Mitsunobu transformation

Dinsmore and Mercer further investigated this reaction using DBU as a base and n-Bu3P/DBAD (di-tert-butyl azodicarboxylate) as Mitsunobu s reactants, and found an unexpected steroselectivity in the Mitsunobu transformation [75b], In fact, the stereochemical course of the Mitsunobu reaction (Scheme 6.11) depended on whether the carbamic acid intermediate was N-substituted with hydrogen (retention) or with carbon (inversion). 

This reaction was first reported by Mitsunobu in 1967. It is the alkylation of compounds with active protons by using primary or secondary alcohols as the alkylating agents in combination with triphenylphosphine and diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD), to form molecules like esters, ethers, thioethers, and amines. Therefore, this reaction is generally known as the Mitsunobu reaction or Mitsunobu coupling. In addition, the specific reaction for forming esters by means of DEAD (or DIAD) and PPhs is generally referred to as the Mitsunobu esterification." Occasionally, the Mitsunobu reaction is also called the Mitsunobu transformation (for the conversion of alcohol into amines) or Mitsunobu cyclizafion (for the formation of cyclic compounds). Because of its intrinsic features of stereospecificity, as well as its occurrence in neutral media and at room temperature without a prerequisite activation of alcohol, this reaction has been extensively studied and used to synthesize a variety of compounds since 1970. 

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. 

A similar strategy served to carry out the last step of an asymmetric synthesis of the alkaloid (—)-cryptopleurine 12. Compound 331, prepared from the known chiral starting material (l )-( )-4-(tributylstannyl)but-3-en-2-ol, underwent cross-metathesis to 332 in the presence of Grubbs second-generation catalyst. Catalytic hydrogenation of the double bond in 332 with simultaneous N-deprotection, followed by acetate saponification and cyclization under Mitsunobu conditions, gave the piperidine derivative 333, which was transformed into (—)-cryptopleurine by reaction with formaldehyde in the presence of acid (Scheme 73) <2004JOC3144>. 

The Mitsunobu reaction offers a powerful stereochemical transformation. This reaction is very efficient for inverting the configuration of chiral secondary alcohols since a clean SN2 process is generally observed ( Mitsunobu inversion ). Considering the fact that Mitsunobu chemistry is typically carried out at or below room temperature, high-temperature Mitsunobu reactions performed under microwave con-... 

Under cathodic reduction condition, 2-bromo-2-cyanoacetophenone is transformed into 5-amino-4-benzoyl-3-phenylfuran-2-carbonitrile in good yield <00H(53)1337>. Cyanoketones react with glycolate under Mitsunobu conditions to produce vinyl ethers which give rise to 3-... 

Another interesting class of five-membered aromatic heterocycles has recently been published by Tron et al. [54]. These compounds have biological activity in the nM range. An example of the formation of these furazan (1,2,5-oxadiazole) derivatives is shown in Scheme 9. The diol 50 was oxidized to the diketone 51 using TEMPO and sodium hypochlorite. Transformation to the bisoxime 52 was performed in an excess of hydroxylamine hydrochloride and pyridine at high temperature for several days. Basic dehydration of 52 formed two products (53a and b). A Mitsunobu reaction was then employed using toluene as solvent to form compound 53b in 24% yield. 

A synthesis of 149, cucujolide VIII, proceeded via the tert-butyldimethylsi-lyl-(TBS)-ether of methyl (E)-12-hydroxydodec-4-enoate B [293] (Fig. 7). Deprotonation in a-position and reaction with di(4-methoxyphenyl)diselenide furnished C. This was transformed to the macrolide E after saponification of the ester moiety, deprotection of the hydroxy group, and Mitsunobu lactonization. Alternatively, the unsaturated lactone F was synthesized from B following a sequence similar to that from C to D. Oxidative elimination of the arylseleno group... 

Transformation of a primary amine to a secondary amine using 2,4-dinitro-benzenesulfonyl chloride and an alcohol. Also known as Fukuyama-Mitsunobu procedure. 

The hydroxymethyl and carboxyl group of Ser can participate in pyrazole-ring formation, as shown in the transformation of A -protected L-Ser with the Mitsunobu reagent into a /3-lactone which afforded the N-protected serine hydrazide upon treatment with methyl hydrazine. Cyclization to 25 was achieved by diisopropyl azodicarboxylate (DIAD) and TPP [90H(31)79]. 

