J. Am. Chem. Soc. 2001, 123, 8149-8150
8149
Table 1. Catalytic Hydroxylation of L-Valine: Optimization
Selective Functionalization of Amino Acids in Water:
A Synthetic Method via Catalytic C-H Bond
Activation
Brian D. Dangel, James A. Johnson, and Dalibor Sames*
catalyst/oxidant
(mol%/equiv)
yielda
anti/syn
isolated
mass balance
(%)
(1, %)
1a/1b
TON
0
yieldb (2, %)
Department of Chemistry, Columbia UniVersity
c
K2PtCl4/K2PtCl6
16/0.33
K2PtCl4/CuCl2
New York, New York 10027
21
5:1
91
d
ReceiVed May 25, 2001
ReVised Manuscript ReceiVed July 2, 2001
1/5
20
39
12
37
56
47
67
0
3:1
3:1
3:1
3:1
3:1
3:1
3:1
20
15
5
7
11
9
14
20
10
20
27
22
35
80
65
79
80
59
65
55
2.5/5
2.5/10
5/3
Amino acids are valuable building units and precursors for a
variety of organic compounds ranging from small molecules to
proteins. In living systems, the diversity of amino acid-derived
products is readily expanded by amino acid functionalization at
various stages of biosynthesis.1 Accordingly, a synthetic meth-
odology that would allow for the direct and selective function-
alization of available amino acids would be of significant
importance. However, most metal reagents and catalysts for C-H
activation are sensitive to functional groups or an aqueous
environment, two typical features of amino acid chemistry.2
Against such odds, there were two seemingly unrelated areas
which stimulated our investigation in this direction: first, the
original Shilov reaction (Pt(II)/Pt(IV)-mediated oxidation of
alkanes) is performed in aqueous acid solution,3 second, the
coordination chemistry of Pt(II) salts with amino acids and
proteins has been intensely studied due to the clinical use of
cisplatin in tumor therapy.4 In the process of merging these two
fields we discovered that the stoichiometric Shilov reaction was
compatible with amino acid substrates, and furthermore, we
developed a catalytic system capable of selective functionalization
of free R-amino acids in water.
Initial experiments involved submitting L-valine to an aqueous
solution of K2PtCl4 in the presence of K2PtCl6 as the oxidant.5
Surprisingly, heating the reaction mixture at 100 °C for 12 h
yielded two major products identified as diastereomers of γ-hy-
droxyvaline 1a and 1b in 5:1 ratio (anti/syn) (Table 1). Although
the conversion was low (<20% yield), this experiment demon-
strated that the chelation ability of the amino acid did not inhibit
the reaction but may in fact be responsible for the observed regio-
and stereoselectivity (see discussion below).
5/7
5/10
10/10
Na2S2O8/CuCl2
7
e
a Product/start. material ratio (×100) determined by 1H NMR of the
isolated crude mixture. b Isolated yields of 2 over three-step sequence
including hydroxylation, amino group protection and lactonization.
c Conditions: L-valine, 0.33 M in H2O, 100 °C, 10 h. Conditions:
d
L-valine, 0.33 M in H2O, 160 °C, 10 h. e Conditions: L-valine, 0.91 M
in H2O, 1 equiv of Na2S2O8 and 1 equiv of CuCl2 (or NaCl), 90 °C
(ref 12).
syn). Additionally, only limited racemization of the major products
and recovered starting material was found (<5% in 5 h, see
Supporting Information).8
Hitherto, CuCl2 and CuBr2 proved to be the only oxidants
capable of regenerating the active platinum species, while other
metal salts were ineffective (CuSO4, Cu(OAc)2, Cu(OTf)2, Cu-
(OMs)2, Cu(O3SPh)2, FeCl3). Screening the 1-10 mol % range
of K2PtCl4 in the presence of 1-10 equiv of CuCl2 was conducted
(Table 1). In most cases maximum conversion was reached within
10 h at 160 °C, whereas lower temperatures (∼130 °C) required
longer reaction times. The highest number of turnovers (20
turnovers based on the crude yield) was achieved in the presence
of 1 mol % of K2PtCl4 and 5 equiv of CuCl2. After the reaction
yield was balanced with the amount of the platinum catalyst
required, the most practical conditions were determined to be 5
mol % of platinum catalyst and 7 equiv of copper chloride, to
furnish a 56% yield of hydroxyvaline isomers 1a and 1b. The
products were converted to N-Boc-lactones, obtained in 27%
overall yield.
