Development of Chiral Alkali Metal Binaphthyldisulfonate Catalysts for Enantioselective Aza–Friedel-Crafts Reaction and Strecker–type Reaction of Imines

名古屋大学Nagoya University博士(工学)doctoral thesi

Organocatalytic Asymmetric Biomimetic Transfer Hydrogenations of Olefins. New catalytic routes to saturated beta-branched ketones, beta,beta-disubstituted nitroalkanes as well as beta-nitroesters as precursors of beta-amino acids

This work describes the successful development of highly efficient and enantioselective organocatalytic approaches to the synthesis of chiral b-substituted ketones, b,b-disubstituted nitroalkanes as well as b-nitroesters. The latter could be efficiently converted to the corresponding b2-amino acids. Inspired by the in vivo enzymatic conjugate reductions with NAD(P)H cofactors, we established biomimetic transfer hydrogenations, for which dihydropyridines and organocatalysts were employed as NAD(P)H and enzyme analogues, respectively. The asymmetric conjugate reduction of enones was achieved via iminium catalysis using a salt composed of a protonated valine tert-butyl ester and a chiral BINOL phosphate counteranion. The process was particularly well-suited for cyclic a,b-unsaturated ketones. Acyclic enones could also be successfully used, although yielding the products with slightly lower enantioselectivities. A Jacobsen-type thiourea efficiently catalyzed the transfer hydrogenation of b,b-disubstituted nitroalkenes via hydrogen bonding catalysis. The reaction had a broad substrate scope and a number of aromatic and aliphatic nitroalkenes could be utilized. Moreover, we successfully established a concise new strategy to enantioenriched b2-amino acids. The key step in this process was a highly enantioselective and efficient thiourea-catalyzed conjugate reduction of b-nitroacrylates to the saturated analogues. The nitroesters were then easily and efficiently converted into the corresponding b2-amino acids. In addition, a convenient synthesis of the required b-nitroacrylates via a Henry reaction-dehydration process was developed

Development and application of asymmetric organocatalytic Mukaiyama and vinylogous Mukaiyama-type reactions

This is the peer reviewed version of the following article: "Development and application of asymmetric organocatalytic Mukaiyama and vinylogous Mukaiyama-type reactions", Chemistry - A European Journal 24.43 (2018): 10906-10933 ,which has been published in final form at https://doi.org/10.1002/chem.201801866. This article may be used for non-commercial purposes in accordance with Wiley terms and conditions for use of self-archived versionsOrganocatalysis is a growing area that is benefiting from advances in many fields. Its implementation has begun in areas such as supramolecular chemistry, organic chemistry and natural product synthesis. While a considerable number of important publications in the field of organocatalytic Mukaiyama-type additions have been reported, they are yet to be fully covered in a review. Therefore, we would like to highlight the applications of various kinds of organocatalysts in Mukaiyama-type reactions, while also including the vinylogous Mukaiyama variation. Herein we describe and discuss the development and current state of the art of the organocatalytic Mukaiyama reaction, vinylogous Mukaiyama and related reactionsFinancial support from the Spanish Government CTQ2015-64561-R (MINECO/FEDER) is gratefully acknowledged. M.F. thanks the UAM for an FPI-UAM fellowshi

Asymmetric Counteranion-Directed Transition Metal Catalysis: Enantioselective Epoxidation and Sulfoxidation with Ion-Pair Catalysts

Based on the concept of “asymmetric counteraion-directed catalysts (ACDC)”, a series of ion-pair catalysts containing an achiral metallosalen cation and a chiral anion was designed and prepared for the asymmetric epoxidation of unfunctional alkenes and the oxidation of sulfides. With the optimal ion-pair catalyst that consits of an achiral Mn-salen cation and a chiral BINOL-derived phosphate anion, high yields and enantioselectivities were obtained in the epoxidation of various alkenes like chromenes and cinnamates. With this type of ion-pair catalysts, a level of enantioselectivity similar to Jacobsen’s Mn-salen catalyst was observed in the asymmetric oxidation of sulfides. The corresponding iron complex was found much more efficient for sulfoxidation, and the high enantioselectivities observed in the cases of electron-poor sulfides are unprecedented in Mn- or Fe-based metallosalen systems. The combination of chiral salen ligands and chiral counteranions has also been investigated. In the epoxidation of alkenes with the configuration-matched ion pairs the enantioselectivity of the Mn-salen complexes consisting of only chiral salen ligands can be further improved. The application of the ACDC concept to porphyrin chemistry was also attempted. Substantial albeit low enantioselectivity was observed in epoxidation reactions. These results further demonstrate that ACDC can be employed as a general strategy in the arena of asymmetric transition metal catalysis

Beiträge zur nachhaltigen Synthese und Anwendung von BINBAM-Derivaten und aminosäurebasierten ionischen Flüssigkeiten

In der vorliegenden Arbeit wurden Beiträge zur Derivatisierung des Katalysators (R)-BINBAM und der Synthese und Anwendung aminosäurebasierter ionischer Flüssigkeiten geleistet. Der Fokus lag auf möglichst nachhaltigen Synthesewegen, sodass die Herstellung der Katalysatorderivate und ionischen Flüssigkeiten in Zukunft auch für die industrielle Nutzung sinnvoll wird. Es wurde versucht, verschiedene Substituenten in 3,3‘-Position des BINBAM-Katalysatorgerüst einzuführen, um den sterischen Anspruch und die Acidität des Katalysators zu beeinflussen. Desweiteren wurden chirale ionische Flüssigkeiten ausgehend von natürlich vorkommenden (S)-Aminosäuren in guten Ausbeuten und Reinheiten synthetisiert. Eine Auswahl dieser ionischen Flüssigkeiten wurde im Rahmen dieser Arbeit bereits in der oxidativen Faltung von nativen Conopeptiden getestet. Conopeptide sind aufgrund ihrer sehr spezifischen Bioaktivität für die Arzneimittelforschung interessant, deshalb besteht ein hohes Interesse an einer unkomplizierten Laborsynthese

