Periodic Reporting for period 1 - CATKERB (Total Syntheses of Catharanthine and Keramaphidin B by an Iridium-Catalyzed Reductive Cyclization Cascade)
Reporting period: 2020-08-03 to 2022-08-02
Introduction: The functionalization of organic molecules with difluoro- and trifluoromethyl groups has gained considerable attention in pharmaceutical and agrochemical research as well as in material science due to the remarkable impact of fluorine atoms on the physical, chemical, and biological properties of the original molecule. More specifically, the β-fluorinated-α-amino motif represents a key building block in many bioactive molecules such as gemcitabine, GDC-0077, seletalisib, cevipabulin and LGD-2226 (Scheme 1A), owing to the electronic influence of the fluorine atoms on the neighboring nitrogen center. Therefore, the development of concise and selective methods for the introduction of fluorine-containing groups into various nitrogen-containing scaffolds is a highly desirable target in synthetic organic chemistry. A well-known instrument to obtain β-fluorinated-α-amino compounds is the addition of nucleophilic di- or trifluoromethyl sources on to electrophilic species such as imines or nitriles and several methods have been developed to carry out these types of reactions. However, the direct nucleophilic di- or trifluoromethylation of the amide group ubiquitous in pharmaceutically active molecules and natural products remains extremely underdeveloped, which might constitute in the low electrophilicity of the amide group compared to the previously mentioned electrophiles. Nevertheless, there are a few sporadic reports by Brigaud, Leadbeater and Huang enabling the challenging direct trifluoromethylation of amides and overcoming this reactivity problem by either using already activated more electrophilic starting materials such as Weinreb-amides or N-Boc protected lactams or by using stoichiometric activating reagents such as triflic anhydride. Another general and highly chemoselective approach for amide functionalization can be achieved under reductive transition metal-catalyzed conditions as demonstrated by Dixon and others. Using catalytic amounts of rhodium or iridium complexes and silanes as reductants led to the formation of meta-stable O-silylated hemiaminal intermediates, which are precursors to reactive iminium ions that can undergo subsequent nucleophilic functionalization with various nucleophiles such as silylenolethers, isonitriles, allytributylstannane, trimethylsilyl cyanide, Grignard reagents, alkynes, and indoles. Surprisingly, to the best of our knowledge, only one seminal report by Huang includes two examples where they utilized this partial reduction approach of amides to incorporate the trifluoromethyl group, using the Ruppert-Prakash reagent (TMSCF3) and tetrabutylammonium difluorotriphenylsilicate (TBAT) to insitu generate the nucleophilic CF3-source.
Objectives: Therefore, the overall objectives of this project can be summarized as follows: a) To develop general reductive transition metal-catalyzed di- and trifluoromethylations of tertiary amides and lactams to furnish valuable fluorinated cyclic and acyclic tertiary amines and b) to systematically apply these methods to the late-stage functionalization of various drugs and natural products to point out the great value of this reaction for medicinal chemistry and society (Scheme 1B).
Conclusion: A broadly applicable and efficient method for the synthesis of acyclic and cyclic α-difluoroalkylated tertiary amines with good overall yields has been developed. The mild iridium-catalyzed reductive difluoroalkylation shows excellent functional group tolerance with respect to both coupling partners; amides/lactams and organozinc reagents, which is among other things highlighted by the late-stage derivatization of four drug molecules. Furthermore, the synthetic utility of this method was demonstrated by a satisfying performance on gram scale and several useful downstream functionalizations (Scheme 2).
Objectives: Therefore, the overall objectives of this project can be summarized as follows: a) To develop general reductive transition metal-catalyzed di- and trifluoromethylations of tertiary amides and lactams to furnish valuable fluorinated cyclic and acyclic tertiary amines and b) to systematically apply these methods to the late-stage functionalization of various drugs and natural products to point out the great value of this reaction for medicinal chemistry and society (Scheme 1B).
Conclusion: A broadly applicable and efficient method for the synthesis of acyclic and cyclic α-difluoroalkylated tertiary amines with good overall yields has been developed. The mild iridium-catalyzed reductive difluoroalkylation shows excellent functional group tolerance with respect to both coupling partners; amides/lactams and organozinc reagents, which is among other things highlighted by the late-stage derivatization of four drug molecules. Furthermore, the synthetic utility of this method was demonstrated by a satisfying performance on gram scale and several useful downstream functionalizations (Scheme 2).
Work performed: After varying different reaction parameters such as solvents and concentrations, reagent equivalents, reaction time and temperature, a new method for the reductive difluoroalkylation of abundant tertiary amides and lactams was established, using 1-2 mol% of Vaska’s complex (IrCl(CO)(PPh3)2), tetramethyldisiloxane (TMDS) and difluoro-Reformatsky reagents (BrZnCF2R). The excellent chemoselectivity of this mild method (reactions were carried out at 0 °C to room temperature for 40 minutes) was demonstrated by a broad tertiary amide scope including more than twenty examples bearing different reactive functional groups such as boronic and carboxylic esters, acetals, iodo and nitro groups. Additionally, four different pharmaceutical active compounds have been reductively functionalized with overall good yields to highlight the potential application of this method for pharmaceutical drug discovery and lead structure optimization. This reaction was also successfully expanded to benzyl, phenyl and challenging heteroaromatic substituted lactam starting materials of different ring sizes (7 examples). The scope of difluoro-Reformatsky reagents was investigated by changing the substitution on the difluoroacetates or switching to difluoroacetamides furnishing the desired β-difluorinated tertiary amines in good to excellent yields (11 examples). Furthermore, the reaction was readily performed on gram scale without a significant loss in yield and several CF2-containing derivates were made by common downstream transformations.
Exploitation and dissemination: The works of this project have been presented and discussed in several internal Dixon group seminars as well as in poster sessions of the university’s chemistry department. So far, the fellowship has resulted in the publication of one paper: P. Biallas, K. Yamazaki, D. J. Dixon Org. Lett. 2022, 24, 10, 2002–2007. At the moment, there is a manuscript in preparation on the results of the CATKERB project. It will be submitted in a few weeks to the leading journal JACS. Also, a new reductive trifluoromethylation method developed during this project and their applications will be patented in the near future.
Exploitation and dissemination: The works of this project have been presented and discussed in several internal Dixon group seminars as well as in poster sessions of the university’s chemistry department. So far, the fellowship has resulted in the publication of one paper: P. Biallas, K. Yamazaki, D. J. Dixon Org. Lett. 2022, 24, 10, 2002–2007. At the moment, there is a manuscript in preparation on the results of the CATKERB project. It will be submitted in a few weeks to the leading journal JACS. Also, a new reductive trifluoromethylation method developed during this project and their applications will be patented in the near future.
This fellowship has enabled great improvement in the state-of-the-art of active organic molecule synthesis through a powerful and effective synthetic methodology, raising the standing of EU chemistry within this field on a global scale. The reactions studied provided some important strategies for the construction of small fluorinated organic molecules, a class of compounds of immense importance in pharmaceutical and agrochemical research, as well as in materials science, due to the unique influence of fluorine atoms on physical, chemical and biological properties. The methods developed in this project are directly useful for the preparation of drug target molecules with biological activity as well as lead structure optimization in drug discovery programs. Therefore, this fellowship has constituted a significant contribution to the field, and will be of great benefit to organic and medicinal chemists in the pharmaceutical, agrochemical and fine-chemicals industries in the EU, who have already shown interest for the projects developed in this fellowship.