Development and Scale-Up of Stereoretentive α-Deuteration of Amines

Article abstract of DOI:10.1021/acs.oprd.7b00227

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 labeled compounds were obtained by a simple filtration process.

Full text of DOI:10.1021/acs.oprd.7b00227

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Full Paper
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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Development and Scaleꢀup of a Stereoretentive αꢀ
Deuteration of Amines
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Alessia Michelotti, Fabien Rodrigues and Maxime Roche *
CortecNet, 15ꢀ17 Rue des Tilleuls, 78960, VoisinsꢀleꢀBretonneux, France
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KEYWORDS : Deuteration, Ruthenium, Heterogenous catalysis, Amino Acids, Amines
ABSTRACT
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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 scaledꢀup 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
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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
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nucleus like H or C, and this is less expensive than C or 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 bioꢀ
organic6or 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 preꢀfunctionalized
starting materials enabling reductive deuteration at wellꢀdefined positions) and costꢀconsuming
(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 lateꢀstage functionalization of the desired compound
by hydrogenꢀdeuterium exchange (H/D exchange).11 Despite the attention that H/D exchange has
gained recently, the development of chemoꢀ 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 CꢀH bond adjacent to an heteroatom17 have been reported. In this field, a
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major breakthrough was achieved by Pieters and coꢀworkers in 2015, who reported an
enantiospecific deuteration of amino acids through CꢀH 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 coꢀworkers use
nonꢀcommercial catalyst in glove box and run the reaction in mediumꢀpressure 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 industrialꢀapplicable method for the stereoretentive αꢀdeuteration of
amino acids.
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RESULTS AND DISCUSSION
New reaction conditions avoiding the need of highꢀpressure reaction vessel, the use of nonꢀ
commercial nanocatalysts, or the application of electrochemistry must be identified. On the basis
of the work published by Sajiki and coꢀworkers 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 Lꢀ
alanine 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
CꢀH bond,16b and probably do not enable CꢀH activation via the mechanism proposed by Pieters
and coꢀworkers 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
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under various conditions
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Entry
Conditions
Ru/C (40%), without NaOH, 90 °C, 12h
Ru/C (40%), 90 °C, 12h
Pd/C (40%), 90 °C, 12h
Pt/C (40%), 90 °C, 12h
Ru/C (10%), 90 °C, 12h
Ru/C (10%), 70 °C, 12h
Ru/C (10%), 70 °C, 12hb
70 °C, 12h
D content (%)a
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40
>95
0
0
>95
>95
>99
0
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 Nꢀmethylvaline 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 GlyꢀGly 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 NꢀBocꢀalanine 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 αꢀpositons.
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Table 2. H/D exchange of amino acids and related compounds
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O
Me
OH
D NH2
Me
2a: 96%a
2d: 91%
2b: 96%b
2c: 96%
2e: 95%, 74%
2f: 90%, 92% c,d
2g: 94%, 96%
2j: 0%
2h: 95%, 62%
2k: 53%d
2i: 99%b,c
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.
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Scheme 1. Multiꢀgram 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
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CONCLUSION
In conclusion, we reported a scalable method for the stereoretentive deuteration of amino acids
and amines at αꢀpositions. 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. Eꢀmail: mroche@cortecnet.com
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ORCID
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Maxime ROCHE: 0000ꢀ0002ꢀ3902ꢀ8452
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Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENT
AM thanks Research Executive Agency (REA) Marie SklodowskaꢀCurie Innovative Training
Network for PhD fellowship (EUROPOL project, grant number 642773). We thank Dr. Bernard
Rousseau (CEA Saclay) for informative discussions, we thank Florence CharnayꢀPouget
(Université ParisꢀSud) for chiral HPLC analysis. And we also thank Dr. Cécile Santos (Institut
de recherche Servier) and Dr. Abdallah Hamze (Université ParisꢀSud) for advices in the
manuscript preparation.
REFERENCES
(1)
(2)
Mutlib, A. E. Chem. Res. Toxicol. 2008, 21 (9), 1672.
