Transannular Diels-Alder/Intramolecular Aldol Tandem Reaction as a Stereocontrolled Route to (+)-Aphidicolin and its Isosteric C8-Epimer

Article abstract of DOI:10.1021/jo00129a021

The trans,syn,cis A.B.C.<6.6.7>tricyclic subunit of aphidicolin could be derived from the transannular Diels-Alder (TADA) reaction of a trans,cic,cis (TCC) cyclopentadecatriene.On the other hand, a trans,trans,cis (TTC) isomeric cyclopentadecatriene could lead to the trans,syn,trans tricyclic skeleton of aphidicolin's C8-epimer.Interestingly, semiempirical calculations have shown the latter to be isosteric with aphidicolin in respect to the four hydroxyl groups.The required TCC and TTC 15-membered macrocyclic trienes 46 and 59 were synthesized using modern methods of acyclic stereoselection such as an organocopper-based difunctionalization reaction, Evans' asymmetric aldol methodology and Wittig-Horner-Wadsworth reactions.At the end, an effecient macrocyclization protocol served in achieving the synthesis of the desired optically active precursors 46 and 59.Whereas TCC substrate 46 failed to realize a TADA cycloaddition for steric and conformational reasons, TTC cyclopentadecatrienal 59 led to a stereospecific TADA/aldol tandem reaction.In the first report example of such a transformation, macrocycle 59 was thermolyzed (toluene, sealed tube, 210 deg C, 18 h) in a single operation into tetracyclic product 61 containing six new stereogenic centres.Mechanistic considerations of this impressive conversion along with transition-state modeling are also presented.Further transformations of compound 61 culminating in stereospecific functionalization at C16 were performed by making use of an hydroxyl-directed epoxidation reaction leading to the advanced intermediate 67.Thus, this exploratory work demonstrates the value of a TADA/aldol route for the synthesis of the titled compounds and analogs thereof.