New Synthetic Applications of Nitroso Diels-Alder Reactions

NEW SYNTHETIC APPLICATIONS OF NITROSO DIELS-ALDER REACTIONS Abstract by Fangzheng Li The focus of this dissertation is to develop new synthetic applications of nitroso Diels-Alder reactions, which have been powerful synthetic tools for the formation of 1,4-C-O and C-N bonds in a single step. Four projects have been evolved from this main research theme. In Chapter two, efficient and practical chemoenzymatic syntheses of both enantiomerically pure 4-Boc-aminocyclopent-2-ene-1-ols are presented based on an acylnitroso Diels Alder reaction approach. Starting from one enantiomer, total syntheses of (+)-carbocyclic uracil polyoxin C and its Ì_å±-epimer were accomplished in eight steps. The synthesis incorporates a Pd(0)-catalyzed allylic alkylation, a mild reduction of an Ì_å±-nitro ester and a modification of Shaw and WarrenerÌøåÀå_s procedure for uracil formation. Starting from the other enantiomer, the stereoselective total synthesis of a lipophilic antibiotic, (+)-streptazolin is described in Chapter 3. The synthetic sequence highlights an intramolecular aldol condensation strategy to construct the piperidine core and a silicon-tethered ring closing metathesis strategy to install the Z exocyclic ethylidene side chain of streptazolin. The overall yield was 4.8% for a total of 16 steps. Meanwhile, a highly efficient and selective pyridine nitroso DA reaction was used to synthesize novel streptazolin derivatives. In the next Chapter, the stabilized iminonitroso Diels-Alder reaction, particularly the pyridine NDA (nitroso Diels-Alder) reaction, is demonstrated to be a remarkably efficient method for derivatization of complex diene-containing natural products. Natural products, turimycin H3, ergosterol, reductiomycin, colchicine and thebaine were found to react with nitrosopyridines in a highly efficient and completely regio- and stereo-selective fashion. In most cases, NDA cycloadducts were obtained in more than 90% purity without any work-up or purification. Meanwhile, pyridine NDA reactions of piperine, oligomycin A, rifampicin quinone and flavofungin were also investigated. Interestingly, apoptolidin was found to undergo ene reaction instead of DA reaction again in a highly efficient and stereroselctive fashion. Preliminary bioactivity evaluations of cycloadducts are also presented. Finally, efforts toward developing a catalytic enantioselective acylnitroso Diels-Alder reaction by using three approaches are discussed in Chapter 5. Those approaches include a Cu Lewis acid based dual function catalyst system, a gem-C-acetoxynitroso DA reaction as an acyl nitroso DA reaction equivalent and a use of organocatalysts to incorporate chiral elements into the diene part of the acylnitroso DA reaction.