Preparation Of A Chiral Cyclopropan Biology Essay

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Mycolic acid is already vital laboratory chemical substance, with the most common is being the well-synthesis; It has the advantage of a simple structure that with a slight variation of component proportions and compounds show a great range of advantages. This versatility means that the mycolic acid has a place in the commercial world as well as the laboratory, by treatment different kinds of diseases. 21

The incidence of mycolic acids in the cell cover of pathogenic Mycobacterium tuberculosis is thought to be responsible for the abnormal resistance of TB to antibiotics and chemotherapeutic treatments. In order to determine their precise structure and natural stereochemistry and also to identify whether the specific structure has any effect on biological properties, the preparation of the synthetic analogues is required. 21

It is known that glycerol esters of complex mixtures of natural mycolic acids that are components of biological cells have potent effects in the immune system. This project will seek to prepare glycerol esters of single synthetic mycolic acids and to study structure-activity effects that maximise the beneficial properties of these compounds in controlling diseases of the immune system. The aim is being able to distinguish which specific of these synthetic components produce noticeable beneficial effects with the minimal side effects and to synthesis of the mycolic acids by coupling a different units to simple model acids. 21

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References 22

Area of Study

Mycolic acids are significant components of the cell walls of M.tuberculosis.1 They are thought to contribute to the special hydrophobic structure of the cell envelope of M. tuberculosis which is responsible for the characteristic resistance of mycobacteria to most antibiotics and chemotherapeutic agents. Because the cell wall resists degradation by impeding drug entry it prevents effective treatment of the disease.2 Investigations have also revealed that mycolic acid moieties are antigens to TB antibodies.3 The mycolic acids have good potential for serodiagnosis of TB and related disease. 4 This was reflected by the existence of a high quantity of antibodies in the sera of individuals infected with active TB. Under these circumstances, mycolic acids could be potential agents for TB diagnosis. The chemical pathways involved in the preparation of synthetic mycolic acids, would help to identify the exact structure, establish the stereochemistry and facilitate the understanding of the chemical and physical properties of natural mycolic acids. The biosynthesis could also expose methods to inhibit or alter the formation of mycolic acids in the cell wall which could lead to changes that would destroy the mycobacterial cell. In addition, the antigenic properties for targeting and producing antibodies would be better understood and could offer avenues for improved methods of TB detection and treatment such as the manufacture of mycolic acid based sensors.

Hypothesis

1-A simple cyclopropane can be used as a starting material, which will result in the synthesis of mycolic acids.

2-Glycerol esters of complex mixtures of single synthetic mycolic acids have strong effects in the immune system.

3-The synthesis of the mycolic acids will result in a fuller knowledge of the immune system.

Introduction

Mycolic acids

Mycolic acids are long chain α-alkyl, β-hydroxylated fatty acids, and mycolic acids are now known to be characteristic of all mycobacteria, however, the mycolic acids present in the cell envelope of different mycobacteria vary in the number and the functional groups present in the molecules. The incidence of mycolic acids in the cell wall play a major component of the cell wall of mycolata species also give mycolata a individual nasty morphological quality known as "cording."

It is thought that mycolic acids, which are major constituents of the M. tuberculosis cell envelope, as well as other cell wall-associated lipids, contribute to determine the virulence of a given strain. However, endogenous receptors for mycolic acids on susceptible cells exposed to mycobacterial infections had not been fully identified. In Lit. review showed that galectin-3, a multifunctional ß-galactoside binding lectin presented mainly in the cytoplasm of inflammatory cells and also accessible on the cell surface, and identified mycobacterial mycolic acids. The role of MA was reserved the lectin self-association but not its carbohydrate-binding abilities and selectively interfere in the interaction of the lectin with its receptors, so mycolic acids take part in their interaction with host cells.5

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There are many practical reasons for the synthesis of mycolic acids. A single synthetic enantiomer of mycolic acids may help in understanding the physical and chemical properties of natural mycolic acids. The synthesis of these compounds is important for the identification of the exact structure of natural mycolic acids. In particular, the arrangement of the different chiral centres present in the meromycolate chain could be exposed through comparison between the natural compounds or their derivatives with the synthetic analogues. Additionally, through a more accurate analysis of the stereochemistry of the chiral centres present in the meromycolate chain.

