Glyoxylic acid, reaction with amines

Petasis reported an efficient addition of vinyl boronic acid to iminium salts.92 While no reaction was observed when acetonitrile was used as solvent, the reaction went smoothly in water to give allyl amines (Eq. 11.54). The reaction of the boron reagent with iminium ions generated from glyoxylic acid and amines affords novel a-amino acids (Eq. 11.55). Carboalumination of alkynes in the presence of catalytic Cp2ZrCl2 and H2O affords vinylalane intermediates, which serve as nucleophiles in the subsequent addition to enantiomerically enriched... 

C. Crotyl diazoacetate. A solution of 10.0 g. (0.038 mole) of the />-toluenesulfonylhydrazone of glyoxylic acid chloride in 100 ml. of methylene chloride is cooled in an ice bath. Crotyl alcohol (2.80 g. or 0.038 mole) (Note 7) is added to this cold solution, and then a solution of 7.80 g. (0.077 mole) of redistilled triethyl-amine (b.p. 88.5-90.5°) in 25 ml. of methylene chloride is added to the cold reaction mixture dropwise and with stirring over a 20-minute period. During the addition a yellow color develops in the reaction mixture and some solid separates near the end of the addition period. The resulting mixture is stirred at 0° for 1 hour and then the solvent is removed at 25° under reduced pressure with a rotary evaporator. A solution of the residual dark orange liquid in approximately 200 ml. of benzene is thoroughly mixed with 100 g. of Florisil (Note 8) and then filtered. The residual Florisil, which has adsorbed the bulk of the dark colored by-products, is washed with two or three additional portions of benzene of such size that the total volume of the combined benzene filtrates is 400-500 ml. This yellow benzene solution of the diazoester is concentrated under reduced pressure at 25° with a rotary evaporator, and the residual yellow liquid is distilled under reduced pressure. (Caution This distillation should be conducted in a hood behind a safety shield) (Note 9). The diazo ester is collected as 2.20-2.94 g. (42-55%) of yellow liquid, b.p. 30-33° (0.15 mm.), n T) 1.4853 - 1.4856 (Note 10). 

A further development of the Mannich reaction is the boronic Mannich reaction, which has been described extensively by Petasis and co-workers under conventional heating methods. Gupta et al. (Personal Chemistry, Uppsala, Sweden, internal report) have performed this reaction under microwave condition in acetonitrile (Scheme 5.11). A reaction time of 4 min at 120° C afforded the products in yields ranging from 25 to 100%. Alternative amines and boronic acids could be used, but the glyoxylic acid was essential for product formation. The major drawback with this reaction under microwave conditions at present is that the outcome is highly substrate dependent. 

The Hulme group has reported two three-step, one-pot solution-phase procedures for the preparation of 2,5-diketopiperazines, based on the UDC strategy. The first method [74a] used ethyl glyoxylate as a bifunctional carbonyl input in an Ugi-4CR with amines, isocyanides, and N-Boc a-amino acids that afforded adducts 121, which were N-deprotected and cyclized to the desired products 122 (Scheme 2.44). The second method [8c] used Armstrong s convertible isocyanide 1 in a reaction with N-Boc a-amino acids, aldehydes, and amines that afforded products 123, which were deprotected and cyclized to diketopiperazines 124 (Scheme 2.44). 

Addition of nucleophiles to electrophilic glycine templates has served as an excellent means of synthesis of a-amino acid derivatives [2c, 4—6]. In particular, imines derived from a-ethyl glyoxylate are excellent electrophiles for stereoselective construction of optically active molecules [32], This research and retrosyn-thetic analysis led us to believe that amine-catalyzed asymmetric Mannich-type additions of unmodified ketones to glyoxylate derived imines would be an attractive route for synthesis of y-keto-ce-amino acid derivatives [33], Initially, L-proline-catalyzed direct asymmetric Mannich reaction with acetone and N-PMP-protected a-ethyl glyoxylate was examined in different solvents. The Mannich-type reaction was effective in all solvents tested and the corresponding amino acid derivative was isolated in excellent yield and enantioselectivity (ee >95 %). Direct asymmetric Mannich-type additions with other ketones afford Mannich adducts in good yield and excellent regio-, diastereo- and enantioselectivity (Eq. 8). 

A convincing reaction from organometallic chemistry was a long time coming. Petasis and Zavialov now report [7a-b] that vinylboronic acids 18 [7c-d], which are readily accessible and easy to handle, can participate in a three-component reaction with primary and secondary amines 19 and with a-keto acids 20. The process, which proceeds at room temperature, leads to )ff,y-unsaturated a-amino acids 21 in good yields. The reaction of vinylboronic acid 22 with the chiral amino alcohol 23 and glyoxylic... 

A simple reaction that creates both chiral centres in one step was already in the literature.3 It is a cross between a Mannich and a Prins reaction involving the condensation of an unsaturated amine 24 with glyoxylic acid (25 available as an aqueous solution - fortunately the reaction works in water) to give a heterocyclic bridged lactone 26 with the right relative stereochemistry (but of course racemic). 

The similarity in reaction mechanisms between amino acid- and 2-deoxyribose-5-phosphate aldolase-catalyzed direct asymmetric aldol reactions with acetaldehyde suggested to us that a chiral amine would be able to catalyze stereoselective reactions via C-H activation of unmodified aldehydes [38, 39]. In this context, proline catalyzes the direct catalytic asymmetric Mannich reaction between umnodified aldehydes, and A -PMP-protected a-ethyl glyoxylate proceeds with excellent chemo-, diastereo-, and enantio-selectivity (Scheme 4.7) [40]. 

Sol 11. (i) On heating iV-benzylbut-3-en-l-amine with glyoxylic acid monohydrate in methanol, iV-benzylallylglycine is formed by involving a tandem Aza-Cope/iminium ion solvolysis reaction. 

The Petasis method involves the use of organoboron compounds to produce a side chain on a Mannich product derived from the imine condensation product between an amine and an a-ketocarboxylic acid. Thus, as shown in Scheme 12.64, as an example of this three-component reaction, when the styrylboronic acid derived from the reaction of phenylacetylene with catecholborane was allowed to react with glyoxylic acid (CHOCO2H) and (5)-2-phenylglycinol, a single diastereomer was isolated, which gave an enantiomerically pure (7 )-homophenylalanine hydrochloride on reduction. This procedure is limited only by the availability of the components. 

Microwave acceleration of reactions is a valuable tool for organic synthesis [39], and various specialized instruments are now commercially available. Tye and co-workers have reported the microwave-assisted Petasis borono-Mannich reaction of arylboron-ic acids and primary or secondary amines with either glyoxylic acid or salicylaldehyde [40]. Optimized reaction conditions employed didiloromethane as solvent, and microwave assisted heating at 120 °C for 10 min. Products were obtained in generally modest yields (10-83%), in part due to incomplete reaction conversion imder the reported conditions. 

---