Chem 242b Chemical Synthesi s Scott Virgil, California Institute of Technology, Feb. 11, 2013 Lecture 15 Vinyl Cyclopropane Rearrangements A special case of the [1,3] sigmatropic migration is the vinylcyclopropane rearrangement. Although the thermal rearrangement of simple unsubstituted systems do not proceed until temperatures in excess of 300 °C, the rearrangement finds use in systems which contain stabilizing groups and proceed by an ionic mechanism. > 300 °COXHHXO!X OHX = alkyl, OR 15A. Retigeranic Acid (Hudlicky JACS 1989, 111, 6691) Hudlicky’s convergent synthesis of retigeranic acid utilizes a vinylcyclopropane rearrangement under the conditions of flash vacuum pyrolysis (which was a popular field of development in the 1980s). The vinyl cyclopropane precursor is prepared by a nucleophilic cyclopropanation reaction. It is a bit surprising that a sesterterpene (C25) ester has any vapor pressure at all, but such conditions effect the rearrangement in an unselective manner and suitable yield for completion of the synthesis. HMeCO2EtBrMeOHMe+THF, HMPA-105 to -50 °CLDAHMeCO2EtMeOHMe10-4 mmHgFVP (585 °C)HMeCO2EtMeOHMeHMeHMeOMeHCO2Et!-H: 24% yield1. NaBH42. NaH, CS2, MeI3. nBu3SnH4. LiOH, H2O(xanthatereduction)"-H: 27% yieldHMeHMeMeCO2HHRetigeranic Acid 15B. Antheridic Acid (Corey JACS 1985, 107, 5574) Corey’s synthesis of antheridic acid was planned using the vinylcyclopropane to construct the gibberelin nucleus. The unusual bicyclo [2.2.2] system in this natural product was envisaged as a straightforward Diels Alder retron using a ketene dienophile equivalent. Upon completion of the synthesis, it was discovered that the original assignment was erroneous at the hydroxyl group stereochemistry. OHCO2HOOCH3XYX = OH, Y = H Original Assign.X = H, Y = OH Antheridic AcidROOCH3OHHOROOCH3HOHROOCH3OHHkey VCP rgt.HChem 242b Chemical Synthesi s Scott Virgil, California Institute of Technology, Feb. 11, 2013 15B. Antheridic Acid (cont.) In Corey’s synthesis of antheridic acid, the vinylcyclopropane rearrangement is effected under more standard conditions catalyzed by Lewis Acid. Other highlights of this synthesis include: (1) use of Semmelhack’s π-allyl nickel methodology (highly toxic nickel(0) tetracarbonyl on first step, danger!); (2) Birch reduction with methylation of anionic intermediate; (3) development of reagent for diazoester installment (published in TL); (4) use of highly effective Cu(TBS)2 reagent for cyclopropanation. IMeOCO2MeBr, Ni(CO)4DMF, 40 h(via !-allyl nickel)MeOCO2MeHthen MeINa, NH3tBuOHMeOH85%Me CO2MeH3O+OHMe CO2Me3. DiBAl-HTBSOHMe1. Zn(BH4)22. TBSClOH2. Et3NTBSOHMe1. TsNHN=CHCOCl PhNMe2, CH2Cl2O ON2toluenereflux (84%)ONtBuCu22. DBU(48%)(recycle)TBSOOCH3OHHH1. Br2, CCl40 °C(80%)TBSOOCH3OHHEt2AlCl,CH2Cl2TBSOOCH3OHH2. LiNEt2THF, 0 °C(79%)TBSOOCH3O1. CH3CO3HHHH(76%)TBSOOCH3OHH(epoxide)OHNO2NO23. CH2N2(68%)1. KOH2. RuCl3, K2S2O8OHCO2MeHMeCHOTBSO2. DBU, THF1. (CF3CO)2O, pyOCOCF3CO2MeHMeCHOTBSOO2. CF3CH2OH1. NaClO2, tBuOH (Cl2 scav.)NCO2MeMeTBSO3. NaBH41. TMSCl, Et3N2. CH2=NMe2+I–OOOHCO2MeMeTBSOthen invert tocorrect stereochem.1. HF•py2. LiOHOOHOCH2AAnOHChem 242b Chemical Synthesi s Scott Virgil, California Institute of Technology, Feb. 11, 2013 15C. Cope, Claisen and oxy-Cope Rearrangements 136425~136425bondto bebrokenbondformedbetween 1 and 6OO136425~314625X X314625~314625O O314625OX = H, OMe, NMe2 etc.reaction driven bystrength of C=O vs C=C.79 vs 67 kcal/molCope Rearrangement:Claisen Rearrangement:oxy-Cope Rearrangement: Retrosynthetically and mechanistically, you must train yourself to count along the molecule and search for possible Cope, Claisen and oxy-Cope set-ups. Note that the Claisen-type rearrangements are keyed by counting 1-6 from the double bond through the carbonyl group while the oxy-Cope retron is keyed by counting 1-6 to the carbonyl carbon. Example: (Masamune JACS 1969, 91, 7512) !Pericyclic rearrangement problem:1. Only use WH-allowed reactions – no retro- [2+2]2. What is the most reasonable first step?3. search for possible [3,3]~ rearrangementspasteanswerhere Stereochemistry of [3,3]~ Rearrangements: The Cope and Claisen rearrangements operate under stereospecific control via chair transition states. In cases where the ee of the product is diminished, the boat transition state is responsible for loss of ee. MePhMeSE[3,3]~150 °CMeMePhchair T.S.MeMePhHRE95% opt. purePhMechair T.S.95% opt. pureMeMeMePhHSZMePhboat T.S.MeMePhMeHSE(leakage of eecomes from boat