Direct synthesis of pterocarpans via aldol condensation

Abstract

English: Pterocarpans, representing the second largest group of natural isoflavonoids, have received considerable interest on account of their medicinal properties over the last few years. These phytoalexins not only serve as antitoxins but also display antifungal, antiviral and antibacterial properties. Despite this, the study of these metabolites are restricted by their limited availability from natural sources. Furthermore, synthetic protocols allowing ready access to these compounds are restricted by the lack of availability of suitable starting materials and the potential introduction of stereoselectivity. Owing to the demand for enantiopure pterocarpans a direct stereoselective synthetic approach, based on the aldol condensation between appropriate phenylacetates and benzaldehydes, was developed. 2-Hydroxybenzaldehydes, protected as 2-0-methoxymethyl ethers, and 2- hydroxyphenylacetates, protected as TBDMS ethers, were subjected to aldol condensation employing lithium diisopropylamide, to afford the 2,3-diphenyl-3- hydroxypropanoates (40-76%, de = 22-100%). Subsequent reduction (LiAIH4), followed by Lewis acid (SnCI4, BnSH) deprotection of the 2'-O-MOM ethers, yielded the 3- benzylsulfanyl-2,3-diphenylpropanols (29-56%). Improved yields of these propanols were obtained by simply reversing the order of reactions (54-81%). B-ring formation using Mitsunobu conditions (TPP-DEAD) afforded the isoflavan silyl ethers in good yields (80-97%). The 2'-O-TBDMS derivatives were smoothly deprotected (TBAF) to yield the 2'-hydroxyisoflavans in excellent yields (96-99%). Finally, thiophilic Lewis acid (AgBF4, AgOTf or DMTSF) cyclisation produced the cis-pterocarpans in moderate to good yields (39-82%). Initial C-ring cyclisation (AgBF4) of the methyl 3-benzylsulfanyl-2,3-di(2- hydroxyphenyl)propanoates, followed by reduction (LiAIH4) and Mitsunobu (TPPDEAD) B-ring formation, afforded for the first time a trans-pterocarpan in a moderate overall yield of 12%. In order to address the issue of stereo control, we first attempted to introduce stereoselectivity during the aldol condensation. Stereoselective aldolisation employing diisopropylethylamine and chiral boron triflates, was evaluated utilizing achiral dibutylborontriflate. This system, though capable of effecting aldolisation, was ineffective to incorporate a broad range of substrates. Secondly, we converted the methyl propanoates to chiral derivatives of imidazolidin-2-one, bornane-l0,2-sultam and (lR,2S)-p-tol-N-norephedrine. Steric shielding of the enolates generated from these derivatives, prevented aldol condensation. Thirdly, using (-)-sparteine as chiral base afforded achiral products. Finally, in an effort to employ stereoselective epoxidation, attempts were made to synthesize 2-propenoates. All attempts to introduce the double bond gave disappointing yields. Although our attempts to introduce chirality failed, several alternatives still needs to be investigated in future endeavours. We have thus developed a highly efficient synthesis of cis-pterocarpans and succeeded in modifying this protocol to the novel synthesis of Irans-pterocarpanoids. Also, this synthetic protocol was modified to permit the stereoselective synthesis of 6ahydroxypterocarpans in high overall yields. The ease with which these protocols accommodate highly oxygenated substrates, featured by most natural pterocarpans, should contribute substantially to assess the chemical and physiological characteristics that may promote application of this class of phenolics as pharmaceutical or agricultural chemicals.

