Chiral Boron‐Bridged Bisoxazolines: Readily Available Anionic Ligands for Asymmetric Catalysis

Asymmetric cyclopropanation and monobenzoylation reactions of meso diols employing borabox catalysts 1 (M=Cu) result in high enantioselectivities. The borabox ligands are anionic analogues of the bisoxazolines 2 and are readily prepared by lithiation of oxazolines and subsequent trapping with boron halides. The considerable potential of borabox ligands in asymmetric catalysis is shown. The structural motif of the semicorrins 11 has inspired the development of many related chiral ligands for asymmetric catalysis. The closest structural analogues are the bisoxazolines 41, 2a, 2b1 and the aza bisoxazolines 5,3 the backbone of which contains a planar, negatively charged π system. In addition, neutral variants 21 and 3,3 which contain a planar bridging N atom or a neutral dialkylated methylene bridge 6, have been developed. The ligand charge, the geometry of the bridging atom, and the electronic properties of the coordinating N atoms all influence the reactivity and enantioselectivity of a metal catalyst.1, 3 Among the various semicorrin analogues reported to date, the bisoxazolines (box) 6 stand out as particularly versatile ligands that have been successfully applied in a wide range of metal-catalyzed reactions.2 As a further variation of this structural motif, we report herein a class of readily available, anionic bisoxazoline ligands (borabox) 7 that contain a tetrasubstitued B atom that bridges the two oxazoline rings. In contrast to the known anionic ligands 1, 4, and 5, the negative charge in the borabox structure is located in the backbone and the geometry of the bridging atom is tetrahedral as in the neutral box ligand 6. Anionic ligands of this type that can form neutral zwitterionic complexes with metal cations have recently received increased attention, and a number of N, P, and S ligands which contain tetraorganoborate or indenyl anions as structural elements have been reported.4–6 The borabox ligand structure can be readily assembled by reaction of a metalated oxazoline with a dialkyl or diaryl haloborane (Scheme 1). This strategy, which differs from known synthetic approaches to bisoxazolines, is attractive because simple and readily accessible oxazolines 8 can be used as precursors. Lithiation of 8 following the procedure of Meyers and Novachek7 and subsequent treatment with 0.5 equivalents of haloborane at low temperature led to the lithium salts of bora bisoxazolines 7 a–f. These compounds were isolated in analytically pure form as highly hygroscopic white powders in moderate to good yields, depending on the nature of the substituents at the B atom. The lithium salts could be converted into the protonated ligands 9 a–f by chromatographic workup on silica gel using hexanes/ethyl acetate/triethylamine as the eluent. Regeneration of the lithium salts of 7 a–f was readily accomplished by treatment of compounds 9 a–f with one molar equivalent of n-butyllithium in diethyl ether at room temperature. Synthesis of borabox ligands as the lithium salts of 7 a–f (34–98 %) or in their protonated form 9 a–f (44–89 %). a) tBuLi, −78 °C, THF; b) (R1)2BX (X=Cl, Br), toluene, −78 °C; c) hexanes/EtOAc/Et3N, SiO2; d) nBuLi, THF, 0 °C. ArF=3,5-bis(trifluoromethyl)phenyl, Cy=cyclohexyl, Bn=benzyl. A wide variety of sterically and electronically different ligands can be prepared by structural variation of the haloborane and the oxazoline 8. The borabox ligands readily form stable complexes with transition-metal ions, such as CuII, ZnII, PdII, RhI, and IrI ions, starting from the lithium salts [Li(7)] or the protonated precursors 9 in the presence of a base such as K2CO3. Figure 1 shows the crystal structure of the homoleptic CuII complex of 7 a alongside a CuII complex derived from the analogous diphenylmethyl-bridged box derivative 6 a.8, 9 Crystal structures of complexes [Cu(7 a)2] and [CuCl2(6 a)]. Hydrogen and chlorine atoms have been omitted for clarity. In contrast to the slightly distorted boatlike conformation of 6 a, the borabox ligand 7 a adopts an almost flat conformation. The average bond lengths between the bridging atom and the oxazoline rings, as well as the bite angle, are larger in complex [Cu(7 a)2] than in complex [CuCl2(6 a)] (BCoxa=1.61 Å versus CCoxa=1.50 Å (oxa=oxazoline), and N-Cu-N=94.5° versus N-Cu-N=89.9°). As a consequence, the substituents at the stereogenic