Rifamycin synthesis

Rifamycins.—Contained within the rifamycin skeleton, for example that of rifamycin S (169), is a C7-N unit (heavy bonding) which has been deduced to arise from an intermediate of the shikimic acid pathway. Fresh evidence arising from a study using mutants of Nocardia meditenanei confirms this view, and it is apparent that divergence from the shikimate pathway to rifamycin synthesis occurs between sedoheptulose-7-phosphate and shikimic acid itself. 

A reiterative application of a two-carbon elongation reaction of a chiral carbonyl compound (Homer-Emmonds reaction), reduction (DIBAL) of the obtained trans unsaturated ester, asymmetric epoxidation (SAE or MCPBA) of the resulting allylic alcohol, and then C-2 regioselective addition of a cuprate (Me2CuLi) to the corresponding chiral epoxy alcohol has been utilized for the construction of the polypropionate-derived chain ]R-CH(Me)CH(OH)CH(Me)-R ], present as a partial structure in important natural products such as polyether, ansamycin, or macro-lide antibiotics [52]. A seminal application of this procedure is offered by Kishi s synthesis of the C19-C26 polyketide-type aliphatic segment of rifamycin S, starting from aldehyde 105 (Scheme 8.29) [53]. 

Rifamycin Streptomyces mediterranei Tuberculosis Protein synthesis... 

Polypropionate chains with alternating methyl and hydroxy substituents are structural elements of many natural products with a broad spectrum of biological activities (e.g. antibiotic, antitumor). The anti-anti stereotriad is symmetric but is the most elusive one. Harada and Oku described the synthesis and the chemical desymmetrization of meso-polypropionates [152]. More recently, the problem of enantiotopic group differentiation was solved by enzymatic transesterification. The synthesis of the acid moiety of the marine polypropionate dolabriferol (Figure 6.58a) and the elaboration of the C(19)-C(27) segment of the antibiotic rifamycin S (Figure 6.58b) involved desymmetrization of meso-polypropionates [153,154]. 

Fig. 3. Stepwise synthesis of rifaximin (from De Angelis [39]). The reaction of rifamycin S (I) with pyridine perbro-mide (II) in 2-propanol/chloroform (70/30) mixture at 0°C gives 3-bromorifamycin S (III), which is then condensed with 2-amino-4-methyl-pyridine (IV) at 10°C. The o-quinonimic compound (V) is then obtained. This compound is finally reduced with ascorbic acid to rifaximin. 

To establish whether rifaximin, like the other members of the rifamycin family [36, 58], specifically inhibits bacterial RNA synthesis the effect of this antibiotic as well as that of rifampicin and chloramphenicol on RNA (via 3H-uridine incorporation), DNA (via 3H-thymidine incorporation) and protein (via 35S-methionine incorporation) synthesis was studied in growing cultures of Escherichia coli [59], While chloramphenicol reduced protein synthesis, both rifaximin and rifampicin inhibited RNA synthesis in a concentration-dependent fashion. In contrast, none of them affected 3H-thymidine incorporation into DNA. These data suggest that rifaximin, like rifampicin, inhibits RNA synthesis by binding the (3 subunit of the bacterial DNA-dependent RNA polymerase [60],... 

Lancini GC, Sartori G Rifamycins LXI In vivo inhibition of RNA synthesis of rifamycins. Experientia 1968,24 1105-1106. 

Umezawa H, Mizuno S, Yamazaki H, Nitta K Inhibition of DNA-dependent RNA synthesis by rifamycins. J Antibiot (Tokyo) 1968,21 234-236. 

Cellai L, Colosimo M, Marchi E Synthesis of 3H labeled rifamycin L 105. J Label Comp Radiopharm 1983 20 1287-1296. 

Marchi E, Mascellani G, Montecchi L, Brufani M, Cellai L L/105, a new semisynthetic derivative of rifamycin SV, synthesis and structure-activity relationship. Chemioterapia 1983 2 38. 

Rifaximin is a synthetic rifamycin derivative, which acts by inhibiting bacterial ribonucleic acid (RNA) synthesis [48]. It is virtually unabsorbed after oral administration and is, therefore, used primarily to treat gastrointestinal infections. Rifaximin possesses a broad spectrum of antimicrobial activity, covering Gram-positive and Gram-negative bacteria, both arerobic and anaerobic [49], Several studies [44, 49-62] have shown that in patients with HE rifaximin displays an efficacy similar to that of lactulose and neomycin (table 1). A recently published study [62] compared the efficacy and safety of... 

Among the syntheses of complicated natural products, the total synthesis of rifamycin S (44) is another example that shows how a complicated structure can be constructed by applying the concept of double asymmetric synthesis (see Section 1.5.3 for double asymmetric synthesis). Rifamycin S is one of the an-samycin antibiotics, characterized by a distinct structural feature a macro-... 

The total synthesis of rifamycin S was one of Kishi s many achievements in organic synthesis.6 Kishi recognized that a certain type of (Z)-olefin such as 51 tends to take a conformation in which C-l, C-2, C-3, and H-3 are nearly co-... 

In the application of the above discovery, ( )-3-benzyloxy-2-methyl pro-pionaldehyde 52 is used as the starting material in the synthesis of rifamycin A. As outlined in Scheme 7-12, compound 52 is converted to allyic alcohol 55 via a series of chemical reactions. Epoxidation of 55 proceeded stereoselectively, giving a single epoxide that affords 57 after subsequent treatment. Compound 57 may be converted to 58 upon acetonide formation. 

