Frans-Cinnamate

Figure A8.12 Enzymatic conversion of frans-cinnamic acid to L-phenylalanine.

Conversion of frans-cinnamic acids into the c/s-isomers (Table 8.12)... 

Several building blocks were prepared separately (Chart 7). Methyl frans-cinnamate gave by Sharpless enantiocontrolled dihydroxylation a diol from which by a series of stereo- and regioselective transformations (96) and Ru-catalyzed oxidation for transformation of the phenyl into a carboxyl group accompanied by adequate protection (97) and deprotection steps the protected OHAsp derivative 98 was obtained. 

This enzyme [EC 1.14.13.11], also known as cinnamate 4-hydroxylase, catalyzes the reaction of frans-cinnamate with NADPH and dioxygen to generate 4-hydroxycmna-mate, NADP+, and water. The enzyme, which uses a heme-thiolate as a cofactor, can also replace NADPH with NADH (however, the reaction will proceed slower). 

Catabolism of histidine in most organisms proceeds via an initial elimination of NH3 to form urocanic acid (Eq. 14-44). The absence of the enzyme L-histidine ammonia-lyase (histidase) causes the genetic disease histidinemia 284/285 A similar reaction is catalyzed by the important plant enzyme L-phenylalanine ammonia-lyase. It eliminates -NH3+ along with the pro-S hydrogen in the (3 position of phenylalanine to form frans-cinnamate (Eq. 14-45). Tyrosine is converted to p-coumarate by the same enzyme. Cinnamate and coumarate are formed in higher plants and are converted into a vast array of derivatives (Box 21-E,... 

Benzoic and salicylic acids. Two of the simplest plant acids arising from fraus-cinnamate are benzoic acid, accumulated in plums and cranberries, and salicylic acid, present in all green plants and accumulated as methyl esters or glycosides in some plants, e.g., those of the willow family. Salicylic acid is made by hydroxylation of benzoic acid,177 which can be formed from frans-cinnamate by P oxidation as depicted in Fig. 25-8, but it may also arise from isochoris-mate as shown in Fig. 25-2.178 Salicylic acid plays a central role in resistance of plants to a variety of... 

Condensation of 2-pyrone with dimethyl acetylenedicarboxylate and diethylacetylene proceeds in the expected manner. There is, however, no reaction between di-t-butylacetylene and 2-pyrone, even after solutions of the reactants in bromobenzene have been heated in a sealed tube at 210°C for 5 days. Instead, frans-cinnamic acid is obtained in low yield. 

To understand why solution experiments sometimes fail to produce cocrystal products, and why solvent-drop grinding experiments can work when performed on the same system, the 1 1 cocrystal formed by nicotinamide and frans-cinnamic acid (frans-(2E)-3-phenylacrylic acid) has been studied [56]. In this work ternary isothermal phase diagrams of the cocrystal system was used to understand the crystallization phenomena, and to deduce methodologies and for the experimental design of cocrystal preparation. Cocrystals are most likely to form from solutions in which the two reactants have similar degrees of solubility, and the success of solvent-drop grinding was explained in that crystallization took place in the region of low solvent mole fractions where the cocrystal would be more stable relative to the separated reactants. 

The addition of benzonitrile oxide to acrylic acid gave only the 4-carboxylic acid (441) (59MI41601), while addition to cis- and frans-cinnamic esters gave cis and trans diastereomeric pairs of 4-carboxylic acids (442) (Scheme 100) (59MI41600). Arbisono repeated the experiment and, when methyl c/s-cinnamate was used, in addition to the 4-carboxylic acid some 5-carboxylic acid (442) was isolated (66MI41600). The reaction of vinyl bromides with benzonitrile oxide yielded only an isoxazole and not a bromoisoxazoline (Scheme 101) (78JCR(S)192>. 

Further support for the intermolecular route is provided by the isolation of the substituted frans-cinnamic acid, the normal Perkin product. This arises through elimination of carboxylic acid from the fully acylated species (393) rather than cyclization. For example, a considerable amount of 2-acetoxy-3-methoxycinnamic acid is formed from 3-methoxysalicylaldehyde, perhaps as a result of steric interference with cyclization so allowing the intermolecular process to predominate (39JPR(152)23). It should be noted that trans- 2-hydroxycinnamic acids do not cyclize under normal Perkin conditions, though the cis isomer does so quite readily. Isomerization of the trans acid has been effected by treatment with a trace of iodine in acetic anhydride or by UV irradiation. 

In addition to the identification of crystal moditications, SSNMR has been used to monitor reactivity and phase changes in different polymorphic forms. For instance, Harris and Thomas (1991) followed the photochemical conversion of formyl-fran -cinnamic acid with SSNMR (see also Section 6.4). Variable temperature techniques have been used to study the interconversion of four polymorphic modifications of sulphanilamide (/ -amino-benzenesulphonamide), including interpretation of at least some of the molecular motions during the course of the transformation (Frydman et al. 1990). A similar combination was augmented with colourimetric techniques to study the coexistence of two phases in the course of a phase transition (Schmidt et al. 1999). Of course, differences between unsolvated and solvated or hydrated crystal moditications may also be readily characterized by the SSNMR technique, as was done with the anhydrous and monohydrate of oxyphenbutazone (Stoltz et al. 1991). Due to the availability of the crystal structures for both modifications the SSNMR results could be interpreted directly in terms of the different atomic environments, especially for the differences in hydrogen bonding in the presence... 

In contrast to solutions, solid drugs have a fixed conformation resulting in topochemical reactions. The majority of photoreactions in the solid state, described in the literature, deal with lattice-controlled examples and photodimerizations. A precondition for these reactions is the parallel position of the double bond of two adjacent molecules in the crystal lattice as shown by the example of the trimorphic, frans-cinnamic acid. Irradiation of the a- and the 5-modifications causes the formation of a-truxillic acid and (i-truxinic acid, respectively, whereas the y-modification is photostable due to the distance of the double bonds fixed by the lattice (Fig. 8) (10). 

The development of the principles of solid-state reactions of substituted cinnamic acids was pioneered by Gerhard M. J. Schmidt. The trans-SLcid was found to be polymorphic, and three different crystal forms (designated a, and 7) were identified by him. The finding that the nature of the cyclobutane derivatives formed by the solid-state photochemical reaction on crystals of frans-cinnamic acid depend on which polymorph is irradiated was of great interest. The products of the photo-... 

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