Date of Degree
PhD (Doctor of Philosophy)
Gregory K. Friestad
Chiral 1,5-polyol motifs are found in many biologically active, diverse classes of natural products and pharmaceutical drug candidates. Some notable examples are tetrafibricin (non-peptide fibrinogen receptor antagonist), lydicamycin (antibiotic active against multidrug resistant strains), marinomycin A (antibiotic active against methicillin- and vanomycin-resistant strains, also shown selective cytotoxicity toward melanoma cell lines), muricapentocin (shown cytotoxicity towards various human cancer cell lines including pancreatic carcinoma and colon adenocarcinoma), amphidinol class of compounds (antifungal and hemolytic activity), and sporminarin (antifungal activity against aspergillus flavus). An efficient and cheap synthetic access to these natural compounds and all their diastereomers by a common iterative pathway would further facilitate the biological studies and also simplify the relative or absolute configuration assignment of the remote secondary alcohol stereocenters. There are a few synthetic methodologies available in the literature for the asymmetric synthesis of 1,5-polyols. Cossy's allyltitanation and selective cross- metathesis, Roush's bidirectional double allylboration, Paquette's Julia-Kocienski olefination approach and Oishi and Murata's cross-metathesis are some notable examples. But these examples suffer from limitations like low overall yield, large number of steps from commercially available materials, low yielding regioselective coupling reactions, multiple sequences of protection, oxidation or reduction reactions and ambiguity associated with the configuration of remote polyol stereocenters. In order to overcome these problems we the Friestad's research group, devised a strategically innovative iterative configuration-encoded method based on enantiopure bifunctional sulfone building block and Julia-Kocienski olefination for the asymmetric synthesis of 1,5-polyol stereocenters. The configuration of each hydroxyl group is encoded with in an enantiopure á-silyloxy-ã-sulfononitrile building block prepared by catalytic asymmetric cyanohydrin synthesis. By employing the Hoppe allyl carbamate method, we were able to synthesize the required racemic difunctional sulfone methyl acetal in 41% overall yields in 6 steps starting from Hoppe allyl carbamate. Modified Julia reaction conditions were compatible with the difunctional sulfone methyl acetal and gave high yields and high diastereoselectivities with both aromatic and aliphatic aldehydes. The asymmetric repeating unit, enantiopure difunctional sulfone nitrile, was synthesized in four steps and 88% overall yield starting from inexpensive and commercially available acrolein with 83-86% enantiomeric excess. Both enantiomers of the difunctional sulfone were prepared in equal ease. Recrystallzation from ethyl acetate/petroleum ether improved the enantiomeric excess to >99%. By employing reliable Julia-Kocienski olefination, facile assembly of all stereochemical permutations of any given 1,5-polyol may be readily envisioned, with configurations programmed by selecting the enantiopure building blocks. Starting from (S)-4-(4-methoxybenzyloxy)-2-(tert-butyldimethylsilyloxy)butanal and after two efficient iterative sequences, we were able to prepare the C27-C40 hydroxy fragment tetrafibricin in 7 steps and with 34% overall yield. This fragment synthesis is a testament to the efficiency and effectiveness of our configuration-encoded strategy towards the synthesis of asymmetric 1,5-polyols.
Copyright 2011 Gopeekrishnan Sreenilayam
Sreenilayam, Gopeekrishnan. "Asymmetric 1,5-polyol synthesis: a concise configuration-encoded approach." dissertation, University of Iowa, 2011.