Alcohols, azido cyclization

Cyclization of haloamines 0-46 Cyclization of amino alcohols 0-61 Cyclization of p-azido alcohols 5-31 From 3-iodo azides... 

Cyclization of the furanose derivative 340 was mediated by the action of sodium hydride to afford 341 (R = Ts) in 90% yield. The amine 340 had been obtained from the azide 342 and it was later found that thermolysis of this 1,3-azido alcohol under Staudinger reaction conditions (triphenylphosphine in f-xylene) gave the azetidine 341 (R = H) directly in 99% yield <2003TL5267>. 

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). ... 

In the presence of a palladium catalyst, allyl epoxides (113) react with nitrogen nucleophiles at the al-kenic carbon atom remote from the oxirane ring to give 1,4-adducts (114)." In the absence of a palladium catalyst, azide ion attacks the oxirane ring affording 1,2-adducts (115 Scheme 52 and Table 2)." Vinyl epoxide (116) gave 1,2- and 1,4-azido alcohol in a ratio of 1 1.5 irrespective of the reaction system. " Intramolecular cyclization of vinyl epoxide (117) in the presence of a palladium catalyst afforded isoquinuclidine (118 Scheme 52). ... 

Two bis-imines (94) and (95) have been prepared from the corresponding diepoxides by reaction with NaNa and subsequent cyclization of the trans-azido-alcohols. ... 

Cyclic sulfite 211 derived from a,/3-dihydroxy hydroxamate 210 underwent stereoselective ring opening at the a position to give azido alcohol 212, which further cyclized to )Q-lactam derivative 213 under Mitsunobu conditions (90TL4317) (Scheme 50). A similar Q-lactam synthesis by the ring opening of cyclic sulfate 214 derived from tartaric acid with azide nucleophile followed by reduction has been reported (90JOC5110) (Scheme 51). 

Furthermore, treatment of the crude mixture of azido alcohols 152 and 153, obtained by azidolysis of tosylate precursors, afforded aziridine 154 in high yield. Danishefsky and coworkers reported that reductive cyclization of an exocyclic azido mesylate in the presence of trimethyl phosphite, followed by... 

Scheme 18). Addition of Grignard reagents to the aldehyde gave a mixture of adducts with stereoselectivity varying from 4 1 to > 100 1. Completion of the P-lactam synthesis followed either of two routes. Oxidative cleavage of the polyol side chain provided hydroxy acid 149 while prior conversion of the alcohol to an azido group followed by oxidation afforded 150. Either substrate could be cyclized by known procedures. 

Although the Hemetsberger reaction is clearly a powerful synthesis of indole-2-carboxylates, some problems are encountered in addition to the occasional mixture of nitrene cyclization products. Indeed, often the aldoliza-tion route to the 2-azidocinnamates proceeds poorly. This can be obviated at lower temperatures (-30 °C) to stop the reaction at the azido alcohol stage. Subsequent dehydration with thionyl chloride in pyridine or triethylamine afforded the 2-azidocinnamates. This two-step process was superior to the conventional one-step aldolization/ dehydration reaction, as found by Murakami and coworkers [67]. Tercel s group also observed that a low temperature (-78 °C) aldol condensation, isolation of the azido... 

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. 

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. 

The intramolecular Schmidt reactions of azido tertiary benzylic and propargylic alcohols 32 lead to l-azabicyclo[5.3.0]decanes or 1-azabicyclo[4.3.0]decanes (indolizidines) 36 without formation of the products derived from cation rearrangement. However, simple tertiary alcohols such as 37 undergo cation rearrangement prior to cyclization to give a mixture of regioisomeric indolizidines. 

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