Chem 242b Chemical Synthesi s Scott Virgil, California Institute of Technology, Jan. 11, 2013 Lecture 3 Electrocyclic and Cycloaddition Reactions 3A. Suzuki’s Synthesis of TAN-1085 ACIEE 2004, 43, 3167 (this discussion), ACIEE 2009, 48, 5633 (more recent asymmetric version) OO OHOOHOOHOHTAN-1085(anti-angiogenesis)OPOPPOCHOOH OPOPCHOOBnOOMeOMeOBnOOHOBnOTfITMSO OMeOTBS+1. nBuLiTHF, -78 °C2. HF,CH3CN1. HC(OMe3)TsOH, MeOH2. Swern Ox.Benzocyclobutenone Synthesis (Helv. Chim. Acta 2002, 85, 3589):BSuzuki's TAN-1085 Synthesis:OMOMOTBDPSBnOIOTBS1. tBuLi (2 eq.)THF, -78 °Cthen Athen MeOTf(85%)OMOMOTBDPSBnOOTBSBnOOMeOMeMeOBnOtoluenereflux4!e- then[1,7] H~OMeArOTBSMeO OMeHOMOMCHOBnOCHOBnOOMeOMeMeO1. HF2. Swernundesired productBnO 25 °C 8 hr4!e- electrocyclicaccelerated byenal substituentOMeArCHOHMeOOMeBnO6!e-electrocyclicMeOOMeCHOHOMeAr-MeOHMeOOMeBnOCHOBnOOMOMCHOSmI2, THF, 0 °C2 min then BzCl(86%)MeOOMeBnOBnOOMOMOHOBzCompletion of synthesis:OMOM -> CH2OHPG removal, glycosidation2009 paper prepares opt.active stannane related tointermediate B.Chem 242b Chemical Synthesi s Scott Virgil, California Institute of Technology, Jan. 13, 2013 Lecture 3B. Cyclopropyl Cation Electrocyclic Opening Reactions (2πe-) WithXsolvolyses, T.S. involves simultaneous C-O bond cleavage and ring opening.CH3CH3TsOCH3HHCH3OTsCH3CH3CH3HHCH3OTsTsOnodeLUMO= !*COLUMO= !*COHOMO= !CCAcOH,150 °Crate =41,000 s-1AcOH,150 °Crate =4 s-1CH3HHCH3OTsCH3HHCH3OTsnodeCH3CH3+As ring opening proceedstoward T.S., !CC buildsoverlap with !*COAs ring opening proceedstoward T.S., interaction develops between !CCand the node of !*COThe above analysis involving secondaryorbital interactions allows us to rationalizedifferent reaction rates.Consider also:AcOH, 100 °C:HHHOSO2ArHHArSO2OHvs.rate = 1 s-1rate = 11,000 s-1 Lecture 3C. Nazarov Cyclization: H+ orBF3•OEt24!e-conrot.OHOHO O-H+++ NNHTs2.0 eq. nBuLiTHF, -78 °Cthen TMSCl(Shapiro rxn)SiMe3AlCl3CH2Cl2COClOCH3SO3HP2O5O Silyl-Directed Nazarov Cyclization – Denmark JACS 1982, 104, 2642. CHO1.2. MnO2BrMgSiMe3OSiMe3CH2Cl2, 0 °C4!e- conrot.FeCl3OFeCl3-SiMe3HH+OHHSilyl group accelerates reaction and directly leads to less substituted enone.Dienones also available from vinyl triflates: Stille JACS 1984, 106, 7500, JACS 1984, 106, 2642.Me3SnSiMe3OTfBu+Pd(PPh3)4CO, THF55 °CBuSiMe3O(capnellane