S-DOPA

Fig. 3-4. (A) Changes in chemical shift of protons of cyclophane -CH2- groups between bipyridinium and phenyl in XH NMR spectra of 3 as a function of (R)-DOPA concentration (a) 0, (b) 0.111, and (c) 0.272 mol L-1. (B) Change in chemical shift plotted against the analytical concentration of (R)- and (S)-DOPA. The solid line is calculated for 1 1 host - guest complexation. (Reprinted with permission from ref. [79]. Copyright 1998, American Chemical Society.)...

S. Yamada and co-workers130) obtained tetrahydroisoquinoline (120) by the condensation of (S)-dopa methyl ester hydrochloride (118) with the carboxylate... 

Homogeneous asymmetric hydrogenation is a practical synthetic method (27). The DIPAMP-Rh-catalyzed reaction has been used for the commercial production of (S)-DOPA [(5)-3-(3,4-dihydroxy-phenyl) alanine] used to treat Parkinson s disease (Monsanto Co. and VES Isis-Chemie) (Scheme 12) (27, 28). (S)-Phenylalanine, a component of the nonnutritive sweetener aspartame, is also prepared by en-antioselective hydrogenation (Anic S.p.A. and Enichem Synthesis) (29). A cationic PNNP-Rh(nbd) complex appears to be the best catalyst for this purpose (15c) (see Scheme 5 in Chapter 1). 

Such a mechanism accounts for the overall stoichiometry of four electrons passed in pairs to molecular oxygen. This stoichiometry must also be preserved in the catecholase reaction see below). The mechanism also requires a second cosubstrate binding site for the activating catechol. A plot of 1/tiag s. DOPA concentration (Figure 13) shows... 

Fig. 7. Oxidation of DOPA catalyzed by poly(S-lysine) - copper(II) complex, reciprocal initial rate (Vo) versus reciprocal DOPA concentration. pH 10.5, 20 C, (Cul/[N1 = 0.13, ICu) = 2.0 X 10 M (a) RS-DOPA, (b) S-DOPA (29)...

Since poly(S-)ysine) — copper(II) complex at pH = 10.5 assumes aTielical conformation while it is random coiled at pH = 6.9, the selective catalysis towards the entantiomeric substrates is considered to be related to the a-helical conformation of the catalyst. This was confirmed also by the comparison of the oxidation rates of R-DOPA and S-DOPA at varkius temperatures in relation to the a-helical content of the catalyst as obtained by the circular diduroic analysis. From these and other (4>servations (SO), a schematic model of the intermediate of the oxidation reacticm has been proposed (Fig. 8) (SI). In this bifunctional coordination of DOPA, the... 

Fig. S. A schematic model for the bifunctional coordination of S-DOPA to pd S-lyane) - copperfll) complex (if)...

One of the early and important achievement was the preparation, in 1975, of dipamp 7 at Monsanto by Knowles et al. [31]. This chiral diphosphine combines the good properties of a C2-symmetric chelating system with the simultaneous presence of two asymmetric phosphorus. It was efficient in the asymmetric hydrogenation of dehydroaminoacids fee s of up to 90-95%), allowing the preparation of (S)-DOPA on an industrial scale from the mid-1970s. This was the first industrial asymmetric synthesis. 

The total synthesis of corlumine by the chiton route beginning with S -dopa (Scheme 5.8) and the auxiliary route (Scheme 5.12c and 5.13c) can now be compared directly. Beginning with the telrahydroisoquinoline species that is metallated and added to the aldehyde, the chiron route proceeds in lf/f overall yield, while the auxiliary route is I7N (30l> based on unreacted starting material in the last step). The comparison neglects the steps necessary for the conversion of 5-dopa into the (linicthoxytelrahydroisoquinoline pivalatnide and lor the synthesis and attachment of the chiral auxiliary. but the steps that are compared cover comparable transformations. 

In the reaction at pH = 10.5, RS-DOPA was found to be oxidized more rapidly than S-DOPA, as seen in Fig. 4, whereas at pH = 6.9 no difference in the reactivities was observed between RS- and S-DOPA (Fig. 5). Poly(RS-lysine) — copper(II) complex showed no difference in catalytic activity towards RS- and S-DOPA (Fig. 6). 

Levodopa is the immediate precursor of dopamine and is able to penetrate the brain, where it is converted to dopamine. The site of this decarboxylation in the parkinsonian brain is uncertain, but a.s dopa decarboxylase is not rate limiting, there may be. sufficient enzyme in the remaining dopaminergic nerve terminals. Another possibility is that the conversion occurs in noradrenergic or serotonergic terminals, because the decarboxylase activity in these neurotics is not specific. In any event, the release of dopamine replaced in the brain by Icvodopa therapy must be very abnormal, and it is remarkable that most patients with Parkinson s disease benefit, often dramatically, from its administration. 

Anotiier metiiod of S5mthesis of S)-DOPA and other alpha- smno acids was elaborated using hydrogenation of a precursor corresponding to the azlactone of substituted acrylic acids on a [PdCl2 (S)-(l-phenylethyl)-amine) ] complex tiiat was prepared in situ fKarpeiskaya et al. ) (Scheme 7.2.). 

In the DIPAMP diphosphine, the two phosphorus atoms themselves are optically active. Rhodium DIPAMP complexes, discovered by Knowles (recipient of the Nobel Prize in 2001) (120,121), have been used by Monsanto for the commercial synthesis of (S)-3-(3,4-dihydroxyphenyl)alanine,(S)-DOPA, extensively used for the treatment of Parkinson s disease. Cationic rhodium complexes with these chiral diphosphines are very effective for the asymmetric hydrogenation of prochiral olefins, such as the interesting a-acetamidoacrylates, which can bind... 

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