User:Norenhirani

Background
The Tipson-Cohen reaction was first discovered in Washington D.C. by Stuart Tipson and Alex Cohen. The Tipson-Cohen reaction occurs when two neighboring secondary sulfonyloxy groups in a sugar molecule are treated with zinc dust (Zn) and sodium iodide (NaI) in a refluxing solvent such as N, N-dimethylformamide (DMF) to give an unsaturated carbohydrate. Unsaturated carbohydrates are desired as they are versatile building block that can be used in a variety of reactions. For example, they can be used as intermediates in the synthesis of natural products, or as dienophiles in the Diels-Alder reaction, or as precursors in the synthesis of oligosaccrides.

The Tipson-Cohen reaction goes through a syn or anti elimination mechanism to produce an alkene in high to moderate yields. The reaction depends on the neighboring substituents. A mechanism for glucose and mannose is shown below.



Scheme 1: Syn elimination occurs with glucose. Galactose follows a similar syn mechanism. Whereas, anti elimination occurs with mannose. Note that R could be a methane sulfonyl CH2O2S (Ms), or a toluene sulfonyl CH3C5H4O2S (Ts).

Mechanism Study


Scheme 3: The scheme illustrates the first displacement, the rate determining step and slowest step, where the starting material is converted to the iodo-intermediate. The intermediate is not detectable as it is rapidly converted to the unsaturated sugar. Experiments with azide instead of the iodide confirmed attack occurs at the C-3 as nitrogen-intermediates were isolated. The order of reactivity from most reactive to least reactive is: β-glucose > β-mannose > α-glucose> α-mannose.

The reaction with β –mannose gives low yields and longer reaction times than with β-glucose due to the presence of a neighboring axial substituent (sulfonyloxy) relative to C-3 sulfonyloxy group in the starting material. The axial substituent increases the steric interactions in the transition state, causing unfavorable eclipsing of the two sulfonyloxy groups. α-glucose posses a β-trans-axial substituent relative to C-3 sulfonyloxy (anomeric OCH3 group) in the starting material. The β-trans-axial substituent influences the transition state by also causing an unfavorable steric interaction between the two groups. In the case of α-mannose sugar, both a neighboring axial substituent (2-sulfonyloxy group) and a β-trans-axial substituent (anomeric OCH3 group) are present, therefore significantly increasing the reaction time and decreasing the yield.

Reaction Conditions
aSubstrates possess benzylidene protecting groups at C-4 and C-6, OMe groups at anomeric position and OTs groups at C-2 and C-3. Reaction temperature 95-100˚C

Table 1: Reaction times and yield vary on the substrate. β-glucose was found to be the best substrate for the Tipson-Cohen reaction as the reaction time and yield were much superior that any other substrate proposed in the study.

Reaction Scope
The reaction has been attempted in the microwave, improving yields of α -glucose to 88% and reducing the reaction time significantly to 14 minutes.

The original paper by Tipson and Cohen used acyclic sugars to illustrate the utility of the reaction. Thus the reaction is not limited to cyclic sugars.

Sulphonoxy groups such as Ms and Ts were both used, however it was found that substrates with Ts groups gave higher yields and lower reaction times. , ,