Photolabile protecting group

PPGs enable high degrees of chemoselectivity as they allow researchers to control spatial, temporal and concentration variables with light.

[1][2][3] Since their introduction in 1962,[4] numerous PPGs have been developed and utilized in a variety of wide-ranging applications from protein science[5] to photoresists.

The first reported use of a PPG in the scientific literature was by Barltrop and Schofield, who in 1962 used 253.7 nm light to release glycine from N-benzylglycine.

[4] Following this initial report, the field rapidly expanded throughout the 1970s as Kaplan[6] and Epstein[7] studied PPGs in a variety of biochemical systems.

The list of functional groups that can be protected include, but are not limited to, phosphates, carboxylates, carbonates, carbamates, thiolates, phenolates and alkoxides.

[2] Additionally, while the rate varies with a number of variables, including choice of solvent and pH, the photodeprotection has been exhibited in both solution and in the solid-state.

[26][27] This mechanism yields the carboxylic acid as the exclusive photoproduct; the key benefit of the pHP PPG is the lack of secondary photoreactions and the significantly different UV absorption profiles of the products and reactants.

While the quantum yield of the p-hydroxyphenacyl PPG is generally in the 0.1-0.4 range, it can increase to near unity when releasing a good leaving group such as a tosylate.

The photoextrusion of the leaving group from the pHP PPG is so effective, that it also releases even poor nucleofuges such as amines (with the quantum yield in the 0.01-0.5 range, and dependent on solution pH).

The quantum yield of this mechanism directly corresponds to the ability of the protected substrate to be a good leaving group.

Barltrop and Schofield first demonstrated the use of a benzyl-based PPG,[4] structural variations have focused on substitution to the benzene ring, as well as extension of the aromatic core.

For example, insertion of a m,m’-dimethoxy substituent was shown to increase the chemical yield ~75% due to what has been termed the “excited state meta effect.”[2][34][35] However, this substitution is only able to release good leaving groups such as carbamates and carboxylates.

[36][37] Finally, the carbon skeleton has been expanded to include PPGs based on naphthalene,[38] anthracene,[39] phenanthrene,[40] pyrene[41] and perylene[42] cores, resulting in varied chemical and quantum yields, as well as irradiation wavelengths and times.

For example, Ly et al. developed a p-iodobenzoate-based photocaged reagent, which would experience a homolytic photoclevage of the C-I bond.

However, upon exposure to 260 ± 20 nm light, the PPG would be removed yielding 2-nitrosobenzaldehyde and a carboxylic acid that was soluble in aqueous base.

[54] This process was first reported by Solas in 1991;[55] protected nucleotides were attached to a surface and spatially-resolved single stranded polynucleotides were generated in a step-wise “grafting from” method.

[63][64] Finally, PPGs have been utilized to cross-link numerous photodegradable polymers, which have featured linear, multi-dimensional network, dendrimer, and branched structures.

Figure 1. Barltrop and Schofield's initial demonstration of a photolabile protecting group.
Figure 2. Norrish Type II mechanism for the photocleavage of a 2-nitrobenzyl-based PPG. The aci -nitro compound is drawn in the lower right.
Figure 3. A series of common nitrobenzyl-based PPGs.
Figure 4. The standard phenacyl carbon skeleton (left) with two known modifications: 3',5'-dimethoxybenzonin (DMB, top right), and p-hydroxyphenacyl (bottom right).
Figure 5: Benzyl-based PPGs with polycyclic aromatic cores: A) benzene; B) naphthalene; C) anthracene; D) phenanthrene; E) phyene and; F) perylene.
Figure 7. The total synthesis of (-)-diazonamide A (above) requires the use of PPGs.
Figure 6. The final step in Busuyek's synthesis of ent-Fumiquinazoline is the removal of a 2-nitrobenzyl PPG through a Norrish Type II mechanism.
Figure 8. A photocaged reagent, neurotransmitter, and therapeutic from left to right, respectively.
Figure 9. Many of the photoresists developed at Bell Laboratories centered around the 2-nitrobenzyl cholate motif.
Figure 10. Schematic of light directed polynucleotide synthesis on surfaces.