StereochemistryChapter 6

Classic Terminology

• Confusion arises regarding terms such as “optically active” and “chiral center”.

• “Optically Active”: ability of a collection of molecules to rotate polarized light. At one time almost synonymous for chiral, but such use is discouraged.

samples containing chiral molecules may not be optically active or may not rotate plane polarized light to any measurable extent.

• “Chiral Center/Chiral Carbon”: defined as an atom, or specifically carbon, that has four different substituents/ligands attached to it.

“Chiral Carbon” also referred to asymmetric carbon.

Problem is that “asymmetric carbons” and “chiral centers/carbons” can exist in molecules that are neither asymmetric nor chiral.

Moreover, molecules can exist in enantiomeric forms without having “chiral centers”.

• Much of the confusion that arises from classic terminology can be eliminated with the introduction of the term “stereogenic center” (or “stereocenter”) as an organizing principle in stereochemistry.

• An atom or grouping of atoms is considered to be a stereogenic center if the interchange of two substituents attached to it can produce a new stereoisomer.

• A non-stereogenic center is one in which the exchange of any pair of substitutents does not produce a stereoismer.

• Stereogenic center is a broader term than “chiral center”.

• Stereogenic unit: an atom or grouping of atoms such that interchange of a pair of attached substituents produces a new stereoisomer. (broader concept than stereogenic center)

• In dealing with chiral molecules that lack defined “chiral centers”, many have adopted terms such as: “planar chirality” (such as biphenyl) and “axial chirality” (such as allene). These molecules lack stereogenic centers, but rather have stereogenic units. Terms have yet to be clearly defined.

Modern Terminology

Examples• Two prototypes of organic stereochemistry:

• Molecule containing carbon with four different substituents, WXYZ - such as 2-butanol.

• If we interchange substituents at C2 of 2-butanol, we obtain a stereoisomer, the enantiomer.

• Consider molecules with more than one stereogenic center... for example tartaric acid.

• Begin with meso-tartaric acid (contains internal mirror plane), if we exchange two substituents at either C2 or C3 we obtain new stereoisomer: R, R or S, S.

• While meso compounds are achiral, they contain stereogenic centers.

• CWXYZ center does not guarantee a chiral molecule, but the group is always a stereogenic center.

• Typically a compound with n stereogenic centers will have 2n stereoisomers and 2n-1 diastereomers.

• The 2n rule quickly creates complexity in molecules with multiple stereogenic centers.

• Epimers are stereoisomers that differ only in their configuration at one stereocenter.

CH3

HOH

HH

H3C

CH3

OHH

HH

H3C

CO2H

HOH

HOH

HO2C

CO2H

OHH

HOH

HO2C

(R)-2-Butanol (S)-2-Butanol

Stereogenic Center

Interconverting two substituents produces a new stereoisomer

meso-Tartaric acid (R,R)-Tartaric acid

Stereogenic Center

Interconverting two substituents produces a new stereoisomer

R, S and Cahn-Ingold-Prelog System

• For tetracoordinate carbon and similar systems, the Cahn-Ingold-Pre log s y s tem prov ides a nomenclature that unambiguously indicates the configuration of the stereocenter.

• Substituents on the atom are ranked in order of priority.

• View stereocenter with lowest priority group directed back… into the page.

• If priority of substituent groups decreases going clockwise around the stereocenter, then designate it R.

• If counterclockwise, designated S.

HO C H

CHO

CH2OH

!

CHO

HOH2C OHH

HOH2C OH

CHO

H(w)

(x)

(y)

(z)

(z)

(w)(y)

(x)

w > x > y > z

L-Glyceraldehyde (S)-Glyceraldehyde

+H3N C H

CO2-

CH3

C

CO2-

H3C NH3+

HH3C NH3

+

CO2-

H(w)

(x)

(y)

(z)

(z)

(w)(y)

(x)

L-Alanine (S)-Alanine

SH > OH > NH2 > COOH > CHO > CH2OH > C6H5 > CH3 > 2H > 1H

!

Order of prioirity functional grouips common in biomolecules

Prochiral Center

• Two chemically identical substituents on a tetrahedral carbon may be geometrically distinct.

