Diastereomeric derivatives, formation

An extremely important aspect in pharmaceutical research is the determination of drug optical purity. The most frequently applied technique for chiral separations in CZE remains the so-called dynamic mode where resolution of enantiomers is carried out by adding a chiral selector directly into the BGE for in situ formation of diastereomeric derivatives. Various additives, such as cyclodextrins (CD), chiral crown ethers, proteins, antibiotics, bile salts, chiral micelles, and ergot alkaloids, are reported as chiral selectors in the literature, but CDs are by far the selectors most widely used in chiral CE. 

Few methods are available to determine enantiomeric purity of aldehydes by NMR spectroscopy of diastereomeric derivatives. The formation of imines. oxazolidines and more recently the advantageously C2-symmetrical imidazolidines with optically pure reagents can be utilized. 

Alternative synthetic approaches include enantioselective addition of the organometallic reagent to quinoline in the first step of the synthesis [16], the resolution of the racemic amines resulting from simple protonation of anions 1 (Scheme 2.1.5.1, Method C) by diastereomeric salts formation [17] or by enzymatic kinetic resolution [18], and the iridium-catalyzed enantioselective hydrogenation of 2-substituted quinolines [19]. All these methodologies would avoid the need for diastereomer separation later on, and give direct access to enantio-enriched QUINAPHOS derivatives bearing achiral or tropoisomeric diols. Current work in our laboratories is directed to the evaluation of these methods. 

Just like the common amino acids, the enantiomeric purity of y-amino-P-hydroxy acids is established by formation of diastereomeric derivatives and their analysis by HPLC or NMR spectrometric techniques. In addition to derivatization of the y-amino group, the P-hydroxy moiety of this class of compounds may also possibly be derivatized. 

Such racemic lactones as substituted -butyrolactones and -valerolactones are resolved by means of the diastereomeric salt formation or the diastereomeric amide formation method.24,25 For example, -decalactone is successfully resolved in the form of its diastereomeric amides derived from a-methylbenzylamine (Figure ll).24... 

Leusen et al. studied the crystal packing of ephedrine with several phosphoric acid stereoisomers to verify whether a relationship between enthalpy of formation and separation of enantiomers via diastereomeric salt formation exists.They considered four different force fields and determined that the CHARMM program, as implemented in QUANTA, was the best for their application. Their decision was based mainly on the knowledge that non-bonded cutoff distances are larger in CHARMM. A larger cutoff distance is necessary to account for the interaction between different hydrophobic layers in the crystal (interlayer distances of 14—16 A). These authors were unable to quantitatively determine the validity of their hypothesis, although qualitative explanations were derived for their observations. 

Formation of Esters. One frequently used approach to the formation of diastereomeric derivatives of carboxylic acids is esterification with an optically active alcohol (Eq, 9)... 

A short three-step synthesis has been developed for the -N(Et)2 derivative 291. (—)-N-Boc-0-benzyl (S) tyrosine among 63 optically pure resolving agents was found suitable for a large-scale resolution via diastereomeric salt formation. The (S) configuration was assigned to the (—) form by X-ray of the diastereomeric complex (03JOC7379). 

Bagi P, Kdllay M, Hessz D, Kubinyic M, Holczbauer T, Czugler M, Fogassy E, Keglevich G (2014) Resolution of l-n-propoxy-3-methyl-3-phospholene 1-oxide by diastereomeric complex formation using TADDOL derivatives and calcium salts of O, 0 -dibenzoyl-(2R,3R)-or O, 0 -di-P-toluoyl-(2R,3R)-tartaric acid. Tetrahedron Asymmetry 25 318-326... 

Formation of substituted oxycarbonyl amino acid diastereomeric derivatives... 

Methods for the chiral separation of amino acids can be divided into two categories one is an indirect method based on the formation of diastereomers by the reaction of amino acids with a chiral derivatiza-tion reagent and separation of the diastereomeric derivatives on an achiral stationary phase. The other is a direct method based on the formation of diastereomers on a stationary phase or in a mobile phase, where the former uses a chiral stationary phase (CSP) and the latter adds a chiral selector in a mobile phase and uses an achiral stationary phase. 

