Systems retrosynthetic analysis

A) Synthesis of A ring system Retrosynthetic analysis of cyclohexanone 2a leads to diene 5 and 2-chloroacrylonitrile 6 as a ketene equivalent (Scheme 13.6.2) as the starting materials. 

To recognize the different levels of representation of biochemical reactions To understand metabolic reaction networks To know the principles of retrosynthetic analysis To understand the disconnection approach To become familiar with synthesis design systems... 

The Japanese program system AlPHOS is developed by Funatsu s group at Toyo-hashi Institute of Technology [40]. AlPHOS is an interactive system which performs the retrosynthetic analysis in a stepwise manner, determining at each step the synthesis precursors from the molecules of the preceding step. AlPHOS tries to combine the merits of a knowledge-based approach with those of a logic-centered approach. 

Intramolecular cycloadditions are among the most efficient methods for the synthesis of fused bicyclic ring systems [30]. From this perspective, the hetisine skeleton encompasses two key retro-cycloaddition key elements. (1) a bridging pyrrolidine ring accessible via a [3+2] azomethine dipolar cycloaddition and (2) a [2.2.2] bicyclo-octane accessible via a [4+2] Diels-Alder carbocyclic cycloaddition (Chart 1.4). While intramolecular [4+2] Diels—Alder cycloadditions to form [2.2.2] bicycle-octane systems have extensive precedence [3+2], azomethine dipolar cycloadditions to form highly fused aza systems are rare [31-33]. The staging of these two operations in sequence is critical to a unified synthetic plan. As the proposed [3+2] dipolar cycloaddition is expected to be the more challenging of the two transformations, it should be conducted in an early phase in the forward synthetic direction. As a result, a retrosynthetic analysis would entail initial consideration of the [4+2] cycloaddition to arrive at the optimal retrosynthetic C-C bond disconnections for this transformation. 

Since in the systems containing two adjacent heteroatoms it is not usual that the ring clorure involves the formation of the bond between them (exceptions may be found in the cases of functional groups such as nitro, nitroso or diazonium), in the retrosynthetic analysis the bond between the two adjacent heteroatoms should not be disconnected. 

Curran s retrosynthetic analysis of fused and bridged polycyclic systems through homolytic disconnections... 

We have already referred to the retrosynthetic analysis of dissonant open chain molecules (see Heading 5.5). In this chapter we will deal with Curran s ideas in connection with fused and bridged polycyclic systems present in many natural products. Emphasis on cyclisations leading to 5-membered rings is maintained because ... 

Previously, Ireland-Claisen ester-enolate rearrangement of the corresponding a-propionyloxy-allylsilane led to model system 5.44 Therefore, elaboration to 4 via rearrangement of 15 was pursued. To complete our retrosynthetic analysis, a plausible route to 15 was devised, involving straightforward homologation of 2P,3a-disubstituted cyclohexanone 17 to cyclohexene-carboxaldehyde 16, which in turn undergoes silylanion addition and subsequent acylation (Eq. 8). 

The mobile Jt-electrons of unsaturated systems, responsible for the stabilization of the carbocations, provide equally efficient stabilization for carbanions. Consequently, a retrosynthetic cleavage of a benzylic, allylic, or propargylic C-C bond has additional merits since the resulting fragments can be visualized as either an electrophile or a nucleophile. The dual synthetic value of the allylic moiety has been extensively utilized in the synthesis of a large number of natural acyclic isoprenoids. The structures of many of these compounds look like they were purposely tailored for this type of retrosynthetic analysis. In fact, the 1,5-diene system, usually present in their structure (Scheme 2.19), immediately suggests the cleavage of its central C-3-C-4 bond, which leads to two allylic precursors. 

Keeping in mind the availability of a Birch reaction for the partial reduction of an aromatic system, the retrosynthetic analysis of 4-rerr-butyl-3-cyclohex-... 

In much the same way, if the structure contains heteroatoms that are not a part of the heteroaromatic system, it makes sense to start the analysis by rupturing a carbon-heteroatom bond as the reverse reaction represents, essentially, a trivial transformation of functional groups. The presence of small ring fragments such as cyclopropane or epoxide rings in the structure of the target molecule almost automatically dictates the retrosynthetic scission of these moieties in the initial steps of retrosynthetical analysis, as both these groups can be easily introduced with the help of very reliable methods. 

In regard to simple monocyclic systems, the basic principles of disconnection for the synthetic target molecule differ very little in essence from those of an acyclic system. In fact, here again the retrosynthetic analysis is more or less directly related to existing methods for the creation of rings (see Section 2.7). We will not regress to a second examination of these methods and will limit our discussion to a few specific points. 

A number of natural sesquiterpenes like hirsutene 90 or corioline 91 have as their common structural unit a system of linearly fused five-membered rings (Scheme 3.21). The standard pathway of the retrosynthetic analysis of this system involves the search for strategic bonds in one of the rings. A, B, or C, disconnection of which would lead to the simplification of the target molecule and eventually to simple cyclopentane derivatives as available starting materials. As a result, diverse synthetic plans were devised and successfully employed in numerous synthetic studies in this field(see also the set of syntheses described in Section 2.23.2). 

---