Optimization, diastereomeric salt

As mentioned, asymmetrically pure compounds are important for many applications, and many different strategies are pursued. However, in spite of many methods being developed, the classic resolution technique of diastereomeric crystallization is still preferentially used to prepare optically active pure compounds in bulk quantity. Crystallization is commonly used in the last purification steps for solid compounds because it is the most economic technique for purification and resolution. Attempts to achieve crystallization after completed reaction without workup and extraction is called a direct isolation process. This technique can be cost-effective even though the product yield obtained is lower. Special conditions may be needed in this case, and the diastereomers can be classified into two types diastereomeric salts and covalent diastereomeric compounds, respectively. Diastereomeric salts can, for example, be used in the crystallization of a desired amine from its racemic mixture using a chiral acid. Covalent diastereomers can, on the other hand, be separated by chromatography, but are more difficult to prepare. Another advantage of crystallization is the possibility of combining in situ racemi-zation reactions and diastereomeric formation reactions to get the desired pure compounds. This crystallization-induced resolution technique is still under development because of its requirements for optimized conditions [55, 56],... 

Crystallization of diastereomeric salts obtained from an optically pure acid or an optically pure base is a classical method for the resolution of atropisomeric heterocycles presenting the complementary basic or acid functions. The method requires several trials to find the optimal resolving agent. Atropisomers bearing mono or diphosphine groups are separated using optically pure Pd(ll) complexes. Table 2 reports some selected examples. 

Very high levels of induced diastereoselectivity are also achieved in the reaction of aldehydes with the titanium enolate of (5)-l-rerr-butyldimethylsiloxy-1-cyclohexyl-2-butanone47. This chiral ketone reagent is deprotonated with lithium diisopropylamide, transmetalated by the addition of triisopropyloxytitunium chloride, and finally added to an aldehyde. High diastereoselectivities are obtained when excess of the titanium reagent (> 2 mol equiv) is used which prevents interference by the lithium salt formed in the transmetalation procedure. Under carefully optimized conditions, diastereomeric ratios of the adducts range from 70 1 to >100 1. 

After identifying the optimal etherification conditions, our attention turned to isolation of 18 in diastereomerically pure form. Diastereomers 18 and 19 were not crystalline, but, fortunately, the corresponding carboxylic acid 71 was crystalline. Saponification of the crude etherification reaction mixture of 18 and 19 with NaOH in MeOH resulted in the quantitative formation of carboxylic acids 71 and 72 (17 1) (Scheme 7.22). Since the etherification reaction only proceeded to 75-80% conversion, there still remained starting alcohol 10. Unfortunately, all attempts to fractionally crystallize the desired diastereomer 71 from the crude mixture proved unfruitful. It was reasoned that crystallization and purification of 71 would be possible via an appropriate salt. A screen of a variety of amines was then undertaken. During the screening process it was discovered that when NEt3 was added... 

The Merck process group subsequently published a more detailed route amenable towards multikilogram scales (Blacklock et al., 1988). This synthesis begins with treatment of alanine with phosgene to produce A-carboxyanhydride (NCA) 16 (Scheme 10.3). Under basic aqueous conditions this anhydride is coupled with proline to produce, upon acidic work-up, the dipeptide alanyl-proline (14). Enalapril is then prepared in one synthetic step by a diastereoselective reductive amination between ethyl-2— oxo-4-phenylbutyrate (13) and 14. This reaction was the subject of extensive optimization, and it was found that the highest diastereoselectivity was obtained by hydrogenation over Raney nickel in the presence of acetic acid (25%), KF (4.0 equiv.), and 3 A molecular sieves (17 1 dr). Enalapril is then isolated in diastereomerically pure form as its maleate salt (Huffman and Reider, 1999 Huffman et al., 2000). 

Optimal reaction conditions were used for ball milling of stoichiometric amounts of variety of Boc-protected a-amino acid A-carboxyanhydrides (Boc-AA-NCA) 92 or Boc-protected a-amino acid A-hydroxysuccinimide esters (Boc-AA-OSu) 95 with a-amino acid alkyl ester salts (Schemes 3.26 and 3.27, Tables 3.9 and 3.10). In this way, di- to pentapeptides 97 and 100 were produced in high yield and environmentally benign manner. For some of the reactions, iBuOAc was used as a grinding auxiliary. Furthermore, it was established that no racemization could be observed as the diastereomeric excess of some products was checked and was found to be superior to 98%. After completion of Boc-AA-OSu reactions, mixture was milled for 5 min at 30 Hz with aqneous NaOH solution, diluted with EtOAc, and washed with sodium carbonate and dilnted acid. Pentapeptide Boc-Tyr(Bn)-Gly-Gly-Phe-Leu-OBn product obtained mechanochemically was successfully converted to Leu-enkephaUn by classical methods. 

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