We report a novel fragmentation and functionalization method using a cyclic iminyl radical. Formation of this radical occurs by microwave heating under mild conditions and short reaction times. The reaction avoids the use of explosive or toxic radical initiators and propagating agents. This reaction is versatile, with the ability to install two functional groups that are ultimately derived from a ketone in the substrate precursor. A variety of radical traps capable of forming both carbon-carbon bonds and carbon-heteroatom bonds have been tested, and the products are obtained in good yields. We demonstrate the power of this reaction by functionalizing complex natural products.

Two different research projects are described in this dissertation. The first one focuses on microwave-promoted iminyl radical cyclization for the formation of azaheterocycles which are embedded within numerous pharmaceuticals and biologically active natural products (such as clindamycin, eletriptan, moxiflaxin, etc.). We are quite interested in this project because of the significance of nitrogen-containing heterocycles as pharmaceuticals and organocatalysts combined with the need for safe, simple, and economical means of constructing them. We have successfully developed an efficient one-step synthesis of 2-acylpyrroles and diastereoselective dihydropyrroles from readily available oxime ether substrates. This remarkably efficient and environmentally friendly methodology should be useful for rapid and easy preparation of potent drugs containing pyrrolidine ring systems. The second project focuses on the total synthesis of yaku'amide A. The natural compound, isolated from a marine sponge in 2010, is a medium-sized peptide that contains bulky dehydroamino acids. It has an excellent IC50 value (14 ng/mL) against leukemia cells, making it a promising anticancer agent. Because of the unique anticancer profile, potent bioactivity, and limited supply, the natural product was attractive to us for an efficient synthesis and mechanistic investigation. We have devised more efficient strategies compared to Inoue's methods for the synthesis of bulky ∆AAs and their incorporation into peptides, which are innovative and will allow us to synthesize yaku'amide A rapidly and conveniently. A one-pot sequence consisting Martin sulfurane mediated anti dehydration, azide reduction, and O→N acyl transfer was developed for the construction of E- and Z-dehydroisoleucine-containing peptides. We also developed a three-step synthesis of N-terminal acyl group involving a one-pot indium-catalyzed cross-Claisen condensation/reduction from a known compound. The most hindered coupling reaction of pentapeptide acid and nanapeptide amine in the late stage is accomplished. Our total synthesis of yaku'amide A can be completed in 19 longest linear steps and 66 total steps. Further identification of yaku'amide A for elucidation of its biological target and mode of action will be explored, which will open up new avenues in the fight against cancer.

The first project in this dissertation describes the use of microwave-promoted iminyl radical fragmentations to form functionalized nitriles. Nitrogen-centered radical chemistry is a useful tool to construct valuable C-N bonds commonly found in pharmaceuticals and biologically active molecules. Classically, these reactions require the use of toxic initiators and propagators. Iminyl radical chemistry has been gaining momentum as a means of avoiding these harsh conditions. This project utilizes the fragmentation of cyclic iminyl radicals via irradiation of O-phenyl oxime ethers to produce a synthetically useful nitrile tethered to an alkyl radical in the absence of metal catalysts and redox chemistry. The efficacy of this synthetic method was demonstrated by the diverse functionalization of estrone. We believe this useful chemistry can be a powerful tool when applied to both early and late-stage synthetic endeavors. The latter half of this dissertation focuses on the total synthesis of yaku'amide A, a natural product isolated from a marine sponge. This peptide contains potent anticancer activity and exhibits a novel, unique mode of action. Due to its scarcity in nature, comprehensive biological studies have remained elusive. The structure of yaku'amide A contains complex, unsymmetrical bulky dehydroamino acids such as E- and Z- dehydroisoleucine which pose a synthetic challenge. Despite the efficient strategy developed in our lab, the synthesis remains lengthy. Simpler symmetrical dehydroamino acids dehydrovaline and dehydroethylnorvaline were substituted in place to prepare two analogues of yaku'amide A that closely resemble the conformation of the natural peptide. Activity profile of the simplified analogues showed comparable potency to that of yaku'amide A.