• Two such atoms are referred to as being prochiral.

• Designated as pro-R or pro-S based on same criteria as R and S.

• Property of prochirality also applicable to planar carbon centers.

• Faces are designated as re face or si face.

!Ha C Hb

CO2-

CH3

H3C CO2-

Hb

HaH3C CO2

-

Ha

Hb

(pro-R)

(pro-S)

H3C

H

O H

CH3

O

re face si face

Tetrahedral centers

Triganol planar centers

• Stereochemistry and olefins.

• Use the same priority rules as used in Cahn-Ingold-Prelog.

• Divide double bond in half (lengthwise) and compare the two halves.

• If the two high priority groups are on the same side of the double bond, then the double bond is said to be Z (zusammen).

• If the two high priority groups are on opposite sides... then the double bond is E (entgenen)

• If there is an H atom at each end of the olefin, can also use traditional cis and trans nomenclature.

E, Z System and Olefins

H CH3

O

H3C

Cl

H3C H

O

H3C

Cl

(Z)-3-chloromethyl-3-penten-2-one

(E)-3-chloromethyl-3-penten-2-one

Higher Priority

Lower Priority

Higher Priority

Lower Priority

D and L and Fischer Projections• D and L stereochemical assignments are older

nomenclature, used prevalently in the life sciences to refer to the stereochemistry of biomolecules.

• Configuration of groups around a carbon stereocenter can be related to glyceraldehyde.

• Designate: (+) isomer -> D-glyceraldehyde. (-) isomer -> L-glyceraldehyde.

• All α-amino acids from proteins have the L stereochemical configuration (glycine being achiral, is an exception.).

• Fischer Projections: way of drawing molecules in which horizontal lines represent bonds coming out of the plane of the page and vertical lines represent bonds projecting behind the plane.

• In carbohydrates with multiple stereogenic centers, L/D assigned based only on the configuration of the tetrasubstituted C at the bottom, farthest from the carbonyl group.

CHO

CH2OH

HHO

CHO

CH2OH

OHH

CHO

CH2OH

HHO

CHO

CH2OH

OHH

L-Glyceraldehyde D-Glyceraldehyde

CHO

CH2OH

HHO

CO2-

R

H+H3N

L-Glyceraldehyde L-!-Am ino acid

CH2OH

CHOH OH

HO CH2OH

CHOH

CH2OH

CHOH OH

D-Glyceraldehyde D-Glyceraldehyde

CH2OH

CHOHO H

H CH2OH

CHOHO

CH2OH

CHOHO H

L-Glyceraldehyde L-Glyceraldehyde

Fischer Projections and Stereochemistry

R

S

Monosaccharide Stereoisomers!

•  The L sugars are the mirror images of their D isomer counterparts.!

•  Epimers are stereoisomers that differ only in their configuration at one chiral carbon atom.!

CH2OH

H OH

H OH

HO H

H OH

CHO

CH2OH

HO H

HO H

H OH

HO H

CHO

CH2OH

H OH

H OH

HO H

H OH

CHO

CH2OH

H OH

H OH

HO H

HO H

CHO

D-Glucose L-Glucose

D-mannoseD-Glucose

D isomer L isomer

Epimers

Enantiomers

Helical Descriptions - M and P• Many chiral molecules lack a conventional center that

can be described using R/S or E/Z.

• These molecules can typically be viewed as helical (may have propeller or screw shape).

• A descriptor can be assigned based on the sense of the twist of the molecule....

• Sight down the axis of the “helix” and consider “near” vs. “far” substituents.

• Determine highest priority “near” group and highest priority “far” group.

• Sighting down the axis... if going from the highest priority near group to the highest priority far group involves a clockwise rotation, then we have a right-handed helix, designated P (plus).

• Conversely, sighting down the axis... if going from the highest priority near group to the highest priority far group involves a counterclockwise rotation, then we have a left-handed helix, designated M (minus).

• In case of molecules with more propeller-like conformations, M/P most easily assigned through use of a screw/bolt analogy.

