Asymmetric Catalysis In Organic Synthesis

  • Nagoya R
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The 1,4-conjugate addition of organometallic reagents to enones is widely used process for carbon-carbon bond formation giving-substituted carbonyl compounds which are versatile synthons to further organic transformations. Although considerable efforts have been made to develop efficient chiral catalytic systems for asymmetric 1,4-addition, the successful examples are rare in terms of enantioselectivity, catalytic activity, and generality. 1-4 Very recently, a part of the authors discovered the rhodium-catalyzed 1,4-conjugate addition of aryl-and alkenylboronic acids to enones. 5 This new catalytic reaction has several advantages over other 1,4-addition reactions. (1) The organoboronic acids used in this reaction are stable to oxygen and moisture, permitting us to run the reaction in protic media or even in an aqueous solution. (2) The organoboronic acids are much less reactive toward enones in the absence of a rhodium catalyst than the organometallic reagents so far used, such as organomagnesium or-lithium reagents, and no 1,2-addition to enones takes place in the presence or absence of the catalyst. (3) The reaction is catalyzed by transition-metal complexes coordinated with phosphine ligands. Since chiral phosphine ligands are the chiral auxiliaries most extensively studied for transition-metal-catalyzed asymmetric reactions, 6 one can use the accumulated knowledge of the chiral phosphine ligands for the asymmetric reaction. Here we report asymmetric 1,4-addition of aryl-and alkenylboronic acids which proceeds with high enantioselectivity in the presence of a chiral phosphine-rhodium catalyst. 7 Our initial studies were focused on the development of reaction conditions including reaction temperature, solvent, rhodium precursor, and chiral ligand for the asymmetric addition of phenylboronic acid (2m) to 2-cyclohexenone (1a) producing 3-phenylcyclohexanone (3am). Under the conditions reported previously, 5 that is, in the presence of rhodium catalyst generated from Rh(acac)(CO) 2 and a phosphine ligand at 50 °C for 16 h, the reaction is very slow with any chiral ligands examined, 8 giving only <2% yield of 3am. It was found that the reaction is efficiently catalyzed by a rhodium complex generated in situ by mixing Rh(acac)(C 2 H 4) 2 with 1 equiv of (S)-binap in an aqueous solvent at 100 °C (eq 1). Thus, a mixture of 1a (39 mg, 0.40 mmol), 2m (68 mg, 0.56 mmol, 1.4 equiv), Rh(acac)(C 2 H 4) 2 (3.1 mg, 0.012 mmol, 3 mol %), and (S)-binap (7.5 mg, 0.012 mmol) in dioxane/H 2 O (1.0 mL/0.1 mL) was heated at 100 °C for 5 h. After aqueous workup, silica gel chromatography (hexane/EtOAc) 5/1) gave 44 mg (64% yield) of (S)-3-phenylcyclohexanone (3am) whose enantiomeric excess is 97% (entry 1 in Table 1). The absolute configuration of (S) was determined by comparison of the specific rotation ([R] 20 D-21 (c 0.96, chloroform)) with that reported for (R)-3am, 9 and the enantiomeric excess was determined by HPLC analysis using a chiral stationary phase column (Chiralcel OD-H, hexane/2-propanol) 98/2). Use of Rh(acac)(CO) 2 in place of Rh(acac)(C 2 H 4) 2 as a catalyst precursor significantly lowered both catalytic activity and enantioselectivity (entry 2). 1 H and 31 P NMR studies revealed that Rh(acac)(C 2 H 4) 2 reacts immediately with 1 equiv of (S)-binap in C 6 D 6 to give Rh-(acac)[(S)-binap] quantitatively. 10 The isolated Rh(acac)[(S)-binap] complex showed essentially the same catalytic activity and stereoselectivity (entry 3) as the in situ catalyst generated from Rh(acac)(C 2 H 4) 2 and (S)-binap, indicating that Rh(acac)[(S)-binap] is a catalytically active species or a key precursor. In contrast, addition of (S)-binap to Rh(acac)(CO) 2 in the same solvent gave a complex mixture consisting of two main species, Rh(acac)[(S)-binap] and an unidentified species. The lower selectivity of the catalyst generated from Rh(acac)(CO) 2 is attributed to the formation of the complex mixture. It was found that phenylboronic acid (2m) undergoes hydrolysis giving benzene as a competing reaction under the reaction (1) For reviews, see: (a) Schmalz, H.