Dioxinones chiral—

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... 

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). 

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 ... 

Dioxinones Obtained by Resolution or Prepared with a Chiral Auxiliary. 2-Phenyl-4//-1,3-dioxin-4-ones (15) derived from formylacetate or acetoacetate can be readily prepared in enantiopure form by preparative resolution " on cellulose triacetate. These have been used for Michael additions and hydrolysis to long-chain p-hydroxycarboxylic acids, for example the tride-canoic acid (16) from (/ )-(15a). The cuprate adducts formed with the methylphenyldioxinone (i f-flSb) can be hydrogenolyti-cally cleaved directly to p-branched p-hydroxy acids with benzyl protection of the hydroxy functional group see (17) in eq 9. ... 

The chiral auxiliary approach involving dioxinones has been chosen by Demuth et al. and, most extensively, by Kaneko and... 

Aldol-type reactions. Chiral dioxinone derivatives and a-amino y-keto esters are readily obtained. 

Dioxinones 27, with an endo double bond attached to a chiral auxiliary derived from (—)-men-thone, yield the corresponding adducts on addition to cyclopentadiene (9) with excellent diastereoselectivity 31. 

Photocycloadditions of dioxinones have also been reported by Sato et al., particularly with chiral-2-spirocyclic dioxinones. Both inter- and intramolecular versions have shown high regio-and stereoselectivity (Equation (7)) <90H(30)217,90H(3i)2ii5>. 

Seebach and co-workers have explored the uses of enantiomerically pure dienolates (18) and silyl dienol ethers derived from dioxinones as chiral synthetic equivalents of the acetoacetic ester dianion. Reactions were carried out principally with aldehydes, and are regio- and diastereoselective (Scheme 7) <89AG(E)472,91CB1845>. 

CPB397i> and [4 + 2] <89CPB2615> pericyclic reactions can take place with variously substituted dioxinones with very high facial selectivities, particularly in the case of chiral 2-spirocyclic-l,3-dioxin-4-ones having a ( —)-menthone unit at the 2-position (e.g. (26)) where exclusive selectivity is observed (Scheme 11). A mechanism has been proposed to explain the high selectivity <90JCS(P1)1779>. 

The Diels-Alder reaction of these chiral dioxinones with cyclopentadiene has provided a highly stereoselective route to carbocyclic C-nucleoside precursors (27) (Scheme 11) <89CPB2615>. The [2 + 2] cycloaddition of the same menthone-derived dioxinone with cyclopentene has also been observed <87CPB3539>. 

The reactions of similarly derived dioxinones, but containing a 6-alkenyl substituent (28), with A-phenylmaleimide have demonstrated the complementary ability of these systems to act as chiral dienes (Scheme 12) (95LA1455>. 

Incorporation of an auxiliary into a cyclic system has been used for the diastereoselective addition of cuprates to unsaturated 6-membered ring dioxinones, which are perhaps less important for their synthetic potential than for the mechanistic insight they provide. The dioxinones shown in Scheme 4.12a were obtained from / -3-hydroxybutanoic acid using the self-regeneration of chirality centers concept discussed in Chapter 3 (c/., Scheme 3.9 and 3.10). After the addition, hydrolytic removal of the achiral auxiliary (pivaldehyde) liberates a 3-alkyl-3-hydroxybutyrate that is essentially enantiomerically pure [134]. 

Chiral, optically pure exo-methylene compounds, as for example dioxolanes and 1,3-oxazolidinones B, have been successfully examined as dienophiles in thermal Diels-Alder reactions with 1,3-butadiene or cyclopentadiene. Similarly highly diastereoselective reactions of dioxinones C with cyclopentadiene in benzene at 80°C have been reported in the literature. Non-catalyzed cycloaddition reactions of Meyers bicyclic lactam with acyclic dienes proceed at moderate temperature (60°C) highly stereoselective furnishing the products in excellent yield. Equally high endolexo selectivities and diastereoselectivities were reported for the reactions that have been carried out at low temperature in the presence of Lewis acids, e.g. ZnCL. ... 

Dimethyl-4//-l,3-dioxin-4-one 139 has been used as the photochemical equivalent of formylacetate, which is inactive as the enone partner in the photoaddition with alkenes. Irradiation of dioxinone 139 in the presence of symmetrical cyclopentene 140 leads to the cyclobutane adduct 141. This intermediate upon subjection to hot water undergoes retro-aldol fragmentation and spontaneous lactonization to give lactone 143, a useful prostaglandin intermediate. Enantiomerically pure lactone 143 is prepared by using a chiral version of dioxinone 139. ... 

A versatile y-vinylogous aldol reaction of a dioxinone-derived silyl enol ether, by enolate activation with an appropriate Lewis base, has been developed. Using chi- ral 2-(methylsulfinyl)benzaldehyde, adduct (69) has been obtained in high de and ee. 0 This 1,4-asymmetric induction features a dual role for the sulfinyl group chiral inductor and activator of a silyloxydiene. 

Paterson et al. [98] in their attempt used a similar disconnection for rhizopodin as described by Menche (fragments 144 and 149) (Scheme 2.151). However, unlike, Menche, they used silyl ketene acetal 16 in an asynunetric VMAR for the addition to ( )-iodoacrolein (142) to obtain dioxinone 143 in 94% ee. Methanolysis removed the aceto-nide, and the subsequent Narasaka reduction [99] provided the syn-diol 144 in 80% yield and a 10 1 selectivity for the desired isomer. The synthesis of segment 149 started with aldehyde 145, which was ultimately derived from Roche ester. Carbon chain extension was achieved through a chelation-controlled Mukaiyama aldol reaction with silyl ketene acetal 146, which installed the new chiral center with excellent stereocontrol (20 1 dr). For the installation of the third secondary alcohol, six-membered lactone 148 was obtained by treatment with K COj in methanol. Subsequent borane reduction provided stereospecifically the desired alcohol, which was then further transformed to the desired acid (149). 

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