Synthesis Of Aza Spirocyclic Dienones And Their Application Toward Natural Product Synthesis And Synthesis And Evaluation Of Anticancer Tetracyclic Indole Containing Compounds
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Synthesis of Aza-spirocyclic Dienones and Their Application Toward Natural Product Synthesis and Synthesis and Evaluation of Anticancer Tetracyclic Indole Containing Compounds
A novel route to access the aza-spirocyclic cross-conjugated dienone motif was developed utilizing an intramolecular phenolic C-alkylation and Suzuki coupling to form the key quaternary carbon center. A chemoselective addition of crotyl silane to the azaspirocyclic dienone motif was developed in an effort to synthesize the spirobicyclononane core of (±)-aspernomine and (±) sespenine. The structure-activity-relationship of anticancer tetracyclic indole containing compounds was developed via the synthesis and biological evaluation of 48 novel derivatives. Additionally, tool compounds containing a biotin and photoaffinity crosslinker were synthesized for use in future target identification studies.
Design and Synthesis of Bioactive Macrocyclic Natural Products
Chapter 1 discusses the background of peptides and their potential as therapeutics; specifically as anti-cancer and antibacterial agents. The synthesis of linear peptides via solution and solid-phase is discussed as well as macrocyclization strategies. Sansalvamide A, a macrocyclic depsipeptide, exhibits micromolar cytotoxicity activity against multiple cancer cell lines. Chapter 2 focuses on the synthesis and structure-activity relationship of Sansalvamide A derivatives. Some of the structural features explored in the SAR include: D-amino acids, N-methyl amino acids, polar amino acids and heterocyclic moieties. This chapter includes a discussion of the synthesis for seven SanA derivatives and structure-activity relationship conclusions drawn from biological testing of these compounds. Chapter 3 discusses the design, synthesis and evaluation of histone deacetylase inhibitors. More than half of all human cancers have non-functioning or mutated genes that are the result of overexpression of histone deacetylases; thus, the development of histone deacetylase inhibitors is critical for combating cancers. Chapter 3 describes the synthesis of six histone deacetylase inhibitors that I contributed to a library of 17 derivatives based on two macrocyclic tetrapeptide natural products: FR235222 and apicidin. Upon biological evaluation of these histone deacetylase inhibitors, a discussion of the structure-activity relationship is presented. Chapter 4 describes the total synthesis of Sanguinamide B. This natural product contains two thiazoles and one oxazole, and is a modified octapeptide macrocycle; unlike other natural products isolated from this sponge, Sanguinamide B contains two proline residues, where these two residues are expected to control the conformation of the macrocycle. The potent cytotoxic and antibiotic properties of other macrolides isolated from the same nudibranch species, and the small microgram quantities of the compound that are available from the natural source, make this natural product very attractive to synthesize. The synthetic strategy to assemble this natural product and conformation of its structure is described in Chapter 4; as well as a discussion of Sanguinamide B's thermodynamic stability and biological activity.
Development of Novel Methods and Applications in Total Synthesis of Natural Products
The olefin cross metathesis reaction has been sequenced with four common organic transformations in a one-pot manner to rapidly access useful building blocks. Those reactions are: (1) phosphorus-based olefination (e.g., Wittig and Horner- Wadsworth-Emmons); (2) hydride reduction; (3) Evans propionate aldol reaction; and (4) Brown allyl- and Roush crotylboration. The products of these reactions include stereodefined 2,4-dienoates, trans allylic alcohols, syn-propionate aldols and chiral non- racemic homoallylic alcohols, respectively, which can be carried further in the context of chemical synthesis. Two approaches toward the total synthesis of cytotoxic polyketide natural product (+)-crocacin C have been accomplished. The first-generation approach used a Crimmins aldol reaction and reagent-controlled double asymmetric crotylboration (Brown and Roush) reaction, which was not selective. The first-generation approach was replaced altogether with a second that afforded (+)-crocacin C in 10 steps from commercially available Evans' chiral propionimide (5% overall yield). The key reactions in the second-generation approach included an Evans dipropionamide aldol reaction, 1,3-anti reduction and a vinylogous Horner-Wadsworth- Emmons olefination. No protecting groups were utilized in the total synthesis of (+)- crocacin C. A novel method to access the ABCE tetracyclic framework of the Strychnos alkaloids has been developed. Five different strategies were utilized toward this goal, out of which the first four were unsuccessful. The fifth-generation strategy featured a novel sequential one-pot bis-cyclization method. Specifically, the AgOTf-mediated spirocyclization of an appropriately functionalized indole 3-carbinamide afforded a stable spiroindolenine intermediate; subsequent addition of DBU to the reaction mixture effected an unprecedented intramolecular aza-Baylis-Hillman reaction, delivering tetracyclic product in 70% isolated yield. The bis-cyclization was showcased in concise racemic total syntheses of akuammicine and strychnine in six and thirteen operations, respectively. Key steps include (1) the vinylogous Mannich reaction; (2) our sequential one-pot spirocyclization/intramolecular aza-Baylis-Hillman reaction; and (3) a Heck cyclization. The synthesis of strychnine proceeded via the Wieland-Gumlich aldehyde. We have also utilized our method to prepare other biologically active Strychnos alkaloids (-)- akuammicine, (-)-leuconicines A and B, (-)-norfluorocurarine, (-)-dehydrotubifoline, (-)- dihydroakuammicine, (-)-tubifoline and (-)-valparicine in a concise, asymmetric manner.