A Highly Enantioselective Amino Acid-Catalyzed Route to Functionalized α-Amino Acids

Abstract

The development of syntheses providing enantiomerically pure alpha-amino acids has intrigued generations of chemists and been the subject of intense research. This report describes a general approach to functionalized alpha-amino acids based on catalytic asymmetric synthesis. Proline catalyzed Mannich-type reactions of N-PMP-protected alpha-imino ethyl glyoxylate with a variety of unmodified ketones to provide functionalized alpha-amino acids in high yields with excellent regio-, diastereo-, and enantioselectivities. Study of seven examples yielded six with product ee values of > or = 99%. In reactions involving ketone donors where diastereoisomeric products could be formed, two adjacent stereogenic centers were created simultaneously upon carbon-carbon bond formation with complete syn-stereocontrol. Significantly, this methodology utilizes readily available and rather inexpensive starting materials, does not require any preactivation of substrates or metal ion assistance, and can be carried out on a gram scale under operationally simple reaction conditions. The keto-functionality present in the products provides a particularly attractive site for versatile modifications. This study compliments and extends our bioorganic approach to asymmetric synthesis to a versatile synthon class. Given that we have shown that a variety of optically active amino acids can be synthesized with proline catalysis, where an L-amino acid begets other L-amino acids, our results may stimulate thoughts concerning prebiotic syntheses of optically active amino acids based on this route.

Hydroxy-L-prolines as asymmetric catalysts for aldol, Michael addition and Mannich reactions

“…As the distance between carboxyl group and hydroxyl group increases, the intramolecular forces decrease and the selectivity of Mannich reaction increases. In the Hyp-derivative 6, the substitution of hydroxyl with t-butoxy group showed no effect on the conversion and had a strong effect on the stereoselectivity in comparison with its precursor 5 ( Table 3) Knoevenagel reaction Compounds 1-6 were also tested as catalysts for the Knoevenagel reaction of dimethyl malonate (15) and 3-methylbutyraldehyde (16). Excellent yields of product dimethyl 2-(3-methylbutylidene)malonate (17) were obtained for all catalysts 1-6.…”

“…[2][3][4] It is used as an asymmetric catalyst for the synthesis of β-hydroxy ketones via aldol additions, [5][6][7][8][9][10][11] Michael addition reactions, [12][13][14][15] and β-amino ketones via Mannich reactions. 16,17 The importance of L-proline (1) -more than all other amino acids as catalystderives from the fact that it is the only secondary proteinogenic amino acid, and it has a special rigidity which could control the stereochemistry through the formed imine/enamine intermediate.…”

Solvent-controlled diastereoselectivity in tryptophan-catalyzed Mannich reactions

“…Since the pioneering work of List [4,5] and Barbas III [6] on the enantioselective, proline-catalyzed direct Mannich reaction, asymmetric organocatalytic Mannich reactions have become an extraordinarily active area of research. [7][8][9][10] High syn-diastereoselectivity and enantioselectivity can easily be achieved for Mannich adducts derived from substituted aldehyde or ketone donors, [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22] but a general organocatalyst that can achieve high levels of anti-diastereoselectivity (together with high yields and enantioselectivities) for a wide range of substrates is spotted under UV light (254 nm). Purification by column chromatography was carried out on silica gel Merck 60 (particle size: 0.0040-0.063 nm) using mixtures of DCM/ EtOAc as eluent.…”

Pyrrolidine-2-carboxylic Acid(l-Proline)

“…Pyrrolidine-2-carboxylic acid commonly known as LProline (I) has shown, in recent times, excellent catalytic activity, in catalyzing a wide variety of reactions such as aldol, 1,2 Mannich, [3][4][5][10][11][12] Michael, 6-9 in a highly enantioselective manner. These reactions have produced a variety of useful chiral materials for organic synthesis.…”