Mitsunobu reaction aziridines

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. 

Cydization of P-hydroxy-a-amino esters under Mitsunobu reaction conditions is an alternative approach to aziridine-2-carboxylic esters [6b, 13-16], In this case the P-hydroxy group is activated by a phosphorus reagent. Treatment of Boc-a-Me-D-Ser-OMe 13 (Scheme 3.5) with triphenylphosphine and diethyl azodicarboxylate (DEAD), for example, gave a-methyl aziridinecarboxylic acid methyl ester 14 in 85% yield [15]. In addition to PPh3/DEAD [13b, 15], several other reagent combi-... 

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). 

Another similar, but less frequently used method for incorporation of dihydrothiazole units into cyclic peptide precursors is the Mitsunobu reaction.15135641 This reaction, however, is not suitable for the simultaneous production of dihydrooxazole rings, because of predominant aziridine formation. 571 ... 

Employing the Mitsunobu reaction with diisopropyl azodicarboxylate and triphenyl-phosphine, aminoacylserine (in contrast to aminoacylthreonine) is converted into (ami-noacyl)oxazolidine-2-carboxylic acid. 54 By the same procedure a/Zo-threonine peptides are converted into the oxazoline derivatives, whilst the threonine peptides are apparently converted into the aziridines in good yields. 86 ... 

Lactams (10, 447-448 11, 589). Cyclization of p-hydroxy aryl amides to p-lactams by a Mitsunobu reaction is stereospecific. Thus the protected derivative 1 of phenylserine cyclizes to 2 as the only p-lactam and an aziridine. The configuration at C, of 1 is retained, whereas the configuration at C., is inverted. 

A stepwise formal [3+3] cycloaddition reaction entailed the generation of the dianion of 168, transmetalation with MgBr2, and addition of aziridine 169 to give intermediate 170. A Mitsunobu reaction to give 171 completed the sequence with an overall yield of >90% <05OL2993> (Scheme 48). This strategy was applied to other aziridines in the preparation of 3-methylenepiperidine intermediates for the total synthesis of several Nuphar alkaloids <05JOC207>. 

N-Alkylations. Various amine derivatives are obtained by usingIV-alkyltriflamides, V.fJ-bisbenzyloxycarbonylhydroxylamine, and 5-substituted tetrazoles as nucleophiles in the Mitsunobu reaction. V-Tosylserine f-butyl ester gives an aziridine in 60% yield. ... 

The aziridine-ring closure based on the Mitsunobu reaction, the Staudinger reaction, and isomerization of aminooxiranes also involves nucleophilic displacement as the key step of the reaction mechanism. Other reactions rarely reported in the synthesis of carbohydrate aziridines involve nonstandard, " even unusual procedures lacking a general application. 

Mitsunobu reaction of p-hydroxy-a amino acid peptides. Reaction of the Cbz-prolyl-threonine N-methyl amide 1 with P(C6Hs)3 and DIAD provides the peptide aziridine 2 in 84% yield. 

Wipf and Miller reported a number of approaches for the preparation of acid and base labile oxazolines and thiazolines (e.g., 158)/ The Mitsunobu reaction or Burgess reagent proved to be the most effective methods for the preparation of these heterocycles, but the Burgess reagent was much general in its applicability. In some cases, competitive aziridine (159 to 160) or elimination reactions (161 to 162) dominated under the Mitsunobu reaction conditions vide infra). 

The Mitsunobu reaction has been extensively used for the formation of aziridines. Recently, Cossy et al. were interested in inverting the benzylic hydroxyl group in 167 to prepare a precursor of (phenol derivative 169. Increasing the concentration of 2-ethoxyphenol to 20 equiv led to the formation of the desired phenol ether in good yield. The Mitsunobu reaction has also been used for the preparation of amino acid derived aziridines these compounds can then be used for the synthesis of pseudopeptides. 

Neoplasm inhibitors at C-4 aziridine-bearing paclitaxel (taxol) analogues (134-136) were synthesized. The key step in the synthesis is the aziridine ring formation at the C-4 position via an intramolecular Mitsunobu reaction [139]. Biological activity of paclitaxel analogues is shown in Table 30.6. 

R)-aspartic acid derivative (—)-1492, prepared in three steps from the amino acid and characterized by X-ray crystallography, were reduced to primary alcohols before intramolecular Mitsunobu reaction followed by silyl protection afforded the functionalized aziridine (+)-1493. When this was... 

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