Crystallization induced asymmetric

The technique of purification based on seeded crystallization of the desired isomer and simultaneous racemisation of the undesired isomer, termed crystallization induced asymmetric transformation , has been covered by Davey (1994) with the example of a chiral pesticide, paclobutrazol (P). 

Yoshioka R (2007) Racemization, Optical Resolution and Crystallization-Induced Asymmetric Transformation of Amino Acids and Pharmaceutical Intermediates. 269 83-132 You C-C, Dobrawa R, Saha-Moller CR, Wiirthner F (2005) Metallosupramolecular Dye Assemblies. 258 39-82 Yu J, see Dittrich M (2007) 268 319-347... 

Vedejs, E. and Donde, Y., Stereogenic P-trisubstituted phosphorus by crystallization-induced asymmetric transformation A practical synthesis of phe-nyl(o-anisyl)methylphosphine borane, /. Am. Chem. Soc., 119, 9293, 1997. 

Deoxy-a-D-ribosyl-l-phosphate 20, a key substrate in the preparation of 2 -deoxynucleosides, was stereoselectively prepared by crystallization-induced asymmetric transformation in the presence of an excess of ortho-phosphoric acid and tri( -butyl)amine under strictly anhydrous conditions (Scheme 2).7 Initial Sn2 displacement of Cl in ot-glycosyl chloride 16 by phosphoric acid resulted in a 1 1 a/p anomeric mixture of 17 and 18 due to the rapid anomerisation of the a-chloride in polar solvents. Under acidic conditions, in the presence of an excess of H3P04, an equilibration between the a and p anomers gradually changed in favour of the thermodynamically more stable a-counterpart. By selective crystallization of the mono tri( -butyl)ammonium salt of the a-phosphate from the mixture, the equilibrium could be shifted towards the desired a-D-ribosyl phosphate 18 (oc/p = 98.5 1.5), which was isolated as bis-cyclohexylammonium salt 19 and deprotected to furnish compound 20. 

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). 

Asymmetric Strecker Synthesis of a-Amino Acids via a Crystallization-Induced Asymmetric Transformation Using (/Q-Phenylglycine Amide as Chiral Auxiliary... 

Diastereoselective Slrecker reactions based on (R)-phenylglycine amide as chiral auxiliary are reported. The Strecker reaction is accompanied by an In situ crystallization-induced asymmetric transformation, whereby one diastereomer selecliveiy precipitates and can be isolated in 76-33% yield and dr > gsti. The diastereomeilcaily pure a-amino nitrtie obtained from pivaidehyde (R, = t-Bu, Rj = H) was converted in three steps to (S)-tert-leucine in 73% yieid and >98% ee. 

Because in methanol crystallization of amino nitrile 3 did not take place, first the solvent was varied in order to attempt to find conditions for a crystallization-induced asymmetric transformation. At a MeOH/2-PrOH ratio of 1/9, the amino nitrile (R,S)-3 was isolated in 51% yield and dr 99/1 (entry 2). Other combinations of alcoholic solvents failed to lead to a higher yield of precipitated (R,S)-3 in high dr (entries 3 and 4). On further screening of solvents, it was observed that upon addition of HjO to the methanol solution selective precipitation of amino nitrile (R,S)-3 occurred giving (R,S)-3 and (R,R)-3 in a ratio of 81 19 and 69% yield (entry 5). The asymmetric Strecker reaction was further studied in HjO alone using temperature as a variable. The results of these experiments are given in Table 1 (entries 6-9). After addition of NaCN/AcOH at 23-28 °C... 

Figure2. Crystallization-induced asymmetric transformation of amino nitrile 3.

The observed diastereoselectivity in the asymmetric Strecker step via the crystallization-induced asymmetric transformation can be explained as shown in Figure 2. Apparently, the re face addition of CN to the intermediate imine 4 is preferred at room temperature in methanol and results in a dr 65/35. At elevated temperatures in water, the diastereomeric outcome and yield of the process are controlled by the reversible reaction of the amino nitriles 3 to the intermediate imine and by the difference in solubilities of both diastereomers under the applied conditions. . .. 

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. ... 

Diastereoselective Strecker reactions based on (R)-phenylglycine amide as chiral auxiliary are reported. The Strecker reaction is accompanied by an in situ crystallization-induced asymmetric transformation, whereby one diastereomer selectively precipitates and... 

