A Publication
of Reliable Methods
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Annual Volume
Org. Synth. 2011, 88, 197-201
DOI: 10.15227/orgsyn.088.0197
Submitted by Robert M. Williams*1
Original Article: Org. Synth. 1993, 71, 97
The use of the palladium-catalyzed Stille cross-coupling reaction4 for the synthesis of biaryls has become a popular and practical method5 mainly due to the air and moisture stability of organostannanes, the wide functional group compatibility under the reaction conditions and the generally readily available starting materials. Since the initial Organic Syntheses report of the preparation of 4-methoxy-4'-nitrophenyl,6 numerous advances have been made regarding substrate scope, improved reaction conditions and catalyst design. Herein we report on some of these advances7 as well as recent applications in total syntheses.8
The majority of the recent advances of the Stille coupling have come concomitantly with the advancement of ligand design for palladium catalysis.9 The advent of electron rich, bulky phosphine and carbene ligands allowed for much milder reaction conditions and increased substrate scope. Initially, the Stille reaction was limited to aryl iodides, bromides and triflates, typically at elevated temperature. In 1999 Fu and co-workers reported the first general method for the Stille cross-coupling of aryl chlorides using tri-t-butyl phosphine as a ligand for palladium and cesium fluoride to activate the tin reagent.10 More recently, Fu and co-workers have shown that similar reaction conditions can be utilized to cross-couple arylbromides at room temperature. In an analogous manner, Verkade and co-workers have shown that proazaphosphatrane ligands behave in a similar manner to the tri-t-butyl phosphine system utilized by Fu.11 Finally, Baldwin and co-workers have shown that the inclusion of copper(I) salts12 to the conditions reported by the Fu group significantly enhanced the reactivity of a variety of aryl bromides.
The Stille reaction has contributed significantly to numerous applications in the total synthesis of complex natural products because of the chemical stability of the coupling partners, the mild reaction conditions, and the functional group compatibility. In 2001, we reported a Stille coupling of 7-iodoisatin 1 and a suitably protected stannyl tyrosine derivative 2 (Scheme 1).13 Treatment of these coupling partners under routine conditions afforded biaryl 3 as a model system towards the total synthesis of TMC-95A/B (4).
Scheme 1. Albrecht and Williams' Studies toward TMC-95A/B
Scheme 1. Albrecht and Williams' Studies toward TMC-95A/B
In 2003, the Hoveyda and Snapper labs utilized a Stille biaryl coupling as a key macrocycle-forming reaction to provide a 17-membered ring in the total synthesis of chloropeptin 5.14 Macrocyclic precursor 6 was treated under the conditions reported by Fu, in the presence of collidine forming macrocycle 7 (Scheme 2). It is thought that the presence of collidine in the reaction stabilizes the active palladium complex thus preventing palladium black precipitation. The completion of chloropeptin was accomplished in an additional two steps.
Scheme 2. Hoveyda and Snapper's total synthesis of chloropeptin.
Scheme 2. Hoveyda and Snapper's total synthesis of chloropeptin.
Danishefsky and co-workers utilized a Stille biaryl coupling in the total synthesis and stereochemical revision of himastatin.15 Stannylation of aryliodide 8 afforded stannane 9 which was resubjected to aryliodide 8 under standard Stille conditions to afford dimer 10 (Scheme 3). This advanced biaryl intermediate was ultimately converted to himastatin thus allowing for the correct stereochemical assignment.
Scheme 3. Danishefsky's total synthesis of himastatin.
Scheme 3. Danishefsky's total synthesis of himastatin.
