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>. 

Although aliphatic alcohols are typically poor acceptors in the Mitsunobu-type glycosylation, Szarek and coworkers have highlighted one advance to this end [95]. For the triphenylphosphine and diethylazodicarboxylate promoted glycosylation of a monosaccharide acceptor, the addition of mercuric bromide is necessary to promote the reaction. For example, the (1,6)-disaccharide 44 was obtained in 80% yield using this modified Mitsunobu protocol. Unlike previous examples with phenol or N-acceptors, preactivation of the hemiacetal donor was performed for 10 min at room temperature prior to addition of the aliphatic alcohol nucleophile. 

Dodd, D. S. Kozikowski, A. P. Conversionof Alcohols to Protected Guanidines Using the Mitsunobu Protocol, Tetrahedron Lett. 1994, 35, 977-980. 

Phosphonate Coupling To Give 60 Via the Mitsunobu Protocol General Procedure 81 ... 

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. 

Lewis acids, such as boron trifluoride etherate, zinc triflate <2000H(53)1421>. N-Unsubstituted tetrazoles 24 can be alkylated with primary aliphatic alcohols using the Mitsunobu protocol (Equation 26) <1996SC2687>. 

In 1991, Duncia et al. reported on the synthesis of 1,5-disubstituted tetrazoles from secondary amides and azidotrimethylsilane under the conditions of the Mitsunobu reaction <1996CHEC-II(4)621>. The Mitsunobu protocol was successfully applied to the conversion of AT(cyanoethyl)amide into tetrazole 510. The tetrazole ring in this event forms by the cyclization of an imidoyl azide (not shown in the scheme) whose precursor is the phosphonium imidate 509 (Scheme 67) <2000JME488>. 

A concise and efficient synthesis of racemic five steps from precursor diethyl oxalopropionate <02TL9513>. In the first step, racemic diethyl oxalopropionate was alkylated under basic conditions. The lactonization is the last step of the synthesis and was achieved according to the Mitsunobu protocol. 

Various nucleophiles substitute cyclic sulfamidates such as 521 at C(5) at room temperature and provide good yields of 522, e.g., <1996S259, 1999J(P1)1421, 1999TL3831, 2002TL1915>. The introduction of the N-substitutent to make compounds like 521 is best achieved via a base-catalyzed phase-transfer method or using the Mitsunobu protocol <2002JOC5164>. 

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... 

The first total synthesis of the tricyclic marine alkaloid (+)-fasicularin was completed by the research team of C. Kibayashi." The secondary alcohol functionality was inverted using the Mitsunobu protocol. The resulting p-nitro benzoate was readily hydrolyzed under basic conditions. 

N-Alkylations. The Mitsunobu protocol is applicable to Af-aUcylation of protected... 

C-Glycosidation of enol silane 279 to lactol acetate 278, prepared from 277 in two steps, furiushed ynone 280 as a single isomer. Reduction of the ketone with L-selectride furnished alcohol 270 with poor selectivity, but the minor isomer can be converted into the desired isomer via the Mitsunobu protocol Dihydroxylation of the terminal alkene, reduction of alkyne, and oxidative cleavage of the resulting triol gave the intermediate hydroxy aldehyde, which was spontaneously transformed into macrolactol 281 as a single diastereomer. 

Because (in part) of its expansion to include a variety of nucleophiles that allow for carbon-carbon, carbon-halogen, carbon-nitrogen, and carbon sulfur as well as carbon-oxygen bond formation and because (in part) of the variety of subtle changes that are employed to effect the desired overall reaction and because (in part) the changes can be carried out in one or more of the steps in the process, the overall technique has become known as the Mitsunobu protocol. 

Scheme 833. The Mitsunobu protocol. Conversion of an alcohol (shown here as secondary) to an enantiomeric species by the displacement of the (modified) hydroxyl group. There are three steps shown. The first activates the phosphine (shown here as triphenylphosphine) for reaction with the alcohol the second produces a good leaving group as the alcohol reacts with phosphorus and, in the third, the activated hydroxyl group is lost.

Scheme 10.23. Use of the Mitsunobu protocol (alcohol, triphenylphosphine, diethyl azodi-carboxylate, and phthalimide in THF) in reaction with (5)-(+)-2-octanol to produce (R)-(-)-2-octylamine. See Corelli, F. Summa, V. Brogi, A. Monteagudo, EBotta, M. J. Ore. Chem., 1995,60,2008.

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). 

As already noted, the amino group can affect displacement reactions on halogen (vide supra) and, in the presence of activating reagents (see, e.g., the Mitsunobu protocol, Chapter 8, Scheme 8.32 and this chapter. Scheme 10.23), can also displace oxygen. In that vein, it is worthwhile noting that P-aminoalcohols can be prepared by attack of amines on relatively unhindered epoxides (oxiranes) (Equation 10.59). 

Once hydroxy groups have been installed by any of the methods described above, their further constitutional and configurational manipulations are easy to accomphsh with reliable inverting nucleophilic substitutions, such as tosylate substitution or the Mitsunobu protocol [141]. 

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