Overview. To solve these problems, we present the first example of a crystallization-induced asymmetric transformation using optically pure (R)-phenylglycine amide 1 as a chiral auxiliary. The (R,S)-3 diastereomer precipitates out of solution in 76-93% yield with a diastereomeric ratio (dr) > 99/1. (106 words)... 

We present the hrst example of a crystallization-induced asymmetric synthesis. 

The asymmetric synthesis of a-amino acids is an important topic due to their extensive use in pharmaceuticals and agrochemicals and as chiral ligands. The Strecker reaction is historically one of the most versatile ways to produce a-amino acids, but this method has a maximum yield of only 50% for a single enantiomer. Higher yields can be achieved by using chiral auxiliaries, but auxiliaries have other drawbacks, such as high cost, low availability, the need for purification, and high loss rates. A possible solution to these problems would be to use a chiral auxiliary in a crystallization-induced asymmetric transformation. 

Troger s base, the resolution of which with a strongly acidic resolving agent is accompanied by a crystallization-induced asymmetric transformation (also see p426)87. 

A subsequent paper (05TA1969) reported the preparation of four pyrrolo fused TBs, 34a, 34b, 35a and 35b from 33a,b (no chiral induction was observed) (see reaction of 30, 31a,b and 32). The absolute configuration of 34a, [a]o = -193, was determined by X-ray crystallography. A CIAT experiment (crystallization-induced asymmetric transformation) allows the transformation of the crude mixture of 34b and 35b into pure 35b (Scheme 7). The thiophene derivative WADPIB (03AX(E)o745) (see VI.A) also belongs to this section. 

The general drawback of all these resolution concepts is the maximum yield of 50%. In the last part of this chapter the state-of-the-art and recent developments in 100% yield concepts in crystallization-induced resolution are discussed. This so-called crystallization-induced asymmetric transformation combines classical resolution with in situ racemization. Most examples in this chapter originate from day-to-day research efforts at DSM Pharma Chemicals and at Syncom. 

Combination of (classical) resolution with in situ racemization is a powerful but highly underestimated technology. This technology is often referred to as crystallization-induced asymmetric... 

Crystallization-induced asymmetric transformation has already been described by Leuchs in 1913 during the resolution of 2-(2-carboxybenzyl)-l-indanone with brucine.34 In this case spontaneous racemization occurred. More recently researchers at Sanofi observed spontaneous racemization during the resolution of 3-cyano-3-(3,4-dichlorophenyl)propionic acid (7), most likely as a result of the basic resolving agent [>-(-)-N-1 n etli y I g I near nine [d-(-)-MGA] (8) (Scheme 7.6).35 The enantiopure cyano acid, obtained in 91% overall yield, is subsequently reduced to (+)-4-amino-3-(3,4-dichlorophenyl)-l-butanol (9), a key intermediate in the phase 2 synthesis of tachykinin antagonists. 

Other examples of crystallization-induced asymmetric transformation have been described in the literature and have been reviewed.38-39... 

Alternatively, to increase the yield to more than 50%, a classical resolution can be further developed into a crystallization-induced asymmetric transformation. 

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. 

In a second example using 3,4-dimethoxyphenylacetone (8) and (R)-PGA (1), it was found that an equilibrium composition of 55 45 exists between the two diastereoisomers (R,S)-9 and (R,R)-9 in methanol as solvent. By fine-tuning the reaction, it was found that in a mixture of methanol and water (6 1), almost diastereoisomerically pure (de >98%) amino nitrile (R,S)-9 precipitated in 76% isolated yield (Scheme 25.4). Clearly, in this case a crystallization-induced asymmetric transformation has also occurred. 

Few examples of crystallization-induced asymmetric transformations in Strecker reactions based on arylalkyl-methyl ketones have been reported a) Weinges, K., Gries, K., Stemmle, B., Schrank, W. Chem. Ber. 1977, 110, 2098 b) Weinges, K., Klotz, K-P., Droste, H. Chem. Ber. 1980, 113, 710. 

KanomataN, Ochiai Y (2001) Stereocontrol of molecular jump-rope crystallization-induced asymmetric transformation of planar-chiral cyclophanes. Tetrahedron Lett 42 1045-1048... 

Kanomata N, Mishima G, Onozato J (2009) Synchronized stereocontrol of planar chirality by crystallization-induced asymmetric transformation. Tetrahedron Lett 50 4094-12... 

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