Catalytic enantioselective synthesis of quaternary carbon stereocentres.

Quaternary carbon stereocentres-carbon atoms to which four distinct carbon substituents are attached-are common features of molecules found in nature. However, before recent advances in chemical catalysis, there were few methods of constructing single stereoisomers of this important structural motif. Here we discuss the many catalytic enantioselective reactions developed during the past decade for the synthesis of single stereoisomers of such organic molecules. This progress now makes it possible to incorporate quaternary stereocentres selectively in many organic molecules that are useful in medicine, agriculture and potentially other areas such as flavouring, fragrances and materials

Asymmetric Synthesis of 1,3-anti-Diol Containing Subunits using Phosphorus-Based Tethers: Application in the Total Synthesis of Dolabelide C

The focus of this dissertation is the desymmetrization of C2-symmetric 1,3-anti-diols through the construction of pseudo-C2-symmetric phosphorus heterocycles, bearing a chirotopic, non-stereogenic center at phosphorus. Diastereotopic differentiation is achieved through cyclization via ring-closing metathesis (RCM), affording a chiral, non-racemic bicyclic P-heterocycle, which is stereogenic at phosphorus. This strategy is central to building skeletally diverse polyol subunits, which are commonly seen in polyketide-based natural products. Terminus differentiation and chain elongation through selective transformations on the previously reported bicyclo[4.3.1]phosphate (both antipodes), e.g. cross-metathesis, regioselective olefin reduction and regio- and diastereoselective allylic phosphate displacements, provide a rapid protocol to accessing the aforementioned motifs. The development of this methodology advanced into an application toward the total synthesis of dolabelide C (bearing two separate 1,3-anti-diol containing fragments), which exhibits cytotoxicity against cervical cancer HeLa-S3 cells with an IC50 value of 1.9 μg/mL. A route to this target was devised, where the final step was amending the 24-membered marcocycle through RCM. The result provided a diastereomeric mixture of E and Z isomers, which proved to be difficult to separate during initial efforts. However, LC-MS analysis of the mixture showed the contaminants were by-products arising from isomerization events occurring prior to RCM. Other reports coincide with this observation, mainly in the synthesis of medium to larger sized rings. Scale-up was required after this initial study to provide ample material for final characterization and the re-synthesis provided a copious amount of the RCM precursor. The large amount of material allowed for optimization studies and finally resulted in 14 mgs of analytically pure dolabelide C and 10 mgs of the non-natural Z-isomer, which to the best of our knowledge is the first synthesis of both compounds and the most synthetic material available of each to date

Zirconium-Catalyzed Desymmetrization of Aminodialkenes and Aminodialkynes through Enantioselective Hydroamination

The catalytic addition of alkenes and amines (hydroamination) typically provides α- or β-amino stereocenters directly through C–N or C–H bond formation. Alternatively, desymmetrization reactions of symmetrical aminodialkenes or aminodialkynes provide access to stereogenic centers with the position controlled by the substrate’s structure. In the present study of an enantioselective zirconium-catalyzed hydroamination, stereocenters resulting from C–N bond formation and desymmetrization of a prochiral quaternary center are independently controlled by the catalyst and reaction conditions. Using a single catalyst, the method provides selective access to either diastereomer of optically enriched five-, six-, and seven-membered cyclic amines from aminodialkenes and enantioselective synthesis of five-, six-, and seven-membered cyclic imines from aminodialkynes. Experiments on hydroamination of aminodialkenes testing the effects of the catalyst:substrate ratio, the absolute concentration of the catalyst, and the absolute initial concentration of the primary amine substrate show that the latter parameter strongly influences the stereoselectivity of the desymmetrization process, whereas the absolute configuration of the α-amino stereocenter generated by C–N bond formation is not affected by these parameters. Interestingly, isotopic substitution (H2NR vs D2NR) of the substrate enhances the stereoselectivity of the enantioselective and diastereoselective processes in aminodialkene cyclization and the peripheral stereocenter in aminodialkyne desymmetrization/cyclization

Enantioselective and Enantiospecific Transition-Metal-Catalyzed Cross-Coupling Reactions of Organometallic Reagents To Construct C–C Bonds

The stereocontrolled construction of C−C bonds remains one of the foremost challenges in organic synthesis. At the heart of any chemical synthesis of a natural product or designed small molecule is the need to orchestrate a series of chemical reactions to prepare and functionalize a carbon framework. The advent of transition-metal catalysis has provided chemists with a broad range of new tools to forge C−C bonds and has resulted in a paradigm shift in synthetic strategy planning. The impact of these methods was recognized with the awarding of the 2010 Nobel Prize in Chemistry to Richard Heck, Ei-ichi Negishi, and Akira Suzuki for their seminal contributions to the development of Pd-catalyzed cross-coupling

Phosphate Tether-Mediated Synthetic Studies- Applications in Natural Products Synthesis.

