Dihydropyrones, substituted

A simple, commercially available chiral alcohol, a,a,a a -tetraaryl-l,3-dioxo-lane-4,5-dimethanol (TADDOL, 7a), catalyzes the hetero- and carbo-Diels-Alder reactions of aminosiloxydienes with aldehydes and a-substituted acroleins to afford the dihydropyrones and cyclohexenones, respectively, in good yields and high enan-tioselectivities. More recently, it was reported that axially chiral biaryl diols 7b and 7c were more highly effective catalysts for enantioselective hetero-Diels-Alder reactions (Scheme 12.5). ... 

Dihydropyrones are valuable intermediates for the synthesis of a variety of substituted tetrahydropyran rings. Recently, stereoselective aldol reactions of p-chlorovinyl ketones using the dienol boronate derivative derived from chiral IpC2BOTf was utilized for enantioselective formation of dihydropyrones. No detectable racemization was reported on the cyclization step (eq 4). ... 

The neurological effects of kava are attributed to a group of substituted dihydropyrones called kava lactones (1). The main bioactive constituents include yangonin, desmethoxyyangonin, 11-methoxyyangonin, kavain (kawain), dihydrokavain, methysticin, dihydromethysticin, and 5,6-dehydromethysticin (8). It is believed that the components present in the lipid-soluble kava extract, or kava resin, are responsible for the central nervous system (CNS) activities of kava including sedation, hypnosis, analgesia, and muscle relaxation (9). Aqueous kava extract was not active orally in mice or rats. 

Work in the pyrone series delineated the beneficial effect of substituting ortho to the sulfur linkage on the S-phenyl with an isopropyl moiety. Modeling of the ortho isopropyl functional group with the 5,6-dihyropy-rone template indicated that it probably filled the S, pocket This observation led to modifications of the initial dihydropyrone lead, resulting in agents with improved enzyme potency (Table 7). 

Initial attempts to improve cellular potency centered on the addition of polar functional groups to the dihydropyrone parent. Compound 66 was chosen as the parent structure for these preliminary studies. Examination of the X-ray crystallographic structure of analogue 68 bound to the protease enzyme indicated that several possible sites existed for such synthetic modification. It was hoped that these substitutions could modulate physical properties as well as pick up additional interactions with the protein. With these caveats in mind, several sites for potential modification were identified the 4 position of the aryl ring at C-3, the 3 or 4 position in the phenethyl ring at C-6, or the 4 position of the phenyl ring at C-6. 

The Pd(OAc)2/dppb-catalyzed cascade reaction of o-iodophenol with 1,2-nonadiene and CO starts with a CO insertion which is followed by carbopalladation of the allene and subsequently terminated by an intramolecular nucleophilic substitution to afford O-con-taining six-membered a-methylenebenzo-y-dihydropyrones (Scheme 34). ... 

The behavior of a-keto-a,p-unsaturated esters is slightly different. The Michael reaction between aldehydes and these kinds of doubly activated olefins proceeded smoothly in the presence of 31a as catalyst but the conjugate addition products underwent spontaneous intramolecular hemiacetalization via the corresponding enol form of the a-ketoester moiety. Consequently, this reactivity was exploited for setting up a very efficient and simple protocol for the enantioselective synthesis of highly substituted dihydropyrones by carrying out the in situ oxidation of these Michael adducts (Scheme 2.30). ° The final heterocyclic derivatives were obtained in excellent overall yield and outstanding enantioselectivity. Moreover, the reaction could also be carried out in water as solvent. 

Subsequently, the Xiao group described the NHC-catalysed annulations of ynals with 1,3-dicarhonyl compounds.Functionalised dihydropyrones 88 were obtained with high enantioselectivity for aryl-substituted ynals, regardless of the position and electronic nature of the substituent on the aryl ring (Scheme 20.39). 

The approach developed by Danishefsky and co-workers for the construction of sugar derivatives (see Vol.l6,p.126), which employs the initial synthesis of a dihydropyrone derivative by a Lewis acid-catalyzed hetero-Diels-Alder reaction, has been extended to the synthesis of the glycoside derivative (36), x>f DL-llncosamine (Scheme 10). Introduction of the amino-function at C-6 required a circuitous approach Involving 6,7-bromohydrin, 6,7-epoxide, and N-substituted 6,7-aziridine intermediates. ... 

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