Control of Stereochemistry

When the target has a defined stereostructure it is necessary to conduct the reaction steps so that a correct configuration can be obtained at double bonds, at rings and at chiral centers. 

In the past, it was rather common that racemic mixtures were obtained in complex synthesis. The desired enantiomer was then obtained by resolving the racemic mixture. However, this reduces the overall yield by 50 %. 

the trend is to synthesize complex molecules in optically pure form. This is possible due to an ever increasing number of available optically active starting materials (the chiral pool) and the fact that new stereoselective procedures are being developed at a steadily increasing rate. The armoury to achieve stereocontrol is impressive and it is beyond the scope of this chapter to go into any details only a few brief comments will be given. 

Double bonds can be created by a number of available stereospecific reactions (E2 elimination, pyrolytic elimination, e.g. Cope, Chugaev reactions), stereoselective Wittig and related reactions, reduction of triple bonds, by cisitrans isomerisation of existing double bonds either photochemically or by wet chemistry, e.g. the Corey-Winter procedure. [17] 

Ring stereochemistry can be efficiently created through multicenter reactions, and in this respect the Diels-Alder reaction is extremely useful. Other tricks are to use intramolecular reactions, e.g. iodolactonisation.[18] 

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Diastereoselective Hydrogenation since -OH directs the H2, there is a possibility for control of stereochemistry - sensitive to H2 pressure catalyst cone, substrate cone, solvent. 

When topological strategies are used concurrently with other types of strategic guidance several benefits may result including (1) reduction of the time required to find excellent solutions (2) discovery of especially short or convergent synthetic routes (3) effective control of stereochemistry (4) orientational (regiochemical) selectivity (5) minimization of reactivity problems and (6) facilitation of crucial chemical steps. 

Mechanism-Control of Stereochemistry. Stereocontrol in a reaction or transform as a result of mechanistic factors rather than substrate structure alone. 

Aromatic rings can be reduced without difficulty. Major problems connected with these reductions concern maintenence of other functions, control of regioselectivity in polycyclic aromatics, and control of stereochemistry. 

Complete control of stereochemistry was also obtained in a total synthesis of ptilocaulin. As the key step, addition of trimethyl(2-propenyI)silane to an enantiomerically pure 5,6-di-aikylcyclohexenone in the presence of titanium(IV) chloride was used to establish a new stereocenter at C-5 with appropriate configuration31. 

Stereochemical Control Through Chiral Auxiliaries. Another approach to control of stereochemistry is installation of a chiral auxiliary, which can achieve a high degree of facial selectivity.124 A very useful method for enantioselective aldol reactions is based on the oxazolidinones 10,11, and 12. These compounds are available in enantiomerically pure form and can be used to obtain either enantiomer of the desired product. 

Scheme 2.6. Control of Stereochemistry of Aldol and Mukaiyama Aldol Reactions Using...

The degree of control of stereochemistry that is necessary during synthesis depends on the nature of the molecule and the objective of the synthesis. The issue... 

The Prelog-Djerassi lactone (abbreviated here as P-D lactone) was originally isolated as a degradation product during structural investigations of antibiotics. Its open-chain equivalent 3 is typical of the methyl-branched carbon chains that occur frequently in macrolide and polyether antibiotics. The compound serves as a test case for the development of methods of control of stereochemistry in such polymethylated structures. There have been more than 20 different syntheses of P-D lactone.24 We focus here on some of those that provide enantiomerically pure product, as they illustrate several of the methods for enantioselective synthesis.25... 

In order to control both the stereochemistry and enantioisomerism of the photocyclization product, design of a good host compound is necessary. It seems adequate to design an optically active 2,2-biphenyldicarboxamide derivative, since 4 is very useful for the control of stereochemistry of the photocyclization of 74. 

Micellar control of stereochemistry has also been realized in SN1 hydrolyses of chiral sulfonic esters (Okamoto et al., 1975 Sukenik and Bergman, 1976). 

In certain cases, the C-H activation/Cope rearrangement is so favorable that double C-H functionalization can occur as illustrated in Equation (38). The product 33 was formed in 99% ee with excellent control of stereochemistry at four centers due to the involvement of a cascade process rather than a direct C-H insertion. 

The data in Table 6.7 illustrate that when the non-racemic (ebthi)Zr system is used to catalyze the hydrogenation of prochiral alkenes, moderate levels of enantiofacial differentiation are observed (23—65% ee). Enantioselective deuteration of pentene occurs in low yield but shows noticeable enantioselection (23% ee). The same reaction with styrene proceeds in 61% yield and with moderate enantioselectivity (65% ee). Hydrogenation of 2-phenyl-l-pentene proceeds in excellent yield but with poor control of stereochemistry (95% yield, 36% ee). 

As indicated by the aforementioned examples U5-U8>5 the most useful feature of the intramolecular trapping of o-xylylenes generated from benzocyclobutenes is the control of stereochemistry so that high purity of ( )-estrone could be obtained. Subsequent molecular manipulation of synthetic estrone may give rise to alternative routes to other medicinally important steroid drugs. 

Among the various methods proposed to produce selectively isolated enantiomers, the use of enantioselective catalysis is by far the most attractive one. The control of stereochemistry by use of a minute amount of an asymmetric catalyst offers clear advantages. Therefore, the design and development of catalytic enantioselective organic reactions is considered as one of the most attractive and challenging frontiers in synthetic organic chemistry. 

The masked disilene approach, while offering major improvements in polymer structural control, has a few drawbacks monomers bearing bulky groups (e.g., 1,1-di-f-Bu, aryl) and Si-OR substituents cannot be polymerized the overall synthetic scheme from commonly available reagents is rather involved. Despite these, however, the route remains attractive, and further developments, such as in the control of stereochemistry, will likely be explored. 

A large number of studies have addressed the condensation of cyclic ketones with both aliphatic and aromatic aldehydes under conditions that reflect both thermodynamic (cf. Table 2) and kinetic control of stereochemistry. The data for cyclohexanone enolates are summarized in Table 8. Except for the boryl enolates cited (6), the outcome of the kinetic aldol process for these enolates... 

Diethyl malonate has been proposed for use as a proton source in these cyclization reactions [124], It is not a sufficiently strong acid to protonate the radical-anion rapidly. However it irreversibly protonates the enol intermediate generated after carbon-caibon bond formation. In one case, control of stereochemistry in favour of the traHS-sunstituted five membered ring 39 was achieved by the addition of cerium(Ill) ions [124],... 

The preceding reactions illustrate control of stereochemistry by aldehyde substituents. Substantial effort has also been devoted to use of chiral auxiliaries and chiral catalysts to effect enantioselective aldol reactions.71 72 Avery useful approach for enantioselective aldol condensations has been based on the oxazolidinones 1-3, which are readily available in enantiomerically pure form. 

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