A Stereoselective Synthesis of 1-Acetyl-2-aminomethylcyclopropanes from Allylsulfonamides and Phenyl(alkynyl)iodonium Salts

Abstract

A versatile and stereoselective synthesis of 1-acetyl-2-aminomethyl cyclopropanes from the reaction of anions of tosylallylamines and phenyl(propynyl)iodonium salt was developed.Peptidomimetics play an important role in understanding enzyme-substrate and receptor-ligand interaction as well as in developing non-peptidic drugs in medicinal chemistry. 1 The most popular form of peptidomimetics is peptide bond isostere 2 that converts peptides into nonpeptides effectively without losing structural integrity of the peptide bonds. Among many peptide isosteres, cyclopropane ring offers sites of appendages for extra binding sites as well as conformational rigidity with defined stereochemistry. 3 Though there are many reports of cyclopropane-peptideisosteres and synthetic methodologies for functionalized cyclopropane rings, 4 stereoselective construction of cyclopropane ring system has been difficult and lengthy in synthesis. 5Herein we like to report a new and facile synthetic methodology for the stereoselective construction of various 1-acetyl-2-aminomethylcyclopropanes. During the course of our synthetic program utilizing methylenecyclopropane ring system with high strain energy, 6 we studied reaction of the anion of 1 7 with phenyl(propynyl)iodonium triflate (2) with an anticipation of obtaining an azatriquinane compound (3). Instead, we obtained azabicyclo[3.1.0]hexane compound (4) (Scheme 1).The structure of 4 was determined through spectroscopic analysis 8 and confirmed by comparison to the earlier report of similar reaction by Feldman. 9 In his report, a plausible mechanism for the formation of a methylene compound from the alkylidene cyclopropane was proposed. While examining the general applicability of this reaction to the synthesis of natural products, 10 we found out that methylene azabicyclo[3.1.0]system was not stable under acidic condition of silica-gel chromatography and slowly decomposed at room temperature even in the pure state. Unstable nature of related methylene azabicyclo[3.1.0] system was reported by Baird. 11 He observed that methylene azabicyclo[3.1.0] system underwent hydration reaction to form hemiaminals under acidic environment and eventually decomposed to unidentifiable products. There also was a report that even methylenepyrrolidines were not stable during purification. 12 Since our enamines were sulfonamides, they might more prone to hydrolysis reaction and thus treatment with acid could yield substituted 1-acetyl-2-aminomethylcyclopropanes through the acid hydrolysis of enamines to the corresponding aminoketone. To verify that possibility, various allylamine derivatives were subjected to the reaction with 2 and the reaction products were treated with acid (Scheme 2).When the reaction of anions of tosylallylamines with phenyl(propynyl)iodonium triflate was treated with aqueous acid after the completion of the addition reaction, 13 1-acetyl-2-aminomethylcyclopropanes (7) 14 were produced without any other decomposition products. As expected, Scheme 1 I + Ph -OTf n-BuLi N Ts Ph Ph HN Ts Et...

Trimethylenemethane Diyl Mediated Tandem Cycloaddition Reactions: Mechanism Based Design of Synthetic Strategies

“…Instead of generating the TMM diyl intermediate by breaking the cyclopropane ring, the olefin of the methylenecyclopropane Scheme 7. Alkylidene Carbene from Alkynyl Iodonium Salt for Tandem Cycloaddition Reaction toward Linearly Fused Triquinane 26 The rearrangement resulted in the formation of stereochemically intact, substituted cyclopropanes after hydrolysis of enamine to the ketosulfonamide 71 in good yield (Table 5). This result confirmed that formation of TMM diyls from methylenecyclopropanes is sensitive to the strain associated with the structural features of 69.…”

“…Even a slight alteration of the structural features prevented the formation of TMM diyls. 17a, 26 The special nature of the TMM diyl 6 enabled a study that probed the characteristics and reactivity of the TMM diyl. 18 Information obtained from Berson's thorough investigation led to the application of TMM diyl in organic synthesis.…”

Recent Developments in the Chemistry of Polyvalent Iodine Compounds

“…Lee and Lee recently reported a stereoselective synthesis of 1-acetyl-2-aminomethyl cyclopropanes 563 based on a similar reaction of anions of tosylallylamines 562 and phenyl(propynyl) iodoniumtriflate followed by an acidic hydrolysis of the intermediately formed azabicyclo[3.1.0]hexane products (eq 234) …”

1‐Azido‐1‐Alkynes: Synthesis and Spectroscopic Characterization of Azidoacetylene

“…After we had repeated the experiment with 3-hexyne instead of 2,3-dimethyl-2-butene, we found exclusively the 3-cyanocyclopropene 19 a (43 %). Whereas general trapping of vinylidenes by olefins to produce methylidenecyclopropanes is well-known, [18] the analogous reaction with alkynes has seldom been investigated because the corresponding methylidenecyclopropenes are highly unstable and could only be characterized after interception by Diels-Alder reaction. [19] Thus, it is not surprising that no methylidenecyclopropenes were detected from the reaction mixture of 10, QN 3 , and alkynes.…”