Meromycolic acid was first synthesised by Gensler as depicted in Figure 1 as a mixture of four stereoisomers containing two cis-cyclopropane rings.6

Figure 1: The first synthesis meromycolic acid

Mycolic acid Structures

There are two moieties in each mycolic acid. The main branch is called the meromycolate moiety, while the other branch is called the mycolic motif which has distal position and the proximal position.

These two positions contain different functional groups such as a methoxy group, cyclopropanes, double bonds, epoxy, carbonyl, carboxyl or a methyl group

The mycolic acids produced by M. tuberculosis are composed of five principal types, as illustrated in Figure 2 each type having a range of homologues with different chain lengths.

They are comprised of three principal classes, α-, methoxy- and keto-, which can be separated.7

Figure 2: Essential structures of the main components of the five main homologous series of mycolic acids from M. tuberculosis.

Pulmonary Tuberculosis

Tuberculosis kills some three million people each year and accounts for about 25% of preventable deaths. It has been estimated that between a quarter and a half of the world population is infected with the organism. South Africa currently has the highest per capita rate of TB in the world. In 2007 alone 112,000 people died of TB in South Africa, of whom 94,000 were co-infected with HIV. HIV/AIDS continues to increase the tuberculosis epidemic, mainly in Africa. Furthermore, other risk factors and essential common determinants help to preserve tuberculosis in the public.8

Furthermore, one of the biggest challenges facing clinicians is the time it takes to accurately diagnose TB. Currently, using the conventional methods, it takes on average 4 weeks to diagnose TB, which leads to a delay in the treatment of the disease. Two thirds of TB deaths could be prohibited by early diagnosis. With fast diagnosis patients could be put on anti-TB therapy immediately and become non-infective within a few days. With the current methods of diagnosis, patients with persistent symptoms have to remain in quarantine for several weeks while awaiting the results.

Mycolic acids and the cell wall

On the other hand the effect of mycolic acid (MA), the most abundant mycobacterial cell wall lipid, on the surface activity of phospholipid mixtures from lung surfactant was investigated using Langmuir monolayers and atomic force microscopy (AFM). In the presence of mycolic acid, all the surfactant lipid mixtures attained high minimum surface tensions (between 20 and 40 mN/m) and decreased surface compressibility moduli <50 mN/m. AFM images as depicted in Figure 4 showed that the smooth surface topography of surfactant lipid monolayers was altered with addition of MA.

Aggregates with various heights of at least two layer thicknesses were found in the presence of mycolic acid. The level of the effect of mycolic acid depended on the original state of the monolayer, with fluid films of DPPC-POPC and DPPC-CHOL being least affected as depicted in Figure 3. The results imply inhibitory effects of mycolic acid toward lung surfactant lipids and could be a mechanism of lung surfactant dysfunction in pulmonary tuberculosis.9

Figure 3: Inhibition of DPPC surface activity by mycolic acid in the presence of other lung surfactant lipids: effect on minimum surface tension. CHOL = cholesterol, POPC = palmitoyloleoylphosphatidylcholine,PE = phosphatidylethanolamine, PA = palmitic acid, MA = mycolic acid.9

Figure 4: AFM images of surface topography and line section analysis of DPPC films and DPPC + MA films.9

In addition, another paper described three kinds of mycolic acids (MAs) (α-, keto and methoxy-MAs) extracted from some species of mycobacteria in the research of monolayer films on water, and the surface pressure-area (p-A) isotherms diagram of the monolayers were compared, as a result the monolayer characteristics of the MAs exposed, since the monolayer molecular aggregation was related to drug permeability via molecular packing. It was accepted that the limiting molecular areas of the isotherms distorted only a little, which reflected the minor difference in chemical structure and conformation of the mycobacteria.10

Biosynthesis of mycolic acids

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Experimental observations, accumulated during few decades, have certified an overall scheme for the biosynthesis of the mycolic acids, which are very long chain fatty acids of Mycobacteria,. But, in almost every step, several hypotheses were compatible with the experimental results, leading to variations of the overall scheme. The aim of this review is to point to some additional possibilities.

