Mitsunobu with benzoic acid

We misassigned the structure of the main product produced by the reaction of styrene glycol with benzoic acid, DEAD and PhsP O. Mitsunobu, J. Kimura, K. lizumi and N. Yanagida, Bull. Chem. Soc. Jpn., 1976, 49, 310. 

The encouraging result of the trans-epoxy acylates with the chiral spiro compounds was appUed to the optically active system (Scheme 15). Asymmetric reduction of the enone 31 by Corey s method [72] afforded the allyl alcohol (-)-34 (90% ee). Epoxidation of (-)-34 by the stereoselective Sharpless epoxidation [73] afforded the cts-epoxy alcohol, cfs-(-)-35, as the sole product. The Mitsunobu reaction [74] of czs-(-)-35 with benzoic acid gave the trans-epoxy benzoate, trans- -)-36, (90% ee) in 89% yield. Treatment of trans-(-)-36 with BF3-Et20 afforded the optically active spiro compound (+)-37 in 89% yield with retention of the optical purity (90% ee). This means that the rearrangement occurs stereospecifically. The optically pure epoxy camphanate (-)-38 could be obtained after one recrystallization of the crude (-)-38 (90% de), which was obtained by the Mitsimobu reaction of cfs-(-)-35 with D-camphanic acid. The optically pure spiro compoimd (+)-39 (100% de) was obtained from the optically pure (-)-38 in 89% yield. 

Reaction with Di- and Polyols. Although intermolecular dehydration between two molecules of alcohols to afford acyclic ethers usually does not occur with the DEAD-TPP system, intramolecular cyclization of diols to produce three to seven-membered ethers is a common and high yielding reaction. Contrary to an early report, 1,3-propanediol does not form oxetane. Oxetanes can be formed, however, using the trimethyl phosphite modification of the Mitsunobu reaction. The reaction of (5)-1,2-propanediol and ( )-l,4-pentanediol with DEAD and TPP affords the corresponding cyclic ethers with 80-87% retention of stereochemistry at the chiral carbon, while (5)-phenyl-1,2-ethanediol affords racemic styrene oxide. In contrast to the reaction of the same 1,2-diols with benzoic acid (eq 4), oxyphos-phonium salts (25a) and (25b) have been postulated as key intermediates in the present reaction (eq 20). ... 

Tosylate Formation with Inversion of Configuration. Alkyl tosylates can be formed directly from secondary alcohol functionality with retention of carbon stereochemistry by treatment withp-Toluenesulfonyl Chloride and Pyridine. However, conversion of an alcohol to the corresponding tosylate of opposite stereochemistry typically requires a minimum of three steps. For example, inversion of the stereocenter with benzoic acid under Mitsunobu reaction conditions, hydrolysis of the resulting ester, and finally conventional tosylation of the alcohol, provides an attractive route for this transformation. A similar route, the inversion of a secondary alcohol directly with p-TsOH, Diethyl Azodicarboxylate (DEAD), and Triphenylphosphine, does not produce the desired tosylate product. ... 

It was suggested that this anomaly could be explained by the intermediacy of a cyclopropylmethyl/homoallylic species, trapped by addition of tosylate ion. Indeed, the more vigorous Mitsunobu reaction of (3a) with benzoic acid leads to a mixture of four products, confirming involvement of this type of homoallylic rearrangement. 

Enantioselective Birch reduction-alkylation The chiral benzoic acid derivative 1, prepared by condensation of o-hydroxybenzoic acid with L-prolinol followed by cyclization (Mitsunobu reaction), undergoes Birch reduction (K, NH3, THF, t-butyl alcohol) followed by alkylation with C2H5I to give essentially only 2. Acid hydrolysis returns the chiral auxiliary and provides the 2-alkylated cyclo-hexenone 3. 

A different chemical method for the preparation of 5-thioaldopyranosides was chosen by Hashimoto and coworkers [40] (Scheme 9.2). They converted per-O-benzylated methyl (3-d-glucopyranoside 33 into the open-chain mixed acetal 34, which, in turn, was treated with the Mitsunobu system triphenylphosphine and diethyl azodicarboxylate in the presence of benzoic acid to yield protected 5-thio-L-idopyranosides 35. 

Inversion of hindered alcohols. In the Mitsunobu reaction a positive relationship between dissociation constant of the acid component (nucleophile) with reaction efficiency is indicated. Product yields are higher when using acids of lower pK . Among substituted benzoic acids, 4-nitro, 4-methanesulfonyl, and 4-cyano derivatives give better results. 

Emantioseieetive Birch redmction-atkylation. lire chiral benzoic acid deriv ativc 1. prepared hy ccuidcnsatioit irf o-bydroxybenzcM add with L olinol fob lowed by cycltzation (Mitsunobu reaction), undergoes Birch reduction (K. NHt. HfF, r-butyl aloohot) (oltow cd by alkylation with essentially only 2. 

Finally, because benzoic acid is an excellent partner in the Mitsunobu reaction, benzoate formation with inversion has been used to prepare protected variants of relatively rare carbohydrates from readily available precursors. Thus, Mitsunobu esterification at the 3- and 6-positions in methyl (3-D-glucopyranoside proceeded with inversion of the C-3 configuration to provide an efficient synthesis of methyl 3-D-allopyranoside after Zemplen methanolysis (Figure 2.49). The a-anomer was reactive only at the 6-position (to maintain the gluco-configuration) under the same conditions [67]. 

Another route to this cyclohexyl derivative involves the preparation of 6.183 via an olefmation reaction with a substituted phenylalinal derivative followed by reduction of the phenyl ring. The alcohol moiety in 6.183 was converted to the N-phthal-oyl derivative (6.184) by a Mitsunobu inversion.m Conjugate addition with a higher order silyl cuprate gave 6.185. The silyl moiety was converted to an alcohol (6.186) by treatment with tetrafluoroboric acid and then KF/m-chloroperoxy-benzoic acid. Removal of the phthalimidoyl group with hydrazine led to an amino-ester, which cyclized to lactam 5.757.11 Hydrolysis gave 4-amino-5-cyclohexyl-3-hydroxypentanoic acid (6.188) in 60% yield. 

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