Second order asymmetric transformation

It is obvious from the above that there is no clear-cut distinction between first-order asymmetric transformations, second-order asymmetric transformations, and the process of resolution by salt formation. An acid so optically stable that it does not undergo configurative inversion within the accessible range of experimental conditions will show straightforward resolution but an acid with a marked temperature coefficient of optical inversion might be made to show all three variations of the phenomenon under a ppropriate temperature conditions. 

Starting from a racemate, it is possible to prepare mixtures of enantionmers with a preponderance of one form in them. We have described this in asymmetric transformations, consequently we have first and second order asymmetric transformations. In a first order there is a shift of the equilibrium to the side of formation of one of the enantiomers in solution while in a second order there is a complete conversion of the racemate into one of the optically active forms. 

When p-chlorobenzophenone dichloride reacts with methylamine there results an oil consisting of similar amounts of the syn and anti Schiff base 19. This oil, on standing at room temperature for 2 weeks, transforms to crystals of only the syn isomer. If these crystals are heated above their melting point (125°) for a few minutes, or are dissolved in cyclohexane and allowed to stand at room temperature for 2 weeks, the syn isomer reconverts to a mixture of the two isomers (61a). [This seems to be an example of the so-called second-order or crystallization-induced asymmetric transformations (61b).] A number of systems of this series were known, from previous work, to be dimorphic however, Curtin and Hausser found no case in which it was established that two crystal forms correspond to different isomers (61a). 

Quite a few complexes with the bidentate pentasulfido ligand are also known. The first reported was the homoleptic and optically active complex [Pt(85)3] (15) (53, 64, 65, 68, 69, 176). Brick-red (NH4)2[Pt(85)3] 2H20 is formed from the reaction of K2[PtCl6] with aqueous (NH4)28 solution. Addition of concentrated HCl results in the separation of maroon (NH4)2[Pt8i7] 2H20 (54). The [Pt(85)3] ion crystallizes from the solution as a racemate, which can be resolved by forming diastereoisomers. Upon crystallization, [Pt8,7] undergoes a second-order asymmetric transformation, so that the solid contains an excess of the (—) enantiomer (54). 

A subsequent process, still reliant on salt resolution, is described in Scheme 14.8. In this case, (3-keto amine 34 was converted to carbamate 35, which was then transformed into the desired amino alcohol intermediate 36. The resolution was performed in three distinct stages (1) initial resolution of the racemate, (2) racemization of the (/J)-enriched mixture, and (3) second-order asymmetrically induced crystallization of the (5)-salt. 

However, cases known as second-order asymmetric transformation, which involve preferential crystallization of one diastereomer from an equilibrating mixture, can be excluded. 

A second method requires the formation of diastereomeric salts or covalent derivatives, which are in a mobile equilibrium in solution ( First-Order Asymmetric Transformation"). Again, one of the diastereomers crystallizes ( Second-Order Asymmetric Transformation ). 

The optical purity of the iminazoline consisting of alanine and 2-aminopiperidine can be increased to 93.8 (e.e.)% by crystallizing it In Figure 14(a), once a crystal is removed to the outside of the system, it forms the solution in which asymmetric transformation is carried out the second-order asymmetric transformation where further transformation develops is obtained. In the case of crystallization of a dia-stereomer, 100 (e.e.)% might be possible. In this instance, the alanine appears to be racemized when the iminazoline ring is decomposed with strong acid. 

The deprotonation of (E)-2-butenyl A/,A/-diisopropyl-carbamate leads to (lS,2E)-l-(A(ALdiisopropylcarbamoyloxy)-2-butenyllithium-(—)-sparteine with >90% de after crystallization, combined with a second-order asymmetric transformation (eq 3). It has been applied in the enantioselective synthesis of y-lactones, such as (+)-eldanolide (eq 3), dihydroavermectin Bib, and doubly branched sugar analogs. ... 

It is noteworthy that the higher-melting R, R diastereomer of 75 crystallizes preferentially in a typical second-order asymmetric transformation - from an equilibrium mixture of the two diastereomers in methanol containing hydrochloric acid and sodium iodide, thereby provding a simple method of converting almost all of the original mixture of 75 into the more desirable R, R diastereomer ... 

The achiral 14-membered trans-diimine macrocycle (f , S )-102, in the presence of trifluoroacetic acid, rearranges quantitatively into the chiral seven-membered monoimine ( )-103 (Section Ill.C.l.h)". If the rearrangement of (i , S )-102 is carried out in methanol containing a suspension of ( )-(—)-78, an orange solution is obtained from which pure [I ,(Sas,I as)] ( )-1 6 can be isolated by the addition of ammonium hexafluorophosphate. The yield of the complex was ca 50%. The addition of more acid and halide in an attempt to facilitate racemization of the free arsine and thereby promote the further crystallization of the complex by second-order asymmetric transformation was unsuccessful. Nevertheless, this highly stereoselective synthesis of [H,(Sas,IIas)] ( ) 106 is a more expedient route to (R,I )-(—)-102 than the one involving resolution of the benzyl alcohol complex (R, SA.)-(-)-92a. 

Second-Order Asymmetric Transformations. A modification of the classical resolution occurs in the specific case where equilibration of the chiral center can be achieved during the resolution. By judicious choice of reaction conditions, one diastereomeric salt can be induced to crystallize under the equilibration conditions. As this material precipitates, solution equilibrium is reestablished by racemization of the now-major isomer remaining. In the best cases, over 90% of a single diastereomeric salt can be obtained. 

Examples of second-order asymmetric transformations are relatively rare. By far the best known case (Fig. 1) is the preparation of methyl... 

The finding of a second-order asymmetric transformation involves not only the empiridsm of the classical resolution but also the finding of resolution conditions that simultaneously allow the diastereomeiic interconversion. It is not, then, surprising that these rigid criteria have kept the number of demonstrated examples small. 

Resolution can also be accomplished through kinetic resolution and second-order asymmetric transformations. 

Only reactions taking place under kinetic control will be considered. Asymmetric protonations resulting from second-order transformations wall not be taken into account [127, 551]. 

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