It is generally assumed that the classical elongation process of fatty acid synthesis produced two long chains, the condensation of which led to the direct precursors of mycolic acids. But three condensations of four fatty acids, usually synthesized by Mycobacteria, was another hypothesis that could be considered. In the first hypothesis, some methyl or methylene substituents or oxygenated functions were added to the double bonds of an unsaturated precursor, whereas in the second hypothesis, the methylations could assist in the construction of very long aliphatic chains, and determined the location of double bonds or ramifications. The hypothetical coexistence of two pathways for mycolate biosynthesis was also discussed. 11

All chemical biology genetics showed that mycolic acid methyltransferases are essential for the viability of M. tuberculosis cell wall structure and intrinsic resistance to antibiotics. The tool compound dioctylamine as depicted in Figure 5 which inhibited the function of multiple mycolic acid methyltransferases, resulted in loss of cyclopropanation, cell death, and loss of acid fastness. These results revealed that mycolic acid methyltransferases were a promising antibiotic target and that a family of virulence factors can be chemically inhibited with effects not expected from studies of each individual enzyme.4

Figure 5: Structures of M. Tuberculosis in Complex with Dioctylamine.4

A gene encoding a reductase resulted in the biosynthesis of a mycolic acid without affecting cell viability. The precursors could not be isolated directly due to their inherent instability during base treatment; their presence was established by prior reduction of the ß-oxo group by sodium borohydride. Interestingly, the transformed parts also accumulated unsaturated ketones, similar to tuberculenone from M. tuberculosis, which were shunt products derived from spontaneous decarboxylation of α-alkyl, ß-oxo fatty acid precursors of mycolic acids.12

Effect of different diseases on the immune system

Mycobacteria were resistant to many common antibiotics, chemotherapeutic agents and disinfectants. This conflict was partly because the cell wall, containing a complex heteropolymer involving a series of esters of very long chain 'mycolic acids', is particularly resistant. The wall was probably caused by a parallel coalition of mycolic acids in the inner leaflet. This changes membrane permeability and hence resistance to a therapeutic agent occurred due to the balance of the structures of the mycobacterial species.13

A colonial morphology of pathogenic bacteria is often diseases for cording These morphologies often expose slight bioassociated with virulence.14

While for the treatment of asthma, the mycolic acid motif is common to MAs from all mycobacteria which have an R, R configuration. These complex waxes are recognized by antibodies and therefore showed potential for use in TB therapy and new diagnostic techniques such as biosensor assays. In addition, they have been shown to re-programme the macrophages to promote a telerogenic response in experimental asthma and are being explored for their potential in the prevention and treatment of asthma.15

The immune system

A system of biological structures and processes within an organism protects against disease, by identifying and killing pathogens and cells. It detects a wide immunity and creates immunological memory. Detection is difficult as pathogens can evolve rapidly; producing adaptations that keep away from the immune system and allow the pathogens to effectively contaminate their hosts as depicted in Figure 6.

Figure 6: The effect of low immune system.

Information of the rules and importance of lipid immunogenicity is also accumulating. This knowledge has been facilitated by the integrated exploitation of many different approaches, including biochemistry, cellular and molecular biology, immunology and clinical medicine. Unexpected novel discoveries on the importance and immunological functions of lipids are foreseen in the near future, driven by the increasing number of studies employing new approaches in an integrated manner. Several issues remain to be investigated, including those addressing the impact of lipid metabolism on immune-mediated diseases, the immunological function of intracellular organelles where lipid synthesis and catabolism occur, and the correlations of lipid trafficking and immunogenicity.

Lipids acting as antigenic molecules ; therefore, they are vital in the immunotherapy by controlling the autoimmune diseases and anti-tumor immune responses. after all, the antigenicity of microbial-derived lipids and the confirmation of the protective role of lipidspecific T cells during infections may suggest the chance for the development of novel subunit vaccines.16

8Lipid antigenicity is determined by their mode of uptake, membrane trafficking properties, degradation within endosomal compartments and capacity to form stable complexes with CD1.

