Synthesis Of Erythromycin Research Articles

Synthesis and characterization of Erythromycin loaded PLGA and PCL microspheres: Antimicrobial application

Synthesis and characterization of Erythromycin loaded PLGA and PCL microspheres: Antimicrobial application

17 鎖状立体制御を基盤としたエリスロマイシンAの形式全合成(口頭発表の部)

17 鎖状立体制御を基盤としたエリスロマイシンAの形式全合成(口頭発表の部)

ChemInform Abstract: The Thiopyran Route to Polypropionates

AbstractReview: 92 refs.

On the Macrocyclization of the Erythromycin Core: Preorganization is Not Required

The erythromycins, discovered and isolated in the early 1950s, are the best-known members of the clinically important macrolide class of antibiotics. The 14-membered macrolactone core imbedded in these natural products has inspired new synthetic methods for the construction of large ring lactones, beginning with the landmark synthesis of erythronolide B by the Corey group in 1978. During these studies, a single acetonide protecting group was utilized at the C-3/C-5 position. Similarly, this protecting group was used by the Masamune group years later for the synthesis of 6-deoxyerythronolide B (6-dEB). While no rationale was given for the use of this acetonide at the time, its function was revealed during the historic synthesis of erythromycin A in 1981 by Woodward et al. In three consecutive reports, the Woodward group extensively explored the conformational requirements for efficient acylation-based macrolactonization of erythromycin A seco acid derivatives. In particular, cyclic protecting groups were placed at various positions to serve as biasing elements, that is, artificial structural features intended to aid macrocyclic ring closure through substrate preorganization. The results from this study led the Woodward group to conclude that “certain structural features such as ... cyclic protecting groups at C-3/C-5 and C-9/C-11 are required for efficient lactonization” and that “these structural requirements probably arise from conformation requirements for lactonization.” This conclusion—that preorganization is required for efficient cyclization—has become a wellaccepted doctrine that has influenced the planning of all ensuing erythromycin syntheses (see below). We now report for the first time that conformational restraining elements are in fact not required for attaining efficient lactonization of the erythromycin core structure, 6-deoxyerythronolide B (6dEB). Moreover, we demonstrate that the removal of biasing elements allows for more stereochemical flexibility in the cyclization of 6-dEB, thus enabling access to stereochemical analogues that are not readily accessible with the biasing elements in place. Overall these findings require revision of the 30-year-old dogma that preorganization is mandatory for achieving macrocyclization of the erythromycins. Inspired by the Woodward report, synthetic endeavors by the research groups of Stork, Nakata, Yonemitsu, Danishefsky, Kochetkov, Hoffmann, Evans, Woerpel, Nelson, and us have reduced the conformational space available to the seco acid backbones of the erythronolide series (that is, 6-dEB, erythronolide B, and erythronolide A) through the use of sixmembered-ring protecting groups on C-3/C-5 and C-9/C-11 (Scheme 1). In addition to scaffolds with cyclic protecting

The thiopyran route to polypropionates

The strategic use of thiopyran templates to facilitate polypropionate synthesis was first demonstrated in Woodward's landmark total synthesis of erythromycin A in 1981 where the topology of a fused bicyclic system was exploited. In the ensuing three decades, various alternative strategic applications of thiopyran motifs to achieve key stereoselective transformations have emerged including, inter alia, unique substrates for chemoenzymatic syntheses, surrogates for 3-pentanone in enantioselective aldol reactions, and templates for enantiotopic group selective reactions. This review summarizes these developments.

ChemInform Abstract: Highly Stereocontrolled Synthesis of 2,6-Dideoxy Sugars and Its Application to Synthesis of Natural Products

Novel methodologies for stereocontrolled synthesis of 2, 6-dideoxy sugars by efficient use of 2, 6-anhydro-2-thio sugar and its application to synthesis of natural products are described. This article involves highly stereocontrolled and powerful glycosylations of 2, 6-anhydro-2-thio sugar for synthesis of 2, 6-dideoxy-α- and β-glycosides and highly sterecontrolled creations of C-3 configuration of 2, 6-dideoxy sugar by an addition of a nucleophilic reagent to 2, 6-anhydro-2-thio sugar. Further, the efficient total synthesis of erythromycin A, which is a most typical and clinically important macrolide antibiotic, from (9S) -9-dihydroerythronolide A is achieved by the successful application of the present novel methodologies.

