COMMUNICATIONS
Laura Buglioni et al.
References
yields under mild reaction conditions. From a compari-
son of all three strategies (Table 1) the following con-
clusions can be drawn: (i) all four syntheses require
the use of protected amino acid derivatives as starting
materials; (ii) the N-Boc-protected tert-butyl esters of
methionine and buthionine (6c and 7c, respectively)
are the optimal starting materials because both pro-
tecting groups can finally be cleaved under acidic con-
ditions in one single step; (iii) in terms of step-econo-
my and overall yield the process involving the visible
[1] H. R. Bentley, E. E. Dermott, J. Pace, J. K. Whitehead,
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[6] Among all stereoisomers, l-methionine-(S)-sulfoximine
and the analogous buthionine derivative are the most
relevant ones. a) For MSO, see: J. M. Manning, S.
Moore, W. B. Rowe, A. Meister, Biochemistry 1969, 8,
2681–2685; b) B. W. Christensen, A. Kjær, S. Neidle, D.
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BSO, see: J. P. Fruehauf, S. Zonis, M. Al-Bassam, A.
Kyshtoobayeva, C. Dasgupta, T. Milovanovic, R. J.
Parker, A. C. Buzaid, Chem.-Biol. Interact. 1998, 111–
112, 277–305.
[7] The significance of BSO is indicated by a SciFinder
search performed on April 4, 2014, which provided
5840 references containing the concept of “buthionine
sulfoximine”.
[8] For selected recent applications of BSO, see: a) G. M.
Solecki, I. A. M. Groh, J. Kajzar, C. Haushofer, A.
Scherhag, D. Schrenk, M. Esselen, Chem. Res. Toxicol.
2013, 26, 252–261; b) I. Romero-Canelon, P. J. Sadler,
Inorg. Chem. 2013, 52, 12276–12291.
[9] For overviews on modifications of the glutathione me-
tabolism and their relevance to health, see: a) A. Meis-
ter, Science 1983, 220, 472–477; b) G. Wu, Y.-Z. Fang, S.
Yang, J. R. Lupton, N. D. Turner, J. Nutr. 2004, 134,
489–492.
[10] a) G. K. Balendiran, R. Dabur, D. Fraser, Cell. Bio-
chem. Funct. 2004, 22, 343–352; b) J. S. Lewis-Wambi,
V. C. Jordan, Breast Cancer Res. 2009, 11, 206.
[11] H. H. Bailey, Chem.-Biol. Interact. 1998, 111–112, 239–
254.
[12] For a list of clinical trials with BSO provided by the
clinicaltrials/search/results?protocolsearchid=6821964.
[13] H. R. Bentley, E. E. McDermott, J. K. Whitehead,
Proc. R. Soc. London Ser. B 1951, 138, 265–272.
[14] Due to the large required excess of NaN3/H2SO4 (up to
80 equiv.) the potential hazard of hydrazoic acid is
even more pronounced in direct approaches towards
MSO and BSO that start from methionine or buthio-
nine, respectively. For key references, see: a) J. K.
Whitehead, H. R. Bentley, J. Chem. Soc. 1952, 1572–
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light-promoted
ruthenium-catalyzed
imidation
(Scheme 4) is superior over the metal-free (Scheme 2)
and iron-catalyzed approaches (Scheme 3).
Compared to the existing technologies for the prep-
arations of MSO and BSO significant advances have
been achieved which we expect to be useful in other
areas of our research program focused on challenges
in syntheses of biologically active compounds.
Experimental Section
Typical Procedure for the Synthesis of MSO (and
BSO) by the One-Pot Imidation/Oxidation Sequence
Followed by Acidic Deprotection
To
a solution of amino acid derivative 6c (76.0 mg,
0.25 mmol) and dioxazolone 15 (25.6 mg, 0.25 mmol,
1 equiv.) in dry toluene (1 mL) under argon, was added Ru-
ACHTUNGTRENNUNG(TPP)CO (1.8 mg, 0.0025 mmol, 1 mol%). The reaction mix-
ture was irradiated with a 125 W high-pressure mercury
lamp at room temperature for 1 h. After evaporation of the
solvent, the mixture was dissolved in dichloromethane
(2.5 mL), and a solution of sodium periodate (107.0 mg,
0.5 mmol, 2 equiv.) in H2O (1.25 mL) was added. Using
a magnetic cross-shaped stir bar, strong stirring of the reac-
tion mixture was performed overnight. The mixture was
then extracted with dichloromethane (3ꢁ5 mL) and dried
over magnesium sulfate. After evaporation of the solvent,
protected MSO derivative 12cc was purified by column
chromatography. For the deprotection, 12cc (85.0 mg,
0.22 mmol) was dissolved in conc. HCl (2 mL/0.1 mmol) and
heated at 808C for 12 h. The product was then lyophilized,
purified on Dowex 50Wx8 (H+ form) and lyophilized again,
to give the MSO 1 as a white solid; yield: 25.0 mg
(0.14 mmol, 62%).
BSO (2) was prepared in 45% overall yield (23.6 mg,
0.11 mmol) in an analogous manner starting from amino
acid derivative 7c (86.9 mg, 0.25 mmol).
Acknowledgements
VB acknowledges the Alexander von Humboldt foundation
for a postdoctoral fellowship. The authors would like to
thank Prof. Jun Hiratake for technical advices and Dr. Seong
Jun Park as well as Dr. Victoria Vaillard for helpful discus-
sions.
[15] For MSO/BSO syntheses with NaN3/H2SO4 (3 equiv.)
starting from the corresponding 2-[2-(alkylthio)ethyl]
malonic acids (in yields of 25% and 30%), see: K. Hay-
ashi, Chem. Pharm. Bull. 1960, 8, 177–182.
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