Chiral pseudoephedrine-based

Inspired by the previous results, Leighton et al. reported the enantioselective [3 + 2] acylhydrazone-enol ether cycloaddition reaction by employing the same pseudoephedrine-based chiral silane. The pyrazohdine product was obtained in 61% yield with 6 1 dr and 77% ee in 24 h. The use of tert-butyl vinyl ether led to an improvement in both diastereoselectivity and enantioselectivity as shown in Scheme 34 [108]. 

Several methods promoted by a stoichiometric amount of chiral Lewis acid 38 [51] or chiral Lewis bases 39 [52, 53] and 40 [53] have been developed for enantioselective indium-mediated allylation of aldehydes and ketones by the Loh group. A combination of a chiral trimethylsilyl ether derived from norpseu-doephedrine and allyltrimethylsilane is also convenient for synthesis of enan-tiopure homoallylic alcohols from ketones [54,55]. Asymmetric carbonyl addition by chirally modified allylic metal reagents, to which chiral auxiliaries are covalently bonded, is also an efficient method to obtain enantiomerically enriched homoallylic alcohols and various excellent chiral allylating agents have been developed for example, (lS,2S)-pseudoephedrine- and (lF,2F)-cyclohex-ane-1,2-diamine-derived allylsilanes [56], polymer-supported chiral allylboron reagents [57], and a bisoxazoline-modified chiral allylzinc reagent [58]. An al-lyl transfer reaction from a chiral crotyl donor opened a way to highly enantioselective and a-selective crotylation of aldehydes [59-62]. Enzymatic routes to enantioselective allylation of carbonyl compounds have still not appeared. 

Asymmetric aldol reactions mediated by zirconium enolates with chiral auxiliary were reported (Equations 1 and 2). The zirconium enolate derived firom pseudoephedrine-based amide (1) and Cp2ZrCl2 was treated with a series of aldehydes to afford the corresponding aldol adducts (2) in high yields with excellent diastereoselectivity [2]. The high syn selectivity was explained by dinu-dear cyclic intermediates. In contrast, the aldol reactions with norephedrine-based ester (3) proceed with highly anti-selective manner (Equation 2) [3]. In both cases, 2 equivalent of Cp2ZrCl2 were necessary to achieve such high stereoselectivity. 

S,S)-(+)-pseudoephedrine propionamide as chiral auxiliary. The obtained p-amino esters were subjected to a reported base-promoted cyclization [182, 183] affording the p-lactams in good yields and as unique detectable stereoisomer (Scheme 82). 

Based on the observation that the best ee is obtained with bifunctional chiral agents (ephedrine, pseudoephedrine, norephedrine, and valinol see Scheme 43), we tentatively conclude that a multipoint interaction between the reactant molecule, the chiral inductor, and the zeolite interior is necessary to induce preferential adsorption of tropolone alkyl ether from a single enantiotopic face. The dependence of chiral induction (% ee) on the nature of cations (Scheme 45) suggests a crucial role of the cation present in the supercages in the chiral induction process. This is further strengthened by the results observed with wet and dry zeolites. The presence of water decreases chiral selectivity (Scheme 45). Water molecules... 

Catalytic reduction from the exo-face gave achiral 68 ready for desymmetrisation. Elimination with the chiral base (simply the sodium salt 69 of pseudoephedrine 53) gave a single enantiomer of 66 ready for conjugate addition of the pyridine and conversion into epibatidine 70. 

The. V-alkylation of ephedrine is a convenient method for obtaining tertiary amines which are useful as catalysts, e.g., for enantioselective addition of zinc alkyls to carbonyl compounds (Section D. 1.3.1.4.), and as molybdenum complexes for enantioselective epoxidation of allylic alcohols (Section D.4.5.2.2.). As the lithium salts, they are used as chiral bases, and in the free form for the enantioselective protonation of enolates (Section D.2.I.). As auxiliaries, such tertiary amines were used for electrophilic amination (Section D.7.I.), and carbanionic reactions, e.g., Michael additions (Sections D. 1.5.2.1. and D.1.5.2.4.). For the introduction of simple jV-substituents (CH3, F.t, I-Pr, Pretc.), reductive amination of the corresponding carbonyl compounds with Raney nickel is the method of choice13. For /V-substituents containing further functional groups, e.g., 6 and 7, direct alkylations of ephedrine and pseudoephedrine have both been applied14,15. 

Bases N-protected amino acids Tartaric acid and derivatives (dibenzoyl- and di-p-toluyltartaric acids) Mandelic acid and derivatives (O-acetylmandelic acid and O-methylmandelic acid) l,l -Binapthylphosphoric acid Camphorsulfonic acid Deoxycholic acid Cyclic phosphoric acid Others (malic acid, lactic acid and derivatives, Mosher s acid, N-derivatized amino acids, etc.) The same reagents as for acids (brucine, quinine, ephedrine, pseudoephedrine and synthetic chiral bases) [32-35] [36-38] [39-40] [41] [42] [29] [43-45]... 

Juge developed a powerful method (Juge-Stephan method) [1, 51] for the preparation of / -stereogenic phosphines based on the use of ephedrine as a chiral auxiliary. The key reactants in this methodology are 1,3,2-oxazaphospholidine boranes 78, prepared by a one-pot reaction from bis(diethylamino)phenylphosphine and (—)-ephedrine, followed by protection with BH3. The cyclization of the (—)-ephedrine takes place stereoselectively, with preferential formation of the (/ p)-diastereoisomer in 90% de [52, 53]. The absolute configuration at the phosphorus atom has been determined by chemical correlations and NMR analysis, and proved by X-ray analysis [54]. Oxazaphospholidines react readily with electrophiles or nucleophiles to provide various chiral phosphorus compounds. Enantiomeric antipodes of tertiary phosphines (Sp)-79 and (Rp)-81 were obtained from (-1-)- or (-)-ephedrine, as shown in Scheme 25. The configuration at the E-atom is controlled by the configuration at the Ph-substituted Cj of (-i-)-pseudoephedrine or ( )-ephedrine, respectively. This was confirmed by X-ray crystal-structure analyses of two intermediate compounds in the synthetic route to the chiral triarylborane-phosphine adducts [54]. 

Two other alkylations were based on readily-available chiral auxiharies. PhUippe Karoyan of the Universite Pierre et Marie Curie observed Tetrahedron Lett. 2008, 49, 4704) that the acylated Oppolzer camphor sultam 20 condensed with the Mannich reagent 21 to give 22 as a single diastereomer. Andrew G. Myers of Harvard University developed the pseudoephedrine chiral auxiliary of 23 to direct the construction of ternary alkylated centers. He has now established J. Am. Chem. Soc. 2008,130, 13231) that further alkylation gave 24, having a quaternary alkylated center, in high diastereomeric excess. 

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