Chem 242b Chemical Synthesi s Scott Virgil, California Institute of Technology, Jan. 25, 2013 Lecture 8 Ketene Cycloadditions in Synthesis 8A. Retigeranic Acid (Corey JACS 1985, 107, 4339, Engler - Strategies and Tactics vol. 2, pp. 91-121) Corey’s synthesis of the complex sesterterpene ( = 2½ x C10) Retigeranic acid took advantage of the DA-ozonolysis-aldol tactical combination which had been applied to his gibberelic acid synthesis. Construction of the triquinane was planned using an intramolecular ketene-olefin [2+2] and subsequent ring expansion. HMeMeHCO2HHMeDiels-Alder/O3/Aldol TCHHMeOHMeHMeHHMeMeMeCO The synthesis got off to a rocky start when it was found that the hydrindenone below cleanly gave the undesired cis- ring fusion when it was reduced with lithium in liquid ammonia. So unexpected was this result that the cis material was carried several steps further until an X-ray analysis of a Diels-Alder adduct showed it to be erroneous. Although there are hydroxyl-directed hydrogenation methods available, these were attempted to no avail. Finally, the stereospecific concerted allylic sulfenic acid rearrangement was used to obtain the hydrindene with the desired trans- fusion. Several additional steps were used to convert this to the originally sought after hydrindenone and then the DA adduct shown. CHOMeOMeOMeOHMeOHLi, NH31 eq. EtOHLi/NH3 wasexpected togive trans-LiAlH4EtAlCl276%1.2.NHOCH3COSHDEAD, PPh3(Mitsunobu)Me1. LiAlH42. mcpba,CH2Cl2-90 °C to rtSCOCH3Me40 - 50 °C[3,3]~sulfenic acidrearrangementSOHOHMe1. 9-BBN2. H2O23. Jones ox.HMe1. CH2=CHMgBr2. H+, !HOMeHCO2MeCHOMeMeHHMeCHOCO2Me5.3:1.3:1 prep hplcChem 242b Chemical Synthesi s Scott Virgil, California Institute of Technology, Jan. 25, 2013 8A. Retigeranic Acid (cont.) As the “real system ” was being stockpiled, a simpler model system served to test out the ketene-olefin cyclization. Heating the acid chloride with Hunig’s base gave a mixture of two cyclobutanones, however neither was the desired poroduct. In addition to the crossed adduct, the incorrect cyclobutanone was obtained resulting from fragmentation of the initially formed crossed adduct. This fragmentation to regenerate a ketene is best understood by hemolytic fragmentation of the acyl bond (~) followed by breaking the dashed bond. The interconversion was reversible at 120 °C and required considerable detective work to elucidate. HHCOCliPr2NEttoluene,120 oCMeMeHMeHOHOMecrossed adductIncorrect cyclobutanoneHC OMeMeMe(vinyl ketene)~ The original plan was modified as shown below affording the cyclobutanone product which was ring expanded to the cyclopentenone, equilibrated and deoxygenated. Dihydroxylation and lead tetraacetate cleavage afforded a ketoaldehyde which was cyclized and oxidized (CHO -> CO2H) to retigeranic acid. MeHHMeCHOCO2MePh3POOOMeHHMeCO2Me1. LiAlH42. o-NO2C6H4SeCN3. [O]OOOMeHHMe3. (COCl)2 benzene, cat. DMF4. Et3N, benzene, !OOOCH21. H+2. NaOHMeHHMeCH2C OMeHTHF, -78 °CHOHMeLiSMeMeSMeHHMeOSMeMeSMeCuOTfHHMeSMeMeO2. NaOMe (base equil.)1. H2, Pd(C)(Kabalka deoxyg.)C=O -> CH21. TsNHNH22.OBHOHMeHMeMeH3. neutral Al2O34Å sieves4. NaClO21. OsO4, py2. Pb(OAc)4Retigeranic