Two classes of C5 azido-modified pyrimidine nucleosides were synthesized and explored as radiosensitizers. The 5-azidomethyl-2'-deoxyuridine (AmdU) was prepared from thymidine and converted to its cytosine counterpart (AmdC). The 5-(1-azidovinyl) modified 2'-deoxyuridine (AvdU) and 2'-deoxycytidine (AvdC) were prepared employing regioselective Ag-catalyzed hydroazidation of 5-ethynyl pyrimidine substrates with TMSN3. AmdU and AmdC were converted to 5'-triphosphates AmdUTP and AmdCTP, and incorporated into DNA-fragments via polymerase-catalyzed reaction during DNA replication and base excision repair. Radiation-mediated prehydrated electrons formed in homogeneous aqueous glassy (7.5 M LiCl) systems in the absence of oxygen at 77 K led to site-specific formation of π-type aminyl radicals (RNH•) from AmdU, AmdC, AvdU, and AvdC. The ESR spectral studies and DFT calculations showed RNH• undergo facile conversion to thermodynamically more stable σ-type iminyl radicals, R=N•. For AmdU, conversion of RNH• to R=N• was bimolecular involving α-azidoalkyl radical as intermediate; however, for AvdU, RNH• tautomerized to R=N•. Our work provides the first evidence for the formation of RNH• attached to C5 position of azidopyrimidine nucleoside and its facile conversion to R=N• under reductive environment. These aminyl and iminyl radicals can generate DNA damage via oxidative pathways. The azido-nucleosides were successfully applied as radiosensitizers in EMT6 cancer cells in both hypoxic and normoxic conditions. To explore the generation and reactivity of 2'‑deoxyguanosin-N2-yl radical (dG(N2-H)•) postulated to generate from guanine moiety towards •OH, 2-azido-2'-deoxyinosine (2-N3dI) was prepared by conversion of 2-amino group in protected dG into 2-azido via diazotization with tert-butyl nitrite followed by displacement with azide and deprotection. The investigation of dG(N2-H)• generated from 2-N3dI and its subsequent reactions using ESR will be discussed. Cycloaddition between 5-ethynylpyrimidine or 8-ethynylpurine nucleosides and TMSN3 in the presence of Ag2CO3, CuI, or CuSO4/sodium ascorbate provided N-unsubstituted 1,2,3-triazol-4-yl analogues of the parental DNA bases (i.e. 5-TrzdU, 5‑TrzdC, 8-TrzdA, and 8-TrzdG). These novel triazolyl nucleosides showed excellent fluorescent properties: 8-TrzdA exhibits the highest quantum yield (ΦF) of 44% while 8‑TrzdG had ΦF of 9%. The 5-TrzdU and 5-TrzdC showed a large Stokes shift of ~110 nm. The application of these fluorescent nucleosides to cell imaging and DNA modifications will also be discussed.

The first project in this dissertation endeavors to outline the total synthesis of yaku'amide A and its analogs. Yaku'amide A is a natural product comprised of dehydroamino acids, including E-dehydro isoleucine, and unprecedented Z-dehydro isoleucine. These amino acids present a significant challenge to their synthesis owing to their unsymmetrical nature. To simplify the synthesis process, we synthesized analogs by substituting the E and Z dehydroamino acids with symmetrical subunits. This substitution facilitated the synthesis process and enabled us to obtain a similar three-dimensional structure to that of the natural product. Furthermore, biological testing of the simplified analogs revealed potency similar to yaku'amide A. The second part of this project describes the synthesis of the bicycle core of virosinine A, commencing with an enantioselective Evans glycolate aldol reaction. Following a series of transformations, an oxime phenyl ether is generated, which, upon microwave irradiation, triggers an iminyl radical cascade reaction. The iminium formed in the microwave reactor is reduced with red-Al, obtaining the desired diastereomer.