Amine, enamine/imine, or enamide moieties, as are accessible by hydroamination or -amidation reactions, are widely encountered in the scaffolds of natural products or synthetic drugs (Figure 1). Monomorine is one of the first natural products that became accessible by a synthetic sequence involving a hydroamination step. 2

Within the past years, several catalyst systems have been discovered that promote the carboxylation of terminal alkynes with formation of propiolic acids. This reaction concept is particularly topical in that it involves the functionalization of a C–H bond and the incorporation of CO2 into an organic molecule without need for strong bases or aggressive organometallic reagents. The present article reviews the development of this new reaction type and critically compares the reaction and catalyst concepts disclosed in the literature.

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The ruthenium-catalyzed hydroamidation of terminal alkynes has evolved to become a broadly applicable tool for the synthesis of enamides and enimides. Depending on the catalyst system employed, the reaction leads chemo-, regio-, and stereoselectively to a single diastereoisomer. Herein, we present a comprehensive mechanistic study of the ruthenium-catalyzed hydroamidation of terminal alkynes, which includes deuterium-labeling, in situ IR, in situ NMR, and in situ ESI-MS experiments complemented by computational studies. The results support the involvement of ruthenium-hydride and ruthenium-vinylidene species as the key intermediates. They are best explained by a reaction pathway that consists of an oxidative addition of the amide, followed by insertion of a π-coordinated alkyne into a ruthenium-hydride bond, rearrangement to a vinylidene species, nucleophilic attack of the amide, and finally reductive elimination of the product.

In recent years, interest in b-amino acids has continued to grow, being driven by their successful application in peptidomimetics and as valuable building blocks.[1] Therefore, development of new enantioselective approaches to b-amino acids and their derivatives remains in the focus of the fine chemicals industry, in spite of the existence of numerous methodologies, [2,3] . Readily available b-ketoesters 1 or related b-ketonitriles 2 can serve as convenient precursors of bamino acids, into which they can be converted, for example, by asymmetric reduction of the corresponding enamines 3 and 4 (Scheme 1). Catalytic hydrogenation, a preferred methodology in industry, generally requires the presence of an N-acyl steering group to attain high enantioselectivity [4] and works best when pure enamine isomers are used.[4b] Recently, improved catalytic systems were reported to attain high selectivity with (E/Z) mixtures [2d, 4b, 5] and the methodology was further extended to unsubstituted enamines (3, Ar = H) [6] and their N-aryl derivatives. [7] On the other hand, the sensitivity of asymmetric hydrogenation to the steric bulk of the substituents surrounding the enamine moiety makes the synthesis of certain b -amino acids a significant challenge.[8] Herein, we present a new methodology based on the organocatalytic asymmetric hydrosilylation of enamines that allows a direct access to a range of b 3 -and b 2, 3 -amino acid derivatives for some of which other methods proved less satisfactory.We have recently developed an efficient procedure for the asymmetric reduction of prochiral N-arylketimines with trichlorosilane ( 95 % ee), catalyzed by Lewis-basic form-A C H T U N G T R E N N U N G amides, such as Sigamide (8).[9-11] The method was then extended to the reduction of a-chloro imines and successfully applied to an enantioselective synthesis of N-arylaziridines.[12] To further expand the scope, we have now turned to the synthesis of b-amino acids. Treatment of the b-ketoester/nitrile 1 a/2 a (R 2 = H, R 3 = Ph; Scheme 1) with p-anisidine produced enamines 3 a/4 a, which themselves cannot be reduced by Cl 3 SiH.[13] On the other hand, a slow equilibration of the E-and Z-isomers of enamines 4, observed by NMR spectroscopy, is likely to proceed through the imine form (5), the reduction of which with Cl 3 SiH can be envisaged. Because the enamine-imine equilibration is facilitated by Brønsted acids, traces of HCl in commercial Cl 3 SiH may have a beneficial effect on the reaction. Indeed, under standard reduction conditions (enamine (1 equiv), Cl 3 SiH (2 equiv), and 8 (5 mol %) in toluene at RT), [9,12] enamine 3 a afforded the amino ester (S)-6 a in 78 % yield and 92 % enantiomeric excess (ee); however, the reaction suffered from poor reproducibility, giving a wide distribution of