The Fischer proof of the structure of (+)-glucose

Started in 1888, 12 years after the proposal that carbon was tetrahedral, and thus had stereoisomers. Tools: - melting points - optical rotation (determine whether a molecule is optically active) - chemical reactions

Fischer knew: - (+)-glucose is an aldohexose. - Therefore, there are 4 stereocenters and 24 = 16 stereoisomers (8 D-sugars and 8 L-sugars) - At this time could not determine the actual configuration (D or L) of sugars - Fischer arbitrarily assigned D-glyceraldehyde the following structure.

CHO H OH

CH2OH

- In 1951 Fischer was shown to have guessed correctly.

CO2H CHO H OH HO H HO H CH2OH CO2H L-Tartaric acid L-glyceraldehyde

Which of the 8 D-aldohexoses is (+)-glucose???

1) Oxidation of (+)-glucose with nitric acid gives an aldaric acid, glucaric acid, that is optically active. Therefore (+)-glucose cannot have structures 1 or 7, which would give optically inactive aldaric acids.

HNO3 (+)-glucose Glucaric acid Optically active CHO CO2H H OH H OH 1 H OH HNO3 H OH Mirror plane H OH H OH H OH H OH Since these aldaric CH2OH CO2H acids have mirror planes they are meso structures. CHO CO2H They are not optically H OH H OH active HO H HNO3 HO H 7 Mirror plane HO H HO H H OH H OH

CH2OH CO2H

2) Ruff degradation of (+)-glucose gives (-)-arabinose. Oxidation of (-)-arabinose with nitric acid gives arabanaric acid, which is optically active. Therefore, (-)-arabinose cannot have structures 9 or 11, which would give optically inactive aldaric acids. If arabinose cannot be 9 or 11, (+)-glucose cannot be 2 (1 was already eliminated), 5 or 6, which would give 9 or 11 in a Ruff degradation.

1) Br2, H2O 2) Fe2(SO4)3, H2O2 HNO3 (+)-glucose (-)-arabinose arabinaric acid Optically active Ruff degradation

CHO CO2H H OH H OH HNO3 9 H OH H OH Mirror plane--meso structure H OH H OH

CH2OH CO2H

CHO CO2H H OH H OH HNO3 11 HO H HO H Mirror plane--meso structure H OH H OH CH2OH CO2H

CHO CHO CHO HO H H OH HO H H OH H OH H OH H OH HO H HO H H OH H OH H OH

CH2OH CH2OH CH2OH 2 5 6 3) Killiani-Fischer chain extension of (-)-arabinose gives (+)-glucose and (+)-mannose. Both of which give optically active aldaric acids when oxidized with nitric acid. Therefore, (-)-arabinose cannot be structure 12. 12 would give 7 and 8 in a Killiani- Fischer chain extension. 8 would give an optically active aldaric acid, but 7 would give an optically inactive aldaric acid.

1) NaCN, HCN 2) Ba(OH)2 3) Na(Hg) (-)-arabinose (+)-glucose + (+)-mannose Killiani-Fischer synthesis HNO3 HNO3

glucaric acid mannaric acid optically active optically active

Different

CHO 1) NaCN, HCN CHO CHO 2) Ba(OH) H OH 2 H OH HO H 3) Na(Hg) HO H HO H HO H + H OH Killiani-Fischer HO H HO H synthesis H OH H OH CH2OH CH2OH CH2OH

HNO 3 HNO3

CO2H CO2H H OH HO H Mirror HO H HO H plane HO H HO H H OH H OH

CO2H CO2H Meso structure Optically active Optically inactive 4) The structure of arabinose is 10. Therefore the structures of (+)-glucose and (+)- mannose are 2 and 3, but which is which????

CHO CHO CHO H OH HO H HO H HO H HO H H OH H OH H OH H OH H OH H OH CH2OH CH2OH CH2OH 10 2 3 (-)-aribinose (+)-glucose and (+)-mannose

5) Fischer had previously developed a method to interchange the ends of a sugar (the

aldehyde is converted to a CH2OH and the CH2OH is converted to an aldehyde, but we won't worry about how this is done). Fischer reasoned that if ends of 2 were interchanged, a new L-aldohexose would be obtained. On the other hand, if the ends of 3 were interchanged, the product would be the same (structure 3). When the ends of (+)-glucose were interchanged a new sugar was obtained, which Fischer named L-gulose. When the ends of (+)-mannose were interchanged, the product was (+)-mannose. Therefore the structure of (+) glucose is structure 2, and strucutre 3 is (+)-mannose!!!

CHO CH2 OH CHO H OH End H OH HO H interchange HO H HO H HO H H OH H OH H OH H OH H OH HO H CH OH 2 CHO CH2OH 2

CHO CH2OH CHO HO H End HO H HO H HO H interchange HO H HO H H OH H OH H OH H OH H OH H OH CH2 OH CHO CH2OH 3 Same structure

CHO CHO CHO End H OH HO H HO H interchange HO H HO H HO H (+)-glucose New sugar-- (+)-L-gulose End H OH H OH H OH interchange H OH HO H H OH (+)-mannose (+)-mannose CH2 OH CH2OH CH2OH D-(+)-glucose L-(+)-gulose D-(+)-mannose