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.

Asymmetric nucleophilic boronate reactions have been developed using organic chiral diols, specifically binaphthols, as catalysts. A highly enantioselective allylboration of acyl cyanides under solvent-free conditions was catalyzed by (S)-Br2BINOL. The reaction proceeds through single exchange of boronate with the chiral catalyst, promoted by tert-butanol. Allylation products were obtained in yields up to 97% and enantioselectivities up to 99:1 er. Syn- and anti-crotylborations of benzoyl cyanide were also performed, and the corresponding a-methyl products were isolated in good yields and moderate to good enantioselectivities, with the E-boronate producing a single diastereomer. This methodology represents a new route to enantioenriched homoallylic cyanohydrins through nucleophilic addition of the allyl group to acyl cyanides. The enantioselective Petasis reaction of glycolaldehyde dimer to synthesize b- amino alcohols was also investigated. With commercially available aldehyde dimer, boronic acids, and amines, electron-rich a-arylglycinols were obtained in up to 92% yield and up to 99.5:0.5 er. Direct inject mass spectrometry studies revealed a single exchange between p-methoxyphenylboronic acid and (S)-Br2BINOL, as well as coordination of the imine intermediate to the catalyst-boronate complex. This reaction was further optimized to include electron-deficient boronic acids. Addition of Lewis acidic triethylborate had a two-fold effect on the reactivity; it facilitated both the exchange of boronic acid with catalyst, and the formation of the imine intermediate. Using chloroform as the solvent, and (S)-Ph2BINOL, halogenated phenylboronic acids participated well in the Petasis reaction. This methodology is the first asymmetric Petasis reaction of glycolaldehyde to produce b-amino alcohols. / 2018-12-06T00:00:00Z

Disclosed herein are comprehensive details of a study on the total chemical synthesis of daphnane diterpene orthoesters (DDOs), a large group of secondary metabolites isolated from the plant families Eurphorbiacaea and Thymelaeaceae which are known to possess a broad spectrum of powerful biological activities. Characterized by a tricyclo[9.3.0.0]tetradecane core ring system with two trans-fused ring junctures, an average of nine oxygen appendages, and an unusual orthoester functionality, DDOs are amongst the most complex and structurally varied diterpene natural products and present a significant challenge towards de novo chemical synthesis. These studies culminated in short (10-12 steps from known starting materials, 16-18 total operations), stereocontrolled syntheses of tricyclic DDO cores containing seven contiguous stereocenters, of which six directly correspond to all known DDOs. Key to their assembly was the development of a concise p-quinol functionalization choreography that enabled rapid access to C-ring stereopolyads from simple precursors. Efforts to apply this strategy to the total synthesis of (±)-resiniferatoxin (RTX) are described in addition to a discussion for future work from this laboratory. / 2019-11-27T00:00:00Z

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