Stereochemistry

1. Stereochemistry Chapter 6 Is the study of the static and dynamic aspects of the three-dimensional shapes of molecules. 6.1 Stereogenicity and stereoisomerism

2. 6.1.1 Basic concepts and terminology • Constitutional isomers: molecules with same molecular formular but different connectivity • between the atoms. e.g.) 1-bromo and 2-bromobutane • Stereoisomers: molecules that have the same connectivity but differ in the arrangement • of atoms in space. e.g) cis- and trans-2-butene • 1. enantiomers: nonsuperimposable mirror images of each other • 2. diastereomers: stereoisomers that are not enantiomers • - conformational isomers: are interconvertible by rotations about single bonds • configurational isomers: stereochemical isomers including enantiomers and diastereomers. • configuration: the relative position or order of arrangement • of atoms in space which characterizes a particular stereoisomer. • - chiral: any object that is nonsuperimposable with its mirror images • - achiral: if an object is not chiral, it is achiral. A molecule is achiral if it is superimposable on its mirror image. A molecule which has a plane of symmetry, a center of symmetry or rotation-reflection symmetry is achiral. An axis of symmetry (C2 axis) -> achiral과 관계 없음

3. A molecule is achiral if it is superimposable on its mirror image. A molecule which has a plane of symmetry, a center of symmetry or rotation-reflection symmetry is achiral. (나중에 다시 설명) (s, S1) (i, S2) meso: compounds that contain stereogenic centers but are nevertheless achiral.

5. Classic terminology Optically active: refers to the ability of a collection of molecules to rotate plane polarized light - must have an excess of one enantiomer. Racemic mixture (or racemate): a 50:50 mixture of enantiomers and is not optically active. However, enantiomers that do not have dramatically different refractive indices would not result in measurable rotations. -> in this case, they are optically inactive even though they are chiral. 따라서 optically active란 말은 사용하지 않는 것이 좋음. Chiral center or chiral (asymmetric) carbon: an atom or specifically carbon, respectively, that has four different ligands attached. Chiral carbons exist in molecules that are neither asymmetric nor chiral. Many molecules can exist in enantiomeric forms without having a chiral center. 이 말도 사용하지 않는 것이 좋음. chiral center achiral compound

6. More modern terminology Stereocenter (stereogenic center): use this term instead of chiral center, it is stereogenic center if the interchange of two ligands attached to it can produce a new stereoisomer. A non-stereogenic center is one in which exchange of any pair of ligands does not produce a stereoisomer. -> the term ‘stereogenic center’ is broader than the term ‘chiral center’. A CWXYZ center does not guarantee a chiral molecule. However, a CWXYZ group is always a stereogenic center.

7. stereogenic center: 두개의 치환기를 바꾸면 stereoisomers 가 생긴다 meso form Typically, a molecule with n stereogenic, tetracoordinate carbons will have 2n stereoisomers - 2n-1 diastereomers that exist as a pair of enantiomers. Epimers: are diastereomers that differ in configuration at only one of the several stereogenic centers. Carbohydrates: a- and b-anomers도 epimers의 한 형태임.

8. 6.1.2 Stereochemical descriptors R, S system (Cahn-Ingold-Prelog system) rectus (right) sinister (left) higher atomic number: higher priority isotopes (the one with higher mass is assigned the higher priority) Tricoordinate -> stereogenic center

9. E, Z system lower higher If an H atom is on each of the double bond, conventionally, cis and trans can be used. Opposite: E (entgegen) (cf) same: Z (zusammen)

10. D, L system mainly used for amino acids and carbohydrates Fischer projection Horizontal lines: bonds coming out of the plane of the paper Vertical lines: bonds projecting behind the plane of the paper The most oxidized group: top CH2OH (carbohydrates) or R (amino acids): bottom D: dextro, right L: levo, left D D L D L Natural amino acids: L-amino acids Important point No direct relationship between the R/S and D/L and the sign of optical rotation of the molecule.

11. Helical descriptors – M, P system Many chiral molecules lack a conventional center that can be described by R/s or E/Z. -> typically helical, propeller, screw-shaped structures -> a right-handed helix (clockwise): P (plus), a left handed helix (anti-clockwise): M (minus)

12. 6.1.3 Distinguishing enantiomers Chiral column chromatography

13. Enantiomeric excess = (Xa – Xb) x 100, Xa: mole fraction of a, Xb: mole fraction of b High field NMR spectroscopy with chiral shift reagents NMR spectroscopy of derivatives that are diastereomeric Chromatography (HPLC and GC) with chiral stationary phases

14. NMR spectroscopy of derivatives that are diastereomeric (Mosher’s reagent) Methods: (R/S) racemate + (R)-MTPA-Cl 50 : 50 (R-R-MTPA : S-R-MTPA) OH, NH2, SH 등 R S ppm R, S peak 결정 sample + (R)-MTPA-Cl Derivatives ee 80% R S 90 10

15. a-H OMe NH L D D D L D D L D > 98%ee a-H OMe NH L D D D L D D L D > 98%ee

16. Optical activity and chirality Optical activity: the ability of a sample to rotate a plane of polarized light. A rotation to the right: + or dextrorotatory (d) A rotation to the left: - or levorotatory (l) Optical activity establishes that a sample is chiral, but a lack of optical activity does not prove a lack of chirality.

