Amino acid carbonyl compounds

Ugi I, Horl W, Hanusch-Kompa C, Schmid T, Herdtweck E (1998) MCR 6 chiral 2, 6-piperazinediones via Ugi reactions with alpha-amino acids, carbonyl compounds, isocyanides and alcohols. Heterocycles 47(2) 965-975... 

All aliphatic compounds containing primary or secondary amine group react in browning reaction but at different rates depending upon the molecular structure. The reactivity of the reactants (amino acids, carbonyl compounds) in the browning reaction had been reported in the literature as ... 

Allyltrialkoxy- or -tris(dialkylamino)titanium reagents are not capable of chelation-controlled addition reactions with oxy- or amino-substituted carbonyl compounds due to their low Lewis acidity87. To attain chelation control, the application of allylsilanes (Section 1.3.3.3.5.2.2.) and allylstannanes (Section I.3.3.3.6.I.3.2.) in the presence of bidentate Lewis acids like titanium(IV) chloride, tin(lV) chloride or magnesium bromide are the better options. 

A general method for the preparation of 2-hydroxymethyl-3-quinoli-necarboxylic acid lactones 8 (70-100%) from an o-amino aromatic carbonyl compound uses tetronic acid 7 (Scheme 4) (58JOC1996). 

Isocyanoacrylic acid esters are useful as precursors of heterocyclic and unsaturated amino-acids. These compounds are prepared in a stereoselective manner and in good yield using the Wittig-Horner reaction of t-butyl(diphenylphosphinyl)isocyanoacetate with aldehydes. cw-Enoates have been prepared by the reaction of a-diazoesters with Rh(OAc)2. An interesting one-pot synthesis of a-fluoro-a,/3-unsaturated esters from ethyl chloromalonate and carbonyl compounds works well using spray dried potassium fluoride but not with other forms of this salt (Scheme 47) the E-ester was the major product with a stereoselectivity of 86—96%. 

The most general methods for the syntheses of 1,2-difunctional molecules are based on the oxidation of carbon-carbon multiple bonds (p. 117) and the opening of oxiranes by hetero atoms (p. 123fl.). There exist, however, also a few useful reactions in which an a - and a d -synthon or two r -synthons are combined. The classical polar reaction is the addition of cyanide anion to carbonyl groups, which leads to a-hydroxynitriles (cyanohydrins). It is used, for example, in Strecker s synthesis of amino acids and in the homologization of monosaccharides. The ff-hydroxy group of a nitrile can be easily substituted by various nucleophiles, the nitrile can be solvolyzed or reduced. Therefore a large variety of terminal difunctional molecules with one additional carbon atom can be made. Equally versatile are a-methylsulfinyl ketones (H.G. Hauthal, 1971 T. Durst, 1979 O. DeLucchi, 1991), which are available from acid chlorides or esters and the dimsyl anion. Carbanions of these compounds can also be used for the synthesis of 1,4-dicarbonyl compounds (p. 65f.). 

Oxidative cleavage of P-aminoacyl complexes can yield P-amino acid derivatives (320,321). The rhodium(I)-catalyzed carbonylation of substituted aziridines leads to P-lactams, presumably also via a P-aminoacyl—metal acycHc compound as intermediate. The substituent in the aziridine must have 7T or electrons for coordination with the rhodium (322,323). 

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 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). ... 

In summary, the Bucherer-Bergs reaction converts aldehydes or ketones to the corresponding hydantoins. It is often carried out by treating the carbonyl compounds with potassium cyanide and ammonium carbonate in 50% aqueous ethanol. The resulting hydantoins, often of pharmacological importance, may also serve as the intermediates for amino acid synthesis. 

The A-phthalimidomalonic ester 8 can be further alkylated at the malonic carbon center with most alkyl halides, or with an o ,/3-unsaturated carbonyl compound thus offering a general route to a-amino acids 9. 

Reductive alkylation with chiral substrates may afford new chiral centers. The reaction has been of interest for the preparation of optically active amino acids where the chirality of the amine function is induced in the prochiral carbonyl moiety 34,35). The degree of induced asymmetry is influenced by substrate, solvent, and temperature 26,27,28,29,48,51,65). Asymmetry also has been obtained by reduction of prochiral imines, using a chiral catalyst 44). Prediction of the major configurational isomer arising from a reductive alkylation can be made usually by the assumption that amine formation comes via an imine, not the hydroxyamino addition compound, and that the catalyst approaches the least hindered side (57). 

All three elimination reactions--E2, El, and ElcB—occur in biological pathways, but the ElcB mechanism is particularly common. The substrate is usually an alcohol, and the H atom removed is usually adjacent to a carbonyl group, just as in laboratory reactions. Thus, 3-hydroxy carbonyl compounds are frequently converted to unsaturated carbonyl compounds by elimination reactions. A typical example occurs during the biosynthesis of fats when a 3-hydroxybutyryl thioester is dehydrated to the corresponding unsaturated (crotonyl) thioester. The base in this reaction is a histidine amino acid in the enzyme, and loss of the OH group is assisted by simultaneous protonation. 

More recently Hand et al. (ref. 9) have studied the decomposition reaction of N-chloro-a-amino acid anions in neutral aqueous solution, where the main reaction products are carbon dioxide, chloride ion and imines (which hydrolyze rapidly to amine and carbonyl products). They found that the reaction rate constant of decarboxylation was independent of pH, so they ruled out a proton assisted decarboxylation mechanism, and the one proposed consists of a concerted decarboxylation. For N-bromoamino acids decomposition in the pH interval 9-11 a similar concerted mechanism was proposed by Antelo et al. (ref. 10), where the formation of a nitrenium ion (ref. 11) can be ruled out because it is not consistent with the experimental results. Antelo et al. have also established that when the decomposition reaction takes place at pH < 9, the disproportionation reaction of the N-Br-amino acid becomes important, and the decomposition goes through the N,N-dibromoamino acid. This reaction is also important for N-chloroamino compounds but at more acidic pH values, because the disproportionation reaction... 

Palladium-catalysed asymmetrie allylations of various carbonyl compounds have been studied by Hiroi et al. using various types of chiral sulfonamides derived from a-amino acids. In particular, the chiral bidentate phosphinyl sulfonamide derived from (5)-proline and depicted in Scheme 1.63 was employed in the presence of palladium to eatalyse the allylation of methyl aminoacetate diphenyl ketimine with allyl aeetate, leading to the eorresponding (7 )-product with a moderate enantioseleetivity of 62% ee. This ligand was also applied to the allylation of a series of other nueleophiles, as shown in Seheme 1.63, providing the eorresponding allylated produets in moderate enantioseleetivities. 

In recent years, the variety of useful diazo substrates for asymmetric intramolecular cyclopropanation processes has really expanded. As another example, Charette and Wurz have reported the first example of an intramolecular cyclopropanation involving a-nitro-a-diazo carbonyl compounds.This reaction, catalysed by Rh2[(S)-DOSP]4, led to the formation of nine-membered nitrocyclopropyl lactones in good yields and enantioselectivities with extremely high diastereoselectivities (Scheme 6.17). This novel methodology constituted an efficient entry into chiral functionalised macrocyclic-fused cyclopropane oc-amino acids. 

---