Aldol reactions amino acids

Diastereoselective radical allylations have been studied in many different contexts, and a plethora of information exists regarding stereocontrol in these reactions. Allylations have been performed using the traditional trapping and )9-elimination sequence occurring typically with allylstannanes as well as a stepwise atom transfer/ elimination sequence found to occur with allylsilanes. Stereochemistry is commonly controlled through the use of chiral auxiliaries or by 1,2-induction, and functionalized anh -aldol and amino acid products are available using this established methodology. 

Induction of Asymmetry by Amino Acids. No fewer than sis types of reactions can be carried out with yields of 75—100% usiag amino acid catalysts, ie, catalytic hydrogenation, iatramolecular aldol cyclizations, cyanhydrin synthesis, alkylation of carbonyl compounds, hydrosdylation, and epoxidations (91). 

The biologically active form of vitamin Bg is pyridoxal-5-phosphate (PEP), a coenzyme that exists under physiological conditions in two tautomeric forms (Figure 18.25). PLP participates in the catalysis of a wide variety of reactions involving amino acids, including transaminations, a- and /3-decarboxylations, /3- and ") eliminations, racemizations, and aldol reactions (Figure 18.26). Note that these reactions include cleavage of any of the bonds to the amino acid alpha carbon, as well as several bonds in the side chain. The remarkably versatile chemistry of PLP is due to its ability to... 

The azlactones of a-benzoylaminocinnamic acids have traditionally been prepared by the action of hippuric acid (1, Ri = Ph) and acetic anhydride upon aromatic aldehydes, usually in the presence of sodium acetate. The formation of the oxazolone (2) in Erlenmeyer-Plochl synthesis is supported by good evidence. The method is a way to important intermediate products used in the synthesis of a-amino acids, peptides and related compounds. The aldol condensation reaction of azlactones (2) with carbonyl compounds is often followed by hydrolysis to provide unsaturated a-acylamino acid (4). Reduction yields the corresponding amino acid (6), while drastic hydrolysis gives the a-0X0 acid (5). ... 

A series of chiral boron catalysts prepared from, e.g., N-sulfonyl a-amino acids has also been developed and used in a variety of cycloaddition reactions [18]. Corey et al. have applied the chiral (S)-tryptophan-derived oxazaborolidine-boron catalyst 11 and used it for the conversion of, e.g., benzaldehyde la to the cycloaddition product 3a by reaction with Danishefsky s diene 2a [18h]. This reaction la affords mainly the Mukaiyama aldol product 10, which, after isolation, was converted to 3a by treatment with TFA (Scheme 4.11). It was observed that no cycloaddition product was produced in the initial step, providing evidence for the two-step process. 

Since most often the selective formation of just one stereoisomer is desired, it is of great importance to develop highly selective methods. For example the second step, the aldol reaction, can be carried out in the presence of a chiral auxiliary—e.g. a chiral base—to yield a product with high enantiomeric excess. This has been demonstrated for example for the reaction of 2-methylcyclopenta-1,3-dione with methyl vinyl ketone in the presence of a chiral amine or a-amino acid. By using either enantiomer of the amino acid proline—i.e. (S)-(-)-proline or (/ )-(+)-proline—as chiral auxiliary, either enantiomer of the annulation product 7a-methyl-5,6,7,7a-tetrahydroindan-l,5-dione could be obtained with high enantiomeric excess. a-Substituted ketones, e.g. 2-methylcyclohexanone 9, usually add with the higher substituted a-carbon to the Michael acceptor ... 

Jager and coworkers have used the TBAF catalyzed-stereoselective niho-aldol reaction for the synthesis of cyclic amino alcohols such as iminopolyols, imino sugars, and cyclic amino acids. They are important classes of compounds and have the potential utility as anh-diabetic. 

Another interesting example is SHMT. This enzyme catalyzes decarboxylation of a-amino-a-methylmalonate with the aid of pyridoxal-5 -phosphate (PLP). This is an unique enzyme in that it promotes various types of reactions of a-amino acids. It promotes aldol/retro-aldol type reactions and transamination reaction in addition to decarboxylation reaction. Although the types of apparent reactions are different, the common point of these reactions is the formation of a complex with PLP. In addition, the initial step of each reaction is the decomposition of the Schiff base formed between the substrate and pyridoxal coenzyme (Fig. 7-3). 

Organic-Base Catalyzed. Asymmetric direct aldol reactions have received considerable attention recently (Eq. 8.98).251 Direct asymmetric catalytic aldol reactions have been successfully performed using aldehydes and unmodified ketones together with chiral cyclic secondary amines as catalysts.252 L-proline and 5,5-dimethylthiazolidinium-4-carboxylate (DMTC) were found to be the most powerful amino acid catalysts for the reaction of both acyclic and cyclic ketones as aldol donors with aromatic and aliphatic aldehydes to afford the corresponding... 

