Development and Scale-Up of Stereoretentive Î±-Deuteration of

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Development and Scale-up of a Stereoretentive #-Deuteration of Amines Alessia MICHELOTTI, Fabien RODRIGUES, and Maxime ROCHE Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.7b00227 • Publication Date (Web): 26 Sep 2017 Downloaded from http://pubs.acs.org on September 26, 2017

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Organic Process Research & Development

Development and Scale-up of a Stereoretentive αDeuteration of Amines Alessia Michelotti, Fabien Rodrigues and Maxime Roche * CortecNet, 15-17 Rue des Tilleuls, 78960, Voisins-le-Bretonneux, France

ACS Paragon Plus Environment

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Table of Contents graphic :


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KEYWORDS : Deuteration, Ruthenium, Heterogenous catalysis, Amino Acids, Amines

ABSTRACT

A stereoretentive deuteration of amino acids and amines has been developed using ruthenium on carbon catalyst, hydrogen gas at atmospheric pressure and deuterium oxide as a source of deuterium. The process was successfully scaled-up avoiding the use of expensive and sensitive catalyst, and avoiding the use of deuterium gas under pressure. High deuterium incorporation and high yield of labelled compounds were obtained by a simple filtration process.


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INTRODUCTION Isotopically labelled compounds find applications in various fields including the study of absorption, distribution, metabolism and excretion (ADME) in the drug development process. Among all isotopes used to this end, deuterium plays a key role.1 Indeed, this is not a radioactive nucleus like 3H or

14

C, and this is less expensive than

13

C or

15

N. The versatility of deuterium

labelled molecules had been demonstrated in a wide range of applications, from proteomic,2 metabolomic,3 medical imaging,4 drug discovery,5 to tools for mechanistic investigations of bioorganic6or organic reaction.7 In recent years, the demand for deuterium labelled molecules also increased due to development of quantitative mass spectrometry analysis.8 This new demand goes along with the development of synthetic methods for easy access to deuterated materials. One strategy for the synthesis of deuterium labelled compounds is the use of classical transformations in multistep synthesis (reduction with deuterium gas,9 reduction with metal deuteride,10 etc). This strategy is often time (it requires the synthesis of pre-functionalized starting materials enabling reductive deuteration at well-defined positions) and cost-consuming (deuterated reagents are often expensive, indeed all deuterium atoms present in chemicals are either directly or indirectly derived from heavy water and require multistep synthesis for their preparation). A possible alternative is the late-stage functionalization of the desired compound by hydrogen-deuterium exchange (H/D exchange).11 Despite the attention that H/D exchange has gained recently, the development of chemo- and regioselective H/D exchange methodologies is still a challenge for organic chemists. Numerous methods using homogeneous and heterogeneous catalysis for H/D exchange of various functionalized molecules have been described. For example exchange of aromatic,12 heteroaromatic,13 vinylic,14 allylic15 or aliphatic protons,16 and exchange of protons of C-H bond adjacent to an heteroatom17 have been reported. In this field, a


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major breakthrough was achieved by Pieters and co-workers in 2015, who reported an enantiospecific deuteration of amino acids through C-H activation using ruthenium nanocatalyst.18 Jackson’s group reported one year later an alternative to Pieters’s procedure using an electroactivated ruthenium heterogenous catalyst,19 and avoiding the use of deuterium gas (D2). However these two methods suffer from several disadvantages which do not allow the preparation of large quantity of deuterated materials. For example Pieters and co-workers use non-commercial catalyst in glove box and run the reaction in medium-pressure reaction vessel with D2, and electrochemistry require specific apparatus. In past decades, isotopically labelled amino acids became of great interest. Their incorporation into proteins enables the study of their structure or function by biomolecular NMR.20 Following the interest in deuterated amino acids, we considered to develop an industrial-applicable method for the stereoretentive α-deuteration of amino acids. RESULTS AND DISCUSSION New reaction conditions avoiding the need of high-pressure reaction vessel, the use of noncommercial nanocatalysts, or the application of electrochemistry must be identified. On the basis of the work published by Sajiki and co-workers who demonstrated that deuterium gas (D2) could be replaced by hydrogen gas (H2) under transition metal catalysis in heavy water (D2O),21 we decided to avoid the use of expensive and regulated D2 gas. We started our investigation with Lalanine 1a as the substrate in the presence of 5% ruthenium on carbon (Ru/C) (40 w/w %) at 90 °C in D2O under one atmosphere of H2. Under these conditions we obtained an encouraging 40 % deuterium incorporation with a total retention of configuration (measured by chiral HPLC analysis, see supporting information for details) (Table 1, Entry 1). The amount of deuterium incorporated substantially increases with the addition of a base (Entry 2). Platinum or palladium


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on carbon revealed to be ineffective catalysts for this transformation (Entries 3 and 4), which is consistent with literature reports. They are often used in H/D exchange reaction of unactivated C-H bond,16b and probably do not enable C-H activation via the mechanism proposed by Pieters and co-workers for ruthenium.18 The catalyst loading can be decreased to 10% without any loss in deuterium incorporation (Entry 5), and the temperature can be decreased to 70 °C (Entry 6). Finally the deuterium incorporation can reach 99% by diluting the media and so by reducing the isotopic dilution (Entry 7). Two control experiments demonstrate the need of ruthenium and H2 atmosphere to promote the deuteration (Entries 8 and 9).


