Chem 242b Chemical Synthesi s Scott Virgil, California Institute of Technology, Feb. 13, 2013 Lecture 16 Divinyl Cyclopropane Rearrangements HMe0 °CMeviaHMeHMenot(would giveboth db trans)correctboat T.S.wrong boat T.S.HHHHMeHchair T.S. woudgive back db E, not The divinylcyclopropane rearrangement is a special case for the [3,3]~ Cope rearrangement. The rearrangement in this case affords a cycloheptadiene product. The strain energy of the cyclopropane lowers the activation barrier so that in many cases the reaction proceeds at room temperature or below. However, the divinylcyclopropane rearrangement requires the correct boat transition state to produce the cycloheptadiene product with both double bonds having cis- geometry. 16A. Alkyne Metathesis – DVCp rearrangement (Diver, Davies JACS 2005, 127, 1342) A combination of alkyne metathesis, matched asymmetric cyclopropanation using an enantioselective catalyst and spontaneous divinylcyclo-propane rearrangement was demonstrated by Diver and Davies in 2005. The synthesis of the diene by alkyne cross metathesis is described by Diver (OL 2003, 5, 1793). Further demonstration of the DVCp rearrangement was performed by synthesizing the natural product tremulenolide A in racemic form (asymmetric catalysis failed to give favorable ee in this case). PhOAcMesN NMesRuPCy3ClClPhOEtbenzene, 80 °C(90%)PhOAcOEt1.4:1 E:ZNSO2OOdodecylRhRh41 mol% cat.CO2MeN2PhEHHPhAcOHPhOEtHE = CO2MePhAcOEtO PhCO2Me(65% yield)>94% d.e. 16B. Tremulenolide A (Davies JOC 1998, 63, 657) CO2Me CO2Mequench withCF3CO2HLiNCO2MeEt3NArSO2N3N2Rh2[octanoate]4hexane, refluxOAcCO2MeHHMeHAcOMeOMeHCH2OAcO[3,3]~Me1. H2, Pd(C)2. K2CO3, MeOHOOChem 242b Chemical Synthesi s Scott Virgil, California Institute of Technology, Feb. 13, 2013 16C. Gelsemine (Fukuyama JACS 1996, 118, 7426) In cases where the concerted divinylcyclopropane rearrangement would be unattainable, a stepwise mechanism may operate to effect the transformation. Such was the case in Fukuyama’s synthesis of gelsemine. Although the intramolecular cyclopropanation afforded the product with the propenyl group trans to the five membered ring, the divinyl cyclopropane rearrangement proceeded in high yield and is presumed to initially involve isomerization of the stereochemistry. The iodoaryl ring was incorporated in the synthesis to enforce the orientation of the isatoin group and was subsequently deiodinated. OMeOOthen RCHO2. , H+1. NaHthen nBuLiOEtOMeOOOEE2. Cu(acac)285°C (68%)1. TsN3 Et3NOCO2MeHHMeEEO2. TsOH3. O3, Me2S1. NaBH4then Ac2OOAcCO2MeHHOHO2. [O]3. Et3N1. 4-I-isatoinpiperidine, cat.CO2MeHHONHOI(iodo group enforcesdb geometry)45 min (98%)90 °C, tolueneCO2MeHHONHOImechanism mustbe stepwiseCO2MeHHOHNOINHOIOMeO2COMeNNHO12 steps123 456Gelsemine 16D. Gibberellic Acid Intermediate (Corey JACS 1982, 104, 6129) Corey’s synthesis of gibberellin intermediate follows a cope rearrangement strategy. BrBrCpLi, thenDBU, ether(87%)Br(2:1 mix)ECOMeCO2MeCOMeBr1. TMSOTfEt3NCO2MeBrOTMSCO2MeBrOTMSHBrCO2MeOTMSNaCl,H2O, DMSO,150 oC (71%)BF3 etherate-78 oC, 53%2. tol 160 oC123456Chem 242b Chemical Synthesi s Scott Virgil, California Institute of Technology, Feb. 13, 2013 16D. Gibberellic Acid Intermediate (cont.) The use of dibutylcuprate to effect halogen-metal exchange and cyclization completes the synthesis. HBrOHBrOO1. 9-BBN2. H2O23. PDC ox.1. (nBu)2CuLihexane/ether-78 oC2. MEMCl, baseHOOMEM 16E. Lycoramine (Malachowski JOC 2007, 72, 6792) Malachowski’s synthesis of lycoramine utilizes his chiral auxiliary-controlled alkylation of enolates derived from Birch reduction of aromatic precursors. The allyl group was migrated by Cope rearrangement to the desired position. However, the thermodynamic driving force for this rearrangement was not strong and the material had to be moved through this step by multiple equilibration-separation cycles. NOCH2OMeOMeOMeLi, NH3then isoprenethen allylBr(70%)ArNOCH2OMeOMe>99:1 d.r.H3O +ArXcOO160 oC63% after3 equilibrationsArNOCH2OMeOBBr3-40 oCXcOMeOOOMeOMeOOOHNMe10