Distinguishing Enantiomers

• Enantiomers are distinguishable only when placed in a chiral environment.

• A l l me thod s t o s ep a r a t e o r characterize enantiomers are based on this principle.

• Enantiomeric excess (EE%) defined as:

EE% = 100% x (Xa-Xb)

Whe re Xa a nd Xb correspond to the mole fraction of enantiomer a and b, respectively.

• Stereochemistr y and symmetry are intimately connected.

• Basic Symmetry Operations:

• A symmetry operation is a transformation of a system that leaves an object in an indistinguishable position.

• Two types of symmetry operation:

Proper Rotations (Cn): rotation around an axis by (360/n)° that has the net affect of leaving the object unchanged. Proper rotations are physically possible.

Improper Rotations (Sn): involve a rotation of (360/n)° combined with reflection across a mirror plane, perpendicular to the axis of rotation. Improper rotations are not physically possible.

• S1 = a mirror plane.

• C1 = identity operation.

Symmetry and Stereochemistry

• Stereochemistr y and symmetry are intimately connected.

• Basic Symmetry Operations:

• A symmetry operation is a transformation of a system that leaves an object in an indistinguishable position.

• Two types of symmetry operation:

Proper Rotations (Cn): rotation around an axis by (360/n)° that has the net affect of leaving the object unchanged. Proper rotations are physically possible.

Improper Rotations (Sn): involve a rotation of (360/n)° combined with reflection across a mirror plane, perpendicular to the axis of rotation. Improper rotations are not physically possible.

• S1 = a mirror plane.

• C1 = identity operation.

Symmetry and Stereochemistry

Chirality and Symmetry

• For rigid molecules, a necessary and sufficient criterion for chirality is an absence of any Sn axes.

• The presence of an Sn axis renders an object achiral (due to presence of internal mirror plane).

• When a chiral molecule i s s u b j e c t e d t o a n improper rotation, it is c o n v e r t e d t o i t s enantiomer.

• Chiral molecules need not be asymmetric - just c a n n o t h a v e a n y improper axes.

• Chiral compounds can have one or more proper axes of rotation.

Symmetry Arguments

• Symmetry argument: a statement from first principles that depends only on the symmetry of the system, not its exact nature.

• Two important features must always be remembered:

The most compelling symmetry arguments are based on an absence of symmetry.

If two objects cannot be interconverted by a symmetry operation, then they are expected to be different, essentially in all ways.

• Must be careful about using symmetry arguments to declare that two objects are equivalent.... no law that molecules will adopt a conformation that results in highest symmetry.

• Symmetry arguments tell us nothing about magnitude.

Focusing on Carbon

• Consider the desymmetrization of methane (CH4).

• Things get more interesting when all four substituents on C are different (CWXYZ).

• In CX3Y, we now have two different valence angles: X-C-Y and X-C-X. this reduction in symmetry leads to dipole moment, molecular property not present in CX4.

• In CX2Y2, we now have three different valence bond angles: X-C-Y, X-C-X and Y-C-Y.

• These systems no longer correspond to regular tetrahedra.... still tend to refer to them as being “tetrahedral”.

• Full desymmetrization (CWXYZ) gives four bond lengths and six diostinct valence bond angles... and chirality.

Topicity Relationships

Convenient to describe relationships between regions of molecules....

Topicity: Homotopic, Enantiotoptic and Diastereotopic

• If two groups cannot be intereconverted by a symmetry operation, they are expected to be different.

• This principle is applicable not just to molecules in their entirety but is also applicable to groups/regions within molecules.

• When groups can be interconverted by means of a symmetry operation, then they are chemically identical.

• Yet, depending on the nature of the symmetry operation, they can act differently.

• When identical groups or atoms are in inequivalent environments, they are said to be heterotopic.

• They can be either constitutionally heterotopic or stereoheterotopic.

- Constitutionally heterotopic: connectivity of the groups or atoms is different in the molecule.

- Stereoheterotopic: groups or atoms have different stereochemical relationships in the molecule.

