Problem Session (3)2022/8/27 Yosuke Nakata

Please provide the structure of 2-2 and explain the reaction mechanisms and the selectivities
1.

2.

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Problem Session (3) -Answer-

2022/8/27 Yosuke Nakata

Topic: site-selective acylation of glucose by organocatalysts
0. Introduction
0-1. glucose⚫

5 hydroxy groups: hemiacetal (1-OH), 1̊ OH (6-OH) and trans-positioned 2̊ OH (2, 3, 4-OH)⚫

Site-selective acylation of OH groups is a major task for synthesis of glucose derivatives (e.g. tannins).

0-2. Site-selective acylation
0-2-1. Reactivity of OH groups(i) hemiacetal (1-OH) vs alcohol (2, 3, 4 ,6-OH)⚫

Selective acylation at 1-OH is generally conducted by Mistunobu conditions (problem 2, step 1).

⚫

Site-selectivity was explained by relatively high acidity of 1-OH.

(ii) 1̊ OH (6-OH) vs 2̊ OH (2, 3, 4-OH)⚫

Acetylation with Ac2O and DMAP proceeds with inverted reactivity of 1̊ OH (6-OH) and 2̊ OH (3, 4-OH).

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It was proposed that intra- or intermolecular hydrogen bonding between OH groups affect the reactivity.

0-2-2. Site-selective acylation by organocatalysts⚫

For highly site-selective acylation of 2, 3, 4, 6-OH, organocatalysts have been developed.

(i) 6-OH selective (vs 2, 3, 4-OH)⚫

Steric repulsion against 0-A, which acts both acylation reagent and base, is dominant.

(ii) 4-OH selective (vs 2, 3, 6-OH)⚫

H-bonding between 6-OH of 0-4 and amide C=O of 2-A is important for catalyst-substrate recognition(problem 2, step 2)(iii) 2-OH vs 3-OH⚫

Interaction between the neighbor O-atom and the catalysts is important for the selectivity (problem 1).

31. Problem 1
1-0. Benzotetramisole 1-A⚫

The direction of carbonyl C=O bond is restricted by chalcogen bonding.
(a) Yang, X.; Liu, P.; Houk, K. N.; Birman, V. B. Angew. Chem., Int. Ed. 2012, 51, 9638.
(b) Abbasov, M. E.; Hudson, B. M.; Tantillo, D. J.; Romo, D. J. Am. Chem. Soc. 2014, 136, 4492.

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Substrate can approach from the opposite site to Ph group.

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The interaction between positively charged catalyst and cation stabilizing group enhances the selectivity.

example 1. kinetic resolution by selective acylation of racemic alcohol

example 2. Selective acylation of 1-OH of glucosides

41-1. answer for problem 1

1-1-1. Acylation by 1-B-(R)5⚫

It is assumed that cation-n interaction of OH (2-OH and 3-OH) is stronger than that of O-alkyl (4-O-acetal and1-OMe) due to its electron richness derived from H-bonding with carboxylate.

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TS1-(C3)a (weaker cation-n) is more stable than TS1-(C3)b (stronger cation-n) due to the π-π interaction
between Ph of benzylidene acetal and the catalyst.

⚫

TS1-(C3)a and TS1-(C3)b is destabilized by steric repulsion between 1-OMe and the catalyst, yielding tosuppression of 2-OH acylation.

1-1-2. Acylation by 1-B-(S)⚫

TS2-(C2)b is most stable, yielding the high selectivity of 2-OH acylation.

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TS2-(C3)b and TS2-(C2)a is destabilized by steric repulsion between 1-OMe and the catalyst.

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As is the case with acylation by 1-B-(R), TS2-(C3)a (weaker cation-n) is stabilized by π-π interaction but stillless stable than TS2-(C2)a.

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Probably, the order of the factor for stabilizing the TS of acylation by 1-A is
steric repulsion (1-OMe) > cation-n interaction ≥ π-π interaction
In fact, the site-selectivity was completely lost in the acylation of β-anomer 1-5.

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2. Problem 2

2-1. answer for step 17

e.g. The yield and stereoselectivity was not affected when mixture of α- and β-D-glucose was used.

discussion 1. Stereoselectivity⚫

The stereoselectivity was significantly affected by the stereochemistry of 2-OH.

2-2. answer for step 2 and 38

Discussion 2. 4-OH selective acylation by 2-A
2-1. Transition states for the products

92-2. Effect of indole at the side chain of 2-A

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Discussion 3. 2-OH selective acylation by 2-B
3-1. decreasing reactivity of 6-OH⚫

The reactivity of 6-OH is decreased by modification of 4-OH, indicating that 6-OH of 2-9 is less likely to form
H-bond with amide carbonyl O atom the catalyst 2-B-(acyl).

3-2. Transition states for the products

113-3. Optimization of catalysts derived from 2-A12