Enantioselective copper-catalyzed allylic substitution

It may be concluded from die different examples sliown here tiiat die enantio-selective copper-catalyzed allylic substitution reaction needs ftirdier improvemetiL High enantioselectivities can be obtained if diirality is present in tiie leaving group of die substrate, but widi external diiral ligands, enantioselectivities in excess of 9096 ee have only been obtained in one system, limited to die introduction of die sterically hindered neopeatyl group. 

AUylic substitution catalyzed by copper is a transformation that is related to ally-lie substitutions catalyzed by other transition metals discussed previously in this chapter, but several features of copper-catalyzed allylations make them worth differentiating. First, copper-catalyzed allylic substitutions are conducted with different types of nucleophiles tiian most allylic substitutions catalyzed by other metals. Second, the regioselectivity of the copper-catalyzed reactions is typically different from that of reactions catalyzed by complexes of other metals, particularly of reactions catalyzed by complexes of palladium. Thus, this last section of tiie chapter describes studies on allylic substitution catalyzed by copper, witii an emphasis on enantioselective examples. 

The scope of enantioselective, copper-catalyzed allylic substitution reactions is not limited to so-called hard carbon nucleophiles and achiral acyclic linear electrophiles. A recent report from Ito, Sawamura, and co-workers showed that a diboron reagent can serve as a pronucleophile for enantioselective, copper-catalyzed boronation of (Z)-aUylic carbonates (Equation 20.85). The corresponding chiral allylboronates were isolated in good yields with high enantioselectivities. 

A procedure for the highly enantioselective synthesis of chiral chromenes and tetrahydroquinolines was achieved in 2012 by Feringa and co-workers. By combining asymmetric copper-catalyzed allylic substitution with Grignard reagents and an efficient palladium-catalyzed intramolecular Heck... 

Very similar ligands were used by Hoveyda et < /.298,298a,298b for the enantioselective copper-catalyzed SN2 -substitution of allyl phosphates, allowing the highly enantioselective formation of tertiary und quarternary... 

Van der Molen NC, Tiemersma-Wegman TD, Fanands-Mastral M, Feringa BL (2015) Regio-and enantioselective copper-catalyzed allylic alkylation of ort/to-substituted cinnamyl bromides with Grignard reagents. J Org Chem 80 4981-4984... 

Dabrowski JA, Gao F, Hoveyda AH (2011) Enantioselective synthesis of alkyne-substituted quaternary carbon stereogenic centers through NHC-Cu-catalyzed allylic substitution reactions with ( Bu)2(alkynyl)aIuminum reagoits. J Am Chem Soc 133 4778-4781 Fananas-Mastral M, Feringa BL (2010) Copper-catalyzed regio- and enantioselective synthesis of chiral enol acetates and beta-substituted aldehydes. J Am Chem Soc 132 13152-13153... 

Similar to the conjugate addition, the focus of the last decade has been put on the development of chiral copper catalysts for enantioselective S -substitutions of prochiral substrates.197,197a,197b 271,285 These represent a useful alternative for the preparation of those substitution products which cannot be obtained by anti-stereoselective copper-promoted or -catalyzed SN2 -substitution of chiral substrates (see Section 9.12.2.1.2). The first reported example for such a transformation is the reaction of the allyl acetate 333 with //-butylmagnesium bromide in the presence of 15 mol.% of the copper arenethiolate 334 which gave the substitution product 335 with exclusive y-selectivity and 50% ee (Equation (18)),286 286a... 

Knochel, P. Duebner, F. Copper-Catalyzed Enantioselective Allylic Substitution Reactions, PCT Int. Appl. 2000. 

Much effort has been devoted to developing catalysts that control the enantioselectiv-ity of these substitution reactions, as well as the regioselectivity of reactions that proceed through unsymmetrical allylic intermediates. A majority of this effort has been spent on developing palladium complexes as catalysts. Increasingly, however, complexes of molybdenum, tungsten, ruthenium, rhodium, and iridium have been studied as catalysts for enantioselective and regioselective processes. In parallel with these studies of allylic substitution catalyzed by complexes of transition metals, studies on allylic substitution catalyzed by complexes of copper have been conducted. These reactions often occur to form products of Sj 2 substitution. As catalylic allylic substitution has been developed, this process has been applied in many different ways to the synthesis of natural products. ... 

AlexaMs A, Backvall JE, Krause N, Pamies O, Dieguez M (2008) Enantioselective copper-catalyzed conjugate addition and allylic substitution reactimis. Chem Rev 108 27%-2823... 

Langlois JB, Alexakis A (2012) Copper-catalyzed enantioselective allylic substitution. Top Organomet Chem 38 235-268... 

Karlstrom ASE, Huerta FF, Meuzelaar GJ, Backvall JE (2001) Ferrocenyl thiolates as ligands in the enantioselective copper-catalyzed substitution of allylic acetates with Grignard reagents. Synlett 923-926... 

Gao F, Lee Y, Mandai K, Hoveyda AH (2010) Quaternary cartxni stereogenic centers through copper-catalyzed enantioselective allylic substitutions with readily accessible aryl- or heteroaryllithium reagents and aluminum chlorides. Angew Chem Int Ed 49 8370-8374... 

Independent from the work of Oestreich and co-workers, the group of Shintani and Hayashi presented another example of NHC-copper(I)-catalyzed asymmetric allylic substitution of allylic phosphates by nucleophilic silicon (Scheme 28) [61]. The NHC precursor L23 in combination with CuCl and NaOH as base allowed for the enantioselective preparation of several a-chiral allylic silanes. The choice of base is cmcial as aUcoxides had a negative effect on the regioselectivity (not... 

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