J. Am. Chem. Soc. 1999, 121, 9449-9450
9449
Scheme 1
Bio-organometallic Organosulfur Chemistry. Transi-
tion Metal-Catalyzed Cross-Coupling Using Coen-
zyme M or Thioglycolic Acid as the Leaving Group
Jiri Srogl, Wansheng Liu, Daniel Marshall, and
Lanny S. Liebeskind*
Sanford S. Atwood Chemistry Center, Emory UniVersity,
1515 Pierce DriVe, Atlanta, Georgia 30322
ReceiVed May 18, 1999
Metal-thiol and -thiolate interactions occur commonly and
are of seminal importance in the biochemistry of life-sustaining
processes.1 Given the stability of the bond between a mercaptide
ligand and various redox-active metals, it is of interest that Nature
has evolved significant metalloenzymatic processes, which use
key interactions of sulfur-containing functionalities with metals
such as Ni, Co, Cu, and Fe (methanogenesis,2 acetyl CoA
synthesis,3 biological methyl transfers,4-6 and the mediation of
metal bioavailability by metallothioneins7-9). From a chemical
perspective, it is striking that these metals can function as robust
biocatalysts in vivo, even though they are often “poisoned” as
catalysts in vitro through formation of refractory metal thiolates.
Insight into the nature of this chemical discrepancy is essential
for a more complete understanding of biochemical processes and
could open the way to new procedures in synthetic organic and
organometallic chemistry.
Consider, for example, metal-catalyzed cross-coupling proto-
cols.10-15 Although some examples are known,16-19 thioorganic
compounds do not participate in as wide a range of metal-
catalyzed cross-coupling reactions as do iodoorganics. Why? Both
iodoorganics and thioorganics undergo oxidative addition reactions
with low-valent metals,20-24 so the answer must reside in the
difference between the metal-iodide and metal-thiolate bond
strengths. The metal-iodide bond is relatively weak and easily
substituted, whereas the metal-thiolate bond is strong. It resists
substitution and therefore retards catalysis, except under reaction
conditions where thiolate displacement from the metal is favored,
such as with potent nucleophilic reagents (RMgX).25
How might refractory metal thiolates be activated under mild
conditions and thus ensure the robust behavior of metal catalysts
in thiol/thiolate-rich environments? Transfer of thiolate to a metal
of greater thiophilicity has clear support in the domain of
biochemistry. For example, Zn(2+), a ubiquitous, non-redox-
active metal, is found throughout biological systems, and, of the
biologically relevant divalent metals, it has an affinity for thiolate
second only to that of copper.26 Therefore, the equilibrium M-SR
+ Zn2+ ) M+ + Zn+SR can be displaced toward the zinc
mercaptide with liberation of the metal M. Examples of this
principle are found in biology, medicine, and chemistry.27-29
We demonstrate herein a new synthetic process that uses the
above-mentioned principle and has its conceptual basis in a
bioorganometallic transformation with presumed primordial ori-
gins; namely, the putative final steps in methanogenesis, the
production of methane from methyl coenzyme M (CH3SCH2CH2-
SO3-) mediated by methyl coenzyme M reductase.2,30 In this
remarkably efficient process, a nickel hydrocorphinoid cofactor
(F430) ruptures the CH3-S- bond of CH3SCH2CH2SO3-, generat-
ing a CH3-Ni intermediate, which subsequently suffers proto-
nation to methane. If the C-S cleavage of S-substituted coenzyme
M derivatives by nickel catalysts a general process, then inhibition
of the biologically relevant protonation might allow interception
of the organonickel intermediate for alternative processes, such
as the formation of carbon-carbon bonds by way of a cross-
coupling protocol (Scheme 1).
* To whom correspondence should be addressed. Tel.: (404) 727-6604.
(1) Handbook of Metal-Ligand Interactions in Biological Fluids; Berton,
G., Ed.; Marcel Dekker: New York-Basel-Hong Kong, 1995.
(2) Ermler, U.; Grabarse, W.; Shima, S.; Goubeaud, M.; Thauer, R. K.
Science (Washington, D.C.) 1997, 278, 1457.
(3) Ragsdale, S. W.; Kumar, M. Chem. ReV. 1996, 96, 2515-2539.
(4) Matthews, R. G.; Goulding, C. W. Curr. Opin. Chem. Biol. 1997, 1,
332-339.
To test this hypothesis, salts of S-(p-tolyl)thioethanesulfonate
(1) were prepared and assayed as substrates in nickel-catalyzed
(5) Goulding, C. W.; Matthews, R. G. Biochemistry 1997, 36, 15749-
15757.
(6) Jablonski, P. E.; Lu, W.-P.; Ragsdale, S. W.; Ferry, J. G. J. Biol. Chem.
1993, 268, 325-329.
