Flow Photocleavage for Automated Glycan Assembly (AGA)

Abstract

Automated glycan assembly (AGA) is contingent on the development of simple, efficient cleavage strategies to liberate complex, high value products from a solid support resin. Given the rapid advances in the structural complexity of carbohydrates that can be constructed via this enabling technology, effective cleavage is a persistent challenge. Photolabile linkers have a venerable history in AGA and mitigate potential complications arising from chemically induced release protocols. However, photochemical cleavage strategies have traditionally relied upon mercury vapor lamps, which present challenges in establishing welldefined, reproducible, and nonhazardous conditions for this ultimate step of the AGA sequence. To complement the existing batch strategies, a safe and sustainable approach for the continuous flow photocleavage from solid support using LEDs has been developed. By employing a custom-built LED flow reactor, photocleavage yields of up to 80% were achieved in less than 1 h. Efficiency could be further improved by merging flow photochemistry with pregrinding. Validation of this strategy is showcased in a proof of concept AGA synthesis of a model dimannoside.

Technological Innovations in Photochemistry for Organic Synthesis: Flow Chemistry, High-Throughput Experimentation, Scale-up, and Photoelectrochemistry

“…After initial work of Seeberger et al on the use of photolabile groups as linkers for solid phase synthesis of saccharides, more publications appeared to either exploit this technology, − or to improve the photocleavage method. , Additionally, a commercially available instrument for the automated glycan assembly was developed …”

“…After initial work of Seeberger et al on the use of photolabile groups as linkers for solid phase synthesis of saccharides, 532 more publications appeared to either exploit this technology, 533−538 or to improve the photocleavage method. 539,540 Additionally, a commercially available instrument for the automated glycan assembly was developed. 541 One approach for increasing the efficiency of the photocleavage method was proposed by Hurevich et al, 539 who found that grinding of the porous polystyrene beads to expose more surface area to the irradiation significantly improved the photocleavage efficiency.…”

Development of Kilogram-Scale Convergent Liquid-Phase Synthesis of Oligonucleotides

“…Consequently, the 3′-OH protecting group needs to be removed without use of either acids or bases. Heat and light − sensitive protecting groups were briefly investigated, but satisfactory reaction profiles were not obtained. Transition metal catalyst or hydrazine deprotection schemes gave only low yields.…”

Developing flow photo-thiol–ene functionalizations of cinchona alkaloids with an autonomous self-optimizing flow reactor

“…[33][34][35] In addition the heat generated by the light source can be more efficiently controlled by a precise control of the flow rate and quickly dissipated thanks to the high surface area to volume ratio of capillary flow reactors. Therefore, it is now widely accepted that photochemical transformations are, in general, much more reproducible, cleaner and faster when carried out in a continuous flow reactor [36][37][38][39][40][41][42][43] even on large scales. [44][45][46][47] In this contribution we describe our effort toward the development of a general strategy for the functionalization of cinchona alkaloids through photochemical thiol-ene reactions conducted in a custom built flow photochemical reactor.…”

“…33–35 In addition the heat generated by the light source can be more efficiently controlled by a precise control of the flow rate and quickly dissipated thanks to the high surface area to volume ratio of capillary flow reactors. Therefore, it is now widely accepted that photochemical transformations are, in general, much more reproducible, cleaner and faster when carried out in a continuous flow reactor 36–43 even on large scales. 44–47…”