Protecting dispiroketal

PhCH(OCH2CH2CH=CH2)2, CSA, NBS. Standard methods failed because of cleavage of the dispiroketal (dispoke) protective group. 

As a second approach to stabilizing the pz-diols, bulky substituents at appropriate positions were employed to hinder electrophilic attack. The first synthesis of pz-diols was accomplished by removal of the dispiroketal protecting group from the centrally metalated porphyrazines, M[pz(AB3)], A = di-ferf-butyl phenyl, B = dipiroketal (197) (M = Ni) 198 (M = Cu) with acetic acid to form the stable, iso-lable porphyrazines, M [pz(AB3)], A = di-ferf-butyl phenyl, B = diol (203) (M = Ni) 204 (M = Cu) (Scheme 41) (10). 

Until recently, the protection of the trans-hydroxyl groups of sugars has been an inefficient process.2 This protection has now been simplified by the introduction of the dispiroketal protecting group,3 and the cyclohexane diacetal (CDA) protecting group.4... 

Some additional examples, where the stereochemical outcome of the cycloaddition to chiral alkenes has been explained in terms of the Honk—Jager model, should also be mentioned. The diastereomer ratio found in the reaction of y-oxy-a,p-unsamrated sulfones (166), with Morita-Baylis-Hillman adducts [i.e., ot-(a -hydro-xyalkyl)-acrylates (167)] (Scheme 6.27), with dispiroketal-protected 3-butene-l,2-diol (168), and with a,p-unsamrated carbonyl sugar and sugar nitroolefin (169) derivatives, all agree well with this model. 

Benzylidene and isopropylidene acetals of irons-1,2-diols are very labile as a result of ring strain and are not often used for synthetic applications. Fortunately, the protection of these diols can be accomplished with the recently developed dispiroketal (dispoke)35 and cyclohexane-1,2-diacetal (CDA) groups.36... 

Diacetal Protecting Groups The pioneer work of Ley s group concerning the application of 1,2-diacetals such as the dispiroketal (dispoke) [141,142,143,144,145], the cyclo-hexane-... 

The dispiroketal protection of monosaccharides is controlled by the stabilizing influence of multiple anomeric effects leading to a single diastereomeric derivative. In certain examples, where there is more than one diequatorial diol pair present in the molecule, as for example in D-glucose derivatives, reaction affords a mixture of diacetals (O Scheme 22). The reaction, often giving crystalline compounds, is carried out by treatment of the polyol with 3,4,3, 4 -tetrahydro-6,6 -bis-2H-pyran in chloroform at reflux in the presence of a catalytic amount of CSA[151]. 

Examples of protection of diequatorial vicinal diols with dispiroketals... 

Reaction of methyl a-D-galactopyranoside 102.1 with 6,6 -bis(3,4-dihydro-2//-pyran) (bis-DHP, 1023) in refluxing chloroform (thermodynamic conditions) gives the dispoke (dispiroketal) derivative 102.2 in 64% yield. - The preference for rram-diequatonal protection is a consequence of steric interactions and multiple stabilising anomeric effects of the two acetal functions in the dispoke derivative. The pure bis-DHP reagent 1023 is a low melting solid (mp 49-50 C) that is stable at -10 °C in the absence of acid and moisture. It is prepared in 55% yield by the oxidative dimerisation of 6-lithio-3,4-dihydro-2//-pyr-an. As can be seen from Scheme 3.103, the preference for frum-diequatorial protection is excellent in the fiico, manno, and fyxo series but it is poor in the case of the arabino and rhamno series. 

Cyclohexane-1,2-diacetal (CDA) and dispiroketal (dispoke) protocols provide bulkier groups for rran -I,2-diol protection [86]. 

Scheme 1 Dispiroketal or dispoke protection of trans-1,2-diols...

In 1992, Ley and co-workers demonstrated the inherent selectivity of 3.3, 4.4 -tetrahydro-6,6 -bis-2//-pyran (bis-DHP) 1 for trans diequatorial vicinal diols in polyol systems in carbohydrate derivatives (Scheme 1) [26]. In a typical experiment, the carbohydrate polyol was reacted with an excess of bis-DHP 1 in refluxing chloroform and in the presence of a catalytic amount of camphorsulfonic acid to afford the corresponding dispiroketal. For representative examples see Table 1. The protection process proceeds in moderate to good yields and gives diequatorial diol protection as the major outcome in all cases. In a few cases some c/s-diol protection was noticed as a minor process when steric interactions were of lesser magnitude. 

To overcome these problems, 1,1,2,2-tetramethoxycyclohexane (TMC) 2 was developed as an alternative to bis-DHP for carbohydrate protection (Scheme 2) [28]. Initially, TMC 2 was easily prepared from inexpensive cyclohexane-1,2-dione although it is currently commercially available. TMC 2 allows the use of more polar solvents, such as methanol, and cyclohexane-1,2-diacetals (CDA) are obtained in higher yields than the corresponding dispiroketals. 

The usefulness of dispiroketal to act as practical glycosyl donors was further illustrated in a facile one-pot synthesis of a trisaccharide fragment from the capsular polysaccharide of Group B Streptococci [80]. In the following example (Scheme 29), armed perbenzylated ethyl l-thio-oj-L-rhamnopyranoside donor 157 was treated with semidisarmed dispiroketal 158 under IDCP promoted glycosylation to provide disaccharide 159 in 59% yield. Glycosidation of acceptor 159 with acceptor 160 with the more potent NIS/TfOH couple afforded protected... 

There are some other remote protecting groups which are not the usual electron-withdrawing groups, but they still deactivate glycosyl donors 4,6-benzyUdene acetal, 3,4-cyclohexylidene diacetal (cyclohexane-1,2-diacetal CD A), dispiroketal (dispoke), and butane diacetal (BDA) (Fig. 2). 

The 3,4-cyclohexylidene diacetal, which was introduced for the selective protection of trans diequatorial vicinal diols [33], is resistant to the flattening of carbohydrate ring required for the generation of an oxocarbonium ion intermediate and thus a torsionally disarming protecting group [15]. Similarly, the dispiroketal [15, 34]... 

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