Cyclizations aziridine synthesis

The alkene pseudohalogen adducts (15) of Scheme 8 are also useful intermediates for aziridine synthesis. These adducts are discussed later in Sections 3.5.6.2-4. The iodine azide " and bromine azide ° adducts may be reduced to aziridines with many reagents recent references report use of lithium aluminum hydride and dimethylamineborane. TTie iodine isocyanate aziridination continues to prove useful, as in Scheme 10. Since the recent reviews, - the mechanism of the triphenylphosphine-based cyclization of azido alcohols has appeared (Scheme 11) there are clear steric consequences. Alkenes can be chlorinated in acetonitrile to give intermediates which can be worked up to yield aziridines (Scheme 12). ... 

Aube and co-workers have reported an aziridine synthesis which involves a radical cyclization (Scheme 83) (92JA5466). 

Somfai and Ahman have applied the Blum aziridine synthesis to the total synthesis of indolizidine 209D (20). ° Epoxide 18 was opened with sodium azide and the primary alcohol protected as the silyl ether. The azide was then treated with triphenylphosphine and heat, resulting in concomitant reduction and cyclization to give intermediate 19. Aziridine 19 was eventually processed to indolizidine 209D (20). 

Robinson and co-workers reported the preparation of aromatase inhibitors that used the Blum aziridine synthesis as a key step. Epoxy-steroid 27 was opened with sodium azide to form the azido-alcohol, which was then reductively cyclized with triphenylphosphine and heat to provide the desired aziridine 28. Analog 28 exhibited modest inhibitory activity toward human placental aromatase. 

Researchers at Lexicon Pharmaceuticals found that limonene aziridines could be efficiently prepared from the corresponding limonene oxides using the Blum aziridine synthesis. Epoxide 32 was opened with sodium azide to produce the regioisomeric azido-alcohols 33 and 34 in an approximate 1 1 ratio. The secondary azide was reductively cyclized with triphenylphosphine at ambient temperature, whereas the tertiary azide required heating to effect the same transformation. In this way, the desired aziridines 35 and 36 were prepared in good yield on multigram scale. 

Only one report is concerned with the synthesis, molecular structure, and X-ray analysis of this ring system as 2 (86KGS477). The synthesis of 2 was achieved by the cyclization of 2-aziridine carboxylic acid hydrazide with acetone as shown in Scheme 2. 

A general method for the synthesis of N-unsubstituted aziridine-2-carboxylates involves a triphenylphosphine-mediated reductive cyclization of hydroxy azido esters [17-22]. A recent example involves the treatment of [1-hydroxy-a-azido ester 15 (Scheme 3.6) with PPh3 to give aziridine 16 in 90% yield [19]. a-Hydroxy- 3-azido esters undergo similar reactions to give aziridine-2-carboxylates [20-22],... 

Methodology for the cyclization of a-hydroxy-P-amino phosphonates has also been developed and employed in synthesis of aziridine-2-phosphonates [79, 80]. Mesyla-tion of a-hydroxy-P-amino phosphonates 89 (Scheme 3.29), for example, gave a-mesyloxy-P-amino phosphonates 90. Treatment of 90 with K2CO3 afforded azir-idine-2-phosphonates 91 in 93-95% yield [79]. 

An aza-Darzens reaction, involving the addition of chloromethylphosphonate anions to enantiopure N-sulfinimines, has also been developed by Davis and others for the asymmetric synthesis of aziridine-2-phosphonates [81-84], As an example, treatment of the lithium anion generated from dimethyl chloromethylphos-phonate (93 Scheme 3.30) with N-sulfmimine (Ss)-92 gave the a-chloro-P-amino phosphonate 94, which could be isolated in 51% yield. Cyclization of 94 with n-BuLi gave cis-N-sulfmylaziridine-2-phosphonate 95 in 82% yield [81],... 

Azirines (three-membered cyclic imines) are related to aziridines by a single redox step, and these reagents can therefore function as precursors to aziridines by way of addition reactions. The addition of carbon nucleophiles has been known for some time [52], but has recently undergone a renaissance, attracting the interest of several research groups. The cyclization of 2-(0-tosyl)oximino carbonyl compounds - the Neber reaction [53] - is the oldest known azirine synthesis, and asymmetric variants have been reported. Zwanenburg et ah, for example, prepared nonracemic chiral azirines from oximes of 3-ketoesters, using cinchona alkaloids as catalysts (Scheme 4.37) [54]. 

The concept for the synthesis of4-hydroxy-4,5-dihydroisoxazoles by Righi and coworkers was discussed earlier, in Chapter 7. Here, an extension of this methodology by utilizing polymer-bound nitroacetate (hydroxylated Merrifield resin) is described [10], Thus, the one-pot domino oxidation/nitroaldol cyclization of aziridine 10-28 with immobilized nitroacetate 10-29 furnished 10-30 which, after detachment from the resin, led to the desired product 10-31 in good yield and excellent trans-selectivity (Scheme 10.7). 

As shown for the aziridines, BETMIP (68) has proved to be useful in the synthesis of azepines (Scheme 118). Treatment with methylenephosphorane leads to a phosphonium salt which in turn is deprotonated with BuLi and cyclized with benzene-l,2-dialdehyde in a Wittig and aza-Wittig step to form benzazepine 326 (93JOC1987). 

Weinreb and co-workers (77) reported a similar protocol in the total synthesis of sarain A. The five-membered ring of the tricyclic central array was constructed via thermolysis of aziridine 244 to furnish the intramolecular [3 + 2]-cycloaddition product 245 in 73% as a single regio- and stereoisomer. Further chemical elaboration to 245 followed by FeCla induced cyclization delivered the advanced synthetic intermediate 247 (Scheme 3.83). 

Sugar azides are also important starting-materials for the synthesis of epimino sugars an azido group adjacent to a p-tolylsulfonyloxy group, as in 6 or 8, may be simultaneously reduced and cyclized with Raney nickel to form an aziridine ring, as in 7, especially if the two groups are in the frans-diaxial position.19 22... 

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