Carbohydrate Stereochemistry

There are a ton of different ways to represent carbohydrates from Fischer projections, space-filling models, chair conformation, Haworth projects, and straight-up wedges and dashes. This makes interpreting the stereochemistry of sugars a bit challenging since it seems like there is a different set of rules for each representation. Ultimately the rules for each are all really similar we just need to know what to focus on and an understanding of how to interconvert between the different forms.

Fischer

A Fischer projection is a two-dimensional representation of sugars that is typically used when sugars are in their linear form. Since the aldehyde or ketone in this representation is the highest priority group we will being numbering the parent chain from that side.

Additionally, we have to remember that in a Fischer projection the horizontal lines act as wedges while the vertical ones act as dashes. The easiest way to remember this is by thinking about the orientation of a bow tie. Since a bowtie is horizontal and looks like wedges we can remember that the wedges are oriented horizontally in a Fischer projection.

The orientation of the wedges and dashes is important because it allows us to determine the R and S configuration of each chiral carbon in a sugar molecule. Since all but a couple of the carbons in a sugar molecule are chiral, meaning they are connected to four different substituents, it is important to remember and review the rules for determining stereochemistry now.

R and S

To do this we will use glucose as an example model and determine the configuration for the carbon 5 in a Fischer projection. Following the steps listed below:

1. Draw out the sugar molecule with wedges and dashes on the carbon of interest
2. Determine the priority 1 and 4 by looking at the first attached atom and comparing their atomic numbers

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3. For 2 and 3 go out additional atoms until one of the groups no longer has the same connections. The one attached to a higher atomic number atom is the higher priority group.
4. Trace the stereochemistry if the groups are listed in a clockwise fashion the preliminary stereochemistry is R. If the groups are listed counterclockwise the preliminary stereochemistry is S.

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5. Check to see if the lowest priority group (#4) is on a wedge if it is flip the stereochemistry so R becomes S and S becomes R.

Here we can see that carbon 5 of this glucose molecule is in the R orientation. For sugars and most amino acids except cysteine (who is weird), this indicates a D relative configuration so this molecule would be D-glucose.

L and D

There is actually a much faster and easier way to determine this though, by looking at whether the OH on carbon 5 points to the left or to the right. So long as the aldehyde or ketone is at the top of the molecule in a Fischer projection we can look at the last chiral carbon. In this case, it points to the right meaning it is a D-glucose. If this OH were pointing to the left it would be an L-sugar molecule. Additionally, this would switch the absolute configuration of this carbon from R to S.

Due to carbon 5’s role in determining the L and D configuration in a sugar, I will refer to it as the L and D carbon from here on out.

Enantiomers, Diastereomers, and Epimers

As we saw above switching the direction of an OH on a carbon switches its stereochemical designation. This means it is really easy to determine the relationship of two carbohydrate stereoisomers with a Fischer projection.

Since enantiomers are mirror images they have the opposite orientation of their stereochemistry at each chiral center. In a Fischer projection, this means the OH’s between enantiomer pairs will point in opposite directions at each chiral center.

Additionally, enantiomeric sugar molecules have the same name but switch between L and D prefixes. For example, L-glucose and D-glucose are enantiomers while L-glucose and L-galactose are not.

Instead, sugars with different names are classified as diastereomers or epimers. Diastereomeric sugars differ at one or more but not all of their chiral centers. While we could go through each chiral center and assign R and S centers to each it would be a big waste of time. Instead, we can again look at the orientation of each OH and see if one or more point in opposite directions. So long as they aren’t all reversed we are dealing with a diastereomer. Here the names of the sugar will change so D-mannose and D-galactose will be diastereomers.

Epimers are a specific subtype of diastereomers that only differ at one of the chiral carbons. So if one and only one of the carbons are flipped in a Fischer projection the two sugars are epimers. For example, both galactose and mannose are epimers of glucose while galactose is only classified as a diastereomer of mannose.

Haworth

Up to this point, we have been discussing the linear form of sugars. However, sugars are often represented in their cyclic forms. Haworth projections are by far the most common way of displaying these cyclic sugars and have a lot in common stereochemistry wise with Fischer projections.

Since we already learned so much about Fischer projections it would be a waste of time to learn a completely new set of rules for Haworth projections. Instead, we will focus on how to interconvert between the two and identify how the stereochemistry of both is quite similar.

The easiest way to go from Fischer to Haworth is to tip over a Fischer projection to the right. In this orientation, the OHs and Hs will now point up and down in their proper orientation. From here we need to complete the loop by drawing a line from C1 to C5.

