Metallated chiral asymmetric alkylation

The mechanism of the asymmetric alkylation of chiral oxazolines is believed to occur through initial metalation of the oxazoline to afford a rapidly interconverting mixture of 12 and 13 with the methoxy group forming a chelate with the lithium cation." Alkylation of the lithiooxazoline occurs on the less hindered face of the oxazoline 13 (opposite the bulky phenyl substituent) to provide 14 the alkylation may proceed via complexation of the halide to the lithium cation. The fact that decreased enantioselectivity is observed with chiral oxazoline derivatives bearing substituents smaller than the phenyl group of 3 is consistent with this hypothesis. Intermediate 13 is believed to react faster than 12 because the approach of the electrophile is impeded by the alkyl group in 12. 

Asymmetric reduction of ketones or aldehydes to chiral alcohols has received considerable attention. Methods to accomplish this include catalytic asymmetric hydrogenation, hydrosilylation, enzymatic reduction, reductions with biomimetic model systems, and chirally modified metal hydride and alkyl metal reagents. This chapter will be concerned with chiral aluminum-containing reducing re-... 

One problem in the anti-selective Michael additions of A-metalated azomethine ylides is ready epimerization after the stereoselective carbon-carbon bond formation. The use of the camphor imines of ot-amino esters should work effectively because camphor is a readily available bulky chiral ketone. With the camphor auxiliary, high asymmetric induction as well as complete inhibition of the undesired epimerization is expected. The lithium enolates derived from the camphor imines of ot-amino esters have been used by McIntosh s group for asymmetric alkylations (106-109). Their Michael additions to some a, p-unsaturated carbonyl compounds have now been examined, but no diastereoselectivity has been observed (108). It is also known that the A-pinanylidene-substituted a-amino esters function as excellent Michael donors in asymmetric Michael additions (110). Lithiation of the camphor... 

The choice of the base and the solvent is crucial for the yield of a-sulfinyl carbanion alkylation. A high diastereoselection (80%) was observed in the alkylation of an a-sulfinyl carbanion with a-bromoacrylate56. In this ease the choice of the base appears to be decisive the highest asymmetric induction is found when the metalation is carried out using highly hindered bases, e.g., lithium tetramethylpiperidide. An interesting asymmetric synthesis of chiral 5-alkyl(or phenyl)dihydro-3-methylene-2(3f/)-furanoncs is based on this reaction56. 

Among several chiral cyclic and acyclic diamines, (R,R)-cyclohexane-l,2-diamine-derived salen ligand (which can adopt the gauche conformation) was most effective in providing high enantioselectivity [38]. Further, the introduction of substituents at the 3,4, 5 and 6 positions on the aromatic ring of catalyst 39c was not advantageous, and resulted in low enantioselectivity [32,37,39]. The metal ions from first-row transition metals - particularly copper(II) and cobalt(II) - that could form square-planar complexes, produced catalytically active complexes for the asymmetric alkylation of amino ester enolates [38]. 

Metal-based asymmetric phase-transfer catalysts have mainly been used to catalyze two carbon-carbon bond-forming reactions (1) the asymmetric alkylation of amino acid-derived enolates and (2) Darzens condensations [5]. The alkylation ofprochiral glycine or alanine derivatives [3] is a popular and successful strategy for the preparation of acyclic a-amino acids and a-methyl-a-amino acids respectively (Scheme 8.1). In order to facilitate the generation of these enolates and to protect the amine substituent, an imine moiety is used to increase the acidity of the a-hydrogens, and therefore allow the use of relatively mild bases (such as metal hydroxides) to achieve the alkylation. In the case of a prochiral glycine-derived imine (Scheme 8.1 R3 = H), if monoalkylation is desired, the new chiral methine group... 

Meyers, A. I. Dickman, D. A. Absence of an isotope effect on the metalation of chiral form-amidines. The mechanism of asymmetric alkylations leading to chiral amines. J. Am. Chem. Soe. 1987, 109,1263-1265. 

Jorgensen and co-workers employed chiral bis-sulfonamide catalyst 27, a proven ligand for metal-based asymmetric catalysis, for the Friedel-Crafts alkylations of N-methylindoles (24) using -substituted nitroolefins [52]. Using optimized conditions, 2 mol% 27 gave the desired indole alkylation products of substituted aryl and heteroaryl nitroolefins in moderate to high yields (20-91%) and moderate enantiopurities (13-63% ee Scheme 6.3). Aliphatic -substitution... 

We turned our efforts to a synthesis in which a chiral 5-carbon unit would be coupled to a 6-carbon structure bearing functionality permitting resolution. The 5-carbon fragment would contain the hydrocarbon asymmetric center (C-8 of VII) the other unit would provide C-2. Commercially available (S>)-2-methyl 1-butanol was determined to be >99% pure. However, the R-alcohol (acid, aldehyde, etc.) would have to be synthesized. Asymmetric alkylations of chiral a-metallated amides were performed, but the enantiomeric excesses were not sufficiently high. In particular we noted that alkylations involving a short chain bifunctional compound (e.g., 3-methoxy-propyl iodide) provided slightly lower ee s than did the parent alkyl iodide. 

Stereoselective functionalization of enolates derived from 2-acyl-2-alkyl-1,3-dithiane 1-oxides Stereoselective enolate alkylation. There has been much interest over recent years in the enantio- and diastereocontrol of enolate alkylation.19 Most methods which do not rely on asymmetric alkylating agents hinge on a derivatization of the ketonic substrate with an enantiomerically pure auxiliary. Examples of such chiral auxiliaries include oxazolines20 and oxazolidi-nones.21 We reasoned that the sulfoxide unit present in our 2-acyl-2-alkyl-1,3-dithiane 1-oxide substrates might be expected to influence the transition-state geometry of a ketone enolate, perhaps by chelation to a metal counterion, and hence control the stereochemistry of alkylation. 

Terminal epoxides of high enantiopurity are among the most important chiral building blocks in enantioselective synthesis, because they are easily opened through nucleophilic substitution reactions. Furthermore, this procedure can be scaled to industrial levels with low catalyst loading. Chiral metal salen complexes have also been successfully applied to the asymmetric hydroxylation of C H bonds, asymmetric oxidation of sulfides, asymmetric aziridination of alkenes, and the asymmetric alkylation of keto esters to name a few. 

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. 

Enders, D., Eichenauer, H., Baus, U., Schubert, H., Kremer, K. A. M. Asymmetric syntheses via metalated chiral hydrazones. Overall enantioselective a-alkylation of acyclic ketones. Tetrahedron 1984,40, 1345-1359. 

Fortunately, the use of lithiated hydrazones derived from (S)- or ( )-l-amino-2-methoxymethylpyiro-lidine (SAMP or RAMP) as nucleophiles for asymmetric alkylations have provided a solution to the problems described above with metallated acyclic ketimines and aldimines. Lithiated SAMP or RAMP hydrazones of cyclic ketones are also alkylated in high yields. A major advantage of these chiral hydrazones is that their derivatives of aldehydes, acyclic and cyclic ketones all yield mainly ( )cc-. (Z)cN-Iithiated species on deprotonation with LDA in ethereal solvents under kinetic control. The ( )cc-configuration obtains as a result of the minimization of steric interactions in the usual closed transition... 

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