Configurations of diastereomers

This report presents various methods developed primarily at our laboratory for chromatographic resolution of racemates of several pharmaceuticals (e.g., -blockers, NSAIDS, anta-acids, DL-amino acids, Bupropion, Baclofen, Etodolac, Carnitine, Mexiletine). Recently, we developed methods for establishing molecular dissymmetry and determining absolute configuration of diastereomers (and thus the enantiomers) of (/< .S )-Baclofcn, (/d.SJ-Bctaxolol with complimentary application of TLC, HPLC, H NMR, LCMS this ensured the success of diastereomeric synthesis and the reliability of enantioseparation. 

The relative configurations of diastereomers of 5a-H epimers 7 and 8 were established by X-ray crystallographic analysis (08OL689). 

The specification of the configuration of diastereomers is done by a direct extension of the sequence rule. Each chiral center is designated Rot Shy application of the sequence rule. The structures in Fig. 2.3 can serve as examples for study. 

The / u system of nomenclature, introduced by Seebach and Prelog to describe the relative configuration of diastereomers, can be extended to specify the relative topicity of diastereoseiective reactions. W This involves comparing the/ /5 mdiRe/Si specifications of the stereogenic units and/or enantiotopic faces or groups involved. The combinations (R, Re), (5, Si), (Re, Re) and (Si, Si) are denoted Ik (like) while (R, Si), (S, Re), (Re, Si) and (Si, Re) are denoted ul (unlike). To illustrate the use of this system we will again take the examples of section 1.11 which are representative of the two major types of diastereoseiective reaction. 

Polavarapu PL, Donahue EA, Shanmugan G, Scaltnani G, Hawkins EK, Rizzo C, et al. A Single Chiroptical Spectroscopic Method May Not Be Able to Establish the Absolute Configurations of Diastereomers Dimethylesters of Hibiscus and Garcinia Acids. J Phys Chem A 2011 115 5665-5673. 

A novel technique for dating archaeological samples called ammo acid racemiza tion (AAR) IS based on the stereochemistry of ammo acids Over time the configuration at the a carbon atom of a protein s ammo acids is lost m a reaction that follows first order kinetics When the a carbon is the only chirality center this process corresponds to racemization For an ammo acid with two chirality centers changing the configuration of the a carbon from L to D gives a diastereomer In the case of isoleucme for example the diastereomer is an ammo acid not normally present m proteins called alloisoleucme... 

One often encountered but usually undesirable consequence of backbone modification is the introduction of a chiral center at the phosphoms. Although chiral syntheses are being explored, all commonly used synthetic methods yield a mixture of diastereomers having either R or configuration. 

If a molecule contains several asymmetric C atoms, then the diastereomers show diastereotopic shifts. Clionasterol (28a) and sitosterol (28b) for example, are two steroids that differ only in the absolute configuration at one carbon atom, C-24 Differing shifts of C nuclei close to this asymmetric C atom in 28a and b identify the two diastereomers including the absolute configuration of C-24 in both. The absolute configurations of carboxylic acids in pyrrolizidine ester alkaloids are also reflected in diastereotopic H and C shifts which is used in solving problem 54. 

Diastereomers include all stereoisomers that are not related as an object and its mirror image. Consider the four structures in Fig. 2.3. These structures represent fee four stereoisomers of 2,3,4-trihydroxybutanal. The configurations of C-2 and C-3 are indicated. Each stereogenic center is designated J or 5 by application of the sequence rule. Each of the four structures is stereoisomeric wife respect to any of fee others. The 2R R and 25,35 isomers are enantiomeric, as are fee 2R, iS and 25,3J pair. The 21 ,35 isomer is diastereomeric wife fee 25,35 and 2R,3R isomers because they are stereoisomers but not enantiomers. Any given structure can have only one enantiomer. All other stereoisomers of feat molecule are diastereomeric. The relative configuration of diastereomeric molecules is fiequently specified using fee terms syn and anti. The molecules are represented as extended chains. Diastereomers wife substituents on the same side of the extended chain are syn stereoisomers, whereas those wife substituents on opposite sides are anti stereoisomers. 

Relative to each other, both hydroxyl groups are on the same side in Fischer projections of the erythrose enantiomers. The remaining two stereoisomers have hydroxyl groups on opposite sides in their Fischer projections. They are diastereomers of d- and L-erythrose and are called d- and L-threose. The d and l prefixes again specify the configuration of the highest numbered chirality center. D-Threose and L-threose are enantiomers of each other ... 

The enantiomers are obtained as a racemic mixture if no asymmetric induction becomes effective. The ratio of diastereomers depends on structural features of the reactants as well as the reaction conditions as outlined in the following. By using properly substituted preformed enolates, the diastereoselectivity of the aldol reaction can be controlled. Such enolates can show E-ot Z-configuration at the carbon-carbon double bond. With Z-enolates 9, the syn products are formed preferentially, while fi-enolates 12 lead mainly to anti products. This stereochemical outcome can be rationalized to arise from the more favored transition state 10 and 13 respectively ... 

