Redox-triggered carbonyl addition via transfer hydrogenation, which enables direct primary alcohol C-H functionalization to form C-C bond, avoids usage of premetalated reagents or discrete alcohol to aldehyde redox reactions. Moreover, step-economy could be greatly improved by site-selective transformations of polyfunctional molecules due to bypassing the need to install and remove protecting groups. However, the redox site-selective transformations still pose a significant challenge in the area of synthetic organic chemistry. Efforts have been focused on the development of iridium catalyzed transfer hydrogenative coupling reactions of primary alcohols with different allyl donors through carbonyl addition in a site-selective manner as well as ruthenium catalyzed regioselective hydrohydroxyalkylation of primary alcohols with a basic feedstock-styrene. Additionally, studies towards the total synthesis of type I polyketide natural product (+)-SCH 351448 in the most concise route is presented.

A central tenant of organic synthesis is the construction of carbon-carbon bonds. One of the traditional methods for carrying out such transformations is that of carbonyl addition. Unfortunately, traditional carbonyl addition chemistry suffers various drawbacks: preactivation, moisture sensitivity, and the generation of stoichiometric organometallic waste. The research presented in this dissertation focuses on the development of methods that make use of nucleophile-electrophile pairs generated in situ via transfer hydrogenation, which allow the formation of carbonyl or imine addition products from the alcohol or amine oxidation level; streamlining the construction of complex molecules from simple, readily available starting materials. Additionally, studies toward the total synthesis of the fibrinogen receptor inhibitor tetrafibricin, utilizing the methods developed in catalytic carbon-carbon bond formation through the addition, transfer or removal of hydrogen, are presented.

Carbon-carbon bond forming reactions are fundamental transformations for constructing structurally complex organic building blocks, especially in the realm of natural products synthesis. Classical protocols for forming a C-C bond typically require the use of stoichiometrically preformed organometallic reagents, constituting a major drawback for organic synthesis on process scale. Since the emergence of transition metal catalysis in hydrogenation and hydrogenative C-C coupling reactions, atom and step economy have become important considerations in the development of sustainable methods. In the Krische laboratory, our goal is to utilize abundant, renewable feedstocks, so that the reactions can proceed in an efficient and atom-economical manner. Our research focuses on developing new C-C bond forming protocols that transcend the use of stoichiometric, preformed organometallic reagents, in which [pi]-unsaturates can be employed as surrogates to discrete premetallated reagents. Under transition metal catalyzed transfer hydrogenation conditions, alcohols can engage in C-C coupling, avoiding unnecessary redox manipulations prior to carbonyl addition. Stereoselective variants of these reactions are also under extensive investigation to effect stereo-induction by way of chiral motifs found in ligands and counterions. The research presented in this dissertation represents the development of a new class of C-C bond forming transformations useful for constructing synthetic challenging molecules. Development of transfer hydrogenative C-C bond forming reactions in the form of carbonyl additions such as carbonyl allylation, carbonyl propargylation, carbonyl vinylation etc. are discussed in detail. Additionally, these methods avoid the use of stoichiometric chiral allenylmetal, propargylmetal or vinylmetal reagents, respectively, accessing diastereo- and enantioenriched products of carbonyl additions in the absence of stoichiometric organometallic byproducts. By exploiting the atom-economical transfer hydrogenative carbonyl addition protocols using ruthenium and iridium, preparations of important structural motifs that are abundant in natural products, such as allylic alcohols, homoallylic alcohols and homopropargylic alcohols, become more feasible and accessible.

Since C-C bonds form the backbone of every organic molecule and reside at the heart of chemical science, the development of new efficient methods for promoting C-C bond formation is of great significance. Inspired and expanded from traditional Grignard reactions, the work presented in this dissertation focuses on metal catalyzed neutral redox-triggered carbonyl addition via transfer hydrogenation. Advancing the native reducing capability of alcohols, employment of catalytic transition metals enables the formation of nucleophile-electrophile pairs in situ, en route to the products of formal alcohol C-H functionalization. These redox-triggered reactions circumvent the stoichiometric metallated byproduct waste and streamline the construction of complex molecules from simple and/or readily available feedstocks. The research reported herein discloses new developed methodologies of ruthenium and iridium catalyzed coupling reactions of primary and secondary alcohols with various pi-unsaturates. These studies contribute to the growing body of redox-triggered alcohol C-C couplings - new carbonyl addition chemistry that extends beyond the use of premetalated reagents.

Carbonyl addition is one of the fundamental reactions forming C–C bonds in organic chemistry to construct structurally complex organic molecules, in particular natural products, from small molecules. For this useful carbonyl addition, transition metal catalyzed redox-triggered C–C bond forming reactions of alcohols have been developed via transfer hydrogenation. Combined redox events are more efficient in terms of step- and atom-economy by delivering nucleophile-electrophile pairs in situ from [pi]-unsaturates and alcohols, respectively. Furthermore, transition metal catalyzed redox-triggered C–C couplings bypass the need of stoichiometric (organo)metallic reagents. This dissertation shows the development of new methodologies for this goal including prenylation, vinylation, alkylation and allylation using various ruthenium, osmium and iridium catalysts.