Carbohydrate Synthesis using Fluorous Tags and Separations

Over the last several years, fluorous methods in oligosaccharide chemistry has probably been one of the more active areas of fluorous chemistry with various strategies being employed.  (Visit our website for a fuller explanation of methods to biomolecule synthesis.)

These include:

Just available as a J. Org. Chem. ASAP paper is another synthetic approach with Prof. Gang Liu at the Institute of Materia Medica in Beijing as the primary author.  The paper describes the synthesis and use of a light fluorous tagged glycosyl donor A, pictured below,which can be reacted with 3 equiv. of  glycosyl acceptor B to form the disaccharide.  The excess B is then easily separated, and recovered, from product C using FSPE.  Conversion of C to a trichloroacetimidate then provides a new glycosyl donor so another saccharide unit can be attached.  All intermediates, and the final detagged product, can be easily purified by FSPE.

So what are the similarities and differences to the methods that have been previously described?  The most obvious similarity is to the work of Prof. Pohl, since both approaches are light fluorous methods using fluorous solid phase extraction (FSPE) as the primary purification method.  It  also has something in common with Seeberger’s solid phase syntheses, since a fluorous TIPS tag is used on the 6-OH.

The most obvious difference from Prof. Pohl’s approach, and that of most others, is that the fluorous tag is on the glycosyl donor rather than the glycosyl acceptor.  This means that the synthesis proceeds in the “opposite” direction.  It’s like the difference between C-termini supported peptide synthesis vs. N-termini supported synthesis.  You get to the same place, but by different means.

The other light fluorous glycosyl donor work in oligosaccharide synthesis that I can think of is that of Prof. Xuefei Huang where they used a fluorous leaving group on the acceptor.  In the Liu work an excess of the acceptor is used relative to the fluorous donor.  In the Huang work, a fluorous donor is used and the non-fluorous tagged product separated from the fluorous by-product.  OK, if this is all getting confusing, I’ve tried to depict the differences below.  In each case, however, the product can be separated from the excess by a simple FSPE.

Take-home message:  fluorous chemistry and carbohydrate chemistry is a good match.

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8 Responses to Carbohydrate Synthesis using Fluorous Tags and Separations

  1. Jim says:

    I hate to be a pedant but C is a trichloroacetimidate. Trichloroacetamide is the byproduct of the glycosylation.

    Yes, I am extremely retentive.

    Nice work though…

  2. Marv says:

    Corrected. Thanks, Jim.

  3. Fa says:

    I failed to find the ratio of glycosyl donor and acceptor during glycosylation in Prof. Huang’s work. By the way, the fluorous disulfide rather than the thioglycoside had been recovered after F-SPE.

  4. Marv says:

    Fa, corrected. My memory of the details of the Huang work did not serve me well. It does still represent an example of a light fluorous glycosyl donor.

  5. Jeff says:

    Fa is correct is saying that the fluorous disulfide created during glycosylation was removed / recovered by FSPE, but the author also reports using FSPE to purify the thioglycoside donors (Scheme 2 in the paper). Here’s an excerpt of the text:

    All fluorinated compounds synthesized maintain normal chromatographic behavior on standard silica gel, allowing easy monitoring of the course of reactions by TLC. Purification of the desired glycosyl donor obtained from the multiple step syntheses was significantly aided by the fluorous moiety. The reaction mixture was subjected to solid-phase extraction (SPE) on fluorous silica gel. Excess reagents and side products were readily removed by washing with 80% methanol and water mixture, followed by elution of the fluorous compounds with pure acetone.

  6. Fa says:

    Thanks, Marv and Jeff.
    I’m not a contradictious person. I don’t think the trichloroacetimidate can be recovered after activation. The 1-OH glycoside or semiacetal should form as soon as the reaction was quenched. So I think the entry for Prof. Pohl’s work need some modification.

  7. Marv says:

    Fa,

    I never meant to imply that it can be recovered by FSPE. It’s just the excess component of the reaction.

  8. Fa says:

    OK, I got it.
    Thanks.