Extracellular and intracellular lipid binding proteins participate in lipid handling and loading on CD1 molecules within antigen-presenting cells.so that lipid-specific T cells are important in autoimmunity, cancer surveillance, and safety during infections, The immunogenicity of lipids is being exploited in novel approaches to immunotherapy, including inhibition of autoimmunity and anti-cancer and bacterial vaccines.16

TB Diagnosis

The anti-cord factor IgG antibody can recognize the mycolic acid subclasses. The practical part involved the immunization of Rabbits with two kinds of cord factors isolated from Mycobacterium tuberculosis or Mycobacterium avium and the reactivates of the sera were tested against cord factors or the component mycolic acid methyl esters by ELISA. The serum from rabbits immunized with the M. tuberculosis cord factor was highly reactive against M. tuberculosis cord factor. On the other hand it was less reactive against M. avium cord factor. In contrast, the serum from rabbits immunized with M. avium cord factor was highly reactive against M. avium cord factor but less reactive against M. tuberculosis cord factor.

In addition, the serum from rabbits immunized with M. tuberculosis cord factor reacted against mycolic acid methyl esters, especially the methoxy mycolic acid methyl ester. While the serum from rabbits immunized with M. tuberculosis cord factor was less reactive against trehalose-6-monomycolate and not reactive against sulfolipid (2,3,6,6P-tetraacyl trehalose 2P- sulfate).

After all, it was concluded that the anti-cord factor IgG antibody, formed experimentally in rabbits, showed differences in the cord factor structures, i.e. the hydrophobic moiety rather than the carbohydrate moiety.17

Cell wall mycolic acids (MA) from Mycobacterium tuberculosis were presented antigens that used to detect antibodies as surrogate markers of active TB, even in HIV co-infected patients. The use of the complex mixtures of natural MA was complicated by apparent antibody cross-reactivity with cholesterol. The first three recombinant monoclonal antibody fragments in the chicken germ-line antibody were described the possibilities for cross-reactivity: the first recognized both cholesterol and mycolic acids, the second for mycolic acids alone, and the third cholesterol alone .

For TB patients, Mycolic acid structure was experimentally interrogated understanding the cross-reactivity; Therefore, A unique synthetic mycolic acids representative of the three main functional classes showed varying antigenicity against human TB patient sera, depending on the functional groups present and on their stereochemistry. Oxygenated (methoxy- and keto-) mycolic acids are found to be more antigenic than alpha-mycolic acids. Synthetic methoxy-mycolic acids were the most antigenic. Trans-cyclopropane-containing keto- and hydroxy-mycolic acids were also found the most antigenic among each of these classes. However, none of the individual synthetic mycolic acids significantly and reproducibly distinguished the pooled serum of TB positive patients from that of TB negative patients better than the natural mixture of MA.18

The low accuracy in the serodiagnosis of TB depend on cholesterol and mycolic acids ;Therefore, the patient sera cross-linked with mycolic acids and cholesterol in an ELISA experiment

The interaction of mycolic acids with Amphotericin B (AmB), is a known binding agent to ergosterol and cholesterol In addition, a specific attraction was observed between mycolic acid and cholesterol by the gathering of cholesterol from liposomes in suspension onto immobilized mycolic acids containing liposomes which was detected by biosensor technique as a result mycolic acids presumed as a three-dimensional conformation similar to a sterol, and had a hydrophobic surface topology similar that of cholesterol. 19

Mycobacterium tuberculosis is the causative agent of tuberculosis and its pathogenicity depends on the presence of a number of very unusual lipid molecules. Triacylglycerol (TAG) and wax ester (WE) biosyntheses in prokaryotes and the key enzymes involved therein differ fundamentally from the situation of storage lipid synthesis in eukaryotes. These lipids are accumulated as depots of energy and carbon for actively growing cells as well as a measure to remove free fatty acids, since the latter are considered to be potentially membrane damaging. Thus, their incorporation into non-toxic storage compounds enables the cells to protect themselves from high-cellular concentrations of these molecules.20