(a) von Bergen, M.; Jehmlich, N.; Taubert, M.; Vogt, C.; Bastida, F.; Herbst, F.ꢀA.;
Schmidt, F.; Richnow, H.ꢀH.; Seifert, J. ISME J. 2013, 7 (10), 1877. (b) Chahrour, O.; Cobice,
D.; Malone, J. J. Pharm. Biomed. Anal. 2015, 113, 2.
(3)
(a) Ciccimaro, E.; Blair, I. A. Bioanalysis 2010, 2 (2), 311. (b) Fan, T. W.ꢀM.;
Lorkiewicz, P. K.; Sellers, K.; Moseley, H. N. B.; Higashi, R. M.; Lane, A. N. Pharmacol. Ther.
2012, 133 (3), 366.
(4)
(a) Ong, H. H.; Wright, A. C.; Wehrli, F. W. J. Bone Miner. Res. 2012, 27 (12), 2573. (b)
Kennedy, B. W. C.; Kettunen, M. I.; Hu, D.ꢀE.; Brindle, K. M. J. Am. Chem. Soc. 2012, 134
(10), 4969.
(5)
(a) Mullard, A. Nat. Rev. Drug Discov. 2016, 15 (4), 219. (b) Gant, T. G. J. Med. Chem.
2014, 57 (9), 3595.
(6)
(a) Lin, G.ꢀM.; Choi, S.ꢀH.; Ruszczycky, M. W.; Liu, H. J. Am. Chem. Soc. 2015, 137
(15), 4964. (b) Ji, X.; Li, Y.; Jia, Y.; Ding, W.; Zhang, Q. Angew. Chem. 2016, 128 (10), 3395.
ACS Paragon Plus Environment
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Page 13 of 14
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3
4
5
6
7
8
(7)
(a) Erbing, E.; VázquezꢀRomero, A.; Bermejo Gómez, A.; PlateroꢀPrats, A. E.; Carson,
F.; Zou, X.; Tolstoy, P.; MartínꢀMatute, B. Chem. – Eur. J. 2016, 22 (44), 15659. (b) Su, B.;
Zhou, T.ꢀG.; Li, X.ꢀW.; Shao, X.ꢀR.; Xu, P.ꢀL.; Wu, W.ꢀL.; Hartwig, J. F.; Shi, Z.ꢀJ. Angew.
Chem. 2017, 129 (4), 1112.
9
(8)
401. (b)
(a) Stokvis, E.; Rosing, H.; Beijnen, J. H. Rapid Commun. Mass Spectrom. 2005, 19 (3),
Hewavitharana, A. K. J. Chromatogr. A 2011, 1218 (2), 359.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
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40
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42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(9) (a) Hsieh, C.ꢀT.; Ötvös, S. B.; Wu, Y.ꢀC.; Mándity, I. M.; Chang, F.ꢀR.; Fülöp, F.
ChemPlusChem 2015, 80 (5), 859. (b) Neumann, K. T.; Lindhardt, A. T.; BangꢀAndersen, B.;
Skrydstrup, T. J. Label. Compd. Radiopharm. 2017, 60 (1), 30.
(10) (a) Su, F.; Wu, F.; Tang, H.; Wang, Z.; Wu, F. J. Label. Compd. Radiopharm. 2015, 58
(13–14), 479. (b) Upshur, M. A.; Chase, H. M.; Strick, B. F.; Ebben, C. J.; Fu, L.; Wang, H.;
Thomson, R. J.; Geiger, F. M. J. Phys. Chem. A 2016, 120 (17), 2684.
(11) (a) Junk, T.; Catallo, W. J. Chem. Soc. Rev. 1997, 26 (5), 401. (b) Atzrodt, J.; Derdau, V.;
Fey, T.; Zimmermann, J. Angew. Chem. Int. Ed. 2007, 46 (41), 7744.
(12) (a) Burhop, A.; Weck, R.; Atzrodt, J.; Derdau, V. Eur. J. Org. Chem. 2017, 2017 (11),
1418. (b) Ma, S.; Villa, G.; ThuyꢀBoun, P. S.; Homs, A.; Yu, J.ꢀQ. Angew. Chem. Int. Ed. 2014,
53 (3), 734. (c) Piola, L.; FernándezꢀSalas, J. A.; Manzini, S.; Nolan, S. P. Org. Biomol. Chem.
