#	Pagina
attuale pagina	/open-h2020/projects/201033/results.html

Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - LATE-STAGE (Palladium catalyzed C(sp3)â€’H late-stage diversification of biologically active molecules)

Teaser

Summary

Aliphatic amines are central to the function of many biologically active molecules as evidenced by their prevalence in a large number of pharmaceutical agents. The groups appended to these nitrogen atoms are crucial in determining the physical properties of the amine and are linked to how well it interacts with a biological target. Despite the apparent simplicity of the aliphatic amine motif, the number of general methods that enable the functionalization of bioactive compounds are surprisingly limited, and so the development of directed catalytic methods remains an important challenge.
This project entailed the development of novel palladium-catalyzed Câ€“H methodologies to introduce functionalizations on simple aliphatic amines and the application of these new methods on more complex and important bioactive molecules.
In the first year, a method for the C-H carbonylation of methylene beta C-H bonds in secondary aliphatic amines to form trans-disubstituted Î²-lactams was successfully developed and applied to drug analogues as a Î²-adrenergic antagonist (also known as Î² blocker) Propanolol.
In the second year, a Pd(II)-catalyzed Î³-Câ€“H amination process was developed, in which a series of cyclic secondary alkyl amines are converted into highly substituted chiral drug-like azetidines. The novel chiral azetidine derivatives are currently under biological evaluation.

Work performed

1. Methylene carbonylation project.
Upon initial discovery hits, the newly reaction was fully optimized to obtain the desired b-lactam in high efficiency. Evaluation of different variables was performed including temperature, oxidants, additives, metals, carbon monoxide concentration and time. As a result, optimized conditions entailed 10 mol% of Pd(OAc)2, 200 mol% of benzoquinone, 300 mol% of AgOAc and 10 mol% of xantphos over an atmosphere of CO(g). These conditions were found to be the most efficient rendering 80% yield of b-lactam after 16 h. After having the optimized conditions in hand, more than 100 different substrates were prepared. After this, all these substrates were tested on the carbonylation conditions to obtain the corresponding b-lactams ranging from 20-80 % yield. The Propanolol analogue was synthesized and exposed to the carbonylative reaction conditions and the corresponding trans Î²-lactam was successfully obtained in 61% of yield.
Our work has been published in Angewandte Chemie International Edition. (Angew. Chem. Int. Ed. 2017, 56, 11958 â€“11962. DOI: 10.1002/anie.201706303). This publication is open access to general public through the University of Cambridge.
2. Azetidine synthesis project.
Recently, we described a Pd(II)-catalyzed process for Î²-Câ€“H amination on hindered alkyl amines to form aziridines, which proceeded by direct intramolecular Câ€“N reductive elimination from an aminoalkyl Pd(IV) intermediate. We speculated that reaction of a related homologated amine should undergo Î³-Câ€“ H amination to form the corresponding azetidine. We were surprised to find, however, that reaction produced only the Î³-Câ€“H acetoxylation product, with no sign of azetidine, when treated under identical conditions to the aziridine forming process. We conducted computational studies and we found that the acetoxylated product could be formed via a two-step reaction at the Pd(IV) center; dissociative ionization of an axial acetate from Pd(IV) and simultaneous Îº2 binding of the axial acetate forms an octahedral complex. In light of these preliminary computational studies, we re-evaluated our design hypothesis for azetidine formation. We proposed that replacing one of the acetate ligands on the aminoalkyl-Pd(IV) species with a OTs group would promote dissociative ionization of the better leaving group, to form the Î³-amino tosylate. Cyclization of the amine to displace the Î³-tosylate completes the formal Câ€“N reductive elimination process to azetidine. Guided by this mechanistic blueprint, different oxidants, solvents and additives were tested to optimize the reaction conditions. The combination of benziodoxole oxidant containing the tosylate group and the silver acetate was crucial to obtain the desire azetidine in good yields. A range of fully substituted morpholinones undergo efficient Câ€“H amination to azetidines. On the basis that the benziodoxole is less oxidizing than its acyclic counterparts, a range of enantioenriched substrates were prepared starting from different amino alcohols. At 80 ËšC, the Câ€“H amination delivered the chiral azetidines in useful yields and excellent diastereoselectivity.
This work was presented in the American Chemical Society meeting in April 2017, San Francisco, which is one of the most important meetings in Chemistry.
Our work has just been published in Angewandte Chemie International Edition. (Angew. Chem. Int. Ed. 2018, online. DOI: 10.1002/anie.201800519). This publication is open access to general public through the University of Cambridge.

Final results

1. Methylene carbonylation project.
Selective carbonylation of methylene bonds in aliphatic systems is rather difficult. Previous to our work, this type of transformation proceeded via auxiliaries that facilitate the functionalization of methylene bonds. Such auxiliaries have to be removed from the product after the reaction is completed.
The main achievements of our work are the following: 1) For the first time, no auxiliaries are required to facilitate methylene functionalization. Our strategy is based on the coordinating ability of aliphatic amines to direct the carbonylation processes. 2) Our process is highly selective. Our work shows the selective carbonylation of methylene over methyl bonds, which are traditionally easier to activate. 3) The obtained products are polysubstituted b-lactams. Starting from readily available amines, we can synthetize b-lactams tolerating a range of biologically useful functional groups. 4) Successful application of the methodology on biologically active analogues.
2. Azetidine synthesis project.
The control of the reductive elimination processes from alkyl-Pd(IV) intermediates is rather challenging. This is the key for the development of selective C-H amination reaction, previously obtained with the use of specific auxiliary on the substrates or complex ligands for the metal complex.
The main achievements of our work are the following: 1) For the first time, no auxiliaries are required to facilitate the C-H amination reaction in Î³ position of an amine. Our strategy is based on the coordinating ability of aliphatic amines to direct the synthesis of drug-like azetidines. 2) Control of the reductive elimination processes from alkyl-Pd(IV) intermediate. The design of the appropriate oxidant system was crucial to achieve the mentioned selectivity. 3) Tolerance of hydrogen atoms in the alpha positions of the nitrogen, allowing the use of chiral amino-acids for the diastereoselective synthesis of enantiopure azetidines. 4) Synthesis of suitable compounds for a potential biological activity.
Our projects could definitely have an impact on society. These works enable the synthesis of b-lactams and chiral azatidines in one step from simple amines. The reactions were applied to complex and biologically active molecules, showing the utility of the project for the late-stage diversification of important compounds. After establishing the adequate collaborations, our transformations could be employed for the synthesis of drugs and antibiotic potentially reducing the cost of such drugs.