Ephedrine amide

In 1978, Larcheveque and coworkers reported modest yields and diastereoselectivities in alkylations of enolates of (-)-ephedrine amides. However, two years later, Evans and Takacs and Sonnet and Heath reported simultaneously that amides derived from (S)-prolinol were much more suitable substrates for such reactions. Deprotonations of these amides with LDA in the THF gave (Z)-enolates (due to allylic strain that would be associated with ( )-enolate formation) and the stereochemical outcome of the alkylation step was rationalized by assuming that the reagent approached preferentially from the less-hindered Jt-face of a chelated species such as (133 Scheme 62). When the hydroxy group of the starting prolinol amide was protected by conversion into various ether derivatives, alkylations of the corresponding lithium enolates were re-face selective. Apparently, in these cases steric factors rather than chelation effects controlled the stereoselectivity of the alkylation. It is of interest to note that enolates such as (133) are attached primarily from the 5/-face by terminal epoxides. ... 

Smitrovich JH, DiMichele L, Qu C, Boice GN, Nelson TD, Huffman MA, Murry J. Michael Reactions of pseudo-ephedrine amide enolates effect of LiCl on syn/anti selectivity./. Org. Chem. 2004 69 1903-1908. 

Acylation of norephedrine (56) with the acid chloride from benzoylglycolic acid leads to the amide (57), Reduction with lithium aluminum hydride serves both to reduce the amide to the amine and to remove the protecting group by reduction (58), Cyclization by means of sulfuric acid (probably via the benzylic carbonium ion) affords phenmetrazine (59), In a related process, alkylation of ephedrine itself (60) with ethylene oxide gives the diol, 61, (The secondary nature of the amine in 60 eliminates the complication of dialkylation and thus the need to go through the amide.) Cyclization as above affords phendimetra-zine (62), - Both these agents show activity related to the parent acyclic molecule that is, the agents are CNS stimulants... 

Cross coupling between an aryl halide and an activated alkyl halide, catalysed by the nickel system, is achieved by controlling the rate of addition of the alkyl halide to the reaction mixture. When the aryl halide is present in excess, it reacts preferentially with the Ni(o) intermediate whereas the Ni(l) intermediate reacts more rapidly with an activated alkyl halide. Thus continuous slow addition of the alkyl halide to the electrochemical cell already charged with the aryl halide ensures that the alkyl-aryl coupled compound becomes the major product. Activated alkyl halides include benzyl chloride, a-chloroketones, a-chloroesters and amides, a-chloro-nitriles and vinyl chlorides [202, 203, 204], Asymmetric induction during the coupling step occurs with over 90 % distereomeric excess from reactions with amides such as 62, derived from enantiomerically pure (-)-ephedrine, even when 62 is a mixture of diastereoisomcrs prepared from a racemic a-chloroacid. Metiha-nolysis of the amide product affords the chiral ester 63 and chiral ephedrine is recoverable [205]. 

Both enantiomers of 2-methylamino-l-phenylpropanol (ephedrine, 1), which are commercially available and relatively inexpensive, have been used as auxiliaries in many syntheses of chiral compounds. Ephedrine can be used for amide alkylations both directly1-3, or as derived heterocyclic compounds (see Sections 1.1.1.3.3.4.2.1. and 1.1.1.3.3.4.2.2.). Acyclic derivatives of ephedrine are discussed in this section. For example, either enantiomer of ephedrine gives A-acylephedrines 2 in good yield without epimerization if treated with an anhydride at 65 °C for 10 minutes2. 

Analogous to the use of chiral enoates (see previous section), a, -unsaturated carboxylic amides, prepared from chiral amines, may be utilized in asymmetric 1,4-additions. When Grignard reagents are added to unsaturated amides (21), derived from (-)-ephedrine (20),25 highly optically active fi-sub-stituted alkanoic acids (22 R and R = alkyl or phenyl) are obtained in a variety of cases, after hydrolysis of the initially formed adducts (Scheme 7). This method was used for the synthesis of the antibiotic (-) malyngolide and its stereoisomers.26 Recrystallization of the intermediate (saturated) amide was necess-... 

Figure 5. Alkylation of anions derived from amides of (l)-ephedrine (32).

Asymmetric synthesis of ketones and acids A new synthesis of chiral ketones and acids starts with the reaction of an anhydride or an acid chloride with either I-or li-ephedrin to form a chiral N,N-disubstituted amide (1) in almost quantitative yield. The amide (1) is then alkylated via the anion to give 2, which contains three asymmetric centers. Acid hydrolysis of 2 gives a carboxylic acid (3) with an optical yield of 75% (two examples). Cleavage of 2 with methyllithium gives a methyl ketone (4), in optical yields of 45-75%. 

Diastereoselective Alkylation of Chiral Amides Derived from Ephedrine. Chiral amides derived from ephedrine are converted to the corresponding dianion. The subsequent diastereoselective alkylation with alkyl iodides affords chiral a-substituted amides with >90% de. Acid hydrolysis affords optically active a-substituted acids with 78% ee as a result of racemization in the cleavage step (eq 2). 

Diastereoselective Conjugate Addition of Organometallic Reagents to Chiral a,P-Unsaturated Amides and Imidazolidi-nones Derived from Ephedrine. Grignard reagents (2 equiv) add to chiral a,P-unsaturated amides derived from ephedrine in a 1,4-addition manner with high diastereoselectivities. Subsequent acidic hydrolysis affords optically active p-substituted carboxylic acids with 85-99% ee (eq 3). ... 

Povidone K 25 added, jig Lactose Glucose Tartaric acid Acetyl- salicylic acid Thiamine hydro- chloride Brom- isoval Caffeine Ephedrine hydro- chloride Lidocaine Meproba- mate Pheno- barbital Salicyl- amide... 

Blaschke, G. Chromatographic resolutions of racemates. III. Chromatography of racemic mandelic acid on polyacrylic esters and amides of optically active ephedrine derivatives, Chem. Ber., 1974, 107, 237-252. 

Protoalkaloids are bases with a simple structure, e.g. the biogenic amines, which are formed by decarboxylation or N-methylation of an amino acid (tyramine, histamine, choline, ephedrine, mescaline). Capsaicin, which is the amide of vanillylamine (4-hydroxy-3-methoxybenzylamine), has also been included in this group. 

ReO(Tp)(r]2-N-X)] have been synthesized from the reaction of [ReOCl2(Tp)] with chiral bidentate ligands in which r 2-N-X = alcoholates or amidates derived from (lS,2/ )-ephedrine, (I. S, 2.S )-diphcriylcthylcricdiamine, and L-proline. These chiral-at-Re complexes have been fully characterized by NMR, IR, circular dichroism, polarimetry, and X-ray crystallography, and have been found to be stable and resistant to oxo-transfer when subjected to harsh conditions.216... 

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