Functional Groups and Appendages as Keys for Connective Transforms

The y-appendage of 2-cyclohexenone 191 cannot be directly disconnected by an alkylation transform. (y-Extended enolates derived from 2-cyclohexenones undergo alkylation a- rather than y-to the carbonyl group). However, 191 can be converted to 192 by application of the retro-Michael transform. The synthesis of 192 from methoxybenzene by way of the Birch reduction product 193 is straightforward.55 Another synthesis of 191 (free acid) is outlined in 

Aldehyde 198 served as a key intermediate in a synthesis of the alkaloid ajmaline. The Mannich aminomethylation transform triggers disconnection of two bonds in 198 to form dialdehyde 199, which by connective transform application can be converted to cyclopentene 200.58,59 The reduction in functional group reactivity and in structural complexity are both apparent by comparison of 198 and 200. 

Algorithms for machine-generated syntheses by application of connective transforms to target structures containing appendages, medium-sized rings, etc. have been described.62 

7 Functional Groups and Appendages as Keys for Connective Transforms 

The most important connective transforms in retrosynthetic analysis are the family of C=C cleavage transforms, including one-step (e.g. ozonolytic) or two-step (e.g. OSO4 followed by Pb(OAc)4) (Chart 25). There are many elegant syntheses of challenging molecules which depend on such processes. Two examples will provide an idea of the underlying retrosynthetic approach. 

A pair of appendages which are in spatial proximity suggests the application of connective transforms, even if such appendages are not functionalized. Typical of retrosynthetic connections of this type are those shown for targets 201 and 202.  

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