The development of palladium-, zinc-, and magnesium-catalyzed asymmetric transformations [electronic resource] : applications towards the synthesis of peloruside A, vicinal diols, [Beta]--amino acids and polyamine architectures

Natural products have laid the foundation for the discovery and development of medicines for centuries. Early Ayurvedic medicine involved the use of cocktails of several naturally occurring molecules for the treatment of common illnesses. Today natural products remain the mainstay of therapeutic intervention in the treatment of several debilitating diseases. Compounds accessed from natural sources have also been the source of inspiration in the discovery of several non-natural pharmaceuticals. The diverse and complex structural features of natural products and their limited availability, however, presents a significant roadblock in accessing these molecules on scales where they can have the greatest impact. Currently, the de novo synthesis of natural products is challenging, expensive, and low yielding. To address this, chemists strive to access structures with the greatest efficiency and practicality. Despite decades of efforts we are still faced with the challenge of synthetic efficiency. Herein, the cytotoxic agent Peloruside A, the antibiotic tobramycin, the multi-drug resistance reversal agent N-acetyl-ardeemin have inspired the discovery and development of methods to streamline the synthesis of these molecules and their analogs. Detailed is an account of the efforts dedicated towards accessing these natural products in high efficiency and in enantiomerically enriched form using novel disconnections which have led to the development of several new methods. Peloruside A has inspired the development of the asymmetric desymmetrization of 2-alkyl-1,3-propanediols. This method was found to be highly general and rapidly afforded several chiral building blocks. One of these is applied towards the synthesis of an important fragment in this natural product. Peloruside A also highlighted the deficiencies in using esters in direct asymmetric aldol reactions. The development of a diazoester aldol using of commercially available ethyl diazoacetate and a range of aldehydes is a viable alternative to the use of chiral pool-based auxiliaries. To minimize the use of protecting groups the use of an alkyne as a masked [Alpha]-hydroxyketone has been explored in the formation of the pyran ring in peloruside A via a 6-endo-dig cyclization. The development of the asymmetric diazoester aldol reaction led to the synthesis of vicinal diols bearing a tertiary alcohol. The oxidation of [Beta]-hydroxy-[Alpha]-diazoesters affords [Beta]-hydroxy-[Alpha]-ketoesters that undergo alkyl transfer with minimal erosion in chirality and in high diastereocontrol with alkyl, allyl, and propargyl nucleophiles. One of the products from this method is present in azithromycin and related natural products. Furthermore, the asymmetric diazoester aldol reaction enables the exploration of a direct stereospecific C--O to C--N exchange reaction unique to diazoesters towards the synthesis of [Beta]-amido-[Alpha]-diazoesters. The products from this reaction can be transformed into [Beta]-amido-[Alpha]-hydroxyesters and undergo a rather unusual 1,3-C--H insertion reaction to afford aminocyclopropanes. The use of nitrogen nucleophiles in Pd-catalyzed asymmetric allylic alkylations enabled the synthesis of two diastereoisomers of 2-deoxystreptamine. This motif is present in all clinically relevant aminoglycoside antibiotics; however, the biological effects of aminoglycosides that are diastereomeric at the 2-deoxystreptamine core are unexplored. A synthetic sequence that furnishes scaffolds that have the potential of being transformed into novel aminoglycosides is presented. This project highlighted the challenge of generating diamines. Recognizing this, a collaboration with the Du Bois group at Stanford University was initiated where the use of a bifunctional nucleophile in sequential palladium- and rhodium-catalyzed processes afforded several nitrogenated architectures that cannot be readily accessed by pre-existing methods and can serve as building blocks in drug discovery. One interesting facet of this work was the use of [Pi]-prenylpalladium species in directing attack of a nitrogen nucleophile at the more substituted carbon of a prenyl electrophile. The reverse prenylated hexahydropyrrolo[2,3-b]indoline substructure is present in several natural products such as N-acetyl-ardeemin. One reason for the challenge associated in employing [Pi]-prenylpalladium complexes to access these natural products lies in the concomitant control of the regio- and enantioselectivity with sterically more demanding carbon based nucleophiles. Although usually Pd-catalyzed allylic alkylations result in attack at the less hindered terminus of a [Pi]-allyl, described are conditions where the regioselectivity can be controlled in accessing either linear or branched prenylated products in high optical purities. In one example the enantio-, regio- and diastereoselective synthesis of vicinal quaternary stereogenic centers has been achieved using palladium catalyzed allylic alkylations.

Keywords: Chemistry
Advisor: Trost Barry M. primary advisor. Thesis advisor
Du Bois Justin advisor. Thesis advisor
Kanan Matthew William