The Anomeric Effect Cody F. Bender - PowerPoint Presentation

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The Anomeric Effect

Cody F. BenderCharles E. PriceUniversity of Utah

The anomeric effect

was discovered

in

1955 with the work of J.T. Edward, N.-J. Chu, and R.U. Lemieux.

Edward’s

observed axial preference

Edward notice alkoxypyranose rings favored axial positioning, which contradicted previous notions1He was the first to state lone pairs affected conformation by suggesting the cyclic oxygen’s lone pairs interacted with substituents1

Discovery of the Anomeric Effect

1

Edward, J.T. Chem. Ind. (London)

1955

, 1102.

2

Lemieux, R.U.

Explorations with Sugars-How Sweet It Was,

In

Profiles, Pathways, and Dreams,

Seeman

, J.I., Ed.; American Chemical Society: Washington D.C.,

1990.

3

Lemieux, R.U.; Chu, P.

Abstracts of Papers

; 133

rd

National Meeting of the American Chemical Society, San Francisco, CA.; American Chemical Society: Washington D.C.,

1958

; 31N.

Discovery of

the Anomeric Effect

1

Edward, J.T. Chem. Ind. (London)

1955

, 1102.2Lemieux, R.U.

Explorations with Sugars-How Sweet It Was, In Profiles, Pathways, and Dreams, Seeman, J.I., Ed.; American Chemical Society: Washington D.C., 1990.3Lemieux, R.U.; Chu, P. Abstracts of Papers; 133rd National Meeting of the American Chemical Society, San Francisco, CA.; American Chemical Society: Washington D.C., 1958

; 31N.

Chu

and Lemieux’s acetylated

aldohexopyranose

results

Chu and Lemieux noticed a similar effect while observing equilibrium of acetylated

aldohexopyranose rings2The measured energy difference of α- and β-pyranose rings to be 0.94 kcal/mol, favoring the α-conformer (Figure 3)2It was also measured that the free energy difference was 1.48 kcal/mol for α-xylose2.

The term anomeric effect was first coined at an ACS meeting in 1958 due to the frequent occurrence of this phenomenon on the anomeric carbon of sugar molecules

3

The Anomeric Effect Defined

The

anomeric

effect describes the tendency for electronegative substituents

geminally

bound to other heteroatoms within a cyclohexyl

system to prefer the axial position. HyperconjugationHyperconjugation is believed to be the prominent factor for the anomeric effect4Shown is where

the cyclic heteroatom’s lone pairs donate electron density to the σ* oribtal of

the

adjacent carbon-substituent bond, known as a

σ

*-π

interaction4

Due to orbital alignment, this interaction is not possible with equatorial subsitution4π-σ* interaction 4Cuevas, E.; Juaristi, G. (1995). The Anomeric

Effect.

Boca Raton: CRC Press.

The Anomeric Effect Defined

The

anomeric

effect describes the tendency for electronegative substituents

geminally

bound to other heteroatoms within a cyclohexyl

system to prefer the axial position. 4Cuevas, E.; Juaristi, G. (1995). The Anomeric Effect. Boca Raton: CRC Press.

Dipole

minimization

Dipole Minimization

Another

contributing argument is the result of a reduced dipole of the molecule due to lone pair orientation

4

(Figure 5)

Overcoming the

Anomeric

Effect

Since the

anomeric

effect only gives a benefit of 1-2 kcal/

mol, it can easily be overcome by solvent and in synthesis. Solventε% Axial

CCl42.2

83

C

6

H

6

2.382CS22.680CHCl34.771

CH

3

COCH

3

20.7

72

CH

3

OH

32.6

69

CH

3

CN

37.5

68H2O78.552

Solvent EffectsSince equatorial conformers give larger dipoles, solvents with larger dielectric constants, or polarity, can aid in overcoming the anomeric effect5The table shows this trend using 2-methoxytetrahydropyran in various solvents

Solvent effects on axial preference

5

Lemieux, R.U.; Pavia, A.A.; Martin, J.C.; Watanabe, K.A. Can. J. Chem.

1969

, 47,4427.

6

Koenigs, W.; Knorr, E. Eur. J.

Inorg

. Chem.

1901

, 34, 957.

Overcoming the

Anomeric

Effect

Since the

anomeric

effect only gives a benefit of 1-2 kcal/

mol, it can easily be overcome by solvent and in synthesis. 5Lemieux, R.U.; Pavia, A.A.; Martin, J.C.; Watanabe, K.A. Can. J. Chem. 1969, 47,4427.6Koenigs, W.; Knorr, E. Eur. J. Inorg. Chem. 1901

, 34, 957.

Koenigs

-Knorr

Reaction

5

Anti-

Anomeric SynthesisVarious reactions have been developed to produce products that evade the anomeric effect due to low relative energetic benefits, coming from high energy contributions of sterics in the case of a ring flip.6

Example of the

Anomeric

Effect in

Avermectin

1b

The avermectins

are a class of 16-membered macrocyclic lactones with anthelmintic and insecticidal properties. They are natural products that can be isolated from the bacteria Streptomyces avermitilis.7,8 William C. Campbell and Satoshi Omura were awarded the Nobel Prize for Medicine in 2015 for these molecules’ discovery. The

avermectins show three different examples of the anomeric effect, highlighted in

red

. Two occur in the disaccharide moiety and the third occurs in the

spiroketal

structure, in which the

anomeric effect is not entirely observed. The external ring of the spiroketal

follows the anomeric effect as a substituent. But, the isopropyl group on this ring disrupts the ability for the internal ring to occupy the axial position.9 7Omura, S.; Shiomi, K. Pure and App. Chem. 2007. 79. 581.8Pitterna, T. et al. Bioorg. Med. Chem.

2009

. 17. 4085.

9

Springer, J.;

Arison

, B.;

Hirshfield

, J.;

Hoogsteen

, K. J. Am. Chem. Soc.

1981

. 103. 4221.

Structure

of

avermectin

1b3

Practice Problems

1) Predict the

K

eq

for the following equilibrium.

2) What is the preferred position of the

allyl substituted anomeric carbon on this tri-methoxybenzylpyranose ring?

3) What is the position of the vinyl group in the product of the given reaction?

K

eq

> 1

K

eq

= 1Keq < 1AxialEquatorialNo preferenceRacemicAxialEquatorial

10

Shuto, S.

Angew

. Chem. Int. Ed.

2003

. 42. 1021-1023.

11

Aponick, A. Chem. Eur. J.

2013

. 19. 11613-11621.

Solutions: 1) C, 2) A, 3) B

Contributed by:

Cody F.

Bender, Charles

E.

Price (Undergraduates)

University of Utah, 2016