Amino acids Reformatsky reaction

A Rh-catalyzed Reformatsky reaction of chiral imine (24) led to the stereoselective preparation of the a,a-difluoro-jS-amino acid (25). 25 was converted to difluor-oalkene (26), and subsequently L-Val-i/r[(Z)CF=CH]Gly derivative (23) in greater than 82% for both steps. The samarium diiodide-mediated reductive transformation of the y,y-difluoro-a, S-enoates proceeded via successive two-electron transfers to form a dienolate species which upon kinetically controlled trapping with fert-BuOH formed 23 (Scheme 6). 

Diastereoselective a-alkylations of acetoacetic acid derivatives <1995T10795> and amino acid aldimines 582 (R = GOG(R )N=GHAr) <1995TL4069> were reported. Tandem Reformatsky and Mannich-type reactions provide an efficient diastereoselective synthesis of /3-amino acids <2006JOG3332>. 

To avoid side products derived from further addition of the Reformatsky reagent to the newly formed resin-bound ester, careful optimization of the reaction conditions was undertaken. The best yields, without detectable amounts of side products, were obtained by using 10 equiv. of the Reformatsky reagent. For each supported amino acid (except, of course, for glycine), a pair of diastereoisomers was formed, the ratio of which was found to be strongly dependent on the nature of the aldehyde employed. 

Reformatsky reaction with support-hound aminomethylhenzotriazoles (Scheme 110) [395] A nitrogen-flushed reaction tube was charged with benzotriazole (2.62 g, 22 mmol), the resin-bound amino acid (10 tea bags , 1.1 mmol), and the aldehyde (22 mmol) in dry benzene (80 mb). The tube was fitted with a Dean-Stark trap and the mixture was heated under reflux for 3 h. Following washes with CH2CI2, the resin was dried in vacuo and used in the Reformatsky coupling. 

As a part of ongoing efforts to synthesize a potent, orally active anti-platelet agent, xemilofiban 1 [1], development of an efficient chemoenzymatic process for 2, the chiral yS-amino acid ester synthon (Fig. 1) was proposed. The scheme emphasized the creation of the stereogenic center as the key step. In parallel with the enzymatic approach, chemical synthesis of the / -amino acid ester synthon emphasized formation of a chiral imine, nucleophilic addition of the Reformatsky reagent, and oxidative removal of the chiral auxiliary. This chapter describes a selective amida-tion/amide hydrolysis using the enzyme Penicillin G amidohydrolase from E. coli to synthesize (R)- and (S)-enantiomers of ethyl 3-amino-5-(trimethylsilyl)-4-pen-tynoate in an optically pure form. The design of the experimental approach was applied in order to optimize the critical reaction parameters to control the stereoselectivity of the enzyme Penicillin G amidohydrolase. 

Reactions exhibiting diastereofacial selectivity, which occur when the imine or the enolate contains an endogenous stereocenter or a chiral auxiliary, have important applications for the synthesis of optically active 3-l ctams and 3-amino carboxylic acid derivatives. Early work by Furukawa et al. has demonstrated the viability of preparing optically active 3-amino acids from chiral imines. For example, the Schiff base derived from (5)-a-methylbenzylamine (110) reacts with Reformatsky reagent (111) to give, after hydrolysis and removal of the chiral auxiliary, 3-amino-2,2-dimethyl-3-phenylpropionic acid (112) in 33% ee (Scheme 21). Similar Reformatsky reactions have been performed using (-)-menthyl esters but the enantiomeric excess values are lower. ... 

The unusual chiral (3-methoxy-y-amino acid dolaproine (Dap) is the most complex unit of dolastatin 52, which has a remarkable antineoplastic activity and is now in Phase II human cancer clinical trials. Many synthetic strategies such as aldol condensation and a cobalt-catalyzed Reformatsky reaction have been employed in its synthesis. Almeida and Coelho have demonstrated a stereoselective synthetic method for A-Boc-dolaproine (53) through a sequence of MBH reaction, a diastereoselective double bond hydrogenation and hydrolysis of the ester functional group (Scheme 5.8). ... 

Amino acid esters via a homo-Reformatsky reaction (p. 80)... 

Synthesis of Protected jS-Amino Acids. The synthesis of protected /3-amino acids can be accomplished by treatment of an imlne, generated by treatment of an aldehyde with anthracene-sulfonamide in the presence of either TiC or Amberlyst 15 (eq 2), with BrZnCH2C02 Bn in a Reformatsky-like reaction (eq 3). ... 

The condensation reaction of an imine derived from an aldehyde with ethyl bromoacetate under Reformatsky53 conditions led to a mixture of amino-esters and P-lactams. When acetaldehyde was condensed with methylamine, Schiff base 4.116 was the product A Reformatsky reaction with ethyl bromoacetate gave a mixture of the P-lactam (4.117) and the amino-ester (4.118). Acid hydrolysis and hydrogenation led to the P-amino acid N-methyl-3-aminobutanoic acid (4.119). When benz-aldehyde was the aldehyde starting material, 3-(N-methylamino)-3-phenylpropanoic acid (4.120) was the final product. ... 

Dondoni, A., Massi, A., Sabbatini, S. (2005). Multiple component approaches to C-glycosyl p-amino acids by complementary one-pot Mannich-type and Reformatsky-type reactions. Chemistry - A European Journal, 11,7110-7125. 

Oxazolidine 130 is a masked aldimine bearing a chiral N-(2-hydroxy-l-phenyl)ethyl moiety and is readily available from (R)-phenylglycinol. Mannich reaction of 130 with Reformatsky reagent of ethyl bromodifluoroacetate produces difluorolactam 131 in high diastereoselectivity, which is then transformed to enantio-enriched (S)-3-amino-2,2-difluoro-3-phenylpropanoic acid 133 (see Scheme 9.28) [55]. 

Aldol reactions. Aldol products are obtained in good yields from reaction of ketones with glyoxylic acid monohydrate with assistance of ultrasound irradiation. Substrate-control (by 1,3- + 1,5-asynmietric induction) of the aldol reaction involving y-amino-a-ketoesters under solvent-free conditions is very effective.- With lithium dicyclohexylamide and InCl, the reaction of esters with aldehydes furnishes P-hydroxy esters, and that of a-bromo esters affords a,p-epoxy esters." These are typical Reformatsky and Darzens reaction products, respectively. 

The alternative [2 + 2] cycloaddition route to azetidinones, using chloro-sulphonyl isocyanate and functionalized alkenes, has been further used in syntheses of /8-lactam antibiotics. Asymmetric induction in the formation of /3-amino-aa-dimethyl-/8-phenylpropionic acid has been achieved, using a Reformatsky reagent and a chiral Schifif base, the reaction proceeding through a /3-lactam intermediate. ... 

Only a few enantioselective approaches to optically active 2,2-difluoro-3-hjrdroxy esters, key S)mthetic interme ates for a variety of important chiral fluorinated molecules, have been reported. Braun et al and Andrds et al. have independently reported that the Reformatsky reagents generated from bromodifluoroacetates react with aromatic aldehydes in the presence of stoichiometric amounts of chiral amino alcohols such as iV-methylephediine to afford the corresponding desired aldols in good optical yields (22,23). However, these methods are not catalytic, and the decrease in quantity of the chiral ligands dramatically suppresses the enantioselectivity. Thus, we became very interested in developing an unprecedented catalytic asymmetric aidol reaction of difluoroketene silyl acetals promoted by chiral Lewis acids. 

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