COPPER-CATALYZED, ENANTIOSELECTIVE CONJUGATE ADDITION. Reported by Monica Jo Patten December 6, 2004

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1 CPPE-CATALYZED, EATISELECTIVE CJUGATE ADDITI eported by Monica Jo Patten December 6, 2004 ITDUCTI Conjugate addition of carbon nucleophiles to α,β-unsaturated electrophiles is an essential carbon-carbon bond forming process in synthetic organic chemistry. 1 rganocuprates, which are derived from organolithium or Grignard reagents, 2 are the most commonly used nucleophiles for this transformation. The utility of cuprate conjugate addition has been broadened through the development of enantioselective variants. However, the modified cuprates require stoichiometric amounts of chiral ligands and copper, 3 which prompted the development of more efficient systems. The development of methods that require catalytic amounts of copper and chiral ligands for conjugate addition of carbon nucleophiles (Scheme 1) is evolving into two competing systems. The first employs dialkylzinc reagents as the nucleophiles; the second uses Grignard reagents. Although the use of Grignard reagents was the first to be applied to enantioselective conjugate addition, 4 dialkylzinc reagents have dominated the field since their first application 5 in the mid-1990s. Copper-catalyzed dialkylzinc additions have been applied to conjugated cyclic substrates such as cyclohexenones, 6 cyclopentenones, 7 as well as unsaturated lactones, 8 and lactams. 9 The extension to acyclic substrates is more complex because they can exhibit s-cis/s-trans conformational equilibria. More recently, progress has been made on these more challenging acyclic substrates such as chalcones, 10 benzylideneacetones, 11 and aliphatic α,β-unsaturated enones. 11 ther acyclic substrates which do not undergo conformational equilibria, such as malonates 12 and nitroolefins, 13 have also been surveyed. A mechanism for the copper-catalyzed addition of dialkylzinc reagents is proposed. 8 Although it historically has been difficult to achieve high enantioselectivity and chemioselective 1,4-addition with Grignard reagents, much progress has been made recently. 14 Copper-catalyzed enantioselective conjugate addition has broad synthetic potential for diverse targets from anti-tumor agents 15 to perfumes. 16 Scheme 1. Copper Catalyzed Conjugate Addition to Acyclic and Cyclic Enones 3 CuX, L* nm 1 * CuX, L* 2 3 nm by Monica Jo Patten 89

2 BACKGUD The Evolution of rganocuprate Systems In 1952, Gilman was the first to generate lithium dimethylcuprate by the combination of two equivalents of methyllithium with a copper salt to provide a clear, colorless ethereal solution. 17 Although the chemical composition was unknown at the time, Gilman had formed the first of a new family of reagents, LiCu 2, which are now commonly known as Gilman reagents. In 1966 the first use of lithium dimethylcuprates for conjugate addition was reported. 18 The utility of organocuprates has been enhanced by the development of heterocuprates, LiCuX (commonly X=S, t-bu), whose advantages include greater thermal stability and atom efficiency. 19 Enantioselective conjugate additions can be accomplished through the use of cuprates. Two main methods have been employed in enantioselective conjugate additions. 20 modified with a chiral auxiliary and thus induce diastereoselective conjugate addition. 3 also be chirally modified to perform enantioselective conjugate additions. 3 chiral amino acids or alcohols can be used as the heterogroup. 3 The acceptor can be Cuprates can In the case of heterocuprates, Both methods have the same disadvantage: they require either stoichiometric amounts of copper or of chiral ligand or both. The first example of a catalytic enantioselective addition is the addition of butyl magnesium bromide to 2-cyclohexenone which provided 57:43 er. 4 reagent in copper-catalyzed conjugate addition was reported. 5 (Scheme 2). 5 Scheme 2: First Example of Enantioselective Copper Catalyzed Conjugate Addition of Diethylzinc 2 Et 2 Zn, 2 L* 10 mol % CuI L* = P %, 66:34 er In 1993, the first application of a dialkylzinc The substrate used was 2-cyclohexenone With the advantages dialkylzinc reagents possess over Grignard reagents, their domination in the still emerging field of copper catalyzed conjugate addition is not suprising. Dialkylzincs are compatible with a variety of functional groups. 21 is problematic with organomagnesium nucleophiles. This eliminates background reactions such as 1,2-addition which Grignard reagents also give poorer enantioselectivity than dialkylzinc reagents. However dialkylzinc reagents are not without their disadvantages. They possess low atom efficiency, because the stoichoimetry of the desired transfer ligand to zinc is 2:1. They are also more expensive and harder to make than Grignard reagents. 27 this reason, Grignard reagents have actively been pursued, which has resulted in some recent success. 14 For 90