Afrikaans: Gedurende die afgelope paar jaar het pterokarpane, die tweede grootste groep isoflavanoïede, vanweë hul medisinale eienskappe aansienlik aandag ontvang. Hierdie fito-aleksiene dien nie alleen as antitoksiene nie, maar vertoon ook swamdodende, antivirale en antibakteriese eienskappe. Ten spyte hiervan word die studie van hierdie metaboliete gestrem deur hul beperkte natuurlike beskikbaarheid. Verder word sintetiese toegang tot hierdie verbindings gekortwiek deur beskikbaarheid van uitgangstowwe en die potensiaal om stereoselektiwiteit te bewerkstellig. Vanweë die aanvraag na enantiomeries suiwer pterokarpane is In direkte stereoselektiewe sintetiese roete, gebaseer op aldolkondensasie tussen geskikte fenielasetate en bensaldehiede, ontwikkel. Litiumdiisopropielamied gekataliseerde aldolkondensasie tussen 2- hidroksibensaldehiede, beskerm as 2-0-metoksiemetieleters, en 2-hidroksifenielasetate, beskerm as TBDMS-eters, het die 2,3-difeniel-3-hidroksipropanoate gelewer (40-76% opbrengs, de = 22-100%). Daaropvolgende reduksie (LiAlH4) en Lewissuur gekataliseerde (SnCI4, BnSH) ontskerming van die 21-O-MOM eters, het gelei tot die 3- bensielsulfaniel-2,3-difenielpropanole (29-56%). Verhoogde opbrengste (54-81 %) van laasgenoemde propanole is verkry deur wysiging van die reaksievolgorde . B-ring vorming onder Mitsunobu kondisies (TPP-DEAD) het gelei tot goeie opbrengste van die isoflavaan silieleters (80-97%). Die 21-O-TBDMS derivate is maklik ontskerm (TBAF) om 21-hidroksi-isoflavane in uitstekende opbrengste te lewer (96-99%). Laastens is tiofiliese Lewissuur (AgBF4, AgOTF of DMTSF) siklisering gebruik om die cispterokarpane in redelike tot goeie opbrengste te lewer (39-82%). Aanvanklike C-ring siklisering (AgBF4) van die metiel-3-bensielsulfaniel-2,3-di(2- hidrosifeniel)propanoate, gevolg deur reduksie (LiAlH4) en Mitsunobu (TPP-DEAD) Bring vorming, het gelei tot die eerste sintese van ' n trans-pterokarpaan in In redelike totale opbrengs van 12%. Ten einde die kwessie van stereobeheer aan te spreek, is eerstens gepoog om stereoselektiwiteit gedurende die aldolkondensasie teweeg te bring. Die benutting van diisopropieletielamien en chirale borontriflate in stereoselektiewe aldolreaksies is geëvalueer m.b.v. achirale dibutielborontriflaat. Alhoewel die sisteem aldolprodukte gelewer het, was dit oneffektief om 'n wye reeks substrate te akkommodeer. Tweedens is die metielpropanoate na chirale derivate van imidasolidien-Z-oon, bornaan-lO,2-sultam en (lR,2S)-p-toliel-N-norefedrien omgeskakel. Steriese skerming van die enolate verkry vanaf hierdie derivate het egter aldolkondensasie verhoed. Derdens het (-)-sparteïen as chirale basis ook gelei tot die vorming van achirale produkte. Laastens, in 'n poging om stereoselektiewe epoksidasie te benut, is daar gepoog om 2,3-diariel-2-propenoate te sintetiseer. Alle pogings om die dubbelbinding daar te stel het teleurstellende resultate opgelewer. Ten spyte daarvan dat pogings om chiraliteit te induseer misluk het, verskaf dit rigtingwysers vir verskeie alternatiewe wat toekomstig ondersoek kan word. 6a-Hidroksipterokarpane, hoewel minder algemeen as pterokarpane, word ook hoog geag as gesondheidsaanvullende middels. Oksidatiewe termiese eliminasie (NaI04, 60°C) van 4-bensielsulfanielisoflavane, gevolg deur asimmetriese dihidroksilering, m.b.v. stoïgiometriese hoeveelhede OS04 en DHQ-CLB of DHQD-CLB as chirale ligande, het die onderskeie (+)- en (-)-diole (38-43% opbrengs, ee> 99%) gelewer. Daaropvolgende ontskerming van die 2'-0- TBDMS-eters (TBAF) en siklisering (Ms20, piridien) het die cis-6a-hidroksipterokarpane in uitstekende opbrengs en essensieelopties suiwer vorm(70-75% opbrengs, ee > 99%) daargestel. 'n Hoogs effektiewe sintese van cis-pterokarpane is dus ontwikkel en is verder daarin geslaag om hierdie protokol aan te pas vir die sintese van unieke trans-pterokarpanoïede. Hierdie sintetiese protokol is ook gewysigom die hoë opbrengs stereoselektiewe sintese van 6a-hidroksipterokarpane te bewerkstellig. Die toepaslikheid van bogenoemde protokolle op hoogs geoksigeneerde substrate, soos algemeen onder natuurlike pterokarpane aangetref, behoort 'n nuttige bydrae te lewer tot die bepaling van die chemiese en fisiologiese eienskappe wat die gebruik van hierdie klas verbindings as farmaseutiese of landbou chemikalieë kan bevorder.