(25) Metal-catalyzed cross-coupling between Grignard reagents and aryl
and alkenyl sulfides and various dithiane derivatives is known: Fiandanese,
V.; Marchese, G.; Naso, F.; Ronzini, L. J. Chem. Soc., Chem. Commun. 1982,
647. Wenkert, E.; Leftin, M.; Michelotti, E. L. J. Chem. Soc., Chem. Commun.
1984, 617. Okamura, H.; Miura, M.; Takei, H. Tetrahedron Lett. 1979, 43.
Luh, T. Y. Acc. Chem. Res. 1991, 24, 257.
(26) Bertini, I.; Briganti, F.; Scozzafava, A. In Handbook of Metal-Ligand
Interactions in Biological Fluids; Berton, G., Ed.; Marcel Dekker: New York-
Basel-Hong Kong, 1995; Vol. 1, p 176.
(27) Mathews, A. P.; Walker, S. J. Biol. Chem. 1989, 6, 299.
(28) Korbashi, P.; Katzhendlers, J.; Saltman, P.; Chevion, M. J. Biol. Chem.
1989, 264, 8479.
(7) Jacob, C.; Maret, W.; Vallee, B. L. Proc. Natl. Acad. Sci. U.S.A. 1998,
95, 3489.
(8) Maret, W.; Vallee, B. L. Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 3478.
(9) Ka¨gi, J. H. R.; Scha¨ffer, A. Biochemistry 1988, 27, 8509-8515.
(10) Beletskaya, I. P. Pure Appl. Chem. 1997, 69, 471.
(11) Farina, V.; Krishnamurthy, V.; Scott, W. J. In Organic Reactions;
Paquette, L., Ed.; John Wiley & Sons: New York, 1997; Vol. 50, pp 1-652.
(12) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457-2483.
(13) Erdik, E. Tetrahedron 1992, 48, 9577-9648.
(14) Hatanaka, Y.; Hiyama, T. SynLett 1991, 845-853.
(15) Tamao, K.; Sumitani, K.; Kiso, Y.; Zembayashi, M.; Fujioka, A.;
Kodama, S.-i.; Nakajima, I.; Minato, A.; Kumada, M. Bull. Chem. Soc. Jpn.
1976, 49, 1958-1969.
(29) Cheng, C.-C.; Lu, Y.-L. J. Chem. Soc., Chem. Commun. 1998, 253-
254.
(30) Hausinger, R. P. In Biochemistry of Nickel; Plenum Press: New York,
1993; pp 147-180.
(16) Tokuyama, H.; Yokoshima, S.; Yamashita, T.; Fukuyama, T. Tetra-
hedron Lett. 1998, 39, 3189-3192.
(17) Wenkert, E.; Ferreira, T. W.; Michelotti, E. L. J. Chem. Soc., Chem.
Commun. 1979, 637-638.
(31) Please refer to the Supporting Information for experimental procedures.
(32) Typical experimental procedure: Under argon in a 50-mL Schlenk
tube, a solution of 3-carboxymethylsulfanyl benzoic acid ethyl ester (74 mg,
0.307 mmol) and NiCl2(PPh2Me)2 (7.4 mg, 0.014 mmol, 0.05 equiv) in dry,
degassed THF (4 mL) was treated with di-o-tolylzinc (2.1 mL of a solution
prepared from 0.7 mL of 1.0 M ZnCl2 and 1.4 mL of 1.0 M o-tolylMgCl).
After 14 h at 50 °C, the reaction mixture was allowed to cool and diluted
with 20 mL of Et2O. The organic layer was washed with 20 mL of saturated
NH4Cl and 20 mL of brine, dried (MgSO4), filtered, and concentrated to a
viscous yellow oil. Preparative thin-layer chromatography (20% Et2O/hexanes)
provided 2′-methylbiphenyl-3-carboxylic acid ethyl ester (54 mg, 0.226 mmol,
74%) as a colorless oil. Refer to the Supporting Information for details.
(18) Okamura, H.; Miura, M.; Takei, H. Tetrahedron Lett. 1979, 43-46.
(19) Fukuyama, T.; Lin, S.-C.; Li, L. J. Am. Chem. Soc. 1990, 112 , 7050.
(20) Planas, J. G.; Hirano, M.; Komiya, S. Chem. Lett. 1998, 123.
(21) Jones, W. D.; Dong, L. J. Am. Chem. Soc. 1991, 113, 559-564.
(22) Shaver, A.; Uhm, H. L.; Singleton, E.; Liles, D. C. Inorg. Chem. 1989,
28, 847-851.
(23) Osakada, K.; Maeda, M.; Nakamura, Y.; Yamamoto, T.; Yamamoto,
A. J. Chem. Soc., Chem. Commun. 1986, 442-443.
(24) Dobrzynski, E. D.; Angelici, R. J. J. Organomet. Chem. 1974, 76,
C53-C55.
10.1021/ja991654e CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/28/1999