Inversion Mitsunobu protocol

More recently, a preparation of iV-alkylated pyridotriazolones was developed using a Mitsunobu protocol, pointing out the acidity of the NH group. Compound 54 (Equation 3) displaced the hydroxyl group with classical inversion at carbon, leading to 55 <2005SC2939>. 

In order to transform the spirocyclic enone 445 to ( )-elwesine (439) and ( )-epielwesine (449), it was treated with boron trifluoride and dimethylsulfide to cleave the Al-carbobenzyloxy protecting group, and cyclization of the resulting amino enone spontaneously ensued to produce ( )-dihydrooxocrinine (447). Reduction of carbonyl function of 447 with sodium borohydride afforded ( )-3-epielwesine (449), which was converted to ( )-elwesine (439) by inversion of the hydroxyl function at C-3 via a Mitsunobu protocol using diethyl azodicarboxylate, triphenylphosphine, and formic acid. Attempted reduction of 447 directly to 439 by a Meerwein-Ponndorf-Verley reduction or with bulky hydride reagents gave only mixtures of 449 and 439 that were difficult to separate. 

The Mitsunobu protocol has also been investigated in the stereocontrolled synthesis of glycosyl esters (O Scheme 78g) [431]. Complete stereochemical inversion at C-1 of the starting sugar is observed when the esterification is conducted with anomerically pure glycosyl hemiacetals. By corollary, complementary ratios of inverted products are formed when an anomeric mixture of sugars is esterifled. The stereochemical outcome of the esterification is not affected... 

Two years after the synthesis of enf-codeine [50], Hudlicky published a route to the natural enantiomer of the alkaloid [15]. With biocatalytically-derived cyclohexa-diene-c A-diol 49 (Scheme 8), the same starting material in the synthesis of the enantiomer of the natural product was utilized. The strategic difference between the two syntheses is based on the preparation of epoxide 82 obtained via a Mitsunobu inversion/elimination protocol of the diol 80 (Scheme 12). 

More recently, the Mitsunobu protocol (Chapter 8, Scheme 8.32) has been widely used to effect the substitution as, under the proper conditions, diethyl azodicarboxylate can be shown to react with, for example, secondary alcohols, to form products with inverted absolute stereochemistry. Thus, as shown in Scheme 10.23 (and the details of Scheme 8.32), treatment of (5)-(+)-2-octanol, [ajo = +14.3 (heptane) with diethyl azodicarboxylate, triphenylphosphine, and phthalimide in THF at room temperature for several hours produced the corresponding N-1-octylphthalimide in high yield. Then, treatment of the latter with hydrazine hydrate yielded the desired, optically pure, (/ )-(-)-2-octylamine in about 50% overall yield (and with complete inversion of configuration). 

Epimerization of carbohydrate stractures to the corresponding epi-hydroxy stereoisomers is an efficient means to generate compounds with inverse coirfiguration that may otherwise be cumbersome to prepare. Several different synthetic methods have been developed, including protocols based on the Mitsunobu reaction,sequential oxidation/reduction... 

On one hand, the a,P-unsaturated lactone 40, which was derived from di-O-acetyl-L-rhamnal (39) according to reported procedures, was submitted to Mitsunobu inversion with HCO2H, followed by hydrolysis and methoxymethylation to afford 40. On the other hand, the o-methylbenzoate 41 was obtained from 3,5-dihydroxytoluene under the protocols described by Solladig. 

---