3-Substituted 3-hydroxy-oxindoles appear as substructures within a fascinating array of natural products, including the convulutamydines, [1a,b] maremycins, [1c,d] donaxaridines, [1e,f] dioxibrassinins, [1g,h,i] celogentin K, [1j] hydroxyglucoisatisins, [1k] and TMC-95A-D (Figure 1). [1l] Whereas catalytic asymmetric additions to isatins are known, [2-6] highly enantioselective catalytic allylation, crotylation, and reverse prenylation of isatins have remained elusive. In the course of developing hydrogen-mediated C À C couplings beyond hydroformylation, [7-15] chiral ortho-cyclometalated iridium C,O-benzoates were found to catalyze highly enantioselective carbonyl allylation, [14a,b] crotylation, [14c] and reverse prenylation [12d] under transfer-hydrogenation conditions. In contrast to classical allylation procedures which employ stoichiometric organometallic reagents, [16] transfer-hydrogenation protocols exploit allyl acetate, a-methyl allyl acetate, and 1,1-dimethylallene as precursors to transient allyl-, crotyl-, and prenylmetal intermediates, respectively. [12, 14a-c] To further evaluate the scope of this emergent methodology, catalytic enantioselective additions to ketones were explored. [17, 18] In this account, we report that activated ketones in the form of substituted isatins are subject to highly enantioselective carbonyl allylation, crotylation, and reverse prenylation, constituting a convenient synthesis of optically enriched 3substituted 3-hydroxy-oxindoles.
Our initial studies focused on the allylation of N-benzyl isatin (1 a). Using the cyclometalated C,O-benzoate generated in situ from [{Ir(cod)Cl} 2 ], biphep (biphep = 2,2'-bis(diphenylphosphino)biphenyl), and 4-chloro-3-nitrobenzoic acid, [14b] the coupling of allyl acetate (1000 mol %) to 1 a at 100 8C in tetrahydrofuran (0.2 m) delivered the tertiary homoallyl alcohol 2 a in 42 % yield upon isolation. At lower loadings of allyl acetate (200 mol %) and with further optimization of reaction temperature, time, and concentration, the yield of homoallyl alcohol 2 a was increased to 77 %. An assay of chelating chiral phosphine ligands was undertaken, which revealed dramatic enhancement in the level of asymmetric induction at lower reaction temperatures. However, lower temperatures also diminished conversion. This impasse was resolved by increasing the loading of isopropanol from 200 mol % to 400 mol %, which enabled conversion of N-benzyl isatin (1 a) to the homoallyl alcohol 2 a in 73 % yield and 91 % enantiomeric excess using cth-(R)-p-phos (cth-(R)p-phos = (R)-(+ )-2,2',6,6'-tetramethoxy-4,4'-bis(diphenylphosphino)-3,3'-bipyridine) as the ligand. Notably, under analogous reaction conditions employing our initially disclosed iridium catalyst modified by 3-nitrobenzoic acid, [14a,b] 2 a was obtained in 61 % yield and 90 % enantiomeric excess. These data further illustrate how catalyst performance is enhanced through structural variation of the C,O-benzoate moiety. Data pertaining to the optimization of the catalytic enantioselective allylation of N-benzyl isatin (1 a) is tabulated in the Supporting Information.
Optimal reaction conditions identified for the conversion of N-benzyl isatin (1 a) to the hydroxy oxindole 2 a were applied to substituted isatins 1 a-1 g (Table 1). To our delight, the products of ketone allylation, 2 a-2 g, were produced in moderate to excellent yields upon isolation (65-92 %) with uniformly high levels of optical enrichment (91-96 % ee). The absolute stereochemical assignments of the adducts 2 a-2 g are based upon that determined for the 5-bromo derivative 2 b by single-crystal X-ray diffraction analysis using the anomalous dispersion method.
Given these favorable results, the crotylation of substituted isatins 1 a-1 g was attempted under identical conditions employing a-methyl allyl acetate as the crotyl donor (Table 2). The products of ketone crotylation, 3 a-3 g, were produced in moderate to excellent yields upon isolation (64-Figure 1. Examples of naturally occurring 3-substituted 3-hydroxy-oxindoles.