Asymmetric organocatalytic allylation of acetals

The addition of allylmetals to aldehydes, particularly in an asymmetric fashion, is of prime importance in the synthetic chemist’s arsenal of C–C bond-forming methodologies, as the secondary homoallylic alcohol products are primed for further transformations. So far, reagent-controlled approaches with chiral metal-based Lewis acids have been the most effective means for controlling the enantioselectivity of this reaction. However, this approach cannot be used when acetals are employed as the latent electrophiles. Since Brønsted acids also mediate the Hosomi-Sakurai reaction of acetals, we hypothesised that a chiral Brønsted acid HY* has the potential to introduce stereoselectivity into this bond-forming process via the formation of a chiral contact ion pair in which the chiral conjugate base controls the nucleophilic addition to the achiral oxacarbenium ion with which it will be associated. For the investigation, three types of Brønsted acids with different acidity, all based on a binaphthyl core, have been synthesised. These catalysts were employed in the reaction of 1-alkoxyisochromans with allyltrimethylsilane. An optimisation study was carried out and the scope and the limitations of the method were probed. In summary, the first enantioselective asymmetric organocatalytic allylation of acetals is presented

Taming Benzylic Cations via Asymmetric Counteranion Directed

Reactions that proceed via carbocations play a big role in various chemical transformations for over a century. Their applications range from drug discovery, commercial compounds to petroleum industry. Despite their vast reactions in chemical synthesis, taming carbocations in asymmetric synthesis is rather limited. Hydrocarbon-based carbocations lack polarized bonds, which diminishes possible interactions with catalysts. The main objective of this thesis is reaction development, optimization, design and synthesis of enantiomerically pure Brønsted acids, which are capable of generating and stabilizing benzylic carbocations from the corresponding racemic sp3 starting materials. The developed methodology provides a general approach to the synthesis of chiral benzylic compounds with high enantioselectivity. The use of confined counteranions allows for the stabilization of the carbocation intermediate, which is crucial for achieving high enantioselectivity in the subsequent CC-, CO- and CN-bond forming reactions. The highly reactive cationic intermediate can be accessed from different precursors via Lewis- or Brønsted acid catalysis. In conclusion, this work represents a significant contribution to the field of asymmetric synthesis and has the potential to impact the development of new drugs and materials. The design and synthesis of enantiomerically pure Brønsted acids capable of generating and stabilizing benzylic carbocations has opened up new possibilities for the synthesis of enantioenriched benzylic compounds. The use of confined counteranions has proven to be a highly effective strategy for catalytic asymmetric reactions with excellent enantioselectivity. This research has significant implications for the development of new drugs and compounds in the pharmaceutical industry

Catalytic Asymmetric Hydroalkoxylation of C–C Multiple Bonds

Asymmetric hydroalkoxylation of alkenes constitutes a redox-neutral and 100% atom-economical strategy toward enantioenriched oxygenated building blocks from readily available starting materials. Despite their great potential, catalytic enantioselective additions of alcohols across a C–C multiple bond are particularly underdeveloped, especially compared to other hydrofunctionalization methods such as hydroamination. However, driven by some recent innovations, e.g., asymmetric MHAT methods, asymmetric photocatalytic methods, and the development of extremely strong chiral Brønsted acids, there has been a gratifying surge of reports in this burgeoning field. The goal of this review is to survey the growing landscape of asymmetric hydroalkoxylation by highlighting exciting new advances, deconstructing mechanistic underpinnings, and drawing insight from related asymmetric hydroacyloxylation and hydration. A deep appreciation of the underlying principles informs an understanding of the various selectivity parameters and activation modes in the realm of asymmetric alkene hydrofunctionalization while simultaneously evoking the outstanding challenges to the field moving forward. Overall, we aim to lay a foundation for cross-fertilization among various catalytic fields and spur further innovation in asymmetric hydroalkoxylations of C–C multiple bonds

Asymmetric Organocatalysis with bis-Silyl Ketene Acetals

Enantiomerically pure α-stereogenic carboxylic acids are encountered in a variety of natural products and pharmaceuticals and are useful substrates for various transformations. The direct synthesis of such motifs via catalytic asymmetric α-functionalization remains challenging in both metal- and organocatalysis. A general approach toward α-functionalization can be envisioned via formation of bis-silyl ketene acetal intermediates followed by functionalization with an electrophilic counterpart. This thesis focuses on the development of enantioselective transformations with bis-silyl ketene acetals, exploring the generality of this strategy within Brønsted and Lewis acid catalysis for a variety of enantioselective C–H and C–C bond forming reactions, using simple and unactivated substrates. This strategy was successfully applied to the deracemization of α-branched aryl carboxylic acids via catalytic asymmetric protonation of bis-silyl ketene acetals with water or methanol as a proton source, delivering valuable products with high enantiomeric purity and high yields, including non-steroidal anti-inflammatory arylpropionic acids, such as Ibuprofen. Furthermore, this strategy showed great potential under Lewis acidic conditions for a direct aminomethylation, allowing the first asymmetric organocatalytic synthesis of β2-amino acids from aliphatic and aromatic unactivated substrates, in very good enantioselectivities and excellent yields. This work opens the field of catalytic asymmetric transformations with bis-silyl ketene acetals for the direct access of enantioenriched α-branched carboxylic acids