COMMUNICATIONS
generates acyl-catalyst intermediate III. Similar mechanisms
have been observed in the neighboring group participation by
carbonyl hydrates during the hydrolysis of carboxylate and
phosphate esters. However these examples are stoichiometric
reactions that are promoted by intramolecular carbonyl
groups.[9±11] 3) Deacylation of the acyl-enzyme intermediate
regenerates the catalysts. This process is mimicked by reaction
of III with hydroxide to give tetrahedral intermediate IV,
which then breaks down to yield hemithioacetal V. Dissoci-
ation of V releases the carboxylate anion and regenerates the
4-heterocyclohexanone catalyst.
We have performed two additional experiments to probe
the validity of this proposed mechanism. First, we have
synthesized control compound 8 in which the thiol group is
blocked as the methyl thioether in order to determine if a thiol
functionality in the substrate is necessary for catalysis.
Comparison of entries 1 and 10 in Table 1 shows that the
rate of hydrolysis of 8 in the presence of 600mm catalyst is
only sevenfold faster than the rate of hydrolysis of substrate 5
in the absence of catalyst. This comparison shows that a free
thiol group in the substrate is required for catalysis. In
addition, the results shows that the mechanism of the
catalyzed reaction cannot involve simple intermolecular
nucleophilic attack by the anion of the 4-heterocyclohexa-
none hydrate on the carbonyl of the amide substrate.
Keywords: amides
mimetics ´ hydrolyses ´ synthetic proteases
´ electrostatic interactions ´ enzyme
[1] For amide hydrolysis promoted by metals, see a) J. T. Groves, L. A.
Baron, J. Am. Chem. Soc. 1989, 111, 5442; b) A. W. Czarnik, K. Chen,
S. P. Wathen, Tetrahedron Lett. 1992, 33, 6303; c) R. Breslow, A.
Schepartz, J. Am. Chem. Soc. 1987, 109, 1814; d) N. N. Murthy, M.
Mahroof-Tahir, K. D. Karlin, J. Am. Chem. Soc. 1993, 115, 10404;
e) L. M. Sayre, K. V. Reddy, A. R. Jacobson, W. Tang, Inorg. Chem.
1992, 31, 937; f) T. J. Przystas, T. H. Fife, J. Chem. Soc. Perkin Trans. 2
1990, 393; g) J. Chin, V. Jubian, K. Mrejen, J. Chem. Soc. Chem.
Commun. 1990, 1326; for examples of other types of catalysts, see
h) J. W. Keillor, A. A. Neverov, R. S. Brown, J. Am. Chem. Soc. 1994,
116, 4669; i) J. Suh, I. M. Klotz, J. Am. Chem. Soc. 1984, 106, 2373.
[2] For catalytic hydrolysis of esters, see a) B. Zhang, R. Breslow, J. Am.
Chem. Soc. 1997, 119, 1676; b) F. Diederich, G. Schurmann, I. Chao, J.
Org. Chem. 1988, 53, 2744; c) F. M. Menger, L. G. Whitesell, J. Am.
Chem. Soc. 1985, 107, 707; for a related transesterification reaction,
see d) T. Sammakia, T. B. Hurley, J. Am. Chem. Soc. 1996, 118, 8967.
[3] D. H. Kahne, W. C. Still, J. Am. Chem. Soc. 1988, 110, 7529.
[4] J. L. Conroy, T. C. Sanders, C. T. Seto, J. Am. Chem. Soc. 1997, 119, 4285.
[5] J. L. Conroy, C. T. Seto, J. Org. Chem. 1998, 63, 2367.
[6] See the supporting information for representative examples.
[7] The apparent equilibrium constant for addition of 3-mercaptopro-
pionic acid to tetrahydropyranone under neutral conditions in 100%
D2O is 1.3m 1; see reference [4] for details.