In another approach, 2-(alkylamino)alcohol is employed as starting material for aziridine syntheses with the aid of dihalogenophosphoranes (70BCJ1185). Intramolecular transformation of 3-azidopropyloxirane 73 results in a simultaneous formation of a condensed aziridino[l,2-a]pyrrol-idine system (Scheme 39). The azide group is first transformed into imino-phosphorane 74, the nucleophilic N atom cleaves the oxirane to form betaine 75 [as in the Mitsunobu reaction (81S1)], and the phosphorus is shifted from N to O and then eliminated as phosphane oxide under simultaneous cyclization to bicyclic 76 (89JA7500). 

Both intermediates 43a and 43b were converted to the final molecule duloxetine (3), as described in Scheme 14.11. Therefore, route A involved direct transformation of the (5)-chloroalcohol 43a into the corresponding iodide, followed by amination and etherification. In contrast, route B consisted of Mitsunobu inversion of (R)-chloroalcohol 43b... 

O. Mitsunobu, The use of diethyl azodicarboxylate and triphenylphosphine in synthesis and transformation of natural products, Synthesis p. 1 (1981). 

Intermolecular and intramolecular nucleophilic substitution of an alcoholic hydroxy group by the triphenylphosphine/dialkyl azodicarboxylate redox system is widely used in the synthesis and transformation of natural products and is known in organic chemistry as the Mitsunobu reaction.1951 This reaction starts with formation of the zwitterionic phosphonium adduct 19 (Scheme 9) from triphenylphosphine and diethyl (or diisopropyl) azodicarbox-... 

Thus, 1.7-octadiene (79), which was subjected to monohydroboration followed by asymmetric dihydroxylation of the remaining double bond to give triol 80 with approximately 80% ee. Further transformations then afforded the desired butenolide 81. Double asymmetric dihydroxylation of diene 83 and subsequent protection gave hydroxy lactone 84 [98], which was then converted into acetylenic bis(hydroxy)bistetrahydrofuran 82 as the required intermediate for the (+)-asimicin synthesis. Mitsunobu inversion at C-24 gave rise to the diastereomeric (+)-bullatacin precursor. 

In order to transform the spirocyclic enone 445 to ( )-elwesine (439) and ( )-epielwesine (449), it was treated with boron trifluoride and dimethylsulfide to cleave the Al-carbobenzyloxy protecting group, and cyclization of the resulting amino enone spontaneously ensued to produce ( )-dihydrooxocrinine (447). Reduction of carbonyl function of 447 with sodium borohydride afforded ( )-3-epielwesine (449), which was converted to ( )-elwesine (439) by inversion of the hydroxyl function at C-3 via a Mitsunobu protocol using diethyl azodicarboxylate, triphenylphosphine, and formic acid. Attempted reduction of 447 directly to 439 by a Meerwein-Ponndorf-Verley reduction or with bulky hydride reagents gave only mixtures of 449 and 439 that were difficult to separate. 

The Mitsunobu conditions, applied without any carboxylic acid, were shown to provide anhydro (3, 4 -epoxide)284 286 and dianhydro sucrose derivatives.331 Some of these compounds were further transformed by reduction (leading to dehydrosucroses) or ring-opening leading to sucrose epimers and dehydrohalo-or amino sucroses (see also Scheme 7).332... 

It has been found that the results of this new variant of the Mitsunobu procedure are generally comparable with the results of the traditional Mitsunobu reaction both with respect to the yields and enantiomeric excess (ee) of chiral compounds 26. Thus, products prepared from alcohol 86e using both methods had ee 70% and 72%, and from (Tl-methyl lactate 86i 92% and 99%, respectively. However the new variant of the Mitsunobu procedure has a significant synthetic advantage over the traditional procedure imides 26 can be transformed into primary amines under milder conditions in comparison with the deprotection of /V-alkylphthalimides (see Section 6.03.6.1.3). 

Mitsunobu reactions have also been used for the cylization of 7-aminoalcohols toward azetidines. 7-Aminoalcohols 154, prepared from enantiopure ethynylaziridines, have been transformed into azetidines 155 upon treatment with dimethyl acetylenedicarboxylate and triphenylphosphine (Equation 35) <2001JOC1867>. N-Tosyl-substituted 7-aminoalcohols 156 yielded the corresponding 1-tosylazetidines 121 (Equation 36) with excellent diastereomeric (de = 99%) and enantiomeric excess (ee up to 99%) <2004EJ04471, 2005S3508>. 

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