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 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 (C 2 axis) -> achiral 과 관계 없음 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.

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 1 ) (i, S 2 ) 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 active 란 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 2 n stereoisomers - 2 n-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:  - and  -anomers 도 epimers 의 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 higherlower Opposite: E (entgegen) (cf) same: Z (zusammen) If an H atom is on each of the double bond, conventionally, cis and trans can be used.

10. D, L system 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 CH 2 OH (carbohydrates) or R (amino acids): bottom mainly used for amino acids and carbohydrates D: dextro, right L: levo, left L DD 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 Methods: (R/S) racemate + (R)-MTPA-Cl 50 : 50 (R-R-MTPA : S-R-MTPA) OH, NH 2, SH 등 ppm sample + (R)-MTPA-Cl R, S peak 결정 Derivatives R S R S 90 10 ee 80% (Mosher’s reagent)

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

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 (  ) Specific optical activity [  ] [  ] D 25 -> sodium D line (589 nm emission line of sodium arc lamp) Optical purity (%) = [  ] pure enantiomer [  ] mixture of enantiomer x 100

18. 6.2 Symmetry and stereochemistry 6.2.1 Basic symmetry operations Proper rotation (C n ) -> a rotation around an axis by (360/n) o that has the net effect of leaving the position of the object unchanged. C 2 ; 180 rotation, C 3 ; 120 rotation Improper symmetry (S n ) -> 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. S 1 ; just a mirror reflection (  ) S 2 ; equivalent to a center of inversion (i)

19. 90 o 60 o 180 o

20. 6.2.2 Chirality and symmetry A necessary and sufficient criterion for chirality is an absence of S n axes; the existence of any S n axis renders an object achiral. C2C2 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. 6.3.1 Homotopic, enantiotopic, and diastereotopic 6.3 Topicity relationship Topicity: derived from the same roots as topography and topology, relating to the spatial position of an object. Homotopic: is defined as interconvertable by a C n axis of the molecule. C2C2 chiral influence cannot distinguish these methyl groups

23. Heterotopic: the same groups or atoms in inequivalent constitutional or stereochemical environment. - Enantiotopic: interconverted by an S n axis of the molecule (n = 1 in this case). enantiotopic groups, when exposed to a chiral influence (chiral shift reagent 를 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 center 를 갖고 있음 the environments of diastereotopic groups are topologically nonequivalent. -> they can be distinguished by physical probes, especially NMR spectroscopy (AB quartet)

24. AB quartet H1H1 H2H2 2H

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

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

30. stereospecific inversion Syn addition anti elimination

31. Regioselective reaction Markovnikov addition

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

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

34. achiral 20 natural amino acids (L form)

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

36. Bases

37.  -glycosidic linkage

39. Phosphodiester linkages

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

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

42. Polysaccharides - Complex carbohydrates in which many simple sugars are linked. - Cellulose and starch are the two most widely occurring polysaccharides in plants. - 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 ). Cellulose (-Glc  1,4Glc-) n 4 anomeric center - Homopolysaccharides - heteropolysaccharides

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. In human, glycosidases highly selectively hydrolyze 1,4-  -linkage in starch but not 1,4-  linkage in cellulose. amylose (-Glc  1,4Glc-) n Amylopectin

44. Monosaccharides in mammalian glycoconjugates Glycosidic Bonds

45. Blood type

46. Pathogen Infection by Carbohydrate-protein Interactions DNA or RNA pathogens √ 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 Le b -binding adhesin (BabA) and sialyl Le x -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 ( 독감 치료제 ) Tamiflu: a drug for influenza Transition state for action of influenza neuraminidase N-acetyl neuraminic acid O-sugar neuraminidase essential for influenza virus

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 (S n 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 (C 1 of an aldose, or C 2, C 3, 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 C 1 ). 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.

51. Diastereomeric excess (de). In a reaction that produces two diastereomeric products in amounts A and B, de = 100% (|A – B|) / (A + B). Diastereotopic. The relationship between two regions of a molecule that have the same connectivity but are bit related by any kind of symmetry operation. Dissymmetric. Lacking improper symmetry operations. A synonym for “chiral”, but not the same as “asymmetric”. Eclipsed. A term describing a conformation about a single bond. In A-B-C-D, A and D are eclipsed if the torsion angle between them is approximately 0°. Enantiomers. Molecules that are related as non-congruent mirror images. Enantiomeric excess (ee). In a reaction that produces two enantiomeric products in amounts A and A´, ee = 100% (|A – A´|) / (A + A´). Enantiotopic. The relationship between two regions of a molecule that are realated only by an improper symmetry operation, typically a mirror plane. Endo. In a bicyclic system, a substituent that is on a bridge is endo if it points toward the larger of the two remaining bridges. See also “exo”. Epimerization. The interconversion of epimers.

