Automated Chemical Oligosaccharide Synthesis: Novel Approach to Traditional Challenges

Abstract

Advances in carbohydrate chemistry have certainly made common oligosaccharides much more accessible. However, many current methods still rely heavily upon specialized knowledge of carbohydrate chemistry. The application of automated technologies to chemical and life science applications such as genomics and proteomics represents a vibrant field. These automated technologies also present opportunities for their application to organic synthesis, including that of the synthesis of oligosaccharides. However, application of automated methods to the synthesis of carbohydrates is an underdeveloped area as compared to other classes of biomolecules. The overarching goal of this review article is to present the advances that have been made at the interface of carbohydrate chemistry and automated technology.

Figure 1.

Representative structures of common linear and branched oligosaccharide motifs.

Figure 2.

Directing neighboring participating groups at C-2.

Figure 3.

Solid supports for oligosaccharide synthesis: (A) Merrifield’s resin, (B) Tentagel, and (C) JandaJel.

Figure 4.

Recently introduced linkers for polymer-supported oligosaccharide synthesis.

Figure 5.

Split-valve setup for the alternate-pump system.

Figure 6.

Representative 1,2-cis-linked oligosaccharides synthesized using Glyconeer 2.1

Scheme 1.

General Outline of the Chemical Glycosylation Reaction

Scheme 2.

Examples of Urea and Thiourea-Based Organocatalytic Reactions

Scheme 3.

Synthesis of β-Mannosides via Intramolecular Aglycone Delivery

Scheme 4.

Conventional Linear Oligosaccharide Synthesis with Alternating Glycosylation and Deprotection Steps

Scheme 5.

Convergent Block Synthesis of Ganglioside GP3

Scheme 6.

(A) Chemoselective and (B) Selective Activation Approaches to Expeditious Oligosaccharide Synthesis

Scheme 7.

Hexasaccharide Synthesis in Five Selective Activation Steps

Scheme 8.

Orthogonal Activation of Phenylthio Glycosides and Fluorides

Scheme 9.

Glycal-Epoxide Method for Iterative Oligosaccharide Synthesis

Scheme 10.

Two-Directional Approach for the Synthesis of Pentasaccharide 54

Scheme 11.

One-Pot Synthesis of Tetrasaccharide 59 via Chemoselective Activation

Scheme 12.

One-Pot Synthesis of Tetrasaccharide 62 via Sequential Selective Activation of Building Blocks Equipped with Different Leaving Groups

Scheme 13.

Preactivation-Based One-Pot Synthesis of Globo-H Hexasaccharide 67

Scheme 14.

Glycosylation on Polymer Support

Scheme 15.

Acceptor-Bound Approach to the Synthesis of Oligosaccharide 73

Scheme 16.

Chiral Auxiliary-Assisted Synthesis of 1,2-cis-Linked Oligosaccharide 79

Scheme 17.

Donor-Bound Synthesis of Pentasaccharide82

Scheme 18.

Orthogonal Synthesis of a Combinatorial Library on Solid Phase

Scheme 19.

Peptide-Templated Oligosaccharide Synthesis on Polymer Support

Scheme 20.

STICS: Surface-Tethered Iterative Carbohydrate Synthesis

Scheme 21.

Synthesis of Dimeric Le^x Hexasaccharide Using Soluble Polymer Support

Scheme 22.

Fluorous Tag-Assisted Synthesis of Pentasaccharide 105

Scheme 23.

Convergent/Orthogonal Ionic Liquid-Tagged Synthesis of Mannans

Scheme 24.

Solution Phase Automation of the Oligosaccharide Synthesis in One Pot Using Parallel Synthesizer Quest 210^a

Scheme 25.

Synthesis of Oligosaccharides 122a–122c Using a Modified Peptide Synthesizer

Scheme 26.

Automated Synthesis of Globo H Hexasaccharide

Scheme 27.

Automated Synthesis of β-Mannosides

Scheme 28.

Fluorous Tag Supported Synthesis of a Tetrasaccharide 322 in a Microreactor

Scheme 29.

Automated Synthesis of Pentamannose 140 Using Fluorous Support^a

Scheme 30.

Automated Synthesis of β-Mannuronan and β-Mannan

Scheme 31.

Automated Sequence to the Branched Oligomannan Fragment from N-Glycans

Scheme 32.

Automated Synthesis of N-Glycan Core Using the Dedicated Synthesizer

Scheme 33.

Automated Synthesis of Manno Triantamer 160

Scheme 34.

Automated Synthesis a 50-mer 162 Using Glyconeer 2.1^a

Scheme 35.

Automation of the Sialylation Reaction

Scheme 36.

Automation of 1,2-cis Glycosylation

Scheme 37.

Automated Synthesis of β-Manno-Linked Dodecasaccharide 179

Scheme 38.

Synthesis of the Branched Hexasaccharide Composed of Multiple Arabinofuranosyl Residues

Scheme 39.

Synthesis of a Chondroitin Sulfate

Scheme 40.

Synthesis of Hyaluronic Acid Fragments

Scheme 41.

Glycopeptide Synthetic Sequence

Scheme 42.

Synthesis of a Representative Galactosylated Xyloglucan for Generating of Oligosaccharide Libraries

Scheme 43.

HPLC-Assisted Automated Oligosaccharide Synthesis

Scheme 44.

Use of an Autosampler As the Mode for Reagent Delivery for the HPLC-Based Automation

Scheme 45.

HPLC-Assisted Surface-Tethered Synthesis of Disaccharides 209

Scheme 46.

Automated Solution Phase Synthesis Using Electrochemical Activation^a

Scheme 47.

Electrochemical Approach to GPI Anchor’S CoreTrisaccharide