Stereocenters transform

Stereochemical strategies The transform selection is guided by stereocenters that have to be removed in retrosynthesis. The user has to select strategic stereo-centers. 

The reduction of stereochemical complexity can frequently be effected by stereoselective transforms which are not disconnective of skeletal bonds. Whenever such, transforms also result in the replacement of functional groups by hydrogen they are even more simplifying. Transforms which remove FG s in the retrosynthetic direction without removal of stereocenters constitute another structurally simplifying group. Chart 3 presents a sampling of FG- and/or stereocenter-removing transforms most of which are not disconnective of skeleton. 

If the disconnection of a bond found to be strategic by criteria 1-3 produces a new ring appendage bearing stereocenters, those centers should be removed if possible (by stereocontrolled transforms) before the disconnection is made. 

The direct goal of stereochemical strategies is the reduction of stereochemical complexity by the retrosynthetic elimination of the stereocenters in a target molecule. The greater the number and density of stereocenters in a TGT, the more influential such strategies will be. The selective removal of stereocenters depends on the availability of stereosimplifying transforms, the establishment of the required retrons (complete with defined stereocenter relationships), and the presence of a favorable spatial environment in the precursor generated by application of such a transform. The last factor, which is of crucial importance to stereoselectivity, mandates a bidirectional approach to stereosimplification which takes into account not only the TGT but also the retrosynthetic precursor, or reaction substrate. Thus both retrosynthetic and synthetic analyses are considered in the discussion which follows. 

The retrosynthetic elimination of olefinic stereocenters (E or Z) was illustrated above by the conversion 147 => 148 under substrate spatial control. It is also possible to remove olefinic stereocenters under transform mechanism control. Examples of such processes are the retrosynthetie generation of acetylenes from olefins by transforms such as trans-hydroalumination (LiAlH4), ci5-hydroboration (R2BH), or ci -carbometallation... 

Stereoelectronic control also plays a role in mechanistic stereoselectivity. One such case is the very fundamental 8 2 process which proceeds rigorously with inversion of configuration at carbon. Because of that intrinsic and predictable stereoselectivity, the C-C disconnective Sn2 displacement transform is very important even though it does not directly reduce the number of stereocenters, e.g. 153 => 154. 

Enantioselective processes involving chiral catalysts or reagents can provide sufficient spatial bias and transition state organization to obviate the need for control by substrate stereochemistry. Since such reactions do not require substrate spatial control, the corresponding transforms are easier to apply antithetically. The stereochemical information in the retron is used to determine which of the enantiomeric catalysts or reagents are appropriate and the transform is finally evaluated for chemical feasibility. Of course, such transforms are powerful because of their predictability and effectiveness in removing stereocenters from a target. 

In summary, modem synthetic methodology allows the stereoselective generation of one, two, or even more stereocenters in a single reaction with or without spatial control by the substrate. The application of transforms to retrosynthetic simplification of stereochemistry requires the selection of transforms on the basis of both structural and stereochemical information in the target and also validation of the corresponding synthetic processes by analysis for both chemical feasibility and stereoselectivity. 

Some examples of directly clearable (CL) and non-clearable (nCL) stereocenters with respect to a particular transform follow. 

Relationships between stereocenters vary between two extremes. On the one hand, stereocenters may interact strongly in a spatial sense if they are directly joined, proximate to one another, or part of a compact rigid-ring structure. On the other hand, two stereocenters which are remote from one another and/or flexibly connected may be so independent that one cannot be used to provide substrate spatial control for the other. Nonetheless, this latter type of stereorelationship may still be clearable if the target molecule can be disconnected to divide the two stereocenters between two precursors or if an appropriate enantioselective transform is available. 

At the opposite end of the topological spectrum are stereocenters in terminal rings that are eligible for disconnection. Stereocenters in such rings which are elements of a retron or partial retron for a ring disconnective transform should be cleared preferentially by application of that transform. Examples 156, 157 and 158 illustrate such stereocenters (starred). 

Stereocenters in a ring which can be severed by a disconnective transform, but which are not part of the retron, can be eliminated prior to disconnection if they are clearable. Removal of such stereocenters may convert a non-strategic bond into a strategic one. Stereocenters should also be cleared if that sets up the retron for a disconnective transform. Such strategic stereocenter eliminations commonly involve transforms which remove a 3 ° or 4 ° stereocenter to generate C=C (endo- or exocyclic), C=0 or C=N. Elimination of two clearable vicinal stereocenters to generate C=C retrosynthetically is strategically indicated whether or not that leads to a disconnectable retron. 

Apply stereoselective transforms to clear stereocenters by removal or interchange of functional groups with the establishment of the retron for a disconnective transform, especially with retrosynthetic generation of the core groups C=C, C=0 or C=N. 

Apply disconnective transforms which do not alter stereocenters but which separate stereocenters by molecular cleavage. 

Use connective transforms to convert an achiral chain segment of nCL centers into a conformationally fixed ring containing CL stereocenters (Section 5.7). 

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