17. Optical activity (a) Specific optical activity [a] [a]D25 -> sodium D line (589 nm emission line of sodium arc lamp) Optical purity (%) = [a] mixture of enantiomer x 100 [a] pure enantiomer

18. 6.2 Symmetry and stereochemistry 6.2.1 Basic symmetry operations Proper rotation (Cn) -> a rotation around an axis by (360/n)o that has the net effect of leaving the position of the object unchanged. C2; 180 rotation, C3; 120 rotation Improper symmetry (Sn) -> rotation and reflection; involves a rotation of (360/n)o, combined with a reflection across a mirror plane that is perpendicular to the rotation axis. S1; just a mirror reflection (s) S2; equivalent to a center of inversion (i)

19. 90o 60o 180o

20. 6.2.2 Chirality and symmetry A necessary and sufficient criterion for chirality is an absence of Sn axes; the existence of any Sn axis renders an object achiral. C2 Asymmetric is defined as the complete absence of symmetry. However, many chiral molecules have one or more proper rotation axes-just no improper axes are present. These compounds can be referred to as dissymmetric, essential a synonym for chiral. Thus, while all asymmetric molecules are chiral, not all chiral molecules are asymmetric.

22. 6.3 Topicity relationship Topicity: derived from the same roots as topography and topology, relating to the spatial position of an object. 6.3.1 Homotopic, enantiotopic, and diastereotopic Homotopic: is defined as interconvertable by a Cn axis of the molecule. chiral influence cannot distinguish these methyl groups C2

23. Heterotopic: the same groups or atoms in inequivalent constitutional or stereochemical environment. • Enantiotopic: interconverted by an Sn axis of the molecule (n = 1 in this case). • enantiotopic groups, when exposed to a chiral influence (chiral shift reagent를 사용할 시), • become distinguishable, as if they were diastereotopic. • diastereotopic: the same connectivity, but there is no symmetry operation that • interconverts them in any conformation. 이미 stereogenic center를 갖고 있음 • the environments of diastereotopic groups are topologically nonequivalent. -> they can be • distinguished by physical probes, especially NMR spectroscopy (AB quartet)

24. 2H H1 H2 AB quartet

25. 6.3.2 Topicity descriptors – Pro-R/Pro-S and Re/Si pro-S pro-R pro-S pro-R pro-R pro-S

26. Enzymatic reactions

27. 6.4 Reaction stereochemistry: stereoselectivity and stereospecificity 6.4.1 Simple guidelines for reaction stereochemistry

28. 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. 6.4.2 Stereospecific and stereoselective reactions Stereospecific reaction: one stereoisomer of the reactant gives one stereoisomer of the product, while a different stereoisomer of the reactant gives a different stereoisomer of product. Stereospecific reaction is a special, more restrictive case of a stereoselective reaction. Stereoselective reaction: one in which a single reactant can give two or more stereoisomeric products, and one or more of these products is preferred over the others-even if the preference is very small. Regioselective reaction; when more than one site reacts, this reaction is one where an excess of one of the possible products results.

29. stereospecific stereoselective stereoselective

30. stereospecific inversion Syn addition anti elimination

31. Regioselective reaction Markovnikov addition

32. 6.5 Symmetry and time scale Time scale is important. three Hs -> equivalent due to fast rotation of C-C bond three Hs -> equivalent but at low temperature (-90 oC), inequivalent due to slow rotation (very clowded system) achiral <- fast inversion chiral <- slow inversion

33. 6.8 Stereochemical issues in chemical biology 6.8.1 The linkages of proteins, nucleic acids, and polysaccharides Proteins planar ~19 kcal/mol rotation barrier ~4 kcal/mol preference Much smaller cis-trans preference

34. 20 natural amino acids (L form) achiral

35. 3’ Nucleic acids 5’ A = T G ≣ C 5’ Phosphodiester bonds 3’ Nucleic acid (RNA or DNA)

36. Bases

37. b-glycosidic linkage

39. Phosphodiester linkages

40. Toxin Bacteria Antibody Hormone Virus (Tumor) Cell Protein Functional Glycomics Carbohydrates Carbohydrate-protein Interactions Functional Glycomics • Structural and functional studies of whole carbohydrates • Studies of carbohydrate-protein interactions •Understanding biological processes •Development of therapeutic agents Biological processes • Fertilization, development, differentiation, growth, aging Diseases •Tumor metastasis •Inflammation •Bacterial and viral infection • - Inhibitors for carbohydrate biosynthesis • - Inhibitors for carbohydrate-binding proteins • Carbohydrate-based vaccines • Finding disease-related markers

41. Glycoconjugates Carbohydrates exist in the forms of glycoconjugates such as glycolipids and glycoproteins Glycoproteins: glycans attached to proteins Glycolipids: glycans attached to lipids Cell surface carbohydrares

42. anomeric center - Homopolysaccharides- heteropolysaccharides Polysaccharides - Complex carbohydrates in which many simple sugars are linked. - Cellulose and starch are the two most widely occurring polysaccharides in plants. Cellulose (-Glcb1,4Glc-)n 4 - Consists of thousands of D-glucopyranosyl-1,4--glucopyranosides. - form a large aggregate structures held together by hydrogen bonds. - is the main component of wood and plant fiber. - is not digested in human body but is digested in herbivore (초식동물).

