Hemiacetals are generated when an oxygen atom from alcohol reacts with the carbonyl group of an aldehyde or ketone. This occurs due to the hydroxyl group’s nucleophilic attack on the electrophilic carbonyl group. Because alcohols are poor nucleophiles, protonation of the carbonyl oxygen usually promotes the impact on the carbonyl carbon. When this reaction occurs with just an aldehyde, the result is considered hemiacetal, and when it occurs with a ketone, the result is known as hemiketal.
The attachment of alcohol to a ketone or aldehyde is one of the most important instances of a nucleophilic addition process in biochemistry, particularly in carbohydrate chemistry. When alcohol reacts with an aldehyde, the resultant product is a hemiacetal; whenever alcohol reacts with a ketone, the resultant product is known as a hemiketal.
Because hemiacetals and hemiketals have more power than respective aldehyde-alcohol components, the reaction’s equilibrium is to the left. However, as we will demonstrate in glucose and other sugars setting, five- and six-membered cyclic hemiacetals are significantly lower in energy and are preferred at equilibrium.
Aldehydes and ketones reach equilibrium with the hydrate form in an aqueous solution. A hydrate is formed when a water molecule reacts with the carbonyl carbon of such an aldehyde or ketone. Although aldehyde and ketone molecules may persist to a significant amount in their hydration forms in an aqueous solution, depending on their structure, they are usually shown in their non-hydrated state for simplicity. In sugar chemistry, intramolecular hemiketal and hemiacetal production are prevalent. To illustrate, in solution, 99% of glucose occurs in the cyclic hemiacetal form, while just 1% of glucose remains in open form.
Steps in the Ring Closure (Hemiketal synthesis)
Ring-closing metathesis (RCM) is a frequently utilised variety of olefin metathesis in organic chemistry to synthesise different unsaturated rings through the intramolecular metathesis of two output alkenes resulting in the formation of cycloalkene as the E- or Z- isomers and unstable ethylene.
Ring diameters of 5–7 atoms are most often synthesised; nonetheless, published syntheses include 45 to 90-membered macroheterocycles. These types of reactions are catalysed by metals and involve a metal cyclobutane intermediate. Didier Villemin described the Synthesis of an Exaltolide Precursor in 1980, later popularised by Richard R. Schrock and Robert H. Grubbs, who received the Nobel Prize in Chemistry with Yves Chauvin in 2005 for the collective work in olefin metathesis. Ring-closing metathesis is a favourite amongst several organic chemists owing to its artificial value in the production, which was previously difficult for access rings and its extensive substrate breadth. The word ‘hemi’ is included in each name because adding a secondary alcohol nucleophile can occur, producing acetals and ketals. The transformation of alcohol and an aldehyde or ketone to a hemiacetal or hemiketal is reversible.
Didier Villemin reported the first case related to ring-closing metathesis in 1980, in which he manufactured an Exaltolide precursor in 60–65% yield using a WCl6/Me4Sn catalysed metathesis cyclisation.
Sugar as an Intramolecular Hemiketal
As noted, the interactions of hemiacetals and hemiketals are crucial to carbohydrate chemistry. Sugar molecules typically contain a ketone or an aldehyde substituent and numerous alcohol groups. Aldehyde sugars are typically referred to as aldoses, while ketone sugars are called ketoses. Glucose, for example, is an aldose, but fructose is a ketose.
Glucopyranose is the cyclical form of glucose. Nucleophilic attack on a planar carbonyl position can occur along either side of the plane, resulting in two distinct stereochemical results: two distinct diastereomers. These diastereomers are known as the a and b anomers of glucopyranose in carbohydrate nomenclature.
General Mechanism of Hemiketal Synthesis
The mechanism of transition metal-catalysed olefin metathesis has been extensively studied over the last four decades. Ring-closing metathesis follows a mechanistic pathway similar to other olefin metathesis events, including ring-opening metathesis polymerisation, cross-metathesis, and acyclic diene metathesis. Because all phases within the catalytic reactions are considered to be adjustable, relying on the reactive circumstances and substrates, a few other pathways may cross with the ring-closing metathesis. Chauvin hypothesised in 1971 the production of a metallacyclobutane phase by a [2+2] cycloaddition, which further eliminates to generate almost the same alkene and catalytic entity or a catalysed species and an alkylidene. This method has gained widespread acceptance among chemists and provides a framework for the ring-closing metathesis mechanism.
The catalyst’s alkene ligand is substituted with the substrate to initiate the reaction. This reaction involves the production of a new alkylidene via one round of [2+2] cyclic elimination and cycloaddition. In the context of Grubbs catalysts, phosphine ligand association and dissociation also occur.
Ring-closing metathesis has been traditionally employed in several organic syntheses and is still used in the synthesis of a wide range of chemicals. The examples are simply a sampling of the extensive utility of ring-closing metathesis; several other options exist. The importance of ring-closing metathesis in a complete synthesis cannot be overstated. One example is its employment in naturally producing the 12-membered ring in the biosynthesis of found cyclophane floresolide. Floresolide B was derived from an Apidium ascidian and showed cytotoxicity against KB carcinoma cells.