Caged Proline in Photoinitiated Organocatalysis

Abstract

Organocatalysis is an emerging field in which small metal-free organic structures catalyze a diversity of reactions with remarkable stereoselectivity. The ability to selectively switch on such pathways upon demand has proven to be a valuable tool in biological systems. Light as a trigger provides the ultimate spatial and temporal control of activation. However, there have been limited examples of photo triggered catalytic systems. Herein, we describe the synthesis and application of a caged proline system that can initiate organocatalysis upon irradiation. The caged proline was generated using the highly efficient 4-carboxy-5,7-dinitroindolinyl (CDNI) photocleavable protecting group in a 4-step synthesis. Advantages of this system include water solubility, biocompatibility, high quantum yield for catalyst release, and responsiveness to two-photon excitation. We showed the light triggered catalysis of a crossed aldol, a Mannich, and a self-aldol condensation reaction. We also demonstrated light initiated catalysis leading to the formation of a biocide in situ, which resulted in the growth inhibition of E. coli, with as little as 3 minutes of irradiation. This technique can be broadly applied to other systems by which the formation of active forms of drugs can be catalytically assembled remotely via two-photon irradiation.

Competition Between Cyclization and Unusual Norrish Type I and Type II Nitro-Acyl Migration Pathways in the Photouncaging of 1-Acyl-7-nitroindoline Revealed by Computations

“…This is widely referred to as spatio-temporal control. [1][2][3][4] Techniques that possess spatio-temporal advantages have found numerous applications ranging from medicinal chemistry fields with photo targeted therapeutics, 1,3 such as cancer treatments [5][6][7][8] or photoinitiated catalysis, 8 and to the neuroscience where it becomes critical to activate selected neurons to study specific pathways. 1,[9][10][11][12] In the latter, emerging field of optogenetics, light-sensitive channel rhodopsin receptors are genetically engineered in selected neurons rendering them light responsive.…”

“…Caged molecules are inert, and they need an external agent-such as a physical, chemical, or mechanical force- 8,[24][25][26][27] to induce the release of the biologically active compound they are protecting. Light represents the most advantageous activator because it offers the ability to control the precise time and the location of the release.…”

“…The reaction from MDNI-Ac (10 in Scheme 2) to 4-methoxy-5-nitro-7-nitrosoindole (8) and acetic acid is thermodynamically favored, with a calculated ΔG of -35.8 kcal/mol (see Scheme 2 below). According to the CP mechanism, the cyclic intermediate 9 (see below) is the key structure in the reaction mechanisms of MNI and MDNI, regardless of the leaving group.…”

“…52,56 In order to better understand this migration pathway, we computed the energy for an ethyl group migration (in place of the acetyl) and noted that it was higher in energy (21.3 kcal/mol, Figure 3 part c), Ulg, respectively. However, according to their reported data (see Table 1 Furthermore, the hydrolysis product (15) and the uncaging product (8) are different in that the former retains the nitro group while the photo uncaging leads to the nitroso. However, both processes result in the release of acetic acid (from 10 and 13, respectively).…”

Visible Light‐Gated Organocatalysis Using a RuII‐Photocage

“…It is widely recognized that the possibility to externally photocontrol processes with high spatial and temporal precision is very attractive for transducing an optical signal into an amplified and focused response of chemical transformation or other action [31] . Despite these notions and the abundant exploitation of photocaged compounds in the most varied contexts, [36, 37] the observation of light‐gated organocatalysis has been limited to very few literature examples [10–14] . One of them is the UV‐light activation of an adduct of 1,5,7‐triazabicyclo[4.4.0]dec‐5‐ene (TBD) with tetraphenylboric acid.…”