Chapter 1. Introduction Natural product total synthesis has long fulfilled many roles in synthetic organic chemistry, one of the foremost being inspiration of the development of novel methods and strategies to access particular structures. The halogenated natural products represent one class of secondary metabolites that can serve to inspire new chemical methods. Although nature's enzymatic machinery is capable of installing halogen atoms onto organic frameworks efficiently, synthetic chemists often lack these same tools. In particular, the development of halonium-induced polyene cyclization, asymmetric halogenation, and medium-ring haloether formation would facilitate access to hundreds of halogenated natural products, but these reactions have traditionally proven challenging. Chapter 2. The Discovery of BDSB and Initial Investigations into Halonium-Induced Polyene Cyclizations Currently available electrophilic bromination reagents are often not suitable initiators for halonium-induced polyene cyclizations, likely due to competing inter- and intramolecular processes. As such, we explored bromosulfonium salts for this purpose and in doing so developed a novel bromonium reagent (BDSB, bromodiethylsulfonium bromopentachloroantimonate). This easily synthesized and handled reagent proved capable of cyclizing an array of polyene precursors rapidly, in good yield, and with high diastereocontrol. The chlorinated analogue (CDSC) proved somewhat successful for initiating the analogous chloronium-induced polyene cyclizations. Chapter 3. The Total Syntheses of 4-Isocymobarbatol, Peyssonol A, and Peyssonoic Acid A, and Evaluation of Peyssonol A Analogues for Anti-HIV Activity Our novel reagent, BDSB, was applied to the successful total syntheses of three brominated natural products (4-isocymobarbatol, peyssonol A, and peyssonoic acid A). These syntheses were predicated upon bromonium-induced polyene cyclizations of substrates of increasing complexity. The total synthesis of peyssonol A uncovered a structural mischaracterization, one that would require the synthesis of four diastereomeric final products to rectify. Given that the anti-HIV properties of peyssonol A have been documented, we undertook an exploration of the structure-activity relationship of peyssonol A utilizing the many synthetic precursors and analogues at our disposal. These studies indicated that both the aromatic and aliphatic portions of peyssonol A contributed to its observed bioactivity. Chapter 4. Enantioselective Halogenation Chiral variants of BDSB, CDSC, and IDSI (the iodinated analogue) were synthesized from chiral sulfides and applied to halonium-induced polyene cyclizations and other asymmetric halogenation reactions. While no enantioselectivity was observed for cyclization reactions, moderate e.e. values (up to 63%) were observed for both asymmetric dichlorination and asymmetric iodohydroxylation of alkenes. Additionally, we developed an effective two-step surrogate for asymmetric halonium-induced polyene cyclizations that proved capable of affording the desired cyclic products in good yield and with moderate enantiomeric excess (up to 81%). Chapter 5. Bromonium-Induced Ring Expansion for Accessing 8-Membered Bromoethers and Application of this Reaction to the Formal Total Synthesis of (E)- and (Z)-Pinnatifidenyne A fortuitous rearrangement led to the development of a novel method for bromonium-induced ring expansion, one that transforms tetrahydrofurans into brominated oxocanes (8-membered ring ethers). This BDSB-mediated process is high yielding and both regio- and diastereoselective, making it ideal for application to the synthesis of lauroxocanes: a large family of natural products built around an 8-membered ring bromoether core. This synthetic utility was demonstrated during the application of this strategy to the formal total synthesis of (E)- and (Z)-pinnatifidenyne; the completed route represents the most expedient total synthesis (of more than two dozen) of any lauroxocane natural product.

This dissertation presents new approaches towards the asymmetric allylation of the imino and formyl functionalities by using strained silanes as Lewis acids. Here in the Laboratory of Professor James L. Leighton, chiral homoallylic alcohols and amines are considered privileged products given their important role as building blocks in natural product synthesis. The new approaches reported herein are focused on expanding the scope of imine allylation reactions and gaining full synthetic utility of the corresponding homoallylic amine products by means of economic and user-friendly protocols. In addition, the discovery of a novel catalytic and mild approach to the asymmetric allylation of aldehydes will be the focus of discussion at the end of this works. Chapter 1 will give a brief introduction about general concepts in asymmetric allylation of aldehydes and imines as well as in applications of strained silane Lewis acids in these reactions. Chapter 2 will discuss the development of a novel asymmetric allylation method for N-heteroaryl hydrazones and the N-heteroaryl cleavage from the product to unmask the corresponding free amines. Chapter 3 will carry on these studies into different imine activating groups in search for a more general and user-friendly approach towards both allylation and cleavage protocols. Finally, Chapter 3 will discuss the development of a new methodology in which chiral bismuth (III) complexes can catalyze the asymmetric allylation of aldehydes with achiral strained allylsilanes.