Two-stage single-pot derivatization of carboxylic acids (with intermediate formation of chloroanhydrides with thionyl chloride followed by their conversion into amides) was recommended preferably for HPLC analysis, but the simplest dialkylamides and even anilides ° are volatile enough for GC analysis also (the mixture of PhaP and CCLt, instead of SOCI2, can be used in this reaction). Moreover, the same procedure is used for the synthesis of diastereomeric derivatives of enantiomeric carboxylic acids (see below) ... 

Fig. 8 Example of formation diastereomeric derivatives from chiral carbonyl compound and derivatization reagent.

GLC Analysis bv Diastereomer Formation. Conversion of chiral compounds to diastereomeric derivatives that can be analyzed by achiral chromatographic phases offers a procedure that is complementary to those methods that have already been employed with pseudolipids (30), In addition, if a conceptual model can be developed to explain the elution order of diastereomers, then this particular method has the further value of predicting separations. 

Pyrolysis at 190° of the resulting diastereomeric A -pyrazolines (8) and (11) leads to elimination of nitrogen and formation of the cis- and tmns-cydo-propanecarboxylates (9) and (12), respectively. Thermal decomposition of the A -pyrazoline (13) affords methyl tiglate (14) in addition to the cyclopropane derivative (15) in a ratio 2 1, while A -pyrazolines such as (3) give only 0L,[i- or, y-unsaturated esters, and no cyclopropane derivatives. 

The synthesis of the polyol glycoside subunit 7 commences with an asymmetric aldol condensation between the boron enolate derived from imide 21 and a-(benzyloxy)acetaldehyde (24) to give syn adduct 39 in 87 % yield and in greater than 99 % diastereomeric purity (see Scheme 8a). Treatment of the Weinreb amide,20 derived in one step through transamination of 39, with 2-lithiopropene furnishes enone 23 in an overall yield of 92 %. To accomplish the formation of the syn 1,3-diol, enone 23 is reduced in a chemo- and... 

In general, chiral propanoates providing simple diastereoselectivity (in favor of yyn-aldols), combined with a reasonable degree of auxiliary-induced stereoselectivity, are rare. Numerous terpenoid- and carbohydrate-derived propionates do not display satisfactory syn selectivity60. Similarly, the titanium(IV) chloride promoted aldol addition of the following JV-metbylephe-drine derived silylketene acetal leads to the formation of the. mi-adduct in the moderate diastereomeric ratio of 78 22 (syn-adduct sum of the other stereoisomers)61. 

In a similar way, the lithium enolate derived from (2f ,55)-2-tert-butyl-5-methyl-l,3-thioxolan-4-one leads to the predominant formation of one diastereomer when treated with cyclo-hexenone. The diastereomeric ratio is 75 25 (main product/sum of the other stereoisomers)114. 

The addition of the dianion of /j-sulfmylcarboxylic acids to carbonyl compounds leads to the formation of the corresponding hydroxy derivatives which undergo spontaneous eyclization to give y-lactones. It was found that when optically active ( + )-(/ )-3-(4-methylphenylsulfinyl)pro-panoic acid is used for the reaction, the corresponding diastereomeric /i-sulfinyl-y-lactones are formed in a ratio which is dependent on the substituents of the carbonyl component. However, the diastereoselectivity was always moderate. 

Optically active (2R,3R)-dimethoxysuccinimide derivatives 4, prepared from (.R,./ -tartaric acid, arc reduced in excellent yield with high stereoselectivity by sodium borohydride in ethanol at 0- 5 °C to furnish a 20 1 mixture of diastereomeric hydroxylactams 543, which, on treatment with acid, give rise to the formation of the enantiomerically pure chiral /V-acylimini-um ions 6,... 

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