Ephedrine chirality

Procter reported a solid-phase variant of Fukuzawa s asymmetric y-butyr-olactone synthesis (see Chapter 5, Section 5.2) that involves the intermolecular reductive coupling of aldehydes and ketones with a,p-unsaturated esters, immobilised using an ephedrine chiral resin 12.44 For example, treatment of acrylate 13 and crotonate 14 with cyclohexanecarboxaldehyde, employing Sml2 in THF, with tert-butanol as a proton source, gave lactones 15 and 16, respectively, in moderate yield and good to high enantiomeric excess (Scheme 7.11).44 The ephedrine resin 12 can be conveniently recovered and recycled.45... 

Procter [23] has reported the intermolecular, reductive couphng of aldehydes and ketones with o ,/ -imsaturated esters, immobihzed using an ephedrine chiral resin, to give enantiomerically enriched y-butyrolactones. 

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). 

As with ephedrine, chiral resolution can be achieved for 2,2 -ninaphthy 1-1,1 -diamine (DABN) (29) through diastereomer crystallization. Equal molar quantities (0.19mmol) of (i )-DABN, (5)-DABN, and (R)-camphorsulfonic acid (CSA) were first dissolved in methanol (40 mL). The resulting solution was pumped at low flow rates together with CO2 (10 mL/... 

Procter and coworkers" have described a Sm(II)-mediated (106), asymmetric capture and release approach (Scheme 7.22) to y-butyrolactones (107) that involves intermolecular radical additions to a,[3-unsaturated esters (105) attached to resin through an ephedrine chiral linker (108). Resin capture-release is a hybrid technique that combines elements of traditional solid-phase synthesis and the use of supported reagents. Fukuzawa s Sm(II)-mediated, asymmetric method to y-butyrolactones was chosen to demonstrate the feasibility of such a process. y-Butyrolactones (107) were obtained by capture of a reactive intermediate from solution through an asymmetric transformation starting from a,p-unsaturated esters (105) immobilized on an ephedrine chiral resin. Lactone products were obtained in moderate yields with selectivities up to 96% ee. Nevertheless, the ephedrine resin can be efficiently reused for many cycles although in some cases lower yields were obtained on reuse of the chiral resin. 

Progress has been made toward enantioselective and highly regioselective Michael type alkylations of 2-cyclohexen-l -one using alkylcuprates with chiral auxiliary ligands, e. g., anions of either enantiomer of N-[2-(dimethylamino)ethyl]ephedrine (E. J. Corey, 1986), of (S)-2-(methoxymethyl)pyrrolidine (from L-proline R. K. EHeter, 1987) or of chiramt (= (R,R)-N-(l-phenylethyl)-7-[(l-phenylethyl)iinino]-l,3,5-cycloheptatrien-l-amine, a chiral aminotro-ponimine G. M. Villacorta, 1988). Enantioselectivities of up to 95% have been reported. 

In this thiamine pyrophosphate-mediated process, ben2aldehyde (29), added to fermenting yeast, reacts with acetaldehyde (qv) (30), generated from glucose by the biocatalyst, to yield (R)-l-phen5l-l-hydroxy-2-propanone (31). The en2ymatically induced chiral center of (31) helps in the asymmetric reductive (chemical) condensation with methylamine to yield (lR,23)-ephedrine [299-42-3] (32). Substituted ben2aldehyde derivatives react in the same manner (80). 

Only few allyltitanium reagents bearing a removable chiral auxiliary at the allylic residue are known. The outstanding example is a metalated 1-alkyl-2-imidazolinone14, derived from (—)-ephedrine, representing a valuable homoenolate reagent. After deprotonation by butyllithium, metal exchange with chlorotris(diethylamino)titanium, and aldehyde or ketone addition, the homoaldol adducts are formed with 94 to 98% diastereoselectivity. 

Conjugate addition of chiral amines to allenic and acetylenic sulfones has been reported73. The reaction 112 with (—)-ephedrine gives only one of the two possible diastereomeric oxazolines in high yield (equation 89). 

Formation of PAC from benzaldehyde and pyruvate catalysed by PDC and reductive amination of if-PAC to produce the chiral biopharmaceutical product ephedrine. 

Amino alcohols, which have a broad spectrum of biological activities, can be categorized as adrenahne-like with one chiral center at C-1 or as ephedrine-like with two chiral centers at C-1 and C-2 (Scheme 7). Although a variety of methods have been developed for the stereoselective preparation of 1,2-amino alcohols, " in most cases it is easier and more efficient to prepare these important compounds stereoselectively starting from chiral cyanohydrins (Scheme... 