centers in [Cu(7 a)2] are farther away from the metal ion than in [CuCl2(6 a)]. As a first test of the borabox ligands, we carried out a comparative study of the cyclopropanation of styrene with CuI catalysts prepared in situ from CuOTf (Tf=trifluoromethanesulfonyl), lithium salts of 7 a–f, and analogous box ligands 6 a–b, and 6 d (Table 1).1, 10 In this reaction, which often serves as a benchmark for new ligands, the borabox complexes showed similar reactivities to the corresponding box complexes.11 As observed for the box ligands, bulkier tert-butyl substituents at the stereogenic centers of the borabox ligands induced higher ee values than isopropyl groups. However, this effect was less pronounced than in the box series. In the reaction with ethyl diazoacetate, the borabox catalysts gave only moderate enantioselectivities. On the other hand, with tert-butyl diazoacetate and 2,6-di-tert-butyl-4-methylphenyl (BHT) diazoacetate, the performance of the borabox ligands was much better, with ligand 7 f rivaling the most efficient box derivative 6 d. Consistent with previous studies, the more bulky esters gave much higher ratios of trans/cis isomers. The best result, 98 % ee and almost perfect diastereoselectivity, was obtained in the reaction of the BHT ester with borabox derivative 7 f (entry 17). Entry Ligand R1 R2 Diazo ester (R) cis/trans cis[a] ee [%] trans[a] ee [%] Yield [%][b] (cis+trans) 1 6 a[c] Ph iPr Et 36:64 54 51 85 2 6 b[d] Ph tBu Et 33:67 91 89 72 3 6 d[d] Me tBu Et 27:73 97 99 77 4 7 a Ph iPr Et 29:71 58 65 77 5 7 b Ph tBu Et 30:70 66 70 84 6 7 c Cy iPr Et 32:68 24 33 68 7 7 d Et tBu Et 28:72 59 72 75 8 7 e Cy tBu Et 28:72 78 66 79 9 7 f ArF tBu Et 32:68 68 77 89 10 6 b Ph tBu tBu 21:79 93 90 70 11 6 d[e] Me tBu tBu 19:81 93 96 75 12 7 b Ph tBu tBu 15:85 77 67 77 13 7 d Et tBu tBu 13:87 76 73 65 14 7 e Cy tBu tBu 9:91 82 73 63 15 7 f ArF tBu tBu 17:83 86 92 65 16 6 d[d] Me tBu BHT 4:96[f] – 99 85 17 7 f ArF tBu BHT 1:99[f] – 98 89 The borabox catalyst [Cu(7 f)] also performed well with other alkenes (Table 2). Overall, the enantioselectivities were similar to those obtained with box derivative 6 d, but in several cases the trans selectivitiy of the borabox catalyst was higher (compare entries 1, 5, and 9 with 2, 6, and 10, respectively). Entry Ligand R1 R2 R3 cis/trans[a] trans[b] ee [%] Yield[c] [%] (cis+trans) 1 6 d Me tBu Ph 4:96 99 85 2 7 f ArF tBu Ph 1:99 98 89 3 6 d Me tBu p-MeOC6H4 4:96 96 35[d] 4 7 f ArF tBu p-MeOC6H4 4:96 97 65[d] 5 6 d Me tBu p-FC6H4 4:96 99.4 89 6 7 f ArF tBu p-FC6H4 1:99 99.5 91 7 6 d Me tBu PhCH2 7:93 99 ng[e] 8 7 f ArF tBu PhCH2 8:92 97 66 9 6 d Me tBu n-hexyl 2:98 99 51[d] 10 7 f ArF tBu n-hexyl 1:99 95 68[d] To explore further the potential of the borabox ligands, we studied the Cu-catalyzed enantioselective monobenzoylation of meso 1,2-diols, a reaction recently reported by Matsumura et al. (Table 3).12 Entry Ligand R1 R2 meso 1,2-diol Yield [%][a] ee [%][b] 1 6 c Me Bn 0 70 33[c] 2 6 e Me Ph 58 13 3 9 g Et Bn 79 40 4 9 h ArF Bn 73 76 5 6 c Me Bn 0 74 85[c] 6 6 e Me Ph 62 22 7 9 g Et Bn 75 47 8 9 h ArF Bn 83 90 9 6 c Me Bn 0 68 84[c] 10 6 e Me Ph 58 86 11 9 g Et Bn 62 92 12 9 h ArF Bn 65 94 The monobenzoylated products were obtained in good yields (62–83 %) under the optimized conditions. The borabox derivative 9 h proved to be the most effective ligand for all three substrates with ee values of 76, 90, and 94 % being obtained. The corresponding benzyl-substituted bisoxazoline 6 c and the diphenyl analogue 6 e, which in the study of Matsumura et al.12a had given the best results, induced distinctly lower enantioselectivities. In summary, we have developed a new class of anionic, boron-bridged analogues of the box ligands. These ligands are of interest because they are anionic with the negative charge located in the backbone, but otherwise closely resemble the netural box ligands 6. The results obtained in the asymmetric cyclopropanation and, especially, in the desymmetrization of meso diols point to a considerable potential for borabox ligands in asymmetric catalysis. Dedicated to Professor Albert Eschenmoser on the occasion of his 80th birthday Supporting information for this article is available on the WWW under http://www.wiley-vch.de/contents/jc_2002/2005/z501111_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. Any queries (other than missing content) should be directed to the corresponding author for the article.