[8] a) M. L. Bender, R. J. Thomas, J. Am. Chem. Soc. 1961, 83, 4183;
b) R. L. Schowen, H. Jayaraman, L. Kershner, J. Am. Chem. Soc. 1966,
88, 3373; c) L. D. Kershner, R. L. Schowen, J. Am. Chem. Soc. 1971,
93, 2014.
[9] See K. Bowden, Chem. Soc. Rev. 1995, 24, 431, and references therein.
[10] A similar mechanism has been proposed for the hydrolysis of sulfate
esters catalyzed by human arylsulfatase A. This reaction involves
participation by an aldehyde hydrate: G. Lukatela, N. Krauss, K.
Theis, T. Selmer, V. Gieselmann, K. von Figura, W. Saenger, Bio-
chemistry 1998, 37, 3654.
[11] For the hydrolysis of a-aminonitriles assisted by aldehydes and
ketones, see M. Paventi, F. L. Chubb, J. T. Edwards, Can. J. Chem.
1987, 65, 2114, and references therein.
In a second experiment we have independently synthesized
the acyl-catalyst intermediate III (Scheme 1) in which X S,
and we monitored its rate of hydrolysis under the reaction
conditions. We find that this intermediate is hydrolyzed much
faster than the amide substrates in any of the catalyzed
reactions. These two observations are consistent with the
mechanism proposed in Scheme 1, and they suggest that the
rate-limiting step for the catalyzed reaction occurs before
hydrolysis of intermediate III.
In conclusion, we have demonstrated that tetrahydropyr-
anone (4) is an effective catalyst for the hydrolysis of amide
substrates that contain an adjacent thiol functionality. The
reaction displays two features that are most often associated
with enzymatic systems. First, the substrate is bound to the
catalyst through a preliminary equilibrium in order to
decrease the entropic barrier to reaction. The catalysts
employ reversible formation of a hemithioacetal to establish
this equilibrium. We believe that formation of reversible
covalent bonds of this type will prove to be a useful method
for mediating the molecular recognition processes that are
involved in catalysis and self-assembly. Reversible covalent
bonds are complementary to the noncovalent interactionsÐ
such as hydrogen bonds, hydrophobic interactions, and
electrostatic interactionsÐthat are typically observed in
biological recognition processes. A second similarity to
enzymatic catalysis is that the reaction is catalyzed through
the participation of neighboring groups. We are currently
conducting experiments to characterize further the mecha-
nism of the reaction, and also to explore the possibility of
using 4-heterocyclohexanones to catalyze the cysteine-specif-
ic hydrolysis of peptides.
Highly Enantioselective Hydrogenation of
Cyclic Enol Acetates Catalyzed by a
Rh ± PennPhos Complex**
Qiongzhong Jiang, Dengming Xiao, Zhaoguo Zhang,
Ping Cao, and Xumu Zhang*
The growing demand for practical and effective chiral
ligands and/or catalysts has fueled much recent progress in
ligand design. Although benchmark ligands such as 2,2'-
[*] Prof. X. Zhang, Dr. Q. Jiang, D. Xiao, Dr. Z. Zhang, P. Cao
Department of Chemistry
The Pennsylvania State University
University Park, PA 16802 (USA)
Fax : ( 1)814-863-8403
[**] This work was supported by a Camille and Henry Dreyfus New
Faculty Award and Teaching Scholar Award, an ONR Young
Investigator Award, a DuPont Young Faculty Award, Catalytica
Pharmaceuticals, and DuPont Agrochemical Products. We acknowl-
edge a generous loan of precious metals from Johnson Matthey Inc.
and a gift of chiral GC columns from Supelco. PennPhos P,P'-1,2-
phenylenebis(endo-2,5-dialkyl-7-phosphabicyclo[2.2.1]heptanes).
Received: August 17, 1998
Revised version: October 15, 1998 [Z12293IE]
German version: Angew. Chem. 1999, 111, 575 ± 578
516
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