Macrolides, ring product synthesis

Migrastatin (192) (Scheme 37) is a novel macrolide natural product that displays an inhibitory effect on the migration of human tumor cells. After an RCM-based synthesis of the 14-membered macrolide core of 192 [94], Danishefsky also achieved the first total synthesis of the natural compound [95], using the fully functionalized tetraene 191 as the metathesis precursor. Under the conditions shown in Scheme 37, the ring-closing step proceeded (E)-selectively with exclusive participation of the two terminal double bonds in 191, delivering only the ( , ,Z)-trienyl arrangement present in 192. 

The utility of potassium organotrifluroborate salts in natural product synthesis was demonstrated by Molander through a formal total synthesis of the macrolide oximidine II. Alkyne 68 was selectively hydroborated with di(isopropylprenyl)borane and then converted to the potassium trifluoroborate salt 69. Formation of the macrocyclic ring was achieved through intramolecular Suzuki coupling of 69, which generated 70 in a 42% yield. Intermediate 70 was transformed to 71 in two steps to complete the formal synthesis. 

In 2003, Theodorakis et al. described the asymmetric synthesis of a key fragment corresponding to borrelidin (267, Figure 7.7). This macrolide natural product was isolated from Streptomyces rochei in 1949 and exhibits a broad antiviral and antibacterial prolile. Structurally, it contains an atypical 18-membered ring distinguished by a 1,3,5,7-skipped methylene chain, cyclopentane carboxylic acid, and conjugate cyanodiene unit. 

Quinkert and coworkers have also described a clever synthesis of the lichen macrolide (+)-aspicilin (17) using this ring opening/trapping strategy in which the trapping is done intramolecularly by a remote hydroxyl functionality, affording a macrolide product... 

Modular PKS enzymes are responsible for the synthesis of a wide diversity of structures and seem to have more relaxed specificities in several of the enzymatic steps. Their enormous appeal for combinatorial purposes, though, derives from the presence of multiple modules that can be manipulated independently, allowing the production of rings of different sizes and with potential stereochemical variation at each PK carbon. The higher complexity of these pathways has somewhat hindered their exploitation, but recently, several have been fully characterized. Among them, by far the most studied modular multienzyme complex is 6-deoxyerythronolide B synthase (DEBS 240,266,267), which produces the 14-member macrolide 6-deoxyerythronolide B (10.70, Fig. 10.45). DEBS contains three large subunits each of which contains two PKS enzyme modules. Each module contains the minimal PKS enzyme vide supra) and either none (M3), one (ketoreductase KR Ml, M2, MS, and M6), or three (dehydratase DH-enoyl reductase ER-ketoreductase KR, M4) catalytic activities that produce a keto (M3), an hydroxy (Ml, M2, MS and M6), or an unsubstituted methylene (M4) on the last monomeric unit of the growing chain (Fig. 10.45). A final thioesterase (TE) activity catalyzes lactone formation with concomitant release of 10.70 from the multienzyme complex. Introduction of TE activity after an upstream module allows various reduced-size macrolides (10.71-10.73, Eig. 10.45) to be obtained. 

Oxyselenation ofalkeues, - Treatment of olefins with 1 or 2, water, and an acid catalyst (e.g., p-TsOH) in CH2CI2 affords j3-hydroxy selenides in excellent yield. Unsaturated carboxylic acids, phenols, alcohols, thioacetates, and urethanes react with 1 or 2 and an acid catalyst ( —78- 25°) to afford products of oxidative cyclization. These reagents are superior to benzeneselenenyl halides for selenium-induced ring closures. This reaction is also useful for synthesis of 14- and 16-membered lactones. Benzeneselenenyl halides and benzeneselenenic acid do not promote macrolide formation under similar conditions. 

Nakajima, N., Hamada, T., Tanaka, T., Oikawa, Y, and Yonemitsu, O., Chiral synthesis of polyketide-derived natural products. Part 10. Stereoselective synthesis of pikronolidc, the aglycon of the 14-memhered ring macrolide pikromycin, from D-glucose. Role of MPM and DMPM protection, 7. Am. Chem. Soc.. 108, 4645, 1986. 

In recent years, ring-closing olefin metathesis (RCM) has attracted organic chemists as a versatile cyclization method via carbon-carbon bond formation, and had a great impact on the synthesis of natural products [29,30]. In the syntheses of dihydropyrans of marine macrolides, allyl homoallyl ethers 28 have been cyclized to dihydropyrans 29 via RCM. This methodology has been seen in the syntheses of laulimalide by Mulzer [31,32], Crim-mins [33], and Nelson [34] (Scheme 9). 

Many drugs and namral products are (or contain) macro-cyclic structures that require the synthesis, and functionalization, of large rings in an asymmetric fashion. At its simplest, this can involve immobilization of a preassembled macrocyclic core on a solid support, and subsequent modification. This approach was used by Sowin and colleagues to prepare a library of macrolide antibiotics. Aldehyde core 262, readily accessible from 6-0-allyl-erythromycin A, was immobilized on support 263 using a... 

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