4.2 Stereochemical ComplexityClearable Stereocenters...51 4.3 Stereochemical StrategiesPolycyclic Systems...54 4.4 Stereochemical StrategiesAcyclic Systems...56
4.1 Stereochemical SimplificationTransform Stereoselectivity
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 creation of a stereocenter in the synthetic direction may be controlled sterically by one or more stereocenters in a substrate. Such control is especially common in structures which are conformationally rigid, foremost among which are cyclohexane derivatives. Because the preexisting stereocenters are linked to the reaction site by a rigid and relatively short path in such a case, a sufficiently strong steric bias can result so that one particular diastereomeric product is favored, even for a reaction which has no intrinsic stereospecificity. Generally reactions in which a minor reactant or reagent carries no stereochemical information (e.g. NaBH4 or n-BuLi) will be stereoselective only if the substrate (major reactant) displays a strong spatial bias. In retrosynthetic terms the corresponding transforms operate stereoselectively only under spatial control by the substrate; their retrons need not contain stereochemical information. Two examples are provided in the retrosynthetic sequence 143 ⇒ 145. The carbonyl reduction
Me
H OH H
Me
O H
Me
O
143 144 145
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References are located on pages 92-95. A glossary of terms appears on pages 96-98.
transform 143⇒ 144 can be applied provided that a reagent is available (e.g. LiBHEt3) which renders sufficient the spatial bias within 144 favoring approach to only one π-face of the keto group.
Similarly, the α,β-enone reduction transform 144 ⇒ 145 is valid for the reagent Li-NH3 because of substrate spatial bias. Although the stereoselectivity of such processes depends fundamentally on mechanism and relative energetics of competing diastereogenic pathways, reaction mechanism per se does not induce stereoselectivity.
There are also reactions which show stereoselectivity primarily because of mechanism rather than spatial bias of substrate. For instance, the conversion of an olefin to a 1,2-diol by osmium tetroxide mechanistically is a cycloaddition process which is strictly suprafacial. The hydroxylation transform has elements of both substrate and mechanism control, as illustrated by the retrosynthetic conversion of 146 to 147. The validity of the retrosynthetic removal of both
Me
H
Me OH
OH H
Me
H
H
Me Me
H
O
146 147 148
stereocenters depends on the intrinsic stereoselectivity of the transform (for the stereorelationship between the two centers) and also on the olefinic structure and spatial bias of substrate 147. The Z-olefinic stereocenter of 147 can be removed by application of the Wittig olefination transform to generate 148 under substrate spatial control.
There is also a category of intramolecular reactions/transforms which involves total mechanistic stereocontrol with conformationally restricted structures, for example the halolactonization transform 149 ⇒ 150 and the internal cycloaddition 151 ⇒ 152. These transforms are relatively insensitive to steric effects and are powerfully stereosimplifying. In
HO H
O
CHN2
O O H
HO
H O
H
149 150
151 152
I
O O
general the more rigid a target structure is, the more feasible the selective removal of stereocenters will be if mechanism-controlled transforms are available.
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 retrosynthetic generation of acetylenes from olefins by transforms such as trans-hydroalumination (LiAlH4),
cis-hydroboration (R2BH), or cis-carbometallation (Me3Al-Cp2ZrCl2 or R2CuLi). In such cases of cis addition, stereoselectivity originates from a dominant cycloaddition mechanism.
Stereoelectronic control also plays a role in mechanistic stereoselectivity. One such case is the very fundamental SN2 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.
Me
H OH
H
Me
H O H
153 154
Examples were given above of stereocontrol due to substrate bias of a steric nature. Substrate bias can also result from coordinative or chelate effects. Some instances of coordinative (or chelate) substrate bias are shown retrosynthetically in Chart 18.
OH
O
OH
Ph Ph
OMe
Me H
OH
Ph Ph
OMe H
O
OH
H H OH
OH OH OH O
OMe
OH O
OMe
OH O
Chart 18 H2 (R3 P)2 Rh+ NaBH(OAc)3 CH2 I2. Zn (Cu )
MeLi ArCO3H
Spatial and/or coordinative bias can be introduced into a reaction substrate by coupling it to an auxiliary or controller group, which may be achiral or chiral. The use of chiral controller groups is often used to generate enantioselectively the initial stereocenters in a multistep synthetic sequence leading to a stereochemically complex molecule. Some examples of the application of controller groups to achieve stereoselectivity are shown retrosynthetically in Chart 19.
O
HCA, 1981, 64, 2808.
JACS, 1972, 94, 8616.
There are a number of powerful synthetic reactions which join two trigonal carbons to from a CC single bond in a stereocontrolled way under proper reaction conditions. Included in this group are the aldol, Michael, Claisen rearrangement, ene and metalloallyl-carbonyl addition reactions. The corresponding transforms are powerfully stereosimplifying, especially when rendered enantioselective as well as diastereoselective by the use of chiral controller groups. Some examples are listed in Chart 20.
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, modern 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.