A-Pyrones synthesis

Our scheme of a-pyrone synthesis involves the esterification of homoallylic alcohols with acryloyl chloride, followed by ring-closing metathesis (RCM) using Grubbs ruthenium catalyst (Scheme 6) (44). We have identified a large number of such pyrone-containing natural products that can be readily synthesized via our allylboration strategy. Representative examples of our syntheses are described below. 

Synthesis, structure, and transformations of a-pyrone derivatives, viz., xanthy-rones, glaucyrones, and chelated magnesium enolates 98T8243. 

The general features of this elegant and efficient synthesis are illustrated, in retrosynthetic format, in Scheme 4. Asteltoxin s structure presents several options for retrosynthetic simplification. Disassembly of asteltoxin in the manner illustrated in Scheme 4 furnishes intermediates 2-4. In the synthetic direction, attack on the aldehyde carbonyl in 2 by anion 3 (or its synthetic equivalent) would be expected to afford a secondary alcohol. After acid-catalyzed skeletal reorganization, the aldehydic function that terminates the doubly unsaturated side chain could then serve as the electrophile for an intermolecular aldol condensation with a-pyrone 4. Subsequent dehydration of the aldol adduct would then afford asteltoxin (1). 

A novel use of a chlorofluorocarbon is in the synthesis of a pyrone (30) from 1,1,1-trichlorotrifluoroethane. The key step involves Cu(I) catalysis. Pyrone (30) is a useful CF3 aromatic synthon, as it readily underwent (4 + 2) cycloaddition followed by spontaneous elimination of C02 (85-TL3947). 

Later, a nickel-catalyzed cascade conversion of propargyl halides and propargyl alcohol into a pyrone in water was reported. The reaction involved a carbonylation by CO and a cyanation by KCN (Eq. 4.55).96 Recently, Gabriele et al. explored a facile synthesis of maleic acids by palladium catalyzed-oxidative carbonylation of terminal alkynes in aqueous DME (1,2-dimethoxyethane) (Eq. 4.56).97... 

Pyroglycolytic pathway, production, 38 383 Pyrolysis reactions, in synthesis of carbonyl clusters, 30 141-143 a-Pyrone complexes with cobalt, 12 283 with iron, 12 275... 

A similar synthesis of mechanistic interest rather than preparative value involves the thermal reaction of dimethyl 2,5-bisdiazo-3,4-diketoadipate (89, Scheme 23) with benzofuran (91)." The presumed intermediate is the pyrone cation 90 produced from the adipate 89 by the Wolff rearrangement, cyclization, and loss of nitrogen. Electrophilic substitution then affords the benzofuran 92, which can be isolated. Ring opening and cyclization of the resultant ketene 93 then affords the dibenzofuran 94 in poor (0.4%) yield. 

Finally, in a very recent disclosure, Lee et al. (165) approached the total synthesis of arteminolide using a [5 + 2] cycloaddition strategy with an oxidopyrylium ion. Despite its long history of use, Lee was the first to utilize an allene moiety both in an intra- and an intermolecular cycloaddition with oxidopyrylium ions. By utilizing a pyrone cycloaddition precursor (294) similar to those used in the Wender phorbol synthesis, Lee was able to synthesize various ring sizes and... 

The a-pyrone (635) undergoes an exothermic Diels-Alder reaction with 1-diethylamino-1-propyne to afford the cycloadduct (636) (77JOC2930). Only a single regioisomer is produced, which is in line with the expected polarization of these reagents (Scheme 144). A Diels-Alder reaction of the same a-pyrone with 1-dibenzylamino-l-propyne affords an aniline derivative which has been employed in a chiral synthesis of the aromatic portion of the ionophore antibiotic lasalocid (80JA6178). 

Another synthesis of pterocarpans starts from the coumestan system. LAH treatment results in reductive cleavage of the a-pyrone ring (Scheme 52). Benzofuran derivative (242) is thermally cyclized to (243) (64JCS4212 see also 78IJC(B)372), which may also be formed... 

This method affords a-pyrone in quantity and in good yield not achieved previously.3 The compound has considerable possibilities in Diels-Alder reactions, such as a decarboxylative double diene synthesis.5... 

In addition, directions are given in Volume 46 for the synthesis of 3,4-dichloro-l,2,3,4-tetramethylcyclobutene (p. 34), 10-methyl-10,9-borazarophenanthrene (p. 65), perchlorofulvalene (p. 93), and a-pyrone (p. 101), molecules which by any standard deserve the designation unique. 

A synthesis of a-pyrones has been repotted where a key step involved the chemoselective addition of an organocuprate to an a-oxoketene dithioacetal.115 The methodology requires four steps and is quite general since the cuprate can deliver a range of ligands in a selective manner (Scheme 22). 

In this section the synthesis of coumalic acid (92), representing the a(2)-pyrone system, is described. a-Pyrones readily undergo a simple lactone-amide transformation, and the conversion of coumalic acid into the tautomeric 6-hydroxy-nicotinic acid (93) provides a further illustration of the conversion of a six-membered oxygen heterocycle into the corresponding nitrogen system. 

In a recent report, Padwa [64] disclosed a general method of wide applicability for constructing a variety of heterocyclic systems. It involved an amino furan ester as a more reactive four carbon component vis avis a pyrone in intramolecular Diels-Alder addition to an unactivated olefin. This method as applied to the synthesis of anhydrolycorinone consisted of the preparation of the tertiary amide 240 (Scheme 40) and its subsequent thermolysis to the N-o-bromoaroylindoline 241. It is believed that the initially formed cycloadduct 242 opened to the acyl iminium oxyanion 243, which by prototropy and dehydration generated 241. The latter, on photolysis in the presence of bis (tri-n-butyltin), furnished the tetracyclic ester 244, which was hydrolysed and decafboxylated to anhydrolycorinone as in the previous synthesis. 

A convenient synthesis of phosphinines 185 involves the reaction of pyrylium salts 184 with either an excess of tris(trimethylsilyl)phosphine in acetonitrile, or alternatively with PH3 under pressure at 110°C <2001CEJ3106>. Better yields are often obtained using the direct reaction with PH3 (Equation 37). 2-t-Butyl phosphinines 187 can be prepared by reaction under pressure of /-butylphosphaacetylene with the a-pyrone 186 (Equation 38). 

A simple two-step synthesis of the a-pyrone ring system209 has been applied to the synthesis of bufadienolides.210 Reaction of the known a/3-unsaturated aldehyde (416) with the dimethyl acetal of chloroketen [ClCH=C(OMe)2] gave a 57% yield of the intermediate 2,2-dimethoxy-3 -chloro-3,4-dihydropyran (417) which on reaction with sodium methoxide in DMSO afforded the a-pyrone (418) directly in 64% yield. 

Posner and Kinter have demonstrated MAD-promoted highly stereoselective [4 + 2] cycloaddition under mild conditions in the asymmetric total synthesis of an A-ring precursor 171 to hormonally active la,25-dihydroxyvitamin D3 [172]. Reaction of a pyrone sulfone 168 and an enantiomerically pure vinyl ether 169 under the influence of MAD in toluene-CH2Cl2 at -45 °C for 12 h afforded cycloadduct 170 in 93 % isolated yield as a 98 2 ratio of the endo diastereomers. From 170, the synthesis of 171 required 13 steps and proceeded in 34.6 % overall yield as indicated in Sch. 133. 

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