Kcurentjes et al. (1996) have also reported the separation of racemic mixtures. Two liquids are made oppositely chiral by the addition of R- or S-enantiomers of a chiral selector, respectively. These liquids are miscible, but are kept separated by a non-miscible liquid contained in a porous membrane. These authors have used different types of hollow-fibre modules and optimization of shell-side flow distribution was carried out. The liquid membrane should be permeable to the enantiomers to be separated but non-permeable to the chiral selector molecules. Separation of racemic mixtures like norephedrine, ephedrine, phenyl glycine, salbutanol, etc. was attempted and both enantiomers of 99.3 to 99.8% purity were realized. 

In the same study, these authors have prepared another series of amino-sulf(ox)ide ligands based on the (Nor)ephedrine and 2-aminodiphenylethanol skeletons, bearing two chiral centres in the carbon backbone.Their application to the iridium-catalysed hydrogen-transfer reduction of acetophenone generally gave better yields, but the enantioselectivity never exceeded 65% ee (Scheme 9.4). 

Introduction Since we had already developed the novel asymmetric addition of lithium acetylide to ketimine 5, we did not spend any time on investigating any chiral resolution methods for Efavirenz . Our previous method was applied to 41. In the presence of the lithium alkoxide of cinchona alkaloids, the reaction proceeded to afford the desired alcohol 45, as expected, but the enantiomeric excess of 45 was only in the range 50-60%. After screening various readily accessible chiral amino alcohols, it was found that a derivative of ephedrine, (1J ,2S) l-phenyl-2-(l-pyrrolidinyl)propan-l-ol (46), provided the best enantiomeric excess of 45 (as high as 98%) with an excellent yield (vide infra). Prior to the development of asymmetric addition in detail, we had to prepare two additional reagents, the chiral modifier 46 and cyclopropylacetylene (37). 

Among them, (1 R,2S)-l-phenyl-2-(l-pyrrolidinyl)propan-l-ol (46) was selected as a chiral modifier for further optimization. It is interesting to point out that N-methyl ephedrine was not a suitable chiral modifier for ketimine 5 (only 10% ee as shown in Table 1.2), but in the case of ketone 41, N-methyl ephedrine provided a respectable 53% ee, as shown in Table 1.5. 

Chiral modifiers were screened in the zinc chemistry. Once again, in the case of aniline ketone 36, chichona alkaloids, binaphthol, and tartaric acid derivatives gave very poor selectivity and ephedrine derivatives provided good selectivity. The results are summarized in Table 1.8. 

New modifiers have traditionally been discovered by the trial-and-error method. Many naturally occurring chiral compounds (the chiral pool38) have been screened as possible modifiers. Thus, the hydrogenation product of the synthetic drug vinpocetine was discovered to be a moderately effective modifier of Pt and Pd for the enantioselective hydrogenation of ethyl pyruvate and isophorone.39 Likewise, ephedrine, emetine, strychnine, brucine, sparteine, various amino acids and hydroxy acids, have been identified as chiral modifiers of heterogeneous catalysts.38... 

The transformation of the cyano group could also introduce a new chiral center under diastereoselective control (Figure 5.13). Grignard-transimination-reduction sequences have been employed in a synthesis of heterocyclic analogues of ephedrine [81]. The preferential formation of erythro-/3-amino alcohols may be explained by preferential hydride attack on the less-hindered face of the intermediate imine [82], and hydrocyanation of the imine would also appear to proceed via the same type of transition state. In the case of a,/3-unsaturated systems, reduction- transimination-reduction may be followed by protection of the /3-amino alcohol to an oxazolidinone, ozonolysis with oxidative workup, and alkali hydrolysis to give a-hydroxy-/3-amino acids [83]. This method has been successfully employed in the synthesis L-threo-sphingosine [84]. 

Diastereoface-differentiating reactions of a carbenoid with an alkene bearing an easily removable, chiral substituent have been used only ocassionally for the enantioselective production of a cyclopropane 216). A recent example is given by the cyclopropanation of the (—)-ephedrine-derived olefin 223 with CH2N2/Pd(OAc)2 after removal of the protecting group, (1/ , 2R )-2-phenylcyclopropane carbaldehyde was isolated with at least 90% e.e. 37). 

An alternative approach to hydroboration has utilized a chiral B-H source with either achiral or chiral rhodium complexes.58 The enantiomerically pure reagent (21) is derived from ephedrine. Notably in the reactions with BINAP, a higher enantiomeric excess is produced from (R)-BINAP (6) compared to the Y-form (Scheme 13). 

Another chiral auxiliary for controlling the absolute stereochemistry in Mukaiyama aldol reactions of chiral silyl ketene acetals has been derived from TV-methyl ephedrine.18 This has been successfully applied to the enantioselec-tive synthesis of various natural products19 such as a-methyl-/ -hydroxy esters (ee 91-94%),18,20 a-methyl-/Miydroxy aldehydes (91% ee),21 a-hydrazino and a-amino acids (78-91% ee),22 a-methyl-d-oxoesters (72-75% ee),20b cis- and trans-l1-lactams (70-96% ee),23 and carbapenem antibiotics.24... 

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