Ring-Bond Disconnections-Isolated Rings

Listed below are some types of disconnections which have strategic value. 

Disconnection of non-building-block rings which are embedded in a skeleton and also centrally located, either by breaking one bond or a pair of bonds. The one-bond disconnections which are of value are (a) bonds between C and N, O or S and (b) bonds leading to a totally symmetrical, locally symmetrical, or linear skeleton. The bond-pair disconnections which are most effective in simplification are those which generate two structures of roughly equal complexity. 

Disconnection of easily formed rings such as lactone, hemiketal or hemiacetal embedded in the skeleton but in a non-central location. 

In the case of TGT structures which are acyclic or which contain isolated rings, the disconnection of non-ring bonds must be examined to identify those disconnections which may be most effective on topological grounds. However, for such acyclic disconnections the topological factors may be overshadowed by other structural considerations. For instance, if a powerful stereosimplifying disconnective transform, such as stereospecific organometallic addition to carbonyl 

The most useful general criteria for the assessment of acyclic strategic disconnections are summarized below. Most of these are based on the rctrosynthetic preservation of building blocks and expeditious reduction of molecular size and complexity. 

arylalkyl, aryl, and other building-block type groups should not be internally disconnected (preserved bonds). 

A disconnection which produces two identical structures or two structures of approximately the same size and structural complexity is of high merit. Such disconnections may involve single or multiple bonds. 

Bonds between carbon and various heteroatoms (e g. O, N, S, P) which are easily generated synthetically are strategic for disconnection. Specific bonds in this category are ester, amide, imine, thioether, and acetal. 

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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). 

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