Macrolide antibiotics, total synthesis

Macrolide antibiotics, stereo-controlled synthesis of 86YGK206, Macrolide antibiotics, total synthesis of 85T3569. 

Studies on the stereochemical outcome of the reaction of 2-alkenyl organometallic reagents with aldehydes have increased recently, largely because stereoselectively produced homoallylic alcohols are synthetically equivalent, by cleavage at the carbon-carbon double bond, to the type of aldol adduct stereoisomers required for macrolide antibiotic total synthesis. A new stereoselective synthesis of (Z)-2-alkenyltins (46a) or the corresponding silanes (46b) from allyl or vinyl 9-BBN derivatives has appeared (Scheme 20). The... 

The fungus Streptomyces erythreus is the source of a number of structurally related macrolide antibiotics that are collectively known as the erythromycins. The erythromycins occupy a prominent position in medicine by virtue of their useful antibacterial properties. Their use in therapy over the course of the last three decades has been widespread, and has resulted in the saving of many human lives. In this chapter, we address the landmark total synthesis of erythronolide B (1), the biosynthetic precursor of all the erythromycins, by E.J. Corey and his coworkers which was carried out at Harvard in the 1970s.1... 

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... 

The utility of RCM methodology for the synthesis of open-chain building blocks from a,fi-unsaturated d-lactones is exemplified by the partial syntheses of Cossy aimed for (+)-methynolide (the aglycon of the methymicin family of macrolide antibiotics) [45], and the anticancer agent discodermolide [46], as well as during a recent total synthesis of the highly cytotoxic marine natural depsipeptide apratoxin A by Forsyth and Chen [47]. 

The described procedure has been widely used by Smith III and coworkers [250] in the efficient total synthesis of natural products containing extended 1,3-hydroxylated chains. This architecture is often found as a structural element in polyene macrolide antibiotics [251] such as mycotoxin A and B, dermostatin, and roxaticin. The Smith group used the above-mentioned approach (e. g., as five-component coupling) for the synthesis of the pseudo-C2-symmetric trisacetonide (+)-2-471 [252], which was employed by Schreiber and coworkers [253] within the synthesis of (+)-mycotoxin A (2-470a) (Scheme 2.108). Thus, lithiation of 2.5 equiv. dithiane 2-462b followed by treat-... 

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. 

Since ketene is probably the intermediate of the Wolff rearrangement, the choice of solvents dictates the nature of the product. Indeed, water gave carboxylic acids, whereas alcohols or amines led to esters and amides, respectively. These combinations have been applied to the synthesis of more complex molecules. For example, the total synthesis of carbonolide B, a 16-membered macrolide antibiotic, relied on Amdt-Eistert homologation. In this sequence, a protected furanuronic acid was transformed to the corresponding a-diazoketone, which was then converted to its homologous carboxylic ester. The reaction was achieved using catalytic amounts of silver benzoate and excess of triethylamine in methanol (Scheme 3.4).11... 

Since such reactivity has recently been reviewed,8 only a few examples are reported here. Acyl halides or epoxides can be alkynylated with preformed silver acetylides. Such processes have been applied to the total synthesis of the antibiotic macrolide (+ )-methynolide,96 and in the total synthesis of the antitumor agent FR901464 isolated from a Pseudomonas species (Scheme 10.62).97... 

Total synthesis of macrolide and ionophore antibiotics containing fragments of tetronic acid 92YZ358. 

Evans and others used this methodology to complete numerous total syntheses of natural products. For example, they built the spiroketal subunit 29 in the asymmetric synthesis of the macrolide antibiotic rutamycin B13 (Scheme 2.11). The... 

The Evans-Chapman-Carreira reaction was used in the total synthesis of mac-rolactin A(3), one of the polyene macrolide antibiotics, which shows inhibition of HIV replication in T-lymphoblast cells in preliminary studies2(Scheme 4.2c). 

In the total synthesis of the macrolide antibiotic methymycin 49), Masamune and coworkers [28] developed a new macrolactonization method which makes use of the electrophilicity of Hg(II) toward bivalent sulfur. It involves the S -f-butyl thiolester 44 of the hydroxy acid 41 and employs mercuric trifluoroacetate as an activating agent. The required S -r-butyl thiolester 44 can be prepared in high... 

The additional presence of a 3-methoxy substituent on the benzyl group confers greater stability on the intermediate cation, and consequently oxidation of DMPM ethers by DDQ is even more facile. Yonemitsu and cowoikers have used this differential reactivity of substituted benzyl ethers to great effect in the total synthesis of the macrolide antibiotics methynolide, tylonolide, (95)-9-dihydroerythro-nolide and pikronolide. The pikronolide synthesis provides an excellent example of the selective, sequential deprotection of DMPM, MPM and benzyl ether protecting groups (Scheme 7). 

An asymmetric aldolization was successfully applied to the preparation of gibbane. The total synthesis of the macrolide antibiotic erythromycin was developed involving an asymmetric aldolization step catalyzed by proline. Since the mid-1970s, a flood of papers has appeared dealing with the asymmetric aldolization of various triketones. Some results are listed for comparison in Table 1. 

Various examples of use of alkenyltin/vinyl iodide couplings in natural-product synthesis have been provided Evans and Black [33] have obtained the macrolide insecticide (+)-A83 453A [(+)-lepicidin A] (Scheme 4-7), Burke et al. the ionophore antibiotic X-14547A [34] (Scheme 4-8), Kende et al. [35] lankacidin C (Scheme 4-9), while Han and Wiemer [36] have used the combination alkenyltin/vinyl triflate in the total synthesis of (+)-jatrophone. 

Erythromycins, the representative and medicinally important macrolide antibiotics, have been widely studied and are still undoubtedly one of the most challenging target molecules for many synthetic organic chemists (O Fig. 3). Woodward and coworkers accomplished the first total synthesis of erythromycin A (18) in 1981 [8,9,10]. Corey and coworkers synthesized erythronolides A (20) and B (21), the aglycons of erythromycins A (18) and B (19), in 1978 [11,12] and 1979 [13]. 

Paterson, I., Mansuri, M. M. Recent developments in the total synthesis of macrolide antibiotics. Tetrahedron 1985,41, 3569-3624. 

Nakata, T. Total synthesis of macroiides. Macrolide Antibiotics (2nd Edition) 2002,181-284. 

Nakajima, N., Tanaka, T, Hamada, T, Oikawa, Y, and Yonemitsu, O., Highly stereoselective total synthesis of pikronolide, the aglicon of the first macrolide antibiotic pikromycin. Crucial role of benzyl-type protecting groups removable by 2,4-dichloro-5,6-dicyanobenzoquinone oxidation, Chem. Pharm. Bull., 35, 2228, 1987. 

Ditrich, K., Bube, T., Sttirmer, R., and Hoffmann, R.W., Total synthesis of mycinolide V, the aglycone of a macrolide antibiotic of the mycinamycin series, Angew. Chem., Int. Ed. Engl., 25, 1028, 1986. Hoffmann, R.W., and Ditrich, K., Total synthesis of mycinolide V, Liebigs Ann. Chem., 23, 1990. Ditrich, K., Total synthesis of methynolide. Liebigs Ann. Chem., 789, 1990. 

Nicolaou, K.C., Pavia, M.K.. and Seitz, S.P., Carbohydrates in organic synthesis. Synthesis of 16-membered-ring macrolide antibiotics. Part 5. Total synthesis of 0-mycinosyltylonolide. Syntliesis of key intermediates, J. Am. ( hem.. Soc., 104, 2027, 1982. 

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