Oxidative hydrolysis and acid-catalyzed rearrangement of steroidal isoxazolidines

Welwitindolinone C synthetic studies. Construction of the welwitindolinone carbon skeleton via a transannular nitrone cycloaddition

“…Regarding the latter, the use of N- benzyl hydroxylamine (Scheme 4) is representative of several variations which were explored and found to either resist cycloaddition or give large amounts of oxazole side-products via dehydration of the intermediate nitrone (i.e., 18 ) 29,30. Eventually a more satisfactory solution that allowed advancement of the N -methylhydroxylamine adducts was implemented ( vide infra ) 23,24,31,25,26…”

“…As illustrated in Scheme 9, isoxazolidine 23 was advanced by first rearranging to the corresponding aminal ( 39 ) 26,51. Subsequent treatment of 39 with hydroxylamine hydrochloride produced amino-alcohol 40 in 95% yield.…”

“…Unfortunately, numerous attempts to install the bridgehead nitrogen failed;21 thus an alternate strategy was devised. Herein we report the details of this approach (Path B, Scheme 1) which calls for the preparation of intermediate isoxazolidine 7 via a nitrone-mediated transannular [3+2] dipolar cycloaddition of olefin 6 22,23–26. Taking maximum advantage of our prior efforts, olefin 6 was seen as arising from the previously prepared diazoketone 4 by employing a two-step sequence involving rhodium-catalyzed O–H insertion/ring-opening to deliver enol ether 5 followed by Claisen rearrangement 4,27,28…”

Isoxazolidine: A Privileged Scaffold for Organic and Medicinal Chemistry

“…317,318 The same group of investigators developed the acid-catalyzed rearrangement of bridged N-Me-isoxazolidines 386 into the perhydro-3,1-oxazine derivative 387. 319,320 This reaction involved the insertion of the N-methylene group in the N−O bond. On the other hand, treatment of the same steroid derivative 386 by hydroxylamine hydrochloride in boiling ethanol−pyridine led to formation of the aromatic compound 385 (Scheme 108).…”

“…On the other hand, treatment of the same steroid derivative 386 by hydroxylamine hydrochloride in boiling ethanol−pyridine led to formation of the aromatic compound 385 (Scheme 108). 319 Colombi et al 321 realized, to the best of our knowledge, the synthesis of the only spiro-isoxazolidine steroid derivative by reaction between benzonitrile oxide and the terminal unsaturated steroid scaffold. The reaction afforded several stereoisomers having an isoxazolidine-oxadiazoline structure 388 (Figure 27).…”