Ephedrine derivatives

The polymer-bound catalysts A-C. (Table 31) are prepared by reaction of the corresponding amino alcohols with partially chloromethylated 1 -2% cross-linked polystyrene. In the case of A, the enantioselectivity of the addition of dialkylzincs to aldehydes is higher than with the corresponding monomeric ephedrine derivatives (vide supra). Interesting insights into the mechanism of the alkylation of aldehydes by dialkylzinc reagents can be obtained from the experi-... 

Scheme 3.4 Ephedrine-derived S/N ligands for addition of ZnEt2 to benzaldehyde.

While ephedrine derivatives showed some selectivity, the most promising results were obtained with cinchona alkaloids. Lithium alkoxides and lithium acetylides (n-BuLi or LiHMDS used to deprotonate both the acetylene and the alcohol) gave better results than the corresponding sodium or magnesium salts. Higher enan-tioselectivity was obtained in THF (homogeneous) than in toluene or diethyl ether (heterogeneous). 

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. 

On the other hand, asymmetric addition of lithium acetylide in the presence of the ephedrine derivative 46 is a homogeneous reaction and reveals great detail about the reaction mechanism. 

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). 

Kim J and Choi YH. 2000. SPE of ephedrine derivates from Ephedra sinica. Proceedings of 5th International Symposium on Supercritical Fluids, Atlanta, GA, pp. 1—12. 

Clearly, upon using the enantiomeric catalyst [(S,S) instead of (R,R)] the opposite enantioselectivity of the overall process results. However, this effect is also seen with catalysts that are of analogous configuration, but not derived from trans-1,2-diaminocyclohexane (DACH). For example, the pseudo-ephedrine derived catalyst shown in Scheme 5, having (5)-configuration at the centers of chirality, shows some preference for the (5)-azlactone kinetically favors the (5)-azlactone in alcoholytic ring opening [37]. 

Scheme 5 Pseudo-ephedrine derived catalyst which favors the ring opening of ( S)-azlactones...

The addition of alkoxides generated from secondary alcohols (for example, different ephedrine derivatives, [10b,c]) proceeded very slowly and not selectively with yields up to 53 %. tert-Alkoxides did not add to 1-Me, 2 at all [53]. 

High degrees of enantioselectivity have been observed when alkylzinc reagents react with aldehydes in the presence of chiral ligands.120 Among several compounds that have been used as ligands are exo - (dime th y I a m i no )no rb o rn c o I (A)121 122 123 124 and diphenyl(l-methyl-pyrrolin-2-yl)methanol (B) as well as ephedrine derivatives C and D. 

Such observations are naturally simpler in cyclic compounds, such as in ephedrine derivatives (65) when 37(PNCH) are 2-3 and TO Hz depending upon the isomer. (1989 109> This effect is even more pronounced in cyclic Pv compounds(1968,76) such as 66 in which the two 37(PNCH) values are clearly distinguished and have opposite signs ( + 1T5 and -0-31 Hz). 

Various prochiral olefins are hydroborated by Rh complexes of BINAP or DIOP in up to 96% optical yield (30h, 31). Oxidation of the products provides a convenient way to produce optically active alcohols. Reaction of styrene and catecholborane in the presence of a BINAP-Rh complex at low temperature forms, after oxidative workup, 1-phenylethyl alcohol in 96% ee (Scheme 11) (31). Double stereodifferentiation occurs in the BINAP-Rh catalyzed reaction of 4-methoxy-styrene and an ephedrine-derived chiral borane (32). 

Modifier structure. Naturally occuring cinchona alkaloids give best results [31, 58] (see also Section V). Ephedrine derivatives give low to moderate optical yields [33]. 

Another type of chiral Michael acceptor, the oxazepine derivatives (47), is prepared by condensation of the (-)-ephedrine-derived malonic acid derivative (46) with aldehydes (Scheme 18).51 52 Treatment of (47) with a variety of Grignard reagents in the presence of NiCh affords, after hydrolysis and decarboxylation, the 3-substituted carboxylic acids (48), in most cases with more than 90% ee. Diastereoselective Michael additions to (47) were also used for the preparation of optically active cyclopropane derivatives (49)53 and P-substituted-y-butyrolactones (50 Scheme 18).54 A total synthesis of indolmycin is based on this methodology.55... 

Correction.1 Under basic conditions, this ephedrine derivative decomposes to the oxide 1, which has a very high specific rotation. Contamination with this oxide is probably responsible for most or even all the optical activity observed previously on reduction of ketones with NaBH4 NaOH in the presence of this phase-transfer catalyst. 

To improve supercritical C02 solubilities of target alkaloidal salts, an appropriate modifier to raise the polarity of C02 had to be used. As previously mentioned, the most common modifier used in SFE is methanol because of its high solvation parameters, which can greatly increase the resultant polarity of C02. Water has been chosen as another modifier because some alkaloidal salts are freely soluble in water as well as methanol. Moreover, the addition of water into C02 has been reported to improve the extraction yield of some alkaloids [29]. Methanol or water as a modifier was added into the extractor at the concentration levels of 1, 5 and 10% (v/v), respectively. The effect of methanol and water on the solubilities of hyoscyamine (1) and scopolamine (2) is shown in Figure 5. Analogous information on ephedrine derivatives such as methylephedrine (3), norephedrine (4), ephedrine (5), and pseudopehedrine is illustrated in Figure 6. 

Figure 6. Effect of methanol (A) and water (B) as a modifier on the solubilities of the hydrochloride salts of ephedrine derivatives in CO, at 80 C and 34.0 MPa. ME = methylephedrine (3) NE = norephedrine (4) E = ephedrine (5) PE = pseudoephedrine (6) [41]. Reproduced with permission from Vieweg Publishing 1999.

For ephedrine derivatives, basified methanol or water showed solubilities greater than for neutral conditions (Figure 10), similar to the results for hyoscyamine (1) and scopolamine (2). 

Thakur, T. S., Desiraju, G. R., Misassigned C-HCu agostic interaction in a copper(II) ephedrine derivative is actually a weak, multicentred hydrogen bond. Chem. Commun. 2006, 552-554. 

In order to avoid this unfavourable effect of the functional groups in the dendrimer structure, a rigid hydrocarbon backbone without heteroatoms was synthesized. Dendrimers with poly(phenylethyne) backbones, bearing three and six ephedrine derivatives at the periphery, were studied in the alkylation of aldehydes and N-diphenylphosphinylimines and proved to be highly en-antioselective catalysts. For example, the system containing six catalytic sites catalyzed the addition of diisopropylzinc to aldehydes with enantioselectivi-ties of up to 86% ee. As a third backbone a polycarbosilane dendrimer was used, which is chemically inert and more flexible than the poly(phenylethyne)... 

C-N bonds are much harder to lithiate reductively, and the reaction is most successful when accompanied by relief of strain. Aziridines (52) are opened to (3-lithioamines (53) provided only a catalytic amount of naphthalene is used. Enantiomerically pure products are easily obtained using ephedrine-derived aziridines such as 54.69 70... 

Among the very few papers published after the above review appeared, two deserve some comment. The asymmetric protonation of the lithium enolate of a thiopyranic thioester by an ephedrine-derived chiral aminoalcohol described by Ward and coworkers leads to the desired enantiomer in 99% yield and 82% e.e., provided the reaction was performed in carefully designed conditions (Scheme 79)373. 

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