Ketoaldehydes adducts

Adducts from various quaternary salts have been isolated, in reactions with aldehydes, a-ketoaldehydes, dialkylacylphosphonates and dialkyl-phosphonates, isocyanates, isothiocyanates, and so forth (Scheme 15) (36). The ylid (11) resulting from removal of a Cj proton from 3.4-dimethyl-S-p-hydroxyethylthiazolium iodide by NEtj in DMF gives with phenylisothiocyanate the stable dipolar adduct (12) that has been identified by its NMR spectrum and reactional product, such as acid addition and thiazolidine obtention via NaBH4 reduction (Scheme 16) (35). It must be mentioned that the adduct issued from di-p-tolylcarbodiimide is separated in its halohydrogenated form. An alkaline treatment occasions an easy ring expansion into a 1,4-thiazine derivative (Scheme 17) (35). 

The synthesis of chaparrinone and other quassinoids (naturally occurring substances with antileukemic activity) is another striking example [16a-c]. The key step of synthesis was the Diels-Alder reaction between the a,/l-unsaturated ketoaldehyde 1 (Scheme 6.1) with ethyl 4-methyl-3,5-hexadienoate 2 (R = Et). In benzene, the exo adduct is prevalent but it does not have the desired stereochemistry at C-14. In water, the reaction rate nearly doubles and both the reaction yield and the endo adduct increase considerably. By using the diene acid 2 (R = H) the reaction in water is 10 times faster than in organic solvent and the diastereoselectivity and the yield are satisfactory. The best result was obtained with diene sodium carboxylate 2 (R = Na) when the reaction is conducted 2m in diene the reaction is complete in 5h and the endo adduct is 75% of the diaster-eoisomeric reaction mixture. 

On the other hand, doubly deprotonated nitroalkenes are reagents with a double reactivity inversion (Scheme 5.30) provided they are used to prepare normal 0-, A-derivatives [1]. For instance, the 1-nitrobutadiene dianion 43 reacts with electrophiles to give a mixture of a- and y-isomers, 44a and 44b. Addition of the dianion 43 to 2-cyclohexenone gives only the y-adduct 45 which was transfomed into the 1,7-ketoaldehyde 46 by a Nef-type reaction with TiCl3 [38]. As shown in Scheme 5.30, although the resulting product is a "consonant system" (1,7-C), the... 

Since allyl sulfoxides may quite easily undergo racemization at the sulfur atom via a reversible [2,3] sigmatropic process, the configurationally more stable chiral allylic phosphine oxides were also investigated.201 Compounds (184) and (185), prepared as a 1 1 mixture from allylphosphonyl dichloride and (-)-ephedrine, were shown to add to cycloalkenones with reasonably high diastereoselectivities. Ozono-lysis of the initially formed 1,4-adducts affords the respective optically active ketoaldehydes (Scheme 67). With a / /-isopropyl-substituted derivative even higher selectivities (88-98% ee) could be obtained. 

This deprotonation may reform the ketone enolate that was the intermediate en route to the Michael adduct. However, the regioisomeric ketone enolate also can be formed. Figures 13.71-13.74 show such enolate isomerizations B — D, which proceed via the intermediacy of a neutral Michael adduct C. This neutral adduct is a 1,5-diketone in Figure 13.71, a 5-ketoaldehyde in Figure 13.72, and a 5-ketoester in Figure 13.73. 

The samarium-catalyzed reduction was utilized in the asymmetric synthesis of the marine macrolide bryostatin 2 (42) to furnish an intermediate (46)12 (Scheme 4.21). The ketone 43 underwent an aldol reaction with the ketoaldehyde 44 via the isopinylboryl enolate to give the aldol adduct 45 in good yield and 93 7 diastereoselectivity. Subsequent samarium-catalyzed Evans-Tishchenko reduction of the (3-hydroxy ketone 45 provided the p-nilrobenzoale 46 with excellent stereoselectivity. Silylation and saponification readily converted compound 46 into the alcohol 47 in 88% yield over two steps. 

Reactive aldehydes derived from lipid peroxidation, which are able to bind to several amino acid residues, are also capable of generating novel amino acid oxidation products. By means of specific polyclonal or monoclonal antibodies, the occurrence of malonaldehyde (MDA) and 4-hydroxynonenal (4-HNE) bound to cellular protein has been shown. Lysine modification by lipid peroxidation products (linoleic hydroperoxide) can yield neo-antigenic determinants such as N-c-hexanoyl lysine. Both histidine and lysine are nucleophilic amino acids and therefore vulnerable to modification by lipid peroxidation-derived electrophiles, such as 2-alkenals, 4-hydroxy-2-alkenals, and ketoaldehydes, derived from lipid peroxidation. Histidine shows specific reactivity toward 2-alkenals and 4-hydroxy-2-alkenals, whereas lysine is an ubiquitous target of aldehydes, generating various types of adducts. Covalent binding of reactive aldehydes to histidine and lysine is associated with the appearance of carbonyl reactivity and antigenicity of proteins [125]. 

