Journal of Photochemistry and Photobiology A: Chemistry 169 (2005) 289–297 Preparation and photochemistry of o-aminocinnamates Hui Li, Junhai Yang, Ned A. Porter ∗ Department of Chemistry, Vanderbilt University, Box 1822, Station B, Nashville, TN 37235, USA Received 11 May 2004; received in revised form 21 June 2004; accepted 21 June 2004 Available online 23 August 2004 Abstract A series of 2-aminocinnamic acid esters and amides was prepared and the photochemistry of these compounds was studied. The compounds undergo trans–cis photoisomerization followed by cyclization with expulsion of alcohol or amine. The o-amino compounds generally have longer wavelength absorption than the corresponding o-hydroxycinnamates, and alkyl substitution on the amino group generally shifts the absorption to longer wavelength. On the other hand, substitution on the amino group reduces the cyclization rate constants (k c ), as compared to the unsubstituted parent. A solvent effect on lactamization was found for these compounds, as increasing Tris buffer content accelerates the cyclization process. These compounds are suitable for use as protecting groups for alcohols and amines and they also serve as models for new photo-labile serine protease inhibitors. A biotinylated derivative has been prepared which extends their use as photo-cleavable linkers for proteins and avidin via the biotin–avidin complex. This permits binding and photorelease of thrombin and other serine protease enzymes to avidin affinity columns. © 2004 Elsevier B.V. All rights reserved. Keywords: Photo-removable protecting group; o-Aminocinnamate 1. Introduction The use of photo-cleavable groups has seen a marked increase in recent years. Nucleophilic functional groups have, for example, been protected by photo-removable groups in applications in peptide and nucleic acid syn- theses. Photo-cleavable groups such as 2-nitrobenzyl [1,2], substituted benzyloxycarbonyl [3,4], phenacyl, and the 3,5- dimethoxybenzoinyl groups[5] have found widespread use in protecting both carboxylic acids, alcohols and amines in organic synthesis. A more recent addition to the class of compounds used as photo-removable groups for alcohols and amines are the 2-hydroxy-cinnamates. The stable trans- ester isomerizes to the cis form after absorbing a photon, which subsequently lactonizes (1 → 2 in Scheme 1a). The result of this process is the generation of the alcohol ROH. Based on this light-induced reaction, some phenolic esters of 2-hydroxycinnamic acids have been designed as photo- ∗ Corresponding author. Tel.: +6153432693; fax: +6153435478. E-mail address: n.porter@vanderbilt.edu (N.A. Porter). activatable inverse inhibitors for a series of serine proteases, such as trypsin, thrombin, Factor Xa [6], and chymotrypsin [7]. Several examples relating to the therapeutic and diagnos- tic applications of acyl-serine proteases have been reported [8–10]. This system also found recent use as a controlled- release of pro-fragrances, see Scheme 1b [11]. A recent example of 2-hydroxycinnamates illustrated in Scheme 1c is their use in 2-photon photo-release applications when coupled to the well-known o-nitrobenzyl protecting group [12]. o-Aminocinnamates also undergo phototransformations in the same manner as the o-hydroxy compounds and a few reports have shown their utility as photo-cleavable groups. For example, both the solid phase-bound o- hydroxycinnamate and o-aminocinnamate could be photolyt- ically cleaved from beads, Scheme 1d [13]. Also, (E)-3- (2-amino-4, 5-dimethoxyphenyl)-2-methyl-2-propionic acid phenethylamide can be photolyzed to give 6,7-dimethoxy-3- methylcarbostyril and 2-phenethylamine [14]. The aminocin- namate may indeed be a more versatile functionality than the corresponding hydroxycinnamate since the amino group 1010-6030/$ – see front matter © 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.jphotochem.2004.06.021