Mitsunobu inversion method

The sequence detailed here provides 3-(S)-((tert-butyldiphenylsilyl)oxy)-2-butanone in high purity and on a preparative scale from inexpensive (S)-ethyl lactate. This optically active ketone should be a useful intermediate for the preparation of a variety of enantiomerically pure materials. It has been used in our laboratory for an asymmetric synthesis of (+)-muscarine3 and in the preparation of various other optically active tetrahydrofurans.4 Mitsunobu inversion of (S)-ethyl lactate followed by protection to provide 2-(R)-((tert-butyldiphenylsilyl)oxy)propanoate5 affords, by this method, ready access to the enantiomer of the title compound. 

Another synthesis of D-oUvose derivative exploited a tungsten carbonyl catalyzed alkynyl alcohol cycloisomerization reaction [54,55]. This useful method allows for synthesis of variety of glycals from an achiral precursor (35), which after enantioselective reduction and Sharpless epoxidation afforded intermediates 39 and 42 (by Mitsunobu inversion), precursors of unnatural D-rhamnal (40) and valuable L-fucal (43) derivatives, respectively (Scheme 4). 

The inversion of secondary alcohols into the corresponding esters, followed by hydrolysis of the ester intermediate into the inverted alcohol, has been one of the most commonly used applications of the Mitsunobu reaction during the last forty years. After the initial discovery by Mitsunobu, this method has been used hundreds of times to invert alcohols in all kinds of organic molecules. Intermolecular and intramolecular inversion reactions are possible, although the latter reaction to make lactones is used much less... 

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... 

Epimerization of carbohydrate stractures to the corresponding epi-hydroxy stereoisomers is an efficient means to generate compounds with inverse coirfiguration that may otherwise be cumbersome to prepare. Several different synthetic methods have been developed, including protocols based on the Mitsunobu reaction,sequential oxidation/reduction... 

The reaction proceeds with clean inversion, which makes the Mitsunobu Reaction with secondary alcohols a powerful method for the inversion of stereogenic centres in natural product synthesis. 

Note that alkyl azides are potentially explosive. This and the simpler reaction conditions involved is one reason why the reaction described above is mainly carried out as a Mitsunobu reaction. In this method the alkanol is reacted with diethyl diazenedicarboxylate, triphenylphosphane and hydra-zoic acid in a one-pot reaction. The reaction also proceeds with inversion and affords the amine directly because the intermediate azide is reduced by excess triphenylphosphane in situ. 

Previously documented methods for menthol inversion under standard Mitsunobu conditions (benzoic acid, PPha, diethyl azodicarboxylate) result in low yields4 (27%). More effective methods have been reported using extended reaction periods in refluxing toluene via a formic acid/N,N -dicyclohexylcarbodiimide-mediated transformation5 (20-92 hr, 80%). For hindered alcohols in general, representative methods for inverting alcohol stereochemistry necessitate conversion of the alcohol to... 

Preparative Methods both enantiomers of dihydro-5-(hydroxymethyl)-2(3H) furanone and their trityl derivatives are commercially available but expensive. The simplest and by far most popular method for preparing (5)-dihydro-5-(hydroxymethyl)-2(3H)-furanone (2) consists of enantiospecific deamination of L-glutamic acid and subsequent selective reduction of the resulting carboxylic acid (13) (eq 1). Purification of the intermediate acid (13) by crystallization and not by distillation is recommended in order to secure an excellent optical yield (>98% ee). Likewise, (f )-dihydro-5-(hydroxymethyl)-2(3//)-furanone (1) (>98% ee) can be obtained from o-glutamic acid. As the latter is considerably more expensive than its natural antipode, an appealing option is to convert the (5)-lactone into its enantiomer (eq 2)P Also available and equally useful is an inversion route to (f )-dihydro-5-(trityloxymethyl)-2(3H)-furanone (5) by way of the Mitsunobu reaction (eq 3). ... 

An example of an alcohol activation method is the Mitsunobu reaction. This reaction is performed by slow addition of the seco-acid alcohol to a mixture of diethyl azodicarboxylate (DEAD) and PPhs in toluene or THF. In the mechanism, the key intermediate is an alkoxyphosphonium cation, which is formed by DEAD and PPhs in situ. The macrolactone is formed by an intramolecular Sn2 reaction of this intermediate via an attack of the carboxylate moiety and therefore the reaction proceeds with inversion of the configuration at C-co. 

The Mitsunobu procedure has found considerable application, so it has been used for diolide formation in pyrenophorin (equation 138) °° and colletodioF° syntheses. Yamaguchi s method is much infe-rior. As expected, the ring closure in equation (138) proceeds with inversion of configuration. In a... 

The Mitsunobu reaction proved to be useful for the synthesis of aryl alkyl ethers from alcohols and phenols. The method proceeds under mild conditions and tolerates many functional groups with inversion of configuration, as exemplified by the reactions of lactate and ewrfo-5-norbornen-2-ol (equations 4 and Neighboring group participation,... 

Walker et al. have described by tliis method a seven-step synthesis of 4-thio-2-deox-y-i3-eri f/7ro-pentosc (37) from 2-dcoxy-D-erir/ira-pentosc via dithioacetals 35 and 36, involving inversion at C-4 by Mitsunobu reaction and final cyclization of the dithioacetal, accompanied by further inversion at C-4. Secrist et al.- have synthesized 39 from the ribose derivative 38 using the same method. Similarly, Imbach et al. have prepared 1,4-dithio-D-ribofuranosides 39 from L-lyxose and from D-ribose,and 1,4-dithio-L-lyxofuranosides 40 from D-ribose. Mackenzie... 

Theil et al. developed a method for chemoenzymatic synthesis of both enantiomers of cispentacin [89]. frans-2-Hydroxymethylcyclopentanol, obtained by the sodium borohydride reduction of ethyl 2-oxocyclopentanecarboxylate, was monosilylated with tert-butyldimethylsilyl (TBDMS) chloride to afford 55. Lipase PS-catalysed transesterification with vinyl acetate in /erf-butyl methyl ether furnished the ester 56 and the alcohol 57. The deacetylated 58 was obtained by the Mitsunobu reaction with phthalimide, triphenylphosphine and diethyl azodicarboxylate (DEAD) to furnish the cis oriented 59 with inversion of configuration (not retention as mentioned in the original article) (Scheme 9). Desilylation, Jones oxidation and subsequent deprotection with aqueous methylamine gave the ( R,2S) enantiomer 5 [89]. The (15, 2/f) enantiomer was prepared by the same route from the silyl alcohol 57. 

Alkylations. The reagent effects reductive Af-alkylation of A -tosylamines and indole derivatives with alcohols. The Mitsunobu reaction of 2-(l-hydroxy-alkyl)-acrylic esters and that of glycals with phenols follow an Sn2 course. The reaction has been applied to the inversion of configuration at an a-cyanohydrin center, whereas alkyl nitriles are prepared by this method using acetonitrile cyanohydrin as the source of nucleophile. The C-alkylation of o-nitroarylacetonitriles at the ben-zylic position is easily controlled. 

---