Highly Enantioselective Catalytic Fluorination and Chlorination Reactions of Carbonyl Compounds Capable of Two‐Point Binding

Abstract

New tools in drug development: The catalytic enantioselective fluorination and chlorination reactions of carbonyl compounds containing an additional binding site (see scheme) proceed with extremely high enantioselectivity and require low catalyst loadings (2–10 mol % dbfox-Ph/NiII). Asymmetric amplification is also observed in these enantioselective halogenations. The enantioselective electrophilic halogenation of carbonyl compounds represents one of the best established strategies for the construction of chiral CX bonds in organic chemistry.1 The resulting chiral halo compounds, especially fluorine-containing chiral organic molecules, are very fascinating in the field of medicinal chemistry.2 The unique hydrophobic, space-filling, and electronic properties of a fluorine atom can make substrates with CF bonds useful candidates for drug development. Next to fluorination, enantioselective chlorination is also an important topic with regard to some aspects of pharmaceuticals.3 Although recent rapid advances in the methodology of enantioselective halogenations have made great contributions in these fields,4–6 more efficient and more flexible methods are required. In this paper we describe highly enantioselective fluorination and chlorination reactions of carbonyl compounds that are capable of two-point binding. Both of the halogenations are catalyzed by the catalyst dbfox-Ph/NiII with very high enantioselectivity up to 99 % ee. Furthermore, we also present the first significant examples of asymmetric amplification in enantioselective halogenations starting with the catalyst at 45 % enantiopurity to afford the halogenated compounds with significantly increased ee values of >90 %. We initiated the study of asymmetric fluorination reaction of β-keto esters 1 a–g, since α-fluorinated β-keto esters such as telithromycin have attractive antibiotic activity.7 Recently, we found that chiral CuII and NiII complexes of phenylbis(oxazoline) (box-Ph) effectively catalyze the enantioselective fluorination of β-keto esters with N-fluorobenzenesulfonimide (NFSI); however, the enantioselectivity was not high enough.6d In previous works by one of us, the dbfox-Ph ligand1 was highly effective in asymmetric Diels–Alder and Michael addition reactions.8 Thus we turned to this ligand to improve the fluorination reaction. A solution of 1 a in CH2Cl2 was treated with 1.2 equiv of NFSI in the presence of a catalytic amount of dbfox-Ph/Ni(ClO4)2⋅6 H2O at room temperature to afford the α-fluoro compound 2 a in high yield with an extremely high enantioselectivity (Scheme 1; Table 1, entry 1, 99 % ee). The ester 1 a proved to be the ideal yardstick to measure our results, as it has been studied by many investigators under a variety of conditions for enantioselective fluorinations.4–6 Enantioselective halogenations of substrates capable of two-point binding using dbfox-Ph/NiII with NFSI or CF3SO2Cl. Entry Substrate 1 (X=H) Product 2 (X=F) t [h] Yield [%] ee [%] 1 0 a: R=tBu, n=1 3 76 99 (S) 2 b: R=Ad, n=1 2 71 99 3 c: R=L-Men, n=1 2 66 99 4 d: Ad, n=2 3 88 95 5 0 e: tBu, n=1 2 84 93 6 f: tBu, n=2 2 86 99 7[b] 0 g 18 75 83 8[c,d] 0 h: Me 35 73 93 9[c] i: Ph 5 72 96 10[c] 0 j 14 71 93 (S) 11[e] 0 a: R=tBu, n=1 6 93 99 (S) The scope of the fluorination of a series of β-keto esters 1 b–g was investigated; we found that the dbfox-Ph/NiII catalyst exhibits excellent enantioselectivity as well (Table 1, entries 2–7). In most cases, our fluorination was more enantioselective than the reported procedures owing to the remarkable control of the enantioface of enolates by the dbfox-Ph/NiII complex.9 It is notable that catalyst loading can be reduced to 2 mol % without loss of enantioselectivity (entries 1 and 11). To demonstrate the further synthetic utility of this dbfox-Ph/NiII fluorination system, we tested other substrates capable of two-point