The focus of this dissertation is the utilization of phosphate tether mediated approaches to synthesize bioactive natural products and their analogs in аn efficient and effective manner. The several salient features, which are inherent to phosphate triesters, include: (i) orthogonal stability under acid conditions, (ii) leaving group ability, (iii) multivalent activation of carbinol centers, (iv) protecting group attributes, and serving as a (v) temporary tether that can be removed under various conditions. Taken collectively various transformations, including chemoselective reductions as well as oxidations of the exocyclic olefin, a diastereoselective cuprate addition and successful cross-metathesis of type I and type II olefins with the exocyclic double bond, all mediated by phosphate tether, have provided the facile synthetic routes towards the synthesis of several natural products. Application of this protocol toward the total synthesis of fostriecin and 8-epi-fostriecin are reported. Fostriecin, an antitumor antibiotic isolated from Streptomyces pulveraceus, is the most selective and potent inhibitor of protein phosphatases 2A and 4, known to-date (IC50s 3.2 nM and 3 nM, respectively). It has been shown to be active against L1210 and P388 leukemia cells in vivo and in vitro against leukemia, lung, breast, and ovarian cancer cells. Synthetic studies related to diastereoselective ring-closing metathesis reaction, regioselective oxidation, diastereoselective Grignard addition and cross metathesis, all mediated by a temporary phosphate tether, have established a scalable route toward the goal of total and analog synthesis of fostriecin and 8-epi-Fostriecin. In addition to the aforementioned transformations, the coupling of orthogonal transformations in a multi-step, one-pot, sequential RCM/CM/H2 process has also allowed for facile synthesis of advanced intermediates en route to the total synthesis of natural products. Application of three step, one-pot, sequential RCM/CM/H2 protocol in a library amenable, efficient and modular synthesis of strictifolione and (6R)-6-[(4R,6R)-4,6-dihydroxy-10-phenyldec-1-enyl]-5,6-dihydro-2H-pyran-2-one are also discussed. Both anti-fugal natural products were synthesized in seven linear steps starting from readily available 1,3-anti-diene-diol without incorporating additional protecting groups

Advances in Bronsted Acid Catalysis: Reactions of Oxocarbenium Ions.

Oxocarbenium ions are common intermedates or transition states for a variety of biological and synthetic transformations. Due to the fact that oxocarbenium ions are typically much more reactive than iminium ions, their reactivity is difficult to control. Especially challenging reactions of oxocarbeniums are stereoselective transformations. While there are several approaches to perform reactions of oxocarbeniums asymetrically, the Nagorny group is particularly interested in using chiral hydrogen bond donors and Brønsted acids as catalysts for these reactions. Chapter 1 of this thesis provides an introduction to chemistry of oxocarbenium ions, their generation and use in asymmetric reactions. Both anion activation and protonation of acetals and vinyl ethers with chiral hydrogen bond donors and chiral Brønsted acids are covered in this chapter. Chapter 2 discusses ionic Diels-Alder reaction as well as the use of thiophosphoramide as a co-catalysts for promoting this transformation. Thiophosphoramide catalyst was found to bind sulfonate anions and was used to separate the vinyl oxocarbenium/sulfonate ion pair. This effect leads to acceleration of the Diels-Alder reaction of unsaturated acetals. Thiophosphoramides are the most effective cocatalysts because of the stronger counterion activation effect resulting from three, rather than two, hydrogen bonds involved in anion binding. Chapter 3 of this manuscript describes development of the first chiral catalyst-controlled enantioselective ionic Diels-Alder reaction of unsaturated acetals. Chiral BINOL-based N-triflylphosphoramides were used as catalysts for this transformation. Moderate enantioselectivities (up to 80:20 e.r.) have been obtained when α,β-unsaturated dioxolanes were employed as the dienophiles. These reactions demonstrate strong dependence on the counterion coordinating properties and solvent polarity, a behavior characteristic of oxocarbenium ions. Finally, Chapter 4 describes attempts of stereo- and regioselective aminoglycosides via desymmetrization of meso-2-deoxystreptamine using chiral phosphoric acids as catalysts. We showed that chiral phosphoric acids facilitate desymmetrization of meso-diols via glycosylation reactions using mannose-α-trichloroacetimidate. Chiral phosphoric acid-promoted mannosylation of 2-deoxystreptamine produces a mixture of two α-mannosides with up to 1:5 (O-4 : O-6) regioselectivity. This is the first report of desymmetrization of meso-diols via glycosylation using chiral phosphoric acids as catalysts. This method has a potential to be applied for glycodiversification of 2-deoxystreptamine and synthesis of new aminoglycoside antibiotics.PHDChemistryUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/113511/1/mealina_1.pd

