Spiroketal reduction

Regio- and Diastereoselectivity of Spiroketal Reduction 2-3-7. Strategy of Spiroketal Reduction... 

Spiroketal Reduction with Silane-Lewis Acid... 

Ivermectin is the catalytic reduction product of avermectin, a macroHde containing a spiroketal ring system. Two other related antibiotics having significantly different stmctural features and biological properties, moxidectin and milbemycin oxime, were more recentiy introduced into the market. Although these compounds have no antimicrobial activity, they are sometimes referred to as antibiotics because they are derived from fermentation products and have very selective toxicities. They have potent activity against worms or helminths and certain ectoparasites such as mites and ticks. 

Regioselective reduction of 2-nitrocycloalkanones with sodium borohydride affords co-nitro alcohols. This reaction is applied to the synthesis of spiroketals as shown in Eq. 5.17, in which spiro[4,5]- and spiro[4,6]ketal systems are obtained in good yields.32... 

Martin et al. (289) utilized the chiral bicyclic lactone 88 for a total synthesis of (+)-phyllanthocin (Scheme 6.62). Cycloaddition of 88 to acetonitrile oxide, generated in situ from hydroximoyl chloride (89), furnished cycloadduct 90 in 45% yield together with other regio- and stereoisomers. After several steps, methyl glycoside (91) could be obtained. From this, reduction-hydrolysis gave the aldol that was subjected to acid-catalyzed spiroacetalization to produce spiroketal (92), and eventually (+)-phyllanthocin (93) after two additional steps (289). The... 

We should also expect stereoelectronic control when the hydroxyl group is replaced by another nucleophile in the reaction with cyclic oxonium ions. A recent report (110) shows that hydride transfer to cyclic oxonium ion is subject to stereoelectronic control. Tricyclic spiroketal 140 (Fig. 19) undergoes an acid-catalyzed oxidation-reduction reaction to give the equatorial bicyclic aldehyde 147 stereospecifically. Similarly, spiroketals 148 and M9 gave the corresponding equatorial bicyclic ketone 150. 

This rationalization indicates that internal delivery of a hydride is not a requisite for the observed stereospecificity. Reduction of the oxonium ion with an external hydride reagent should also give equatorially oriented bicyclic ether only. Accordingly (112), reduction of tricyclic spiroketal 145 with sodium cyanoborohydride at pH =3-4 yields only the equatorial bicyclic ether alcohol (J47, CHO=CH2OH). Eliel and co-workers (113) have previously suggested that the orientation of the electron pairs of oxygen atoms influence the course of the reduction of 2-alkoxytetrahydropyran with lithium aluminium hydride-aluminium trichloride. 

Spiroketals and oxaspirolactones.1 An improved route to spiroketals from lactones involves use of cerium 3- or 4-cerioalkoxides such as 1, prepared from 3,3-dimethyloxetane by reductive cleavage with lithium di-r-butylbiphenylide (LDBB) followed by transmetallation. Use of the intermediate lithium 3-lithioalkoxide as the... 

The 7-hydroxy telluride 161 is prepared by hydrotelluration of methyl vinyl ketone, followed by in situ reduction with sodium borohydride.154 Treatment of 161 with 2 equiv. of nBuLi, followed by capture of the dianion 162 with electrophiles, gives the corresponding alcohols 163.252 Dianions like 162 can be transmetallated with CeCf , leading to organometallics of the type 164, which on reaction with lactones give spiroketals (Scheme 94).253... 

Recent work from Ireland s group directed to the synthesis of monensin subunits takes as well advantage of the suitability of hetero Diels-Alder reactions for generating spiroketals [495]. In situ generation of the highly labile dienophile 7-19 from 7-18, subsequent cycloaddition to acrolein which acted as 1-oxa-1,3-butadiene and reduction yielded the spiroketal 7-21 accompanied by small amounts of diastereomeric byproducts. A mild acid catalysed rearrangement is the next key transformation to the spiroketal subunit 7-20 of monensin 7-22 (Fig. 7-5). 

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. 

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. 

The organoselenium-mediated intramolecular trapping of a hemiketal by a suitably disposed carbon-carbon double bond can lead to a spiroketal, although with low stereoselectivity. Thus, when 9-hydroxy-l-nonen-5-one (17) is treated with /V-(phenylsclcno)phthalimide and a catalytic amount of zinc bromide in dichloromethane at 20 °C, a 67 33 (ZjE) mixture of the seleno derivatives is obtained in 78% yield. After Raney nickel reduction, the corresponding spiroketals are recovered in 90% yield103-104. 

The spiroketal side-chain of diosgenin has been converted into 22-ketocholes-terol (488) by straightforward reactions. The known enol ether (485), prepared by a modification of Marker s method, was selectively saponified at C(26) and converted into (486) by lithium aluminium hydride reduction of the C(26)-tosylate. Lithium bromide-hydrogen bromide opening of the enol ether ring... 

The diene pcntions of avermectin and milbemycin have been synthesized by application of the Julia coupling. For the total synthesis of milbemycin 3s by Baker and coworkers, the aromatic ring was incorporated as the aldehyde (431) and the spiroketal portion added as the sulfone (430 equation 100). The overall yield was 70-80% of the ( , )-alkene (432), exclusively. The identical bond disconnection was studied by Kocienski, but with the aldehyde (433) and sulfone (434) components reversed (equation 101). The anion was formed with LDA and, following functionalization and reductive elimination, the alkene was isolated in 39% yield in a 5 1 ratio of the ( )- and (Z)-isomers (435). 

In the final stages of the total synthesis of okadaic acid by C.J. Forsyth et al., the central 1,6-dioxaspiro[4,5]decane ring system was introduced by the enantioselective reduction of the Cl6 carbonyl group using (S)-CBS/BH3, followed by acid-catalyzed spiroketalization. ... 

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