Biosynthetic intermediates, chemical syntheses

Deoxy-araWno-heptulosonic acid 7-phosphate (10) is a metabolic intermediate before shikimic acid in the biosynthetic pathway to aromatic amino-acids in bacteria and plants. While (10) is formed enzymically from erythrose 4-phosphate (11) and phosphoenol pyruvate, a one-step chemical synthesis from (11) and oxalacetate has now been published.36 The synthesis takes place at room temperature and neutral pH... 

Semisynthesis can be defined as the use of fragments of proteins, or intact proteins themselves, as ready-made intermediates in the chemical synthesis of proteins. Many modifications to the native structure of a protein can be expected to have profound effects, and produce materials of the greatest academic or practical value, but only involve a change of one or a few atoms out of the thousands that often go to make up the complete molecule. If a semisynthetic method can be found to incorporate, at the correct site, a small synthetic fragment carrying the wanted change, there is no need to go to the trouble of constructing the rest of the molecule when it has already been preformed for us biosynthetically. 

In recognition of the difficulty in obtaining the lipid intermediates in quantities to facilitate detailed mechanistic study of the peptidoglycan biosynthetic enzymes, we initiated an effort directed toward a chemical synthesis of both lipid I and lipid II. As was the case with the fermentation/isolation protocols, we anticipated several technical challenges that would need to be addressed in order to reach the target compounds. These challenges, and their solutions, will be discussed in the sections that follow. 

Even more sophisticated improvements may be possible (Figure 3B). For example, if a microbe produces a molecule E which is nematocidal, and the plant has the biosynthetic machinery to make a key intermediate of this molecule, C,then perhaps genes, coding for the enzymes necessary to complete the biosynthetic pathway, could be moved into the plant, causing the plant to produce its own nematocide. The result is literally chemical synthesis in living tissues. Plant genetic engineering could be competitive with the chemical pesticide business. 

In order to confirm the structures of solanapyrones, chemical synthesis of these phytotoxins were attempted based on biogenetic consideration [55], The retro synthesis envisaged intramolecular Diels-Alder reaction of the achiral polyketide triene (a), a key intermediate, which is further divided into a pyrone moiety (b) and a diene moiety (c). The moieties a and b were prepared from dehydroacetic acid and hexadienyl acetate, respectively. Aldol condensation of the aldehyde (72) with the dithioacetal (73) gave a dienol, which was further converted to a triene (74). The intramolecular Diels-Alder reaction of 74 in toluene at 170-190 °C for 1 hr in a sealed tube yielded a mixture of the adducts (75) and (76) in a ratio of 1 2. This product ratio depends on the solvents, i.e. in water (1 7), and should be useful in differentiating between artificial and enzymatic reactions in biosynthetic studies. Removal of the thioacetal groups in 75 and 76 yielded solanapyrone A (67) and D (70) in a ratio of 3 5. Though solanapyrone D (70) had not been isolated from the natural resources at this stage, the structure and stereochemistry were confirmed by H NMR spectrum. 

A mutant strain of Micromonospora purpurea synthesized gentamicin antibiotics on being fed with the inososes (505) and (506), which are presumably converted into streptamine and 2-deoxystreptamine, respectively, prior to incorporation into the intact antibiotics. A mutant strain of S.fradiae synthesized the pseudotrisaccharide ribostamycin (see Vol. 10, p. 131) instead of the pseudotetrasaccharide neomycin. After a second and reverse mutation, new colonies again synthesized neomycin, indicating that ribostamycin may be an intermediate along the biosynthetic pathway leading to neomycin. A chemical synthesis of neomycin C (507) from a derivative of ribostamycin is shown in Scheme 85. ... 

The mechanism of penicillin biosynthesis from the Arnstein tripeptide, 8-(L-a-aminoadipoyl)-L-cysteinyl-D-valine (ACV), has been extensively studied and reviewed by many chemists. Most of the biosynthetic mechanisms have been ascertained by Baldwin and Bradley using an excellent enzymatic technique.55 However, the first step in the biosynthesis of penicillin, conversion of the Arnstein tripeptide to a cis-P-lactam intermediate, is still a fascinating mechanistic problem. Although Baldwin et al. recently proposed a mechanism involving an iron-bound thioaldehyde formation route via a Pummerer-type cyclization, the intermediate for this mechanism has not been identified. The mechanism of selective formation of the cw-P-lactam ring is still also unknown (Fig. 39).56 These types of biomimetic reactions have been chemically studied. An example of an unsuccessful intramolecular Pummerer cyclization of the sulfoxide involving a cysteine moiety under standard Pummerer conditions was reported by Wolfe et al.57 Although Kaneko reported the conversion of the very simple 3-phenylsulfinyl propionamide into a P-lactam with TMSOTf/triethylamine,58 a successful biomimetic synthesis of... 

Since the initial disclosure of the basic corrin structure, there has been a considerable body of effort devoted toward the synthesis of macrocycles related to this chromophore that may be considered as being intermediates between porphyrin and corrin. These macrocycles, namely the dehydrocorrins (e.g., tetradehydrocor-rin 2.3) and the corroles (e.g., 2.4), represent interesting classes of contracted porphyrins that warrant specific mention here. The interest in these molecules derives in part from the fact that they could represent milestones along the biosynthetic pathway leading to vitamin B12. They are, however, also of interest from a non-biological perspective. Simply stated, this is because corrole-type macrocycles possess unique electronic and chemical characteristics, the study of which can help one to understand better the chemistry of all porphyrin analogs. 

The separation problems associated with the synthesis of pure enantiomers can often be circumvented by forming the material from optically pure intermediates. This approach, however, only moves the problem of purification to a point higher in the synthetic chain. A more common solution is to use a biosynthetic procedure, and choose an organism (e.g. a yeast or bacteria) that will selectively cleave or chemically alter one enantiomer only. 

This biosynthetic proposal became an indirect evidence by Brown et al. who demonstrated a biogenetically patterned synthesis of CPT and 20-deoxycamptothecin starting from strictosidine/vincoside. The complete route from 44 to racemic CPT has been completed by chemical transformation involving all of the postulated intermediates in the biosynthesis scheme [170]. Other biomimetic synthesis of CPT has also been reported [171]. 

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