syn-Selective catalytic asymmetric nitro-Mannich reactions using a heterobimetallic Cu/Sm/Schiff base complex are described. The present method is complementary to the previously reported methods, and products were obtained in high syn-selectivity (>20:1), yield (99−62%), and enantioselectivity (98−83% ee). Both Cu and Sm metals, aligned suitably in a dinucleating Schiff base ligand, were essential to realize high syn-selectivity.

The full details of a catalytic asymmetric syn-selective nitro-Mannich reaction promoted by heterobimetallic Cu/Sm/dinucleating Schiff base complexes are described, demonstrating the effectiveness of the heterobimetallic transition metal/rare earth metal bifunctional catalysis. The first-generation system prepared from Cu(OAc)(2)/Sm(O-iPr)(3)/Schiff base 1a = 1:1:1 with an achiral phenol additive was partially successful for achieving the syn-selective catalytic asymmetric nitro-Mannich reaction. The substrate scope and limitations of the first-generation system remained problematic. After mechanistic studies on the catalyst prepared from Sm(O-iPr)(3), we reoptimized the catalyst preparation method, and a catalyst derived from Sm(5)O(O-iPr)(13) showed broader substrate generality as well as higher reactivity and stereoselectivity compared to Sm(O-iPr)(3). The optimal system with Sm(5)O(O-iPr)(13) was applicable to various aromatic, heteroaromatic, and isomerizable aliphatic N-Boc imines, giving products in 66-99% ee and syn/anti = >20:1-13:1. Catalytic asymmetric synthesis of nemonapride is also demonstrated using the catalyst derived from Sm(5)O(O-iPr)(13).

Chiral b-amino alcohols are useful building blocks found in various biologically active natural products, pharmaceuticals, chiral auxiliaries, and chiral ligands.[1] Various methods for catalytic enantioselective synthesis of b-amino alcohols have been developed over the past decade, [2] and the catalytic asymmetric nitroaldol (Henry) reaction is an efficient method for providing b-amino alcohols by reduction of the nitro moiety in nitroaldol adducts.[3] Since our first report of the catalytic asymmetric nitroaldol reaction, [4] various chiral catalysts, which are effective with nitromethane as a donor, have been developed.[5] However, diastereo-and enantioselective nitroaldol reactions that use nitroethane and other nitroalkanes as donors are limited. To realize direct nitroaldol reactions, chiral Brønsted base catalysts could deprotonate the a proton of the nitroalkane to generate a metal nitronate, but epimerization of the products must be prevented to achieve high diastereoselectivity under kinetic control. Synselective asymmetric reactions have been established by our group and others; [6] but anti-selective asymmetric reactions required pre-activation of nitroalkanes to silylnitronates [7] to avoid basic conditions. Therefore, a new catalyst for antiselective asymmetric nitroaldol reactions for direct use with nitroalkanes is needed in terms of atom economy.[8] Quite recently, Ooi and co-workers [9] reported an elegant chiral Pspiro triaminoiminophosphorane catalyst for the first direct nitroaldol reaction with excellent anti selectivity, enantioselectivity, and broad substrate generality. [10][11] Considering the importance of anti amino alcohols as precursors for various important pharmaceuticals such as b-adrenoceptor agonists, additional studies of the anti-selective reactions are desirable. Herein, we report a new heterobimetallic Pd/La/1 complex (Scheme 1) for anti-selective nitroaldol reactions, and its application to short syntheses of b-adrenoceptor agonists 2 a·HCl (ritodrine·HCl) and 2 b·HCl.2 a·HCl is a selective b 2 -adrenoceptor agonist, clinically used for the prevention of pre-term birth (Scheme 2), [12] and related compound 2 b·HCl is a selective b 3 -adrenoceptor agonist that provides a new therapeutic for urinary dysfunction.[13] The common chiral anti b-amino alcohol unit (4'-hydroxynorephedrine) in both drugs is key for high biological activity, and we anticipated the anti-nitroaldol reaction to be one of the most straightforward methods for constructing two contiguous stereocenters in the common unit (Scheme 2). 2 a and 2 b could be synthesized by reduction of the nitro group of the anti-nitroaldol adduct with subsequent reductive alkylation of the amine moiety. Initially, we planned to utilize antiselective nitroaldol reactions catalyzed by a Nd/Na/chiral amide complex recently developed by our group, [11] but when used with aldehyde precursors suitable for 2 a and 2 b the reactions resulted in low enantioselectivities of the prod- Scheme 2. Structures and retrosynthesis of (À)-rito...

Stereodivergent construction of three contiguous stereocenters in catalytic doubly diastereoselective nitroaldol reactions of alpha-chiral aldehydes with nitroacetaldehyde dimethyl acetal using two types of heterobimetallic catalysts is described. A La-Li-BINOL (LLB) catalyst afforded anti,syn-nitroaldol products in >20:1-14:1 selectivity, and a Pd/La/Schiff base catalyst afforded complimentary syn,syn-nitroaldol products in 10:1-5:1 selectivity.

Out of options? Even though a systematic approach was chosen, which led to a set of four diastereomeric macrolides modeled around the proposed structure of leiodolide B (see picture), the puzzle concerning the stereostructure of this cytotoxic metabolite derived from a deep‐sea sponge still remains unsolved.