Cyclopropylamine, oxidation

We proposed the sequential single-electron transfer mechanism for ethylene biosynthesis based on precedents of cyclopropylamine oxidations by enzymes such as cytochrome P450 (55, 40) and monoamine oxidase (59,40). A syllogism underlying this postulate is that the electrochemical oxidation of ACC must have a close mechanistic relationship to the enzymatic oxidation because each gives the same products with the same stereochemistry. This mechanism was modified slightly by theoretical considerations (5) (eq 10). Key intermediates are 1, the cyclopropylamine radical cation, and 2, the "half-opened radical." The presence of the latter species explains, by free rotation about the -CH2-CH2 bond, the loss of stereochemistry observed with deuterated substrates. It is further consistent with cyclopropylcarbinyl... 

In the hydroxycyclopropanation of alkenes, esters may be more reactive than N,N-dialkylcarboxamides, as is illustrated by the exclusive formation of the disubstituted cyclopropanol 75 from the succinic acid monoester monoamide 73 (Scheme 11.21) [91]. However, the reactivities of both ester- as well as amide-carbonyl groups can be significantly influenced by the steric bulk around them [81,91]. Thus, in intermolecular competitions for reaction with the titanacydopropane intermediate derived from an alkylmagnesium halide and titanium tetraisopropoxide or methyltitanium triisoprop-oxide, between N,N-dibenzylformamide (48) and tert-butyl acetate (76) as well as between N,N-dibenzylacetamide (78) and tert-butyl acetate (76), the amide won in both cases and only the corresponding cyclopropylamines 77 and 79, respectively, were obtained (Scheme 11.21) [62,119]. 

MAO oxidizes amine substrates also by a one-electron route via the cyclopropylamine radical cation 8 which undergoes ready ring opening to the iminium radical cation 9 [11]. Then capture by a flavin radical, may cause the enzyme inactivation [12]. This mechanism was established by labeling experiments, Eq.(4) [13]. 

In the late 1960s, different types of cyclopropylamines, the A/-substituted cyclopropylamines, were reported [111]. One of the most interesting compounds in the new class was A/-[2-o-chlorophenoxy]-ethyl]-cyclopropylamine (Lilly 51641) (42). This compound noncompetitively inhibited the MAO-catalyzed oxidation of serotonin, tyramine, phenylethylamine, and tryptamine in vitro and increased the serotonin concentration in the whole rat brain in vitro. In structure-activity studies on a series of m- and p-aromatic substituted A/-(phenoxyethyl)cyclopropylamines (43), the degree of inhibition correlated well with a and % values [112]. 

Silverman and coworkers have carried out extensive research on the mechanism of inactivation of MAO by cyclopropylamine analogues. They first reported in the early 1980s that A/-cyclopropyl-A/-arylalkylamines are mechanism-based inactivators of MAO [121,125], The mechanism proposed was enzyme-catalyzed one electron oxidation of A/-cyclopropylamines to give reactive ring-opened products which further react with either flavin and/or a cysteine residue, depending on the structure of the inactivator. According to their reports [120,125, 126], 1-phenylcyclopropylamine (50) attached reversibly to a cysteine residue and irreversibly to the flavin when it activated MAO B, whereas 50 modified only the flavin during inactivation of MAO A. In the case of frans-2-phenylcyclopropy-lamine (8a) and A/-cyclopropyl-a-methylbenzylamine (51), both MAO A and B are inactivated by attachment to a cysteine residue (Fig. 3). 

On the other hand, a recent crystallographic study revealed that the trans-2-phenylcyclopropylamine (8a) forms a cyclopropyl ring-opened adduct with MAO B at the flavin C(4a), and no evidence was obtained for inhibitor binding at Cys-365 [70,127]. From this observation, Edmondson and coworkers suggested [70] that the inhibition mechanism might be accommodated by a mechanism similar to that proposed by Sayre et al. for the quinone-mediated oxidative cleavage of cyclopropylamines [128]. 

Inhibition mechanisms by A/-cyclopropyl MPTP analogues are also discussed in terms of two catalytic pathways, one of which is based on an initial SET step from the nitrogen lone pair, as proposed by Silverman, and the second is based on an initial a-carbon hydrogen atom transfer (HAT) step, as proposed by Edmondson, leading to a radical and dihydropyridinium product formation. The observation that MAO B catalyzes the efficient oxidation of certain 1-cyclopropyl-4-substituted-1,2,3,6-tetrahydropyridines to the corresponding dihydropyridinium metabolites suggests that the catalytic pathway for these cyclic tertiary allylamines may not proceed via the putative SET-generated aminyl radical cations [122], Further studies will be necessary to clarify all the facets of the mechanism of inhibition of MAO by cyclopropylamines. 

L.M. Sayre, M.P. Singh, P.B. Kokil, F. Wang, Non-electron-transfer quinone-mediated oxidative cleavage of cyclopropylamines. Implications regarding their utility as probes of enzyme mechanism, J. Org. Chem. 56 (1991) 1353-1355. 

