Introduction
1-Aminocyclopropanecarboxylic acid 5 (ACC) is a disubstituted cyclic α-amino acid in which a cyclopropane ring is fused to the Cα atom of the amino acid. It is a white solid. Many cyclopropane-substituted amino acids are known, but this one occurs naturally.[2][verification needed] Like glycine, but unlike most α-amino acids, ACC is not chiral.
Abstract
The derivatives of 1-Aminocyclopropanecarboxylic acid 5 ACC) over recent decades have attracted close attention from synthetic chemists owing to their high physiological activity as plant growth regulators, conformationally rigid analogs of natural amino acids, and peptidomimetics. The present review considers contemporary approaches to the methods of preparation of amino acids of the ACC series, namely, the alkylation of glycine equivalents with 1,2-electrophiles, the intramolecular cyclization of γ-substituted amino acid derivatives, alkene cyclopropanation under the action of diazo compounds, ylides, and carbene intermediates, as well as other synthetic approaches.
1. Biochemistry
1-Aminocyclopropanecarboxylic acid 5 is the precursor to the plant hormone ethylene.[3][4] It is synthesized by the enzyme ACC synthase (EC 4.4.1.14) from methionine and converted to ethylene by 1-Aminocyclopropanecarboxylic acid 5 oxidase (EC 1.14.17.4).[5]
ACC also exhibits ethylene-independent signaling that plays a critical role in pollination and seed production by activating proteins similar to those involved in nervous system responses in humans and animals.
More specifically, 1-Aminocyclopropanecarboxylic acid 5 signaling promotes secretion of the pollen tube chemoattractant LURE1.2 in ovular sporophytic tissue thus enhancing pollen tube attraction. Additionally, ACC activates Ca2+-containing ion currents via glutamate receptor-like (GLR) channels in root protoplasts.[6]
ACC can be used by soil microorganisms (both bacteria and fungi) as a source of nitrogen and carbon.[7] As such, using ACC to incubate soils has been proven to induce the gene abundance encoding ACC-deaminases, which may have positive consequences on plant growth and stress tolerance.[7][8]
2. Ring-opening, cycloaddition and rearrangement reactions of nitrogen-substituted cyclopropane derivatives
Aminocyclopropanes are easily oxidised to radical cation species (Scheme 1, equation 3). This triggers cleavage of the cyclopropane ring and the formation of a distonic cation radical. Theoretical calculations and experimental studies involving mass spectrometry and ESR spectroscopy suggest that this elementary step is extremely fast and essentially barrier-free.75–77 However, in the special case of cation radicals generated from N-aryl aminocyclopropanes, the ring cleavage appears to be much slower: using electrochemical studies conducted with N-cyclopropyl-N-methylaniline, the ring opening rate constant has been estimated to be 4.1×104 s−1.78
This process, single electron oxidation followed by ring cleavage, is of high biological significance. For instance, ethylene, which plays a major role as a phytohormone, is produced in plants from 1-aminocyclopropanecarboxylic acid (ACC). This transformation is catalysed by the enzyme 1-Aminocyclopropanecarboxylic acid 5 oxidase, with a mechanism thought to proceed by oxidation of ACC to generate a cation radical.79–81 trans-2-Phenylcyclopropylamine, the antidepressant drug known as tranylcypromine, is a suicide inhibitor of several other oxidative enzymes such as monoamine oxidases A and B (MAO A and MAO B),41,82–84 horseradish peroxidase (HRP),85–87 Caldariomyces fumago chloroperoxidase (CPO)88 and histone demethylases LSD1 and LSD2.41,89–92 The mechanism of action of tranylcypromine, as well as of a range of other active.
1. 2.4.2 Formal [3+2] cyclisation with alkenes and alkynes
The groups of Iwata and Cha independently developed intramolecular [3+2] cyclisations with alkenes according to the concept depicted in Scheme 23 (top).103,104 Examples are presented in Table 6. Using several equivalents of ceric ammonium nitrate (CAN), the final cyclised nitrogen-centred cation radical loses a proton,
And the resulting α-amino radical is oxidised again, resulting in eventual dealkylation (entries 1–6). Cha et al. used 1,4-dicyanobenzene (DCB) under irradiation with a medium-pressure mercury lamp as the oxidising system (entries 7–10). In that case, the last cation radical intermediate is reduced by DCB•− to the final product. However, a drawback of this method is a problem of selectivity of the oxidation process with respect to the starting materials versus the products.
