Chem 242b Chemical Synthesi s Scott Virgil, California Institute of Technology, Jan. 30, 2013 Lecture 10 Cycloaddition Strategies in Synthesis 10A. Guanacastepene (Sorenson JACS 2006, 128, 7025) Guanacastepene ACHOOHMeMeOAcOOMeMeOOOMeMeOOAr(Danishefsky intermediate) Sorenson’s synthesis of Guanacastepene A was planned as a convergent route in which the rings A and C were each prepared in optically active form and brought together using a [2+2] photocycloaddition. It was expected that such a convergent route would provide an especially short synthesis of this target. The first synthesis of Guanacastepene A by Danishefsky using the intermediate above required 27 steps. OMeOOArMe~ The synthesis of the stannane from (S)-(+)-carvone is shown below. The cyclopentane-1,2-dione (represented as the enol form) was converted to the nonaflate and then to the trimethyltin derivative using palladium 1,1’-bis(diphenylphosphinoferrocene) dichloride as the catalyst. For this synthesis, the nonaflate was greatly superior to the triflate and trimethylstannyl was superior to tributylstannyl. O2. LDA, MeI1. H2, PtO2(0.2 mol%)O2. NaCN, TsOHTHF. H2O1. O3then H2, Pd(C)CO2HOHCNEtN=C=N(CH2)3NMe2(EDCI)CH2Cl2, 0 °C (79%)OLiN(SiMe3)2(3.0 eq.)OCNTHF, rt(50-58%)OOCNOOH2. Pd(dppf)Cl2Me3SnSnMe3NMP, 60 °C (63%)1. C4F9SO2FEt3N (Nf-F)OSnMe3 In addition, the right hand portion of the molecule involved a short route from the DMAD Diels-Alder adduct shown with clever manipulation of protecting groups. MeO2C OHCO2MeCO2MeMeOMeMeO2CMeO2CmCPBANaHCO3CH2Cl2OPMBCH2OHMe1. PMB protect2. LiAlH43. MeOC6H4CHOOOAr1. o-NO2C6H4SeCNPBu3, then H2O22. H+, MeOHChem 242b Chemical Synthesi s Scott Virgil, California Institute of Technology, Jan. 30, 2013 10A. Guanacastepene (cont.) Continuing the synthesis of the right half, the two hydroxymethylene groups were differentiated by DDQ oxidation of the PMB group which closed it to the p-methoxybenzylidene acetal. Coupling with the stannane using palladium tetrakis afforded the photocyclization substrate. As shown below, the isopropyl group directs the enone facial selectivity of the photocyclization. Reduction with samarium diiodide in HMPA and enolate trapping gave a selenium intermediate which was oxidized to afford the dienone related to Danishefsky’s intermediate. OPMBMeHOHOOMe(DDQ)OOCNCNClClOArXX = OHX = OAc2. Pd(PPh3)4CuCl, LiCl60 °C, DMSO(91%)stannaneAr = C6H4OMeMeHiPrOMeHOOArh! (254 nM)iPr2NEt, ether(82%)[2+2] adductSmI2, HMPAthen PhSeBr2. mCPBAOMeMeOOC6H4OMe 10B. Phorbol [3+2] Synthesis (Wender JACS 1989, 111, 8954, 8957, JACS 1997, 119, 7897) The structure of phorbol presents a stereochemical challenge because the two t rans ring fusions (A/B and B/C) require the central B ring to adopt a boat conformation. Wender’s 2nd generation synthesis maintained the oxa- bridged strategy to facilitate meeting this stereochemical challenge, but targeted this ring system by a novel oxypyrylium ion dipolar cycloaddition. Although the [5+2] cycloaddition reaction effectively describes the carbocycle assembly, the reaction is mechanistically a dipolar [3+2] cycloaddition reaction. MeMeOAcMeOHOHMeOOTMSOHOOHMeH OHOHHOHHMeMeOHHMeHMeOAcHOROO~ ~OOORPhorbol (A and C rings trans fused)Chem 242b Chemical Synthesi s Scott Virgil, California Institute of Technology, Jan. 30, 2013 10B. Phorbol [3+2] Synthesis (cont.) In the synthetic direction, the furan is converted to the pyranone by epoxidation and rearrangement. Upon reaction with diazabicycloundecane the oxidopyrylium species is generated which undergoes [3+2] cycloaddition with high diastereoselectivity (chair transistion state). ORMeOHOTBSOR = H standard Evans AldolR = AcORMe2. Ac2O, py1. VO(acac)2tBuOOHCH2Cl2OHOOTBSO~OHOOTBSOAcDBUCH3CNROOOTBSOAc-AcOROOOTBSROOOTBSOOOTBSMeHAcOalkene addition to frontMeOAcHOTBSOO This enone is elaborated to the exo-methylene ketone for further annulation of the A-ring. In the 1997 paper, the zirconocene cyclization affords a product that is converted to phorbol in 20 additional steps. In the original 1989 reference, a nitrile oxide cyclization was used which required 34 additional steps. ZrCl2nBuLi, THFthen AcOHMeOAcHOTBSOMeOAcHOTBSOO3. SeO2 tBuOOH4. MnO21. H2, Pd(C)2. Ph3P=CH22. PhCCLi, LiBrTHF, HMPAthen TMSCl1. (CH2=CH)2Cu(CN)Li2PhTMSOMeOAcHOTBSOHOTMSPhMePhTMSOCp2ZrOTMSCp2ZrPhH93%MeOAcHOTBSOOTMSOH2. DiBAl-H1. TMSCNZnI2allylketone2. NaOClTHF, H2O1.