1. SYNTHESIS OF a- & b-C- GLYCOSYL AMINO ACIDS USING OLEFIN METATHESES
Thank you Marie and thank you to the program organizers. It is a privilege to speak in such a big room and be here to honor the outstanding career of Charlie Beam. Congratulations on this award.
For the first few minutes I would like to explain the title I have here:
Glycosyl Amino Acid ---importance
Carbon-Linked---?
Before I dive into our synthetic efforts utilizing the Olefin Metathesis, I’d like to share a couple of stories that can only happen while working with undergraduates.
Ernest G. Nolen
ACS-PRF
2008

2. Cell-surface carbohydrates act as ligands for receptors on other cells or pathogens.
Many of these glycoconjugates are glycoproteins formed by a C-O bond between Ser/Thr and a glycoside.
The design and synthesis of glycopeptide mimetics may provide structures with biochemically interesting properties.
I’ll start with the cover of Science. Before you is a cartoon landscape of the cell membrane. Protruding outside of the lipid bilayer are glycoproteins or glycolipids. The blue balloon-animals represent carbohydrates, you can see large oligosaccharides as well as monosaccharide. The carbohydrates play several critical roles not only by altering the physico-chemical properties of the protein, but by acting as ligands for receptors….

3. O-GalNAc Ser/Thr Truncated glycosylation patterns
characteristic of many tumors.
The N-acetyl galactosamine (GalNAc) is the
core structure of the O-mucins, and is
known as Tn antigen.

4. C-Linked Glucosyl Peptide Mimic
O-Linkage Degradation by:
Acidic hydroysis of acetal
Basic elimination to dehydroalanine and glucose
3. Glycosidase and glycosyltransferase action
For example, stable to acidic, basic and enzymatic action.
By increasing their stability these molecules are more robust to conditions in vivo, hence not as easily metabolized…a worthwhile feature when considering the development of therapeutic agents.
Numerous groups have reported their synthetic efforts toward this class of compounds.

5. Cross-Metathesis + Hg-mediated Cyclization Access to C-Glucosyl Serine
Currently we are exploring an alternative route to the 2-carbon linkage or serine connection. We envision a CM between glyco-heptenitols and allylglycine, followed by an electrophilic cyclization. Two concerns or opportunities…

6. Cross-Metathesis of Heptenitols
Both are Type I
The CM chemistry was then explored. The metathesis with allyl glycine and cmpd 12 the heptenitol with the allylic benzyl ether gave no reaction to our surprise. We observed on self-metathesis with the allyl glycine. In contrast, cmpd 11 with the allylic alcohol does undergo CM, albeit in modest yields. statistics
Cite example of Basu at Brown OL 2004 with allylic benzy ether

7. Hg-mediated Cyclization
The mercury mediated cyclization proceeded as planned to afford about 70% of a single isomeric product, however the stereochemistry could not be assigned due to the many overlapping signals. So this material was reduced with NaBH4 under phase transfer conditions (benzyltriethylammonium chloride dichloromethane and 10%aq NaOH to give cleanly (but low yield) the demercuration product, and subjected to hydrogenolysis and formation of the acetates to give a C-glucosylserine that corresponds to the alpha-C-linked glucosyl serine prepared by the enolate chemistry described earlier.
Nolen Org Lett 2005

8. Origin of a-Stereoselectivity
The alpha-selectivity is presumed to originate from the C-2 stereochemistry. For intramolecular cyclizations the reaction proceeds through a mercury-pi complex with the OR in the plane of the alkene. The Hg adds to the face by the H vs the alkly chain. Leaving the nucleophilic site to attack anti yielding the cis isomer (alkyl Hg to the OR). This is in accordance to calculations by Houk and others.
Known as the inside-alkoxy effect

9. “Extension” of CM/Hg-Cyclization Approach
Access to C-Gluco-Alanine

10. Summary of CM-Cyclization Approach to C-Glycosyl Serines
CM is successful, but requires excess of one olefin.
Hg-mediated cyclization is highly stereoselective. Toxicity of Hg.
Completed the synthesis of a-C-Glc Serine & a-C-Glc Ala.
summary

11. Ring-Closing Metathesis Strategy for a- or b-C-Glycosyl Serines

12. Initial Synthetic Foray
Add percentages…and ratio….

13. Cyclization onto Oxepenone
Tentatively 8.5:1

14. Cyclization of Z-alkene
Tentatively 8.5:1