• Homotopic: groups/atoms are interconvertible through a Cn operation. CH2 in propane is an example

• Diastereotopic (special case of stereoheterotopic): absence of a symmetry operation that results in two otherwise ident ica l atoms/groups (such as protons) be ing interconverted (the molecule that already contains at least one defined stereogenic center).

• Example: the protons on C3 of 2-butanol.

• Enantiontopic (special case of stereoheterotopic): two atoms/groups that are equivalent based on a symmetry element (mirror plane, S1), but this equivalence is destroyed by the presence of a chiral influence. In the absence of a chiral influence/element, the groups are equivalent.

• Example: CH2 of ethyl chloride.

• Topicity becomes important when dealing with trigonal centers (such as carbonyls and alkenes). The faces of the trigonal center can be enantiotopic or diastereotopic.

Topicity: Homotopic, Enantiotoptic and Diastereotopic

Ha

HO H

Hb

R

Cl

Ha Hb

Equivalent unless in a chiral

environment.

Topicity: Pro-R/Pro-S and Re/Si• Describing “tetrahedral” carbon atoms:

- It is useful to be able to identify enantiotopic hydrogens.

- If replacement of an H with a D would result in an R stereogenic center, then then it is denoted as pro-R.

- If replacement of an H with a D would result in an S stereogenic center, then then it is denoted as pro-S.

- A carbon atom with enantiotopic hydrogens is said to be a prochiral center.

- Enantiotopic groups need not be H... thus pro-R/S not limited to H’s.

• Describing trigonal “planar” faces:

- Re: if priority of substituents are in a clockwise direction.

- Si : if priority of substituents are in a counterclockwise direction.

Chirotopicity

• The terms enantiotopic and diastereotopic describe the relationship between a pair of atoms or groups within a molecule.

• Can be useful to describe the local environment of a single atom, group or location in a molecule.

• Chirotopic: atom or point in a molecule that resides in a chiral environment.

• Achirotopic atom or point in a molecule does not reside in a chiral environment.

• Two examples:

- Rotamers of meso-1,2-dibromoethane

- Chiral acetal

Reaction Stereochemistry

• In (R)-3-chloro-2-butanone, the two faces of the carbonyl are diastereotopic, and the carbonyl is expected to be nonplanar.

• In carbonyls where the two faces are inequivalent, the carbonyl cannot be planar (based on symmetry argument).

• Cannot predict magnitude of deviation from planarity.

Reaction Stereochemistry• Consider reactivity of three carbonyls:

- Acetone: reaction with an achiral reagent such as LiAlH4 produces the same product regardless of which face is involved with the reaction. The faces are homotopic.

- 2-butanone: the carbonly is enantiotopic and reaction with an achiral reagent results in an enantiomeric product.

- (R)-3-Chloro-2-butanone: the faces of the carbonyl are diastereotopic, and reaction with an achiral reagent yields a diastereomeric product.

- Symmetry properties of transition states cane be evaluated - enantiotopic vs diastereotopic- impacts reaction kinetics.

• What if a chiral reagent is used...

• Acetone: reduction with chiral reagent yields a singly product.

• 2-butanone: expect enantiotopic faces of carbonyl to differentially react with chiral reagent (chiral reducing agent).

• General rules:

1. Homotopic groups cannot be differentiated by chiral reagents

2. Enantiotopic groups can be differentiated by chiral reagents

3. Diastereotopic groups are differentiated by achiral and chiral reagents.

Stereospecifc vs. Stereoselective Reactions

• Describe the stereochemical outcomes of reactions.

• Stereospecific reaction: one stereoisomer of the reaction gives one stereoisomer of the product, while a different stereoisomer gives a different stereoisomer product.

- To determine if a reaction is stereospecific look at the product ratios from different stereoisomers.

- In stereospecifc reactions, a common intermediate cannot be involved in the reaction mechanism for the two stereoisomeric reactants.

• Stereoselective reactions: a single reactant can give multiple stereoisomeric products, favoring production of one or more of them.

• Alternatively... can be stereoselective when two stereoisomers of the starting material give the same stereoisomeric product ratio.

• Diastereoselective... products are diastereomer... stereospecific reaction.

