Studies on the Synthesis of Aza Analogues of Illudins by Cycloadditions to Highly Strained Methylenecyclopropanes

Abstract

A series of 3-spirocyclopropane-tetrahydropyrid-4-ones has been synthesized by the method consisting of nitrone cycloaddition to bicyclopropylidene and thermal rearrangement of the adducts. Regioisomeric 5-spirocyclopropanetetrahydropyrid-4-ones and 5-spirocyclopropanedihydropyrid-4ones were instead obtained by cycloaddition of nitrones and nitrile oxides, respectively, to methylenespiropentane, followed by thermal rearrangement. Methylenedispiro[2.0.2.1]heptane gave, in turn, 5,6-bis(spirocyclopropane)dihydropyrid-4-ones. The new compounds were prepared as simple aza analogues of the cytotoxic natural products illudins and ptaquiloside in order to study their activity in cleaving a DNA plasmid. The activities shown by several of the compounds are moderate, but from a comparative qualitative analysis of the results a useful structure-activity relationship for this new class of compounds could be derived.

3‐Spirocyclopropanedihydro‐ and ‐tetrahydropyridin‐4‐ones from Nitrone Cycloadducts of Bicyclopropylidene via 1‐(1′‐Aminomethylcyclopropyl)cyclopropanol under PdII Catalysis

“…All isoxazolidine‐4,5‐dispirocyclopropanes 7 used as starting materials in this work were obtained by 1,3‐dipolar cycloaddition of the appropriate nitrone 5 to BCP (Scheme ). Whereas compounds 13 and 14 have previously been described,10b the analogues 15 , 16 , and 17 were newly prepared in excellent yields (Table 1) from 6 and the nitrones 10 ,11 11 ,12 and 12 13. The cycloadditions were carried out at a relatively low temperature (60 °C) with extended reaction times to avoid thermal isomerization of the adducts.…”

“…Only the amino alcohol 22 provided the expected dihydropyridone 29 in excellent yield (90 %) (Table 2, entry 5). All the other substrates gave almost 1:1 mixtures of dihydropyridones 25 – 28 and tetrahydropyridones 30 – 33 10b which could be separated by flash chromatography in good overall yields (Table 2, entries 1–4).…”

“…for C 17 H 20 NO 3 + : 286.1443; found 286.1442. The reaction mixture afforded also compound 30 : yield 68 mg, 47 % 10b…”

“…C 71.46, H 8.99, N 5.95; found C 71.58, H 8.67, N 5.73. The reaction mixture afforded also compound 31 : yield 47 mg, 40 % 10b…”

Thermal Rearrangements of Bicyclopropylidene and Substituted Bicyclopropylidenes − A Gas Phase Kinetic and Product Study

“…As far as the practical application of this rearrangement to production of methylenespiropentane (5) as a building block for organic synthetic applications was concerned, [26] the conditions for it to occur cleanly and rapidly needed to be optimized. When heated to 230°C in a flow system, bicyclopropylidene (1) did not isomerize, but at 350°C it underwent a clean rearrangement to methylenespiropentane (5), which was obtained in 90% yield and in Ն 95% purity on a preparative scale (17.4 g) (see Exp.…”