Acrolein adduct

Carini, M., Aldini, G., Beretta, G., Arlandini, E., and Facino, R. M. (2003). Acrolein-sequestering ability of endogenous dipeptides Characterization of carnosine and homocarnosine/ acrolein adducts by electrospray ionization tandem mass spectrometry. J. Mass Spectrom. 38,996-1006. 

Lam et al. (1985) found a dose-related depletion of glutathione in the nasal respiratory mucosa of rats after exposure to 0.1-2.5 ppm of acrolein for 3 hours. This finding is consistent with a chemical reaction leading to the formation of a glutathione-acrolein adduct. 

Smith RA, Williamson DS, Cohen SM. 1988. Detection and characterization of an acrolein adduct in polydeoxyadenylic acid. In 72nd Annual Meeting Federation of American Societies for Experimental Biology, Las Vegas, NV, May 1-5, 1988 [Abstract], Fed Am Soc Exp Biol J 2 4991. 

What are the biological consequences of the covalent modifications caused by alkylating agents One that we have already noted is the introduction of mutations opposite a modified base. Another one is the inhibition of DNA synthesis e.g., some of the acrolein adducts of guanine (Figure 13.8b) inhibit the incorporation of any base opposite to them, thus interfering with DNA s3uithesis and repair. Of note, many of these chemical adducts are removed by DNA repair enzymes only inefficiently or not at all the enzymes are apparently not accustomed to these peculiar types of modifications . 

Scheme 9 Acrolein adducts to deoxyguanosine to yield 1 AP-propano-2 -deoxyguanosme...

Pawlowicz, A.)., Munter, T., Zhao, Y., and Kronberg, L (2006) Formation of acrolein adducts with 2 -deoxyadenosine in calf thymus DNA. Chem. Res. 

FIGURE 6.4 The structures of 2-aIkenal adducts, (a) The structures of acrolein adducts (1 3). (b) The structures of 2-nonenal adducts (cis- and frans-HHP-lysine) (4 and 5). 

Burcham PC, Fontaine FR, Petersen DR, Pyke SM. Reactivity with Tris(hydroxy-methyl)aminomethane confounds immunodetection of acrolein-adducted proteins. Chem Res Toxicol 2003 16 1196-1201. 

Myrcenol (20), which has been available synthetically for a long time by hydration of (1), was found in hop oil (188). Together with the corresponding acetate (243) and its acrolein adduct (LYRAL ) (312, 628), alcohol (20) counts among the modern perfumery base materials which are used in substantial quantities. The three oxygen-containing... 

Reaction of triethylsilane with a, /3-unsaturated aldehydes catalyzed by Pd on carbon gives a /raff5-l,4-adduct as the main product. Reaction of acrolein gave the adduct in 86% yield, in which the 1,4-adduct 48 was 97% and the 1,2-adduct was 3%[44]. 

Donor substituents on the vinyl group further enhance reactivity towards electrophilic dienophiles. Equations 8.6 and 8.7 illustrate the use of such functionalized vinylpyrroles in indole synthesis[2,3]. In both of these examples, the use of acetyleneic dienophiles leads to fully aromatic products. Evidently this must occur as the result of oxidation by atmospheric oxygen. With vinylpyrrole 8.6A, adducts were also isolated from dienophiles such as methyl acrylate, dimethyl maleate, dimethyl fumarate, acrolein, acrylonitrile, maleic anhydride, W-methylmaleimide and naphthoquinone. These tetrahydroindole adducts could be aromatized with DDQ, although the overall yields were modest[3]. 

To overcome these problems with the first generation Brmsted acid-assisted chiral Lewis acid 7, Yamamoto and coworkers developed in 1996 a second-generation catalyst 8 containing the 3,5-bis-(trifluoromethyl)phenylboronic acid moiety [10b,d] (Scheme 1.15, 1.16, Table 1.4, 1.5). The catalyst was prepared from a chiral triol containing a chiral binaphthol moiety and 3,5-bis-(trifluoromethyl)phenylboronic acid, with removal of water. This is a practical Diels-Alder catalyst, effective in catalyzing the reaction not only of a-substituted a,/ -unsaturated aldehydes, but also of a-unsubstituted a,/ -unsaturated aldehydes. In each reaction, the adducts were formed in high yields and with excellent enantioselectivity. It also promotes the reaction with less reactive dienophiles such as crotonaldehyde. Less reactive dienes such as isoprene and cyclohexadiene can, moreover, also be successfully employed in reactions with bromoacrolein, methacrolein, and acrolein dienophiles. The chiral ligand was readily recovered (>90%). 