• Enantioselective.... preferentially forming one enantiomeric product over another.

• Regioselecive: Site where a reaction could occur, and difference in the reactivity of various sites in the molecule, when more than one site can react.

Symmetry and Time Scale

• When considering the symmetry of any system, we must always include a time scale.

• Symmetry arguments and stereochemistry are much easier if we treat all molecules as rigid geometric objects.

• Real molecules are in motion and the motion is fast compared to the observation time scale.

• Must include motion in our consideration of stereochemistry.

• When considering the CH3 of 2-butanol:

• At room temperature rapidly rotating... thus all 3 H atoms interconvert...

• The methylene protons, under the same conditions, do not interconvert.... thus are diasterotopic.

• If temperature could be lowered to freeze rotation of CH3 group, then the 3 H atoms would each be unique. (reflected in computational models)

• Generally safe to three CH3 H’s as equivalent.

Ha

HO H

Hb

H

H H

Symmetry and Time Scale

• Symmetry and time scale are tightly coupled.

• Typically, if a molecule can adopt a reasonable conformation that contains a symmetry element, then it behave as if it has that symmetry element.

• Tri-substituted amine is classic example: The pyrimidal form is chiral, but the two enantiomers interconvert rapidly by pyrimidal inversion.

• Time scale is important for all stereochemical concepts.

• Even stereogenic tetracoordinate carbon can undergo inversion/exchange at high enough temperatures and long enough time scales.

R1N

R2R3

R1N

R2R3

Symmetry and Time Scale• Many chiral molecules where enantiomeric forms can be

interconverted by rotation about a single bond.

• If the rotation that interconverts a pair of enantiomers is slow at ambient temperature (or at readily accessible and maintained temperatures), then the enantiomers can be separated and used.

• Atropisomers: stereoisomers that can be interconverted by rotation around single bonds, and for which the barrier to ration around the bond is so high that the stereoisomers do not rapidly interconvert at RT and can be separated.

• Substituted binaphthol provides a classic example. More sterically crowded variant on biphenyl model of a chiral molecule that lacks a “chiral center”.

• trans-cyclooctene is another example... hydrocarbon chain must loop over either face of the double bond, with enantiomers arising based on the position of the loop relative to the double bond.

HO OH

Binaphthol

trans-Cyclooctene

Symmetry and Time Scale

• Facile rotation does not guarantee interconversion of conformational isomers.

• Triarylborane: correlated rotation of the rings - the two-ring flip - is facile at RT, with three different two-ring flips possible depending on which ring does the “non-flip”.

All two-ring flips are rapid, but in highly substituted systems, not all possible conformations can interconvert.

As long as only two-ring flips can occur, we have two sets of rapidly interconverting isomers, but no way to completely go from one set to another.

• Situation is termed residual stereoisomerism. We have two separate stereoisomers, each of which is a population of rapidly interconverting isomers.

B

ca

b

B

ab

c

B

Topological and Supramolecular Stereochemistry• Preparation and characterization of molecules with novel

topological features.

• Supramolecular chemistry has produced a number of structures with novel topologies such as catenanes and rotaxanes.

• Mathematical definition of topology - concerns studies of the features of geometrical objects that derive solely from their connectivity patterns.

• Metric issues, numerical values such as bond lengths and angles, are unimportant in topology.

• Consider two-dimensional topology as the study of geometric figures that have been drawn on a rubber sheet.

You can stretch and bend and flex the sheet without changing the topology of a figure drawn on the sheet.

Thus a circle, triangle and square are topologically equivalent.

All three are essentially just a closed loops.

• Applicable to three-dimensional structures.... with additional requirements:

- Cannot break a line or allow lines to cross.

- Cannot destroy a vertex.

Topological and Supramolecular Stereochemistry

• With few exceptions, all stereoisomers are topologically equivalent.

• Distortions are possible with almost every molecule allowing the stereoisomers to interconvert.

• Consistent with definition of stereoisomers: molecules with the same connectivities but different spatial arrangement of atoms.

• There are stereoisomers that have different topologies...

• Topology deals with graphs – objects that consist of edges and vertices.

