Di-p-nitrobenzyl azodicarboxylate (DNAD): an alternative azo-reagent for the Mitsunobu reaction

Di-p-nitrobenzyl azodicarboxylate is prepared in 83.6% yield in two steps as a bright yellow solid, which can be used as an azo-reagent in the Mitsunobu reaction. When a chiral secondary alcohol was used, sufficient configurational inversion of alcohol occurred under Mitsunobu conditions. That the hydrazine produced from DNAD is semisoluble in some solvents such as THF and CH₂Cl₂ makes it separated easily from the reaction mixture just via filtration. Then the recovered hydrazine compound can be re-exposed to oxidant to produce DNAD. Because DNAD is more stable than DIAD at ambient temperatures and allows easy separation, it is a good alternative azo-reagent for the Mitsunobu reaction.     

Mitsunobu Reaction: A Powerful Tool for the Synthesis of Natural Products: A Review

The Mitsunobu reaction plays a vital part in organic chemistry due to its wide synthetic applications. It is considered as a significant reaction for the interconversion of one functional group (alcohol) to another (ester) in the presence of oxidizing agents (azodicarboxylates) and reducing agents (phosphines). It is a renowned stereoselective reaction which inverts the stereochemical configuration of end products. One of the most important applications of the Mitsunobu reaction is its role in the synthesis of natural products. This review article will focus on the contribution of the Mitsunobu reaction towards the total synthesis of natural products, highlighting their biological potential during recent years.     

The Mitsunobu Reaction: Origin,Mechanism, Improvements,and Applications

The Mitsunobu reaction is a widely used and versatile method for the dehydrative oxidation–reduction condensation of an acid/pronucleophile usually with a primary or secondary alcohol that requires the combination of a reducing phosphine reagent together with an oxidizing azo reagent. The utility of this reaction stems from the fact that it is generally highly stereoselective and occurs with inversion of the stereochemical configuration of the alcohol starting material. Furthermore, as carboxylic acids, phenols, imides, sulfonamides, and other compounds can be used as the acid/pronucleophile, this reaction is useful for the preparation of a wide variety of functional groups. This Focus Review of the Mitsunobu reaction summarizes its origins, the current understanding of its mechanism, and recent improvements and applications.     

A stereodivergent route to two epimeric 2-pyrrolidinylglycine derivatives

A new route to two epimeric 2-pyrrolidinylglycine derivatives is developed, which features Mitsunobu amination of a chiral allyl alcohol and ring-closing metathesis as key steps.     

A new class of heterocycles: 1,4,3,5-oxathiadiazepane 4,4-dioxides

This work reports the synthesis of novel 1,4,3,5-oxathiadiazepanes 4,4-dioxides from the reaction of N'-benzyl-N-(2-hydroxyethyl)-sarcosine or proline sulfamide with aromatic aldehydes under acid catalysis. To prepare the starting materials N-Boc-sulfamide derivatives of sarcosine or proline were alkylated with benzyl alcohol under Mitsunobu reaction conditions, the Boc group was removed chemoselectively by acidolysis, and the resulting product reduced to the corresponding alcohol in good yields.     

Solid-phase synthesis of a library of hydroxyproline derivatives

The synthesis of a library of N-alkylated O-arylated hydroxyproline derivatives has been achieved on solid phase. The choice of O-protection and the optimization of the Mitsunobu reaction involving a secondary alcohol were key to the success of this synthesis. First, acylation of resin-bound amines with N-Fmoc-O-THP-hydroxyproline was accomplished readily. Subsequent deprotection of the Fmoc and reductive amination with different aldehydes resulted in the tertiary amine intermediate. The deprotection of the THP group by p-toluenesulfonic acid was followed by a Mitsunobu reaction with a series of phenols. Finally, the products were cleaved from the resin using trifluoroacetic acid to produce a 10 200 member library.     

The Hendrickson reagent and the Mitsunobu reaction: a mechanistic study

The alkoxytriphenylphosphonium ion intermediate of the Mitsunobu reaction can be generated using the Hendrickson reagent, triphenylphosphonium anhydride trifluoromethanesulfonate, 1. Strangely, while the reagent 1 can be used in place of the Mitsunobu reagents (triphenylphosphine and a dialkylazodicarboxylate) for the esterification of primary alcohols, secondary alcohols such as menthol undergo elimination. Evidence is presented to show that this unexpected result is due to the presence of trialkylammonium triflate salts. Such salts lead to a dramatic decrease in the rate of esterification relative to competing elimination. The Mitsunobu esterification of menthol with p-nitrobenzoic acid was re-examined and the occurrence of elimination reported for the first time. The presence of traces of tetrabutylammonium triflate led to a dramatic reduction in the yield of inverted ester and a corresponding increase in the yield of anti elimination product 2-menthene. The mechanism of the Mitsunobu reaction is discussed in the light of the dramatic salt effect on both the rate and outcome of the reaction and the possible involvement of ion pair clustering. In contrast, use of the reagent 1 resulted in syn elimination to give a 1:2 mixture of 2- and 3-menthenes. Finally, 1 and sodium azide can be used to convert a primary alcohol into an azide in high yield. There was no reaction under Mitsunobu conditions.     

Chemoselective esterification of phenolic acids and alcohols

[formula: see text] The Mitsunobu reaction can distinguish between alcohol and phenol hydroxyls in esterification reactions, providing an expeditious and broadly applicable entry into various phenolics and polyphenolics of biomedical and nutritional relevance.     

