Erythronolide preparation

A stereoselective total synthesis of erythronolide A, using two Mg/z-mediated cycloadditions of nitrile oxides has been described. Of broader significance, the strategy not only facilitates the synthesis of specific polyketide targets (i.e., natural products) but also opens up new possibilities for the preparation of nonnatural analogs (482). 

A stereoselective osmylation approach was applied to the synthesis of C(l)—C(7) and C(7)—C(13) subunits of erythronolide A41. A key synthon of the erythronolide A seco acid, 30, was prepared in an enantiomerically pure form by utilizing a stereoselective osmylation of the chiral hydroxy (Z, )-diene ester 31 and subsequent hydrogenation of the resulting butenolide 32 (equation 24). 

Erythromycins are macrolide antibiotics produced by bacterial fermentation. Fluoiination of erythromycin has been studied as a strategy to insure better stability in acidic medium and/or to achieve better bioavailability. An erythromycin, fluorinated at C-8, flurithromycin, was launched several years ago. Its preparation involves an electrophilic fluorination, with CF3OF [119] or with an N-F reagent A/-fluorobenzenesulfonimide (NFSI) [120], of the 8,9-anhydroerythromy-cin-6,9-hemiacetal or of the erythronolide A (Fig. 44). 

Flurithromycin is an erythromycin fluorinated at C-8, which was launched several years ago (cf. Chapter 8). Its preparation involves an electrophilic fluorination with or with an N— F reagent (NFSI) of 8,9-anhydroerythromycin-6,9-hemiacetal or of erythronolide A. Glycosylations have also been performed by fermentation (Figure 4.57). ... 

Although almost all kinds of thiocarbonyl compounds are good dienophiles, synthetic applications derived from the Diels-Alder adducts of thioketones, thionesters and dithioesters remain rather rare and focused on specific targets, as in the preparation of a fragment of the antibiotic erythronolide from the cycloadduct formed regioselectively from 2-methyl-l,3-pentadiene and an a-oxodithioester, a particularly efficient dienophile [524]. 

As shown below, the attack of epoxide 6 with lithium dimethylcuprate is a key step of Hanessian et al. s erythronolide synthesis [23]. This methodology was also applied to the preparation of other polyketide-derived macrolides. Specific to erythronolide, introduction of the methyl group at C2 was achieved according to Scheme 11.3. 

Kinoshita, Nakata, and coworkers synthesized erythronolide A (20) (O Fig. 4) [14,15,16,17]. Erythronolide A (20) was divided into three segments, 22 (C1-C6), 23 (C7-C9), and 24 (CIO-C13), of these fragments 22 and 24 were prepared from monosaccharides as chiral starting materials. 

The C10-C13 segment 24 was prepared from D-ribose (35) (O Scheme 2). In this case, selective protection of the hydroxy groups was realized by isopropylidenation (from 35 to 36). One of the other procedures for conversion of cyclic monosaccharides to acyclic derivatives is nucleophilic addition to the anomeric position in free monosaccharides. Grignard reagent, MeMgl, was added to 36 to provide 37 as the sole product. The subsequent manipulation of 37 to the C10-C13 segment 24, which is not restricted in monosaccharides chemistry, is summarized in O Scheme 2. After the completion of the synthesis of erythronolide A (20), Toshima, Nakata, Tatsuta, Kinoshita, and coworkers achieved the total synthesis of erythromycin A (18) by their own glycosidation method [18,19]. 

The C9-C13 segment 44 of erythronolide B (21) was prepared (O Scheme 4) from the synthetic intermediate 47 of the C1-C6 segment 42. Instead of the methyl group introduction. 

The C27-C35 segment 238 was prepared from 32 (O Scheme 30), which is the synthetic intermediate of erythronolide A. Oxidative cleavage of 32 gave aldehyde 251, which was subjected to aldol reaction with TBDMS-enol ether and TiCl4 to provide 252. Hydrolysis of thioester and deacetalization with TFA were accompanied by furanose-to-p)ranose interconversion and... 

As an application in natural product synthesis, the C -Cg macrolide subunit of ery-thronolide B aglycon is prepared by stereoselective cnolatc Claisen rearrangement of diox-anone 1 to dihydropyran 2533. Dihydropyran 2 is further transformed to give an intermediate in the synthesis of erythronolide B aglycon. 

A.iv. Reaction with Acid Chlorides. As briefly mentioned in Section 8.4.C.ii, the reaction of a dialkyl cuprate and an acid chloride is a preferred method to synthesize ketones.399,400 -phe reaction with acyl halides usually requires low temperatures to isolate the ketone product.388,387 -p is method is usually preferable to and more general than one that uses dialkylcadmium reagents (sec. 8.4.C.ii). Masamune et al. used this reaction to convert acid 422 to ketone 423 in a synthesis of erythronolide. In this case, oxalyl chloride was used to prepare the requisite acid chloride because of the sensitive nature of the molecule. 

