Asymmetric Transformation of Enantiomers

M Mass Tansfer Rate from Bulk to Crystal Face ksaT 

These dimensionless numbers can also be combined. For example, the ratio DaR/DaD compares the dissolution rate to the reactor throughput while the product DurNnu compares the nucleation rate with the reactor throughput. The exact form of the dimensionless numbers would change as the reaction kinetics, the growth rate expressions, etc. change, but the meanings would remain the same. 

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It is well-known that catalytic amounts of aldehyde can induce racemization of a-amino acids through the reversible formation of Schiff bases.61 Combination of this technology with a classic resolution leads to an elegant asymmetric transformation of L-proline to D-proline (Scheme 6.8).62 63 When L-proline is heated with one equivalent of D-tartaric acid and a catalytic amount of n-butyraldehyde in butyric acid, it first racemizes as a result of the reversible formation of the proline-butyraldehyde Schiff base. The newly generated D-proline forms an insoluble salt with D-tartaric acid and precipitates out of the solution, whereas the soluble L-proline is continuously being racemized. The net effect is the continuous transformation of the soluble L-proline to the insoluble D-proline-D-tartaric acid complex, resulting in near-complete conversion. Treatment of the D-proline-D-tartaric acid complex with concentrated ammonia in methanol liberates the D-proline (16) (99% ee, with 80-90% overall yield from L-proline). This is a typical example of a dynamic resolution where L-proline is completely converted to D-proline with simultaneous in situ racemization. As far as the process is concerned, this is an ideal case because no extra step is required for recycle and racemization of the undesired enantiomer and a 100% chemical yield is achievable. The only drawback of this process is the use of stoichiometric amount of D-tartaric acid, which is the unnatural form of tartaric acid and is relatively expensive. Fortunately, more than 90% of the D-tartaric acid is recovered at the end of the process as the diammonium salt that can be recycled after conversion to the free acid.64... 

Either (S)-specific aminopeptidase catalyzed hydrolysis of racemic PGA11 or crystallization-induced asymmetric transformation of racemic PGA with (.S l-mandelic acid as resolving agent12 can be used to prepare (R)-PGA. As a result of its ready availability on large scale within DSM, we envisaged the application of (R)-PGA for the production of enantiomerically pure amine functionalized compounds using the chirality transfer concept. Obviously, (S)-phenylglycine amide is also available and can be used for the preparation of the opposite enantiomer of the amines described. 

This chapter describes in a step-by-step manner a generic strategy that we have been using for the development of various industrial processes. The chapter begins with a discussion of the overall workflow for process development, followed by a description of the way in which a process is synthesized, which relies heavily on the use of phase diagrams. The deviation from equilibrium behavior is accounted for using a model-based approach. This is illustrated with an example on the asymmetric transformation of an enantiomer. 

Fig. 11.4. MS-based ee-screening of isotopically labeled substrates [50]. a) Asymmetric transformation of a mixture of pseudo-enantiomers involving cleavage of the functional groups FG and labeled functional groups FG. b) Asymmetric transformation of a mixture of pseudo-enantiomers involving either cleavage or bond formation at the functional group FG isotopic labeling at R2...

A practical and total spontaneous resolution process for the asymmetric transformation of ( )-narwedine (269) into either of its enantiomers, depending on which enantiomer is used as the seeds, and a highly stereospecific conversion of (-)-narwedine (269) into (-)-galanthamine (261) by reduc-... 

Shieh WC, Carlson JA (1994) Asymmetric transformation of either enantiomer of narwedine via total spontaneous resolution process, a concise solution to the synthesis of (—)-galantha-mine. J Org Chem 59 5463-5465... 

As stated earlier, resolution processes give a maximum yield of 50% of the desired enantiomer, but in practice it is usually less than 40%. The yield can be raised beyond 50% if the diastereomer that remains in solution can be made to undergo spontaneous epimerization. An example is the synthesis of dextropropoxyphene by asymmetric transformation of the diastereomeric salt formed from the Mannich reaction product using dibenzoyl-L-tartaric acid (reaction 9.3). 

Scheme 6.4 Crystallization induced asymmetric transformation of ( )-l-methyl-3-amino-5-pheny 1-1,4-benzodiazepine (6) into the (3S)-enantiomer...

