SCHEME 1
Rh od iu m -Ca ta lyzed Asym m etr ic Rin g
Op en in g of Oxa bicyclic Alk en es w ith
Su lfu r Nu cleop h iles
Paul Leong and Mark Lautens*
Davenport Research Laboratories, Department of Chemistry,
University of Toronto, Toronto, Ontario, Canada M5S 3H6
TABLE 1. Effect of Ha lid e/P r otic Ad d itives on
En a n tioselectivitya
mlautens@chem.utoronto.ca
Received November 25, 2003
Abstr a ct: The synthesis of 2-sulfanyl-1,2-dihydro-naph-
thalen-1-ols is described. This methodology is based on
rhodium catalysis and enables various thiols to undergo an
asymmetric SN2′ ring opening of oxabenzonorbornadiene.
Under the reaction conditions ([Rh(COD)Cl]2 (2.5 mol %),
(S)-(R)-PPF-PtBu2 (6 mol %), AgOTf (7 mol %), NH4I (1.7
equiv), galvinoxyl (5 mol %), THF, 85 °C), aryl- and alkyl-
sulfide adducts are obtained in good to excellent yield and
in high enantiomeric excess (>90% ee).
entry
nucleophile
additive
% eeb
1
2
3
4
5
6
7
8
thiophenol
thiophenol
thiophenol
thiophenol
thiophenol
thiophenol
thiophenol
thiophenol
38
36
51
64
50
80
88
94
TBAF
NH4F
TBABr
NH4Br
TBAI
NH4I
Transition metal sulfur chemistry is prevalent in both
biological systems and industrial applications. Here, the
metal-sulfide component is an essential part for bioac-
tivity in enzymes such as ferredoxin and nitrogenase, as
well as in industrial technologies such as corrosion and
lubrication.1 However, the affinity of sulfur to form strong
bonds with transition metals invariably complicates
catalytic reactions. Consequently, there are very few
reports of transition-metal-catalyzed reactions involving
thiols,2 in particular, those used to form C-S bonds.3
Our group has a long-standing interest in metal-
catalyzed desymmetrization reactions of meso compounds
as a strategy to generate stereocenters in a single
enantio-determining step.4 Depending on the metal, these
reactions include addition of nucleophiles such as hy-
dride, stabilized and nonstabilized carbanions, alcohols,
amines, and carboxylates.5 Particular attention has been
placed on the desymmetrization of oxobenzonorborna-
diene 1, as the products are precursors to the medicinally
important tetrahydronaphthalene moiety (Scheme 1).6
NH4Ic
a
Conditions: 2.5 mol % [Rh(COD)Cl]2, 6 mol % ligand, 1.5 equiv
of nucleophile, 2 equiv of halide additive, in 0.1 M THF. For typical
b
conditions see Supporting Information. ee was determined by
CSP HPLC with a Chiracel OD column. c Prior to the addition of
reagents, a halide exchange was performed; see Supporting
Information for experimental details.
In contrast to our previous studies, the high polariz-
ability and redox capability of sulfur-containing nucleo-
philes make them more prone to catalyst poisoning and
background reactions. Herein, we report methodology
that overcomes these obstacles and enables a highly
enantioselective nucleophilic addition of thiols to oxa-
benzonorbornadiene 1 in good to excellent yield.
Our previous efforts in the asymmetric ring opening
of 1 with oxygen- and nitrogen-based nucleophiles uti-
lized [Rh(COD)Cl]2 in combination with an electron-rich
J osiphos-type ligand, PPF-PtBu2. From this starting
5
point, screening of catalyst systems revealed that both
the halide counterion and the protic additive dramatically
affected the enantioselectivity of the desymmetrization
reaction.7 An increase in enantioselectivity was observed
in changing the halide from F f Cl f Br f I (Table 1);8
with triflate as a counterion, an intractable mixture of
products was obtained. Furthermore, the protic nature
of the ammonium halide additive proved beneficial,
(1) Stiefel, E. I.; Matsumoto, K. Transition Metal Sulfur Chemis-
try: Biological and Industrial Significance; ACS Symposium Series
653; American Chemical Society: Washington, DC, 1996.
(2) (a) Arisawa, M.; Yamaguchi, M. J . Am. Chem. Soc. 2003, 125,
6624-6625. (b) Bates, C. G.; Gujadhur, R. K.; Venkataraman, D. Org.
Lett. 2002, 4, 2803-2806.
(3) (a) Kwong, F. Y.; Buchwald, S. L. Org. Lett. 2002, 4, 3517-3520.
(b) Adam, W.; Bargon, R. M.; Bosio, S. G.; Schenk, W. A.; Stalke, D. J .
Org. Chem. 2002, 67, 7037-7041. (c) J acob, J .; Reynolds, K. A.; J ones,
W. D. Organometallics 2001, 20, 1028-1031. (d) Kanemasa, S.;
Oderaotoshi, Y.; Wada, E. J . Am. Chem. Soc. 1999, 121, 8675-8676.
(e) Zhang, X.; Ma, M.; Wang, J . Catalytic Asymmetric S-H Insertion
Reaction of Carbenoids. ARKIVOC Gainsville, FL, U.S. 2003, 2, 84-
91.
(6) (a) Snyder, S. E.; Aviles-Garay, F. A.; Chakraborti, R.; Nichols,
D. E.; Watts, V. J .; Mailman, R. B. J . Med. Chem. 1995, 38, 2395-
2409. (b) Kamal, A.; Gayatri, N. L. Tetrahedron Lett. 1996, 37, 3359-
3362. (c) Kim, K.; Guo, Y.; Sulikowski, G. A. J . Org. Chem. 1995, 60,
6866. (d) Perrone, R.; Berardi, F.; Colabufo, N. A.; Leopoldo, M.;
Tortorella, V.; Fiorentini, F.; Olgiati, V.; Ghiglieri, A.; Govoni, S. J .
Med. Chem. 1995, 3, 8, 942-949.
(7) For halide effects in transition metal catalyzed reactions, see:
(a) Fagnou, K.; Lautens, M. Angew. Chem., Int. Ed. 2002, 41, 26-47.
(b) Lautens, M.; Fagnou, K. J . Am. Chem. Soc. 2001, 123, 7170-7171.
(8) This trend in enantioselectivity is different than that observed
for oxygen- and nitrogen-based nucleophiles; see ref 7b.
(4) Lautens, M.; Fagnou, K.; Hiebert, S. Acc. Chem. Res. 2003, 36,
48-58.
(5) (a) Lautens, M.; Rovis, T. J . Org. Chem. 1997, 62, 5246-5247.
(b) Lautens, M.; Hiebert, S.; Renaud, J . L. J . Am. Chem. Soc. 2001,
123, 6834-6839. (c) Lautens, M.; Fagnou, K.; Rovis, T. J . Am. Chem.
Soc. 2000, 122, 5650-5651. (d) Lautens, M.; Fagnou, K.; Taylor, M.
Org. Lett. 2000, 2, 1677-1679. (e) Lautens, M.; Fagnou, K. Tetrahedron
2001, 57, 5067-5072. (f) Lautens, M.; Dockendorff, C.; Fagnou, K.;
Malicki, A. Org. Lett. 2002, 4, 1311-1314.
10.1021/jo035730e CCC: $27.50 © 2004 American Chemical Society
Published on Web 02/13/2004
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J . Org. Chem. 2004, 69, 2194-2196