Hindered secondary and tertiary alcohols can be silylated with TBSOTf (bp 60 C/0.9 kPa) using 2,6-lutidine as the base as illustrated by the silylation of the secondary alcohol 61.1 in a synthesis of the diterpene Zoapatanol [Scheme 4,61] and the tertiary alcohol 62.1 [Scheme 4.62] originating in a synthesis of Erythronolide A. The reactions can be run at molar concentrations using dichloromethane as a co-solvent and the recommended ratio of reactants is alcohol TBSOTf 2,6-lutidine = 1 1.5 2. TBSOTf is both expensive and very moisture sensitive and in our experience commercial samples do not store well consequently, it may be best to prepare it fresh from the reaction of /er/-butyldi-methylsilyl chloride and triflic acid. For the silylation of p-hydroxybutyrolac-lones, which are prone to dehydration during silylation with TBSOTf under the standard conditions, 2,6-di-/m-butylpyridine has been recommended as the base. Owing to their higher acidity, phenols can be silylated selectively in the presence of alkanols [Scheme 4.63]. ... 

Intramolecular cyclization products (8) and (9) were converted into novel 9,12-epoxy derivatives, such as A-69334 (24), which possessed better pharmacokinetic properties than erythromycin [134]. The structurally related bicyclic macrolide, L53-18A, was found in culture broths of an unidentified Saccharopolyspora species [135]. Several 8,9-difluoro-6,9-epoxy derivatives of erythromycin and 8-bromo derivatives of erythronolide B have been prepared [136, 137]. 

Kinoshita s erythronolide synthesis is based on the preparation of (9S)-9-dihydroerythronolide A (76), which is constructed from the three chiral segments, Ci-Cg (69), C7-C9 (70) and C10-C13 (72). 

Kochetkov s erythronolide synthesis is based on the construction of the seco-acid from the Cj-Cg (91) and C9-C13 (93) segments, both of which are prepared from levoglucosan 88 through the C-methyl derivatives 89 and 92, respectively. 

Paterson s synthesis is based on a short and eflScient asymmetric route to the simplified erythronolide derivative 120 (R=TBS) by using an Evans aldol reaction for the preparation of the C2-C4 and Cg-Cjo fragments. 

Another successful approach for blocking the intramolecular decomposition illustrated in Fig. 2 involved inhibition of the dehydration step leading to the anhydrohemiketal by replacement of the C-8 proton of erythromycin with fluorine. Preparation of flurithromycin (8-fluoroerythromycin, see Fig. 4) has been achieved by both chemical and biochemical methods. Addition of 8(S)-8-fluoroerythronolide A to a mutant strain of Streptomyces erythreus blocked in biosynthesis of its endogenous lactone (erythronolide) yielded the desired fluorinated erythromycin [40]. This technique of mutasynthesis has been further employed for the production of other fluorinated derivatives of erythromycin [40, 41]. Fluorination of different 8,9-anhydro-6,9-hemiketal derivatives of erythromycin by chemical means with reagents such as trifluoromethyl hypo-fluorite or perchloryl fluoride (with subsequent reduction of the N-oxide) has also been reported [42, 43]. 

During a synthesis of erythronolide A, carried out by our group at Marburg, we needed the chiral aldehyde 35 as starting material. Perusal of the list of commercially available chiral starting materials [13] suggested a synthesis of lactone 36 from D-fructose (Scheme 4.8). With this in mind, aldehyde 35 was prepared from fructose in eight steps [16]. 

In anticipation of the final carbon-carbon bond construction that is required to prepare the intact seco acid of erythronolide B using a directed aldol reaction to form the C(10)-C(l 1) bond, it was first necessary to prepare the requisite chiral aldehyde 80. Although the synthesis of 80 had been previously reported, we elected to devise an alternative route to access this material that commenced with the addition of the chiral boron enolate 37 0 to propionaldehyde to furnish 81 (Scheme 12). The sequential protection of the secondary hydroxyl group and removal of the chiral auxiliary gave 82, which was then converted to 80 by over-reduction followed by reoxidation under Swem conditions. 

Upon examination of the reactions outlined in Schemes 9, 11, and 12, it is evident that the present route to the seco acid of erythronolide B is remarkably concise, involving a longest linear sequence of a mere 14 chemical operations from the commercially available 2-ethylfuran (64). Even counting the steps required for the preparation of the aldehyde 80, the total number of operations is only 19. We anticipate that the analogous aldol reaction of the enolate derived from 79 with the... 

---