Chem 242b Chemical Synthesi s Scott Virgil, California Institute of Technology, Jan. 14, 2013 Lecture 4 Electrocyclic and Cycloaddition Reactions 4A. Favorskii and Quasi-Favorskii Mechanisms The facility of the Favorskii rearrangement of α-haloketones to cyclopropanones resulting in ring contraction is best understood as involving the formation of an oxyallyl cation which undergoes 2πe- electrocyclic reaction to the cyclopropanone. Substrates which cannot form planar enolates can instead react via the Quasi-Favorskii mechanism. NaOEt,EtOHOClNaOEt,EtOHOClOCl- Cl-O2!e-HHOEtO-HHEtO-HOOEtCO2EtQuasi-Favorskii Mechanism (Eaton's Cubane Synthesis- Eaton, JACS 1964, 86, 962):OOBrBrOOBrBr(DA dimer)aq. EtOHrefluxKOHOBrBrOEtOHH(not enolizable)OBrCO2Etcubane Handout 2. Preclavulone A Biosynthesis in the gorgonian coral Plexaura homomalla In addition to prostaglandin A2 (produced by standard endoperoxide route), P. homomalla also produces the racemic Preclavulone A via an unsaturated allene oxide intermediate. This intermediate was isolated by Brash in 1989 from the coral by preparative HPLC at -15 °C. Opening of the allene oxide to the oxyallyl cation is followed by 4π e- conrotatory electrocyclic cyclization to the cyclopentenone. 4B. Synthesis of Forskolin (Corey JACS 1988, 110, 3672) Corey and Ziegler retrosynthetic plans almost identical. OMe MeMeOHMe MeOHHOOHOAcOMeMeOMeORORMeMeO OMe MeOHMe MeOHROOOCH3OHCHOMe MeHMe MeOHROOOOHCHOMeHMe MeROOOMeMeMe MeOOMeproblematic diene• s-cis unfavored• ionizable• product sensitiveChem 242b Chemical Syn thesis Scott Virgil, California Institute of Technology, Jan. 14, 2013 Lecture 4B. Forskolin (cont.) Due to the difficulty expected in effecting Diels-Alder addition to the hindered diene system (which has steric hindrance associated with the required a planar s-cis geometry), an intramolecular DA reaction with the doubly-activated dienophile was employed. The product was reacted with Gilman’s reagent to afford the key intermediate (The direct DA reaction was later achieved under scrupulous acid-free conditions). Treatment with DBN base isomerized the double bond out of conjugation (molecular models point to the release of ring strain). This diene is subjected to singlet oxygen conditions to afford endoperoxide product. 1. AcOOH2. NaBH4O OO1. O3, MeOHthen Me2S2. KOH, MeOHCHOOHracemicOHPh3P=CH2TsCCCO2HCHCl3(from TsCCH,BuLi, CO2)OOSO2ArOSO2ArOMe2CuLiBF3•OEt2OMeOsee TL 1996, 1015(direct syn. via DA)(DBN, pKa 12.7)CH2Cl2OMeOOMeOOOHthermodynamicNhv, O2sunlampCHCl3, 0 °C0.1%methyleneblue (1O2)BzOMeMe1. Al(Hg)THF2. Bz2OOOBzOMeMe1. PCC, 80 °C2. Al(Hg)3. CH2N2HOHOCO2Me OMeMeDiBAl-Htoluene,-78 °CHOHOOMeMeHOHOt-BuOOHMo(CO)6OOMeMeHO1. KOH,MeOH2. TsOH, aceOMeMeOOOAll attemts to effect OsO4 additionto double bond failed. During thistime, Ziegler's synthesis appeared:(which employed OsO4 addition- see intermediate at right)(JACS 1987, 109, 8115)TBSOMeOAcOOHOHOHNChem 242b Chemical Synthesi s Scott Virgil, California Institute of Technology, Jan. 14, 2013 Lecture 4B. Forskolin (cont.) The publication of Ziegler’s forskolin synthesis necessitated an original and impressive end-game for Corey’s synthesis. Oxygenation was introduced by a selective singlet oxygen addition to the pyran formed by in situ electrocyclic reaction. OMeMeHO1. LiC2. Me2NCOClAgOTf,OOC-RNMe2NCO2MeMeHOOOOTBSMe2NCO2MeMeHOOOOTBSOOHOCH2CH2OHK2CO3, THFMe2NCO2MeMeH1. oxalic acid2. TBSCl, imid3. TlOEtthen AcClEt2O, -45 °COOOAcOOTBSMe2NCO2MeMeHh!, O2CHCl3, 10 °C2% methyleneblueOOOAcOOTBSacetatemigrationMe2NCO2MeHOOAcOOMeR6 !e-electrocyclic1O2[4+2]Me2NCO2MeHOOAcOOROOMeBu3PEtOH0 °CHOOOORNaOEtOOOMeMeHOOOOOOOMeMeMeCu•PBu3BF3•OEt2-78 °C to -50 °CMeORR = TBSR = HHFHOOOOOOOMeMePBu3 then H2O2(Grieco's method)MeSeCNNO21. HOAc2. LiOH3. Ac2O, pyBu3P CNArSe( via