An efficient synthesis of the 4'-epimer of 2-fluoronoraristeromycin

The 4'-epimer of 2-fluoronoraristeromycin was synthesized by employing bis-t-butoxycarbonyl (Boc) protected 2-fluoroadenine as a superior substrate for the Mitsunobu reaction with the appropriate cyclopentenol. Unlike the unsubstituted counterpart 2-fluoroadenine, this substrate is completely soluble in THF and resulted in a very good yield in the Mitsunobu coupling reaction as well as subsequent steps.     

Mitsunobu reactions of aliphatic alcohols and bulky phenols

Alkylation of hydrazinedicarboxylate (a Mitsunobu by-product) is not a notable problem in common Mitsunobu alkyl aryl etherification reactions. Good yields can be obtained with a wide range of solvents. However, this side reaction can cause yield reduction for the reactions of sterically hindered phenols and primary alcohols. To suppress the side reaction, solvent effect was investigated. It was found that hydrazinedicarboxylate is about five times less soluble in diethyl ether than in THF, and the yields are improved for ortho-substituted phenols of a wide range of steric hindrance using diethyl ether as the solvent instead of THF which is the more commonly used for Mitsunobu reactions.     

Total synthesis of bassiatin and its stereoisomers: novel divergent behavior of substrates in Mitsunobu cyclizations

Total syntheses of the morpholine-2,5-dione, Bassiatin, and its stereoisomers have been completed. A key step in the syntheses was the Mitsunobu cyclization of hydroxyacid acyclic precursors. The hydroxyacid precursors are hindered alcohols and two substrates underwent Mitsunobu cyclization with retention of configuration. The other two substrates underwent Mitsunobu cyclization with either retention or inversion of configuration depending on reaction conditions. This divergence in outcome of the Mitsunobu reaction for the same substrate depending on effective concentration is novel.     

Capture-ROMP-release: application for the synthesis of O-alkylhydroxylamines

[reaction: see text] A new capture-ROMP-release method for chromatography-free purification of N-hydroxysuccinimde Mitsunobu reactions is described. The Mitsunobu reaction captures a variety of alcohols onto a norbornenyl N-hydroxysuccinimide monomer. Subjection of the resulting crude reaction mixture to ROM-polymerization generates a polymer that can be precipitated with methanol and filtered from the Mitsunobu byproducts. Treatment of the polymer with hydrazine releases the substrate from the water-soluble polymer, producing a variety of O-alkylhydroxylamines with good purity.     

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.     

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.     

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.     

Regioselective <Emphasis Type="Italic">N</Emphasis>-alkylation of (2-chloroquinolin-3-yl) methanol with <Emphasis Type="Italic">N</Emphasis>-heterocyclic compounds using the Mitsunobu reagent

The Mitsunobu reaction is a well-established fundamental reaction and has been widely applied in organic synthesis. In this paper, under Mitsunobu conditions dehydration proceeds between (2-chloroquinolin-3-yl)methanol and nitrogen heterocyclic compounds such as quinazolinone, pyrimidone, 2-oxoquinoline in dry THF in the presence of triethylamine, triphenylphosphane and diethyl azodicarboxylate to give the corresponding products. As part of our recent research, we attempted to couple two N-heterocyclic compounds under Mitsunobu reaction conditions to provide efficient building blocks for natural product synthesis.     

Unusual regioselection in the Mitsunobu reactions of syn-2,3-dihydroxy esters: synthesis of statine and its diastereomer

Mitsunobu reactions of syn-2,3-dihydroxy esters exhibit a complete regioselection for the beta-hydroxyl group. Benzoylation, azidation, and tosylation have been performed under these conditions. Beta-functionalizations of syn-2,3-dihydroxy esters are uncommon, and the Mitsunobu reactions are complementary to other diol chemistries in the regioselection. In addition, the configurational inversion accompanying the Mitsunobu protocol offers a means for diastereochemical diversity, as exemplified by a synthesis of statine and its anti diastereomer. These findings will further expand the synthetic utilities of the Sharpless AD process.     

Mechanistic study of the Mitsunobu reaction

The Mitsunobu reaction occurs typically with inversion of configuration in secondary alcohol derivatives. In this paper, a mechanistic explanation for lactonizations of hindered alcohols under Mitsunobu conditions with retention is proposed. This involves the intermediacy of an acyloxyphosphonium salt followed by acyl transfer to the alcohol.     

Mitsunobu Reactions Catalytic in Phosphine and a Fully Catalytic System

The Mitsunobu reaction is renowned for its mild reaction conditions and broad substrate tolerance, but has limited utility in process chemistry and industrial applications due to poor atom economy and the generation of stoichiometric phosphine oxide and hydrazine by‐products that complicate purification. A catalytic Mitsunobu reaction using innocuous reagents to recycle these by‐products would overcome both of these shortcomings. Herein we report a protocol that is catalytic in phosphine (1‐phenylphospholane) employing phenylsilane to recycle the catalyst. Integration of this phosphine catalytic cycle with Taniguchi’s azocarboxylate catalytic system provided the first fully catalytic Mitsunobu reaction.     