More recently, asymmetric Mannich-type reactions have been studied in aqueous conditions. Barbas and co-worker reported a direct amino acid catalyzed asymmetric aldol and Mannich-type reactions that can tolerate small amounts of water (<4 vol%).53 Kobayashi found that a diastereo- and enantioselective Mannich-type reaction of a hydrazono ester with silyl enol ethers in aqueous media has been successfully achieved with ZnF2, a chiral diamine ligand, and trifluoromethanesul-fonic acid (Eq. 11.31).54 The diastereoselective Mannich-type reaction... 

Diastereoselective catalytic nitro-aldol reactions of optically active iV-phthaloyl-L-phenyl-alanal with nitromethane in the presence of LLB proceed with high diastereoselectivity (anti syn = 99 1) as shown in Eq. 3.76.125 The product is converted via the Nef reaction into (2S,3S)-3-amino-2-hydroxy-4-phenylbutanoic acid, which is a subunit of the HIV-protease inhibitor... 

Another chiral auxiliary for controlling the absolute stereochemistry in Mukaiyama aldol reactions of chiral silyl ketene acetals has been derived from TV-methyl ephedrine.18 This has been successfully applied to the enantioselec-tive synthesis of various natural products19 such as a-methyl-/ -hydroxy esters (ee 91-94%),18,20 a-methyl-/Miydroxy aldehydes (91% ee),21 a-hydrazino and a-amino acids (78-91% ee),22 a-methyl-d-oxoesters (72-75% ee),20b cis- and trans-l1-lactams (70-96% ee),23 and carbapenem antibiotics.24... 

Ligands for catalytic Mukaiyama aldol addition have primarily included bidentate chelates derived from optically active diols,26 diamines,27 amino acid derivatives,28 and tartrates.29 Enantioselective reactions induced by chiral Ti(IY) complex have proved to be one of the most powerful stereoselective transformations for synthetic chemists. The catalytic asymmetric aldol reaction introduced by Mukaiyama is discussed in Section 3.4.1. 

The synthesis of the rare amino acid 3-hydroxy-4-methylproline (8)3 involves an aldol reaction of the oxazoiidinone 5 with methacrolein to provide the a-bromo-0-hydroxy adduct 6. Azide displacement and removal of the chiral auxiliary gives 7. On treatment with dicyclohexylborane, 7 undergoes hydroboration-cycloalkyl-ation to provide, after hydrolysis, the methyl ester hydrochloride (8) of (2S,3S,4S)-3-hydroxy-4-methylproline in >97% de. This cycloalkylation should be a useful route to cyclic amino acids as well as pyrrolidines. 

This same picture unfolds when we examine the use of chiral amines in base-catalyzed reactions. Although in several individual cases (91,92) such as epox-idations (84), one Michael reaction (36), and an intramolecular aldol reaction (93), amino acids (11) or polypeptides (84) are better catalysts than quinine, the range of usefulness of quinine appears to warrant the term miracle catalyst. ... 

The fragment attached to pyridoxal will be the same in both cases, and after hydrolysis it is released as the amino acid glycine. In case this seems a bit complicated, consider the reverse reaction, which would be attack of an electron-rich system on to the carbonyl group of an aldehyde, i.e. an aldol reaction. Therefore, what we are seeing here is merely a reverse aldol-type reaction (see Section 10.3). 

Aldol and Related Condensations As an elegant extension of the PTC-alkylation reaction, quaternary ammonium catalysts have been efficiently utilized in asymmetric aldol (Scheme 11.17a)" and nitroaldol reactions (Scheme ll.lTb) for the constmction of optically active p-hydroxy-a-amino acids. In most cases, Mukaiyama-aldol-type reactions were performed, in which the coupling of sUyl enol ethers with aldehydes was catalyzed by chiral ammonium fluoride salts, thus avoiding the need of additional bases, and allowing the reaction to be performed under homogeneous conditions. " It is important to note that salts derived from cinchona alkaloids provided preferentially iyw-diastereomers, while Maruoka s catalysts afforded awh-diastereomers. 

Type A enamine catalysts include simple amino acids, such as proline 6, and most of their derivatives (such as the tetrazole 44 and various sulfonamides, e.g. 45). They are typically used for aldol, Mannich, a-amination and a-oxygenation reactions - these are all reactions where the electrophile can readily be activated by hydrogen bonding (Scheme 12) [8, 9, 12, 46],... 

Since 2000, remarkable advances in the ntility of the enamine-catalyzed aldol reaction have been made [83]. A massive effort has been devoted to the development of more effective variants of prohne [13, 26, 64, 68, 84-174]. In addition, alternative amino acids and peptides bearing primary amino groups [175-184] as... 

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