• In considering molecular topologies, we are considering chemical graphs in which edges are bonds and vertices are atoms.

Loops and Knots

• Simplest systems that can produce topological stereoisomers?

• Just need a cyclic structure.

• Molecular realizations of the circle and trefoil knowt would be examples of topological stereoisomers.

• Since they are not non-congruent mirror images, it is possible to call them topological diastereomers.

• Knots are relatively common in biochemistry.

• Topological stereoisomers vs. conventional diastereomers:

• Topological isomers (circle & trefoil knot models) cannot be interconverted without breaking or crossing any bonds, but conventional stereoisomers can be interconverted by distorting stereocenter(s) of the molecule without breaking or crossing any bonds.

• Conventional stereoisomers referred to in terms of geometric or Euclidian isomerism.

Topo

logi

cal S

tere

oiso

mer

s

Enan

tiom

orph

ous T

refo

il K

nots

Topological Chirality

• Is there topological chirality?

• Trefoil knots provide a simple example of topological chirality.... enantiomorphs.

• No general rule for proving that a knot is chiral. Can be proved to be achiral simply by finding a way to draw the knot such that it is itself achiral.

• Failure to find an achiral presentation is not sufficient to determine a knot to be chiral.

Enan

tiom

orph

ous T

refo

il K

nots

Nonplanar Graphs

• We can draw a two-dimentional representation for the overwhelming majority of organic molecules, with no bonds crossing each other.

• Such two-dimensional presentations are known as planar graphs.

• If you cannot represent the connectivity of a system without crossing some lines, you have a nonplanar graph.

• Graph theory dictates that all nonplanar graphs will conform to one of two prototypes:

• K5 = simply five vertices, maximally connected

• K3,3 = contains two sets of three vertices, with every vertex of one set connected to every vertex of the other set.

K5

K3,3

Achievements in Topological and Supramolecular Stereochemistry

• Recent efforts have produced chemical structures that successfully realize many interesting and novel topologies, including the synthesis of a trefoil knot using Sauvage’s Cu+/phenanthroline templating strategy.

• Another seminal advance in the field was the synthesis and characterization of a “Möbius strip” molecule. A Möbius strip can be thought of as a closed ribbon with a twist.

• First Möbius strip molecule generated in 1980’s based on tetrahydroxyethylene ethers. Ring closure results in mixture of products (w/and w/out twist).

• Structure without the twist represents K3,3 topology.

• Facile synthesis of complex catenanes and rotaxanes using preorganization strategies has led to the consideration of a number of novel stereochemical situations.

• Other types of isomerism that really don’t fit any pre-existing categories are perhaps best regarded as supramolecular stereoisomerism.

• Rotaxanes and catenanes can often exist in different forms that are stereoisomers, but with some unique properties.

• The provided rotaxane exists in two forms, in which the macrocycle can be electrochemically driven from one position to the other.

• A catenane in which one of the rings contains two different building blocks can exist in two forms, differing in the orientation of the rings.

• Similar supramolecular stereoisomerism arises in “container compounds” when the container has two distinguishable poles... an unsymmetric guest orient in isomeric positions.

• Represent stereoisomers – structures with the same connectivities but differing arrangements of the atoms in space.

• They are not enantiomers, and therefore must be diastereomers that interconvert by the translation/reorientation of one component relative to the other.

Achievements in Topological and Supramolecular Stereochemistry

Achievements in Topological and Supramolecular Stereochemistry

a [3] catenane comprised of two distinct ring types. diastereomers arise based on the position of the “odd” ring. [topological diastereomers]

More subtle topological isomerism can arise in a [2] catenane in which the two rings have directionality.

Sauvage, et al. generated such a [2] catenane by using o f Cu+/phenan thro l i ne templating.

E v e n m o r e s u b t l e topological isomerism can arise in a [2] catenane in which one of the two rings has directionality.

The two enantiomers c a n i n t e r c o n v e r t through rotation of the 1,5-dihydroxy naphthyl group and translating the other macrocycle.

