Synthesis of isoflavonoid-neoflavonoid oligomers

Abstract

English:A recent phytochemical study on the heartwood of the Purplewood Dalbergia (Dalbergianitidula) in our laboratories led to the isolation of the first pterocarpan-neoflavonoid dimers, Daljanelins A-C, and an isoflavan-neoflavonoid dimer, Daljanelin D. Although the structure of Daljanelin C has been confirmed by synthesis previously, synthetic evidence regarding the exact structures of Daljanelins A, Band D was still pending. This dissertation outlines the total syntheses of Daljanelins Band D, as well as the preparation of a suitable precursor to Daljanelin A. The crucial step in the retrosynthesis of Daljanelin B is the nucleophilic coupling of a suitably functionalized pterocarpan precursor with a benzofuranone. The electrophilic methylene bridge required at C-4 of (6aS, llaS)-medicarpin was introduced via 3-0-allylation, Claisen rearrangement, isomerization and oxidative cleavage of the olefin, benzylic reduction and in situ bromination, affording (6aS, llaS)-4-bromomethylmedicarpin. The requisite benzofuranone synthon was synthesized from vanillin by Dakin oxidation, Houben-Hoesch acylation, cyclization, protection of the hydroxy group and conversion to the tert-butyldimethylsilyl enol ether. The subsequent coupling of the pterocarpanoid and benzofuranoid fragments was achieved by means of desilylation of the latter with a strongly siliconophilic fluoride source. Grignard reaction of the resulting dimer with phenyl magnesium bromide and subsequent acid catalyzed dehydration and deprotection then afforded synthetic Daljanelin B, which exhibited the same IH NMR and CD properties as the natural product. Reductive cleavage of the pterocarpan C-ring in Daljanelin B afforded Daljanelin D, identical to the natural compound. It should be noted that the standard method for benzylic ether cleavage, i.e. hydrogenolysis on Pd(O) catalysts, was ineffectual. Good results were obtained, however, with a Na(CN)BHr TFA system. A suitable precursor to Daljanelin A, i.e. a 2-ethoxycarbonyl-substituted medicarpin, was synthesized from (6aS, llaS)-medicarpin via 2,8-dibromination, 3-0-methoxymethylation, selective lithium-bromine exchange and carboxylation at C-2, followed by 8-debromination. Reduction of the resulting ethyl benzoate, in situ bromination, benzylic coupling to a benzofuranoid, Grignard reaction and phenolic deprotection, as used in the synthesis of Daljanelin B, should prove instrumental in affording the desired dimer. Over and above structural elucidation, this research project has led to the following significant results: o The introduction of a hydroxy methyl group to position 4 of the pterocarpan skeleton constitutes an unusual accomplishment, since substitution on resorcinol-type pterocarpan A-rings is usually hampered by low aromatic nucleophilicity, as well as sensitivity of the C-ring towards the typically employed Bronsted and/or Lewis acids. o Electrophilic aromatic substitution on such A-rings, if observed at all, takes place in low yields at position 2. An analogue situation is encountered in natural and synthetic 5-deoxyflavonoids, where A-ring substitution is found exclusively at position 6. It is thus hoped that the protocol developed for the synthesis of Daljanelin B will alleviate these difficulties. o Although the yields In the bromination-carboxylation-debromination protocol towards Daljanelin A are still low, an alternative route for C-2-alkylation ofpterocarpans has been established. The novel synthetic routes towards Daljanelins A and B may thus collaborate in circumventing some of the problems typically associated with flavonoid and isoflavonoid A-ring functionalization.

