Abstract:The first example of a catalytic enantioselective addition to and nitronate protonation of trisubstituted nitroalkenes to produce highly enantioenriched products with a tetrasubstituted carbon is reported. Thioacids added in excellent yields and with high enantioselectivities to both activated and unactivated nitroalkenes. The 1,2-nitrothioacetate products can be readily converted in two steps to biomedically relevant 1,2-aminosulfonic acids without loss of enantiopurity.Catalytic enantioselective additions of numerous nucleophiles to nitroalkenes have been extensively studied and provide entry to many important enantioenriched compounds.[1] However, catalytic enantioselective additions to a-substituted nitroalkenes are much less common due to the difficulty in setting the a-stereocenter with high fidelity (Figure 1). These types of additions have primarily been investigated for a,b-disubstituted nitroalkenes in which the bstereocenter has the potential to influence the stereochemistry of protonation at the a-site (Figure 1 a).[2] Recently, we reported the first and to date the only example of an enantioselective nitronate protonation with the catalytic enantioselective addition of Meldrums acid to a-monosubstituted nitroalkenes (Figure 1 b).[3] Herein, we report the first example of a catalytic enantioselective addition and nitronate protonation for trisubstituted nitroalkenes to produce highly enantioenriched products with a tetrasubstituted carbon atom (Figure 1 c).[4] In particular, thioacids are added in high yields and with 86-96 % ee, using 5 mol % of commercially available thiourea catalysts.[5] Moreover, the 1,2-nitrothioacetate products can readily be converted without any loss in stereochemical purity to enantioenriched 1,2-aminosulfonic acids, a structural motif found in natural products and drugs. [6] We first evaluated conditions that we had previously developed for the addition of thioacetic acid to b-nitrostyrenes, namely, with N-trisylsulfinyl urea 4 (Figure 2) as the catalyst and cyclopentyl methyl ether (CPME) as the solvent.[7] Our study began with oxetane-containing nitroalkene 1 a because the oxetane ring is a motif utilized in medicinal chemistry to modulate drug properties.[8] Additionally, incorporating a strained ring facilitated the optimization process by increasing the reactivity of these fully substituted nitroalkenes. At À25 8C the reaction proceeded in high conversion but with poor enantioselectivity (Table 1, entry 1). By using catalyst 5, which is the diastereomer of 4, Figure 1. Enantioselective additions of a-substituted nitroalkenes.
