Spiroketals stereoselective synthesis

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). 

Spiroketalization. The synthesis of talaron ycin B (3) with four chiral centers by cyclization of an acyclic precursor presents stcrcot hcmical problems. A solution involves cyclization of a protected (3-hydroxy ketone witii only one chiral center. Because of thermodynamic considerations (i.e.. all substituents being equatorial and the anomcric effect), cyclization of 1 with HgCl, in CH,CN lollowcd by acetonation results in the desired product (2, 65% yield) with a stereoselectivity of —10 1. Final steps involve conversion of the hydroxymethyl group to ethyl by tosylation and displacement with lithium dimethylcupratc (80% yield) and hydrolysis of the acetonidc group. 

Stereoselective synthesis of the substituted 1,7-dioxaspiro[5.5]undecane 2 has been performed by a simple treatment of the 3,4-dihydro-2//-pyran 1 with 4-methylbenzenesulfonic acid/water in benzene at 55 °C for 3 hours. The cydization proceeds with total stereoselectivity and only one isomer is recovered in 55% yield. The corresponding unprotected spiroketal can be obtained as a single diastereomer and the structure is determined on the basis of H-NMR data98. 

Because of their complex chemical structures and significant biological properties, polyether ionophore antibiotics have stimulated intensive studies of their total synthesis, which primarily require new synthetic methodologies for the control of stereochemistry in acyclic systems two excellent reviews covered the results until 1981 [1]. However, since then, only a few total syntheses have been achieved, because the extremely complex structures of the polyethers have required formidable efforts for synthesis, and much attention has focussed on efficient and stereoselective synthesis of the molecular framework of substituted tetrahydrofurans and tetrahydropyrans and spiroketal systems [2]. This review deals with the total synthesis of three representative complex polyethers, okadaic acid (1), antibiotic X-206 (2), and salinomycin (3) mainly focussing on the latter half of their synthesis. 

Stereoselective synthesis with carbon dioxide, including preparation of cyclic carbonates, polycarbonates, and oxazolidinone 13ASC2115. Strategies for spiroketal synthesis based on transition metal catalysis ... 

Noda, T, Ishiwata, A., Uemiua, S., Sakamoto, S., and Hiiama, M. (1998) Synflietic study of pitmatoxia A stereoselective synthesis of the BCD-ring unit, a novel 6,5,6-bis-spiroketal system. Synktt, 298-300. 

Finally, oxidative cyclization (HgO, I2, hiA of tqjpropriately substituted alcoholic ethers formed the basis of Kay s stereoselective syntheses of both 4-hydroxy-l,7-dioxaspiro[S.S]undecane, an olive fly pheromone component, and ( )-talaromycin B (equations 4 and 5). More recently, Danishefsky et at have further extended the scope of this spiroketal-forming reactitm in their elegant total synthesis of avermectin Ai (equation 6). ... 

The synthesis of analogues of the spiroketal-containing pyranonaphthoquinone antibiotic griseusin A can be achieved by the regio- and stereoselective hydroxyalkylation of 4,8-dimethoxy-l-naphthol (equation 29). ... 

Spiroketals have been obtained by RCM of cyclic ketals 18 without loss of stereochemical integrity at the spiro linkage <04TL5505> and a stereoselective solid-phase synthesis of 6,6-spiroketals has been reported in which aldol reactions of boron enolates are the key feature <04AG(E)3195>. Spiro orthoesters are accessible from thiophenyl ketene acetals and diols (Scheme 5) <04SL2013>. 

There have been several recent solid-phase and solution-phase libraries reported that contain the spiroketal moiety (Figure 7.5). These libraries introduce additional structural complexity and new interaction modes of carbohydrate-like molecules with biological targets. Ley and cowoikers reported the solid-supported synthesis of spiroketals. Using stereoselective aldol reactions of boron enolates, the Waldmann and Paterson groups reported the solid-phase synthesis of 6,6-spiioketals. The 1,7-dioxaspiro [5.5]undecane spiroketal served as the core template for Porco s three-point diversity library to explore protein-protein interactions. ... 

Waldmann and coworkers employed the aldol reactions of chiral boron enolates as the key stereoselective transformations toward the solid-phase synthesis of 6,6-spiroketals, a scaffold often found in biologically interesting complex natural products. The polymer-bound aldehyde 1 with a loading of 0.75 mmol/g was treated at —78°C with the preformed (Z)-diisopinocampheyl borinate 2 in dichloromethane for 1.5 h (Scheme 7.1). After storing the reaction mixture at —27°C for 16 h, the resin was filtered and the whole process was repeated once. An oxidative workup followed by TBS protection of the secondary alcohol yielded immobilized s yw-aldol product 3. 

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