Amides macrolactonization

Paquette et al. start with the bis-vinylogation of the same compound 29 [14], by Wittig-Horner reaction, reduction, and oxidation (Scheme 5). For the formation of the C17-C16 bond, the onti-aldol 41 (ds not reported) is obtained by treatment of the aldehyde 39 with the (Z)-boron enolate 40, bearing a dithioketal moiety that is later to be the C51-C54 side chain. 3-Hydroxy-assisted, diastereoselective reduction of the keto group at C15 gives 41, which is converted into intermediate 42 in five more steps. The dethioketalization of 41 is achieved with phenyliodine(m) bis(trifluoroacetate) [16], As in Nicolaou s synthesis, the N12-C13 amide bond is formed first, followed by a low-yielding (21%, even at a concentration of 1 him) macrolactonization to 3. Table 1 summarizes the benchmark data of the two total syntheses of sanglifehrin A (1). 

Total synthesis of the antibiotic globomycin is achieved via macrolactonization, from the key intermediate 50. Coupling of hydroxy acid 48 and amide 49 is mediated by DEPC without protection of the hydroxyl group in 48.20... 

Synthetic approaches in the field of peptide macrolactones have been basM upon classical peptide coupling to form a linear peptide and subsequent cyclization by formation of either the ester or amide bonds. For example, both these approaches have been successfully employed for the synthesis of the peptide macrolactones belonging to the actinomycin class of antibiotics [46, 47, 48, 49, 50]. 

The following year, the same team isolated, from an unspecified species of Symbiodinium, an inseparable mixture of five 61- to 66-membered macrolactones, related to zooxanthellamides these were overall called zooxanthella-mides C1-C5 (ZAD-Cs). The presence of the macrolactone could be responsible for the vasoconstrictor activity of these amides (Onodera et al, 2005). Zooxanthellamide D (ZAD-D), isolated in 2007 from a Symbiodinium associated with the cnidarian Sarcophyton glaucum (strain JCUCS-1), is a molecule without a spiroketal or sulfate group, and is much smaller (C54Hg3NOi9) than zooxanthellamides A and B. Itis also only moderately cytotoxic, with an IC50 of about 5 pg ml to human carcinoma A431 (Fukatsu et al, 2007). 

Many of the early examples of maerocyeles in drug discovery relied on these classical reaction types for the formation of the ring and they remain in regular use. This was due, in part, to the peptidomimetic nature of many of these structures, which often were targeted at protease enzyme inhibition, and thus lent themselves readily to macrolactamization for amide bond formation or macrolactonization for cyclic depsipeptide-like compounds. Representative examples of these two general transformations are shown in Scheme 11.1 (BOP (benzotriazol-l-ylo5ytris(dimethylamino)-phosphonium hexafluorophosphate, Castro s reagent), EDC (l-ethyl-3-(3-dimethylamino-propyl)-carbodiimide), DMAP (4-dimethylamino-pyridine)) for the matrix metalloproteinase (MMP) inhibitor template 2 and the renin inhibitor scaffold 4. °... 

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