Amphotericin synthesis

Masamune as an intermediate in his amphotericin synthesis.15 Disconnection to the hydroxyacid 36 was particularly attractive as optically active 36 was available. Cyclopropyl-lithium 35 M=Li is actually easier to make than other -alkyl-lithiums as the three-membered ring stabilises the anion in the o-complex.16 Acylation with 36 needed three molecules of 35 R = Li as two are consumed by the acidic OHs, but the reaction is an efficient acylation at carbon. 

The body of chemistry described above for amphotericin B (1) allowed, for the first time, the preparation of a series of novel derivatives of this polyene macrolide antibiotic and set the stage for a total synthesis of this target molecule. Below we unfold the adventure that led to the accomplishment of this goal.910... 

In the selection of suitable chiral starting materials for the total synthesis of amphotericin B (1) and amphoteronolide B (2), the recognition of subtle symmetry in the targets played a crucial role. 

The described chemistry leading to the synthesis of key building blocks 16-19 sets the stage for the completion of the total synthesis of both amphotericin B (1) and its aglycon, amphoteronolide B (2). 

Finally, although ultimately successful, the glycosidation studies on amphotericin B (1) reemphasize the difficulties encountered in this important area of synthesis. Of course, the /J-glycosidic bond linking the aglycon with the mycosamine, in combination with the... 

This procedure has been recently applied to the synthesis of L-lyxitol and the polyhydroxylated chain of amphotericin Interesting results have also been obtained in the reduction of ) -oxo derivatives of dithioacetal monoxides. In the reaction sequence of equation 322 two successive asymmetric inductions are involved. After the first reaction, involving acylation of the carbanion, a diastereoisomeric mixture in a 65 35 ratio is produced. When this mixture is reduced with NaBH4 in MeOH-conc. aqueous solution of ammonia, among four possible diastereoisomeric alcohols, the stereoisomer 523 is obtained with a stereoselectivity of 98% . Guanti and coworkers have found that the LiAlH4 reduction of the same substrates at — 78° in THF/ether leads to 523 with a stereoselectivity 99 i6i3.6i4... 

In order to demonstrate the efficiency and applicability of their method, Car-reira et al. described the synthesis of the C1-C13 polyol segment of amphotericin (Fig. 2). The vinylogous aldol reaction was utilized twice, during the... 

As an example of the usefulness of the Sharpless asymmetric epoxidation the enantioselective synthesis of (-)-swainsonine and an early note by Nicolaou on the stereocontrolled synthesis of 1, 3, 5...(2n + 1) polyols, undertaken in connection with a programme directed towards the total synthesis of polyene macrolide antibiotics, such as amphotericin B and nystatin Aj, will be discussed. 

Mozaffarian N, Berman JW, Casadevall A. Enhancement of nitric oxide synthesis by macrophages represents an additional mechanism of action for amphotericin B. Antimicrob Agents Chemother 1997 41 1825. 

Flucytosine is converted in Candida fungi to 5-fluorouracil by the action of a specific cytosine deaminase. As an antimetabolite, this compound disrupts DNA and RNA synthesis (p. 298), resulting in a fungicidal effect Given orally, flucytosine is rapidly absorbed. It is well tolerated and often combined with amphotericin B to allow dose reduction of the lattet... 

DHAP-dependent aldolases have also been used in the synthesis of the C3-C9 fragment of aspicilin [46] and of the C12-C20 fragment of amphotericin [47]. 

Flucytosine is a fluorinated derivative of pyrimidine. Its spectrum of activity is narrower than that of amphotericin B. However, it exhibits a synergetic effect when used in combination with amphotericin B. In sensitive fungi, flucytosine is transformed into 5-fluorouracil, which in turn is turned into 5-fluorodeoxyuracilic acid, an inhibitor of thymidylate synthetase, and correspondingly, DNA synthesis. 5-Fluorouracil triphosphate, which causes the formation of defective RNA, may also be involved in this process. The mechanism is highly selective because mammahan cells are not able to turn a large amount of flucytosine into 5-fluorouracil. 

Flucytosine is an oral antifungal pro-drug. It has to be enzymatically deaminated by the fungi to the active metabolite, fluorouracil. Fluorouracil inhibits thymidylate synthetase and DNA synthesis. Its indications are treatment of cryptococcal meningitis and serious systemic candidiasis. Resistance develops rapidly, due to altered drug-permeability. For this reason Amphotericin B and flucytosine are often given in combination as they have synergistic effects. 

In a very recent example, Chiu and co-workers (84-86) used the tandem ylide-cycloaddition methodology to prepare advanced intermediates directed toward the synthesis of the pseudolaric acids. Pseudolaric acids are a family of diterpenes isolated from the root bark of Pseudolarix kaempferi. These novel compounds have shown antimicrobial activity comparable to that of amphotericin B and have demonstrated cyctotoxicity against several cancer cell lines (Fig. 4.5). 

Flucytosine is converted into the anti metabolite 5-fluorouracil that inhibits thymidilate synthetase, thereby disrupting DNA synthesis. It also interferes with protein synthesis by incorporation of fluorouracil into RNA in place of uracil. Although active against most Candida species, its spectrum of antifungal activity, overall, is narrow. Since resistance can develop rapidly it is usually coadministered with another agent and its main value is that it facilitates a reduction in the dose (and, presumably, the toxic effect) of amphotericin when co-prescribed in this way. The main adverse effects are marrow aplasia and hepatotoxicity. 

Flucytosine Interferes with DNA and RNA synthesis selectively in fungi Synergistic with amphotericin systemic toxicity in host due to DNA and RNA effects Cryptococcus and chromoblastomycosis infections Oral duration, hours renal excretion Toxicity Myelosuppression... 

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