The enantiomerically pure perhydro-l,3-oxazine-2,6-dione (72 R = menthyl Ar = 4-methoxyl-phenyl) reacts with benzaldehyde to give the benzylidene derivative (73). This compound shows high diastereofacial selectivity ( 98%) when used as either an oxadiene, or as a Michael acceptor. For example, with 2-methoxypropene, followed by thermolysis of the adduct in boiling 1,4-dioxane, it affords the ketoaldehyde (74) and with ethyl magnesium bromide it gives the adduct (75), acidic hydrolysis of which yields the chiral acid (76) (Scheme 15) <92CL485,92CPB1972). 

Fig. 2.3 Reaction of IsoK/LG with primary amines to form stable adducts. Primary amines including lysine react with IsoK/LGs to form a hemiaminal adduct. Unlike most aldehydes which can only form the highly reversible Schiff base adduct, the hemiaminal adduct of y-ketoaldehydes can undergo a second nucleophilic attack to form a pyrrolidine adduct which dehydrates to form an irreversible pyrrole adduct. In the presence of oxygen, the pyrrole is converted to lactam and hydroxylactam adducts. Oxidation of the pyrrole leads to formation of stable crosslinked species...

How selective are pyridoxamine and lipophilic pyridoxamine analogs for scavenging y-ketoaldehydes compared to other reactive lipid peroxidation products The reactivity of pyridoxamine with a,p-unsaturated aldehydes is completely trivial, and pyridoxamine does not protect proteins from HNE adduction (Amarnath et ah, 2004 Davies et al., 2006). Pyridoxamine does react with a-ketoaldehydes such as methylglyoxal that form from the oxidative decomposition of carbohydrates and lipids (Voziyan et al., 2002), and these adducts can be detected in the mine of rodents fed pyridoxamine in their drinking water (Metz et... 

Brame, C.J., Salomon, R.G., Morrow, J.D., and Roberts, L.J. Identification of extremely reactive gamma-ketoaldehydes (isolevuglandins) as products of the isoprostane pathway and characterization of their lysyl protein adducts. J Biol Chem 274 (1999) 13139-13146. 

Davies, S.S., Amarnath, V., Brame, C.J., Boutaud, O., and Roberts, L.J. Measurement of chronic oxidative and inflammatory stress by quantification of isoketal/levuglandin gamma-ketoaldehyde protein adducts using liquid chromatography tandem mass spectrometry. Nat Pro toe 2 (2007) 2079-2091. 

The ABCD segment 538 was then constructed (Scheme 76). The Julia coupling of 528 and 535 followed by methylenation afforded adduct 536. The AB spiroketal system was constructed by functional group manipulation to give 537, which was converted into ketoaldehyde 538 via protective group manipulation and oxidation. The spiroketal 539, which is a key intermediate for Kishi s total synthesis of altohyrtin A (4a), was also synthesized from 537. 

The aldol reaction of 6 proceeded analogously to that of the model ketoaldehyde 12, although in lower yield. Treatment of crude 6 with Kr-BuO in t-BuOH followed by a cleavage-step of the Boc group provided 41% of a unseparated mixture of the desired aldol adduct 25 and the bad regioisomer 27, compound 26 being isolated in 16% yield. The use of NaOMe in MeOII in this process did not improve the yield of the desired compound 25. 

Subsequently, Amadori products may degrade irreversibly to a-ketoaldehyde compounds such as 1- and 3-deoxyglucosones, which may again react with proteins to form cross-links as well as fluorescent adducts called Maillard products (McLaughlin et al., 1980 Njorge et al., 1987 Monnier, 1989). 

The aqueous medium influences not only the reaction rate but also the stereoselection of the aldol addition. One significant example [13] is the intramolecular cyclization of ketoaldehyde depicted in Scheme 7.2. In organic solvents there is a preference for syn or anti adduct depending on the presence of coordinating cations (K, Na, Li, MgBr ) or a complexing agent such as... 

Thus, following hydrozirconation of 8, transmetallation and 1,4-addition of cuprate 12, followed by treatment of the final adduct 13 with NBu+F in THF smoothly affords the ketoaldehyde 14 in 93% yield (Scheme 12.11) [13]. 

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