Analogous addition to benzaldehyde afforded a 80 20 mixture of diastereomers 37 A. However, both diastereomers have an anti configuration between C-2 and C-3. The stereochemical difference between the two diastereomers is located at C-l. X-ray crystallography shows that the dia-stereomer bearing a / -configurated hydroxy group is predominant. Therefore, the diastereose-lectivity with respect to C-2 and C-3 in 37 A and C-l and C-2 in 36 is virtually complete in both cases. 

Control experiments, performed with the ( + )-(R)-diastereomer of 1, which differs only in the configuration of the stereogenic center at the metal, afford the enantiomeric homoallylic alcohol, (S)-3-methyl-1-phenyl-3-butenol, also with high enantiomeric excess, indicating that the chiral cyclopentadienyl ligand has no dominating influence1-2. 

When the following a-substituted lithium (Zi)-enolate is added to 2-phenylpropanal, simple diastereoselectivity leads exclusively to products with 2,3-induced stereoselectivity is also moderate in this ease, as indicated by the 80 20 ratio of diastereomers (25,3.5,47 )- and (27 ,37 ,47 )- 28. 

The obtained adducts are not configurationally stable within 24 hours the solid crude product isomerizes to a 31 69 (syn/ami) mixture of diastereomers. 

Metalated SAMP- or RAMP-hydrazones derived from alkyl- or arylethyl ketones 3 add to arylaldehydes both diastereo- and enantioselectively. Substituted / -hydroxy ketones with relative syn configuration of the major diastereomer are obtained with de 51-80% and 70-80% ee. However, recrystallization of the aldol adducts, followed by ozonolysis, furnishes diastereo- and enantiomerically pure (lS, S )-. yn-a-mcthyl-/3-hydroxy ketones 5 in 36-51% overall yield. The absolute configuration of the aldol adducts was established by X-ray crystallographic analysis. Starting from the SAMP- or RAMP-hydrazone either enantiomer, (S,S) or (R,R), is available using this methodology16. 

Reaction of (57 )-4,5-dihydro-3-[(R)-(4-methylphenylsulfinyl)methyl]-5-pentylisoxazole (22) with hexanal, followed by cleavage, furnishes predominantly the (R,/ )-/ ,/J -dihvdroxy ketone, which is easily distinguished from the (R,S )-me.TO-diastereomer. This establishes the absolute configuration of the newly created stereocenter23 24. 

Double metalation of the protected (2/ .3S)-4-nitro-l, 2,3-butanetriol 4 and addition of benzaldehyde furnished, after removal of the protecting groups, a single crystalline diastereomer. The absolute configuration of the newly formed asymmetric carbons is assumed to be cither (4R,5S) or (4S,5R)ls. 

In order to prove the utility of this method and to ascertain the absolute configuration of the products, (S)-alanine has been enantioselectively prepared. The key step is the addition of methyllithium to the AjA -dimethyl hydrazone acetal 4c, derived from diol 3c. In accordance with 13C-NMR investigations it can therefore be assumed that all major diastereomers resulting from the addition of organolithium reagents to hydrazone acetals 4a-c derived from diols 3a, 3b or 3c (Table 3, entries 1 -6) have an S configuration at the newly formed stereogenic center. 

The ( + )-(/ )-methyl 4-tolyl sulfoxide anion from 1 reacts with nitrones 2 to afford optically active hydroxylamines with very high fi stereoselectivity5. The diastereomeric ratio of the products 3 a, b varies from d.r. 75 25-100 0, the highest being for R = t-Bu. The configuration of the diastereomers 3 a, b has not been determined. 

The addition to 2-cyclohexcnone or (fj-d-phenyl-S-penten -one gave products with d.r. 99 1. Since the configuration of 5 was not determined, a detailed interpretation of the stereoselectivity is not possible. The 1,4 addition of the chiral cuprate reagent, lithium [2-(l-dimethylamino-ethyl)phenyl](2-thienyl)cuprate, to ( )-2,2-dimethyT5-phenyl-4-penten-3-one produced predominantly one diastereomer with d.r. 99 1, while the 1,4-addition of [2-(l-dimethylaminoethyl)-phenyl]lithium to the same enone gave predominantly the opposite diastereomer (d.r. 3 97). 

The addition of the anion of the 1,3-dimethyl-2-butenyl sulfoxides to 2-cyclopentenone was examined2. The anion of rar-2-methyl-4-(phenylsulfinyl)-2-pentene gave a 50 50 mixture of ( )- and (Z)-y-1,4-adducts which differed in the relative configuration of the new stereocenter regarding the stereocenter at sulfur. That is, for either the (Z)- or the ( )-product there is complete asymmetric induction from the stereocenter at sulfur, but in the opposite direction. When the rm-butyl analog, ruc-4-(/wt-butylsulfinyl)-2-methyl-2-pcntcne, was reacted, it gave exclusively the ( )-adduct, likewise as a single diastereomer. 

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