Asymmetrically Induced Crystallization

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. 

The absence of asymmetric carbon atoms in IER could explain why the strain-induced crystallization is more pronounced in this case. Numerous strong reflections of the type shown in Figure 11 were obtained by X-ray diffraction of stretched IER samples at 30 °C. It is therefore evident that a well-formed crystal lattice exists. 

These solvents include tetrahydrofuran (THF), 1,4-dioxane, chloroform, dichloromethane, and chlorobenzene. The relatively broad solubility characteristics of PSF have been key in the development of solution-based hollow-fiber spinning processes in the manufacture of polysulfone asymmetric membranes (see Hollow-fibermembranes). The solvent list for PES and PPSF is short because of the propensity of these polymers to undergo solvent-induced crystallization in many solvents. When the PES structure contains a small proportion of a second bisphenol comonomer, as in the case of RADEL A (Amoco Corp.) polyethersulfone, solution stability is much improved over that of PES homopolymer. 

The fundamental component (aE) is linear in E and represents the linear optical properties discussed above. The second (jfiE-E) third ( yE-E-E) and subsequent harmonic terms are nonlinear in E and give rise to NTO effects. The / and values are referred to, respectively, as the first and second hyperpolarisabilities. The second harmonic term gives rise to second harmonic generation (SHG), the third results in frequency tripling effects, and so on. Importantly, since only the time-averaged asymmetrically induced polarisation leads to second-order NLO effects, the molecule and crystal must be non-centrosymmetric, otherwise the effects will cancel one another. Third-order effects, however, may be observed in both centrosymmetric and non-centrosymmetric materials. 

Solubility of the three commercial polysulfones follows the order PSF > PES > PPSF. At room temperature, all three of these polysulfones as well as the vast majority of other aromatic sulfone-based polymers can be readily dissolved in a handful of highly polar solvents to form stable solutions. These powerful solvents include NMP, DMAc, pyridine, and aniline. 1,1,2-Trichloroethane and 1,1,2,2-tetrachloroethane are also suitable solvents but are less desirable because of their potentially harmful health effects. In addition to being soluble in the aforementioned list, PSF is also readily soluble in a host of less polar solvents by virtue of its lower solubility parameter. These solvents include tetrahydrofuran (THF), 1,4 dioxane, chloroform, dichloromethane, and chlorobenzene. The relatively broad solubility characteristics of PSF have been key in the development of solution-based hollow-fiber spinning processes in the manufacture of polysulfone asymmetric membranes (see Membrane Technology). The solvent list for PES and PPSF is short because of the propensity of these polymers to undergo solvent-induced crystallization in many solvents. When the PES structure contains a small proportion of a second bisphenol comonomer, as in the case of RADEL A (British Petroleum) polyethersulfone, solution stability is much improved over that of PES homopolymer. 

The next stage in the development of a systematic asymmetric synthesis strategy addressed the question of whether or not there was any feedback mechanism whereby the seeding of the initial growth solution with product of one chirality (say D, and formed from an earlier solid state reaction) would modify product formation by induced crystallization such that even more D isomer may be formed on further reaction. Green and Heller proposed a cyclic process as shown in Scheme 6.12a. It transpired, however, that in such experiments the product obtained from a crystal grown in the presence of right-handed product repeatedly caused preferential crystallization into a crystal of the left-handed form — the so-called inversion or reversal rule. ... 

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). 

In these systems, after the crystal chirality induced the chirality of asymmetric carbon in external organic compound, the subsequent asymmetric autocatalysis gives the greater amount of enantiomerically amplified product. These results clearly demonstrate that the crystal chirality of achiral organic compound is responsible for the enantioselective addition of /-Pr2Zn to pyrimidine-5-carbalde-hyde Ic. 

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)... 

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