Synthesis of Aryl Ethers via a Sulfonyl Transfer Reaction

A general synthesis of aryl ethers from primary and secondary alcohols and aryl mesylates is presented. The reaction proceeds via a sulfonyl-transfer mechanism. In this paper, we compare the sulfonyl transfer reaction to Mitsunobu ether formation. The reaction can be employed in a multistep synthesis where the aryl mesylate is used as a phenol protecting group and then as an activating group for ether formation. This protecting/activating group strategy is demonstrated using raloxifene as the target.     

Efficient, mild, parallel and purification-free synthesis of aryl ethers via the Mitsunobu reaction

A wide range of commercial diazodicarboxylates and phosphines were screened in an attempt to find purification-free conditions for application in parallel synthesis. The combination of immobilized triphenylphosphine and TMAD proved to be suitable for the synthesis of aryl ethers via the Mitsunobu reaction. Nine ethers were synthesized in good yield and excellent purity, the purification being limited to a filtration step.     

A Facile Synthesis of Aryl Ethers of Ethynyl-Carbinols Using the Mitsunobu Reaction

The facile synthesis of a few aryl ethers of ethynyl carbinols using the Mitsunobu reaction is reported.     

Base catalyzed Mitsunobu reactions as a tool for the synthesis of aryl sec-alkyl ethers

A facile and versatile method for the synthesis of aryl sec-alkyl ethers from phenols with alcohols in the presence of base via a Mitsunobu reaction is described.     

Stereocontrolled synthesis of (-)-galanthamine

An enantioselective synthesis of (-)-galanthamine has been realized in 11 linear steps starting from isovanillin. A Mitsunobu aryl ether forming reaction was used to assemble the galanthamine backbone, which was stitched together using enyne ring-closing metathesis, Heck, and N-alkylation reactions affording the tetracyclic ring system. Control of relative and absolute stereochemistry was derived from an easily accessible enantiomerically enriched propargylic alcohol 13.     

Highly convergent route to cyclopeptide alkaloids: total synthesis of ziziphine N

[structure: see text]. A highly convergent protocol to cyclopeptide alkaloids, as demonstrated by the first total synthesis of antiplasmodial agent ziziphine N, is developed. The key elements include construction of its aryl ether unit via Mitsunobu reaction, installation of its enamide part via CuI/N,N-dimethylglycine-catalyzed coupling reaction, and ring closure with coupling agents such as FDDP and DPPA.     

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.     

Synthesis of lupiwighteone via a para-Claisen-Cope rearrangement

The lanthanide catalysed para-Claisen-Cope rearrangement has been used as the key step in a short synthesis of the prenylated isoflavone, lupiwighteone. The Mitsunobu reaction was employed for the 5-O-prenylation of the acid/base sensitive acetylated isoflavone to afford the allyl aryl ether precursor, which was then rearranged under mild conditions in good yield. Rearrangement of the isoflavone gave the 8-prenylisoflavone as a single product, in good yield.     

Syntheses d'aryltetrahydropyrannyl ethers

Tetrahydropyranylation of methoxyphenols by acidic catalysis gives a mixture of C-and/or O-tetrahydropyranylated derivatives. It appears that the electron-donating group and the acidic strength of the catalyst play an important influence in directing such reactions. The synthesis of aryl tetrahydropyranyl ethers 9 has been developed involving the Mitsunobu reaction between substituted 2-carbonyl phenols and tetrahydropyranol derivatives.     

Solid‐Phase Organic Synthesis of Aryl Vinyl Ethers Using Sulfone‐Linking Strategy

A novel facile solid‐phase organic synthesis of aryl vinyl ethers by reaction of polystyrene‐supported 2‐phenylsulfonylethanol with phenols under Mitsunobu conditions and subsequent elimination reaction with DBU has been developed. The advantages of this method include straightforward operation, good yield and high purity of the products. Alternatively, a typical example of Suzuki coupling reaction on‐resin was further applied to prepare 4‐phenylphenyl vinyl ether for extending this method.     

Concise total synthesis of flavone C-glycoside having potent anti-inflammatory activity

The total synthesis of anti-inflammatory active flavone C-glycoside isolated from oolong tea extract is achieved. Introducing a C-glucosyl moiety to an aryl system and constructing a fused tetracyclic ring characteristic to this natural product were conducted based on the O-to-C rearrangement of sugar moiety and the successive intramolecular Mitsunobu reaction, respectively. This concise and efficient synthetic pathway is applicable to the large-scale synthesis of target flavone and for constructing a large library of related compounds.     

Peptidotriazoles on solid phase: [1,2,3]-triazoles by regiospecific copper(i)-catalyzed 1,3-dipolar cycloadditions of terminal alkynes to azides

The cycloaddition of azides to alkynes is one of the most important synthetic routes to 1H-[1,2,3]-triazoles. Here a novel regiospecific copper(I)-catalyzed 1,3-dipolar cycloaddition of terminal alkynes to azides on solid-phase is reported. Primary, secondary, and tertiary alkyl azides, aryl azides, and an azido sugar were used successfully in the copper(I)-catalyzed cycloaddition producing diversely 1,4-substituted [1,2,3]-triazoles in peptide backbones or side chains. The reaction conditions were fully compatible with solid-phase peptide synthesis on polar supports. The copper(I) catalysis is mild and efficient (>95% conversion and purity in most cases) and furthermore, the X-ray structure of 2-azido-2-methylpropanoic acid has been solved, to yield structural information on the 1,3-dipoles entering the reaction. Novel Fmoc-protected amino azides derived from Fmoc-amino alcohols were prepared by the Mitsunobu reaction.     