Therefore, the reactions have to be stopped before full conversion is reached. Experiments conducted with both diastereoisomers of the same compound give essentially the same result (entries 7 and 8), in agreement with the mechanism displayed in Scheme 23, where the same distonic radical cation is generated when the three-membered ring is cleaved. Good results can be obtained with electron-poor as well as with electron-rich alkenes (for instance entry 1 vs entry 4), which can be attributed to the intramolecular nature of the nucleophilic radical attack. It is worthy of note that the method is also applicable to alkyne substrates (entry 5).
2. 2.4.3 Formal [3+2] cyclisation with dioxygen
The first single electron oxidations of aminocyclopropanes conducted in the presence of oxygen to form 1,2-dioxolane species, as formulated in Scheme 23 (bottom), were reported as early as in 1975 by Japanese scientists.109 Catalytic amounts of cobalt- or copper halides like CuCl2 were found to mediate these reactions.
With the substrates under study and under the conditions used, involving reaction times of several hours, the expected unstable peroxides were not actually observed but were proposed as likely intermediates in the formation of the only isolated products, bicyclic epoxides obtained in low yields (18–28%). Recently, another study established that N-arylcyclopropylamines are slowly converted, upon simple exposure to air, to amide oxidation products, the formation of which can also be explained from 1,2-dioxolane intermediates. Depending on the substrate substitution pattern, complete conversion typically takes several days or weeks and is accelerated by irradiation with a floodlight equipped with a 150 W lamp.110
3. 2.4.4 Other processes
Several interesting methods, also based on the generation of a distonic cation radical by single electron oxidation (Scheme 1, equation 3), involve transformations that do not eventually lead to cyclisation onto the iminium function. In these reactions, final hydrolysis typically leads to the loss of the nitrogen-containing substituent initially attached to the cyclopropane ring.
An early application was reported by Cha et al. consisting of the conversion of aminocyclopropanes like 49 into ring-opened ketones like 50 using 1,4-dicyanobenzene (DCB) under UV irradiation. The mechanism involves isomerisation of the cation radical 51 by 1,5-hydrogen transfer (SHi), followed by reduction into an azomethine ylid species 52 that is eventually hydrolysed to afford the products (Scheme 29).118 Inferior results are obtained using ceric ammonium nitrate (CAN) as the oxidising reagent: further oxidation of the intermediates tends to take place and mixtures of products are typically obtained.103 Using DCB/hν, aminocyclopropanes fitted with an alkene group are tolerated if the generated radical and the carbon-carbon double bond are separated by a long enough chain to avoid competitive cyclisation as in Table 6 (Scheme 29, bottom).104
4. 2.4.4 Other processes
Several interesting methods, also based on the generation of a distonic cation radical by single electron oxidation (Scheme 1, equation 3), involve transformations that do not eventually lead to cyclisation onto the iminium function. In these reactions, final hydrolysis typically leads to the loss of the nitrogen-containing substituent initially attached to the cyclopropane ring.
An early application was reported by Cha et al. consisting of the conversion of aminocyclopropanes like 49 into ring-opened ketones like 50 using 1,4-dicyanobenzene (DCB) under UV irradiation. The mechanism involves isomerisation of the cation radical 51 by 1,5-hydrogen transfer (SHi), followed by reduction into an azomethine ylid species 52 that is eventually hydrolysed to afford the products (Scheme 29).118
Inferior results are obtained using ceric ammonium nitrate (CAN) as the oxidising reagent: further oxidation of the intermediates tends to take place and mixtures of products are typically obtained.103 Using DCB/hν, aminocyclopropanes fitted with an alkene group are tolerated if the generated radical and the carbon-carbon double bond are separated by a long enough chain to avoid competitive cyclisation as in Table 6 (Scheme 29, bottom).104
3. Ring-opening, cycloaddition and rearrangement reactions of nitrogen-substituted cyclopropane derivatives
1. 2 Electron-rich compounds: cyclopropyl-amines, amides and carbamates
As mentioned in the introduction section, aminocyclopropanes, because of their ability to undergo protonation or reactions with electrophiles at a C’ alt=”single bond” v:shapes=”_x0000_i1027″> C bond adjacent to the nitrogen atom (Scheme 1, equations 1 and 2), have sometimes been called ‘homoenamine equivalents’.35,36 As amines, they are also susceptible to undergo single-electron oxidation at the lone pair of the nitrogen atom, which triggers cleavage of the cyclopropane ring (Scheme 1, equation 3). This behaviour is also consistent with a homologous enamine equivalent.