52. Epimers. Diastereomers that have the opposite configuration at only one of two or more stereogenic centers. Erythro and threo. Descriptors used to distinguish between diastereomers of an acyclic structure having two stereogenic centers. When placed in a Fischer projection using the convention proper for carbohydrates, erythro has the higher priority groups on the same side of the Fischer projection, and threo has them on opposite sides. Exo. In a bicyclic system, a substituent that is on a bridge is exo if it points toward the smaller of the two remaining bridges. See also “endo”. E, Z. stereodescriptors for alkenes (see discussion in the text). Gauche. A term describing a conformation about a single bond, In A-B-C-D, A and D are gauche if the torsion angle between them is approximately 60°(or -60°). See section 2.3.1. Geminal. Attached to the same atoms. The two chlorines of 1,1-dichloro-2,2-difluoroethane are geminal. See also “vicinal”. Helicity. The sense of chirality of a helical or screw shaped entity ; right (P) or left (M).

53. Heterochiral. Having an oppsite sense of chirality. For example, D-alanine and L-leucine are heterochiral. See also “homochiral”. Heterotopic. The same groups or atoms in inequivalent constitutional or stereochemical environments. Homochiral. Having the same sense of chirality. For example, the 20 natural amino acids are homochiral – they have the same arrangement of amino, carboxylate, and side chain groups. Has also been used as a synonym for “enantiomerically pure”, but this is not recommended, because homochiral already as a well-defined term before this alternative usage became fashionable. Homotopic. The relationship between two regions of a molecule that are related by a proper symmetry operation. Isotactic. A term describing the relative configuration along a polymer backbone. In an isotactic polymer, all stereogenic centers of the polymer backbone have the same sense of chirality. Meso. A term describing a achiral member of a collection of diastereomers that also includes at least one chiral member. Opitcally active. Rotating plane polarized light. Formerly used as a synonym for “chiral”, but this is not reconmmended.

54. Prochiral. A group is prochiral if it contains enantiotopic or diastereotopic ligands or faces, such that replacement of one ligand or addition to one face produces a stereocenter. See section 6.3.2. R, S. The designations for absolute stereochemistry (see earlier discussion in the text). Racemic mixture or racemate. Comprised of a 50:50 mixture of enantiomers. Relative configuration. This refers to the configuration of any stereogenic center with respect to another stereogenic center. If one center in a molecule is known as R, then other centers can be compared to it using the descriptors R* or S*, indicating the same or opposite stereochemistry, respectively. Resolution. The separation of a racemic mixture into its individual component enantiomers. Scalemic. A synonym for “non-racemic” or “enantiomerically enriched”. It has not found general acceptance, but is used occasionally. S-cis and s-trans. Descriptors for the conformation about a single bond, such as the C2-C3 bond in 1,3-buadiene, or the C-N bond of an amide. If the substituents are synperiplanar, they are termed s-cis (“s” for “single”); if they are antiperiplanar, they are termed s-trans.

55. Stereocenter. See “stereogenic center”. Stereogenic center. An atom at which interchange of any two ligands produces a new stereoiosmer. A synonym for “stereocenter”. Stereogenic unit. An atom or grouping of atoms at which interchange of any two ligands produces a new stereoisomer. Stereoisomers. Molecules that have the same connectivity, but a different arrangement of atoms in space. Stereoselective. A term describing the stereochemical consequences of certain types of reactions. A stereoselective reaction is one for which reactant A can give two or more stereoisomeric products, B and B’, and one or more product is preferred. There can be degrees of stereoselectivity. All stereospecific reactions are stereoselective, but the converse is not true. Stereospecific. A term describing the stereochemical consequences of certain types of reactions. A stereospecific reaction is one for which reactant A gives product B, and stereoisomeric reactant A’ gives stereoisomeric product B’. There can be degrees of stereospecificity. Stereosprcific does not means 100% stereoselective.

56. Syn. Modern usage is to describe the relative configuration of two stereogenic centers along a chain. The chain is drawn in zigzag form, and if two substituents are on the same side of the plane of the paper, they are syn. See also “anti”, “synperiplanar”, and “synclinal”. Synclinal. A term describing a configuration about a single bond. In A-B-C-D, A and D are synclinal if the torsion angle between 30° and 90° (or -30° and -90°). See Figure 2.7. Syndiotactic. A term describing the relative configuration along a polymer backbone. In a syndiotactic polymer, the relative configuration of backbone stereogenic centers alternate along the chain. Synperiplanar. A term describing a conformation about a single bond. In A-B-C-D, A and D aresynperiplanar if the torsion angle between them is between + 30° and –30°. See Figure 2.7. Tacticity. A generic term describing the stereochemistry along a polymer backbone. See “atactic”, “isotactic”, and “syndiotactic”. Trans. A term describing the stereochemical relationship between two ligands that are on opposite sides of a double or a ring system. For alkenes only. E is preferred. Vicinal. Attatched to adjacent atoms. In 1,1-dichloro-2,2-difluoroethane, the relationship of either chlorine to either fluorine is vicinal. See also “geminal”.