ChemInform Abstract: Evaluation of the Efficiency of the Macrolactonization Using MNBA in the Synthesis of Erythromycin A Aglycon

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Evaluation of the Efficiency of the Macrolactonization Using MNBA in the Synthesis of Erythromycin A Aglycon

Various intermediates for the synthesis of erythronolide A, an aglycon of erythromycin A, are prepared from the corresponding seco-acids using 2-methyl-6-nitrobenzoic anhydride (MNBA) in the presence of 4-(dimethylamino)pyridine (DMAP) with or without triethylamine. The efficiency of the MNBA lactonization is assessed by studying this method and comparing the results with those of the other established macrocyclization protocols. It has been finally concluded that (i) the conformationally appropriate substrate for the monomeric cyclization gave the desired lactone in excellent yield under mild reaction conditions in the presence of MNBA and DMAP, (ii) the highly-strained substrate for the cyclization also afforded the monomeric lactone in relatively good yield at 100 degrees C in toluene, and (iii) the seco-acid having stable linear conformation, which preferred dimerizing more than forming the monomeric lactone, provided the corresponding diolide in high yield with the constant ratio of the monomer to dimeric lactone (approximately 1/5).

A key developmental regulator controls the synthesis of the antibiotic erythromycin in Saccharopolyspora erythraea

Saccharopolyspora erythraea makes erythromycin, an antibiotic commonly used in human medicine. Unusually, the erythromycin biosynthetic (ery) cluster lacks a pathway-specific regulatory gene. We isolated a transcriptional regulator of the ery biosynthetic genes from S. erythraea and found that this protein appears to directly link morphological changes caused by impending starvation to the synthesis of a molecule that kills other bacteria, i.e., erythromycin. DNA binding assays, liquid and affinity chromatography, MALDI-MS analysis, and de novo sequencing identified this protein (M(r) = 18 kDa) as the S. erythraea ortholog of BldD, a key regulator of development in Streptomyces coelicolor. Recombinant S. erythraea BldD bound to all five regions containing promoters in the ery cluster as well as to its own promoter, the latter with an order-of-magnitude stronger than to the ery promoters. Deletion of bldD in S. erythraea decreased the erythromycin titer in a liquid culture 7-fold and blocked differentiation on a solid medium. Moreover, an industrial strain of S. erythraea with a higher titer of erythromycin expressed more BldD than a wild-type strain during erythromycin synthesis. Together, these results suggest that BldD concurrently regulates the synthesis of erythromycin and morphological differentiation. The ery genes are the first direct targets of a BldD ortholog to be identified that are positively regulated.

Synthesis of (-)-Membrenone B

(+)-Membrenone B was isolated from the skin of a Mediterranean mollusc Pleurobranchus membranaceus. It is a feeding deterrent for some of its natural predators. This concise synthesis focuses on two aldol reactions, using thiopyrans to control enolate geometry. A similar strategy was used in the synthesis of erythromycin: R. B. Woodward et al. J. Am. Chem. Soc. 1981, 103, 3210.

Total Synthesis of Erythromycin B.

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Synthesis of Ring-Contracted Erythromycin A Derivatives via Microwave-Assisted Intramolecular Transesterification

The synthesis of ring-contracted derivatives of erythromycin A via intramolecular transesterification under microwave irradiation of 8,9-anhydroerythromycin A 6,9-hemiketal and its derivatives is described. It was found that microwave irradiation could significantly improve the yields and shorten the reaction times under either solvent-containing (method A) or solvent-free (method B) conditions.

Total synthesis of erythromycin B

We report the details of the first total synthesis of erythromycin B using two different strategies for the end game. The first of these follows a classical approach in which the desosamine and cladinose residues are sequentially appended to a macrocyclic lactone, which was formed by cyclization of a seco acid derivative, to give a bis-glycosylated macrolide intermediate that is converted into erythromycin B. The second strategy features an abiotic approach in which a seco acid bearing a desosamine residue is cyclized to give a monoglycosylated macrocyclic lactone that is then transformed into erythromycin B via a sequence of steps involving refunctionalizations and a glycosylation to introduce the cladinose moiety. Attempts to prepare a bis-glycosylated seco acid by de novo synthesis were unsuccessful. The syntheses of the key seco acid intermediates feature the oxidative transformation of a furan containing C(3)–C(10) to provide a dioxabicyclo[3.3.1]nonenone that served as a template on which to create the stereocenters at C(6) and C(8). A stereoselective aldol reaction was used to establish the C(11)–C(15) segment, and a stereoselective crotylation was implemented to introduce the propionate subunit comprising C(1)–C(2).

