Oxidation Pinnick

HCIO scavenger (10-50 equiv) solvent / room temp. 

The total synthesis of the complex bioactive indole alkaloid ditryptophenaline, having two contiguous quaternary stereocenters related by C2 symmetry, was accomplished in the laboratory of L.E Overman.In the late stages of the synthetic effort the complex diol substrate was oxidized to the dicarboxylic acid using a two-step procedure first, a Dess-Martin oxidation to the dialdehyde followed by the Pinnick oxidation. The mild reaction condition ensured that the integrity of the stereocenters at the a-positions was preserved. 

NaCI02 (4 equiv) NaH2P04 (8 equiv) THFiHgOif-BuOH (4 4 1) 

NaCI02 (15.2 equiv) NaH2P04 (15.2 equiv) f-BuOH 2-Me-2-butene 

The formal total synthesis of the selective muscarinic receptor antagonist (+)-himbacine was accomplished by M.S. Sherburn and co-workers using an intramoiecuiar Dieis-Aider reaction, a Stiiie cross-coupling, and a 6-exo-trig acyi radical cyclization as the key steps.In order to prepare the selenoate ester precursor for the radical cyclization step, the aldehyde-enyne substrate was converted to the carboxylic acid via the Pinnick oxidation without affecting the delicate enyne moiety. 

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After successful installation of the first two stereocenters, our attention was focused on elaboration of the terminal alkene in 64 (Scheme 6.9). Treatment with disiamylborane followed by oxidative workup afforded primary alcohol 65 in good yield (70-85 %). A side product containing a mixture of two diastereomers (66) was also observed and resulted from conjugate addition of the alkoxide formed during basic workup onto the unsaturated ester. Maintaining the temperature at 0 °C by a slow, dropwise quench during the oxidative workup was necessary to minimize the amount of the undesired cyclization product (66). Subsequent oxidation of the primary alcohol 65 using Dess-Martin periodinane [28] and a Pinnick oxidation afforded carboxylic acid 67 [29]. 

Pinnick oxidation Mild oxidation of aldehydes directly to the corresponding carboxylic acids using NaCI02 as the oxidant. 354... 

Before giving up oti the samarium-mediated fragmentation approach, we decided to investigate one additional substrate that would not be able to form a cyclobutane because one of the 1,4-dicarbonyl partners was an ester (186, Scheme 35). The requisite substrate was readily accessed by converting aldehyde 186 to carboxylate 187 using a Pinnick oxidation followed by treatment with TMS diazomethane. Ketone 186 reacted with samarium diiodide but no fragmentation took place, only reduction of the ketone to a mixture of secondary alcohol products, one of which further reacted to form lactone 189. 

The aldehyde was then converted to a carboxylic acid via a Pinnick oxidation. Further elaboration to generate acyl telluride 185 was achieved by initial activation of the acid as a mixed anhydride using isobutyl chloro-formate under basic conditions. Nucleophilic displacement with sodium phenyl telluride, generated in situ from borohydride reduction of diphenyl ditelluride, completed the transformation. With acyl telluride 185 in hand, nitrogen deprotection employing TFA, followed by a reductive amination with aldehyde 186 furnished alkyne 187, which was envisioned to be a substrate for radical cyclization (Scheme 19). 

Somewhat in contrast to these results, the Cordova group reported excellent results of using D-proline for reaction between aldehyde 2m and the A(-acylated imine 28a (Scheme 5.17). This specific application led to the Mannich adduct 29 in excellent stereoselectivity, which via subsequent Pinnick oxidation provided the Taxol side chain (30) in 82% yield [24]. 

The description of several more modem synthetic methods were added, including the Swern, Dess-Martin, and Pinnick oxidations. 

Another inexpensive method for oxidizing an aldehyde to a carboxylic acid is the Pinnick oxidation. This reaction uses sodium chlorite (NaC102) with a phosphate buffer (NaHjPO ) to create chlorous acid, along with a structure to scavenge the hy-pochlorous acid (HOCl) by-product (see the Mechanism box below). While many scavengers are used, the most common is 2-methyl-2-butene. This is a very selective procedure. It will not oxidize alcohols, so they do not have to be protected. 

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