Mitsunobu alkylation

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... 

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 Mitsunobu conditions can be used for alkylation of 2-pyridones, as in the course of synthesis of analogs of the antitumor agent camptothecin. 

A further extension to this concept was (dimethylsilyl)propionic acid linker 75 used for the solid-phase synthesis of aryl-containing organic compounds [86], The linker was cleaved smoothly with TFA and has been used for the synthesis of compounds which involved alkylation, acylation, and Mitsunobu reactions. 

N-Alkylation of 2//-pyrido[l,2- ][ 1,3,5 tria/inc-2,4(3//)-dionc 81 was carried out with the alcohol 82 to obtain 83 under standard Mitsunobu reaction conditions (Equation 3) <2003JME3840>. 

The use of more polar solvents (acetonitrile, DMF) improved the N 0 ratio in the Mitsunobu alkylation of 3-benzoyl thymine with cyclopentanol <06SL324>. N vs. O-selectivity in the alkylation of 2-pyrimidinones has been investigated and the results rationalised on the HSAB principle <06T6848>. 

Thiadiazolidinone 1,1-dioxides 71 undergo O- rather than the expected iV-alkylation under Mitsunobu conditions <1998TL7435>. iV-Acylation can subsequently be performed on the O-alkylated product 72 using acetic anhydride to give thiadiazolines 73 (Scheme 7). 

Phenylamino-l,3-thiazolines have been synthesized from /V-(2-hydroxy-ethyl)-/V -alkyl thioureas by a one-pot intramolecular Mitsunobu reaction. 

For X=OH and R=EWG group or alkyl, the Mitsunobu reaction (10) is evidently the most convenient procedure for the synthesis of the corresponding nitronates (35a) (Scheme 3.34). 

More recently, a preparation of iV-alkylated pyridotriazolones was developed using a Mitsunobu protocol, pointing out the acidity of the NH group. Compound 54 (Equation 3) displaced the hydroxyl group with classical inversion at carbon, leading to 55 <2005SC2939>. 

Preparation of the donor 46 was started from 4,6-0-benzylidene protected thiomannoside 47 (Scheme 7.24). Alkylation with p-allyloxybenzyl chloride under phase transfer conditions78 was followed by 3-O-silylation and Pd(0)-mediated deallylation79 to give 48. The phenolic OH group was alkylated with ethyl 6-bromohexanoate and carboxylic acid, liberated by alkaline hydrolysis, was reacted with PEG monomethyl ether (MW -5000) under Mitsunobu conditions to afford 46. 

Asymmetric introduction of azide to the a-position of a carbonyl has been achieved by several methods. These include amine to azide conversion by diazo transfer,2 chiral enolate azidation,3 and displacement of optically active trifluoromethanesulfonates,4 p-nitrobenzenesulfonates,5 or halides.6 Alkyl 2-azidopropionates have been prepared in optically active form by diazo transfer,2 p-nitrobenzenesulfonate displacement,5 and the Mitsunobu displacement using zinc azide.7 The method presented here is the simplest of the displacement methods since alcohol activation and displacement steps occur in the same operation. In cases where the a-hydroxy esters are available, this would be the simplest method to introduce azide. 

Intermolecular reactions of hydroxylamines with secondary alkyl halides and mesylates proceed slower than with alkyl triflates and may not provide sufficiently good yield and/or stereoselectivity. A nseful alternative for these reactions is application of more reactive anions of 0-alkylhydroxamic acids or 0-alkoxysulfonamides ° like 12 (equation 8) as nucleophiles. The resulting Af,0-disubstituted hydroxamic acids or their sulfamide analogs of type 13 can be readily hydrolyzed to the corresponding hydroxylamines. The same strategy is also helpful for synthesis of hydroxylamines from sterically hindered triflates and from chiral alcohols (e.g. 14) through a Mitsunobu reaction (equation 9). 

Sulfahydantoins 87 and 88 are analogues of hydantoins and provide heterocyclic scaffolds with a great potential for the construction of bioactive compounds. A total of 28 derivatives, with crude purity generally higher than 85%, were prepared by parallel synthesis using an oxime resin as a solid support (Scheme 46) . The results constitute the first report of successful Mitsunobu reactions and reductive alkylations on the oxime resin. 

In the case of the thiazolidinedioxides (38), the increased acidity of the cyclic sulfamide determines the reactivity. Metallation (NaH) occurs at N—H producing an anion which is readily alkylated <93TL4705>. Treatment with triphenylphosphine produces a stable betaine which can be used to couple alcohols and acids in a variant of the Mitsunobu reaction <94JOC2289>. 

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