Afrikaans: 'n Onlangse fitochemiese ondersoek in ons laboratoriums van die kernhout van die blinkplatboontjie (Dalbergia nitidulaï het gelei tot die isolering van die eerste pterokarpaanneoflavonoïed dimere, Daljanelins A-C, asook 'n isoflavaan-neoflavonoïed dimeer, Daljanelin D. Alhoewel die struktuur van Daljanelin C al vantevore m.b.v. totale sintese bevestig is, het soortgelyke struktuurbewyse vir Daljanelins A, B en D tot op hede ontbreek. Hierdie proefskrif beskryf die totale sinteses van Daljanelins B en D, asook die bereiding van 'n geskikte voorloper tot Daljanelin A. Die grondliggende stap in die retrosintese van DaIjaneJin B is die nukleofiJiese koppeling van 'n bensofuranoon aan 'n geskikte gefunksionaliseerde pterokarpaan. Die nodige elektrofiliese metileenbrug is by C-2 van (6aS, llaS)-medikarpin ingestel deur 3-0-allilering, Claisenherrangskikking, isomerisasie en oksidatiewe splyting van die olefien, bensiliese reduksie en in situ brominering, om (6aS, llaS)-4-bromometielmedikarpin te lewer. Die benodigde bensofuranoon is vanaf vanillien gesintetiseer d.m.v. Dakin-oksidasie, Houben-Hoesch-asilering, siklisering, beskerming van die hidroksigroep en omskakeling na die tert-butieldimetielsiliel enol eter. Die koppeling van die pterokarpaan- en bensofuranoongebaseerde fragmente is vervolgens bewerkstellig deur desililering van die laasgenoemde tussenproduk met 'n sterk silikonofiliese fluoriedbron. Grignardreaksie van die verkrege dimeer met fenielmagnesiumbromied, gevolg deur suurgekataliseerde dehidrasie en ontskerming, het gelei tot sintetiese Daljanelin B, wat volgens IH KMR en SD identies was aan die natuurproduk. Reduktiewe splyting van die pterokarpaan-C-ring in Daljanelin B het natuuridentiese Daljanelin D gelewer. Dit is opvallend dat hierdie bensiliese etersplyting nie met die standaardmetode kon bewerkstellig word nie, d.w.s. hidrogenolise op Pd(O)-kataliste. 'n Na(CN)BH3- TF A-sisteem het egter gelei tot goeie resultate. 'n Geskikte voorloper tot Daljanelin A, te wete 'n 2-etoksikarbonielgesubstitueerde medikarpin, IS vanaf (6aS, II as)-medikarpin gesintetiseer via 2,8-dibrominering, 3-0-metoksimetilering, selektiewe litium-broomuitruiling en karboksilering by C-2, gevolg deur 8-debrominering. DaljaneJin A behoort sinteties toeganklik te wees deur reduksie van hierdie etielbensoaat, gevolg deur in situ brominering, bensiliese koppeling aan 'n bensofuranoonvoorloper, Grignardreaksie en fenoliese ontskerming, analoog aan die sintese van Daljanelin B. Afgesien van struktuurbevestigings, het hierdie navorsingsprojek die volgende betekenisvolle resultate gelewer: o Die hidroksimetilering van C-4 op die pterokarpaanskelet is 'n beduidende mylpaal, aangesien substitusiereaksies van resorsiliese pterokarpaan-A-ringe gewoonlik belemmer word deur lae aromatiese nukleofilisiteit, asook gevoeligheid van die C-ring teenoor die Brensred- en/of Lewissure wat tipies vir sulke reaksies gebruik word. o lndien elektrofiliese aromatiese substitusie hoegenaamd op sulke A-ringe waargeneem word, vind dit in lae opbrengste by posisie' 2 plaas. Natuurlike en sintetiese 5-deoksiflavonoïede vertoon soortgelyke eienskappe, deurdat A-ringsubstitusie uitsluitlik by posisie 6 aangetref word. Hierdie probleme kan hopelik aangespreek word met die protokol wat vir die sintese van Daljanelin B ontwikkel is. o Die protokol vir Daljanelin A, d.w.s. brominering, karboksilering en debrominering, vertoon huidig lae opbrengste, maar nietemin is daar 'n alternatiewe roete tot C-2-alkilering van pterokarpane daargestel. Die nuwe sintetiese roetes tot Daljanelins A en B mag dus behulpsaam wees om sommige probleme te omseil wat tipies geassosieer word met die funksionalisering van flavonoïed- en isoflavonoïed-A-ringe.