Mitsunobu

A very mild and efficient synthesis of N-substituted -lactams uses the Mitsunobu reaction (see section 2.6.2) for the ring closure of seryl dipeptides protected at the terminal N as 4,5-diphenyloxazol-2(3f/)-one ( Ox ) derivatives (see section 2,6.3)... 

The stereoselective allylic rearrangement of the allylic alcohol 798 catalyzed by PdCl2(MeCN)2 and Ph3P under Mitsunobu inversion conditions is explained as proceeding via a rr-allylpalladium intermediate[496]. The smooth rearrangement of the allylic p-tolylsulfone 799 via a rr-allylpalladium intermediate is catalyzed by a Pd(0) catalyst[497]. 

In the olivanic acid series of carbapenems the ( )-acetamidoethenyl grouping can be isomerised to the (Z)-isomer (19) (22) and reaction with hypobromous acid provides a bromohydrin that fragments to give a thiol of type (20) when R = H, SO H, or COCH. The thiol is not isolated but can react to provide new alkyl or alkenyl C-2 substituents (28). In the case of the nonsulfated olivanic acids, inversion of the stereochemistry at the 8(3)-hydroxyl group by way of a Mitsunobu reaction affords an entry to the 8(R)-thienamycin series (29). An alternative method for introducing new sulfur substituents makes use of a displacement reaction of a carbapenem (3)-oxide with a thiol (30). Microbial deacylation of the acylamino group in PS-5 (5) has... 

The Mitsunobu reaction is usually used to introduce an ester with inversion of configuration. The use of this methodology on an anomeric hydroxyl was found to give only the /3-benzoate, whereas other methods gave mixtures of anomers. Improved yields are obtained in the Mitsunobu esterification when p-nitrobenzoic acid is used as the nucleophile/ Bis(dimethylamino) azodicarboxylate as an activating agent was... 

The Mitsunobu reaction is used to convert an alcohol and an acid into an ester by the formation of an activated alcohol (Ph3P, diethyl diazodicar-boxylate), which then undergoes displacement with inversion by the carboxylate. Although this reaction works very well, it suffers from the fact that large quantities of by-products are produced, which generally require removal by chromatography. 

Primary alcohols may be phosphorylated by use of the Mitsunobu reaction (Ph, , DEAD, HBF4, Pyr). Of several salts examined, the potassium salt of the phosphate was the best. 

The Wenker aziridine synthesis entails the treatment of a P-amino alcohol 1 with sulfuric acid to give P-aminoethyl sulfate ester 2 which is subsequently treated with base to afford aziridine 3. Before the discovery of the Mitsunobu reaction, wbicb transforms an amino alcohol into an aziridine in one step under very mild conditions, the Wenker reaction was one of the most convenient methods for aziridine synthesis. However, due to the involvement of strong acid and then strong base, its utility has been limited to substrates without labile functionalities. 

Cyclization of 2-(4-hydroxypentyl)quinazolin-4(3//)-ones 422 under Mitsunobu s conditions afforded only linearly fused 6,7,8,9-tetrahydro-1 l/f-pyrido[2,l-6]quinazolin-l l-ones 423 without angularly fused 1,2,3,4-tetrahydro-6//-pyrido[l, 2-n]quinazolin-6-ones 424 (98CPB928). 

The terc-butyldimethylsilyl groups of pyrido[l,2-c]pyrimidine 154 was eliminated with BU4NF to afford 6-hydroxy-8-hydroxymethyl derivative 155 (00TL1849). Compound 155 gave tricyclic derivative 156 under Mitsunobu conditions. 

An 1 5 epimeric mixture of piperidine derivatives 191 was cyclized under Mitsunobu condition to afford a mixture of l-iminoperhydropyrido[l,2-c] pyrimidines 153 and 192 (00TL1849). 

Hydroxyl group of 7-hydroxymethylperhydropyrido[l,2-u]pyrazines 382 was arylated by Mitsunobu coupling with phenols and 4-fluorothiophenol... 

The major application of the Mitsunobu reaction is the conversion of a chiral secondary alcohol 1 into an ester 3 with concomitant inversion of configuration at the secondary carbon center. In a second step the ester can be hydrolyzed to yield the inverted alcohol 4, which is enantiomeric to 1. By using appropriate nucleophiles, alcohols can be converted to other classes of compounds—e.g. azides, amines or ethers. 

In summary the Mitsunobu reaction can be described as a condensation of an alcohol 1 and a nucleophile—NuH—11, where the reagent triphenylphosphine is oxidized to triphenylphosphine oxide and the azodicarboxylate reagent 12 is reduced to a hydrazine derivative 13 ... 

Alkyl aryl ethers and enol ethers are also accessible by the Mitsunobu method. Cyclic ethers can be obtained by an intramolecular variant, which is especially suitable for the synthesis of three- to seven-membered rings ... 

The conversion of an alcohol to an amine can be achieved in a one-pot reaction the alcohol 1 is treated with hydrazoic azid (HN3), excess triphenylphosphine and diethyl azodicarboxylate (DEAD). The initial Mitsunobu product, the azide 14, further reacts with excess triphenylphosphine to give an iminophosphorane 15. Subsequent hydrolytic cleavage of 15 yields the amine—e.g. as hydrochloride 16 ... 

Suitable starting materials for the Mitsunobu reaction are primary and secondary alcohols. Tertiary alcohols are less suitable since these are bad substrates for a SN2-mechanism. 

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