By the Mitsunobu reaction

The corresponding syn-compound can also be synthesized by simply inverting the stereochemistry of the hydroxyl group of the epoxy alcohol by the Mitsunobu reaction [54], Therefore, this method provides a simple and reliable method for the synthesis of any enantiomers and diastereomers of straight-chain 1,2-polyols. 

Ring closure of (3-hydroxy-a-amino acids with sulfuryl chloride/triethylamine 68 is accompanied by formation of (3-chloroalanine,16 1 whereas cyclization of urethane-protected serine and threonine by the Mitsunobu reaction 54 69 70 leads to oxazoline and dehydroalanine formation as side products. 47,71 Formation of dehydroalanine can be prevented by bulky carboxy protecting groups such as tert-butyl esters. 69 ... 

The first synthesis of optically pure N-methylated derivatives of Ala, Leu, Phe, and Tyr was published by Fischer and Lipschitz in 1915 73 using the sulfonamide method. Two main developments have ensured that this method remains useful for the preparation of TV-alkyl amino acids both in solution and solid phase (1) the introduction of the Mitsunobu reaction for the alkylation step and (2) the introduction of replacements for Tos (such as the Fukuyama Nbs) that allow easy removal of the sulfonamide protecting group after the alkylation step. Sulfonamide-protected amino acid derivatives can be alkylated in two different ways. Because of the acidity of the sulfonamide hydrogen it is possible to introduce the N-substituent either by direct alkylation (e.g., alkyl halides) or by the Mitsunobu reaction 74 (Scheme 4). 

Phenols can be etherified with resin-bound benzyl alcohols by the Mitsunobu reaction [554,555], or, alternatively, by nucleophilic substitution of resin-bound benzyl halides or sulfonates [556,557], Both reactions proceed smoothly under mild conditions. Aliphatic alcohols have been etherified with Wang resin by conversion of the latter into a trichloroacetimidate (C13CCN/DCM/DBU (15 100 1), 0°C, 40 min), fol-... 

Alternatively, alkyl aryl ethers can be prepared from support-bound aliphatic alcohols by Mitsunobu etherification with phenols (Table 7.13). In this variant of the Mit-sunobu reaction, the presence of residual methanol or ethanol is less critical than in the etherification of support-bound phenols, because no dialkyl ethers can be generated by the Mitsunobu reaction. For this reason, good results will also be obtained if the reaction mixture is allowed to warm upon mixing DEAD and the phosphine. Both triphenyl- and tributylphosphine can be used as the phosphine component. Tributyl-phosphine is a liquid and generally does not give rise to insoluble precipitates. This reagent must, however, be handled with care because it readily ignites in air when absorbed on paper. 

Protection of primary alcohols p-Anisyl ethers are readily prepared from primary alcohols by the Mitsunobu reaction [P(C6H5)3 DEAD]. The ethers are stable to 3 N HC1 or 3 N NaOH at 100°, to Jones or PCC oxidation, and to LiAlH4. Deprotection is effected in 85-95% yield by oxidation with CAN in aqueous CH3CN. 

Fukumoto, S. Fukushi, S. Terao, S. Shiraishi, M. Direct and enantiospecific ortho-benzyla-tion of phenols by the Mitsunobu reaction. 

Inversion of the stereocenter of (S)-l by the Mitsunobu reaction provides (R)-l. This bromonaphthalene is converted by the same sequence as above into the pery-lenequinone calphostin D (5). In this case the axial stereoselectivity in the dimerization step is opposite to that observed with (S)-l. 

Treatment of L-biopterin with DMFDMA (or DMFDEA), then acetic anhydride in pyridine, gives l 2 -di-0-acety]-/V -(/V,ALdimethylaminoethylene)-L-biopterin (87). This can be converted by the Mitsunobu reaction into 3-methyl and 3-p-nitrophenethyl derivatives. The protective groups on the side chain diols and N1 of these compounds can be selectively cleaved to give biopterin. These reactions indicate their potential for biopterin modification [95MI31. 