The mechanism of the reaction of benzoic acid with cyclohexyl isonitrile leading to N-cyclohexyl-N-formylbenzamide has been studied quantitatively. The reaction is first order in each reagent and has the activation parameters delta H = 16.9(5) kcal mol-1 and delta S = 26(1) cal mol-1K-1 in toluene. There is a dramatic solvent effect: hydrogen bond accepting solvents retard the rate of the reaction by deactivation of the carboxylic acid. A plot of log(rate constant) vs beta (hydrogen bond acceptor basicity of the solvent) is a straight line with a substantial negative slope, implying that the reaction is retarded by hydrogen bonding to the solvent but not affected significantly by other solvent properties. It is speculated that the related Passerini reaction is affected in a similar matter, although quantitative data for this reaction are sparse in the literature. Variation of concentrations allows control over the product distribution in the reaction of carboxylic acids and isonitriles. With low concentrations of the acid, the N-formylamide is obtained in good yield because low concentrations suppress the nucleophilic interception of the intermediate formimidate carboxylate mixed anhydrides (FCMAs), which leads to the undesired anhydride and formamide. With arylacetic acids, N-formylamides (the products of a unimolecular process) are obtained with low concentrations of the reactants and high reaction temperatures. At low temperatures and high concentrations, captodative alkenes (the products of a bimolecular process) are obtained instead. In contrast to the high temperatures needed for RNC + RCO2H -- N-formylamide, thioacids react at ambient temperature with isonitriles to give N-thioformylamides. Transient intermediates can be observed during the reaction. Two thio-analogues of the FCMA are suggested by NMR spectral evidence. However, the structure of a third intermediate (which forms more slowly than the other two) remains unknown. Several mechanisms for this reaction are kinetically indistinguishable because the three intermediates interchange more rapidly than the product-forming step (which is irreversible). The solvent effect observed with carboxylic acids is not observed with thioacids, presumably because of the weaker hydrogen bond donating strength of the S-H in the thioacid. The mechanism and temperature dependence of the hydride ring opening of a phenyl azetidinium cation has been studied. The reaction with CpRu(dppm)H (dppm = bis(diphenylphosphino)methane) is first order in both the hydride and the azetidinium. Extrapolation of the rate constant to -64 °C (the temperature at which an analogous aziridinium ring opening was previously examined) shows that aziridiniums undergo hydride ring opening 10^6 - 10^7 times faster. This result implies that aziridiniums are much more electrophilic than azetidiniums, although these two rings have a strain energy difference of only 2.1 kcal mol-1. Nucleophilic attack on azetidiniums generally occurs at the less substituted position in accords with an SN2 mechanism. However, with a phenyl substituent, hydride transfer by half-sandwich ruthenium complexes occurs preferentially at the more substituted position (ca. 5:1) giving the straight-chain amine. More reactive hydrides (borohydrides, LiAlH4) erode this preference. As is the case with electrophilicity, there is a significant difference in the reduction potential between a phenyl aziridinium (Epc = -0.93 V vs FcH+/FcH) and a phenyl azetidinium (Epc = -1.43 V). While the phenyl aziridinium has been previously shown to undergo single electron reduction by Cp*Ru(dppf)H (E1/2 = -0.63 V, dppf = 1,1'-bis(diphenylphosphino)ferrocene), the phenyl azetidinium failed to react with the same reagent. The azetidinium did react with decamethylcobaltocene (E1/2 = -1.94 V) giving the expected straight-chain ring-opened amine among a mixture of products; none of the branched amine was detected.

The projects discussed in this thesis cover the total syntheses of molecules in two different areas of natural products chemistry: the polyphenolic compounds dalesconols A and B and the coccinellid alkaloids psylloborine A, isopsylloborine A, and related monomeric structures. While polyphenols and alkaloids generally have little in common, the studies detailed herein have employed cascade-based strategies to access the rigid, strained cores contained within all selected targets. The ability of cascade chemistry to rapidly form high levels of molecular complexity and introduce elements of considerable difficulty, such as rigid fused-ring systems and quaternary chiral centers, has been applied to the chosen molecules. The results of these studies have demonstrated the power of cascade-based core formation to rapidly assemble complex, polycyclic architectures in two different classes of natural products.

