Stereochemistry chiral chromatography

For a discussion on chiral chromatography, see E. Juaristi, Introduction to Stereochemistry and Conformational Analysis, Wiley New York, 1991, pp. 132-136. 

In the first section of this chapter a brief review of stereochemistry is provided along with a justification for why scientists need to separate enantiomers. The following section provides a brief review of the principles of chromatography with an emphasis on chiral chromatography. In the next section we provide a working definition of what molecular modeling means followed by a section describing the different kinds of commercially available stationary phases and how they work. The... 

On the other hand, optically active telluroxides have not been isolated until recently, although it has been surmised that they are key intermediates in asymmetric synthesis.3,4 In 1997, optically active telluroxides 3, stabilized by bulky substituents toward racemization, were isolated for the first time by liquid chromatography on optically active columns.13,14 The stereochemistry was determined by comparing their chiroptical properties with those of chiral selenoxides with known absolute configurations. The stability of the chiral telluroxides toward racemization was found to be lower than that of the corresponding selenoxides, and the racemization mechanism that involved formation of the achiral hydrate by reaction of water was also clarified. Telluroxides 4 and 5, which were thermodynamically stabilized by nitrogen-tellurium interactions, were also optically resolved and their absolute configurations and stability were studied (Scheme 2).12,14... 

Two equivalents of the tertiary amine base are required, and a significant improvement in the diastereoselectivity was observed with TMEDA over DIPEA. Purification and further enrichment of the desired RRR isomer to >98% ee was achieved by crystallization. Oxidative removal of the chiral auxiliary followed by carbodiimide mediated amide formation provides (3-keto carboxamide 14 in good yield. Activation of the benzylic hydroxyl via PPha/DEAD, acylation, or phosphorylation, effects 2-azetidinone ring-closure with inversion of stereochemistry at the C4 position. Unfortunately, final purification could not be effected by crystallization and the side products and or residual reagents could only be removed by careful chromatography on silica. 

Further process optimization by Thiruvengadam and co-workers (Thimvengadam et al., 1999), led to a novel, stereoselective, scalable two-step process devoid of chromatography for chiral 2-azetidinone construction (Scheme 13.4). As above, the titanium-enolate of chiral oxazolidinone 11a was preformed, but now when reacted with well behaved imines of type 16, affords the unexpected anti-addition product. This surprising result was further supported by careful comparison to minor antiproducts obtained in the earlier aldol-addition methodology and determination that the major product was indeed 17a (undesired RSR series). Adjustment of the oxazolidinone absolute stereochemistry to the fortuitously less expensive 2S-series afforded the desired diastereo-mer 17b in 95% de and in 50-70% yield. Recrystallization improved the stereochemical purity to >99% de. 

Leal, W. S Shi, X., Liang, D., Schal, C. and Meinwald, J. (1995). Application of chiral gas chromatography with electroantennographic detection to the determination of the stereochemistry of a cockroach sex pheromone. Proceedings of the National Academy of Sciences, USA 92 1033-1037. 

This type of disconnection is mainly used for the preparation of dipeptides of type Xaai >[ , CH=CH]Gly. It allows control of the stereochemistry of the Xaa residue by starting from chiral a-amino aldehydes. For the construction of the /ram -p,y-unsaturated carboxylic acid moiety, the use of the triphenylphosphonium salt 31 (Scheme 9) derived from 3-chloro-propanoic acid was not suitable.14 Instead, the trimethylsilylprop-2-ynyl phosphonium salt 33 serves as a three-carbon unit, which can be converted into the P,y-unsaturated acid by hydroboration and oxidation. The required Boc-protected a-amino aldehyde 32 can be prepared using virtually racemization-free procedures. 37 However, at the end of the reaction sequence, racemization has been detected, especially for Boc-Phet )[ , CH=CH]Gly-OH, but not for the Ala and Pro analogues. 63 A mixture of E- and Z-enynes 34 and 35 is formed (8 2 to 9 1), which can be separated by column chromatography. 4,48 50 53 64 65 ... 

The resolution of the racemic mixture of modafinil acid 6 using thiazolidinethione 19 as the chiral auxiliary was achieved in 88% yield (Scheme 6) in the presence of DCC.33 Two diastereomeric intermediates 20 and 21 were easily separated by silica gel column chromatography and the absolute stereochemistry was assigned based on the single A-ray crystallographic analysis. Finally, the addition of ammonia to diastereomeric thiazolidinethione 20 yielded armodafinil 1. 

