Dioxinones

Pyran-4-ones are formed when acyl ketenes derived from dioxofurans and dioxinones react with vinyl ethers. Intermediate products are 1,3,5-triketones and reduced pyranones <96CPB956,96H(43)2457,96TL6499>. 

In Entry 13, the dioxinone ring undergoes thermal decomposition to an acyl ketene that is trapped by the solvent methanol. The resulting (3-keto-y,8-enoate ester then undergoes stereoselective cyclization. The stereoselectivity is controlled by the preference for pseudoequatorial conformations of the C(6) and C(9) substituents. 

Miriyala and Williamson have described the synthesis of /i-kctocarboxam idcs from primary and secondary amines and 2,2-dimethyl-2H,4H-l,3-dioxin-4-ones as reactive a-oxoketene precursors (Scheme 6.158) [304], The experimental procedure involved heating a mixture of the dioxinone with 2-3 equivalents of the amine at ca. 180 °C for 1-3 min under solvent-free conditions in a sealed vessel by microwave irradiation. A small collection of 18 /3-ketocarboxamides was prepared in very high yields using this protocol. 

Bismuth-Catalyzed Mukaiyama Aldol Reaction of Dioxinone-Derived Silyl Dienol... 

Electrophiles also react at C-5 of 1,3-dioxin-4-ones. Two ways of activation have been reported (1) magnesiation of 5-iodo-l,3-dioxin-4-ones afforded the Grignard reagents which can be cross-coupled with allyl halides in the presence of copper cyanide <2001TL6847> or with iodoalkenes under Pd(0) catalysis <2002T4787> and (2) Sc(OTf)3-catalyzed reaction of a side-chain-hydroxylated l,3-dioxin-4-one with aldehydes provided the bicyclic dioxinone in 60-85% yield (Scheme 27) <20050L1113>. 

Esterification of resin-bound alcohols with 3-oxo carboxylic acids (which readily undergo decarboxylation) or with malonic acid is best performed using the corresponding ketenes, which can be generated in situ by thermolysis of dioxinones or other precursors (Entries 6-9, Table 13.12). PEG can also be acetoacetylated with acetyl ketene generated by thermolysis [171]. 

Conjugate addition of dialkylcuprates to the homochiral dioxinone (57), prepared from (/ )-3-hydroxy-butyric acid (56), produces single diastereomers (58), which can be hydrolyzed to the homochiral products (59).60 61 The overall process (Scheme 22) constitutes an example for self-regeneration of a stereogenic center . Interestingly, the high stereoselectivity can not be attributed to simple steric effects. 

The pyramidalization of the trigonal centers (a common feature found in the X-ray structures of several related dioxinones) is probably responsible for the high selectivity.61 The nucleophile preferentially attacks the electrophilic center from that (convex) face into which it is pyramidalized, in accordance with the principle of minimization of torsional strain. A related example for asymmetric 1,4-addition to chiral dioxinones was reported.62... 

Catalysis with Ti(IV) Complexes and Boronates. Carreira has documented the addition of dienolsilane 105 to a broad range of aldehydes [28], Enolization of the commercially available acetone-ketene adduct 104 with LDA, followed by quenching with chlorotrimethyl silane, gave 105 in 78% yield as a clear colorless liquid that can be conveniently purified by distillation (Eq. 8B2.24). The addition reactions are conducted at 23°C utilizing 5 mol % 72 to give adducts with up to 94% ee (Eq. 8B2.25, Table 8B2.13). The aldol adducts 106 were isolated fully protected as the corresponding 0-silyl ethers with the P-keto ester masked in the form of a dioxinone. 

Winkler and Shao85 have examined the first bond formation in the photoaddition of labeled dioxinones 143 and 146. Irradiation of 143 afforded an epimeric mixture of the more strained photoproducts 145, while irradiation of 146 gave 148 as a single product. These results are consistent with diradicals 144 and 147 as the intermediates in the photoaddition of 143 and 146, respectively, pointing out that the first bond formation in both cases takes place exclusively at the /1-carbon of the dioxinone chromophore (Scheme 31). 