2014, 12 (43), 8683.
(13) (a) Pony Yu, R.; Hesk, D.; Rivera, N.; Pelczer, I.; Chirik, P. J. Nature 2016, 529 (7585),
195. (b)
Prechtl, M. H. G.; Hölscher, M.; BenꢀDavid, Y.; Theyssen, N.; Loschen, R.;
Milstein, D.; Leitner, W. Angew. Chem. Int. Ed. 2007, 46 (13), 2269.
(14) (a) Di Giuseppe, A.; Castarlenas, R.; PérezꢀTorrente, J. J.; Lahoz, F. J.; Polo, V.; Oro, L.
A. Angew. Chem. Int. Ed. 2011, 50 (17), 3938. (b) Marek, A.; Pedersen, M. H. F.; Vogensen, S.
B.; Clausen, R. P.; Frølund, B.; Elbert, T. J. Label. Compd. Radiopharm. 2016, 59 (12), 476.
(15) (a) Erdogan, G.; Grotjahn, D. B. Top. Catal. 2010, 53 (15–18), 1055. (b) Erdogan, G.;
Grotjahn, D. B. J. Am. Chem. Soc. 2009, 131 (30), 10354.
(16) (a) Klei, S. R.; Golden, J. T.; Tilley, T. D.; Bergman, R. G. J. Am. Chem. Soc. 2002, 124
(10), 2092. (b) Yamada, T.; Park, K.; Yasukawa, N.; Morita, K.; Monguchi, Y.; Sawama, Y.;
Sajiki, H. Adv. Synth. Catal. 2016, 358 (20), 3277.
(17) (a) Sawama, Y.; Yabe, Y.; Iwata, H.; Fujiwara, Y.; Monguchi, Y.; Sajiki, H. Chem. –
Eur. J. 2012, 18 (51), 16436. (b) Chatterjee, B.; Gunanathan, C. Org. Lett. 2015, 17 (19), 4794.
(c) Neubert, L.; Michalik, D.; Bähn, S.; Imm, S.; Neumann, H.; Atzrodt, J.; Derdau, V.; Holla,
W.; Beller, M. J. Am. Chem. Soc. 2012, 134 (29), 12239. (d) Maegawa, T.; Fujiwara, Y.;
Inagaki, Y.; Monguchi, Y.; Sajiki, H. Adv. Synth. Catal. 2008, 350 (14–15), 2215. (e) Pieters, G.;
Taglang, C.; Bonnefille, E.; Gutmann, T.; Puente, C.; Berthet, J.ꢀC.; Dugave, C.; Chaudret, B.;
Rousseau, B. Angew. Chem. Int. Ed. 2014, 53 (1), 230.
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Organic Process Research & Development
Page 14 of 14
1
2
3
4
5
6
(18) Taglang, C.; MartínezꢀPrieto, L. M.; del Rosal, I.; Maron, L.; Poteau, R.; Philippot, K.;
Chaudret, B.; Perato, S.; Sam Lone, A.; Puente, C.; Dugave, C.; Rousseau, B.; Pieters, G. Angew.
Chem. Int. Ed. 2015, 54 (36), 10474.
7
8
9
(19) Bhatia, S.; Spahlinger, G.; Boukhumseen, N.; Boll, Q.; Li, Z.; Jackson, J. E. Eur. J. Org.
Chem. 2016, 2016 (24), 4230.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(20) (a) Yu, W.; Dawson, P. E.; Zimmermann, J.; Romesberg, F. E. J. Phys. Chem. B 2012,
116 (22), 6397. (b) Verardi, R.; Traaseth, N. J.; Masterson, L. R.; Vostrikov, V. V.; Veglia, G. In
Isotope labeling in Biomolecular NMR; Atreya, H. S., Ed.; Advances in Experimental Medicine
and Biology; Springer Netherlands, 2012; pp 35–62.
(21) Sajiki, H.; Kurita, T.; Esaki, H.; Aoki, F.; Maegawa, T.; Hirota, K. Org. Lett. 2004, 6
(20), 3521.
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