Page 5 of 7
Journal of the American Chemical Society
In conclusion, a series of 13C-labeled acyl nickellacy-
cles have been efficiently prepared via the carbonylation
of 4-membered azametallacycles with stoichiometric car-
bon monoxide, and their reactivity has been studied. Sub-
jecting these organometallic scaffolds with a variety of
nucleophiles allowed for the isolation of 13C-labeled b-
amino acids and derivatives thereof, as well as b-amino
ketones. The utility of the metallacycles was demon-
strated by the rapid synthesis of a 13C-labeled variant of
the anti-diabetic drug sitagliptin. We envision that these
air-stable Ni-acyl complexes will provide new opportuni-
ties for the selective incorporation of carbon isotopes into
bioactive molecules.
Drug Discov. 2011, 6, 1247-1262. (c) Goodman, C. M.; Choi, S.;
Shandler, S.; DeGrado, W. F. Foldamers as versatile frameworks for
the design and evolution of function. Nat. Chem. Biol. 2007, 3,
252-262.
1
2
3
4
5
6
7
8
(5) (a) Nguyen, N. H.; Hughes, A. B.; Sleebs, B. E. Stereoselective
Synthesis and Application of b-Amino Ketones. Curr. Org. Chem.
2014, 18, 260-289. (b) Altmeyer, M.; Amtmann, E.; Heyl, C.;
Marschner, A.; Scheidig, A. J.; Klein, C. D. Beta-aminoketones as pro-
drugs for selective irreversible inhibitors of type-1 methionine ami-
nopeptidases. Bioorg. Med. Chem. Lett. 2014, 24, 5310-5314. (c) Sim-
plicio, A. L.; Clancy, J. M.; Gilmer, J. F. b-Aminoketones as prodrugs
with pH-controlled activation. Int. J. Pharm. 2007, 24, 208-214. (d)
Du, Y.; Li, Q.; Xiong, B.; Hui, X.; Wang, X.; Feng, Y.; Meng, T.; Hu,
D.; Zhang, D.; Wang, M. Aromatic b-amino-ketone derivatives as
novel selective non-steroidal progesterone receptor antagonist. Bioorg.
Med. Chem. 2010, 18, 4255-4268.
9
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
(6) For selected examples, see: (a) Ford, A.; Miel, H.; Ring, A.; Slat-
tery, C. N.; Maguire, A. R.; McKervey, M. A. Modern Organic Syn-
thesis with a-Diazocarbonyl Compounds. Chem. Rev. 2015, 115,
9981-10080. (b) Podlech, J.; Seebach, D. The Arndt-Eistert Reaction
in Peptide Chemistry: A Facile Access to Homopeptides. Angew.
Chem. Int. Ed. 1995, 34, 471-472. (c) Pace, V.; Verniest, G.; Sinisterra,
J.-V.; Alcántara, A. R.; De Kimpe, N. Improved Arndt-Eistert Synthe-
sis of a-Diazoketones Requiring Minimal Diazomethane in the Pres-
ence of Calcium Oxide as Acid Scavenger. J. Org. Chem. 2010, 75,
5760-5763.
ASSOCIATED CONTENT
The Supporting Information is available free of charge on
the ACS Publications website. Experimental procedures,
compound characterization, copies of NMR spectra and X-
ray crystallographic data (PDF).
AUTHOR INFORMATION
Corresponding Author
(7) For examples on 11C-labeling, see: (a) Andersen, T. L.; Friis, S. D.;
Audrain, H.; Nordeman, P.; Antoni, G.; Skrydstrup, T. Efficient 11C-
Carbonylation of Isolated Aryl Palladium Complexes for PET: Appli-
cation to Challenging Radiopharmaceutical Synthesis. J. Am. Chem.
Soc. 2015, 137, 1548-1555. (b) Andersen, T. L.; Nordeman, P.; Chris-
toffersen, H. F.; Audrain, H.; Antoni, G.; Skrydstrup, T. Application of
Methyl Bisphosphine-Ligated Palladium Complexes for Low Pressure
N-11C-Acetylation of Peptides. Angew. Chem. Int. Ed. 2017, 56,
4549-4553. (c) Neumann, K. T.; Donslund, A. S.; Andersen, T. L.;
Nielsen, D. U.; Skrydstrup, T. Synthesis of Aliphatic Carboxamides
Mediated by Nickel NN2-Pincer Complexes and Adaption to Carbon-
Isotope Labeling. Chem. Eur. J. 2018, 24, 14946-14949. (d) Norde-
man, P.; Friis, S. D.; Andersen, T. L.; Audrain, H.; Larhed, M.;
Skrydstrup, T.; Antoni, G. Rapid and Efficient Conversion of 11CO2 to
11CO through Silacarboxylic Acids: Applications in Pd-Mediated Car-
bonylations. Chem. Eur. J. 2015, 21, 17601-17604. (e) Lee, H. G.;
Milner, P. J.; Placzek, M. S.; Buchwald, S. L.; Hooker, J. M. Virtually
Instantaneous, Room-Temperature [11CO]-Cyanation Using Biaryl
Phosphine Pd(0) Complexes. J. Am. Chem. Soc. 2015, 137, 648-651.