Chemoselective synthesis of erythromycin A ketolides substituted in the C10-methyl group

The substrate for selective substitution in the C10-methyl group in erythromycin A derivatives was 10,11-anhydro-6 O-methyl-descladinosylerythromycin. The latter, as an N-oxide, was reacted with NBS in acetic acid to form an allylic acetate. Nucleophilic substitutions and carbylation by Pd-catalysed cross-coupling reactions provided products substituted in the C10-methyl group. Methods for the preparation of 10-methylene derivatives of 11 N,12 O-cyclocarbamate 3-ketolides are described. The methylene group is part of an α,β-unsaturated carbonyl system involving the 9-keto group. The products from conjugated addition are substituted in the C10-methyl group.

Conformation‐Directed Macrocyclization Reactions

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Conformation‐Directed Macrocyclization Reactions

AbstractThe importance of conformational pre‐organization in successful macrocyclization reactions has been recognized ever since Eschenmoser’s synthesis of vitamin B12 and Woodward’s synthesis of erythromycin. Different approaches to productive preorganization are possible depending mainly on the degree of freedom in the choice of the structural elements. In diversity‐oriented synthesis, in which it is not imperative that the molecular framework has a fixed structure, matching building blocks can be used to assemble a macrocycle. In target‐oriented synthesis, more subtle structural elements have to be considered in order to pre‐organize the linear substrate into a folded conformer suitable for ring closure. In this microreview, some selected examples of macrocyclization reactions are presented to illustrate the different rational approaches. Special attention is paid to the role of intramolecular weak forces and protecting groups in the conformational pre‐organization that facilitates macrocyclization reactions. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)

Synthesis of Two and Antibacterial Activity of One Novel Oxime Ether Derivatives of Erythromycin A.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Synthesis of two and antibacterial activity of one novel oxime ether derivatives of erythromycin A

The synthesis of novel erythromycin A 9- O-(2-ethenesulfony-ethyl)-oxime and erythromycin A 9- O-(3-oxo-butyl)-oxime from erythromycin A (EA) by the Michael reaction is described and to describe the effects of transformation of ketone in position 9 of EA to an oxime ether. This transformation occurred in a single step without protecting of any functional moiety of erythromycin oxime and zero waste manner in good yield. The antibacterial screen of EA 9- O-(2-ethenesulfony-ethyl)-oxime is also reported.

An abiotic strategy for the enantioselective synthesis of erythromycin B.

An abiotic strategy for the enantioselective synthesis of erythromycin B.

Studies on macrolide antibiotics I. Synthesis and antibacterial activity of erythromycin A 9-O-substituted oxime ether derivatives against Mycobacterium avium complex.

A series of erythromycin A 9-O-substituted oxime ether derivatives have been synthesized and evaluated for antibacterial activity against Mycobacterium avium complex (MAC) and Staphylococcus aureus. These compounds possessed stronger in vitro activity against MAC including macrolide-resistant strains than clarithromycin (2), although in vitro antibacterial activities of these compounds were less than that of 2 against Staphylococcus aureus. Our studies found that several factors contribute to the antibacterial activity against MAC. The length and spatial orientation of the substituent at 9-position were found to significantly influenced the anti-MAC activity, especially against macrolide-resistant strains. Of all the compounds prepared, erythromycin A 9-[O-(4-phenylbutyl)oxime] (12q) and erythromycin A 9-[O-(3-phenoxypropyl)oxime] (12t) possessed 16 times stronger antibacterial activity than 2 against clarithromycin-resistant strains. Surprisingly, the minimum inhibitory concentrations (MICs) of 12q and 12t against the resistant strains were almost same as those against the susceptible strains. These results suggest that the erythromycin A 9-O-substituted oxime ether derivatives would be promising macrolide antibiotics.