Ketals 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. 

Regioselecdve reducdon of 2-nitrocycloalkanones withsndiiun borohydnde affords Oj-nitro alcohols. This reacdon is applied to the synthesis of spiroketals as shovm in Eq. 5.17, in which spiro[4,5 - and spiro[4,6 ketal systems are obtained in good yields. "... 

The general features of the monensin synthesis conducted by Kishi et al. are outlined, in retrosynthetic format, in Scheme 1. It was decided to delay the construction of monensin s spiroketal substructure, the l,6-dioxaspiro[4.5]decane framework, to a very late stage in the synthesis (see Scheme 1). It seemed reasonable to expect that exposure of the keto triol resulting from the hydrogen-olysis of the C-5 benzyl ether in 2 to an acidic medium could, under equilibrating conditions, result in the formation of the spiroketal in 1. This proposition was based on the reasonable assumption that the configuration of the spiroketal carbon (C-9) in monensin corresponds to the thermodynamically most stable form, as is the case for most spiroketal-containing natural products.19 Spiro-ketals found in nature usually adopt conformations in which steric effects are minimized and anomeric effects are maximized. 

Deprotection of the spiroketal protected porphyrazines to generate the pz-diols proved difficult because the desired product is easily oxidized before isolation or derivitization. It was therefore anticipated that the high electron density of the de-protected pz-diol would be reduced by core-metalation, so attempts were made to deprotect ketal 193 with TFA to give enediol 201. However, 201 rapidly decomposed during purification attempts. To avoid this problem pz (201) was trapped with terl-bu(yIdiinc(liyIsi IyI triflate to give the ferf-butyldimethylsilyl derivative 202 (79%) as a stable compound (Scheme 40) (10). 

In the designed synthesis, gold first catalyzed an exo-addition of an OH group across an alkyne resulting in an enol ether. This transient enol ether could engage a ketal oxygen under protic conditions to form the bis-spiroketal [103]. 

The possibility that olefin-carbon monoxide copolymers can exist in the isomeric poly-spiro ketal structure (Scheme 8.5) was recognized soon after the first synthesis of the copolymers of propene. Using dialkyl diphosphines as the modifying ligands [27], copolymers were obtained with blocks with the spiroketal form [28]. 

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>. 

Pd(OH)2/C in the presence of HC1 and cyclohexene provided 45 in 64% yield. This reaction is believed to proceed via intermediate oxime 44, which undergoes acid-mediated hydrolysis and ketalization to afford the product.25 Use of other reducing agents, such as TiCb/NH40Ac/H20, or hydrogenation with Pd/C and H2 provided lower yields of the desired compound. The spiroketal 45 is a substructure of the y-rubromycin family of natural products, which have shown activity against HIV reverse transcriptase and DNA helicase. 

Fig. (9). Modified aryl E-ring possessing o-quinone, ketal, and spiroketal functionalities...

A radical-mediated two-step synthesis of spiroketals has recently been reported the strategy (an example is shown in Scheme 8) involves an intramolecular radical cyclization of a ketal precursor (14), which could be easily prepared from 2-methylene-3,4-epoxyoxolanes (13). As alternative to tin-hydride mediated cyclization of alkynyl halides, samarium(II) iodide has been used to generate the alkyl radical which adds intramolecularly to the triple bond. ... 

The routes leading from lactone A have the advantage of a chiral source of starting materials. With the two chiral centers at C24 and C25 set, the problem reduces down to elaborating the B ring with the appropriate substituents. An early solution was provided in an unusual cyclization of the B ring via an intramolecular Michael addition to the unsaturated aldehyde formed from a nitrile oxide 1,3-dipolar cycloaddition to the allyl methyl ketal of lactone A [76]. This clever use of relative stereocontrol provided by the highly constrained and predictable transition states of both key reactions unfortunately resulted in a low yield. A more conventional approach conceptualized the addition of a sulfoxide [77] to 2 to yield a masked diol-ketone precursor which cyclizes under acidic catalysis. Elimination of the sulfoxide permitted the introduction of the hydroxy substituent at C19 of the spiroketal. 

Haag, R. et al.. New polyethylene glycol polymers as ketal protecting groups — a polymer supported approach to symmetrically substituted spiroketals, Synth. Commun., 31, 2965, 2001. 

Depending on the reaction conditions of PCO and OCO copolymerizations, polyketones are obtained either in a linear or in a spiroketal structure. The equilibrium of the keto- and ketal stmcture depends on the energetic difference between both forms, which is fairly small in OCO copolymers of higher olefins (the stability of the spiroketal form increases with the length of the a-olefin). Investigation of the dynamic behavior was carried out by NMR spectroscopy in solution and in the solid state. The spiroketal form can be converted into the linear poly( 1,4-ketone) at higher temperatures or by treatment with l,l,l,3,3,3-hexafluoro-2-propanol (HFIP) and precipitation (Figure 40). 

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