3 PGESS I CPPE-CATALYZED CJUGATE ADDITIS The Challenge of Acyclic Systems Ligands are usually surveyed to optimize three main types of substrates, namely cyclic ketones, chalcones, and aliphatic α,β-unsaturated ketones (Figure 1). Most cyclic substrates, such as 2- cyclohexenone 3 are, as configured, enones locked into the s-trans conformation. Acyclic substrates, however can undergo s-cis/s-trans conformational equilibrium. When dialkylzinc reagents are used, zinc can bind to the carbonyl oxygen in anti or syn orientation with respect to the carbon-carbon double bond (Scheme 3). Although chalcone is conformationally flexible, some bias is induced by 1,3-allylic strain favoring the s-cis conformation (83 mol % s-cis). 22 With less 1,3-allylic strain, most aliphatic α,β-unsaturated ketones have bias towards the s-trans conformation Cyclohexenone, 3 s-cis Chalcone, 6 s-trans aliphatic α,β-unsaturated enone, 1 Figure 1. Substrates For Copper-Catalyzed Conjugate Addition Scheme 3. Conformational equilibria Zn 2 2 Zn 2 Zn Zn Anti-s-trans, 7a Syn-s-trans, 7b Syn-s-cis, 7c Anti-s-cis, 7d Additions of Dialkylzinc eagents H HBu H HBu t-bu Figure 2. Peptidic Ligands for Copper-Catalyzed Conjugate Additions of Dialkylzinc eagents Peptidic ligands are effective for the copper-catalyzed conjugate addition of dialkylzinc reagents to a variety of electrophiles (Figure 2). Peptidic ligand 8 has been shown to give high yields and enantioselectivities for the addition of a variety of dialkylzinc reagents to 2-cyclohexenone (71-98%; 98:2 to >99:1 er). 7 The more difficult substrate, 2-cyclopentenone, also gave good results (56-92%; 90:10 to >99:1 er). 7 Conjugate addition of diethylzinc to benzylideneacetone and benzylideneacetones substituted with electron withdrawing and electron donating groups was found to be successful with peptidic ligand 9 (72-93%; 95:5 to 97:3 er). 11 H Et 2 Bn Peptidic ligand 9 has also provided the conjugate addition 91

4 product for α,β-unsaturated aliphatic enones (69%-87%; 94:6 to 98:2 er). 11 Conjugate additions to a variety of substituted nitroolefins were achieved through utilization of peptidic ligand 10 (60-89%; 90:10 to 98:2 er). 13,16 osphoramidite ligand 11 (Figure 3) has shown to add dimethyl and diethylzinc to 2- cyclohexenone in high yields and high enantioselectivity (72-94; >99:1 er). 6 osphoramidite 11 has also been successful in the addition of a variety of dialkylzinc reagents to nitroolefins with good to excellent enantioselectivity (77:23 to 99:1 er). 15,24 osphoramidite 11 has shown to add to protected lactams in up to 98:2 er 9 and malonates with up to 68:38 er. 12 P P P H Figure 3. Ligands for Dialkylzinc Additions Diphosphite ligand 12 has been shown to affect the conjugate addition of dialkylzinc reagents to lactones (60%-95%; 92:8 to 97:3 er). 8 Both diphosphite ligand 12 which has a backbone, which connects the two phosphite moieties, derived from -BIL and the analogous ligand with a S-BIL backbone have provided the conjugate addition product of diethylzinc and 2-cyclopentenone with the S- configuration. 25 Conjugate addition to chalcones has been accomplished with high enantioselectivity (98:2 to 99:1 er) with the utilization of phosphine ligand chanism for Dialkylzinc Conjugate Additions A mechanism for copper-catalyzed conjugate addition of a dialkylzinc reagent to 2- cyclohexenone (Figure 4) has been proposed. 6 Either Cu(I) or Cu(II) salts can be employed, since there will be in situ reduction of the copper salt. 6 After ligation of copper(i) to form chiral complex 14, transfer of an alkyl group from dialkyl zinc reagent 15 gives copper nucleophile 16 and organozinc 17. rganometallics 16 and 17 can coordinate to cyclohexenone 3 to form bimetallic complex 18, where the copper reagent inserts into the carbon-carbon double bond while the zinc coordinates to the carbonyl. Zinc coordination activates the electrophile for conjugate addition, via reductive elimination of intermediate 19, which yields zinc enolate 20. Evidence supporting this mechanism includes the rate enhancement of copper-catalyzed diethyl zinc to 2-cyclohexenone in the presence of Lewis acids. 27 This supports the proposed zinc activation of 92