Fig. 78 Oxidative ring opening of cyclopropylamines and subsequent epoxidation...

An elegant extension of this work has been contributed by Lee et al., who showed that aryl-cyclopropylamines easily obtained by a Kuhnkovich cy-clopropanation could also imdergo the oxidative fragmentation/cycHzation reaction (Scheme 76) [217]. Interestingly, the radical issued from the cycH-zation of 262 was trapped by molecular oxygen and afforded alcohol 263 after... 

Identification of 74 on incubation of MAO with 69 confirmed the initial formation of the 1-phenylcyclobutylaminium radical. That a variety of cyclopropylamines and cyclobutylamines inactivate MAO and result in ring-opened adducts is consistent with the intermediacy of the aminyl radicals. These results strongly suggest that the MAO-catalyzed oxidation of amines involves one-electron transfer as the first step. 

Search for new mechanism based investigations for deducing the mechanism of the enzyme catalyzed activity continues to be active area of research. Mariano and coworkers have used activated flavins such as 5-ethylflavinium perchlorate, whose ground state reduction potentials are high enough to promote oxidative dealkylation of amines, as enzyme models [209]. Studies on the inactivation of the model enzymes by cyclopropylamines and a-silylamines suggest a polar mechanistic model. Silverman attributes this result to the drastically altered nature of the flavin used in these studies, which could favor a nucleophilic mechanism [16]. 

Cyclopropylamine (77) could be oxidized to nitrosocyclopropane (432) by oxygen difluoride or m-chloroperbenzoic acid (equation 106). Azo compounds 433 and 435 were obtained by oxidation of 434 by IF5 (equation 107) or condensation of 77 with a nitroso compound (equation 106). Interconversions of an aminocyclopropane into an isocyano or azido cyclopropane are described, for example, in Refs 105,479-481,515,516 and Refs 89, 461, 517, respectively. For formation of an N-cyclopropyl iminiophos-phorane see Ref. 518. Nitrosation of iV-cyclopropylurea derivatives was usually performed... 

Opening of the vicinal carbon-carbon bond in aminocyclopropane derivatives was achieved by oxidation with various reagents, e.g. Pb(OAc)4 , NaOCP r-BuOCpi Cu2 /0 Cu/0 0s04/0 K3Fe(CN) Cu or fiv/Oa/sens., anodic oxidation Oxidation with halogenating reagents such as NaOCl or t-BuOCl proceeds via N-chloro compounds (see equation 105), which opened the C(l)-C(2) cyclopropane bond when the cyclopropylamine had one substituent at the iV-atom (e.g. 489- 490 equation 125) or a phenyl moiety in the C(2) position. 

The product obtained by oxidation of cyclopropylamines depends on the structure of the amine. The 4-phenyl-l,2-dihydro-l,2,4-triazole-3,5-dione adduct 1 of 7-benzyl-7-azatricyclo-[4.3.1.0 ]deca-2,4-diene reacted with 3-chloroperoxybenzoic acid to give the corresponding A -oxide 2 in 93 /o yield. Analogously, the sulfinyl A-oxide of tra i-2-(4-chlorophenylsul-fanyl)-Af,A,3,3-tetramethylcyclopropylamine was formed with two equivalents of 3-chloro-peroxybenzoic acid when one equivalent was used only sulfur oxidation to the corresponding sulfinyl derivative occurred. Treatment of cyclopropylamine with hydrogen peroxide in the presence of sodium tungstate, on the other hand, afforded azoxycyclopropane in 50 /o yield." ... 

Information in support of this hypothesis has been obtained in detailed studies on the inactivation kinetics and mechanism of pig and beef liver MAO-A by A -cyclopropyl-A-arylalkylamines. The structures and some kinetic properties of this second group of MAO inhibitors are summarized in Table III. The inactivation characteristics of the A/-cyclopropylamines are generally similar to those of the propargylamines (1) time-dependent, first-order loss of enzyme activity, saturation kinetics, and protection from inactivation by substrate or product (2) pH-dependent rate of inactivation corresponding to the pH dependence of enzyme activity (3) little activity recovery after exhaustive dialysis (4) partitioning between normal product formation and inactivation and (5) time-dependent conversion of the covalently bound FAD cofactor from the oxidized to a reduced form, which is fairly resistant to reoxidation. An important differ-... 

Watanabe et al. (134) and Miwa et al. (135) have suggested a single-electron transfer mechanism for the enzymic N-demethylation reaction based on the small kinetic isotope effect, since the deprotonation of the a-hydrogen of the aminium radicals prepared by several means is known to proceed with smaller values (134, 135). The oxidation of cyclopropylamine by P-450 has been shown to afford products believed to be derived from the aminium radical intermediate... 

Scheme XXIV. Proposed oxidation mechanism for cyclopropylamine by P-4S0.

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