(f) Zhao, W.; Lee, H. G.; Buchwald, S. L.; Hooker, J. M. Direct 11CN-
Labeling of Unprotected Peptides via Palladium-Mediated Sequential
Cross-Coupling Reactions. J. Am. Chem. Soc. 2017, 139, 7152-7155.
(8) For examples on 18F-labeling, see: (a) Lee, E.; Kamlet, A. S.; Pow-
ers, D. C.; Neumann, C. N.; Boursalian, G. B.; Furuya, T.; Choi, D. C.;
Hooker, J. M.; Ritter, T. A Fluoride-Derived Electrophilic Late-Stage
Fluorination Reagent for PET Imaging. Science 2011, 334, 639-642.
(b) Lee, E.; Hooker, J. M.; Ritter, T. Nickel-Mediated Oxidative Fluor-
ination for PET with Aqueous [18F]Fluoride. J. Am. Chem. Soc. 2012,
134, 17456-17458. (c) Taylor, N. J.; Emer, E.; Preshlock, S.; Schedler,
M:; Tredwell, M.; Verhoog, S.; Mercier, J.; Genicot, C.; Gouverneur,
V. Derisking the Cu-Mediated 18F-Fluorination of Heterocyclic Posi-
tron Emission Tomography Radioligands. J. Am. Chem. Soc. 2017,
139, 8267-8276. (d) Graham, T. J. A.; Lambert, R. F.; Ploessl, K.;
Kung, H. F.; Doyle, A. G. Enantioselective Radiosynthesis of Positron
Emission Tomography (PET) Tracers Containing [18F]Fluorohydrins.
J. Am. Chem. Soc. 2014, 136, 5291-5294. (e) McCammant, M. S.;
Thompson, S.; Brooks, A. F.; Krska, S. W.; Scott, P. J. H.; Sanford, M.
S. Cu-Mediated C–H 18F-Fluorination of Electron-Rich (Het-
ero)arenes. Org. Lett. 2017, 19, 3939-3942.
Notes
T.S. is co-owner of SyTracks A/S, which commercializes
the two-chamber system (COware®) and 13COgen.
ACKNOWLEDGMENT
We thank the Danish National Research Foundation (grant
no. DNRF118), NordCO2 and Aarhus University for finan-
cial support. We thank Magnus H. Rønne and Benjamin A.
Wahlqvist for assistance with the electrochemical setup and
13C NMR of the acyl nickellacycles, respectively.
REFERENCES
(1) Elmore, C. S.; Bragg, R. A. Isotope chemistry: a useful tool in the
drug discovery arsenal. Bioorg. Med. Chem. Lett. 2015, 25, 161-171.
(2) (a) Bronic, I. K.; Horvatinic, N.; Baresic, J.; Obelic, B. Measure-
ment of 14C activity by liquid scintillation counting. Appl. Radiat. Isot.
2009, 67, 800-804. (b) Solon, E. G.; Balani, S. K.; Lee, F. W. Whole-
body autoradiography in drug discovery. Curr. Drug. Metab. 2002, 3,
451-462. (c) Galimov, E. M.; Sevastyanov, V. S.; Kulbachevskaya, E.
V.; Golyavin, A. A. Isotope ratio mass spectrometry: d13C and d15N
analysis for tracing the origin og illicit drugs. Rapid. Commun. Mass
Spectrom. 2005, 19, 1213-1216. (d) Schellekens, R. C. A.; Stellaard,
F.; Woerdenbag, H. J.; Frijlink, H. W.; Kosterink, J. G. W. Applications
of stable isotopes in clinical pharmacology. Br. J. Clin. Pharmacol.
2011, 72, 879-897.
(3) (a) Cabrele, C.; Martinek, T. A.; Reiser, O.; Berlicki, L. Peptides
Containing b-Amino Acid Patterns: Challenges and Successes in Me-
dicinal Chemistry. J. Med. Chem. 2014, 57, 9718-9739. (b) Koyack,
M. J.; Cheng, R. P. Design and synthesis of beta-peptides with biolog-
ical activity. Methods Mol. Biol. 2006, 340, 95-109. (c) Czekster, C.
M.; Robertson, W. E.; Walker, A. S.; Söll, D.; Schepartz, A. In Vivo
Biosynthesis of a b-Amino Acid-Containing Protein. J. Am. Chem. Soc.
2016, 138, 5194-5197. (d) Kudo, F.; Miyanaga, A.; Eguchi, T. Biosyn-
thesis of natural products containing b-amino acids. Nat. Prod. Rep.
2014, 31, 1056-1073.
(9) For application of oxidative addition complexes in modification of
pharmaceuticals and peptides, see: (a) Vinogradova, E. V.; Zhang, C.;
Spokoyny, A. M.; Pentelute, B. L.; Buchwald, S. L. Organometallic
palladium reagents for cysteine bioconjugation. Nature 2015, 526,
687-691. (b) Lee, H. G.; Lautrette, G.; Pentelute, B. L.; Buchwald, S.
(4) (a) Cheng, R. P.; Gellmann, S. H.; DeGrado, W. F. b-Peptides: from
structure to function. Chem. Rev. 2001, 101, 3219-3232. (b) Horne, W.
S. Peptide and peptoid foldamers in medicinal chemistry. Expert Opin.
ACS Paragon Plus Environment