Betalamic acid synthesis

For betaxanthins, partial synthesis is quite common and presents a viable tool for identification by co-injection experiments. - Starting from a red beet extract or semi-purified betanin-isobetanin blend, alkaline hydrolysis by addition of 32% ammonia is initiated. Spectrophotometric monitoring at 424 nm allows the release of betalamic acid to be followed. Betaxanthins are obtained through the addition of the respective amino acid or amine in at least 20-fold molar excess followed by careful evaporation. Since the starting material most often consists of a racemic betacyanin mixture, the resulting betaxanthin will also consist of two stereoisomers that may not easily be separated by HPLC. ... 

The feasibility of partial synthesis has been demonstrated in the course of structural confirmation of a great number of betaxanthins. Due to incomplete hydrolyses, residual betanin and isobetanin may also accompany the respective target betaxanthin. Most importantly, the purification of betalamic acid does not appear to be possible because it exhibits both amino and aldehyde functions (Stintzing, unpublished observations), resulting in self-condensation. Therefore, data by Barth and co-workers reporting NMR data on purified betalamic acid should be carefully interpreted. ... 

Scheme 1. Synthesis of betalamic acid derivative 66. i, H2, Rh-AlzOs MeOH-HCl ii, DMSO-polymeric carbodiimide-Py-CF3C02H iii, (EtO)20PCH2CH=NN(Me)CONMc2-NaH iv, t-BuOCl.

Homer-Wittig reagent had to be developed. In the first version of the synthesis (11,90) the olefination was carried out with a reagent derived from simple semicarbazide. It was found later (91), however, that the fully methyl-protected reagent gave much better yields. The trimethylsemicarbazone 65 was isolated in 55% yield and appeared to be the pure anti compound ( H NMR 8 7.52, d, 8-H). On treatment with tert-butyl hypochlorite followed by addition of triethylamine, 65 yielded a 7 3 mixture of the 4(7) and 4(7)Z stereoisomers of the corresponding betalamic acid derivative 66, which on recrystallization afforded the pure 4(7) compound. 

Scheme 2. Synthesis of betalamic acid (3). i, (Me0)3CH-CF3C02H-Me0H, H2C=CHCH2MgBr iii, BZ2O2-DMF-K2CO3 AC2O-DMAP iv, HO2C-CO2H, H2O NaOH-H2O V, NCS, Me2S-NEt3 vi, O, Pb(OAc)4-PhH-MeOH vii, silica gel chromatography.

The betalamic acid derivatives obtained by total synthesis have been used for the preparation of natural and unnatural betalains following the procedures developed for amino acid exchange described earlier (Scheme 4). Reaction of the 9 1 ElZ mixture of semicarbazone 66 with the p-toluenesulfonate salt of (S)-cyclodopa methyl ester in dilute methanolic HCl afforded betanidin trimethyl ester (9), which was hydrolyzed with aqueous HCl to yield a 4 6 mixture of betanidin and isobetanidin 91). In the case of L-proline, the reaction had to be carried out in dilute aqueous ammonia because of the sensitivity of the resulting indicaxanthin (2) toward acids. Most likely, an inseparable mixture of 2 and its C-13 epimer T was obtained under these conditions. 

Cleavage of a 1,2-diketone. Buchi and co-workers have published an interesting synthesis of the dimethyl ester of betalamic acid (2), a unit in the red and yellow pigments of plants of the order Centrospermae. The acid is a dihydropyridine derivative and is very sensitive to oxidation. Consequently a synthesis was devised in which the dihydropyridine structure was obtained only in the final step. This step was the oxidative cleavage of the nonenolizable diketone 1 with lead tetraacetate in benzene-methanol (1 1, 0°) to give the dimethyl ester of betalamic acid. 

The structure of all musca-aurins has been confirmed by a partial synthesis using an appropriate amino acid and betalamic acid derived in situ from betanine in the presence of aqueous ammonia (Scheme 20). The transi-mination equilibrium was displaced toward the desired product by using a 5- to 10-fold excess of the amino acid. The progress of the reaction was monitored spectroscopically, following the change of absorption intensity at 540 and 475 nm (69). 

The Biichi synthesis of betalamic acid dimethyl ester (cf. Vol. 9, p. 49) has been described in detail. ... 

In addition, the synthesis of nor-anatoxin-or and -a from cocaine was published. As a new development, betalamic acid, the major building block of the betalaine pigments, was prepared as its dimethyl ester (19) from N-benzyl-norteloidinone (16) via the major intermediates (17) and (18), as shown in Scheme 1. 

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