Chiral imide system

Treatment of a mixture of alcohol 10 and chiral imidate 67 with catalytic TfOH only afforded a 1.2 to 1.3 1 mixture of 18 19 in a combined HPLC assay yield of 91%. Clearly, under these conditions, the reaction was proceeding under an SN1 reaction pathway. The use of other acid catalysts (TMSOTf, HC1, H2S04, TFA, MsOH) in a variety of solvent systems and under a number of reaction conditions did not improve the diastereomeric ratio of 18 19 (typically 1.2 1), or simply resulted in no reaction. 

Imide Systems. Imide compounds 22 and 23, or Evans reagents, derived from the corresponding oxazolidines are chiral auxiliaries for effective asymmetric alkylation or aldol condensation and have been widely used in the synthesis of a variety of substances. 

This imide system can also be used for the asymmetric synthesis of optically pure a,a-disubstituted amino aldehydes, which can be used in many synthetic applications.31 These optically active a-amino aldehydes were originally obtained from naturally occurring amino acids, which limited their availability. Thus, Wenglowsky and Hegedus32 reported a more practical route to a-amino aldehydes via an oxazolidinone method. As shown in Scheme 2 20, chiral diphenyl oxazolidinone 26 is first converted to allylic oxazolidinone 27 subsequent ozonolysis and imine formation lead to compound 28, which is ready for the a-alkylation using the oxazolidinone method. The results are shown in Table 2-6. 

Chiral amide and imide enolates are amongst the most effective reagents providing. yv -3-hy-droxycarboxylic acids in both high simple diastereoselectivity and induced stereoselectivity, e.g., the amides 1 and 2, and especially, the imides 3 and 4 (derived from (S(-valine and (l/ ,2S)-norephedrine, respectively)93 and the C2-symmetric amide 594 are highly effective systems ... 

Cyclic amines (including local anesthetic drugs) and amides were among the first classes of chiral compounds investigated in the early stages of the application of macrocyclic antibiotics as chiral selectors therefore, they were screened on vancomycin [7], teicoplanin [30], and ristocetin A [33] CSPs, under RPmode systems. Cyclic imides (including barbiturates, piperidine-2,6-diones, and mephenytoin) have been separated on a vancomycin CSP [157], under NP and RP mobile phase conditions. 

Since one or more of the interactions in these systems might originate from the stationary phase, only a two- or a one-point interaction between the solute and the selector is necessary for mechanisms (2) and (3) to occur [50]. However, some of the CMPAs used in HPLC [37,40,51,52] have also been used as chiral selectors in CE [53-56], which indicates that at least one of the separation mechanisms between the selector and enantiomers is selective complex formation in the mobile phase in these cases, since there is no stationary phase present in CE. A recent example by Yuan et al. [57] is presented in Eigure 17.1. The authors introduced the use of (R)-A,A,A-trimethyl-2-aminobutanol-bis(trifluoromethane-sulfon)imidate as the chiral selector for enantioseparation in HPLC, CE, and GC. This chiral liquid serves simultaneously as a chiral selector and a co-solvent. 

Due to these limitations Evans et al. focussed on the exploration of imide-derived enolates (165). They expected these systems to react stereoselective in carbon-carbon bond formation and that the derived imides might be readily hydrolized or reduced under the mild conditions required for the construction of complex products, One of the two chiral 2-oxazolidones (175) chosen for study by Evans et al.179) is derived from (S)-valine and was readily prepared from this inexpensive commercially available a-amino acid having an optical purity exceeding 99 %. The preparation of the related imide-derived enolate (165) is shown in the next scheme. Alkylation reactions employing (175) resulted in excellent diastereoface selection, as summarized in Table 4 179). 

Asymmetric Alkylations. The use of nitrogen derivatives of carbonyl compounds (imines, imides, amides, sultams, oxazo-lines) is often the most efficient procedure for achieving a-alkylations. Chiral auxiliaries bearing heteroatoms in a 1,2-relationship appear to work best, as they have chelation sites for the metal cation. High levels of asymmetric induction can thus be achieved due to the system rigidity. Cyclic ketones have been alkylated via the lithiated enamine formed from L-f-leucine f-butyl ester (eq 1). High enantiomeric excesses and predictability of absolute configuration make this method attractive. 

Alkylations of acyclic enolates containing a collection of chiral auxiliary groups have been used successfully for the asymmetric synthesis of carboxylic acids. The chiral, nonracemic substrates that have been used include amides, imides, esters, imine derivatives of glycinates and acyl derivatives of chiral transition metals. In these systems either extraannular or chelate-enforced intraannular chirality transfer may control the sense of the alkylation step. 

Two distinct chiral metal complexes operate cooperatively to catalyze a highly enantioselective conjugate addition of cyanide to unsaturated imides (Scheme 5). Under optimized conditions, the dual-catalyst system afforded distinctly superior results relative to the (salen)AlCl complex. 

Sibi et al. demonstrated for the first time that intermolecular radical addition to a,P-disubstituted substrates (12) followed by hydrogen atom transfer proceeded with high diastereo- and enantioselectivities (Scheme 4.6) [4]. In particular, a chiral bis(oxazoline)s-Mgl2 catalytic system was applied to the enantioselective and highly diastereoselective antijsyn = 99/1) synthesis of anti-aldol-type adducts (13). This is noteworthy because there have been few examples of highly selective methods for preparing anti aldol despite the array of solutions for the synthesis of syn aldol. The key to increasing the reactivity for a,P-disubstituted substrate (12) was N-H imide templates that relieve problems, and the promotion of Lewis acid catalysis via... 

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