-G. (2) For recent examples for asymmetric addition of organozinc or magnesium reagents in the presence of nickel or copper catalysts, see: (a) Feringa, B. L.; Pineschi, M.; Arnold, L. A.; Imbos, R.; de Vries, A. H. M. Lambert, F.; Eijkelkamp, D. J. F. M.; Grove, D. M.; van Koten, G. Tetrahedron Lett. 1994, 35, 6135. (h) Asami, M.; Usui, K.; Higuchi, S.; Inoue, S. Chem. Lett. 1994, 297. (i) Soai, K.; Okudo, M.; Okamoto, M. Tetrahedron Lett. 1991, 32, 95. (j) Bolm, C. Tetrahedron: Asymmetry 1991, 2, 701. (3) Asymmetric addition of aryllithiums catalyzed by a chiral ligand has been reported: Tomioka, K.; Shindo, M.; Koga, K. Tetrahedron Lett. 1993, 34, 681. (4) For recent examples for catalytic asymmetric Michael addition of malonate esters, see: (a) Yamaguchi, M.; Shiraishi, T.; Hirama, M. J. Org. Chem. 1996, 61, 3520. (b) Arai, T.; Sasai, H.; Aoe, K.; Okamura, K.; Date, T.; Shibasaki, M. Angew. Chem., Int. Ed. Engl. 1996, 35, 104 and references therein. (5) Sakai, M.; Hayashi, H.; Miyaura, N. Organometallics 1997, 16, 4229. (6) For a review, see: Ojima, I. Catalytic Asymmetric Synthesis; VCH Publishers: New York, 1993. (7) Asymmetric Michael addition forming a chiral carbon center on the nucleophile has been reported to be catalyzed by a chiral bis(phosphine)-rhodium complex: (a) Sawamura, M.; Hamashima, H.; Ito, Y. J. Am. Chem. Soc. 1992, 114, 8295. (b) Sawamura, M.; Hamashima, H.; Ito, Y. Tetrahedron 1994, 50, 4439. (8) The following chiral ligands were examined: 2,2′-bis(diphenylphos-phino)-1,1′-binaphthyl (binap), 2,3-O-isopropylidene-2,3-dihydroxy-1,4-bis-(diphenylphosphino)butane (diop), 2,3-bis(diphenylphosphino)butane (chira-phos), 2,2′-bis[4-(isopropyl)oxazolyl]-1,1′-binaphthyl (boxax), 2-[2-(diphenyl-phosphino)phenyl]-4-(isopropyl)oxazoline (phox), 2-diphenylphosphino-2′-methoxy-1,1′-binaphthyl (mop). (9) The specific rotation of (R)-3-phenylcyclohexanone (3am, 98.7% ee) has been reported to be [R] 20 D +20.5 (c 0.58, chloroform): Schultz, A. G.; Harrington, R. E. J. Am. Chem. Soc. 1991, 113, 4926. (10) Rh(acac)[(S)-binap]: 1 H NMR (C6D6, 23 °C) δ 1.54 (s, 6H, MeCO), 5.35 (s, 1H, COCHCO), 6.45 (br, 4H), 6.52 (t, J) 7.2 Hz, 2H), 6.65-6.68 (m, 2H), 6.72 (d, J) 8.3 Hz, 2H), 6.97-7.00 (m, 2H), 7.15-7.20 (m, 9H), 7.23 (d, J) 8.1 Hz, 2H), 7.64 (quint, J) 4.3 Hz, 2H), 8.03 (br, 4H), 8.21 (br, 3H); 31 P{ 1 H} NMR (C6D6, 23 °C) δ 55.3 (d, JRh-P) 193 Hz). Anal. Calcd for RhC49H39O2P2: C, 71.36; H, 4.77. Found: C, 71.07; H, 4.76. It has been reported that the addition of a bisphosphine to Rh(acac)(cod) forms Rh(acac)(bisphosphine): Fennis, P. J.; Budzelaar, P. H. M.; Frijns, J. H. G.; Orpen, A. G. conditions. The yield of the addition product 3am was greatly improved by use of a large excess of the boronic acid (entries 4 and 5). With 5 times excess of phenylboronic acid (2m), a quantitative yield of 3am was obtained even in the presence of 1 mol % of the catalyst without loss of enantioselectivity (entry 6). The reaction temperature is also important for the high chemical yield (entries 7-10). At 60 °C or lower, the 1,4-addition was very slow giving 3am in not higher than 3% yield. The highest yield was achieved at 100 °C. Interestingly, the enantio-selectivity was kept constant at the reaction temperature ranging between 40 and 120 °C. 11 The scope of the present catalytic asymmetric addition is broad (Scheme 1). Aryl groups substituted with either electron-donating or-withdrawing groups, 4-MeC 6 H 4 , 4-CF 3 C 6 H 4 , 3-MeOC 6 H 4 , and 3-ClC 6 H 4 , were introduced onto 2-cyclohexenone with high enantioselectivity by the reaction with the corresponding boronic acids 2n-q (entries 11-14). Asymmetric addition of 1-alkenyl-boronic acids was also successful, (E)-1-heptenylboronic acid (2r) and (E)-3,3-dimethyl-1-butenylboronic acid (2s) giving the corresponding products of over 90% ee (entries 15 and 16). Cyclopentenone (1b) also underwent the asymmetric addition of phenyl-and 1-heptenylboronic acids with high enantioselectivity under similar reaction conditions to give the corresponding 3-substituted cyclopentanones, 3bm 12 (97% ee (S)) and 3br (96% ee), respectively, in high yields (entries 17 and 18). High enantioselectivity was also observed in the reaction of linear enones 1d and 1e which have trans olefin geometry (entries 20 and 21). Thus, the present catalytic asymmetric 1,4-addition proceeds with high enantioselectivity for both cyclic and linear R,-unsaturated ketones with a variety of aryl-and alkenylboronic acids. The catalytic cycle has been proposed to involve the insertion of carbon-carbon double bond of enone into aryl-rhodium bond as a key step. 5 Scheme 2 shows the stereochemical pathway forming the products of (S) configuration, which is exemplified by the reaction of 2-cyclohexenone. According to the highly skewed structure known for transition-metal complexes coordinated with a binap ligand, 13 (S)-binap-rhodium intermediate A should have an open space at the lower part of the vacant coordination site, the upper part being blocked by one of the phenyl rings of the binap ligand. The olefinic double bond of 2-cyclohexenone coordinates to rhodium with its 2si face forming B rather than with its 2re face, which undergoes migratory insertion to form a stereogenic carbon center whose absolute configuration is (S). All the 1,4-addition products 3 obtained here are expected to have the absolute configuration resulting from the attack of 2si face of enones.




Nagoya, R. (2001). Asymmetric Catalysis In Organic Synthesis. Molecules, 6(12), 1012–1012.

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