Solid-phase synthesis of C-terminal thio-linked glycopeptides

A solid-phase Mitsunobu reaction between a resin-bound 1-thiosugar and an N-Fmoc protected amino alcohol was successfully employed for thio-linked glycopeptide synthesis. Facile cleavage and deprotection in one step afforded the target glycopeptide in good yield and purity.     

Chain elongation of primary alcohols of carbohydrates

The chain elongation of primary alcohol of saccharides (α-d-ribose, α-d-glucose, α-d-mannose) and a disaccharide (α-d-melibiose) has been achieved via a Mitsunobu reaction using bis(2,2,2-trifluoroethyl) malonate as nucleophile.     

Stereoselective formation of carbon-carbon bonds via SN2-displacement: synthesis of substituted cycloalkyl[b]indoles

A general asymmetric synthesis of substituted cycloalkyl[b]indoles has been accomplished. The key features of this approach are (1) the utilization of a Japp-Klingemann condensation/Fischer cyclization to prepare cycloalkyl[b]indolones, (2) the asymmetric borane reduction of these heterocyclic ketones with (S)-OAB to obtain enantiomerically pure alcohols, and (3) the stereoselective S(N)2-displacement of these indole alcohol substrates with a carbon nucleophile under Mitsunobu conditions to set the C1 or C3 tertiary carbon stereocenter. The use of trimethylphosphine (PMe3) and bis(2,2,2-trichloroethyl) azodicarboxylate (TCEAD) was found to have an effect on the Mitsunobu dehydrative alkylation.     

Direct radical polymerization of 4-styryldiphenylphosphine: preparation of cross-linked and non-cross-linked triphenylphosphine-containing polystyrene polymers

We report herein a simple synthesis of 4-styryldiphenylphosphine and the radical copolymerization of it with styrene, both with and without a cross-linker, to directly form cross-linked and non-cross-linked polystyrene supported triphenylphosphine in which the level of phosphine incorporation can be easily and accurately controlled. The utility of these polymers is demonstrated by their use in Mitsunobu and alcohol bromination reactions.     

Stereoselective synthesis of optically active mono and diaminoalcohols

Several optically active mono and diaminopolyols have been synthesized starting from the octadienedioate 1, by regio- and stereo selective azidation of the corresponding alcohol by Mitsunobu/S_N2 substitution.     

Novel chiral bridged azepanes: stereoselective ring expansion of 2-azanorbornan-3-yl methanols

The reaction of 2-azanorbornan-3-yl methanols under Mitsunobu or mesylation conditions with various nucleophiles led to a series of chiral-bridged azepanes with configuration at C-4 dependent on the configuration of the starting alcohol. High yielding, stereoselective ring expansion to novel 2-azabicyclo[3.2.1]octane system occurred via aziridinium intermediates, which were specifically opened by nucleophilic attack at the more substituted carbon.     

Synthesis of thromboxane B2 via ketalization/ring-closing metathesis

Total synthesis of thromboxane B2 using intermolecular ketalization followed by ring-closing metathesis is reported. Other key steps include a Sharpless asymmetric epoxidation to form an oxirane on the endo face of the bicyclic acetal, epoxide opening using lithioacetonitrile, an allylic alcohol 1,3-transposition, and Mitsunobu lactonization.     

Structural Effects in the Mitsunobu Reaction of Calix[4]arene with Benzylic and Allylic Alcohols [1]

A study of the Mitsunobu reaction involving calix[4]arene and a series of benzylic and allylic alcohols reveals the structural effect of the alcohol component on the distribution between Oand C-alkylation of the phenol component in the formation of aryl alkyl ethers and p-alkylated phenols, respectively.     

Total synthesis of C19 lipid diols containing a 2,5-disubstituted-3-oxygenated tetrahydrofuran

The total synthesis of the C(19) lipid diols 5 and 6, the enantiomers of the anthelmintic marine natural products 1 and 3, is described. Key steps in the divergent syntheses include a syn selective epoxidation of a homoallylic alcohol, a one-pot alkoxypalladation-carbonylation-lactonisation reaction sequence and a DMEAD promoted Mitsunobu inversion.     

An unexpected migration of O-silyl group under Mitsunobu reaction conditions

A 1,4 O→O silyl migration followed by nucleophilic substitution with phthalimide was observed under Mitsunobu reaction conditions. This one step secondary alcohol protection and primary alcohol substitution with N-nucleophiles was extended to a variety of 2-hydroxyethyl trialkylsilylether derivatives. A possible mechanism has been postulated based on the pK_a values of the alcohol and nucleophile. The present one-pot silyl migration and substitution reaction might find application in the stereoselective synthesis of novel iminosugar derived anti diabetic agents.     

A Fast Assembly of （-）-Epigallocatechin-3-gallate [（-）-EGCG] via Intra- and Inter-molecular Mitsunobu Reaction

This paper described a concise construction of （-）-EGCG （1f） （with an overall yield of 20% for seven steps based on the starting cinnamyl alcohol derivative 3）, featuring asymmetric dihydroxylation （ADH）, intra- and inter-molecular Mitsunobu reaction as key steps. Our strategy disclosed herein constitutes a new effective general synthetic approach toward the analogues of （-）-EGCG （1f）.     

An efficient synthesis of dienic nucleoside analogues via a Mitsunobu reaction

Nucleoside analogues 9 and 12 were obtained in good yields from alcohol 7 which, under Mitsunobu conditions, led to the title products after deprotection steps.