Chem 242b Chemical Synthesi s Scott Virgil, California Institute of Technology, Feb. 8, 2013 Lecture 14 Arene-Olefin Cycloaddition and Azomethine Ylide Cyclizations 14A. Vindoline (Boger Org. Lett. 2005, 7, 4539, JACS 2010, 132, 3685) MeO NNHOAcEtMeOHCO2MeHMeO NNHOAcEtROHCO2MeHMeO2CNHNHHOEtVinblastine (R = Me), Vincristine (R = CHO) Vincristine The alkaloids vincristine and vinblastine are important medicines for cancer treatment isolated from the Madagascar periwinkle plant. Their activity as potent inhibitors of cell division owes to their inhibition of microtubule assembly during mitosis. The alkaloid Vindoline has been synthesized in racemic form (2005) and optically active form (2010) by Boger using a novel [4+2]/[3+2] cycloaddition cascade of an oxadiazole precursor. After initial [4+2] cycloaddition and loss of nitrogen, the dipoal intermediate undergoes [3+2] cycloaddition with the indole. Both high temperature and high dilution are necessary to achieve satisfactory yields. (imidazole)2C=OthenNH2NHCCO2MeMeONMeNH2MeONMeNHHNHN OOCO2MeOEDCITsClEt3NMeONMeNHNNOCO2MeRCO2HMeONMeNNNOCO2MeOHBnOEt0.001Mdilution250 °CMeONMeNOCO2MeONNEtOBn-N2CO2MeEtOBnONCO2MeOEtOBnMeOONCO2MeOEtOBnONONOHCO2MeOBnEtMe~ ~ZZ -precursor -> 43% yield(E- precursor -> 90% yield of isomer)Dipolar intermediateresonance structures(from text)[3+2]cycloadditionChem 242b Chemical Synthesi s Scott Virgil, California Institute of Technology, Feb. 8, 2013 14B. [1,3] Sigmatropic Rearrangements (Berson, Acc. Chem. Res. 1972, 5, 406) The thermal [1,3] sigmatropic migration is a 4π e- process and therefore one component must participate antarafacially to be symmetry allowed. In the case of alkyl migration, the rearrangement may be accommodated by inversion of stereochemistry at the migrating atom. However, the concerted [1,3] migration of hydrogen would be impossible to achieve antarafacially and therefore can be regarded as thermally forbidden. Migrating groups isparticipating antarafacially.-> Inversion at migrating atom.Thermal [1,3] H~ not possibleHX In 1972, Berson set out to demonstrate the inversion stereochemistry in a [1,3] sigmatropic migration. The stereochemically deuterated acetate was heated to 150 °C to effect [1,3] rearrangement and the norbornene product was isolated with the expected stereochemistry. Even in favorable cases, the thermal rearrangement requires elevated temperatures. HHAcOHDDHHOAcHH150 °COAcHHDHHOAcDHHInversion atmigrating carbon In 1997, Wender utilized the known photochemical [1,3] sigmatropic rearrangement of verbenone to chrysanthenone in the initial stages of his 49 step taxol synthesis. This approach was concurrently investigated by Winkler. (Wender JACS 1997, 119, 2755-2756 and 2757-2758) (Winkler TL 1995, 36, 2211-2214) OCH3CH3CH3CH3CH3CH3Oh!260 nMverbenone R = HTaxol precursor R = CH2CHOchrysanthenone R = HRR 14C. [1,5] Hydrogen Migrations in Cyclopentadienes (Capnellane – Grubbs, JACS 1986, 108, 855) In contrast, [1,5] H~ migrations are generally facile in cyclic and acyclic systems and can complicate Diels-Alder strategies in synthesis. In 1986, Grubbs completed an impressive synthesis of capnellane using tiatanocene olefin metathesis catalyst on an intramolecular Diels-Alder cycloadduct. The alkylation of the tosylate intermediate with cyclopentadienide gave first the 5-substituted cyclopentadiene. At 0 °C isomerization to the 1-substituted cyclopentadiene could be observed, followed by the 2-substituted cyclopentadiene at 23 °C. RHHHRRHH[1,5] H~ [1,5] H~Chem 242b Chemical Syn thesis Scott Virgil, California Institute of Technology, Feb. 8, 2013 14C. Capnellane – Grubbs (cont.) In practice, the product from tosylate alkylation was heated to 75°C to afford a single Diels-Alder cycloadduct as the endo- isomer. The key metathesis reaction was performed using the Tebbe reagent with added DMAP to complex the Me2AlCl byproduct which could be removed by filtration. Upon heating, the metallacycle proceeded to the alternate titanium carbene which was trapped by the pendant ester. Subsequent steps in the synthesis involved conversion of the vinyl group to a methyl group using Ireland deoxygenation of the corresponding primary alcohol and ring expansion using ethyl diazoacetate. CO2tBuHHOO1. DiBAl-H2. (EtO)2PCH2CO2tBuO(Michael add'n)OCO2tBuLDATsCl(88%)CO2tBuOTsEtMgCl,THFthen benzene,75 °C (81%)CO2tBuHHEtMgCl,THFthen benzene,75 °C (81%)Ti(Tebbe Reagent)DMAP, benzene, rtClAlMe2CO2tBuHHTiCp2HH90 °CHHTiCp2CH2HHCH2HtBuOOtBuOTsOHEG(81% overall)OOHHH3. nBuLi, (Me2N)2POCl4. Li, tBuOH, EtNH25. H3O+, acetoneHHHCH31. O3, MeOH2. NaBH4ON2CHCO2EtBF3•OEt2-30 °CHHOCHNCO2EtNBF3HHHCH32. Tebbe rgt.DMAP, benzene1. NaClDMSO–H2O150