Solid Phase Stepwise Synthesis of Polyethylene Glycols

Khanal, Ashok; Fang, Shiyue

doi:10.1002/chem.201703004

Cited by 18 publications

(27 citation statements)

References 66 publications

(102 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, it has proved difficult to identify insoluble supports suitable for effective solidphase synthesis. A recent study has illustrated the limitations of solid phase synthesis of linear ethylene glycol (Eg) oligomers (Eg n , n≥16) via the Williamson ether synthesis 40 . Instead, uniform linear polyethylene glycol (PEG) homopolymers have been constructed using liquid-phase iterative strategies [36][37][38][39] , which have usually depended on chromatographic separation to isolate the growing polyethers after each iteration of the synthesis cycle.…”

mentioning

confidence: 99%

Sequence-defined multifunctional polyethers via liquid-phase synthesis with molecular sieving

et al. 2018

View full text Add to dashboard Cite

Synthetic chemists have devoted tremendous effort towards the production of precision synthetic polymers with defined sequences and specific functions. However, the creation of a general technology that enables precise control over monomer sequence, with efficient isolation of the target polymers, is highly challenging. Here, we report a robust strategy for the production of sequence-defined synthetic polymers through a combination of liquid phase synthesis and selective molecular sieving. The polymer is assembled in solution with real time monitoring to ensure couplings go to completion, on a three-armed star-shaped macromolecule to maximise efficiency during the molecular sieving process. This approach is applied to the construction of sequence-defined polyethers, with sidearms at precisely defined locations that can undergo site-selective modification after polymerisation. Using this versatile strategy, we have introduced structural and functional diversity into sequence-defined polyethers, unlocking their potential for real-life applications in nanotechnology, healthcare and information storage.Natural macromolecules, such as nucleic acids and proteins, are heteropolymers with perfectly defined chain length, monomer sequence and chirality. This precise control of the primary sequence provides structural and functional diversity sufficient to generate the molecular complexity required by all living organisms 1,2 . Polymer chemists have employed strategies such as single monomer insertion 3,4 , tandem monomer addition 5 , kinetic control 6 , segregated templating 7,8 , and sequential growth polymerisation 9,10 , to provide polymers with narrowly disperse, but not uniform, chain lengths and approximately controlled sequences. Nevertheless, these sequence-controlled approaches cannot compete with the precision of nature. To prepare truly uniform sequence-defined polymers, iterative synthesis can afford the required nature-like degree of control over the final sequence. In iterative synthesis specific monomers are added one-at-a-time to the end of a growing polymer chain, reaction debris is then separated from the chain extended polymer, and the cycle is repeated using the next monomer in the sequence 11,12 . Solid-phase iterative synthesis 13 is the premiere method for preparation of sequence-defined polymers, mainly because of the simple reaction and purification processes (i.e. filtration and washing), as well as its ease of automation 14 . However, the insoluble solid supports are often expensive, and the purity of the growing polymer is not readily monitored during synthesis 7,12 . Furthermore, the rates of solid-phase coupling reactions are limited by diffusion into the solid support, ultimately leading to a decline in coupling yields and accumulation of deletion errors 15 . Moreover, solid-phase synthesis is generally difficult to scale up, precluding many industrial applications, particularly in materials science 7,10,12 .Consequently, liquid-phase iterative synthetic methods have long been proposed to ove...

show abstract

mentioning

confidence: 99%

Sequence-defined multifunctional polyethers via liquid-phase synthesis with molecular sieving

et al. 2018

View full text Add to dashboard Cite

show abstract

“…Thus, this method had been put aside. In our lab, we can produce 1 in large quantities without any chromatography [ 25 ], and therefore, we decided to use a route for the synthesis of 2 using 1 as the starting material. As shown in Scheme 3 , 2-phenylethan-1-ol was reacted with 1 under basic conditions to give 7 .…”

Section: Resultsmentioning

confidence: 99%

“…sis [14][15][16][17][18][19][20][21][22][23][24][25][26]. Perhaps, the most widely used methods in academia and in industry involve the use of monomers such as compound 1, which contain the acid-labile DMTr protecting group.…”