At this point, we simply need to redraw the sugar in a hexagon shape. What is important to notice here is that both C1 and C5 are involved in the cyclization. As a result, only C2, C3, and C4 will retain their original orientations.

Enantiomers

Here C5, the L and D carbon, is now oriented to the right of the oxygen heterocycle indicated with the blue highlight as shown below.

When the attached CH₂OH group points upwards the sugar is in the D orientation whereas the CH₂OH points downwards it is in the L orientation. So if you need to determine whether to draw the C5 substituent up or down simply pull the L or D orientation using the previous rule for Fischer projections.

Since C1 changes its orientation we need to make sure C2, C3, and C4 are identical. If they are but the L and D carbon have different orientations then the sugars are enantiomers.

Diastereomers and Epimers

As with Fischer projections we can look at the orientation of the carbon to determine whether or not molecules are diastereomers or epimners. Since only C2-C4 retain their orientation in a cyclic sugar we only need to compare those three. Since we already discussed the diastereomers mannose and galactose during our discussion on Fischer projections we will look at them here.

As seen above one or more of the OHs are flipped in this case two are flipped meaning these molecules are classified as diastereomers but not epimers. Additionally, comparing glucose to both galactose and mannose we can see that they are epimers. Remember here we are only looking for a single OH change somewhere between C2 -C4.

Anomeric Carbon

Up to this point, we have neglected C1 and skipped over it when considering the stereochemistry of cyclic sugars. This carbon does have stereochemistry but it isn’t fixed and depends on how the ring closure reaction occurred. In ring closure, the C5 OH will undergo nucleophilic attack on the carbonyl carbon. Since the carbonyl is planar the OH can attack from either side as would occur in an SN2 type reaction. This results in the formation of two distinct stereochemistry at C1 which is called the anomeric carbon.

These two stereochemistries are labelled alpha and beta respectively and sugar molecules that differ at the C1 carbon or anomeric carbon are called anomers. To determine whether a sugar is in the alpha form or beta form we need to compare the C1 anomeric carbon to the C5 L or D carbon. If the OHs attached to both carbons point in the opposite directions then the molecule is an alpha sugar. Whereas if the two carbons point in the same direction then the molecule is a beta sugar.

I remember this by thinking about the tails of an ⍺ symbol. Since they point in opposite directions an alpha sugar will have opposing C1 and C5 orientations. To remember the beta orientation I think about the β symbol’s single tail. Here the tail only points in one direction so both the C1 and C5 orientations must be the same.

Like enantiomers, anomers don’t change the name of the sugar and this means there are four different stereochemical designations for the same sugar molecule in its cyclic form. Look at the various ones for glucose below and try to justify why each designation is correct on the basis of the L and D carbon and the anomeric carbon.

Chair

Chair conformations are one of the most frustrating stereochemistries to deal with. For me, this frustration stems from the 2D appearance of a chair conformation even though we should interpret them 3-dimensionally. To see what I mean by this look at the chair conformations drawn below.

From here the key to interconverting between the much easier to visualize Haworth projection and a chair conformation is recognizing that the C1 carbon is a down carbon. If you have trouble visualizing this I would recommend memorizing this information. Even though it is an abstract fact it probably better to memorize this and move on rather than spend a ton of time trying to see the 3D nature of a chair conformation.

Regardless of conformation, the numbering of carbons in a sugar molecule doesn’t change. So the C1 carbon is still the carbon just to the right of the oxygen heterocycle in the standard conformation. Additionally. the C1 carbon shows axial down and each carbon will then alternate from there on out. So C2 shows axial up, C3 shows axial down, C4 shows up axial up, and C5 shows axial down.

Now we will fill in the corresponding axial constituents ignoring the equatorial ones.

Now fill in the equatorial position with the other substituent. Since this makes the chair a bit messy get rid of the hydrogens. At this point, we have successfully converted from a Haworth projection to a chair representation.

Once you understand the pattern you can start to go straight from the Haworth projection to the chair projection but for now make sure to practice each step before skipping from one projection to the other.

Standard Wedges and Dashes

Standard wedges and dashes are one of the easier sugar conformations to deal with. Since we have learned how to convert the Haworth projection into all of the others we will use it as an intermediary between the different conformations. Here it is simply a matter of rotating our hexagon so that we are looking at it from the side.

When we do this we the dashed substituents point downwards while the wedged substituents point upwards. Now that our sugar molecule is in its Haworth form we can determine the stereochemistry of the molecule as we would for any other Haworth projection. In this case this is ⍺-D glucose.