The corresponding amide and carbamate substrates are expected to exhibit similar properties, albeit with much reduced reactivity because of the important resonance effect between the lone pair of the nitrogen atom and the carbonyl group, which is a better π-acceptor than the cyclopropane ring.
2.1 Dihydrogenation
2.1.1 Transition-metal catalysed hydrogenation
The hydrogenolysis of aminocyclopropane derivatives to produce ring-opened products has been known at least since the early 1970s.35 This process is thermodynamically favourable and depending on the substrates, the removal of a protecting group under transition-metal catalysed hydrogenation conditions can therefore be accompanied by extensive cyclopropane-ring opening (Scheme 4).37–45 A number of examples can nonetheless be found in the literature, where the cyclopropane ring survives the removal of a protecting group under such conditions.13,16,46–52
2.1.2 Other processes
N-cyclopropyl -amines and -carboxylic amides can undergo formal dihydrogenation of the cyclopropane ring when treated with lithium aluminium hydride. These transformations are reviewed in paragraph 2.5.4 (Schemes 46 and 47)
2.2 Protonation
2.2.1 General considerations
As already mentioned in the introduction section, protonation at the β carbon, with cleavage of the C1′ alt=”single bond” v:shapes=”_x0000_i1026″> C2 bond, is favourable because the resulting cation is stabilised by resonance with the lone pair of the nitrogen atom (Scheme 1, equation 1). However, while cyclopropanols readily undergo ring cleavage under acidic conditions,56 aminocyclopropanes are much more resistant. Indeed, protonation preferentially takes place at the nitrogen atom to produce the corresponding ammonium salts 6 (Scheme 7, path a) and in the absence of additional activating functional groups, heating is necessary to trigger cyclopropane ring cleavage (Scheme 7, path b). From a mechanistic point of view, the protonation of cyclopropanes can occur according to an ‘edge’ or a ‘corner’ attack.57 To the best of our knowledge, this aspect has not been studied in this particular case.
2.2.2 Activation by Pd/C
In their impressive early study, Kuehne and King discovered that the ring-opening of bicyclic aminocyclopropanes can be accelerated significantly in the presence of palladium on charcoal or even, to a lesser extent, in the presence of activated charcoal. Thus, the α-substituted cyclic ketone products can be obtained at the reflux temperature of methanol (65 °C).35 In the absence of Pd/C, these hydrolysis reactions, that sometimes proceed with good regioselectivity with respect to the cyclopropane-ring opening, require more drastic conditions: typically, 150–170 °C in a sealed tube using the same solvent (Scheme 15).
2.2.3 Transformations based on the generation of iminium species
The formation of cyclic hemiaminal ethers 21, described by the group of I. G. Bolesov in 1974 (Scheme 17),68 constitutes an early illustration of a reaction following path c (Scheme 7): the intermediate iminium species are trapped in an intramolecular fashion by the hydroxyl group. As in the related transformations shown in Scheme 10, the introduction of a Brønsted acid catalyst is not necessary under the harsh protic conditions employed.
2.2.4 Transformations based on the generation of enamine intermediates
In 1973, Kuehne and King demonstrated that an aminocyclopropane can be isomerised into an enamine (Scheme 7, sequence of elementary steps b and d) and a new carbon-carbon bond created from this intermediate. Acrylonitrile was used as a Michael acceptor, leading to the formation of ketonitriles (Scheme 19).35.
4. 1-Aminocyclopropane 1-Carboxylic Acid and Its Emerging Role as an Ethylene-Independent Growth Regulator
1-Aminocyclopropane 1-carboxylic acid (ACC) is the direct precursor of the plant hormone ethylene. ACC is synthesized from S-adenosyl-L-methionine (SAM) by ACC synthases (ACSs) and subsequently oxidized to ethylene by ACC oxidases (ACOs). Exogenous ACC application has been used as a proxy for ethylene in numerous studies as it is readily converted by nearly all plant tissues to ethylene. However, in recent years, a growing body of evidence suggests that 1-Aminocyclopropanecarboxylic acid 5 plays a signaling role independent of the biosynthesis. In this review, we briefly summarize our current knowledge of ACC as an ethylene precursor, and present new findings with regards to the post-translational modifications of ACS proteins and to ACC transport. We also summarize the role of 1-Aminocyclopropanecarboxylic acid 5 in regulating plant
development, and its involvement in cell wall signaling, guard mother cell division, and pathogen virulence.