5 the carbonyl for alkyl transfer. The copper complexation is in accordance with the known ability of organocopper reagents to undergo π-complexation. 28 H + Zn Cu II X 2 or Cu I X 2 L 2 Zn, L 2 Cu I X, 14 ZnX Cu III L 19 ZnX Cu III L Figure 4. Proposed Catalytic Cycle for rganozinc System L 18 L L 2 Cu I, 16 ZnX, 17 3 Additions of Grignard eagents P Fe 2 P(p- 2 ) Figure 5. tal Differentiating Ligands for the Conjugate Addition of Grignard eagents Scheme 4: Conjugate Addition to Lactones and Cyclic Enones X MgBr, L* X n( ) Cu salt n( ) X = CH 2, n = 0 or 1 Most successful copper-catalyzed conjugate additions of Grignard reagents employ ligands which can partake in metal-differentiating coordination. Such ligands employ a soft donor atom such as P, S, or Se to bind the copper and a harder donor atom such as or to bind the magnesium (Figure 5). 14 Amide ligands 22 and 23 have been applied to the addition of Grignard reagents to 2- cycloalkenones and unsaturated lactones (Scheme 4). 29 Most straight chain alkyl magnesium halides add to unsaturated lactones and 2-cyclohexenones with good to excellent enantioselectivity (86:14 to 96:4 er). 29 α-/β-branched Grignard reagents add to cyclohexenones in poor yields and enantioselectivities (10-40%; 52:48 to 56:44 er). 29 Ferrocene based ligand 24 has been applied to the addition of a n-butyl magnesium chloride to 2-cyclohexenone (>100:1 chemioselectivity for 1,4- vs. 1,2- addition; 92:8 er). 30 Ferrocene based ligand 24 has also been applied to the conjugate addition of n- 93

6 butyl magnesium bromide to chalcone with good enantioselectivity (80:1 chemioselectivity for 1,4- vs. 1,2-addition; 90:10 er). 30 Diphosphine ligands 27 and 28 bind copper in 8-membered and 6-membered chelates respectively (Figure 6). 14 Interestingly, these ligands yield products with opposite configurations. These diphosphine ligands promote the addition of a variety of nucleophiles such as ethyl and methyl magnesium bromides (83:17 to 99:1 chemioselectivity for 1,4- vs. 1,2-additions; 88:12 to 97:3 er) to 2- cyclohexenones. However, adding branched Grignard reagents to 2-cyclohexenones has been difficult (62:38 to 78:22 chemioselectivity for 1,4- vs. 1,2-additions; 51:49 to 66:34 er). Additions of ethyl magnesium bromide to cyclopentenone and unsaturated lactones have been promoted by both diphosphines 27 and 28 in good to excellent enantioselectivity (74:26 to 96:4 er). Success (74:26 to 99:1 er) has been found for the addition of a variety of Grignards to α,β-unsaturated aliphatic enones using diphosphine Fe 2 P Fe P 2 APPLICATIS β 2 -Amino Acids Figure 6. Diphosphine Ligands for the Conjugate Addition of Grignard eagents Scheme 5: Formation of β 2 -Amino Acids 2 Zn, 2 mol % L* 2 1 mol % Cu(Tf) 2 29 toulene, -55 o C 2 30, 86%, 99:1 er 1. ai 2. Boc 2, Et 3 EtH, rt, 30 min HBoc 31, 64%, 99:1 er L*= H 5 I 6, H 2, 1 mol % Cr 3 C, o C, 30 min P 11 HBoc 32, 82%, 99:1 er Copper-catalyzed conjugate additions of dialkylzinc reagents to nitropropene acetals possess high synthetic utility because the products can be converted to β 2 -amino acids 32 (Scheme 5). 15 The nitroalkane conjugate addition product 30 can be reduced by aney nickel and subsequently protected to give amino acetal 31. The protected aminoacetal can be oxidized to give the protected β 2 -amino acid 32. β 2 -amino acids are important starting materials for many biologically active molecules. ne example of a synthetic target which utilizes a β 2 -amino acid is Crytophycin D, an antitumor agent