Section: Introductionmentioning

confidence: 99%

“…Perhaps, the most widely used methods in academia and in industry involve the use of monomers such as compound 1, which contain the acid-labile DMTr protecting group. PEG elongation is achieved by deprotection under acidic conditions, purifying the intermediate, and setting up a separate reaction to carry out the deprotonation and Williamson ether formation reactions under basic conditions (Scheme 1) [15,16,18,23,25]. It is remarkable that the method has evolved to such a sophistication that the synthesis of (PEG) 16 was achieved in nine steps without any chromatography [18,27].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Stepwise PEG synthesis featuring deprotection and coupling in one pot

D.¹,

Eriyagama²,

Yin³

et al. 2021

Beilstein J. Org. Chem.

Self Cite

View full text Add to dashboard Cite

The stepwise synthesis of monodisperse polyethylene glycols (PEGs) and their derivatives usually involves using an acid-labile protecting group such as DMTr and coupling the two PEG moieties together under basic Williamson ether formation conditions. Using this approach, each elongation of PEG is achieved in three steps – deprotection, deprotonation and coupling – in two pots. Here, we report a more convenient approach for PEG synthesis featuring the use of a base-labile protecting group such as the phenethyl group. Using this approach, each elongation of PEG can be achieved in two steps – deprotection and coupling – in only one pot. The deprotonation step, and the isolation and purification of the intermediate product after deprotection using existing approaches are no longer needed when the one-pot approach is used. Because the stepwise PEG synthesis usually requires multiple PEG elongation cycles, the new PEG synthesis method is expected to significantly lower PEG synthesis cost.

show abstract

“…The use of Chol-PEG conjugates linked through a more stable chemical function, like an ether, can overcome these drawbacks and generate nanoformulation systems with a more predictable behavior. , These stable Chol-PEG conjugates are usually synthesized by polymerization processes, and the final molecules contain non-uniform PEG moieties. However, the synthesis of Chol-PEG units linked through an ether bond containing non-disperse PEGs (ND-PEGs) is arduous. − Given the known correlation between erratic biological activities and non-uniform PEG lengths, − the use of ND-PEGs in drug delivery systems has recently attracted a growing interest. Here, we report the synthesis of a family of non-disperse ether-linked Chol-PEG n -OH derivatives (from 4 up to 20 ethylene oxide units) prepared using a recently described methodology , based on the use of tetraethylene glycol macrocyclic sulfate as the electrophile moiety to allow iterative PEG chain elongation.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Stable Cholesteryl–Polyethylene Glycol–Peptide Conjugates with Non-Disperse Polyethylene Glycol Lengths

et al. 2020

View full text Add to dashboard Cite

A method for conjugating cholesterol to peptide ligands through non-disperse polyethylene glycol (ND-PEG) through a non-hydrolysable linkage is described. The iterative addition of tetraethylene glycol macrocyclic sulfate to cholesterol (Chol) renders a family of highly pure well-defined Chol-PEG compounds with different PEG lengths from 4 up to 20 ethylene oxide units, stably linked through an ether bond. The conjugation of these Chol-PEG compounds to the cyclic (RGDfK) peptide though Lys5 side chains generates different lengths of Chol-PEG-RGD conjugates that retain the oligomer purity of the precursors, as analysis by HRMS and NMR has shown. Other derivatives were synthesized with similar results, such as Chol-PEG-OCH 3 and Chol-PEG conjugated to glutathione and Tf1 peptides through maleimide−thiol chemoselective ligation. This method allows the systematic synthesis of highly pure uniform stable Chol-PEGs, circumventing the use of activation groups on each elongation step and thus reducing the number of synthesis steps.

show abstract

Solid Phase Stepwise Synthesis of Polyethylene Glycols

Cited by 18 publications

References 66 publications

Sequence-defined multifunctional polyethers via liquid-phase synthesis with molecular sieving

Sequence-defined multifunctional polyethers via liquid-phase synthesis with molecular sieving

Stepwise PEG synthesis featuring deprotection and coupling in one pot

Synthesis of Stable Cholesteryl–Polyethylene Glycol–Peptide Conjugates with Non-Disperse Polyethylene Glycol Lengths

Contact Info

Product

Resources

About