Total Synthesis of a PSGL-1 Glycopeptide Analogue for Targeted Inhibition of P-Selectin

Dhakal, Bibek; Mandhapati, Appi; Eradi, Pradheep; Park, Simon; Fibben, Kirby; Li, Kaicheng; DeYong, Ashley; Escopy, Samira; Karki, Geeta; Park, Diane D.; Haller, Carolyn A.; Dai, Erbin; Sun, Lijun; Lam, Wilbur A.; Chaikof, Elliot L.

doi:10.1021/jacs.4c05090

Cited by 4 publications

(3 citation statements)

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“…The subsequent modification of 16 and 17, including acetylation of 4-OH galactose, zinc-mediated reduction of NHTroc and azide, and trifluoroacetic acid-mediated hydrolysis of t -butyl ester provided 1a and 1b suitable for solid phase peptide sequence (SPPS) (Scheme ) . In our recent report, we confirmed the feasibility of subsequently deprotecting the N -acetyl oxazolidinone using DBU/dithiothreitol, and the acetates and ester using NaOMe/LiOH …”

Section: Resultssupporting

confidence: 61%

“…While chemoenzymatic synthesis greatly facilitates the synthesis of complex glycans, limitations include the requirement for costly sugar nucleotide donors and recombinant enzymes, limited enzyme stability, and a need for bioreactor process development and downstream processing. Given our motivation to develop a synthetic approach that is readily scalable, we recently reported a total chemical synthesis of GSnP-6 . An efficient, scalable, hydrogenolysis-free synthesis of C2- O -sLe X -Thr-COOH was identified by both convergent and orthogonal one-pot assembly, which afforded this crucial building block ready for direct use in solid-phase peptide synthesis (SPPS).…”

Section: Introductionmentioning

confidence: 99%

“…It should also be noted that both of these protecting groups can be easily deprotected at the end of the reaction sequence. Specifically, the 2-acetyl group can be cleaved using LiOH in MeOH and the 2-benzyl group using the same reagent at elevated temperatures and over a longer reaction time . Moreover, while more glycosylation-friendly NAP-protecting groups were used in our recently described synthesis of C2- O -sLe X -Thr-COOH, PMB-protecting groups were used in the synthesis of the benzoyl-based C2- O -sLe X -Thr-COOH with excellent yields.…”

Section: Introductionmentioning

confidence: 99%

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Insights Derived from the Synthesis of a Complex Core 2 Glycan

Dhakal,

Mandhapati,

Park

et al. 2024

J. Org. Chem.

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We describe the synthesis of a benzoyl-based C2-O-sLe X -Thr-COOH building block devoid of any aglycone transfer or orthoester-formed byproducts. The absence of byproducts was achieved in the course of both [1 + 1] glycosylation reactions with thiophenol aglycone containing galactose acceptors, as well as a [2 + 2] glycosylation in the presence of a p-methoxy benzyl containing glucosamine-fucose disaccharide. We also report an efficient [2 + 1 + 1] synthesis of a peracetylated sLe X en route to a peracetylated C2-O-sLe X -Thr-COOH. While the total synthesis of the latter compound was recently reported by a related route, the divergent [2 + 1 + 1] synthesis provided good reaction yields for each step of the sequence, establishing this scheme as an alternate approach to the peracetylated C2-O-sLe X -Thr-COOH. Importantly, the current report details the role of a variety of hydroxy-protecting groups, including acetyl, benzoyl, p-methoxy benzyl, and naphthylmethyl that may be considered in designing a route to this complex Core 2 glycan. While we have previously described the use of more glycosylation-friendly naphthylmethyl protecting groups, the current synthesis used p-methoxy benzyl protecting groups with excellent reaction yields, demonstrating the feasibility of applying this side reaction-prone protecting group for this challenging synthesis.

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Section: Resultssupporting

confidence: 61%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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