concise total synthesis of glucosepane - hosted by jonathan
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Concise Total Synthesis of Glucosepane
C. Draghici, T. Wang, D. A. Spiegel Science 2015, 350, 294-298
Advanced Glycation End-Products (AGEs)
AGEs are formed by reactions between sugars and proteins.
Diabetologia 2001, 44, 129-146; Clin. Chem. Lab. Med 2014, 52, 21-32; J. Biol. Chem. 2005, 280, 12310-12315.
PentosidineGlucosepane
Lysine (blue)Arginine (yellow)Negative (red)
AGEs often give rise to cross-links in long-lived proteins (collagen, crystallins).
AGEs have been implicated in diabetes and aging
Glucosepane (pmol/mg collagen) in nondiabetics
Glucosepane (pmol/mg collagen) in diabetics
Up to 4.3 nmol/mg collagen
Glucosepane Nonenzymatic Biosynthesis
J. Biol. Chem. 2001, 276, 23405-23412; Angew. Chem. Int. Ed. 2002, 41, 801-804; Carbohydrate Research 2004, 339, 1609–1618; Rejuvenation Research 2009, 12, 137-148; Science 2015, 350, 294-298.
Glucosapene heterogeneity
Targeting the Correct Tautomer for Total Synthesis
Previous NMR data was consistent with the nonaromatic 4H-imidazole
Angew. Chem. Int. Ed. 2002, 41, 801-804; Comp. Theor. Chem. 2012, 994, 97-104; Science 2015, 350, 294-298.
Computational modeling showed the EDGs at the 2- and 5- positions favored the nonaromatic tautomer.
Model Compound Supports 4H-Imidazole Tautomer
Glucosepane Retrosynthesis
Synthesis of Chiral Epoxide
From Chiral Epoxide to Amadori Product
Azepane Formation
Analysis of crude reaction always showed 15-20% of hemiaminal
Amadori Rearrangement
Attempted Oxidation / Arginine Condensation
Aldehyde Formation
Aldehyde Not Suitable for Arginine Condensation
New Approach to Retrosynthesis
In the Forward Direction
A More Concise Route to Glucosepane
Global Deprotection
Overall: 8 synthetic steps, 12% overall yield
Glucosepane Conformational Exchange
k = 2.89 s-1
Conclusion and Significance
• Site-specific incorporation of glucosepane into synthetic oligopeptides
• Preparation of affinity reagents to identify molecular targets of glucosepane
• Development of immunogens for raising antibodies against glucosepane
• Identification of novel therapeutic strategies for breaking glucosepane cross-links.
Mechanism of Carbonyl Mobility
Carbohydrate Research 2004, 339, 1609-1618
ΔG Calculations Accounting for Different Protonation States