Milbemycins synthesis

In several cases of syntheses of highly functionalized molecules, use of CH3Li-LiBr for ylide formation has been found to be advantageous. For example, in the synthesis of milbemycin D, Crimmins and co-workers obtained an 84% yield with 10 1 Z E selectivity.251 In this case, the more stable E-isomer was required and it was obtained by I2-catalyzed isomerization. 

Phosphine oxide-based olefination has been increasingly used as a synthetic method. The phosphine oxide (62). required for a synthesis of 3-milbemycin (64). has been prepared as a mixture of... 

When one of the reacting partners in the Wittig-Horner reaction, either the phosphine oxide or the carbonyl compound, has a double bond, the product is a diene. The Wittig-Horner reaction was utilized by Smith and coworkers in the total synthesis of milbemycin (equation 98)170. They found that when sodium hexamethyldisilazide was employed as a base, the desired E-diene selectivity is high (85%). Some examples from the literature where the Wittig-Horner reaction has been utilized for the construction of E-double bonds present in dienes and polyenes are given in Table 19171. 

A similar approach to that described above was used by the authors in the synthesis of a milbemycin K fragment, see S. Takano, Y. Sekiguchi and K. Ogasawara, Heterocycles, 1994, 38, 59. 

Lewis acids can also be used to effect deacetalisation under mild conditions. A stringent example comes from a synthesis of Milbemycin by Ley and co-workers [Scheme 2,8),25 in which deacetalisation released a P-hydroxy ketone that was prone to elimination. However, by simply treating the acetal with PdCl2(MeCN)2 in acetone26 at room temperature, the requisite product was obtained in 94% yield. Under these conditions, acetals can be released in the presence of tertiary alcohols or oxiranes without incident [Scheme 2,9].27,28... 

Ley et al. [22] recently applied this method to the total synthesis of the antibiotic ( + )-milbemycin jSi(ii). Thus, hydroxy acid 31 was cyclized to macrolactone 32 in good yield (more than 49%) by slow addition (over 9 h) of a solution of 31 and triethylamine in acetonitrile to a refluxing solution of 28 in acetonitrile (Scheme 11). Another recent application of the Mukaiyama method is due to White and Bolton [23],... 

Another carbodiimide, l-cyclohexyl-3-(2-morpholinoethyl)carbodiimide methyl /t-toluenesulfonate, has been used for macrocyclization in the synthesis of milbemycin /J3 [52]. 

Favorable configuration and efficient activation complement with each other. If the configuration is favorable enough even a methyl ester is as good as an activated ester. For instance, as shown in Scheme 40, in the synthesis of the macrolide antibiotic milbemycin /S3 (120) by Smith et al. [67], alcohol ester 118 was lactonized by potassium hydride to milbemycin fij methyl ether (119) in high yield (more than 76%). 

A more recent example of a functionalized alkyne addition can be seen in Crimmin s synthesis of tala-romycin A (equation 42). ° This particular alkynide is an equivalent of the formyl acetone dianion and its use has been generalized as an entry into the spiroketal portion of the milbemycins (Scheme 20). This approach differs from the Hanessian strategy in that formation of the C(17> (21) pyran ring is constructed last, through use of the alkynic unit. 

The diene pcntions of avermectin and milbemycin have been synthesized by application of the Julia coupling. For the total synthesis of milbemycin 3s by Baker and coworkers, the aromatic ring was incorporated as the aldehyde (431) and the spiroketal portion added as the sulfone (430 equation 100). The overall yield was 70-80% of the ( , )-alkene (432), exclusively. The identical bond disconnection was studied by Kocienski, but with the aldehyde (433) and sulfone (434) components reversed (equation 101). The anion was formed with LDA and, following functionalization and reductive elimination, the alkene was isolated in 39% yield in a 5 1 ratio of the ( )- and (Z)-isomers (435). 

An interesting variation upon these approaches was published by Ley and coworkers. In studies directed toward the synthesis of milbemycin 3i, a vinyl sulfone (43 was deprotonated to form the diene... 

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