Several approaches were usually applied to stabilize liposomes. These include, among others, grafting of hydrophilic polymers like polyethyleneglycol to the head groups of the lipids and bilayer modification by the introduction of lipids with a higher tendency to interact with the surrounding aqueous medium. mycobacterial lipid monomycoloyl glycerol (MMG), referred to as MMG-1, was combined with the cationic surfactant dimethyldioctadecylammonium (DDA). to supply a thorough pharmaceutical characterization of the resulting DDA/MMG-1 binary system and to calculate how incorporation of MMG-1 affected the adjuvant activity of DDA liposomes. Thermal analyses confirmed that MMG-1 was included into the DDA lipid bilayers, and cryo-transmission electron microscopy (TEM) confirmed that liposomes were formed.21

A precise attraction was practical between mycolic acid and cholesterol by the gathering of cholesterol from liposomes in suspension onto immobilized mycolic acids containing liposomes, detected with a biosensor technique. The mycolic acids assumed a three-dimensional conformation similar to a sterol; therefore, it exposed its hydroxyl group and assumed rigidity in its chain structure to generate a hydrophobic surface topology matching that of cholesterol. A particular folded conformation required which was a few different types had already been proven to exist in monolayers of mycolic acids. So the previous reports reported that an interaction between cholesterol and mycolic acids was responsible for the low accuracy in the serodiagnosis of TB,3 as depicted in Figure 7.

Figure 7: Molecules under investigation for their similarity in function.

Glycerol Ester of fatty Acids

There are esters of fatty acids and glycerol or polyglycerol and their derivatives. Glycerol Esters of Fatty Acids include glycerol fatty acid ester, glycerol acetic acid fatty acid ester, glycerol lactic acid fatty acid ester, glycerol citric acid fatty acid ester, glycerol succinic acid fatty acid ester, glycerol diacetyl tartaric acid fatty acid ester, glycerol acetic acid ester, polyglycerol fatty acid ester, and polyglycerol condensed ricinoleic acid ester. These Glycerol Esters of Fatty Acids occur as colorless to brown powders, flakes, coarse powders, or granular or waxy lumps, or are colorless to brown semi-fluids or liquids. STRUCTURE REFERENCES??

Mycobacterial cell envelopes are known to contain a range of characteristic antigenic glycolipids. DO THESE INCLUDE MYCOLIC ACID GLYCEROL ESTERS?

Glycerol esters of complex mixtures of natural mycolic acids have strong effects in the immune system and the synthesis esters of single synthetic mycolic acids will result in a rich knowledge of the nature of the cell wall of Mycobacterium tuberculosis and hence give a better understanding of their effects in the immune system.

Synthetic mycolic acids

The first synthesis of a single enantiomer of an analogue of meromycolic acid was reported by Al Dulayymi et al.22 This involved the preparation of single enantiomers of cyclopropane building blocks followed by the coupling of these units. The aldehyde X was prepared from the anhydride of cyclopropane-cis-1, 2-dicarboxylic acid, then a Wittig reaction of this with nonadecyltriphenylphosphonium bromide and n-butyl lithium, followed by reduction with lithium aluminium hydride, led to the alcohol as mixture of Z- and E-isomers Y. The next step was saturation of the alkene with di-imide, prepared in situ by reaction between hydrazine, sodium periodate and acetic acid, and oxidation of the alcohol led to the aldehyde X.