Synthesis of Cyclopropylboronates and Allylic Alcohols via Copper-Catalyzed Borylation Reactions

Tesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Química Orgánica. Fecha de lectura: 24-11-2017Esta tesis tiene embargado el acceso al texto completo hasta el 24-05-2019Esta Tesis Doctoral ha sido realizada en el Departamento de Química Orgánica de la Universidad Autónoma de Madrid, bajo la dirección de la Doctora Mariola Tortosa Manzanares. Este trabajo ha sido financiado por el ‘European Research Council’ (ERC-337776), así como por MINECO (CTQ2012-35957)

Phosphate Tether-Mediated Metathesis Studies and Application Towards Natural Product Synthesis

Over the past decade, work in our lab has focused on phosphate tether-mediated desymmetrization of C2-symmetric 1,3-anti-dienediol via ring-closing metathesis (RCM) to afford P-stereogenic bicyclo[4.3.1]phosphates. However, efforts in this direction relied solely on phosphate tether-mediated coupling of allylic alcohol cross partners with 1,3-anti-dienediol synthons leading to the formation of simple bicyclo[4.3.1]phosphates and their applications in natural product synthesis. The objective of this dissertation work is to advance the phosphate tether-mediated methods to include the construction of complex bicyclo[n.3.1]phosphates via ring-closing metathesis (RCM). The RCM study, discussed in detail in Chapter 2, highlights the synthetic potential of phosphates as a temporary tethers in facilitating the coupling of complex fragments to produce novel P-stereogenic bicyclic phosphate scaffolds. Chapter 3 describes the development of phosphate tether-mediated one-pot and two-pot sequential metathesis/reduction protocols towards the stereodivergent synthesis of complex polyols. The potential application of phosphate tether-mediated reactions en route to the synthesis of the C9–C25 fragment of spirastrellolide B is discussed in Chapter 4

Synthesis of Semiochemicals via Olefin Metathesis

Semiochemicals are substances or mixtures that carry messages and are used for communication between individuals of the same or different species. Semiochemicals that are used in pest control are called biopesticides. Conventional pesticides, which are generally synthetically derived and unnatural, inactivate or kill the pests, whereas biopesticides are naturally occurring compounds that attract insects to a trap or interfere with their reproduction. There are several advantages to biopesticides. Compared with conventional pesticides, biochemical-based pesticides are often less toxic and therefore have a significantly lower impact on human health and the environment. Moreover, biopesticides are pest-selective and as such do not negatively impact other organisms such as insects, mammals, or birds. Other advantages of biopesticides include high potency, meaning that smaller amounts of biopesticide are required, less resistance by target organisms, and the ability to biodegrade more quickly than conventional pesticides. Although biochemical-based pesticides are very promising materials, their production is often cumbersome, and their application is often limited. To date, most biopesticides have been synthesized by multistep, classical organic reactions that are not economical and have high environmental impact. However, in recent decades many efforts have been made to implement cost-effective and safer chemical procedures for the widespread application of biochemical-based pesticides. The purpose of this Perspective is to draw the attention of the green chemistry community to the applicability of olefin metathesis reactions in environmentally benign and cost-effective biopesticide synthesis. We review seminal work on the total synthesis of biopesticides using olefin metathesis as a key reaction step, and in doing so, we hope to inspire new ideas for forthcoming olefin-metathesis-based biopesticide development