,11,12-pentaol en 6-(3,4,5-trihidrok-sielfeniel)-6,6a,8,12b-tetrahidroisochromeno-[ 3,4-c]chromeen-3,8,10,11,12-pentaol onderskeidelike, onlangs ook uit die hout van hierdie twee bome verkry. Ten einde finale struktuurbewys, veral tov die absolute konfigurasie van die drie chirale sentrums teenwoordig op die C-ring van hierdie verbindings, te lewer, is verskeie pogings tot die sintese van hiedie laktone reed aangewend. Die teenwoordigheid van ‘n karbonielgroep in die gallusuur eenheid wat as nukleofiel tydens vorige sinteses benut is, het egter weens verlaagde nukleofiliteit van die pirogallol ring daartoe gelei dat reaksie met ‘n karbokatioon gegenereer by C-4 van die flavan-3-ol eenheid nie plaasgevind nie. Voorts is bevind dat meer drastiese suur - en basisiese reaksiekondisies, wat toegepas is ten einde die reaksie te forseer, tot die ontbinding van produkte en/of uitgangstowwe aanleiding gegee het. Om genoemde probleme aangaande verlaagde nukleofiliteit van die pirogallol ring te vermy, is besluit om van ‘n alternatiewe nukleofiel, sonder ‘n karbonielfunksionaliteit, gebruik te maak en is die substraat vir die koppelingsreaksies na ‘n pirogallol entiteit met ‘n 1-hydroksipropiel- of alliel substituent, verander. Laasgenoemde groepe kan dan na koppeling deur isomerisasie (allielgroep) or water eliminasie (propanolgroep) gevolg deur osonolise met nie-reduktiewe opwerk kondisies en esterifikasie in die laktoon omgeskakel word. Aangesien beide uitgangstowwe vir die nuwe benadering nie kommersieel beskikbaar is nie, moes beide die 1-(3’,4’,5’-trimetoksifeniel)propan-1-ol en die flavan-3,4-diol self gesintetiseer word. Toepassing van ’n Grignardreaksie tussen 3,4,5- trimetoksibensaldehied en etielmagnesiumbromied het vervolgens die 1-feniel-1- propanol in 64 % opbrengs gelewer, terwyl die flavan-3,4-diol deur manipulasie van die gepaste chalkoon, verkry is. Epoksidasie van trans-2’-etoksimetoksi-3,4,4’- trimetoksiechalkoon, verkry deur die standaard Claisen-Schmidt kondensasie van 2- etoksimetoksi-4-metoksiasetofenoon en 3,4-dimetoksibensaldehied, met dimetiel dioksiraan het vervolgens die chalkoonepoksied in 98% opbrengs gelewer. Omsetting van die chalkoonepoksied na die verlangde 3’,4,4’-trimetoksieflavan-3,4-diol is mbv ‘n twee stap proses bewerkstellig: Eerstens is die dihidroflavonol (67.5 % algehele opbrengs) verkry deur die chalkoonepoksied met bensielmerkaptaan en tin(iv)chloride te behandel, waarna die -hydroksi- -bensielmerkaptodihidrochalkoon met behulp van silwertetrafluoroboraat gesikliseer is. Alhoewel ‘n mengsel van beide die syn- en anti-isomere van die merkaptodihidrochalkoon tydens die sikliserings reaksie benut is, is slegs die trans-dihidroflavonol as produk uit hierdie reaksie verkry. Die flavan- 3,4-diol is vervolgens in 70% opbrengs deur NaBH4 reduksie van die dihidroflavonol daargestel. Aangsien die produkte sowel as die substrate van die koppelingsreaksie suur/basis sensitief is, is daar besluit om die flavan-3,4-diol met ‘n merkaptaan verlatende groep te funksionaliseer, wat dan weer deur ‘n tiofiliese Lewis suur geaktiveer kan word om koppeling met die pirogallol eenheid te induseer. AgBF4 gakataliseerde model reaksies tussen 4-bensielmerkaptochromaan en die nukleofiele