CHEM 114A: Chapter 8 - Lecture 2

Formation of Cyclic Structures in Carbohydrates

  • 5-, 6-, and 7-carbon monosaccharides rarely exist in the linear (Fischer) form inside cells; they spontaneously cyclize.
  • Cyclization arises from a nucleophilic attack of an internal alcohol (most commonly the C-5 hydroxyl in aldoses, the C-5 or C-6 in ketoses) on the carbonyl carbon.
    • Aldose + alcohol → hemiacetal.
    • Ketose + alcohol → hemiketal.
  • General reaction schematic:
    R\text{-}C(=O)H + R'OH \longrightarrow R\,CH(OH)\,OR' \qquad (\text{hemiacetal})
    R\text{-}C(=O)R'' + R'OH \longrightarrow R\,C(OH)(OR')\,R'' \qquad (\text{hemiketal})

Mechanistic Highlights (Hemiacetal vs Hemiketal)

  • Alcoholic oxygen attacks the electrophilic carbonyl carbon.
  • A tetrahedral intermediate forms; proton transfers yield the neutral hemiacetal/hemiketal.
  • Distinction:
    • Hemiacetal: carbonyl carbon now bears one H and one OR.
    • Hemiketal: carbonyl carbon bears two C substituents and one OR.

Haworth vs Fischer Projections

  • Haworth projection depicts the ring as planar; carbons are numbered clockwise from the anomeric carbon.
  • Carbon participation for D-glucopyranose:
    • Carbons 1 \rightarrow 5 + ring oxygen constitute the ring.
    • C6 (CH$2$OH) is exocyclic.
  • Translating stereochemistry:
    • Hydroxyl on RIGHT in Fischer → DOWN (axial/below plane) in Haworth.
    • Hydroxyl on LEFT in Fischer → UP (equatorial/above plane) in Haworth.

The Anomeric Carbon & New Stereochemistry

  • Cyclization creates a new stereocenter at C1 (aldoses) or C2 (ketoses).
  • Terminology:
    • Anomeric carbon: the new chiral center generated upon ring closure.
    • Two stereoisomers: anomers.
  • Assignment rule (using D-sugars and the convention "CH$2$OH is drawn UP"): • \alpha -anomer – OH at anomeric carbon is OPPOSITE side from CH$2$OH (usually down).
    • \beta -anomer – OH at anomeric carbon is SAME side as CH$_2$OH (usually up).

Mutarotation & Solution Equilibria

  • In aqueous solution anomers interconvert through the open-chain form: \alpha \leftrightarrow \text{open} \leftrightarrow \beta.
  • At equilibrium for D-glucose:
    \beta-anomer ≈ 63.6\%
    \alpha-anomer ≈ 36.4\%
    Linear form ≪ 1\% (too small to shift the percentages visibly).
  • The interconversion is slow (requires bond breaking) but biologically relevant.

Ring Size & Nomenclature

  • 6-membered O-heterocycles = pyranoses (root: pyran).
    • Example: \alpha\text{-D-glucopyranose}.
  • 5-membered O-heterocycles = furanoses (root: furan).
    • Example: \alpha\text{-D-fructofuranose}.
  • 3- or 4-membered sugar rings are highly strained and essentially absent in biology; those sugars remain linear.

Conformational Analysis of Pyranoses

  • Carbons are sp^3; the ring is NOT planar.
  • Two principal conformations:
    • Chair (lower energy)
    • Boat (higher energy)
  • Axial vs equatorial positions:
    • Axial (a): perpendicular to mean plane (↑ or ↓).
    • Equatorial (e): roughly parallel to plane.
  • Stability rationale:
    • Bulky groups (OH, CH$_2$OH) prefer equatorial to minimize steric hindrance.
    • In \beta\text{-D-glucose}, the chair places ALL bulky substituents equatorial → maximal stability.

Conformational vs Configurational Changes

  • Conformational change: rotation about single bonds; no bonds broken (e.g., chair ↔ boat). Fast.
  • Configurational change: requires breaking and forming bonds (e.g., \alpha ↔ \beta mutarotation or conversion between epimers). Slow; often enzyme-catalyzed.

