Acetals spiroketals

Many functional groups are stable to alkaline hydrogen peroxide. Acetate esters are usually hydrolyzed under the reaction conditions although methods have been developed to prevent hydrolysis.For the preparation of the 4,5-oxiranes of desoxycorticosterone, hydrocortisone, and cortisone, the alkali-sensitive ketol side chains must be protected with a base-resistant group, e.g., the tetrahydropyranyl ether or the ethylene ketal derivative. Sodium carbonate has been used successfully as a base with unprotected ketol side chains, but it should be noted that some ketols are sensitive to sodium carbonate in the absence of hydrogen peroxide. The spiroketal side chain of the sapogenins is stable to the basic reaction conditions. 

For substituted lactones this method gave a low yield of the spiroketal 189 (<5%). For 5,6-dimethylvalerolactone a second scheme has been suggested involving treatment of ketoalcohol 190 with potassium carbonate in methanol to form enole ether acetal 191 in quantitative yield (90JOC5894). 

In the case of acid hydrolysis of the acetal 191 the yield of spiroketals 192 and 193 approaches 85% (under sonification). 

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. 

Pikho and co-workers50 found that nonanomeric [6,5]-spiroketals (having a pyranoside moiety with an equatorial CO acetal bond) can be formed under conditions of kinetic control. For instance, 62 undergoes acid catalyzed spiroacetalization giving the anomeric (most stable) acetal 63... 

Talaromycin B is a spiro-acetal produced by the fungus Talaromyces stipitatus, the toxicity of which may be due to its ability to block outward potassium fluxes. In an elegant synthesis, the requisite open-chain polyol with hydroxy groups in the y-and y -positions was assembled from nitrile oxide and olefin building blocks 50 and 51, both of which carry a f>w(hydroxyethyl) moiety protected as a cyclohexanone acetal (284). Hydrogenolysis of the N O bond of isoxazoline 52 using Raney nickel, followed by treatment with aqueous acid, gave the spiroketal 53, which was further transformed into racemic talaromycin B (54) (Scheme 6.54) (284). 

Eight naturally occurring, structurally related avermectins are produced by Streptomyces avermitilis [7], The avermectin polyketide structure is derived from seven acetate and five propionate residues, together with a single 2-methylbutyric acid or isobutyric acid residue which forms the sec-butyl or isopropyl group attached to the C25 of the spiroketal moiety [8,9] (Fig. 1). The avermectin agly-cone is further modified by glycosylation at C13, with the attachment of two O-methylated oleandrose residues and O-methylation at C5. Thus, S. avermitilis... 

Acetals such as C are referred to as spiroketals because their acetal carbon is a spiro atom. (In a spiro compound two rings are connected by a single common atom that is called a spiro atom ). The intermediates in this acetalization are lactols B. They resemble those lac-tols whose rapid formation from y- or 5-hydroxyketones was shown in Figure 9.4. Note that because of the unfavorable reaction entropy, there is often no path hack from spiroketals to the open-chain form Usually, spiroketals cannot be hydrolyzed completely. 

Now that you know about the anomeric effect, you should add it to your mental array of ways of explaining unexpected results. Here is an example. Many fruit flies have pheromones based around a spiroketal structure, which we could represent without stereochemistry as shown below. You can imagine the spiroketal (that is, an acetal of a ketone made of two rings joined at a single atom) being made from a dihydroxyketone—and, indeed, this is very often how they are made synthetically. But this is a bad representation because these compounds do have stereochemistry, and the stereochemistry is very interesting. 

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. 

Lewis acid catalyzed aldol coupling of silyl enol ethers with substituted cyclohexanone acetals showed an excellent preference for equatorial attack (95-l(X)%). In accord with this general rule, additions of a silyl enol ether to equatorially or axially substituted chiral spiroketals derived from -menthone gave 00% equatorial attack and formation of a single one of the four possible diastereoisomers (Scheme 9) 3, 4 -pjjjg methodology, followed by protection of the hydroxy group (X = OTHP, (XIPh.i) and alkaline removal of the chiral auxiliary was used for the synthesis of several natural products. ... 

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>. 

Abstraction at acetal centers. Simpkins used a hydrogen atom abstraction from tetrahydrofuranyl and tetrahydropyranyl acetals for the preparation of spiroketals (Scheme 41, Eq. 41.1)] [137]. Malacria has inserted this process in a cascade reaction leading to functionalized cyclopentanone (Eq. 41.2) [138], Bertrand and Crich applied this reaction for the preparation of optically active cyclopentane derivative under chiral auxiliary control (Eq. 41.3) [139]. The synthesis of anomeric spiro-nucleosides was reported independently by Chatgilialoglu [46] and Kittaka [140]. In the example reported in Eq. (41.4), the gem-dibromovinyl derivative was treated with hexabutyldistannane to afford the desired spiro derivatives. This kind of reac-... 

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