1. Magnesium Ion Enhances Lanthanum-
Promoted Monobenzoylation of a
Monosaccharide in Water
Raj Dhiman and Ronald Kluger*
CSC 2011: Carbohydrates and Glycobiology
June 8th 2011 1

2. Overview of research: A biomimetic
approach to selective acylation in
water
 Acylations occur commonly in biology.
 Chemical acylations are non-aqueous.
 A biomimetic reagent would follow
biochemical patterns.
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3. Inspiration: aminoacyl adenylates
 Not suitable as an
acylating agent.
 Functionally
complex due to
adenosine.
 Biomimetic – use
similar reactivity,
avoid adenosine.
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Berg, P. J Biol. Chem. 1958, 233, 608-611.

4. An ideal biomimetic reagent
Parallel reactivity without complexity
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5. Acyl phosphate monoesters
 Reagents persist in water.
 Slow reactions with oxygen nucleophiles.
 React rapidly with amines to form amides.
Kluger, R.; Cameron, L. L. J. Am. Chem. Soc. 2002, 124, 3303-3308. 5
Disabato, G.; Jencks, W. P. J. Am. Chem. Soc. 1961, 83, 4393-4400.

6. Preparation of reagents
 Couple to acid chloride, then demethylate.
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Kluger, R.; Grant, A. S.; Bearne, S. L.; Trachsel, M. R. J. Org. Chem. 1990, 55, 2864-2868.

7. Monoacylation of diols
 Reaction carried out with use of lanthanide ions.
 Biomimetic – Mimics enzymatic aminoacylation of
tRNA by aminoacyl tRNA synthetase.
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Cameron, L. L.; Wang, S. C.; Kluger, R. J. Am. Chem. Soc. 2004, 126, 10721-10726

8. Mimicry in acylation
“Enzyme”
Acyl phosphate; 1,2 – diol;
adenylate mimic ribose mimic
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9. Bis-bidentate coordination
 Lanthanide coordinates reactants and provides
activation.
 Diol ionization, acyl transfer completes the reaction.
 Most effective for cis-1,2 diols.
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Kluger, R.; Cameron, L. L. J. Am. Chem. Soc. 2002, 124, 3303-3308.

10. Extend to carbohydrates
 2-O-Bz and 6-O-Bz esters (2.8:1); opposite to steric
considerations.
 Selectivity influenced by glycosidic geometry.
 LnIII source is present in a two-fold excess over sugar,
BMP.
Gray, I. J.; Kluger, R. Carbohydr. Res. 2007, 342, 1998-2002. 10

11. Establishing catalytic role
Mechanism requires an excess of lanthanide as it
is consumed during the reaction.
Can a catalytic role for the lanthanide be
established?
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12. A synergistic approach?
 Magnesium has a strong affinity for phosphate
dianions.
 Introduce a magnesium source to complex the
byproduct.
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Kluger, R.; Wasserstein, P.; Nakaoka, K. J. Am. Chem. Soc. 1975, 97, 4298-4303.

13. Is regioselectivity affected?
2.2
2 2-O-Bz
1.8
1.6
1.4
Abs. (AU)
1.2
1
0.8 6-O-Bz
0.6
0.4
0.2
[Sugar] = [BMP] = 25 mmol 0
[LaIII] = 2.5 mmol La(OTf)3 -0.2
0 20 40
[MgII] = 1 mmol Mg(OTf)2 Time (Min)
 Preferred formation of 2-O-Bz ester (~ 3:1 ratio).
 Reactions with other substrates show similar
effects.
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14. Relative preferences unchanged
Ratio Ratio
Carbohydrate Esters (LaIII) (LaIII/MgII)
Me-α-Glucopyranose 2-OBz, 6-OBz 2.8:1 3:1
Me-β-Glucopyranose 2-OBz, 6-OBz 1:2.5 1:8
Me-α-Galactopyranose 2-OBz, 3-OBz, 6-OBz 1:1.5:1.5 1:6:6
Me-β-Galactopyranose 2-OBz, 3-Obz, 6-OBz 1:3:4 1:3:4
Me-α-Mannopyranose 2-OBz, 3-Obz, 6-OBz 2:1:1 2:1:1
D-Ribose 2-OBz, 3-Obz, 4-OBz 5:1:3 6:1:3
 Reduction of lanthanide does not change
relative reaction preference.
 MgII does not disrupt bis-bidentate array.
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15. Effect of lanthanide contraction?
Lewis acidity increases
 Charge-to-size ratio increases selectivity for
phosphates over diols.
 Metals could compete with MgII for phosphate
binding.
 LaIII is optimal for this reaction.
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Tzvetkova, S; Kluger, R. J. Am. Chem. Soc., 2007, 129, 15848–15854.

16. Confirming synergistic behavior
 Perform acylation with catalytic LaIII in absence of
MgII.
 Analyze reaction by HPLC over 24 hours.
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17. Complete stop
2
2.2 BMP BMP 3 hrs
2
1.8
0.5 hrs 1.8
1.6
1.6 1.4
Abs. (AU)
1.4 1.2
Abs. (AU)
1.2
Esters 1 Esters
1 0.8
0.8 0.6
0.6
0.4
0.4
0.2 0.2
0 0
-0.2
0 10 20 30
0 10 20 30
T ime (Min)
Time (Min)
 Subsequent analysis shows no significant changes.
 Reaction ends prematurely in the absence of MgII.
 Supports the sacrificial role of divalent ion.
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18. Successful synergistic approach
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Dhiman, R.S.; Kluger, R. Org. Biomol. Chem., 2010, 8, 2006 - 2008

19. Future work
 Improving selectivity of reaction.
 Ligands, selectivity as a function of pH?
 Recovery/reuse of lanthanide.
 Several reports describe recycling of lanthanide
catalysts.
 Chemoselective reactions of amino sugars.
 Amide or ester formation depending on conditions.
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20. Acknowledgements
 Prof. Ronald Kluger
 Kluger group
members.
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