Atropic acid

Atropic acid a-pherryi acrylic acid QH5a CH2)-C02H... 

Tropic Acid. The constitution of both tropic and atropic acids is known from syntheses by Ladenburg et al. from acetophenone. The ketone (I) by treatment with phosphorus pentachloride was converted into a-dichloroethylbenzene (II), and this, by the action of potassium cyanide in alcohol, into ethoxycyanoethylbenzene (III), which on hydrolysis yielded ethylatrolactic acid (TV). The latter was converted by strong... 

Mackenzie and Wood obtained low yields by this method, which is the basis of both the Muller and Wislicenus processes, and recommended instead the hydrolysis of acetophenonecyanohydrin (X) into atrolaetie acid (XI), conversion of the latter by distillation under reduced pressure into atropic acid (XII), which was then treated in ethereal solution with hydrochloric acid and the halogen in the resulting, 8-chlorohydratropie acid replaced by hydroxyl, by boiling the acid with aqueous sodium carbonate solution, giving tropic acid (XIII), thus ... 

The hyoscyamine system is found alone in some adult Duboisia Leichhardtii and possibly in some southern D. myoporoides. It produces tropine and nortropine only, which are esterified with tropic acid, or as in ajooatropine found in belladonna, with atropic acid, and to a small extent with the isoprene acids referred to above. Some tropine or nortropine may occur as such. Scopine, -tropine and dihydroxytropane are absent. 

L-Asparaginyl-L-arginyl-L-valyl-L-tyrosyl-L-valyl-L-histidyl-L-prolyl-L-phenylalanine methyl ester trihydrochloride Angiotensin amide Atropic acid ethyl ester Tilidine HCI Atropine... 

The bis-DIOP complex HRh[(+)-DIOP]2 has been used under mild conditions for catalytic asymmetric hydrogenation of several prochiral olefinic carboxylic acids (273-275). Optical yields for reduction of N-acetamidoacrylic acid (56% ee) and atropic acid (37% ee) are much lower than those obtained using the mono-DIOP catalysts (10, II, 225). The rates in the bis-DIOP systems, however, are much slower, and the hydrogenations are complicated by slow formation of the cationic complex Rh(DIOP)2+ (271, 273, 274) through reaction of the starting hydride with protons from the substrate under H2 the cationic dihydride is maintained [cf. Eq. (25)] ... 

Class II components require high H2-pressure (e.g., atropic acid) [100, 101]. 

Under this aspect, the group of Jessop [102] investigated the influence of the ionic liquid used on enantioselectivity in the hydrogenation of atropic acid as an example... 

Styrene and its derivatives, such as a-methylstyrene, atropic acid, cinnamic acid, and cinnamyl alcohol, were readily reduced (acids were added as their salts), yielding the corresponding dihydro derivatives (Table I). However, propenyl-benzene, tmst/m-diphenylethylene, and stilbene absorbed no hydrogen. 

The diop system is the most effective of the Ru(II) chiral phosphine complexes that we have found for asymmetric hydrogenation (25, 26). The hydrogenation rates are about V50 as large as those using HRuCl(PPh3)3 under corresponding conditions (32) but are reasonably efficient nevertheless. For example, 1M solutions of atropic acid are converted quantitatively to 2-phen-ylpropionic acid (40% enantiomeric excess (ee)) in one day with 10 2 M catalyst at 1 atm H2. 

Wilkinson s (I) discovery that the soluble rhodium(I) phosphine complex, [Rh(PPh3)3Cl], was capable of homogeneous catalytic hydrogenation of olefins immediately set off efforts at modifying the system for asymmetric synthesis. This was made possible by the parallel development of synthetic methods for obtaining chiral tertiary phosphines by Horner (2) and Mislow (3,4, 5). Almost simultaneously, Knowles (6) and Horner (7) published their results on the reduction of atropic acid (6), itaconic acid (6), a-ethylstyrene (7) and a-methoxystyrene (7). Both used chiral methylphenyl-n-propyl-phosphine coordinated to rhodium(I) as the catalyst. The optical yields were modest, ranging from 3 to 15%. 

A solution of 194 grams (2 mols) of fresh-distilled l-(dimethylamino)-l,3-butadiene is combined at room temperature in a 1 liter round-bottom flask with 352 grams (2 mols) atropic acid ethyl ester. After being stirred for about 10 minutes, the reaction mixture gradually becomes exothermic. By cooling with ice water, the contents of the flask are kept at a temperature of 40° to 60°C. After the reaction has ceased, the mixture is kept overnight (about 8 to... 

The first examples of asymmetric hydrogenation based on this principle were reported by Knowles and co-workers (the Monsanto group) in 1968 (12). Rhodium complexes of the type RhL3Cl3 (where L was a chiral phosphine) were used in the hydrogenation of a-phenylacrylic acid (atropic acid) and itaconic acid under the conditions indicated in Fig. 3. When L was (R)-( )-methylphenyl-n-propylphosphine,3 15% optically pure (S)-(+)-a-phenyl-pro-pionic acid and 3% optically pure methylsuccinic acid (configuration unreported) were obtained. 

A number of experiments indicated that the observed effects were related to the formation of a phosphobetaine by the reaction of atropic acid with any ligand in excess of 2 equivalents per equivalent of rhodium. In the presence of the phosphobetaine, atropic acid was hydrogenated rapidly to chiral a-phenyl-propionic acid. It was concluded that the phosphobetaine influenced the rate and optical yield only because it converted the substrate to the carboxylate anion (Fig. 7). This conclusion was supported by an experiment using L/Rh = 2 and the triethylamine salt of atropic acid in which a thirty-fold rate increase, compared to the rate at L/Rh = 2 in the absence of triethylamine, and also increased optical purity (28% ee) were obtained (15). 

FIG. 7. Reaction of a tertiary phosphine with atropic acid to produce a phosphobetaine salt. 

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