Separation-friendly Mitsunobu reactions: a microcosm of recent developments in separation strategies

The Mitsunobu reaction is famous for its scope and power, but infamous for its separation headaches. Typically, the target product is enticed away from the reagent-derived byproducts by careful chromatography. The use of polymer-bound Mitsunobu reagents solves only half of the problem, because polymer-bound diethyl azodicarboxylate (DEAD) and phosphine reagents cannot be employed simultaneously. This article classifies, compares, and contrasts various emerging strategies for product isolation in Mitsunobu reactions. Because so many different strategies have been used, the Mitsunobu reaction is a microcosm for the new field of strategy level separations.     

Carboxylation and Mitsunobu reaction of amines to give carbamates: retention vs inversion of configuration is substituent-dependent

A mild method for the synthesis of carbamates from amino alcohols involves sequential carboxylation with carbon dioxide, followed by a Mitsunobu reaction. Unexpectedly, the stereochemical course of the Mitsunobu reaction is dependent on whether the carbamic acid intermediate is N-substituted with hydrogen (retention) or carbon (inversion).     

A linchpin carbacyclization approach for the synthesis of carbanucleosides

A convenient synthesis of carbanucleosides, with both enantiomers equally accessible, is reported. The key step is a tandem linchpin cyclization process to give access to substituted carbafuranose derivatives having the correct relative stereochemistry for subsequent nucleobase introduction with inversion of configuration at C1. This was illustrated by the synthesis of 2',3'-dideoxycarbathymidine via a convergent nucleobase introduction and of 2',3'-dideoxy-6'-hydroxycarbauridine via a linear nucleobase introduction. Both methods relied on Mitsunobu chemistry, and the first example of the Mukaiyama modification of the Mitsunobu reaction involving nucleobases as nucleophiles is reported.     

An approach to the stereoselective synthesis of syn- and anti-1,3-diol derivatives. Retention of configuration in the Mitsunobu reaction

The Mitsunobu reaction typically proceeds with inversion of configuration at the hydroxyl center. However, with a series of hindered alcohols, the intramolecular version of the Mitsunobu reaction afforded exclusively the product of retention of configuration. A mechanistic rationale for this observation is discussed, wherein this atypical stereochemical outcome is attributed to steric congestion at the reaction center.     

Separation tagging with cyclodextrin-binding groups: Mitsunobu reactions with bis-(2-(1-adamantyl)ethyl) azodicarboxylate (BadEAD) and bis-(1-adamantylmethyl) azodicarboxylate (BadMAD)

A new method for separation tagging with cyclodextrin-binding groups is introduced and is exemplified in the context of the Mitsunobu reaction with adamantyl tags. HPLC experiments showed that molecules containing adamantyl groups were especially well retained on Sumichiral OA7500 β-methylated cyclodextrin bonded silica columns relative to many other types of molecules. Two new Mitsunobu reagents, bis-(1-adamantylmethyl) azodicarboxylate (BadMAD) and bis-(2-(1-adamantyl)ethyl) azodicarboxylate (BadEAD), were prepared, used in typical Mitsunobu reactions and separated with both β-methylated cyclodextrin bonded silica and standard silica.     

A general strategy for the synthesis of azapeptidomimetic lactams

A selection of azapeptidomimetics containing constraining lactam rings have been prepared by Mitsunobu cyclization of serine/homologated serine-azaalanine derivatives. These include sterically-congested β-lactams, as well as γ-butyrolactam and δ-valerolactam analogs. A novel azaamino acid acylation method was developed to prepare the sterically demanding α-benzyl-serine-azaalanine precursor. In all cases, the Mitsunobu conditions were highly efficient in forming the desired azapeptidomimetic lactams. The reported process represents a general strategy for the synthesis of peptidomimetic structures with a constraining lactam ring.     

A Mitsunobu reaction to functionalized cyclic and bicyclic N-arylamines

The scope of an unexpected Mitsunobu cyclisation to prepare N-arylated Fsp³-enriched azacycles was investigated. In the current study, we have identified whether a pKa-dependent Mitsunobu cyclodehydration or a pKa-independent Mitsunobu intramolecular reaction was in operation. A Mitsunobu reaction, creating a leaving group, followed by intramolecular nucleophilic displacement was determined to be the dominant pathway.     

Diversity-oriented synthetic approach to naturally abundant S-amino acid based benzannulated enantiomerically pure medium ring heterocyclic scaffolds employing inter- and intramolecular mitsunobu reactions

The diversity-oriented organic synthesis of enantiomerically pure benzannulated oxazepine, diazepine, thiazepine, oxazocine, and diazocine scaffolds is described from easily accessible naturally occurring S-amino acids as chiral synthons. Inter- and intramolecular Mitsunobu reactions for the formation of carbon-nitrogen, carbon-oxygen, and carbon-sulfur bonds have been used as key transformations to construct these biologically important privileged heterocycles. This is the first example where the Mitsunobu approach has been utilized for the construction of S-amino acid based seven- and eight-membered ring systems.     

O-Alkylation versus C-alkylation under Mitsunobu conditions

A comparative study of the Mitsunobu reaction at C1 and C6 positions of mannose using bis(2,2,2-trifluoroethyl) malonate as nucleophile is disclosed. While C-alkylation was predominant at the C6 position, only O-alkylation occurred at the anomeric position of the carbohydrate. Some factors playing a role in the selectivity of the reaction are discussed and an inverse mechanism of the Mitsunobu reaction for the anomeric position is proposed.