Cinnamic acid derivatives, asymmetric

In recent years, the catalytic asymmetric hydrogenation of a-acylamino acrylic or cinnamic acid derivatives has been widely investigated as a method for preparing chiral a-amino acids, and considerable efforts have been devoted for developing new chiral ligands and complexes to this end. In this context, simple chiral phosphinous amides as well as chiral bis(aminophosphanes) have found notorious applications as ligands in Rh(I) complexes, which have been used in the asymmetric hydrogenation of a-acylamino acrylic acid derivatives (Scheme 43). 

The asymmetric hydrogenation of cinnamic acid derivatives has been developed by Knowles at Monsanto [4], The synthesis of L-dopa (Figure 4.3), a drug for the treatment of Parkinson s disease, has been developed and is applied on an industrial scale. Knowles received the Nobel Prize for Chemistry in 2001 together with Noyori (see below, BINAP ) and Sharpless (asymmetric epoxidation). 

Houpis, I.N., Patterson, L.E., Alt, C.A., Rizzo, J.R., Zhang, T.Y. and Haurez, M. S3mthesis of PPAR Agonist via Asymmetric Hydrogenation of a Cinnamic Acid derivative and Stereo-specific Displacement of (S)-2-Chloropropionic Acid. Org. Lett. 2005, 7, 1947-1950. 

Table I. Optical Yields for the Asymmetric Hydrogenation of a-(Acylamido)cinnamic Acid Derivatives Using Rhodium(I) Complexes Containing (NmenHCeHsJPC C P eHs ...

The first industrially interesting production of a chiral pharmaceutical with a chiral metal complex catalyst is the asymmetric hydrogenation of cinnamic acid derivatives to give L-DOPA, see Fig. 6.21. 

Yang s chiral ketones 75 have also been used as catalysts in the kinetic resolution of acyclic secondary allyl silyl ethers <2001JOC4619>. Dioxiranes generated in situ from dehydrocholic acid derivatives 122 and Oxone have been used in the asymmetric epoxidations of cinnamic acid derivatives with product ee s up to 95% <2001TA1113, 2002JOC5802> and unfunctionalized olefins (up to 98% ee) <2006T4482>. 

In the laboratory of D. Ma, the asymmetric synthesis of several metabotropic glutamate receptor antagonists derived from a-alkylated phenylglycines was undertaken. The preparation of (S)-1-aminoindan-1,5-dicarboxylic acid (AIDA) started with the Perkin reaction of 3-bromobenzaldehyde and malonic acid. The resulting ( )-cinnamic acid derivative was hydrogenated and the following intramolecular Friedel-Crafts acylation afforded the corresponding indanone, which was then converted to (S)-AIDA. 

Syntheses of relatively simple chiral drugs on an industrial scale are the domain of catalytic or enzymatic methods. In the case of the calcium antagonist diltiazem [113] Sharpless asymmetric dihydroxylation (AD-reaction) is employed which works particularly efficiently for cinnamic acid derivatives such as 48-1. In fact diol 48-2 is obtained with good optical enrichment and is then converted into the target compound via 6 routine steps. Alternatively diltiazem is prepared via classical optical resolution or via enzymatic kinetic resolution of suitable intermediates [113]. 

Enzymatic hydrogenations generate optically pure isomers attempts to initiate such processes are made on metal-catalyzed hydrogenations. Asymmetric hydrogenation can fill the need for asymmetric compounds of which only one enantiomorph is active, e.g., amino acids such as L-lysine, 1 (indispensable in animal feeds), L-phenylalanine, 2 (a sweet peptide component), L-dopa 3 (a drug for Parkinsonism), are required in the L-form for human or animal consumption. Consequently, most of the examples investigated are related to the asymmetric hydrogenation of acrylic acid or cinnamic acid derivatives. 

NMR spectroscopy has been used to study the species formed in solution by interaction of cinnamic acid derivatives with asymmetric hydrogenation catalysts. Such studies are necessarily limited to those species which accumulate in adequate concentration and have sufficiently long lifetimes for observation by NMR. In catalytic reactions as rapid as those described here, such complexes appear likely to be outside rather than in the operating catalytic cycle. ... 

Fig. 2 STM images of (a) An isophthalic acid derivative, (h) A semifluorinated isophthalic acid derivative, (c) A model of the area in (b). (d) A terephthalic acid derivative, (e) A monourea compound, (f) A his-ureum compound, (g) A symmetric cinnamic acid derivative, (h) A photodimer monolayer of (g). (i) An asymmetric cinnamic acid derivative (not reactive). The scale bar is 2 nm. (Reprinted in part or adapted with permission from the American Chemical Society.) (View this art in color at www.dekker.com.)...

The chiral center would be installed from either Unear carbamate 15 or branched carbamate 16 via the asymmetric addition of malonate anion to the 7i-allyl Mo complex reported by Trost et al. [11] to afford the branched chiral malonate derivative 17. Decarboxylation of 17 should provide the mono-carboxylic acid 18. Masa-mune homologation with 18 affords our common precursor 14. Linear carbamate 15 was obtained from the corresponding cinnamic acid, and branched 16 was prepared in one pot from the corresponding aldehyde. 

Photodimerization of cinnamic acids and its derivatives generally proceeds with high efficiency in the crystal (176), but very inefficiently in fluid phases (177). This low efficiency in the latter phases is apparently due to the rapid deactivation of excited monomers in such phases. However, in systems in which pairs of molecules are constrained so that potentially reactive double bonds are close to one another, the reaction may proceed in reasonable yield even in fluid and disordered states. The major practical application has been for production of photoresists, that is, insoluble photoformed polymers used for image-transfer systems (printed circuits, lithography, etc.) (178). Another application, of more interest here, is the use that has been made of mono- and dicinnamates for asymmetric synthesis (179), in studies of molecular association (180), and in the mapping of the geometry of complex molecules in fluid phases (181). In all of these it is tacitly assumed that there is quasi-topochemical control in other words, that the stereochemistry of the cyclobutane dimer is related to the prereaction geometry of the monomers in the same way as for the solid-state processes. 

Table 5 Asymmetric hydrogenation of cinnamic and tiglic acid derivatives...

The strategy is impressively simple the phthalazine derivative 15 can readily be prepared from quinine in one step. Being a divinyl derivative, it can be submitted as a cross-linking unit in the radical polymerization of methyl methacrylate (MMA) or 2-hydroxy methacrylate (HEMA). Thereby, an immobilized (DHQ-PHAL) derivative 16 is obtained, which is suited for the asymmetric dihydroxylation of frantr-stilbene (>99 % ee) and ( )-cinnamic acid methyl ester (>99 % ee. Table 1). The insoluble catalyst can be recovered by simple filtration, and its repeated... 

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