1-Aminocyclopropane 1-Carboxylic Acid as a Precursor of Ethylene
Four decades ago, 1-aminocyclopropane 1-carboxylic acid (ACC), a non-proteinogenic amino acid, was discovered to be an intermediate in the biosynthesis of the plant hormone ethylene (Adams and Yang, 1979). Ethylene regulates a wide range of developmental processes and responses to biotic and abiotic stresses, in part by complex interactions with other phytohormones (Muday et al., 2012; Vandenbussche et al., 2012;
Merchante et al., 2013; Dubois et al., 2018). Its biosynthesis starts with the conversion of the amino acid methionine to S-adenosyl L-methionine (SAM) by SAM synthetase and the subsequent conversion of SAM to ACC, which is catalyzed by ACC synthase (ACS) (Figure 1) (Adams and Yang, 1977; Adams and Yang, 1979). The by-product of this reaction, 5’-methylthioadenosine (MTA), is recycled back into the Yang cycle while ACC is oxidized to ethylene by ACC oxidase (ACO) (Murr and Yang, 1975). In Arabidopsis, ACO proteins are encoded by five genes (ACO1–5),
which belong to a superfamily of oxygenases/oxidases (Dong et al., 1992; Zhang et al., 2004). In general, ACS is the rate-limiting step in ethylene biosynthesis, though in some instances, ACO activity is limiting (Vriezen et al., 1999; Van de Poel et al., 2012). This topic, along with current knowledge on ACO phylogeny and their regulation and importance in agriculture, has been comprehensively discussed in a recent review (Houben and Van de Poel, 2019).
2. ACC Transport and LYSINE HISTIDINE TRANSPORTERS
Ethylene is involved in various stress-related responses such as wounding, pathogen infection, neighbor proximity, elevated temperatures, drought, soil waterlogging, and submergence (Vandenbussche et al., 2005; Sasidharan and Voesenek, 2015; Huang et al., 2016; Loreti et al., 2016; Valluru et al., 2016; Dubois et al., 2018). Following the demonstration that ethylene leads to epinasty of petioles in waterlogged tomato plants (Jackson and Campbell, 1975),
Bradford and Yang showed that waterlogging and root anoxia correlated with the shootward transport of ACC, its subsequent conversion to ethylene, and leaf epinasty (Bradford and Yang, 1980). This spatial separation between the biosynthesis of ACC and the its conversion to ethylene is the result of the oxygen dependence of the ACO enzyme (Murr and Yang, 1975). Multiple studies confirmed the phenomenon of ACC transport between roots and shoots in several plant species (e.g. Else and Jackson, 1998).
- ACC in Plant Development and Beyond
A growing body of evidence indicates a role for ACC as a signaling molecule distinct from its role in ethylene biosynthesis. One of the first findings consistent with this was the discovery of the involvement of 1-Aminocyclopropanecarboxylic acid 5 in the regulation of cell wall function in the FEI pathway (Xu et al., 2008) FEI1 and FEI2 are leucine-rich repeat receptor-like kinases (LRR-RLKs) that have been linked to cellulose biosynthesis. fei1 fei2 loss-of-function mutants display root swelling under high concentrations of salt and sucrose, decreased biosynthesis of cellulose, hypersensitivity to the cellulose inhibitor isoxaben, thickening of etiolated hypocotyls, and a decrease in the formation of cellulose rays in seed coat mucilage (Xu et al., 2008; Harpaz-Saad et al., 2011)
5. Biochemistry and Molecular Biology of Plant Hormones
Introduction: Nature, occurrence and functioning of plant hormones
1. What is a plant hormone?
Plant cells have a wealth of information stored in their genome, enough to specify all the proteins that will ever be made by that plant. But each cell uses only a small portion of that information at any one time. Cells can produce one set of proteins at one stage and some different ones at a later stage [1]. For each cell, some set of circumstances must specify which genes are going to be expressed and which will remain silent. Plant cells also have the capacity to carry out a wide variety of ..