Since its first report, the Stille coupling has been a widely utilized carbon-carbon bond forming reaction. Recent advancements in homogenous palladium catalysis have rendered the Stille coupling reaction a much more attractive approach to the synthesis of complex biaryl systems. The examples above fully support the versatility and utility of this simple biaryl coupling reaction to highly functionalized and sterically demanding substrates. Efforts towards optimizing the Stille16 protocol are continuously being pursued allowing for milder reaction conditions and increased substrate scope. These on-going efforts demonstrate that the Stille reaction is one of the most synthetically useful biaryl coupling reactions in the synthesis of complex molecules.17

References and Notes
  1. Department of Chemistry, Colorado State University, Fort Collins, CO 80523 and the University of Colorado Cancer Center, Aurora, Colorado.
  2. Deceased.
  3. Department of Medicinal Chemistry, Amgen, Inc., One Kendall Square, Bldg. 1000, Cambridge, MA 02139.
  4. Stille, J.K. Angew. Chem. Int. Ed. Engl. 1986, 25, 508-524.
  5. For an excellent review of the Stille reaction see: Farina, V.; Krishnamurthy, V.; Scott, W.J. Org. React. 1997, 50, 1-652.
  6. Stille, J.K.; Echavarren, A.M.; Williams, R.M.; Hendrix, J.A. Org. Synth. 1993, 71, 97-106.
  7. For some recent reviews and highlights on the Stille reaction see: (a) Espinet, P.; Echavarren, A.M. Angew. Chem. Int. Ed. 2004, 43, 4704-4734. (b) Echavarren, A.M. Angew. Chem. Int. Ed. 2005, 44, 3962-3965.
  8. For a recent review of the Stille Reaction in natural product synthesis see: Nicolaou, K.C.; Bulger, P.G.; Sarlah, D. Angew. Chem. Int. Ed. 2005, 44, 4442-4489.
  9. Bedford, R. B.; Cazin, C. S. J.; Holder, D. Coord. Chem. Rev. 2005, 248, 2283-2321.
  10. Littke, A.F.; Fu, G.C. Angew. Chem. Int. Ed. 1999, 38, 2411-2413.
  11. Su, W. Urgaonkar, S.; McLaughlin, P.A.; Verkade, J.G. J. Am. Chem. Soc. 2004, 126, 16433-16439.
  12. (a) Mee, S.P.H.; Lee, V.; Baldwin. Angew. Chem. Int. Ed. 2004, 43, 1132-1136. (b) Mee, S.P.H.; Lee, V.; Baldwin. Chem. Eur. J. 2005, 11, 3294-3308. In addition to the inclusion of copper(I) salts a solvent change from dioxane to DMF was made.
  13. Albrecht, B.K.; Williams, R.M. Tetrahedron Lett. 2002, 42, 2755-2757.
  14. Deng, H.; Jung, J-K.; Liu, T.; Kuntz, K.W.; Snapper, M.L.; Hoveyda, A.H. J. Am. Chem. Soc. 2003, 125, 9032-9034.
  15. Kamenecka, T.M.; Danishefsky, S.J. Chem. Eur.J . 2001, 7, 41-63.
  16. Although not relevant to biaryl couplings the following are some noteworthy reports of Stille couplings catalytic in tin and of alkyl halides. For cross-couplings catalytic in tin see Gallagher, W.P.; Maleczka, R.E. J. Org. Chem. 2005, 70, 841-846, and references cited therein. For cross-coupling of alkyl halides see ref. 1b and references cited therein.
  17. The work performed at Colorado State University was financially supported by the National Institutes of Health and the National Science Foundation.
Robert M. Williams recieved his B.A. degree in Chemistry in 1975 from Syracuse University. He obtained the Ph.D. degree in 1979 at MIT (W.H. Rastetter) and was a post-doctoral fellow at Harvard (1979-1980; R.B. Woodward/Yoshito Kishi). He joined Colorado State University in 1980 and was named a University Distinguished Professor in 2002. His interdisciplinary research program at the chemistry-biology interface is focused on the total synthesis of biomedically significant natural products, biosynthesis of secondary metabolites, studies on antitumor drug-DNA interactions, HDAC inhibitors, amino acids and peptides.