Fig. 8.5 The calculated transition-state structure for the reaction of acrolein with butadiene leading to carbo-Diels-Alder adduct catalyzed by BH3 using a RHF/3-21G basis set [6]...

A novel ring closure was discovered by Stork (6) in which the pyrrolidine enamine of a cycloalkanone reacts with acrolein. The scheme illustrates the sequence in the case of 1-pyrrolidino-l-cyclohexene, and the cyclopentane compound was found to undergo the reaction analogously. The procedure details the preparation of the bicyclo adduct and its cleavage to 4-cyclooctenecarboxylic acid. 

In the reaction of a, a -dilithio salts 285 with benzophenone, di-condensation products were obtained367, whereas in the reaction between the dianion 250 and acrolein only the mono-adduct was obtained328. 

Nafion-H (144), a perfluorinated resin-sulfonic acid, is an efficient Bronsted-acid catalyst which has two advantages it requires only catalytic amounts since it forms reversible complexes, and it avoids the destruction and separation of the catalyst upon completion of the reaction [94], Thus in the presence of Nafion-H, 1,4-benzoquinone and isoprene give the Diels-Alder adduct in 80% yield at 25 °C, and 1,3-cyclohexadiene reacts with acrolein at 25 °C affording 88 % of cycloadduct after 40 h, while the uncatalyzed reactions give very low yields after boiling for 1 h or at 100 °C for 3.5 h respectively [95], Other examples are given in Table 4.24. In the acid-catalyzed reactions that use highly reactive dienes such as isoprene and 2,3-dimethylbutadiene, polymerization of alkenes usually occurs with Nafion-H, no polymerization was observed. 

Secondary orbital interactions (SOI) (Fig. 2) [5] between the non-reacting centers have been proposed to determine selectivities. For example, cyclopentadiene undergoes a cycloaddition reaction with acrolein 1 at 25 °C to give a norbomene derivative (Fig. 2a) [6]. The endo adduct (74.4%) was preferred over the exo adduct (25.6%). This endo selectivity has been interpreted in terms of the in-phase relation between the HOMO of the diene at the 2-position and the LUMO at the carbonyl carbon in the case of the endo approach (Fig. 2c). An unfavorable SOI (Fig. 2d) has also been reported for the cycloaddition of cyclopentadiene and acetylenic aldehyde 2 and its derivatives (Fig. 2b) [7-9]. The exo-TS has been proposed to be favored over the endo- IS. 

Grieco utilized an aqueous intermolecular Diels-Alder reaction as the key step in forming the AB ring system of the potent cytotoxic sesquiterpene vernolepin. 87 Cycloaddition of sodium ( >3,5-hexa-dienoate with an a-substituted acrolein in water followed by direct reduction of the intermediate Diels-Alder adduct gave the desired product in 91% overall yield (Eq. 12.28). 

In the synthesis of D-eryt/zro-sphingosine (78 without BOC protection), the key step is the asymmetric aldol reaction of trimethylsilylpropynal 75 with ke-tene silyl acetal 76 derived from a-benzyloxy acetate. The reaction was carried out with 20 mol% of tin(II) triflate chiral diamine and tin(II) oxide. Slow addition of substrates to the catalyst in propionitrile furnishes the desired aldol adduct 77 with high diastereo- and enantioselectivity (syn/anti = 97 3, 91% ee for syn). In the synthesis of protected phytosphingosine (80, OH and NH2 protected as OAc and NHAc, respectively), the asymmetric aldol reaction is again employed as the key step. As depicted in Scheme 3-27, the reaction between acrolein and ketene silyl aectal 76 proceeds smoothly, affording the desired product 80 with 96% diastereoselectivity [syn/anti = 98 2) and 96% ee for syn (Scheme 3-27).50... 

The results suggest that BLA 77 is the best catalyst. For example, the reaction of ( )-methyl acrolein with cyclopentadiene catalyzed by 77 (5 mol%) gives the adduct at 96% yield with 99% ee [(S configuration]. 

In particular, Diels-Alder adducts from the enantioselective reaction of 2-bromo-acrolein and 2-chloroacrolein with a variety of dienes are of exceptional synthetic versatility. Readers are advised to consult the review article by Corey and Guzman-Perez.54 For the purpose of quick reference, chiral ligands commonly used in Diels-Alder reactions are listed in Table 5-6. 

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