Traditionally, C-H bond functionalization has been achieved
via radical processes where regioselectivity in complex substrates
has often been controlled through intramolecular abstraction of a
hydrogen atom by a proximal nitrogen or oxygen-centered radical
(e.g., Hoffmann-Lo¨ffler-Freytag reaction,9 Barton reaction,10
Breslow remote oxidation11). As an important control experiment,
we submitted L-valine to conditions known to generate a carboxyl-
centered radical (Na2S2O8, CuCl2 or NaCl).12 It was determined
that no hydroxyvaline 1 was formed, while simple carboxylic
acids yielded γ-lactones in moderate yields (Table 1)! This
experiment strongly suggested that the catalytic process developed
herein did not proceed via a free radical mechanism, and it
Encouraged by these results we focused our attention toward
the development of a catalytic system based on platinum in
combination with a practical oxidant. Copper(II) salts have been
used to oxidize Pd(0) in the Wacker process,6 and Pt(0)/Pt(II) in
the Shilov and related oxidations.7 Consequently, we treated
L-valine with a catalytic amount of K2PtCl4 (1-10 mol %) in the
presence of a stoichiometric amount of CuCl2 in water. Remark-
ably, at temperatures >130 °C, catalytic turnoVers were obserVed,
and the C-H bond functionalization occurred with regio- and
stereoselectiVity, affording lactones 1a and 1b in a 3:1 ratio (anti:
(1) (a) Herbert, R. B. Nat. Prod. Rep. 1999, 16, 199-208. (b) Sahl, H.-G.;
Jack, R. W.; Bierbaum, G. Eur. J. Biochem. 1995, 230, 827-853.
(2) Jones, W. D. In ActiVation of UnreactiVe Bonds and Organic Synthesis;
Murai, S., Ed.; Springer: Berlin, 1999; pp 9-46.
(3) Shilov, A. E.; Shul’pin, G. B. ActiVation and Catalytic Reactions of
Saturated Hydrocarbons in the Presence of Metal Complexes; Kluwer
Academic Publishers: Dordrecht, 2000.
(8) Smith, G. G.; Khatib, A. Reddy, G. S. J. Am. Chem. Soc. 1983, 105,
293-295.
(9) (a) Corey, E. J.; Hertler, W. R. J. Am. Chem. Soc. 1958, 80, 2903-
2904. (b) Buchschacher, P.; Kalvoda, J.; Arigoni, D.; Jeger, O. J. Am. Chem.
Soc. 1958, 80, 2905-2906.
(4) (a) Appleton, T. G. Coord. Chem. ReV. 1997, 166, 313-359. (b)
Reedijk, J. Chem. ReV. 1999, 99, 2499-2510.
(5) (a) Labinger, J. A.; Herring, A. M.; Lyon, D. K.; Luinstra, G. A.;
Bercaw, J. E.; Horva´th, I. T.; Eller, K. Organometallics 1993, 12, 895-905.
(b) Kao, L.-C.; Sen, A. J. Chem. Soc., Chem. Commun. 1991, 1242-1243.
(6) Tsuji, J. Palladium Reagents and Catalysts; John Wiley and Sons:
Chichester, 1995; pp 19-124.
(10) Barton, D. H. R.; Beaton, J. M. J. Am. Chem. Soc. 1961, 83, 4083-
4089.
(11) Breslow, R.; Baldwin, S.; Flechtner, T.; Kalicky, P.; Liu, S.; Washburn,
W. J. Am. Chem. Soc. 1973, 95, 3251.
(12) (a) Nikishin, G. I.; Svitanko, I. V.; Troyansky, E. I. J. Chem. Soc.,
Perkin Trans, II 1983, 595-601. For photochlorination and photobromination
of amino acids: (b) Kollonitsch, J.; Scott, A. N.; Doldouras, G. A. J. Am.
Chem. Soc. 1966, 88, 3624-3626. (c) Easton, C. J.; Hutton, C. A.; Tan, E.
W.; Tiekink, E. R. T. Tetrahedron Lett. 1990, 31, 7059-7062.
(7) (a) Lin, M.; Shen, C.; Garcia-Zayas, E. A.; Sen, A. J. Am. Chem. Soc.
2001, 123, 1000-1001. (b) VanKoten, G.; Terheijden, J.; van Beek, J. A.
M.; Wehman-Ooyevaar, I. C. M.; Muller, F.; Stam, C. H. Organometallics
1990, 9, 903-912.
10.1021/ja016280f CCC: $20.00 © 2001 American Chemical Society
Published on Web 07/31/2001