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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 vital to the synthesis of natural products and pharmaceuticals. In 2003, the 200 best selling prescription drugs reported in Med Ad News are all organic compounds. Synthesizing these compounds involves many carbon-carbon bond forming processes, which are not trivial and typically generate large amounts of waste byproducts. Thus, development of an atom economical and environmentally benign carbon-carbon bond forming methodology is highly desirable. Hydrogenation is one of the most powerful catalytic reactions and has been utilized extensively in industry. Although carbon-carbon bond forming reactions under hydrogenation conditions, such as, alkene hydroformylation and the Fischer-Tropsch reaction are known, they are limited to the coupling of unsaturated hydrocarbons to carbon monoxide. Recently, a breakthrough was made by the Krische group, who demonstrated that catalytic hydrogenative C-C bond forming reactions can be extended to the coupling partners other than carbon monoxide. This discovery has led to the development of a new class of carbon-carbon bond forming reactions. Herein, an overview of transition metal-catalyzed reductive couplings of [pi]-unsaturated systems employing various external reductants is summarized in Chapter 1. Chapters 2-4 describe a series of rhodium- and iridium-catalyzed asymmetric hydrogenative couplings of various alkynes to a wide range of imines and carbonyl compounds. These byproduct-free transformations provide a variety of optically enriched allylic amines and allylic alcohols, which are found in numerous natural products, and are used as versatile precursors for the synthesis of many biologically active compounds. Transfer hydrogenation represents another important class of reactions in organic chemistry. This process employs hydrogen sources other than gaseous dihydrogen, such as isopropanol. The Krische group succeeded in developing a new family of transfer hydrogenative carbon-carbon bond formation reactions. Chapter 5 presents two novel ruthenium- and iridium-catalyzed transfer hydrogenative carbonyl allylation reactions. The catalytic system employing iridium complexes enables highly enantioselective carbonyl allylation from both the alcohol and aldehyde oxidation level. These systems define a departure from the use of preformed organometallic reagents in carbonyl additions that transcends the boundaries of oxidation level.
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.
Carbon-carbon bond formation is one the fundamental reactions in organic synthesis. The quest for the development of new and more efficient processes for the construction of this bond has been an ongoing focus for years. The transformations that permit the use of simple precursors to access complex structural architectures in the absence of stoichiometric quantities by-products are highly desirable. Hydrogen is a cheapest and cleanest reductant available to the mankind. The catalytic hydrogenation has been widely utilized in the industry, however the construction of the carbon-carbon bond under hydrogenative conditions has been achieved only for alkene hydroformylations and Fisher-Tropsh process and limited to the use of carbon monoxide. The extension of the hydrogenative carbon-carbon bond formations beyond aforementioned processes would be of a great significance to the synthetic community. The overview of allene use in the metal catalyzed reactions to achieve carbonyl and imine allylation and vinylation is presented in Chapter 1. The following chapter vii discusses the development of metal catalyzed hydrogenative and transfer hydrogenative coupling of allenes and carbonyl compounds to afford allylation products. These studies have resulted in the development of the first carbonyl allylation from the alcohol oxidation level. Chapter 3 discusses efforts towards achieving highly enantioselective hydrogenative coupling of alkynes to carbonyl compounds.
The efficient construction of complex organic molecules mandates that an assortment of methods for forming C-C bonds be available to the practicing synthetic chemist. The addition of carbon based nucleophiles to carbonyl compounds represents a broad class of reactions used to achieve this goal. Traditional methodology requires the use of stoichiometrically preformed organometallic reagents as nucleophiles in this type of reaction. However, due to the moisture sensitivity, excessive preactivation and inevitable generation of stoichiometric waste required for the use of these reagents, alternative methods have become a focus of the synthetic organic community. The research presented in this dissertation describes a new class of C-C bond forming reactions enabled through catalytic transfer hydrogenation. Here, the development and implementation of efficient green methods for carbonyl addition employing [pi]-unsaturates as surrogates to preformed organometallic reagents is described. Additionally, this research describes the first systematic studies toward using alcohols as electrophiles in carbonyl allylation, propargylation and vinylation reactions.
In Michael J. Krische research group we are developing new transition metal catalyzed Carbon-Carbon (C-C) forming reactions focusing on atom economy and byproduct free, environmental friendly approaches. We have developed a broad family of C-C bond forming hydrogenations with relative and absolute stereocontrol which provide an alternative to stoichiometric organometallic reagents in certain carbonyl and imine additions. Inspiring from the group work my goal was to develop new reactions, extend the scope of our group chemistry and their application towards synthesis of biologically active natural products. I have been part of enantioselective Rh catalyzed Aldol reaction of vinyl ketones to different aldehydes. Also, we have found that iridium catalyzed transfer hydrogenation of allylic acetates in the presence of aldehydes or alcohols results in highly enantioselective carbonyl allylation under the conditions of transfer hydrogenative. Based on this reactivity a concise enantio- and diastereoselective synthesis of 1,3-polyols was achieved via iterative chain elongation and bidirectional iterative asymmetric allylation was performed, which enables the rapid assembly of 1,3-polyol substructures with exceptional levels of stereocontrol. The utility of this approach stems from the ability to avoid the use of chirally modified allylmetal reagents, which require multistep preparation, and the ability to perform chain elongation directly from the alcohol oxidation level. This approach was utilized for the total synthesis of (+)-Roxaticin from 1,3-propanediol in 20 longest linear steps and a total number of 29 manipulations. Further, advancements were made in iridium catalyzed C-C bond formation under transfer hydrogenation. While methallyl acetate does not serve as an efficient allyl donor, the use of more reactive leaving group in methallyl chloride compensate for the shorter lifetime of the more highly substituted olefin [pi]-complex. Based on this insight into the requirements of the catalytic process, highly enantioselective Grignard-Nozaki-Hiyama methallylation is achieved from the alcohol or aldehyde oxidation levels. Also, a catalytic method for enantioselective vinylogous Reformatsky- type aldol addition was developed in which asymmetric carbonyl addition occurs with equal facility from the alcohol or aldehyde oxidation level. Good to excellent levels of regioselectivity and uniformly high levels of enantioselectivity were observed across a range of alcohols and aldehydes.
Edited by leading experts and pioneers in the field, this is the first up-to-date book on this hot topic. The authors provide synthetic chemists with different methods to activate carbon-carbon sigma bonds in organic molecules promoted by transition metal complexes. They explain the basic principles and strategies for carbon-carbon bond cleavage and highlight recently developed synthetic protocols based on this methodology. In so doing, they cover cleavage of C-C bonds in strained molecules, reactions involving elimination of carbon dioxide and ketones, reactions via retroallylation, and cleavage of C-C bonds of ketones and nitriles. The result is an excellent information source for researchers in academia and industry working in the field of synthetic organic chemistry, while equally serving as supplementary reading for advanced courses in organometallic chemistry and catalysis.