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Table 1. Optimization of the ruthenium catalyzed H/D exchange of alanine 1a at α position under various conditions

Entry

Conditions

D content (%)a

1

Ru/C (40%), without NaOH, 90 °C, 12h

40

2

Ru/C (40%), 90 °C, 12h

>95

3

Pd/C (40%), 90 °C, 12h

0

4

Pt/C (40%), 90 °C, 12h

0

5

Ru/C (10%), 90 °C, 12h

>95

6

Ru/C (10%), 70 °C, 12h

>95

7

Ru/C (10%), 70 °C, 12hb

>99

8

70 °C, 12h

0

9

Ru/C (10%), 70 °C, 12h, under Ar

0

Reactions were performed with 1a (1 mmol, 89 mg), NaOH (3 mmol, 120 mg), catalyst, in D2O (2 mL) under an H2 atmosphere at the corresponding temperature. (a) % Deuterium incorporation determined by 1H NMR. (b) Using 10 mL of D2O.


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With optimized conditions in hand we next explored the scope and limitations of this transformation. With unfunctionalized amino acids like glycine 2b, leucine 2c or valine 2d, high deuterium incorporation is obtained. When proline 2e, lysine 2f, or N-methylvaline 2g are used as substrate, we observed deuteration at all positions adjacent to amino group. For lysine 2f, K2CO3 is used as base instead of NaOH to avoid undesired polydeuteration. With glutamic acid 2h as substrate in addition to deuteration at C2 position, we also observe deuteration at C4 position due to activation by carboxylic acid at C5 position. The dipeptide Gly-Gly 2i is only deuterated in α position to the N terminal moiety (K2CO3 is used as base instead of NaOH to avoid amide bond cleavage). The amide group is probably not nucleophilic enough to coordinate the ruthenium catalyst, and act as a directing group for deuteration in α position to this group. This result is confirmed with N-Boc-alanine 2j, which is not deuterated under our conditions. With amino acids possessing multiple coordination groups (e.g. aromatic ring, sulfur atom) we observe lower deuterium incorporation (2k), or no deuterium incorporation (2l), even with higher catalyst loading or temperature. Finally, hydrosoluble aliphatic amines (2m and 2n) can also be selectively labelled at α-positons.


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Table 2. H/D exchange of amino acids and related compounds

O Me

OH Me D NH2

2a: 96%a

2b: 96%b

2c: 96%

2d: 91%

2e: 95%, 74%

2f: 90%, 92% c,d

2g: 94%, 96%

2h: 95%, 62%

2i: 99%b,c

2j: 0%

2k: 53%d

2l: 0%

2m: 94%

2n: 81%

Reactions were performed with 1 (1 mmol), NaOH (3 mmol, 120 mg), Ru/C 5 % (10 w/w %), in D2O (2 mL) under an H2 atmosphere at 70 °C for the corresponding time (See supporting information for details). (a) % Deuterium incorporation determined by 1H NMR. (b) Using Ru/C 5 % (20 w/w %). (c) Using K2CO3 as base. (d) Using Ru/C 5 % (40 w/w %).


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After the study of the scope and limitations of our method we then demonstrated its industrial applicability by running the reaction on multigram scale. With alanine 1a, lysine 1f and glycylglycine 1i as substrates and with our established conditions we obtained high deuterium incorporation and high yield, consistent with results on milligram scale. Scheme 1. Multi-gram scale labelling of 1a, 1f and 1i

In addition of the ease of purification, the use of a supported catalyst enables its recycling, addressing an important issue for a potential industrial application. No loss in deuterium incorporation was measured when we use a recycled catalyst compared to a commercial one. Finally, when at the end of the reaction, the solvent is distilled off, the catalyst filtered off, and both used again for a new reaction, an acceptable 80% deuterium incorporation is obtained.


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Scheme 2. Recycling experiments

CONCLUSION In conclusion, we reported a scalable method for the stereoretentive deuteration of amino acids and amines at α-positions. Using common reagents and vessel, high deuterium incorporations are obtained with full retention of configuration. The purification of the product by a simple filtration, and the possibility of recycling both catalyst and solvent make this protocol of interest for an industrial application. ASSOCIATED CONTENT Supporting Information. The following files are available free of charge. Experimental procedures and spectroscopic data of all compounds (PDF) AUTHOR INFORMATION Corresponding Author *Tel: +33 (0)169081175. E-mail: [email protected]


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ORCID Maxime ROCHE: 0000-0002-3902-8452 Notes The authors declare no competing financial interest. ACKNOWLEDGMENT AM thanks Research Executive Agency (REA) Marie Sklodowska-Curie Innovative Training Network for PhD fellowship (EUROPOL project, grant number 642773). We thank Dr. Bernard Rousseau (CEA Saclay) for informative discussions, we thank Florence Charnay-Pouget (Université Paris-Sud) for chiral HPLC analysis. And we also thank Dr. Cécile Santos (Institut de recherche Servier) and Dr. Abdallah Hamze (Université Paris-Sud) for advices in the manuscript preparation. REFERENCES (1)

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Development and Scale-Up of Stereoretentive Î±-Deuteration of

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