Synthetic entries to substituted bicyclic pyridones

The synthesis of 6,6- and 5,6-bicyclic pyridone scaffolds has been completed using (i) an intramolecular Mitsunobu reaction and/or (ii) hydrolysis of a bicyclic pyridinium salt intermediate. Regioselective functionalization of the pyridone ring has been achieved via either direct lithiation or use of the "halogen dance" reaction. Suzuki coupling then allows introduction of aryl units at C(7)/C(9) or C(8) onto the bicyclic pyridone scaffold at either an early or late stage in the synthetic sequence. Suzuki couplings involving iodopyridinium intermediates are particularly effective.     

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.     

Synthesis and reactivity profiles of phosphinated poly(alkyl aryl ether) dendrimers

Poly(alkyl aryl ether) dendrimers were utilized to synthesize a series of new triphenylphosphine functionalized dendrimers. Zero, first, second and third generation dendrimers, carrying 3, 6, 12 and 24 triphenylphosphine units, were prepared and characterized. The new triphenylphosphine containing dendrimers were assessed for their reactivity profiles and in this instance, the dendrimers were used as reagents to mediate Mitsunobu etherification reaction between phenol and various primary, secondary and benzylic alcohols. In addition, dendritic poly-phenols were also tested in an O-benzylation reaction. A monomeric methoxy group attached triphenylphosphine acted as a control for comparison of reactivity profiles of dendrimers. It was observed that the etherification reaction was mediated efficiently by the dendritic reagent, and in addition, the dendritic phosphine oxide reagents could be recovered quantitatively by precipitation methods. The recovered dendritic phosphine oxides were reduced subsequently to the corresponding phosphines and used as reagents for the Mitsunobu reaction, repetitively.     

Solid-phase synthesis of a tyrphostin ether library

The solid-phase synthesis of a 4500-member (30 x 15 x 10) tyrphostin library is demonstrated utilizing the Irori-directed sorting system. Fmoc-protected PL-Rink resin was used as the solid support. After Fmoc-deprotection, aryl aldehydes were attached to the resin through reductive amination. Acylation of the resulting secondary amines with cyanoacetic acid was followed by a Knoevenagel condensation with phenolic aldehydes. Mitsunobu coupling of primary alcohols to the resin-bound phenols yielded the final library of compounds 1.     

An exception to the normal Mitsunobu reaction with phenols; the formation of hydrazones from salicylaldehydes

The reaction of 2-hydroxybenzaldehydes with alkanols in the presence of triphenylphosphine and di-tert-butyl azodicarboxylate (DBAD), under the Mitsunobu reaction conditions, gives rise to the formation of hydrazones as the major products rather than the expected alkyl aryl ethers.     

Asymmetric total synthesis of 5′-epi-paecilomycin-F

The asymmetric total synthesis of one of the stereoisomers of the naturally occurring 14-membered ring macrolide paecilomycin-F (5′-epi) has been reported in this article. The main highlight of the synthetic strategy involves the successful application of a ring closing metathesis (RCM) reaction at a late stage. Asymmetric Keck allylation, Sharpless asymmetric dihydroxylation, and Mitsunobu esterification have also been used successfully for the total synthesis of 5′-epi-paecilomycin-F.     

A new supported reagent for the parallel synthesis of primary and secondary O-alkyl hydroxylamines through a base-catalyzed Mitsunobu reaction

The growing field of applications of O-alkyl hydroxylamines in medicinal chemistry and chemical biology has motivated the search for a parallel synthesis. A solid-phase approach based on the alkylation by alcohols of a new supported N-hydroxyphthalimide reagent using a Mitsunobu reaction followed by methylaminolysis has been optimized. This study points out the importance of the linker and a specific base effect for the Mitsunobu reaction. A large variety of alcohols can be used to give with moderate to high yields diverse O-alkyl hydroxylamines in high purity.     

Versatile strategy for oligonucleotide derivatization. Introduction of lanthanide(III) chelates to oligonucleotides

[reaction: see text] Novel nucleosidic phosphoramidite blocks were synthesized by a Mitsunobu reaction between 2'-deoxy-5'-O-(4,4'-dimethoxytrityl)uridine and a primary alcohol containing a conjugate group in its structure (a protected functional group, an organic dye, or a precursor of a lanthanide(III) chelate) followed by phosphitylation. They were used in machine-assisted DNA synthesis in the standard manner. A slightly modified deprotection procedure was used for the preparation of oligonucleotide conjugates tethered to lanthanide(III) chelates. For the latter application one non-nucleosidic block was also synthesized.