Even though the catalyhc (enz5unatic) kinetic resolution [103,104] is in general a powerful method for the separation of enantiomers, the major drawback lies in the limitation of 50% maximum yield from the outset [99]. In order to gain more than 50% product 5deld, alternative techniques based on the asymmetric transformation of a prochiral substrate, DKR [105,106] or deracemization, were established successfully [84,86,107-110]. The latter mentioned technique is either based on the combination of two enantiocomplementary enzymes or by coupling a stereoselective oxidation with a nonstereoselective reduction. This concept is rather powerful as theoretically only seven catalytic cycles are necessary to achieve a single enantiomer in >99% yield [111]. 

A reductive intermolecular Heck heteroarylation (hydroheteroarylation) of A-protected azabicyclo[2,2,l]heptene 165 has been used to construct 7-azabicyclo[2.2.1]heptane 166 in moderate yield [131, 132]. An asymmetric version of such a transformation to provide enantiomerically-enriched iV-protected epibatidine has also been described [128, 133]. It was found that introduction of Noyori s BINAP ligand resulted in the best enantioselectivities with 72-81% ee and a 53% yield. By using either the (R)- or (S)-BINAP ligand, either enantiomer was easily accessible. 

There are two possible approaches for the preparation of optically active products by chemical transformation of optically inactive starting materials kinetic resolution and asymmetric synthesis [44,87], For both types of reactions there is one principle in order to make an optically active compound we need another optically active compound. A kinetic resolution depends on the fact that two enantiomers of a racemate react at different rates with a chiral reagent or catalyst. Accordingly, an asymmetric synthesis involves the creation of an asymmetric center that occurs by chiral discrimination of equivalent groups in an achiral starting material. This can be done either by enan-tioselective (which involves the reaction of a prochiral molecule with a chiral substance) or diastereoselective (which involves the preferential formation of a single diastereomer by the creation of a new asymmetric center in a chiral molecule) synthesis. 

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. 

At that time, as now, the enantiomers of many chiral amines were obtained as natural products or by synthesis from naturally occurring amines, a-amino acids and alkaloids, while others were only prepared by introduction of an amino group by appropriate reactions into substances from the chiral pool carbohydrates, hydroxy acids, terpenes and alkaloids. In this connection, a recent review10 outlines the preparation of chiral aziridines from enantiomerically pure starting materials from natural or synthetic sources and the use of these aziridines in stereoselective transformations. Another report11 gives the use of the enantiomers of the a-amino acid esters for the asymmetric synthesis of nitrogen heterocyclic compounds. 

Quinine and quinidine, as well as cinchonidine and cinchonine, are diastereo-meric pairs. However, at the critical sites—the P-hydroxyamine portions of the molecules—they are enantiomeric. Thus if quinine is used as the chiral catalyst in an asymmetric transformation (i.e., with one enantiomer being formed in excess), the other enantiomer is formed in excess when quinidine is used. Table 2 gives a representative example, the thiol addition reaction (19). 

The complete transformation of a racemic mixture into a single enantiomer is one of the challenging goals in asymmetric synthesis. We have developed metal-enzyme combinations for the dynamic kinetic resolution (DKR) of racemic primary amines. This procedure employs a heterogeneous palladium catalyst, Pd/A10(0H), as the racemization catalyst, Candida antarctica lipase B immobilized on acrylic resin (CAL-B) as the resolution catalyst and ethyl acetate or methoxymethylacetate as the acyl donor. Benzylic and aliphatic primary amines and one amino acid amide have been efficiently resolved with good yields (85—99 %) and high optical purities (97—99 %). The racemization catalyst was recyclable and could be reused for the DKR without activity loss at least 10 times. 

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). 

Figure 2b shows the other extreme, whereby the rate of epimerization is fast relative to the rate of substitution. In this case, Curtin-Hammett kinetics apply, and the product ratio is determined by AAG. In the specific case of organolithium enantiomers that are rendered diastereomeric by virtue of an external chiral ligand, such a process may be termed a dynamic kinetic resolution. Both of these processes are also known by the more general term asymmetric transformation One should be careful to restrict the term resolution to a separation (either physical or dynamic) of enantiomers. An asymmetric transformation may also afford dynamic separation of equilibrating diastereomers, but such a process is not a resolution. "... 

In summary, (R)-phenylglycine amide 1 is an excellent chiral auxiliary in the asymmetric Strecker reaction with pivaldehyde or 3,4-dimethoxyphenylacetone. Nearly diastereomerically pure amino nitriles can be obtained via a crystallization-induced asymmetric transformation in water or water/methanol. This practical one-pot asymmetric Strecker synthesis of (R,S)-3 in water leads to the straightforward synthesis of (S)-tert-leucine 7. Because (S)-phenylglycine amide is also available, this can be used if the other enantiomer of a target molecule is required. More examples are currently under investigation to extend the scope of this procedure. ... 

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