Another synthesis of a single enantiomer of an α-methyl-trans-cyclopropane unit present in a number of mycolic acids and its incorporation into a reported 1,2-dialkylcyclopropane meromycolate that contains one cis-1,2-dialkylcyclopropane and one α-methyltrans- 1,2-dialkylcyclopropane has also been reported.23

Three stereoisomers of a wax ester meromycolate have been prepared starting from mannitol. A detailed comparison of their NMR spectra with those reported for a homologous series of natural wax esters confirmed the relative configurations of the α-methyl group and adjacent trans-cyclopropane. Mycolic acids are major constituents of the cell envelope of Mycobacterium tuberculosis; Therefore, the synthesis of three stereoisomers of a major homologue of the methoxymycolic acids current in Mycobacterium tuberculosis. 24

Synthetic mycolic acids matching the overall structure of the major α- and methoxy-mycolic acids of Mycobacterium tuberculosis were coupled to trehalose to generate the corresponding synthetic trehalose dimycolate (TDM; cord factor) and trehalose monomycolate (TMM). Mycobacteria are unusual in that they contain extremely long chain ß-hydroxy acids, the mycolic acids (MAs) were current in a membrane-bound form, but also as sugar esters including trehalose- 6,6-dimycolates (TDMs, 'cord factors') and trehalose monomycolates (TMMs).25

On the other hand the synthesis of single enantiomers of two epoxy-mycolic acids containing an α-methyl-trans alkene. The two stereocentres at the end ß-positions relative to the carboxylic group had both been found to be in the R-configuration for all the mycolic acids examined Mycolic acids (MAs) were the major constituents of the cell envelope of Mycobacterium tuberculosis and other mycobacteria.26 These were pathogenic to animals and humans. Their existence was thought to be linked to the resistance of these organisms to most current antibiotics and other chemotherapeutic agents.1

While the synthesis of (11R,12S)-lactobacillic acid and its enantiomer from 2,3-O-isopropylidene-D-glyceraldehyde, in a sequence involving asymmetric cyclopropanation, and from cis-cyclopropane-1,2-dimethanol, using enzymatic desymmetrisation. The important step in the former route was the stereochemically controlled cyclopropanation of (1Z,4_S)-(2_,2_-dimethyl-1_,3_-dioxolan-4_-yl)-1-octene via a Simmons-Smith type reaction, using diethylzinc and chloroiodomethane. This product was converted into the key intermediate (1R,2S)-1-formyl-2-hexylcyclopropane, which was also obtained by a known sequence from the (1R,2S)-monobutyrate ester of cis-cyclopropane-1,2-dimethanol. This central aldehyde was converted into (11R,12S)-lactobacillic acid. Using analogous chemistry, the (11S,12R)-enantiomer of lactobacillic acid was prepared from 2,3-O-isopropylidene-D-glyceraldehyde or from the (1S,R)-monobutyrate ester of cis-cyclopropane-1,2-dimethanol.27

In inhibition line, cyclopropene fatty acid esters synthesised as potential structure-based inhibitors.28 Another kind of inhibition or stimulation of mycolic acid synthesis. Minor inhibition (2- %) was shown by the 23- and 24-carbon saturated esters A carbon chain with 23-26- length range of_-19 (1_R,2_S) cyclopropane fatty acids, related to mycobacterial mycolic acids, had been prepared. The key cyclopropyl intermediate, (1_R, 2_S)-(Z)-1-formyl-2-octadecylcyclopropane, underwent a Wittig reaction with various reagents to provide vinylic precursors, which were selectively reduced to the corresponding saturated _-19 cyclopropane fatty acids or esters. The 24-carbon _-19 cyclopropane ester was made by chain elongation of the 23-carbon ester. Saturated and unsaturated chiral cyclopropane acids and esters were assayed, using wall extracts of Mycobacterium smegmatis.29

Furthermore, a new biomimetic approach for the stereoselective synthesis of the (R,R)-ß-hydroxy-α-alkyl fatty acid fragment of mycolic acids, via an asymmetric anti-aldol reaction was described by the illustration of the mycolic acid motif fragment was prepared in three steps for the synthesis of a mycolic acid motif with a 22 or 24 carbon α-alkyl chain and a ß-hydroxy group, and a mero-mycolate chain with variable functional groups as depicted in Figure 8.30

Figure 8: Synthesis of chiral esters 3a and 3b and subsequent anti-aldol reaction with various aldehydes. Reagents and conditions: (i) EDCI, DMAP, CH2Cl2 (3a = 89%, 3b = 91%); (ii) LDA, Cp2ZrCl2, THF, _78 _C; (iii) Na(s), MeOH (70%).