The role of the dioxinone chromophore on the selectivity in the first bond formation, was examined by comparison to the enone analogs 149 and 151, lacking the /1-oxygen found in the dioxinone chromophore. Irradiation of 149 and 151 afforded only the fraws-fused photoproducts 150 and 152 respectively, which indicates that in contrast to dioxinones, the first bond formation in the enone photocycloadditions can take place from either the a- or /1-carbon of the enone via six-membered ring of the corresponding diradical intermediate (Scheme 32). 

An alternative approach was developed by the group of Demuth97, based on the intermolecular photoaddition of chiral l,3-dioxin-4-ones 192 and 194 possessing the (—)-menthone auxiliary that could smoothly be removed after the photoaddition step. The results of Demuth s pioneering studies into the reactions of chiral dioxinones with cyclic... 

Stereoselective intermolecular photoadditions of alkenes to enones have been elegantly utilized in the synthesis of naturally occurring compounds or compounds of special interest. Sato and collaborators100 have applied the photoaddition of dioxinone 208 to the chiral r/.v-diol 207 for a one-pot synthesis of the Corey lactone 210, which possesses considerable utility in the preparation of prostaglandin derivatives (Scheme 45). 

Systematic study on the diastereofacial selectivity in the intramolecular photocycloaddition of alkenes to chiral dioxinones was recently reported by Haddad and coworkers129 on compounds of type 298. Preferred pyramidalization in the direction of the less exposed side (the axial methyl at the acetal center) described in structure 298b, and first bond formation at this position (found to be the case in dioxinones 143 and 146, Scheme 31), are essential features for obtaining selective photocycloadditions of alkenes to chiral dioxinones from this side, leading to the kinetically favored products. In such cases the preferred approach is not necessarily from the more exposed side (Figure 6). 

General and stereoselective synthesis of spiroethers and less thermodynamically stable spiroketals have recently been developed by Hadded and coworkers129,130. The key step is the intramolecular photocycloaddition of chiral dioxinones of type 305 to dihydropyrones. Subsequent fragmentation of the produced four-membered ring provides, after oxidative enlargement of the cyclic ketone, the thermodynamically less stable spiroketal 310 (R = H) as was demonstrated on photoproduct 308 (Scheme 66). 

An intramolecular [2+2] photocycloaddition of allyl ethers with dioxinones followed by a base-induced fragmentation leads to substituted tetrahydropyran-4-ones <1997TL5579>. A one-pot scandium triflate catalyzed diastereoselec-tive cyclization between aldehydes and (3-hydroxy dioxinones 1046 followed by alkoxide addition to the resulting bicycles 1047 leads to 3-carboxy-substituted tetrahydropyran-4-ones 1048 with high levels of diastereoselectivity as a mixture of keto/enol tautomers (Scheme 268, Table 49) <20050L1113>. 

After purification, the dimethyl 1,3-dioxinone unit of 2 was hydrolysed with mild base to furnish the P-keto acid. Acidification then brought about lactonisation to the enolised p-keto lactone 1. To facilitate work-up and isolation, the latter was converted to the vinylogous ester 24 with potassium carbonate and dimethylsulfate in acetone. Mild acid hydrolysis of 24 with 0.1 N H2S04 in EtOAc eventually furnished (-)-ACRL toxin 1 in good yield after six days, completing this very elegant and beautifully crafted synthesis. 

Explanations for the outcome of the photocycloaddition reactions have been proposed. Seebach et al. suggested that carbon atom C-6 is pyramidalized in the excited triplet state in the opposite direction as compared to the ground state [125]. Sato proposed that different dioxinone conformations are responsible which vary depending on the reaction type [126]. 

It is with these factors in mind that Seebach s recent studies [105] on the stereoselective addition to pyramidalized dioxinone systems have caused him to... 

Similarly, dioxolane was added successfully to the chiral dioxinone 213 (Scheme 58) [133]. The radical attack occurred preferentially syn with respect to the isopropyl substituent of the menthone moiety to produce 214 and 215. This site differentiation was rationalized by the favored conformation of the substrate ... 

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