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.
  • $C<em>6$ (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 $C<em>1$ (aldoses) or $C</em>2$ (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 $NH<em>2$ or $NHCOCH</em>3$ → 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.