reagense, resorsinol en gemetileerde pirogallol, het die 4-arielchromane in 62 en 72 % opbrengs onderskeidelik, opgelewer. Die gebruik van 1-(3’,4’,5’-trimetoksifeniel)propan-1-ol asook die gedehidrateerde weergawe daarvan, 1-(3’,4’,5’-trimetoksifeniel)-1-propeen, het egter onder dieselfde kondisies geen koppeling tot gevolg gehad nie. Aangesien gee radikale verskil in die nukleofiliteit van die substrate wat reaksie getoon het en die wat nie gereageer het nie, verwag kan word nie, kan die mislukking van die fenielpropeen en fenielpropanol reaksies waarskynlik aan steriese faktore toegeskryf word. Weens die feit dat die vorige benadering nie suksesvol was nie, en dit bekend is dat radikale ‘n belangrike rol speel in die in vivo sintese van baie natuurprodukte, is ‘n biomimetiese benadering vir die sintese van die 4-arielflavan-3-ol laktone as alternatief oorweeg. Die moontlikheid dat die verlangde laktoon verkry kan word deur die skepping en reaksie van ‘n radikaal op C-2 van die pirogallol ring van ‘n flav-3-een 3-gallaat ester entiteit, is dus voorts ondersoek. Tetra-O-metielkatesjien is gevolglik omgeskakel na die 3-keto analoog in 70% opbrengs deur milde IBX (2- iodoksibensoësuur) oksidasie. Deur die katesjien derivaat met LDA (litiumdiisopropielamied) te behandel en die gevormde enolaat as ‘n t-butieldifenielchlorosilaan derivaat in 84 % opbrengs te isoleer, is bepaal dat die dubbelbinding inderdaad op die regte plek vir latere laktoon vorming, tussen C-3 en C-4 (en nie tussen C-2 en C-3 nie), gevorm word. Die enolaat reaksie is vervolgens met 2-bromobenzoielchloried as model elektrofiel herhaal en die enol ester in 22 % opbrengs verkry. Laasgenoemde reaksie het egter ook die termodinamies minder stabiele 2,3-enolester (43 %) as produk opgelewer. Met al die onsekerhede mbt die oksidasie van die flavan-3,4-diol eenheid en vorming van die verlangde enolaat ester opgeklaar, kan die finale stap in die sintese van die flavan-3-ol laktone nou met vertroue aangepak word.. Radikaal geïnduseerde (AIBN) siklisering van 3-O- (3”,4”,5”-trimetoksibenzoïel)-3’,4’,7-trimetoksiflav-3-een en 3-O-(3”,4”,5”-trimetoksibenzoïel)- 3’,4’,5’-tetrametoksiflav-3-een behoort die metieleters van die geïsoleerde flavan-3-ol laktone te lewer en sal in ‘n komende PhD ondersoek aandag geniet. | af |
| dc.description.sponsorship | National Research Foundation (NRF) | en_ZA |
| dc.identifier.uri | http://hdl.handle.net/11660/2155 | |
| dc.language.iso | en | en_ZA |
| dc.publisher | University of the Free State | en_ZA |
| dc.rights.holder | University of the Free State | en_ZA |
| dc.subject | Dissertation (M.Sc. (Chemistry))--University of the Free State, 2008 | en_ZA |
| dc.subject | Lactones -- Synthesis | en_ZA |
| dc.subject | Flavonoids -- Synthesis | en_ZA |
| dc.subject | Product | en_ZA |
| dc.subject | Natural | en_ZA |
| dc.subject | Enolization | en_ZA |
| dc.subject | Epoxidation | en_ZA |
| dc.subject | Chalcone | en_ZA |
| dc.subject | Benzylmercaptan | en_ZA |
| dc.subject | Catechin | en_ZA |
| dc.subject | Pyrogallol | en_ZA |
| dc.subject | Lactone | en_ZA |
| dc.subject | Flavonoids | en_ZA |
| dc.title | Development of methodology for the synthesis of 4-arylflavan-3-ol lactones | en_ZA |
| dc.type | Dissertation | en_ZA |