Avermectin disaccharide, synthesis

P. G. M. Wuts and S. S. Bigelow, Total synthesis of oleandrose and the avermectin disaccharide, benzyl a-L-oIeandrosyl-a-L-4-acetoxyoleandrolide, J. Org. Chem. 48 3489 (1983). 

TMSOTf activation for coupling of 1-O-acylated glycosyl donors has been employed in a synthesis of avermectin disaccharides (eq 26). ... 

Matsumoto [139] via racemic 115. The use of an alternative chiral precursor is illustrated by the synthesis of L-oleandrose 99 in six steps (16% overall yield) from alcohol 116 (derived from ethyl lactate [140]) by Wuts and Bigelow [141]. The L-oleandrose thus obtained was converted to disaccharide derivative 117 by a five step sequence (26% overall yield) in which glycosidation was accomplished by Pb(C104)2 activation of a 2-pyridylthioglycoside. The synthesis of 117 constituted the first reported total synthesis of a derivative of the avermectin disaccharide. 

The previous discussion clearly shows that total synthesis provides a viable approach to the avermectin disaccharide for use in the synthesis of avermectins. An alternative source of the disaccharide unit is chemical degradation of a natural avermectin. It is worth noting that the chemical degradation approach to the avermectin disaccharide unit could in principle use any natural avermectin or mixture of avermectins as a starting material. The ready availability of several natural avermectins from fermentation makes this approach particularly advantageous when a large amount of material is needed in a short period of time. The first example of this route to an avermectin disaccharide was reported by Albers-Schonberg et al. in 1981 [5]. As part of the structure determination of the avermectins they subjected avermectin A2a 123 to ozonolysis followed by... 

It is clear from the examples described above that there are a number of viable approaches to derivatives of the avermectin disaccharide unit. The availability of these procedures has allowed the synthesis of two natural avermectins and one unnatural analog. In addition, it can be expected that the availability of the disaccharide unit will result in the synthesis of numerous additional avermectins in the near future. 

Sinay introduced the use of phenylselenyl chloride as an electrophile [16], which was exploited by Barrett in the avermectin a-disaccharide synthesis [17]. Ogawa... 

In the synthesis of avermectin Bla, the disaccharide fluoride 48 is prepared and coupled with avermectin aglycon 49 in the presence of SnCl2-AgC104 in dry ether to give protected avermectin Bla50 in 62% yield (Scheme 2.16) [23]. 

The synthetic plan to achieve the total synthesis of avermectin involves the preparation of the aldehyde fragment (A) from D-glucal tripivalate (114), and the ketone fragment (B) from D-ribose aldehyde(125). Coupling of (A) and (B) gives the macrolactone (C). The resulting lactone is reacted with disaccharide (D) to form avermectin A [119]. 

The structural feature of avermectins (3) (Fig. 1) includes 6,6-spiroketal and a disaccharide unit in the northern part and an oxahydrindene unit in the southern part. Because of the sensitive hexahydrobenzofuran subunit, the C3-C4 double bond was incorporated at a late stage during the course of total synthesis. 

An important consideration in the planning of an avermectin synthesis is the source of the optically active disaccharide (L-oleandrosyl-L-oleandrose) unit 98. In principle there are two reasonable solutions to this problem. The first is to prepare L-oleandrose 99 by total synthesis (oleandrose is not commercially available) either from chiral precursors or by asymmetric synthesis then couple two oleandrose units to form disaccharide 98. An alternative approach is to prepare 98 by chemical degradation of a naturally occurring avermectin. In practice there are advantages to both approaches and both have been used for the synthesis of derivatives of oleandrose and disaccharide 98. 

In recent years the discovery of novel methods of asymmetric synthesis has greatly increased the ability of organic chemists to synthesize optically active sugars. For example, the asymmetric epoxidation reaction discovered by Katsuki and Sharpless [142] was recently used as the key step in a synthesis of D-oleandrose 118 from divinyl carbinol 119 by Hatakeyama et al. [143]. An alternative approach to asymmetric synthesis of oleandrose was taken by Danishefsky et al. [144,32] in their synthesis of avermectin which is the first, and currently the only, reported total synthesis of an avermectin. The key step of this synthesis was a cyclocondensation reaction of optically active diene 121 with acetaldehyde catalyzed by the optically active Lewis acid (-h)-Eu(hfc)3 [145]. The resulting chiral pyrone was then elaborated to methyl-L-oleandroside 113. This was further converted to the disaccharide glycal 122 by a 4 step sequence in which glycoside formation was accomplished by iV-iodosuccinimide mediated addition of the alcohol to a glycal followed by tributyltin hydride... 

As we have seen in the previous sections, the avermectin syntheses reported to date have all employed a convergent strategy in which southern half, northern half and disaccharide components are synthesized individually and later assembled to complete the synthesis. In this section we will discuss the problems associated with assembling these components and the methods which have been developed to solve these problems. 

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