Spiroketal cyclization

Spiroketal cyclization. Intramolecular spiroketal cyclization via Michael addition of an alcohol to a chiral a,p-unsaturated sulfoxide can proceed with high stereoselectivity. Reactions with KH are more stereoselective than those with NaH or n-BuLi. Thus cy-... 

The third synthetic scheme is employed when the phenylthio substituent is in the a-position of the lactone function, which interferes with the cyclization (90JOC5894). Acetylenic ketone 194 (95% yield) is readily transformed to the acetal 195 (with potassium carbonate in methanol) however, under the above conditions neither its hydrolysis nor cyclization to the spiroketal occurs. The spirocyclic pyrone 197 is formed in quantitative yield on treatment of 195 with p-toluenesulfonic acid in a 4 1 THF-H2O mixture at reflux for 12 h. 

An easy, silica gel-promoted 6-endo cyclization of y-epoxy alcohol 32 to pyran 33, followed by acid-catalyzed spiroketalization of the keto diol 34, afforded the common tricyclic spiroketal fragment 35 of lituarines A, B, and C (Scheme 8.8) [20b],... 

In another interesting application of this procedure, the acid-mediated cascade cyclization of (3-diketone diepoxide 73 involves the participation not only of the two oxirane rings and of the secondary alcoholic group, but also of one of the two carbonyl groups. In this way, besides the two adjacent C and D THF rings, the simultaneous construction of the spiroketal function between the B and C rings of etheromycin is obtained (compound 74, in a 70 30 mixture with 12 -epi compound Scheme 8.19) [37]. 

Substituted spiroketals can be prepared in good yields (51-61%) by the electrochemical oxidative cyclization of ft)-hydroxytetrahydropyrans in anhydrous ethanol containing lithium... 

Cyclization of a mixture of dl and meso dihydroxyketones T3 and 14 under mild acid conditions gave a mixture of the three isomeric spiroketals 15, 16, and 17. Low temperature C nmr analysis confirmed that isomers lj> and 16 are conformationally rigid and that they exist in the conformations 15A and 16A respectively. Using the same technique, isomer V7 was shown to exist as a mixture of conformers 17A and 17B as predicted. Furthermore, acid equilibration of lj> (or 16) gave a =97 3 mixture of isomers 15 and 16, and when isomer V7 was treated under the same conditions it was converted into a 97 3 mixture of 2j> and 26. These results are completely consistent with the analysis made above. 

A Ti(Oz -Pr)4-mediated kinetic spirocyclization (with C-l retention) for the stereocontrolled synthesis of spiroketals from glycal epoxides such as 485 has been reported (Scheme 87) <2006JA1792>. A complementary methanol-induced kinetic cyclization (with C-l inversion) allows for a synthetically systematic approach for accessing stereo-diversified spiroketals, for example, 486 and 487 from glycals (e.g., 484) <2005JA13796>. 

As reported in Figure 2.5, nitroolefins (26), easily obtained by nitroaldol condensation between 5-nitro ketones (24) and aldehydes (25), are converted directly into the spiroketals (29) by reduction with sodium boronhydride in methanol. The one-pot reduction-spiroketalization of nitroalkenes (26) probably proceeds via the nitronate (27) that by acidification is converted into carbonyl derivatives, which spontaneously cyclize to emiketals (28). Removal of the tetrahydropyranyl group, by heating the acidic mixture during the workup, affords, in a one-pot reaction from (26), the desired spiroketals in 64-66% overall yields. The spiroketalization of (26)-(29b) proceeds in high ( )-diastereoselectivity. 

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. 

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). ... 

Mercuriocyclization has also been utilized in order to obtain spiroketals from hemiketals. Thus, treatment of l,10-undecadien-6-one (11) with mercury(II) acetate in water/tetrahydrofuran affords, with total regioselectivity, 2,8-bis[(chloromercurio)mcthyl]-l,7-dioxaspiro[5.5]undccanc as a diastereomeric mixture. The diastereomeric ratio was not reported but depends on the reaction time, owing to the reversibility of oxymercuration-cyclization steps. Reductive removal of mercury by sodium borohydride under phase-transfer conditions gives a good yield of 2,8-dimethyl-l,7-dioxaspiro[5.5]undecane (12) as a diastereomeric mixture101,102. 

Spiroketals are also obtained in good yield starting from hydroxy enones, although diastereo-meric mixtures are generally recovered. Only 10-hydroxy-l-tetradecen-6-one (15) cyclizes with high stereoselectivity to give 2-butyl-8-methyl-l, 7-dioxaspiro[5.5]undecane (16) in 88 % yield as a 96 4 E,E)j E,Z) diastereomeric mixture102. The major diastcrcomer is separated by preparative GLC and identified on the basis of its H-NMR spectrum. 

Spiroketals can also be obtained by cyclization of 4,5-dihydroisoxazoles containing the 3,4-di-hydro-2//-pyran moiety. Thus, treatment of dihydroisoxazole 22 with iodine in dichlorometha-ne results in excellent internal asymmetric induction, whereas no relative asymmetric induction is observed. The corresponding spiroketal 23 is obtained in 57% overall yield as a 50 50 diastereomeric mixture of epimers at C-238. 

A more detailed study27 was carried out of the spiroketalization reaction. Compounds obtained by C-23 deoxygenation of intermediates in the tetrahydrocephalostatin 12 synthesis were used, with various permutations differing in their C-20 stereochemistry and also the presence or absence of benzylation at C-26. These compounds were subjected to a series of acid-catalyzed cyclizations. 

With the C-26 benzyl derivative, four different 5/5 spiroketals are possible (Scheme 22). All of these were observed in room temperature cyclizations, while equilibration at higher temperatures gave a single 5/5 spiroketal. Again, this is in agreement with calculations, where one product is at least 4 kcal/mol lower in energy than the others. 

The right half of cephalostatin 7 was synthesized32 in an analogous manner to that of tetrahydrocephalostatin 12. The silyl ether of 55 was dihydroxylated to give a pair of inseparable diastereomers in a 4 1 ratio, the major product 57 corresponding to the natural C-25 stereochemistry (Scheme 26). However, no reaction was observed with conditions used for spiroketalization (Scheme 22, vide supra), while harsher conditions led to undesired products. As in the earlier work, the brominated derivative 58 of the desired 5/5 spiroketal was formed by treatment with NBS. A diastereomeric byproduct was also obtained, occurring from cyclization of the minor epimer of 57. 

Compound 73 was reacted with methallylstannane to give a separable pair of diastereomeric alcohols (Scheme 33) in a 1 2.7 ratio favouring the desired product. The unwanted diastereomer was recycled in 79 % yield by Mitsunobu inversion. The alcohol was then benzylated to afford intermediate 74, after which reduction of the C-12 ketone yielded a 1 9 ratio of a- and (3—C-12 epimeric alcohols. The alcohols were osmylated and subjected to periodate cleavage to provide 75. This was reacted with methyl Grignard, followed by acid catalyzed cyclization with (+)-camphorsulfonic acid. Three spiroketal products 76, 77, and 78 were isolated in a 1 15 1 ratio. 

The 6,6-spiroketal system of the northern segment was constructed via their developed LACDAC reaction and oxidative cyclization at C21 (Scheme 63). 

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