Also the Lit. Review showed us that the first synthesis of single enantiomers of two protected ketomycolic acids, one containing a cis-cyclopropane the other an α-methyl-trans-cyclopropane, and of related hydroxy-mycolic acids.31, while the synthesis of single enantiomers of mycobacterial ketomycolic acids containing cis-cyclopropanes which contain three stereoisomers of the cis-ketomycolic acid, having chain lengths matching those of a significant component in many mycobacteria, and the deprotection of one of these to give a single enantiomer of free mycolic acid with S-stereochemistry adjacent to the ketone.32

On the other hand the synthesis of the single enantiomers of hydroxy and ketomycolic acids containing an α-methyl-trans alkene unit containing mycolic acids.33

A characteristic profile of mycolic acids from M. Tuberculosis are reflecting contributions from five major distinct homologous series of mycolate structural types. Diagnosis of tuberculosis in archaeological material, using mycolic acid biomarkers, depended on objective recognition of the key characteristic mycolic acid components. An article claimed that tuberculosis could be confirmed in ancient bones by high product mass spectrometric analysis of mycolic acids. The analysis of the data presented reveals no influential evidence for the presence of mycolic acids, characteristic of the M. tuberculosis complex, in the skeletal remains examined. This communication showed the essential criteria necessary for positive tuberculosis diagnosis, using mycolic acids. 7

While Figure 9 showed the synthesis of (2R,3R,Z)-2-docosyl-3-hydroxytetracont-21-enoic acid, a significant __-mycolic acid of Mycobacterium segment and other mycobacteria.34

Figure 9: characteristic components of mycobacteria.

A cyclopropane obtaining fatty acid found in cascarilla essential oil; therefore a study was regarded the absolute stereochemistry of cascarillic acid. acetic acid of ((1S,2R)-2-Hexylcycloprop-1-yl) had been synthesised from cis-1,2-dihydroxymethylcyclopropane and shown to be identical to cascarillic acid obtained from cascarilla vital oil.35

In addition there was a synthesis of Tuberculostearic acid (10R-methyloctadecanoic acid) and its 10S-enantiomer were synthesised by a chiral pool strategy, in four steps from citronellyl bromide.36

While an approach to synthesie a ß-hydroxy-α-alkyl fatty acid intermediate has been applied in the synthesis of range of mycolic acids, their incidence was thought to be linked to the characteristic resistance of these organisms to most current antibiotics and other chemotherapeutic agents, and the finding of that was in every mycolic acid two moieties can be distinguished: the meromycolate and the mycolic motif.37

Conclusion

Mycolic acid is already vital laboratory chemical substance, with the most common is being the well-synthesis; It has the advantage of a simple structure that with a slight variation of component proportions and compounds show a great range of advantages. This versatility means that the mycolic acid has a place in the commercial world as well as the laboratory, by treatment different kinds of diseases.

The incidence of mycolic acids in the cell cover of pathogenic Mycobacterium tuberculosis is thought to be responsible for the abnormal resistance of TB to antibiotics and chemotherapeutic treatments. In order to determine their precise structure and natural stereochemistry and also to identify whether the specific structure has any effect on biological properties, the preparation of the synthetic analogues is required.

It is known that glycerol esters of complex mixtures of natural mycolic acids that are components of biological cells have potent effects in the immune system. This project will seek to prepare glycerol esters of single synthetic mycolic acids and to study structure-activity effects that maximise the beneficial properties of these compounds in controlling diseases of the immune system. The aim is being able to distinguish which specific of these synthetic components produce noticeable beneficial effects with the minimal side effects and to synthesis of the mycolic acids by coupling a different units to simple model acids.

While my project is about the idea of a simple cyclopropane can be used as a starting material, which will result in the synthesis of mycolic acids, therefore; Glycerol ester of complex mixtures of single synthetic mucolic acids have strong effects in the immune system and the synthesis of the mycolic acids will result in a fuller knowledge of the nature of the cell wall of Mycobacterium tuberculosis and hence boost the wall enveloping of immune system.