Oxidative tether cleavage

Tamao et al. have investigated (dichloromethyl)dimethylsilyl ethers as radical cyclization precursors [69]. Silyl ether 174 was readily prepared from the commercially available silyl chloride and isophorol. 5- xo-trig cyclization could be effected under high-dilution conditions, affording the bicycle 175 as a 6 4 mixture of stereoisomers. Subsequent oxidative tether cleavage afforded 2-formyl alcohols 176 and 177 where unfortunately, the presence of base caused partial epimerization of the center a to the formyl group (Scheme 10-56). 

A variety of oxidative tether cleavage protocols have also been evaluated which allow regioselective monoprotection of the resulting 1,3-diol products, facilitating differentia-... 

Although, as stated above, we wiU mostly focus on hydrolytic systems it is worth discussing oxidation catalysts briefly [8]. Probably the best known of these systems is exemphfied by the antitumor antibiotics belonging to the family of bleomycins (Fig. 6.1) [9]. These molecules may be included in the hst of peptide-based catalysts because of the presence of a small peptide which is involved both in the coordination to the metal ion (essential co-factor for the catalyst) and as a tether for a bisthiazole moiety that ensures interaction with DNA. It has recently been reported that bleomycins will also cleave RNA [10]. With these antibiotics DNA cleavage is known to be selective, preferentially occurring at 5 -GpC-3 and 5 -GpT-3 sequences, and results from metal-dependent oxidation [11]. Thus it is not a cleavage that occurs at the level of a P-O bond as expected for a non-hydrolytic mechanism. 

A rapid access to carbocyclic nucleosides, containing a fused isoxazoline ring has been proposed, starting from cyclopentadiene. The route involves a het-ero Diels-Alder cycloaddition reaction of nitrosocarbonylbenzene followed by a 1,3-dipolar cycloaddition of nitrile oxides, cleavage of the N-0 tether and transformation of the heterocyclic aminols into nucleosides via construction of purine and pyrimidine heterocycles (457). 

Over the past several years, Mascarenas and co-workers (150-153) utilized the oxidopyrylium ion with variously hetero-substituted olefin tethers. Mascarenas has used this methodology in tandem with a Diels-Alder reaction to prepare tricyclic cycloheptanoid substrates. Further, Mascarenas and co-workers (154—156) achieved the synthesis of optically active oxabicyclic[3.2.1]octane derivatives through the addition of a homochiral p-tolylsulfinyl group substituted at the olefin tether. The Mascarenas group has also used this methodology to prepare the THF portion of ( )-nemorensic acid via oxidative cleavage of the substituted a-hydroxyketone moiety (157) (Scheme 4.78). 

O-tethered P-keto esters, through the intermediacy of aiylidene keto esters, have been efficiently utilized for the construction of immobilized dihydropyridines. Ceric ammonium nitrate (CAN) oxidation to pyridines followed by acidolytic cleavage provides a facile entry into nicotinic acid derivatives 57 [42], A three-component Biginelli cyclization of ureas on resin with a solution mixture of aldehydes and P-keto esters provides dihydropyrimidines 58 in high yield and purity [43], Heterocycles such as dihydropyridines and pyrimidines have historically proven to be a rich source of antimicrobial, antitumor, antiviral, and cardiovascular agents. 

X = CH2, 31h-k) and sulfones (Y = S02. X = CH2, 311,m) participated effectively in the oxidative coupling reaction. Dibenzyl ethers (Y = O, X = CH2, 31n-r) were also coupled in fair to good yields. Cleavage of the temporary tether subsequently delivers the acyclic biaryls 33a-r. 

Removal of the tether was realized in two ways. Oxidative cleavage of an activated C-Si bond has been shown to proceed with retention of configuration [11]. Thus treating 19 and 20 with 1 equiv of TBAF and a 30% solution of H2O2 in DMF at 55 °C for 2 h afforded the diastereoisomeric diols 21 and 22, respectively, both in 80% yield. Alternatively hydrodesilylation could be achieved using 2 equiv of TBAF in DMF at 60 °C for 4 h. In the case of the cis-fused, bicyclic Diels-Alder adduct 19, the basic conditions of... 

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