In the Mitsunobu reaction, the C-O bond of the alcohol is broken because the alcohol becomes the electrophile and the acid derivative must be a nucleophile so an acid is better than an acid chloride. The ester is formed with inversion. Note the fate of the oxygen atoms, ester formation from a secondary alcohol with inversion by the Mitsunobu reaction... 

Bitter and co-workers reported that a crown containing two types of bridging units connected to one thiaca-lix[4]anene 168 <2004TL12059> from crown ether having thiacalix[4]arene 167 by the Mitsunobu reaction (Scheme 22). 

Bitter and co-workers have also prepared a thiacalixtube , such as 170, by the Mitsunobu reaction <2004TL12059>. Interestingly, a dimer 169 was prepared from thiacalix[4]arene with thiodiethylene glycol under Mitsunobu condition in 90% yield (Scheme 23). 

In the total syntheses of squamocin A and squamocin D, acetogenins from Annonaceae, a double cyciization has been demonstrated to be feasible for the assembly of bis-tetrahydrofuran motifs (Equation 71) <2000EJ01889>. Intramolecular dehydration to afford tetrahydrofurans can efficiently be carried out by the Mitsunobu reaction <2003JOC4422> and a cationic platinum-catalyzed dehydration <2005SL152>. 

Alcohol inversion. Elimination competes with S, 2 substitution in the inversion of secondary alcohols by the Mitsunobu reaction or by reaction of mesylates with cesium propionate or cesium acetate. Elimination in the inversion of cyclopentyl and cyclohexyl alcohols can be largely suppressed by reaction of the mesylate with cesium acetate (excess) and a catalytic amount of l8-crown-6 in refluxing benzene. Even inversion of an ally lie alcohol can be effected in moderate yield under these conditions (equation I). ... 

Macrolactonization can also be achieved by the Mitsunobu reaction [44] with inversion of the configuration of the alcohol. The reaction principle and mechanism are demonstrated in Scheme 24. Addition of triphenylphosphine to diethyl azodicarboxylate (DEAD, 73) forms a quaternary phosphonium salt 74, which is protonated by hydroxy acid 11, followed by phosphorus transfer from nitrogen to oxygen yielding the alkoxyphosphonium salt 76 and diethyl hydrazinedicarboxy-late 75. Then, an intramolecular Sn2 displacement of the important intermediate 76 results in the formation of the lactone 15 and triphenylphosphine oxide. 

O-Aryl glycidol ethers can be prepared from glycidol by the Mitsunobu reaction with phenols (see eq 3) and are also made from direct displacement by glycidol on activated haloaryls. ... 

By the Mitsunobu reaction l,l -(azodicarbonyl)dipiperidine, MesP, 61-85% yield. This reaction was used for the alkylation of thioglycosides. The addition of imidazole improves the process. ... 

The iso-4 -thiopurine and pyrimidine L-nucleosides 211 were synthesized from 1,4-thio-L-arabinitol (151) via 3-fluoro derivative 209, which was transformed into 210 by a Mitsunobu reaction. Coupling of 210 with purine and pyrimidine bases by the Mitsunobu reaction, followed by deprotection, gave the desired 211. 

A series of novel 3 -thiacarbocyclic nucleosides 240, carrying purine and pyrimidine bases, have been prepared from D-glucose. The key steps were the treatment of dimesylate 237 with Na2S, inversion at C-4 by the Mitsunobu reaction (BzOH, PhsP, and DEAD), and coupling of mesylate 239 with the nucleoside base in the presence of potassium carbonate, followed by deprotection. None of these nucleoside were active against HIV-1. 

Caspi and co-workers (56) have reported the synthesis of n-octane containing a chiral methyl group by the displacement of the mesylate of (R)- and (S)-l-[l-3H]octanol with superdeuteride. A unique feature of their approach (56,57) was the chemical conversion of the more readily available tritiated IS alcohol, obtained from the reduction of [l-3H]octanal by horse liver alcohol dehydrogenase, to the more difficult-to-obtain 1/ alcohol by the Mitsunobu reaction. Using the conditions shown in Scheme 10, the (IS)-alcohol was converted to the (l/ )-benzoate which gave the (17 )-alcohol by reductive cleavage with LiAlH4. 

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