Epimers

  • Epimers: sugars differing in configuration at ONE stereogenic center other than the anomeric carbon.
    • Example: D-glucose vs D-galactose (difference at C-4).
  • Interconversion between epimers in vivo needs specific enzymes (epimerases); spontaneous interconversion is negligible.

Oxidation-Based Sugar Modifications

  • Oxidation at C_1 (aldehyde → COOH): aldonic acids.
    • \text{D-glucose} \to \text{D-gluconic acid}.
  • Oxidation at C_6 (primary alcohol → COOH): uronic acids.
    • \text{D-glucose} \to \text{D-glucuronic acid}.
  • Biological roles: detoxification, polysaccharide structure, extracellular matrix.

Reduction-Based Sugar Modifications

  • Aldehyde/ketone → primary/secondary alcohol: alditols (polyhydroxy alcohols).
    • Examples: ribitol, xylitol, glycerol.
  • Reduction pathway (important example):
    1. \text{D-glucose} \xrightarrow{\text{hexokinase}} \text{glucose-6-phosphate} (adds \text{PO}_4^{2-} at C6).
    2. \xrightarrow{\text{myo-inositol-1-phosphate synthase}} cyclization + reduction → myo-inositol-1-phosphate.
    3. \xrightarrow{\text{phosphatase}} dephosphorylation → myo-inositol.
      • Myo-inositol: critical signalling effector in brain & hormonal pathways.
  • Deoxygenation (reduction of OH to H): e.g., \beta\text{-D-2-deoxyribose} – backbone of DNA.

Amino & N-Acetyl Sugars

  • Replacement of an OH with NH2 or NHCOCH3 → amino sugars (e.g., glucosamine, N-acetylglucosamine).
  • Functions: components of glycoproteins, glycolipids, and structural polysaccharides (e.g., chitin, peptidoglycan).

Glycosidic Linkages

  • Formed when the anomeric OH is replaced by OR, NR, SR, etc.
  • O-glycosidic bond: anomeric carbon–oxygen–R (most common in di- and polysaccharides).
    • Orientation described as \alpha or \beta depending on anomeric configuration.
  • N-glycosidic bond: anomeric carbon–nitrogen–R (nucleosides, some glycoproteins).
  • Naming a specific linkage:
    1. Specify anomer of first sugar (α or β).
    2. Indicate the origin carbon numbers joined (e.g., 1→4).
      Example: lactose has a \beta(1!\rightarrow!4) O-glycosidic bond between galactose (β-configuration) and glucose.

Example: β(1→4) Lactose Linkage

  • Donor sugar: β-D-galactopyranose (OH up with CH$_2$OH up → β).
  • Acceptor: D-glucopyranose, linked through its C-4 hydroxyl.
  • Described as: β-D-Galp-(1→4)-D-Glcp.

Ring Size–Dependent Stability & Biological Preference

  • 6-membered (pyranose) rings: minimal angle and torsional strain, high stability.
  • 5-membered (furanose) rings: slightly higher strain but still common (e.g., ribose in RNA).
  • 3- & 4-membered sugar rings: prohibitively strained; exist, if at all, only transiently or enzymatically protected.

Practical Significance & Connections

  • Understanding hemiacetal/hemiketal chemistry underlies enzymatic mechanisms of glycosidases and glycosyltransferases.
  • Chair ↔ boat equilibria influence recognition by lectins and enzymes (steric fit).
  • Oxidized sugars (uronic acids) supply negative charge to extracellular matrices (e.g., hyaluronate) enabling hydration & mechanical resilience.
  • Alditols (xylitol) employed as low-calorie sweeteners; their metabolism exploits reduction chemistry outlined above.
  • Amino sugars serve as antibiotic targets (e.g., peptidoglycan biosynthesis inhibitors).

Summary Key Equations & Numbers

  • Mutarotation equilibrium of D-glucose: \beta : \alpha = 63.6\% : 36.4\%.
  • General hemiacetal formation: R\,C(=O)H + ROH \rightleftharpoons R\,C(OH)(OR)H.
  • Aldonic acid formation: \ce{R-CHO + [O] -> R-COOH} (at C_1).
  • Uronic acid formation: \ce{R-CH2OH + [O] -> R-COOH} (at C_6).
  • Chair conformation favored because \Delta G < 0 relative to boat due to reduced 1,3\,\text{diaxial} interactions.