Azide-alcohols, cyclization aziridines

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). 

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). ... 

The Blum aziridine isomerization describes the net coversion of epoxides 1 into N-H aziridines 3 via an intermediate azido-alcohol 2. The reaction proceeds by opening of the epoxide with an azide source followed by the Staudinger reduction and cyclization of the intermediate azido-alcohol to give the aziridine. The reaction proceeds with net inversion of stereochemistry around the epoxide. 

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). 

Backvall and co-workers used the Blum reaction in the total synthesis of ferruginine (23)." Epoxide 21 was opened with sodium azide and the resultant azido-alcohol was reduced and cyclized with triphenylphosphine in good yield to give aziridine 22. Intermediate 22 was eventually processed to ferruginine (23). 

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. 

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