2. The history of plant hormones
While it was clear in the 1870s that transportable chemical signals exist in plants, solid evidence for specific hormones required another half century. Fitting [12], who first introduced the term “hormone” into plant physiology, showed that orchid pollinia contain some factor that causes swelling of orchid ovaries. He was not, however, able to isolate or identify the substance. Then in 1926, Went isolated a substance from coleoptile tips which caused coleoptile cell elongation; he called this… Methods
How does one determine whether a particular compound is actually a plant hormone, or whether a particular process is controlled by that hormone? There is no single, simple procedure. One approach is to measure the amount of the putative hormone present in the tissue and then correlate it with the amount of response. For example, the close correlation between the ethylene level in melons and the fruit ripening implicates ethylene as a controlling hormone in this process [27]. Likewise, the…
3. The hormone groups
Since plant cells can be maintained for long periods in the apparent absence of all known plant hormones, it seems safe to conclude that no hormone is essential just to maintain the viability of plant cells. Some plant hormones seem to be needed for essential developmental processes, however, with the result that no plant can develop in their absence. The hormones auxin and cytokinin appear to fit this description. Both are present in all plants at all times, and in all the major organs [39].
6. Synthetic transformations mediated by the combination of titanium(IV) alkoxides and grignard reagents: selectivity issues and recent applications. Part 1: reactions of carbonyl derivatives and nitriles
Section snippets
1. The titanacyclopropane putative reactive intermediates
A common feature of the Kulinkovich-type reactions is the putative formation of titanium species A that can be viewed as the limiting structures, dialkoxytitanacyclopropane A1 and dialkoxy(η2-alkene)titanium complex A2. Two successive transmetallation reactions of the Grignard reagent would occur, first with Ti(Oi–Pr)4 (or ClTi(i-Pr)3) and then with the resulting alkyltitanium(IV) complex. Fast disproportionation would then lead to the formation of the active species A1/A2, along with an..
2. Principles
The carboxylic ester cyclopropanation process described by the group of Kulinkovich in 1989 is historically the first transformation to have been disclosed in the field covered by the present report.1 This reaction, now commonly referred to as the Kulinkovich reaction,42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53 has been initially performed in the presence of 1 equiv of titanium(IV) iso-propoxide and an excess (3 equiv) of ethylmagnesium bromide (Scheme 4). The proposal of the
3. Transformation of imides
Succinimide and glutarimide derivatives display interesting reactivity. Like esters and amides, they are transformed into oxatitanacyclopentane intermediates when treated with Grignard reagents in the presence of titanium(IV) alkoxides. These intermediates Q stem from the initial formation of a dialkoxytitanacyclopropane A (see Section 2 and Scheme 1), followed by 1,2-insertion of one of the imide carbonyl groups into the less substituted C–Ti bond of A (Eq. 2, Scheme 3). In contrast to the
4. Reactions of aldehydes
Aldehydes and ketones are among the most reactive functional groups in reactions mediated by Ti(IV) alkoxide/Grignard reagents. Little is known about the reactivity of aldehydes, but iso-butyraldehyde and benzaldehyde have been shown to undergo reduction to the corresponding primary alcohols when subjected to substoichiometric amounts of pre-formed titanacyclopropane 4 generated from Ti(Oi-Pr)4 and cyclo-pentylmagnesium chloride. In the case of iso-butyraldehyde, the Tishchenko reaction product
5. Transformation of imines
Similarly to ketones, aryl aldimines and ketimines react with diiso-propyloxytitanacyclopropanes following a ligand-exchange pathway (Eq. 4, Scheme 3). However, in contrast to the ketones, the azatitanacyclopropanes R thus formed are reasonably stable at low temperature (−40 °C).254 The chemistry of these complexes is reminiscent of that of the related diaryloxy(η2-imine) titanium255, 256 and (η2-imine)-Cp2Zr complexes,257, 258, 259 and they can be trapped with a variety of electrophilic
6. Transformation of nitriles
The nitrile group is one of the most reactive functions vis à vis dialkoxytitanacyclopropanes, reacting much faster than carboxylic amides and esters, and even alkyne and alkene groups (see Section 2).65, 70, 71, 73 A 1,2-insertion of the nitrile function into one of the C–Ti bonds of the titanacyclopropane partner usually operates (Eq. 3, Scheme 3). This is notably the case in the cyclopropanation process first reported in 2001 by Bertus and Szymoniak.270 A review article on this reaction has
7. Conclusions
The initial discovery by Kulinkovich has given birth to important new processes in synthetic organic chemistry. In particular, the cyclopropanation reactions of esters, amides and nitriles are methods of choice for the preparation of cyclopropanols and aminocyclopropanes, and have become increasing.