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.