The direct organocatalytic enantioselective alpha-chlorination of aldehydes has been developed. The reaction proceeds for a series of different aldehydes with NCS as the chlorine source using easily available catalysts such as l-proline amide and (2R,5R)-diphenylpyrrolidine. The alpha-chloro aldehydes are obtained in up to 99% yield and up to 95% ee. The synthetic utility of the enantioselective alpha-chlorination of aldehydes is demonstrated by transformation of the alpha-chloro aldehydes to the corresponding alpha-chloro alcohols (>90% yield) by standard reduction and further transformation to both a terminal epoxide and amino alcohol, both obtained without loss of optical purity. Oxidation of the alpha-chloro aldehydes followed by esterification gave optically active alpha-chloro esters without loss of optical purity. It is demonstrated that these optically active alpha-chloro esters can be converted into nonproteinogenic amino acids in overall high yields, maintaining the enantiomeric excess obtained in the catalytic enantioselective alpha-chlorination step.

Even though the first reports of enantioselective organocatalysis by Wiechert et al. and Hajos and Parrish appeared almost three decades ago, [1] the field of asymmetric catalysis has been dominated by metal catalysis. It is only recently that asymmetric organocatalysis has received renewed attention and become the focus of intense research efforts. [2] This is primarily due to the operational simplicity, the cheap catalysts, and the obvious industrial applications.Recently, a number of reports on organocatalytic transformations has appeared covering a wide range of reactions including Diels±Alder reactions, [3] aldol reactions, [4] Mannich Experimental Section DBEDOT was obtained according to ref. [14] with 76 % yield: m.p. 96 8C; 1 H NMR (500 MHz, CDCl 3 , 258C, TMS): d = 4.27 ppm (s, 4 H); 13 C NMR (125 MHz, CDCl 3 , 258C, TMS): d = 139.6, 85.4, 64.9 ppm; CP-MAS 13 C NMR (75 MHz, solid state, 25 8C, TMS): d = 140.3, 84.6, 65.1 ppm; MS (70 eV): m/z (%): 302 (55) [M + ], 300 (100), 298 (55); elemental analysis: found: C 23.79, H 1.28, Br 53.00, S 10.86; calcd for C 6 H 4 Br 2 O 2 S: C 24.02, H 1.34, Br 53.27, S 10.69. PEDOT: In a typical experiment, DBEDOT (0.01±2 g) was incubated at 60 8C for 24 h and dried in vacuum (0.1 mbar) at room temperature to give black crystals of bromine-doped PEDOT; elemental analysis: found: C 28.87, H 1.65, Br 38.42, S 12.90; calcd for C 6 H 4 Br 1.2 O 2 S(H 2 O) 0.6 : C 28.01, H 3.50, Br 38.73, S 12.45. The well-ground material was additionally dried in vacuum (0.1 mbar) at 150 8C overnight, then stirred with hydrazine hydrate (50 % aqueous solution, in MeCN) overnight, filtered, and washed with neat MeCN. Vacuum drying afforded a nearly fully dedoped PEDOT; elemental analysis: found: C 46.84, H 2.42, N~2, Br 0.42, S 19.04; calcd for C 6 H 4 O 2 Br 0.01 S(NH 2 NH 2 ¥3 H 2 O) 0.12 : C 47.63, H 3.44, N 2.22, Br 0.53, S 21.19. CP-MAS 13 C NMR (75 MHz, solid state, 25 8C, TMS): d c = 136.5, 108.7, 64.9 ppm; IR (KBr): ñ = 1650, 1431, 1358, 1203, 1066, 984, 918, 832, 690 cm À1 .

In this Perspective, recent advances and challenges in the development of GPR119 agonists as new oral antidiabetic drugs will be discussed. Such agonists are expected to exhibit a low risk to induce hypoglycemia as well as to have a beneficial impact on body weight. Many pharmaceutical companies have been active in the search for GPR119 agonists, making it a highly competitive area in the industrial environment. Several GPR119 agonists have been entered into clinical studies, but many have failed either in phase I or II and none has progressed beyond phase II. Herein we describe the strategies chosen by the different medicinal chemistry teams in academia and the pharmaceutical industry to improve potency, physicochemical properties, pharmacokinetics, and the safety profile of GPR119 agonists in the discovery phase in order to improve the odds for successful development.

A new catalytic enantioselective conjugate addition of nitroalkanes to acyclic alpha,beta-unsaturated enones catalyzed by novel organic catalysts has been developed. A series of chiral amines has been tested as catalysts for the addition of 2-nitropropane to benzylideneacetone, and it is found that a novel imidazoline catalyst, prepared from phenylalanine, can catalyze a highly enantioselective 1,4-addition reaction. The reaction of various acyclic and cyclic nitroalkanes was found to proceed well with enantioselectivities up to 86% ee, and enantiopure products can be obtained by recrystallization. The potential of the reaction is documented by the reaction of a series of substituted alpha,beta-unsaturated enones with different nitroalkanes. Furthermore, the synthetic applicability of the reaction is demonstrated by the formation of optically active functionalized pyrrolines and pyrrolidines by reductive amination of the products. On the basis of the absolute configuration of the conjugate addition products, the mechanism for the reaction is discussed and a transition state proposed.

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The mechanism for the 2,5-diphenylpyrrolidine-catalyzed enantioselective alpha-chlorination of aldehydes with electrophilic halogenation reagents has been investigated by using experimental and computational methods. These studies have led us to propose a mechanism for the reaction that proceeds through an initial N-chlorination of the chiral catalyst-substrate complex, followed by a 1,3-sigmatropic shift of the chlorine atom to the enamine carbon atom. The suggested reaction course is different from previously proposed mechanisms for organocatalytic enamine reactions, in which the carbon-electrophile bond is formed directly. Furthermore, the rate-determining step in the overall reaction was determined and the presence of nonlinear effects was probed.

The catalytic direct Michael addition of cyclic 1,3-dicarbonyl compounds and enamines to unsaturated 2-ketoesters is presented. A series of different 4-hydroxycoumarins, 4-hydroxy-6-methyl-2-pyrone, 3-hydroxy-1H-phenalene-1-one, 2-hydroxy-1,4-naphthoquinone, 5,5-dimethyl-1,3-cyclohexanedione, and various enamines of cyclic 1,3-diketones all add to unsaturated 4-substituted 2-ketoesters in an enantioselective manner. The reaction is catalyzed by chiral bisoxazoline-copper(II) complexes and proceeds in the absence of base to afford Michael adducts in good to high yields and with up to 98% ee. The products formed are substructures found in skeletons of important biological and pharmaceutical molecules. The scope and potential of the new reaction are discussed as well as the mechanism for the catalytic enantioselective reaction.

The first organocatalytic enantioselective alpha-bromination of aldehydes and ketones is presented; a C2-symmetric diphenylpyrrolidine catalyst afforded the alpha-brominated aldehydes in good yields and up to 96% ee, while ketones were alpha-brominated by a C2-symmetric imidazolidine in up to 94% ee; furthermore, the organocatalytic enantioselective alpha-iodination of aldehydes is also demonstrated to proceed with up to 89% ee.