This chapter has introduced the asymmetric synthesis of several types of natural products erythronolide A, 6-deoxyerythronolide, rifamycin S, prostaglandins and baccatin III, the polycyclic part of taxol, as well as the taxol side chain. The... 

The ansamycins (rifamycin B and rifamycin SV) are produced by certain strains of Nocardia mediterranei and act by inhibition of messenger RNA (m-RNA) synthesis, and consequently of bacterial protein synthesis. Structurally, they present a characteristic ansa structure, made of a ring containing a naphthohydroquinone system spanned by an aliphatic chain. The two ansamycins differ in the type of substituent on the... 

Vancomycin was the first macrocyclic antibiotic evaluated as selector for the synthesis of HPLC chiral stationary phases (CSPs) [7], along with rifamycin B (among ansamycins) and thiostrepton (among polypeptides). 

The synthesis of aldehyde 48 proceeds in 16 steps from (S)-39 in 15% yield and 75% stereoselectivity. The brevity, efficiency, and selectivity of this synthesis rivals alternative acyclic diastereoselective approaches to the rifamycin ansa chain, (see footnote 4 in reference 3i), thereby providing a clear testimony to the potential of the tartrate allylboronates as reagents for complex synthetic problems. 

Z)-awh-4-Hydroxy-l-aIkenyl carbamates 363, when subjected to substrate-directed, vanadyl-catalysed epoxidation , lead to diastereomerically pure epoxides of type 364 (equation 99)247,252,269 qqjggg epoxides are highly reactive in the presence of Lewis or Brpnsted acids to form -hydroxylactol ethers 366 in some cases the intermediate lactol carbamates 365 could be isolated . However, most epoxides 364 survive purification by silica gel chromatography . The asymmetric homoaldol reaction, coupled with directed epoxidation, and solvolysis rapidly leads to high stereochemical complexity. Some examples are collected in equation 99. The furanosides 368 and 370, readily available from (/f)-0-benzyl lactaldehyde via the corresponding enol carbamates 367 and 369, respectively, have been employed in a short synthesis of the key intermediates of the Kinoshita rifamycin S synthesis . 1,5-Dienyl carbamates such as 371, obtained from 2-substituted enals, provide a facile access to branched carbohydrate analogues . 

Rifampicin, a semisynthetic derivative of the antimicrobial agent rifamycin B obtained from Strep-tomyces mediterranei, is bactericidal for intra- and extracellular bacteria. Bacterial RNA synthesis is inhibited by binding to the beta-subunit of DNA-dependent RNA polymerase. Human polymerases are not affected. It has activity against gram-positive and gram-negative cocci, chlamydia as well as mycobacteria. It is used in combination with dapsone for leprosy. 

The antibiotic rifamycin (Box 28-A) appears to interfere with initiation by competing for the binding of the initial purine nucleoside 5 -triphosphate. The same bacterial RNAP that synthesizes mRNA also transcribes both rRNA and the tRNAs. Thus, the synthesis of all forms of RNA is inhibited by rifamycin. When a population of bacteria is subjected to this antibiotic, a few individuals survive. These rifamycin-resistant mutants are no longer sensitive to the antibiotic. Among them are some mutants that produce an... 

Rifampicin is a synthetic derivative of a naturally occurring antibiotic, rifamycin, that inhibits bacterial DNA-dependent RNA polymerase but not T7 RNA polymerase or eukaryotic RNA polymerases. It binds tightly to the ft subunit. Although it does not prevent promoter binding or formation of the first phosphodiester bond, it effectively prevents synthesis of longer RNA chains. It does not inhibit elongation when added after initiation has occurred. Another antibiotic, streptolydigin, also binds to the ft subunit it inhibits all bond formation. 

This reaction played a key role in a highly stereocontrolled synthesis of the aliphatic segment 1 of the antibiotic rifamycin S (2),2 as formulated in equation (III). In each of the two Cr(II) mediated reactions, the desired aldol is essentially the only product isolated. Further studies3 indicate that the 2,3-stereoselectivity is sensitive to the large substituent a to the aldehyde. A cyclic acetal group appears to play a specific role in contrast to an acyclic group, but the factors controlling stereoselectivity are not well understood. 

BouzBouz, S. Cossy, J. Efficient strategy for the synthesis of stereopentad subunits of scytophydn, rifamycin S, and discodermolide. Org. Lett. 2001, 3, 3995-3998. 

The antibiotic rifamycin and a semisynthetic derivative, rifampicin, specifically inhibit the initiation of RNA synthesis by interfering with the formation of the first phosphodiester bond of the RNA chain. The elongation of chains already being synthesized is unaffected. 

In order to apply tartrate ester-modified allyl- and crotylboronates to synthetic problems,23 Roush and Palkowitz undertook the stereoselective synthesis of the C19-C29 fragment 48 of rifamycin S, a well-known member of the ansamycin antibiotic group24 (Scheme 3.1u). The synthesis started with the reaction of (S,S)-43E and the chiral aldehyde (S)-49. This crotylboration provided the homoallylic alcohol 50 as the major component of an 88 11 1 mixture. Compound 50 was transformed smoothly into the aldehyde 51, which served as the substrate for the second crotylboration reaction. The alcohol 52 was obtained in 71% yield and with 98% diastereoselectivity. After a series of standard functional group manipulations, the alcohol 53 was oxidized to the corresponding aldehyde and underwent the third crotylboronate addition, which resulted in a 95 5 mixture... 

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