binding. Pharmaceutically important fluorooxindoles10 2 h–j were selected as target molecules. Although we reported the enantioselective synthesis of fluorooxindoles using a combination of cinchona alkaloids and Selectfluor,6c no catalytic enantioselective method has been described. Under similar reaction conditions, a significant degree of enantioselectivity has been obtained irrespective of the substrates used (Table 1, entries 8–10). It is noted that fluorooxindole 2 j was converted into MaxiPost,6c, 10 an effective opener of maxi-K channels, by cleavage of the Boc group. This is the first example of a catalytic enantioselective preparation of MaxiPost. Highly enantioselective chlorinations of ketones, acid halides, and aldehydes have been reported; however, asymmetric chlorination of β-keto esters has relatively low enantioselectivity.5 In addition, no enantioselective syntheses of α-chlorooxindoles, which are potentially important in medicinal chemistry, have been reported.11 We were pleased to find that our dbfox-Ph/NiII system was also effective for the asymmetric chlorination of a series of substrates including β-keto esters 1 a–d and oxindoles 1 i and 1 j (Table 2). The substrates were chlorinated smoothly with CF3SO2Cl under our optimized conditions to produce 3 a–d, 3 i, and 3 j with high enantioselectivity. Chlorooxindole 3 j can be converted to BMS225113, a pharmaceutically important chlorooxindole.11 It is highly noted that CF3SO2Cl as a chlorinating agent is essential to achieve high enantioselectivity, since N-chlorosuccimide (NCS) under the same conditions provided poorer results (entry 2 vs entry 3). Entry 1 R 3 t [h] Yield [%] ee [%] 1 1 a tBu 3 a 10 72 97 2 1 b Ad 3 b 17 85 97 3[b] 1 b Ad 3 b 3 85 54 4 1 c L-Men 3 c 9 66 94 5 1 d Ad 3 d 45 61(71)[d] 98 6[c] 1 i Ph 3 i 20 93 61 7[c] 1 j – 3 j 17 93 60 We finally examined experiments of chiral amplification12, 13 in the halogenations on our systems. Fluorinations of 1 a with NFSI were carried out in the presence of Ni(ClO4)2⋅6 H2O and dbfox-Ph, enantiopurities of which were varied from 11 % to 60 %. Figure 1 shows the relationship between the enantiomeric purity of the dbfox-Ph ligand used and the enantioselectivity observed for 2 a when the molar ratio of dbfox-Ph to Ni(ClO4)2⋅6 H2O was 1.1:1 and the catalyst loading was 10 mol %. When the dbfox-Ph ligand had ee values of 45 % and 11 %, 2 a was obtained with 99 % and 66 % ee, respectively. A similar positive nonlinear effect of chiral amplification was also observed in the chlorination of 1 b with CF3SO2Cl under the same conditions, and dbfox-Ph with >45 % enantiopurity was required to obtain the enantioenriched products 3 b with >90 % ee. Chiral amplification in the halogenations of 1 a,b with NFSI or CF3SO2Cl catalyzed by dbfox-Ph/Ni(ClO4)2⋅6 H2O. In conclusion, the catalytic enantioselective fluorination and chlorination reactions of carbonyl compounds structurally capable of two-point binding were achieved with extremely high enantioselectivity by the use of the dbfox-Ph14/NiII complex. In addition, this system led to not only the first catalytic enantioselective synthesis of MaxiPost and BMS225113, but also the first observation of asymmetric amplification in halogenation reactions of β-keto esters.13 We assumed octahedral complexes coordinated with a water molecule for 1 a/dbfox-Ph/NiII, 1 j/ dbfox -Ph/NiII optimized using MM2 in the light of the X-ray structure of the dbfox-Ph/NiII complex (Figure 2).8 In these complexes, one of the faces is covered so efficiently that the halogenating agents approach from the Si face of the substrates. The details are now under investigation. Optimized structures of the complexes of 1 a/dbfox-Ph/NiII and 1 j/dbfox-Ph/NiII. Supporting information for this article is available on the WWW under http://www.wiley-vch.de/contents/jc_2002/2005/z501041_s.pdf or from the author. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. 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