The construction of polypropionate stereotriads in the synthesis of many non-aromatic polyketide natural products has typically been achieved through the "Roche ester" approach. This process starts with one of the stereocenters purchased as the Roche ester, followed by multiple redox and protecting group manipulations and only one carbon-carbon bond-forming aldol or crotylation reaction to attain the other two stereocenters of the stereotriad. Motivated by a desire for a more direct and rapid synthesis of these stereotriad constructs, we have built upon previous group methodology to develop a new approach utilizing a three step sequence of alkyne silylformylation-crotylation-Tamao oxidation. This strategy was first utilized in the synthesis of the C1-C9 fragment of the epothilones, and then this route applied to the synthesis of a C6 methyl-modified analog of epothilone B. We have also pursued the synthesis of versatile polypropionate building blocks as a way of generalizing our new approach.

A major focus of the Leighton group is on the development of chemistry to aid in the efficient and scalable synthesis of polyketides. Over the past several years, our group has been interested in utilizing strained silanes to rapidly access the structural motifs commonly found in polyketides. Notably, our EZ-CrotylMix methodology allows for the crotylation of deactivated and sterically hindered aldehydes that popular methods, such as the Brown crotylation, fail to achieve. In order to improve the practicality of our crotylation methodology, we have developed a new, more powerfully activating diamine ligand scaffold that provides access to highly active allyl- and crotyl-silanes. These silanes can be generated in situ, precluding the need for a laborious isolation of the moisture sensitive crotylsilane reagents that is necessary for our previously reported methodology. The group’s crotylation methodology has proved useful in our current efforts toward the total synthesis of spongistatin 1 and its analogs. Work on the synthesis of an analog of spongistatin 1, specifically on the completion of the northern ABCD hemisphere, will also be discussed.

This thesis employs cyclopropenium ions as central design elements in a novel catalytic nucleophilic substitution of alcohols and in the preparation and study of a number of extremely strong organic bases. The first chapter describes the use of diphenylcyclopropenone as a catalyst for the substitution of a range of alcohols with sulfonic acids that proceeds with inversion of stereochemistry. The other reagents needed are methanesulfonic anhydride and a simple amine base. The process relies on the concept of cyclopropenium activation developed by the Lambert group. The catalyst is the only material not removed from the product by aqueous workup, and a protocol for its conversion into a water-soluble derivative is outlined. A stoichiometric procedure for more sterically demanding substrates is also detailed. The second chapter outlines the preparation of six new classes of higher-order superbases by novel and robust methods. Five members incorporate the cyclopropenimine function, a superbase recently introduced by the Lambert group. Systematic structure-basicity relationships reveal fundamental electronic properties of guanidines, phosphazenes, and cyclopropenimines. Molecular structures show a number of organizational elements that could assist in the design of next-generation higher-order superbases. Predictive effects of structure on both stability and selectivity between Brønsted basic and nucleophilic behavior are explained. Finally, the first direct neutral Brønsted base catalysis of the relatively non-acidic α-aryl ester pronucleophile class is described, alluding to the increased number of useful and widely available types of starting materials that can be engaged directly by this reaction mode.

Natural products featuring bridged seven- and eight-membered ring systems are relatively rare in nature; however, due to their interesting biological activity, they are commonly found in pharmaceuticals. Despite their importance, no general method to access bicyclic ring systems exists, thus the de novo synthesis of these complex molecules is often a significant challenge. It was with this in mind that we launched our efforts towards the first total synthesis of cyclocitrinol, a unique steroid with a fused ring system possessing a rare bicyclo[4.4.1]undec-7,10-diene A/B ring with a bridgehead double bond. Using knowledge gained from previous model studies of a strain-accelerated tandem Ireland-Claisen/Cope rearrangement to assemble the ABC tricyclic core, two approaches towards the completion of the molecule were explored: 1) an Ireland-Claisen/Cope/Claisen rearrangement followed by RCM and 2) a 1,3-allylic transposition/RCM. Of these approaches, the later, led to the completion of the ABCD tetracyclic core and installation of the fully elaborated C17 side-chain.

Source: Dissertation Abstracts International, Volume: 40-02, Section: B, page: 0755. / Thesis (Ph.D.)--The Florida State University, 1978.

Source: Dissertation Abstracts International, Volume: 37-06, Section: B, page: 2849. / Thesis (Ph.D.)--The Florida State University, 1976.