Macrolactonization step

This synthesis is shown in Scheme 13.59. Two enantiomerically pure starting materials were brought together by a Wittig reaction in Step C. The aldol addition in Step D was diastereoselective for the anti configuration, but gave a 1 1 mixture with the 6S, 1R-diastereomer. The stereoisomers were separated after Step E-2. The macrolactonization (Step E-4) was accomplished by a mixed anhydride (see Section 3.4.1). The final epoxidation was done using 3-methyl-3-trifluoromethyl dioxirane. 

Thiocillin I (158, Figure 8.8) is a member of thiopeptide antibiotics isolated from Bacillus cereus [172]. The seminal work of Walsh et al. [173] has established the significance of this 26-membered macrocycle. Recently, total synthesis of thiocillin I along with its structural assignment has been described (Scheme 8.14) [174]. The synthesis is notable for two reasons use of new methods in the retrosynthetic scheme and chemoselectivity in the macrolactonization step. The synthesis of precursor 159 involved a key step of modified Bohlmann-Rahtz pathway to the pyridine nucleus [175]. This polar carboxylic acid 159 was coupled in crude form with 162 to yield 160. Global deprotection followed by macrocyclization gave thiocillin I 158 that was identical to the natural product. The carboxyl group at... 

Erythronolide B, the biosynthetic progenitor of the erythromycin antibiotics, was synthesized for the first time, using as a key step a new method for macrolactone ring closure (double activation) which had been devised specifically for this problem. Retrosynthetic simplification included the clearance of the stereocenters at carbons 10 and 11 and the disconnection of the 9,10-bond, leading to precursors A and B. Cyclic stereocontrol and especially the Baeyer-Villiger and halolactonization transforms played a major role in the retrosynthetic simplification of B which was synthesized starting from 2,4,6-trimethylphenol. 

Using FmA catalysis and protected 4-hydroxybutanal, compound (97) has been stereoselectively prepared as a synthetic equivalent to the C-3-C-9 fragment of (-F)-aspicillin, a lichen macrolactone (Figure 10.35) [160]. Similarly, FruA mediated stereoselective addition of (25) to a suitably crafted aldehyde precursor (98) served as the key step in the synthesis of the noncarbohydrate , skipped polyol C-9-C-16 chain fragment (99) of the macrolide antibiotic pentamycin [161,162]. 

K. C. Nicolaou s group at Scripps Research Institute developed two synthetic routes to epothilone A. One of the syntheses involves closure of the lactone ring as a late step. Three major fragments were synthesized. The bond connection at C(6)-C(7) was made by an aldol reaction. The C(12)-C(13) bond was formed by a Wittig reaction and later epoxidized. The ring was closed by macrolactonization. 

This material is converted to bryostatin 1 in 11 steps, including Yamaguchi macrolactonization, installation of the B-ring enoate using Fuji s chiral phosphonate [38] and, remarkably, selective hydrolysis of the C20 acetate in the presence of Cl-macrolide, C7 acetate, as well as the Cl3 and C21 enoate moieties (Scheme 5.6). 

The group of Samuel Danishefsky at the Sloan-Kettering Institute for Cancer Research in New York has also been active in the synthesis of the natural epothilones and biologically active analogs. One of these syntheses also uses the olefin metathesis reaction (not shown). The synthesis in Scheme 13.51 uses an alternative approach to create the macrocycle. One of the key steps is a Suzuki coupling carried out at step H-(l,2) between a vinylborane and vinyl iodide. The macrocyclization is an aldol addition reaction at step H-4. The enolate of the acetate adds to the aldehyde, creating the C(2)-C(3) bond of the macrolactone and also establishing the stereocenter at C-3. 

Taking advantage of the same concept in an intramolecular variant, Romo has documented [78] the synthesis of (—)-panteamine A, Fig. 3, in which a (3-lactam-based macrocyclization is the crucial step to construct the (3-amino macrolactone 33. 

Worst Yields (Single Steps) deprotection to 1 33% macrolactonization 21%... 

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). 

Recently, this unique characteristic of vinylic tellurides was explored in the enantioselective synthesis of macro-lactin A 205, an antiviral macrolactone extracted from sea bacteria. The first step of the synthesis featured the chiral epoxide 203 opening by the vinyl cyanocuprate 202, derived from a tellurium-copper exchange reaction using the vinylic telluride 201, obtained by hydrotelluration of 200 (Scheme 111). Further manipulation of 204 led to macrolactin A 205.271... 

Benzylidene acetals also cleave on heating with excess DDQ in aqueous acetonitrile. The reaction is exemplified by the closing steps of a synthesis of Tricolor-in A, an unusual tetrasaccharide macrolactone isolated from Ipomoea tricolor, a... 

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