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Final Report Summary - REDUCTO (AFFORDABLE SOLUTIONS FOR ASYMMETRIC REDUCTIONS OF INDUSTRIALLY RELEVANT SUBSTRATES)

Asymmetric hydrogenation is by far the most industrially relevant enantioselective transformation, due to its inherent atom economy and operational simplicity, as well as to the high level of stereocontrol that it allows to achieve with many substrates. Nevertheless, in spite of the immense academic development in this field, the number of implemented industrial processes is rather limited and is estimated at around 15 worldwide. Despite of all advances in the technology, the majority of chiral pharma intermediates are still prepared via classical resolution of diastereomeric salts. A number of reasons can be given for this scarcity of industrial processes:
1. Time-to-market pressure does not allow sufficient time for the development of a catalytic process.
2. The high cost of the catalysts (both the metal and the ligand) coupled to the relatively low turnover numbers that can be achieved in most cases makes the technology too expensive.
3. Although the technology works fine on a limited number of benchmark substrates, the catalysts are often too slow on real pharma intermediates.

PROJECT OBJECTIVES
The goal of this research programme consists in trespassing two traditional limitations of asymmetric hydrogenation:
(i) Metal limitations: the overwhelming majority of known methodologies require the use of noble metals (Pd, Pt, Rh, Ir, Ru), whose supply is limited and whose cost is very high. The REDUCTO consortium aims at investigating the utilisation of more readily available and cheap first-row transition metals such as Ni, Co, Fe and Cu for the asymmetric hydrogenation or transfer hydrogenation of ketones and ketoimines, and then for the enantioselective hydrogenation of olefins.
(ii) Substrate limitations: very little success has been achieved in the enantioselective hydrogenation of some classes of substrates. Among these, the consortium focuses its efforts on substituted pyridines, which potentially provide access to chiral piperidines of significant pharmaceutical interest.
According to these general objectives, three research Work Packages have been devised and assigned to 2 ESRs, who carried out the proposed research spending half of their time at the University of Milan (UMIL) and half at DSM Innovative Synthesis (DSM):
WP1: Enantioselective double bond reduction catalysed by first-row transition metals.
WP2: Enantioselective reduction of substituted pyridines.

WORK PERFORMED AND MAIN RESULTS ACHIEVED IN THE REPORTING PERIOD 2

WP1 (ESR1)
During the Reporting Period 1 (RP1), the synthesis of a small library of chiral and achiral Fe(II)-complexes was successfully carried out. Tetradentate N-ligands, tridentate N-ligands and isonitrile ligands were complexed to iron. The resulting complexes were tested in the following reactions: (i) hydrogenation of benchmark olefins; (ii) hydrogenation of benchmark ketones; (iii) transfer-hydrogenation of benchmark ketones. Significant levels of conversion (up to 87%) and moderate enantiomeric excess (up to 25% e.e.) could be obtained only in the transfer-hydrogenation of ketones promoted by one of the isonitrile complexes. Towards the end of RP1, we decided to focus our attention on a different class of iron complexes, i.e. (cyclopentadienone)iron complexes. These very stable compounds, upon in situ activation, are able to promote the hydrogenation of ketones, aldehydes and imines. At the end of RP1, the first representatives of a new class of BINOL-derived chiral (cyclopentadienone)iron complexes had been synthesized, and their catalytic properties in the asymmetric hydrogenation (AH) of ketones had been assessed. During the Reporting Period 2, the development of this new class of complexes was continued with the synthesis of a number of pre-catalysts differing from each other in the substituents at the 3,3’-positions of the binaphthyl residue (H, OH, OR, OCOR, OSO2R) or at the 2,5-positions of the cyclopentadienone ring [trimethylsilyl (TMS) or Ph]. Remarkably, eight pre-catalysts with different 3,3’-binaphthyl substitution were synthesized from a common parent complex through direct functional group interconversion reactions of the complexes. The application scope of the best pre-catalyst was assessed in the hydrogenation of several ketones, and the observed e.e. values (up to 77%) were much higher than those previously reported for other chiral (cyclopentadienone)iron complexes.
Taking advantage of the high-throughput screening facilities available at DSM, new applications of (cyclopentadienone)iron complexes were also sought, and it was found that the classical (achiral) “Knölker complex”, upon in situ activation with Me3NO, is able to catalyse the hydrogenation of activated esters (trifluoroacetates) to the corresponding alcohol products. Although no reaction was observed with non-activated esters, this study constitutes the first example of ester hydrogenation with an Fe complex based on a non-pincer ligand.

