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