7 Muscone -(-)-Muscone 34 is a valuable ingredient of the perfume industry. A more efficient synthesis of muscone has been accomplished through the utilization of copper catalyzed conjugate addition to (E)- cyclopentadec-2-en-1-one 33 (Scheme 6). 16 Scheme 6: Synthesis of -(-)-Muscone 2 Zn, L* L* = P CCLUSIS 33 34, -(-)-Muscone 72%, 92:8 er Catalytic, enantioselective variants of the classic conjugate addition process have been developed. These new methods employ catalytic amounts of copper salts and chiral ligands to initiate the addition of carbon nucleophiles to α,β-unsaturated acceptors. Dialkylzinc and Grignard reagents have been the most commonly used nucleophiles in these systems. Dialkylzinc reagents add enantioselectively to a variety of electrophiles including α,β-unsaturated ketones, lactones, lactams, malonates, and nitrocompounds. Examples of highly enantioselective and regioselective Grignard reagent additions have been reported. Because Grignard reagents are more cost effective, atom efficient, and are easier to make than dialkylzinc reagents, future efforts of copper-catalyzed conjugate additions will be focused on organomagnesium reagents. 35 EFEECES (1) Krause,.; Hoffmann-öder, A. Synthesis 2001, 2, 171. (2) Feringa, B. L.; aasz,.; Imbos,.; Arnold, L. A. Copper-catalyzed Enantioselective Conjugate Addition eactions of rganozinc eagents. In Modern rganocopper Chemistry; Krause,., Ed.; Wiley-VCH: Weinheim, Germany, 2002; pp (3) ossiter, B. E.; Swingle,. M. Chem. ev. 1992, 92, 771. (4) Villacorta, G. M.; ao, C. P.; Lippard, S. J. J. Am. Chem. Soc. 1988, 110, (5) Alexakis, A.; Frutos, J.; Mangeney, P. Tetrahedron: Asymmetry 1993, 4, (6) Feringa, B. L.; Pineschi, M.; Arnold, L. A.; Imbos,.; de Vries, H. M. Angew. Chem., Int. Ed. Engl. 1997, 36, (7) Degrado, S. J.; Mizutani, H.; Hoveyda, A. H. J. Am. Chem. Soc. 2001, 123, 755. (8) Liang, L.; Yan, M.; Li, Y.-M.; Chan, A. S. C. Tetrahedron: Asymmetry 2004, 15, (9) Pineschi, M.; Del Moro, F.; Gini, F.; Minnaard, A. J.; Feringa, B. L. Chem. Commun. 2004, (10) Hu, Y.; Liang, X.; Wang, J.; Zheng, Z.; Hu, X. J. rg. Chem. 2003, 68, (11) Mizutani, H.; Degrado, S. J.; Hoveyda, A. H. J. Am. Chem. Soc. 2002, 124, 779. (12) Alexakis, A.; osset, S.; Allamand, J.; March, S.; Guillen, F.; Benhaim, C. Synlett 2001, 9, (13) Mampreian, D. M.; Hoveyda, A. H. rg. Lett. 2004, 6,

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