These both key intermediates were opened with H2S in the presence of diisopro-pylamine. This reaction is known to proceed with full retention of configuration. Therefore we assume, that the obtained thiols 210 and 211 are of the assigned absolute stereochemistry. The optical purity of each enantiomer was directly determined from the relative peak areas and senses of nonequivalence of the resonances of enantiotopic nuclei in chiral solvent, e. g. Eu(TBC)3. We observe optical purities for 210p = 85% and for 211 p = 75%. The addition of 210 to the optically active 212 gave after column chromatography the desired 8 R, 11 R, 12 R, 15 S-13-thiaprostanoid E 213. 

Separation of enantiomers is a technique driven mainly by the needs of pharmaceutical industry to produce drugs with controlled enantiomeric purity. Enantiomeric separation involves more than knowledge of chromatography it requires an in-depth assessment of the stereochemistry of enantiomeric analytes and chiral stationary phase, as well as the interactions involved therein. In this situation, chromatography is just a tool that helps to separate enantiomers. That is why this chapter presents the main types of interactions occurring between the selectands and the selectors. Understanding these relationships, chiral separation becomes a logical process and trial and error is minimized. 

Two new chiral carbon atoms are formed in the condensation and four diastereoisomeric p-sulfinyl y-lactones can therefore in principle be obtained. However, only two dia-stereoisomers, (3S,4, s ) and (3R,4S,Rs), are isolated when the carbanion is condensed with pivalic aldehyde, benzaldehyde, or pinacolone (yield 65-70% for aldehydes, ratio 53 47 yield 47% for pinacolone, ratio 81 19). The diastereoselectivity decreases when the two substituents of the carbonyl group are sterically similar. However, single diastereoisomers can easily be separated through chromatography and transformed in high yield into both enantiomers of optically pure saturated (by desulfurization) and a,(3-unsaturated y-lactones (by pyrolytic sulfoxide elimination) (eq 3). The relative and absolute stereochemistry of all the products have been determined by circular dichroism, nuclear Over-hauser effects, and X-ray analyses. 

In early studies, this stereochemistry was established for a select few lantibiotics by comparison to chemically synthesized standards in combination with gas chromatography using chiral stationary phases. The stereochemistry determined in these early studies is assumed to be the same for lantibiotics that were discovered and characterized subsequently, but for most members this supposition has not been confirmed experimentally. 

Study of the ascidian L. patella (order Enterogona, family Didemnidae) yielded two new closely related cyclic peptide alkaloids namely lissoclinamide 9 389 and lissoclinamide 10 390 <2000T8345>. Their structures were determined by a combination of 2-D NMR, selective 1-D TOCSY, MS, and series-wound electrospray ionization (ESI)-MS (MSn) techniques, and the assignment of absolute stereochemistry was achieved by the hydrolysis of lissoclinamides followed by chiral thin layer chromatography. In the case of lissoclinamide 9, 389, NOE-restrained molecular dynamics studies were also performed confirming the proposed stereochemistry. 

The ultimate stereochemical identity test is, of course, the direct resolution of the enantiomers using chiral liquid or gas chromatography (9). When compared to a reference standard of the racemate, and under experimental conditions that will resolve the peaks of both enantiomers, the occurrence of two equal peaks will identify the racemate, and one peak will signify an enantiopure material. A proof of the stereochemical identity of the analyte can be provided, based on a match of retention times with a reference standard of known stereochemistry. Inequality between the peaks is a measure of enantiomeric enrichment. Therefore, it is conceivable that both stereochemical identity and purity can be established from a single experiment. 

In the laboratory of T.F. Jamison, the synthesis of amphidinolide T1 was accomplished utilizing a catalytic and stereoselective macrocyclization as the key step. ° The Myers asymmetric alkylation was chosen to establish the correct stereochemistry at the C2 position. In the procedure, the alkyl halide was used as the limiting reagent and almost two equivalents of the lithium enolate of the A/-propionyl pseudoephedrine chiral auxiliary was used. The alkylated product was purified by column chromatography and then subjected to basic hydrolysis to remove the chiral auxiliary. 

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