Avermectins glycosidation

The maciocyclic lactone of all avermectins has an a-L-oleandtosyl-a-L-oleanchosyloxy substituent at carbon 13, which is a 2-deoxy sugar glycoside. 

SCHEME 15. Synthesis of an Avermectin B1 analogue by glycosidation of a trichloroacetimidate donor catalyzed by HC104-Si02. 

The glycosylation chemistry in White s total synthesis of avermectin Bia [13] is similar to Hanessian s synthesis of avermectin Bia (Scheme 12.9). Thus, the glycosidation of the... 

The two-stage activation procedure for oligosaccharide synthesis, which was developed by Nicolaou and applied to his synthesis of avermectin Bia [10]> was also employed in his total synthesis of efrotomycin [15] (Scheme 12.11). The chemo- and stereoselective glycosidation of the... 

The aglycon of avermectin has poor antiparasitic activity. Positions 4 and 4" of the olean-drose moieties were modified partly because of feasibility. The synthesis of the 4 -amino-4 G deoxyoleandrose derivative of avermectin Bi and ivermectin was based on the observation that most macrolide antibiotics contained a basic amino group [61]. One of the derivatives, 4 -e/7t-acetamido-4 -deoxyavermectin Bi, is currently under development as a novel avermectin endectoside [61]. Besides, also 2"-a-fluoro (ax.) and 2"- 8-fluoro (eq.) derivatives of avermectins were prepared to strengthen the glycosidic bond. These derivatives have interesting activities in some bioassays compared to the parental compounds [62]. 

Leucomycins (leucomycin A, Fig. 5, 17) [25] and related glycosidic 16-mem-bered ring macrolides are used clinically. Spiroacetal-fused 16-membered ring macrolides, such as avermectins (avermectin Bla, 18) [26] and milbemycins [27],... 

In Section II, the synthetic strategies for macrolide synthesis are introduced and focus in particular on asymmetric synthesis of 1,3-diol, synthetic methodology for macrolactone, and glycosidation. In Section III, the total synthesis of selected macrolide antibiotics is introduced FK506 (tacrolimus 1), rapamycin (sirolimus 2), avermectins (3), altohyrtins (spongistatins 4), and epothilones (5) (Fig. 1). Several other synthesized macrolides are also illustrated. 

The first synthesis of avermectin B,a (3b), the most active avermectin component, was accomplished by the Hanessian group in 1986. The key steps of the synthesis involve eoupling of the C11-C28 northern and Cl-ClO southern segments under Julia conditions, macrolactonization, stereocontrolled glycosidation, and deconjugation to the C3-C4 double bond (Fig. 7). 

The total synthesis of avermectin B,a (3b) by White et al. was accomplished via Julia coupling of the C9-C28 northern and C1-C8 southern segments, macro-lactonization, deconjugation of the C2-C3 double bond to the C3-C4 position, and glycosidation via the pyridylthio glycoside (Fig. 7). 

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