Stereochemical Issues in Polymer Chemistry

• Many unnatural polymers of considerable commercial importance have one stereocenter per monomer (such as polypropylene and polystyrene).

• These unnatural systems usually start with a simple achiral monomer, with the stereogenic centers being generated during polymerization.

• Often, no control over the chiral sense of the polymer.

• Polymer stereochemistry is denoted by tacticity:

- Isotactic: same configuration at all stereocenters.

- Syndiotactic: alternating stereocenter configuration.

- Atactic : random mixture of stereocenter configurations.

• Control over polymer stereochemistry is a major research area in both academic and industrial laboratories.

• Polymers with different stereochemistries often have very different properties.

• Another stereochemical issue is helicity... some polymers can adopt helical conformations.

Isotactic

Syndiotactic

Atactic

Stereochemical Issues in Chemical Biology

• Molecular shape is a crucial concept in chemical biology.

• Despite the apparent diversity and complexity of biomacromolecules, biopolymers are built up from fairly simple monomers and connecting units.

• Proteins: polymers built through concatenation of α-amino acid monomers with defined stereochemistries, and peptide bond formation does not result in formation of new stereogenic centers. Therefore, polymerization of amino acids does not require special stereochemical control in the bond forming reaction. Proteins and peptides are isotactic.

Amino acid chirality plays a major role in defining the structural and chemical properties of proteins. Conformation preferences of proteins reflect amino acid stereochemistry.

• Nucleic Acids: the only stereogenic centers of DNA and RNA are found in the sugar carbons, with the ribose and deoxyribose being enantiomerically pure. Thus nucleic acids are isotactic. While the connecting phosphate groups are not stereogenic centers, the two O- groups on them are diastereotopic.

• Polysaccharides: The linkages formed between saccaride monomers result in stereogenic centers. Thus stereochemical control of the polymerization/oligomerization process is essential.

The anomeric carbon is the site of the stereogenic center. Defined as being α or β based on orientation of the -OH or glycosidic bond. Stereochemsitry of glycosidic bond has a dramatic impact on the structural, mechanical and chemical properties of the oligo or polysaccharide. .... example α-1,4 vs β-1,4

Helicity• Helicity is most often associated with polymers,

especially biopolymers.

• All helicities are chiral, defined by the handedness of the helix, with right-handed and left-handed hel ices being topological ly equivalent.

• In structural biology, helices are associated with proteins, DNA and some polysaccharides.

• While in simple, prototype helices the right- and left-handed conformations are enantiomeric, in enantiomerically pure isotactic systems the two are diastereomeric, with clear thermodynamic preferences for one conformation over the other.

• Isotactic synthetic polymers are similar to biopolymers in that all the stereocenters are homochiral.

• Synthetic isotactic polymers usually do not exhibit the strong helical biases associated with biopolymers.... but in some cases substantial helical biases can be observed in synthetic polymers.

RNCO NaCN

DMF, -58°C O

NN

R

N

OR

R O

NN

OR

R

N

RO

NaCN

DMF, -58°CD

HNCO

DH

N C

O

NaCN

DMF, -58°C

NCO N C

O

HD D

H

Helicity• A series of polyisocyanates represent

remarkable examples of helical synthetic polymers.

• The polyisocyanate backbone contains contiguous amide groupings reminiscent of those of peptides and proteins.

• Steric clashes between carbonyl O’s and the R-groups on N in the isocyanate backbone preclude a planar geometry.

• A helical bias is introduced by incorporating defined stereogenic centers in the side chains (R).

• Making the side-chain sterogenic simply through isotopic substitution results in a large helical bias.

• It has been estimated that the bias for one helical handedness over the other induced by the isotopic substitution is on the order of 1 cal/mol/subunit - very small. Thus the large observed bias reflects cooperativity. (once a small bias is established it propagates)

RNCO NaCN

DMF, -58°C O

NN

R

N

OR

R O

NN

OR

R

N

RO

NaCN

DMF, -58°CD

HNCO

DH

N C

O

NaCN

DMF, -58°C

NCO N C

O

HD D

H

Sergeants and soldiers principle: the initial chiral influence is the sergeant that alines all the soldiers.