By simply hydrogenating enones in the presence of aldehydes at ambient temperature and pressure, aldol adducts are generated under neutral conditions in the absence of any stoichiometric byproducts. Using cationic rhodium complexes modified by tri(2-furyl)phosphine, highly syn-diastereoselective reductive aldol additions of vinyl ketones are achieved. Finally, using novel monodentate TADDOL-like phosphonite ligands, the first highly diastereo- and enantioselective reductive aldol couplings of vinyl ketones were devised. These studies, along with other works from our laboratory, demonstrate that organometallics arising transiently in the course of catalytic hydrogenation offer byproduct-free alternatives to preformed organometallic reagents employed in classical carbonyl addition processes. Existing methods for enantioselective carbonyl allylation, crotylation and tert-prenylation require stoichiometric generation of pre-metallated nucleophiles, and often employ stoichiometric chiral modifiers. Under the conditions of transfer hydrogenation employing an ortho-cyclometallated iridium C,O-benzoate catalyst, enantioselective carbonyl allylations, crotylations and tert-prenylations are achieved in the absence of stoichiometric metallic reagents or stoichiometric chiral modifiers. Moreover, under transfer hydrogenation conditions, primary alcohols function dually as hydrogen donors and aldehyde precursors, enabling enantioselective carbonyl addition directly from the alcohol oxidation level. / text

Chapter One presents an overview of phosphorus reagents for the carbon homologations of aldehydes and ketones leading to functionalized carbonyl derivatives. Select examples are provided to exemplify the utility of carbon homologation methodology in synthesis and asymmetric organocatalysis and in the total synthesis of natural products. The directing effect of acetals on regioselective ylide formation is explored in Chapter Two. Evidence is presented for ylide formation through a complex induced proximity effect with lithium bases under coordinating conditions. Moreover, four-carbon donors represent a limit for useful directed ylide formation with trialkylphosphine-derived Wittig salts in carbonyl homologation reactions. A facile approach to the synthesis of methyl vinyl ketones (MVKs), using acetonyl tripropylphosphoranes under mild conditions, is reported in Chapter Three. A library of diversely functionalized MVKs was synthesized as a demonstration of the scope and generality of the methodology. The application of MVKs as substrates for organocatalysis and as building blocks for useful polyketide intermediates is briefly highlighted. In Chapter Four, the two-carbon homologation methodology that was presented in the previous chapter is applied to the synthesis of the polyketide olivetol and a series of O-methyl derivatives. Cyclic diketone intermediates were aromatized with catalytic iodine and DMSO as a terminal oxidant. Modification of the solvent system allowed for the selective synthesis of mono- or dimethyl ethers of methyl olivetolate. The selectivity of this aromatization is further explored in the final chapter with more complex substrates. Chapter Five focuses on the synthesis of the meroterpene phytocannabinoids found in Cannabis sativa. A synthetic strategy involving the sequential condensation/[3+3]-annulation of citral with cyclic 1,3-diketones synthesized in the previous chapter. This afforded non-aromatic meroterpenes that were subjected to acid-mediated thermal rearrangement and catalytic oxidative aromatization. Evidence for chemoselectivity of the aromatization methodology was demonstrated and a synthesis of methyl cannabinolate is presented. / Thesis / Doctor of Philosophy (PhD) / Methodologies for the extension of aldehydes to functionalized olefins and their application to the synthesis of cannabinolic acid methyl ester are presented.

The development of the interrupted Nazarov cyclization of allenyl vinyl ketones is presented. The intermediate oxyallyl cation, derived from an allenyl vinyl ketone, may be trapped efficiently by a divergent array of nucleophilic species generating functionalized cyclopent-2-enone products. Allenyl vinyl ketones are also a versatile source of cyclic molecules via a tandem reaction sequence terminated via reaction with acyclic dienes, cyclic dienes, aza-heterocycles, electron-rich alkenes, or styrenes by the formation of an additional ring by a [4 + 3] and/or [3 + 2] cyclization or by the formation of one additional carbon-carbon bond. The bicyclic compounds generated by these processes are densely substituted, and would be difficult to access as succinctly in other ways. The products of these interrupted Nazarov reactions generally reflect excellent regio- and stereoselectivity in the trapping reaction. In some instances, equilibrating conditions were shown to enhance the proportion of one product at the expense of another or to provide a different carbon skeleton. This process appears fairly general, and can be conducted with unsubstituted or alkyl, aromatic, or heteroaromatic allenyl vinyl ketones. The exceptional affinity of allenyl vinyl ketones to undergo interrupted Nazarov reactions is likely a result of the increased longevity of the intermediate oxyallyl cation, due in part to the increased resonance stabilization provided by the allene unit. The high regioselectivity noted in the trapping process was computationally and experimentally confirmed to be a result of a localization of the positive charge in the intermediate oxyallyl cation. The application of this recently developed methodology towards the synthesis of the natural product (+)-roseadione is also described. The tandem Nazarov/[4 + 3] cascade of allenyl vinyl ketones provides a unique manner in which to access the tricyclic core of this cyclooctanoid natural product, a molecule which, to date, has never been synthesized.