WP2 (ESR2)
Taking advantage of the high-throughput facilities present at DSM, where up to 96 hydrogenations can be performed in parallel, several screenings were carried out to test the homogeneous hydrogenation of activated pyridines. Activation of pro-chiral pyridine substrates with both Brønsted and Lewis acids was attempted and gave good results when hydrogenation was carried out in the presence of an in situ-formed Rh-dppe catalyst (up to 90% conversion). Unfortunately, no conversion could be obtained when dppe was replaced by chiral ligands. The use of acids along with some transition metal nanoparticles gave good activities, but the use of chiral acids did not achieve any enantiomeric excess. Pyridine substrate activation by N-quaternisation with acetic anhydride or chloroformates was attempted with no positive results. Instead, the activation by N-benzylation gave more promising results and thus was adopted for further tests. At the end of RP1, for 3-substituted pyridinium salts good yields and high e.e. values (up to 90% e.e.) had been obtained in the presence of a Rh-JosiPhos complex and of a base. In the case of 2-substituted pyridinium salts, a mixed ligand approach using [Ir(cod)Cl]2 with a chiral phosphoramidite and an achiral phosphine had led to high yield and enantiomeric excess (up to 77% e.e.). In RP2, for both these new hydrogenation methodologies the reaction conditions were further optimised and the application scope was thoroughly explored. Moreover, remarkable efforts were put to clarify the hydrogenation mechanism as much as possible, with deuteration studies and isolation of some intermediates, whose reactivity was investigated.
Additionally, an alternative approach towards sustainability was also pursued, consisting in a more efficient use of noble metals by means of assisted tandem catalysis. According to this strategy, the first example of tandem olefin metathesis/AH was developed, in which, after a ruthenium-catalysed metathesis step, an olefin AH catalyst is generated in situ by addition of a chiral ligand. Taking a further step, the successful transformation of a 1st-generation Grubbs metathesis catalyst into an asymmetric transfer hydrogenation
(ATH) catalyst was realized. Furthermore, the possibility to perform olefin metathesis and ketone transfer
hydrogenation sequentially in one pot was demonstrated, and the first tandem olefin metathesis–ketone asymmetric transfer hydrogenation was carried out.

SUMMARY OF THE FINAL RESULTS AND EXPECTED IMPACT

The research carried out within the consortium has met its goals to a large extent. Besides the PhD theses of the 2 ESRs, 7 papers were published in international high-impact journals, and 10 scientific communications (oral or poster) were presented at national and international conferences. In particular:
• A new class of chiral (cyclopentadienone)iron complexes has been created and tested in ketone AH, giving the best e.e. so far reported for this type of pre-catalysts.
• The application scope of (cyclopentadienone)iron complexes has been extended to the hydrogenation of activated esters.
• A highly enantioselective Rh-catalysed methodology for the hydrogenation of N-benzylated 3-substituted pyridinium salts has been developed.
• A highly enantioselective Ir-catalysed methodology for the hydrogenation of N-benzylated 2-substituted pyridinium salts has been developed.
• The first example Ru-catalysed tandem olefin metathesis/AH has been developed.
• The possibility to convert a ruthenium olefin metathesis catalyst into a ketone ATH catalyst has been demonstrated, and the first example of tandem olefin metathesis/ketone ATH has been realised.

We are confident that these results will make a remarkable impact in their scientific area, as well as in their socio/economic context. Indeed, improved industrial production processes are vital for the future health of European fine chemical and pharmaceutical industry, and the invention of cheaper and more flexible catalytic methodologies can positively affect the European productive system. The large margin of improvement of current production methodologies represents a tremendous opportunity of growth: the introduction of more efficient processes will significantly reduce the production costs, allowing the European industry to compete favourably on the global market with extra-European manufacturers.

Related information

Reported by

UNIVERSITA DEGLI STUDI DI MILANO
Italy

Subjects

Life Sciences
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