Chemistry 242b Handout 3a. Recognizing the Diels - Alder Retron January 14, 2013Look for potential W (withdrawing) group which is "ortho" or "para" to a strong D (donor) group.WDWDWDvia endo T.S.Make maximum use of regio and stereochemical preferences.* Stereospecific addition enforces C1-C4 and C2-C3 relationships.* Regioselectivity as above.* Endo preference with R1 and/or R2 electron withdrawing (or inverse e- demand)R1R2A BCD1234Syntheses using Intermolecular DA:Avoid problematic dienophiles:RRRcp isomerizationsteric barrier to s-cis conformerOMeOROCOOHFumagillinC2Logic pp. 19-22.OOHCHOBrHAllene oxide not asuitable dienophileviable DA retron(regio and stereo)CHOBrE = CO2MeEEOOHVernolepinGrieco JACS 98, 1612 (1976) 30 stepsDanishefsky JACS 98, 3028 (1976) 18 steps (below)OOHOOOHOOHOOHOHOOHOODanishefskyDiene DA retroniodolactonizationstrategyOHOOOHOETMSOEOMe165 oC,48 hr, 50%1. LiOH2. KI3, NaHCO3OMeIDBUOConsider all six DA disconnections (there are a lot of methods to move the double bond around the ring):ETMS+ETMSEXEChemistry 242b Handout 3b. Recognizing the Diels - Alder Retron January 14, 2013Problem Solving with Intermolecular Diels-Alder1. Addition of extra W group on dienophile (or D group on diene) which may be removed later. Including quinone DA.2. Choice of a Dienophile Equivalent for unsuitable dienophiles.3. Catalysis by Lewis Acids. (increases reaction rate and selectivity). In the extreme case, Lewis acids may make reactions stepwise.4. Intramolecular activation of dienophile.5. Change of Solvent to water (hydrophobic acceleration).6. Chelation of diene and dienophile to make the reaction intramolecular (e.g. Narasaka boronate).7. High pressure Diels Alder (15,000 atm - 25000 atm, special hydraulic system).(more later with Intramolecular Diels Alder)Acceleration of Diels Alder reaction in aqueous media:Diels Alder route to Schlessinger IntermediateGrieco JOC 49, 5257 (1984)Schlessinger JACS 102, 782 (1980)BnOCHOaq. CH2OEt2NH.HCl 70 oC (50%)BnOCHOH2O, 50 oCCOONaNaBH4OOHOBn91%Activation of DA by B(OAc)3:Kraus JOC 45, 4825 (1980)OHB(OAc)3tol, 5 oCOAcOAcHHOOOOHHTBSOOTBSClthenK2CO3Use of Narasaka Boronatein DA route to Taxol C ring:NicolaouClassics Vol. 1CO2EtPhB(OH)2benzene90 oC (-H2O)OHOHHOHOO+OOBOEMeOPhOOOHOEtOOOBnTIPSOOOO+OMeO15,000 atmOCO2MeDauben JACS 98, 1992 (1976):DA has negative volume ofactivation.Forskolin:Ziegler JACS 109, 8115 (1987)Corey JACS 110, 3672 (1988)OOHOAcOOHHOHHO