Introduction
Copper catalyzed allylic substitutions are characterized by their unique regioselectivity compared to other transition metal catalyzed allylic substitutions, the most well-known being the palladium catalyzed Tsuji-Trost reaction[1]. The distinct mechanism of copper catalyzed allylic substitutions has been known to provide high regioselectivity of the gamma substituted product, compared to the alpha substituted isomer[1]. The copper catalyst used can be symmetrical with two identical R groups, or with two different ligands. These reactions typically utilize “hard” carbon nucleophiles such as Grignard, diorganozinc, organolithium, and trialkyl aluminum reagents[1]. This contrasts palladium catalyzed allylic substitutions which involve “soft” nucleophiles. [1]
Mechanism:
The catalytic cycle begins with coordination of the Cu(I) species to the olefin, followed by oxidative addition at the γ position and an allylic shift to displace the leaving group[2]. This generates a Cu(III) allyl complex intermediate[2]. Finally, reductive elimination yields the final product and regenerates Cu(I)[2]. A Cu(III) intermediate has not been confirmed by isolation from allylic substitutions, but Cu(III) intermediates have been isolated before, thus providing credence to the proposed mechanism.[2] If reductive elimination does not occur fast enough, the γ allyl complex can isomerize to the α allyl complex and yield the α substituted isomer as a byproduct. This side pathway can be prevented by using electron withdrawing ligands on copper, typically a cyanide or halide ligand, which promote reductive elimination. [3]
Asymmetric Copper-Catalyzed Allylic Substitution
Mechanistically, oxidative addition is the step that determines which enantiomer is formed[3]. Chiral ligands on the metal center along with low temperatures are the general tactics employed to produce an enantiopure product.[4] In particular, the careful pairing of ligand classes with the type of nucleophile has proven to be essential. With Grignard reagents, ferrocenyl thiolate[5][6], phosphorous[7], and NHC[8] ligands are typically used. There have also been several methods developed using diorganozinc nucleophiles coupled with phosphorous[9][10], amine[11], peptide[12], and NHC[13] ligands. The scope of organoaluminium nucleophiles is comparatively smaller, but there have been a couple examples using NHC ligands[14]. There is a need for more studies to better understand the mechanism of stereoinduction to expand the known set of reactions to encompass a larger overall substrate scope and to potentially allow for enantioselectivity at room temperature[4].
Application in Natural Product Synthesis
There have been several enantioselective versions of this reaction developed, and even employed in synthesis of complex molecules. Hoyveda’s synthesis of (R)-(-)-sporochnol included an asymmetric copper catalyzed allylic substitution with an organozinc nucleophile and peptide ligand[15].
A TaniaPHOS ligand, a ferrocenylphosphine, is used with a methyl Grignard nucleophile to form an allylic stereocenter towards the total synthesis of (S)-(-)-Zearalenone[16].
- ^ a b c d Hartwig, John Frederick (2010). Organotransition metal chemistry: from bonding to catalysis (1 ed.). Sausalito (Calif.): University science books. ISBN 189138953X.
- ^ a b c d Yoshikai, Naohiko; Nakamura, Eiichi (11 April 2012). "Mechanisms of Nucleophilic Organocopper(I) Reactions". Chemical Reviews. 112 (4): 2339–2372. doi:https://doi.org/10.1021/cr200241f.
{{cite journal}}: Check|doi=value (help); External link in|doi= - ^ a b Alexakis, Alexandre; Malan, Christophe; Lea, Louise; Tissot-Croset, Karine; Polet, Damien; Falciola, Caroline (28 March 2006). "The Copper-Catalyzed Asymmetric Allylic Substitution". CHIMIA. 60 (3): 124–124. doi:https://doi.org/10.2533/000942906777674994.
{{cite journal}}: Check|doi=value (help); External link in|doi= - ^ a b Cotton, Hanna K.; Norinder, Jakob; Bäckvall, Jan-E. (12 June 2006). "Screening of ligands in the asymmetric metallocenethiolatocopper(I)-catalyzed allylic substitution with Grignard reagents". Tetrahedron. 62 (24): 5632–5640. doi:https://doi.org/10.1016/j.tet.2006.03.100.
{{cite journal}}: Check|doi=value (help); External link in|doi= - ^ Alexakis, Alexandre; Croset, Karine (1 November 2002). "Tandem Copper-Catalyzed Enantioselective Allylation−Metathesis". Organic Letters. 4 (23): 4147–4149. doi:https://doi.org/10.1021/ol0269244.
{{cite journal}}: Check|doi=value (help); External link in|doi= - ^ Alexakis, Alexandre; Croset, Karine (2002-11-01). "Tandem Copper-Catalyzed Enantioselective Allylation−Metathesis". Organic Letters. 4 (23): 4147–4149. doi:10.1021/ol0269244. ISSN 1523-7060.