43. Starch (녹말 綠末 또는 전분 澱粉) - is digested into glucose. - can be separated into two fractions 1) amylose, insoluble in cold water, 20% by weight of starch, 1,4--glycoside polymer 2) amylopectin, soluble in cold water, 80% by weight of starch contains 1,6-a-glycoside branches approximately every 25 glucose units in addition to 1,4--links. amylose (-Glca1,4Glc-)n Amylopectin In human, glycosidases highly selectively hydrolyze 1,4--linkage in starch but not 1,4- linkage in cellulose.

44. Monosaccharides in mammalian glycoconjugates Glycosidic Bonds

45. Blood type

46. Pathogen Infection by Carbohydrate-protein Interactions pathogens DNA or RNA √ Human influenza viruses (haemagglutinin protein) preferentially adhere to NeuNAca2,6Gal residues on epithelial cells (상피세포) of the lungs and upper respiratory tract. √ Avian influenza viruses (AI, 조류독감 바이러스) are specific for NeuNAca2,3Gal residues on intestinal epithelial cells. √ Some of Helicobacter pyroli expresses Leb-binding adhesin (BabA) and sialyl Lex-binding adhesin (SabA) and thus adhere to the human gastric mucosa expressing these glycans. √ Cholera toxin adheres to ganglioside GM1 in host cells.

47. Tamiflu: a drug for influenza Tamiflu (독감 치료제) Transition state for action of influenza neuraminidase neuraminidase O-sugar essential for influenza virus N-acetyl neuraminic acid

48. Stereochemical Terminology Absolute configuration. A designation of the position or order of arrangement of the ligands of a stereogenic unit in reference to an agreed upon stereochemical standard. Achiral Not chiral. A necessary and sufficient criterion for achirality in a rigid molecule is the presence of any improper symmetry element (Sn including σ and ί). A chirotopic. The opposite of chirotopic. See “ chirotopic” below. Anomers. Diastereomers of glycosides or related cyclic forms of sugars that are specifically epimers at the anomeric carbon (C1 of an aldose, or C2, C3, etc., of a ketose). Anti. Modern usage is to describe relative configuration of two stereogenic centers along a chain. The chain is drawn in zigazg form, and if two substituent s are on opposite sides of the plane of the paper, they are designated anti. See also “syn”, “antiperiplanar”, and “ anticlinal”. Anticlinal. A term describing a conformation about a single bond. In A-B-C-D, A and D are anticlinal if the torsion angle between them is between 90 and 150 or -90 and -150. See Figure 2.7. Antiperiplanar. A term describing a conformation about a single bond. In A-B-C-D, A and D are antiperiplanar if the torsion angle between them is between +150° to -150° . See Figure 2.7.

49. Apical, axial, basal, and equatorial. Terms associated with the bonds and positions of ligands in trigonal bipyramidal structures. Asymmetric. Lacking all symmetry elements (pointing group C1). All asymmetric molecules are chiral. Asymmetric carbon atom. Traditional term used to describe a carbon with four different ligands attached. Not recommended in modern usage. Atactic. A term describing the relative configuration along a polymer backbone. In an atactic polymer, the stereochemistry is random-no particular pattern or bias is seen. Atropisomers. Stereoisomers ( can be either enantiomers or diastereomers) that can be interconverted by rotation about single bonds and for which the barrier to rotation is large enough that the stereoisomers can be separated and do not interconvert readily at room temperature. Chiral. Existing in two forms that are related as non-congruent mirror images. A necessary and sufficient criterion for chirality in a rigid molecule is the absence of any improper symmetry elements. Chiral center. Older term for a tetracoordinate carbon or similar atom with four different substituents. More modern, and preferable, terminology is “stereogenic center” (or “stereocenter”)

50. Chirotopic. The term used to denote that an atom, point, group, face, or line resides in a chiral environment. Cis. Describing the stereochemical relationship between two ligands that are on the same side of a double bond or a ring system. For alkenes only, Z is preferred. Configuration. The relative position or order of the arrangement of atoms in space that characterizes a particular stereoisomer. Conformers or conformational isomers. Stereoisomers that are interconverted by rapid rotation about a single bond. Constitutionally heterotopic. The same groups or atoms with different connectivities. D and L. An older system for identifying enantiomers, relating all stereocenters to the sense of chirality of D- or L-glyceraldehyde. See discussion in the text. Generally not used anymore, except for biological structures such as amino acids and sugars. Diastereomers. Stereoisomers that are not enantiomers.