- ^ Tominaga, Satoshi; Oi, Yukinao; Kato, Toshio; An, Duk Keun; Okamoto, Sentaro (12 July 2004). "γ-Selective allylic substitution reaction with Grignard reagents catalyzed by copper N-heterocyclic carbene complexes and its application to enantioselective synthesis". Tetrahedron Letters. 45 (29): 5585–5588. doi:https://doi.org/10.1016/j.tetlet.2004.05.135.
{{cite journal}}: Check|doi=value (help); External link in|doi= - ^ van Zijl, Anthoni W.; Arnold, Leggy A.; Minnaard, Adriaan J.; Feringa, Ben L. (March 2004). "Highly Enantioselective Copper-Catalyzed Allylic Alkylation with Phosphoramidite Ligands". Advanced Synthesis & Catalysis. 346 (4): 413–420. doi:https://doi.org/10.1002/adsc.200303207.
{{cite journal}}: Check|doi=value (help); External link in|doi= - ^ Tissot-Croset, Karine; Polet, Damien; Alexakis, Alexandre (26 April 2004). "A Highly Effective Phosphoramidite Ligand for Asymmetric Allylic Substitution". Angewandte Chemie International Edition. 43 (18): 2426–2428. doi:https://doi.org/10.1002/anie.200353744.
{{cite journal}}: Check|doi=value (help); External link in|doi= - ^ Goldsmith, Paul J.; Teat, Simon J.; Woodward, Simon (8 April 2005). "Enantioselective Preparation of ?,?-Disubstituted ?-Methylenepropionates by MAO Promotion of the Zinc Schlenk Equilibrium". Angewandte Chemie. 117 (15): 2275–2277. doi:https://doi.org/10.1002/ange.200463028.
{{cite journal}}: Check|doi=value (help); External link in|doi= - ^ Luchaco-Cullis, Courtney A.; Mizutani, Hirotake; Murphy, Kerry E.; Hoveyda, Amir H. (17 April 2001). "Modular Pyridinyl Peptide Ligands in Asymmetric Catalysis: Enantioselective Synthesis of Quaternary Carbon Atoms Through Copper-Catalyzed Allylic Substitutions". Angewandte Chemie International Edition. 40 (8): 1456–1460. doi:https://doi.org/10.1002/1521-3773(20010417)40:8<1456::AID-ANIE1456>3.0.CO;2-T.
{{cite journal}}: Check|doi=value (help); External link in|doi= - ^ Larsen, Andrew O.; Leu, Wenhao; Oberhuber, Christina Nieto; Campbell, John E.; Hoveyda, Amir H. (1 September 2004). "Bidentate NHC-Based Chiral Ligands for Efficient Cu-Catalyzed Enantioselective Allylic Alkylations: Structure and Activity of an Air-Stable Chiral Cu Complex". Journal of the American Chemical Society. 126 (36): 11130–11131. doi:https://doi.org/10.1021/ja046245j.
{{cite journal}}: Check|doi=value (help); External link in|doi= - ^ Geurts, Koen; Fletcher, Stephen P.; Zijl, Anthoni W. van; Minnaard, Adriaan J.; Feringa, Ben L. (2008-01-01). "Copper-catalyzed asymmetric allylic substitution reactions with organozinc and Grignard reagents". Pure and Applied Chemistry. 80 (5): 1025–1037. doi:10.1351/pac200880051025. ISSN 1365-3075.
- ^ Lee, Yunmi; Akiyama, Katsuhiro; Gillingham, Dennis G.; Brown, M. Kevin; Hoveyda, Amir H. (1 January 2008). "Highly Site- and Enantioselective Cu-Catalyzed Allylic Alkylation Reactions with Easily Accessible Vinylaluminum Reagents". Journal of the American Chemical Society. 130 (2): 446–447. doi:https://doi.org/10.1021/ja0782192.
{{cite journal}}: Check|doi=value (help); External link in|doi= - ^ Luchaco-Cullis, Courtney A.; Mizutani, Hirotake; Murphy, Kerry E.; Hoveyda, Amir H. (17 April 2001). "Modular Pyridinyl Peptide Ligands in Asymmetric Catalysis: Enantioselective Synthesis of Quaternary Carbon Atoms Through Copper-Catalyzed Allylic Substitutions". Angewandte Chemie International Edition. 40 (8): 1456–1460. doi:https://doi.org/10.1002/1521-3773(20010417)40:8<1456::AID-ANIE1456>3.0.CO;2-T.
{{cite journal}}: Check|doi=value (help); External link in|doi= - ^ Baggelaar, Marc P.; Huang, Yange; Feringa, Ben L.; Dekker, Frank J.; Minnaard, Adriaan J. (2013-09-01). "Catalytic asymmetric total synthesis of (S)-(−)-zearalenone, a novel lipoxygenase inhibitor". Bioorganic & Medicinal Chemistry. 21 (17): 5271–5274. doi:10.1016/j.bmc.2013.06.024. ISSN 0968-0896.