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Chapter 5 Stereochemistry Chiral Molecules Ch. 5 - 1 1. Chirality & Stereochemistry An object is achiral (not chiral) if the object and its mirror image are identical Ch. 5 - 2 A chiral object is one that cannot be superposed on its mirror image Ch. 5 - 3 1A. The Biological Significance of Chirality Chiral molecules are molecules that cannot be superimposable with their mirror images O O ● One enantiomer NH causes birth defects, N O the other cures morning sickness O Thalidomide Ch. 5 - 4 HO NH HO OMe Tretoquinol OMe OMe ● One enantiomer is a bronchodilator, the other inhibits platelet aggregation Ch. 5 - 5 66% of all drugs in development are chiral, 51% are being studied as a single enantiomer Of the $475 billion in world-wide sales of formulated pharmaceutical products in 2008, $205 billion was attributable to single enantiomer drugs Ch. 5 - 6 2. Isomerisom: Constitutional Isomers & Stereoisomers 2A. Constitutional Isomers Isomers: different compounds that have the same molecular formula ● Constitutional isomers: isomers that have the same molecular formula but different connectivity – their atoms are connected in a different order Ch. 5 - 7 Examples Molecular Constitutional Formula Isomers C4H10 and Butane 2-Methylpropane Cl Cl C3H7Cl and 1-Chloropropane 2-Chloropropane Ch. 5 - 8 Examples Molecular Constitutional Formula Isomers CH O CH C H O OH and 3 3 2 6 Ethanol Methoxymethane O OCH and 3 C H O OH 4 8 2 O Butanoic acid Methyl propanoate Ch. 5 - 9 2B. Stereoisomers Stereoisomers are NOT constitutional isomers Stereoisomers have their atoms connected in the same sequence but they differ in the arrangement of their atoms in space. The consideration of such spatial aspects of molecular structure is called stereochemistry Ch. 5 - 10 2C. Enantiomers & Diastereomers Stereoisomers can be subdivided into two general categories: enantiomers & diasteromers ● Enantiomers – stereoisomers whose molecules are nonsuperposable mirror images of each other ● Diastereomers – stereoisomers whose molecules are not mirror images of each other Ch. 5 - 11 Geometrical isomers (cis & trans isomers) are: ● Diastereomers e.g. Ph Ph Ph and Ph (cis) (trans) Cl Cl Cl H and H H H Cl (cis) (trans) Ch. 5 - 12 Subdivision of Isomers Isomers (different compounds with same molecular formula) Constitutional Isomers Stereoisomers (isomers that have the same (isomers whose atoms have a connectivity but differ in spatial different connectivity) arrangement of their atoms) Enantiomers Diastereomers (stereoisomers that are (stereoisomers that are nonsuperposable mirror NOT mirror images of images of each other) each other) Ch. 5 - 13 3. Enantiomers and Chiral Molecules Enantiomers occur only with compounds whose molecules are chiral A chiral molecule is one that is NOT superposable on its mirror image The relationship between a chiral molecule and its mirror image is one that is enantiomeric. A chiral molecule and its mirror image are said to be enantiomers of each other Ch. 5 - 14 OH (2-Butanol) (I) and (II) are nonsuperposable H OH HO H mirror images of each other (I) (II) Ch. 5 - 15 4. A Single Chirality Center Causes a Molecule to Be Chiral The most common type of chiral compounds that we encounter are molecules that contain a carbon atom bonded to four different groups. Such a carbon atom is called an asymmetric carbon or a chiral center and is usually designated with an asterisk (*) Ch. 5 - 16 Cl Me C* Et H H Cl Cl H Me Et Et Me (III) (IV) mirror (III) and (IV) are nonsuperposable mirror images of each other Ch. 5 - 17 Cl Me C Me H H Cl Cl H Me Me Me Me (V) (VI) mirror (V) and (VI) are superposable ⇒ not enantiomers ⇒ achiral Ch. 5 - 18 4A. Tetrahedral vs. Trigonal Stereogenic Centers Chirality centers are tetrahedral stereogenic centers H OH HO H Me * Et Et * Me (A) (B) Tetrahedral stereogenic mirror (A) & (B) are center enantiomers ⇒ chiral Ch. 5 - 19 Cis and trans alkene isomers contain trigonal stereogenic centers Ph H H Ph H Ph Ph H Trigonal (C) (D) stereogenic mirror center ⇒ achiral (C) & (D) are identical Ch. 5 - 20 4A. Tetrahedral vs. Trigonal Stereogenic Centers Chirality centers are tetrahedral stereogenic centers Cis and trans alkene isomers contain trigonal stereogenic centers Ch. 5 - 21 5. More about the Biological Importance of Chirality (+)-Limonene (-)-Limonene (limonene enantiomer (limonene enantiomer found in oranges) found in lemons) Ch. 5 - 22 Thalidomide The activity of drugs containing chirality centers can vary between enantiomers, sometimes with serious or even tragic consequences For several years before 1963 thalidomide was used to alleviate the symptoms of morning sickness in pregnant women Ch. 5 - 23 In 1963 it was discovered that thalidomide (sold as a mixture of both enantiomers) was the cause of horrible birth defects in many children born subsequent to the use of the drug O O O O NH NH N O N O O O Thalidomide enantiomer of (cures morning sickness) Thalidomide (causes birth defects) Ch. 5 - 24 6. How to Test for Chirality: Planes of Symmetry A molecule will not be chiral if it possesses a plane of symmetry A plane of symmetry (mirror plane) is an imaginary plane that bisects a molecule such that the two halves of the molecule are mirror images of each other All molecules with a plane of symmetry in their most symmetric conformation are achiral Ch. 5 - 25 Plane of symmetry Cl Me Me H achiral Cl Me Et H No plane of symmetry chiral Ch. 5 - 26 7. Naming Enantiomers: R,S-System OH H OH HO H Recall: (I) (II) Using only the IUPAC naming that we have learned so far, these two enantiomers will have the same name: ● 2-Butanol This is undesirable because each compound must have its own distinct name Ch. 5 - 27 7A. How to Assign (R) and (S) Configurations Rule 1 ● Assign priorities to the four different groups on the stereocenter from highest to lowest (priority bases on atomic number, the higher the atomic number, the higher the priority) Ch. 5 - 28 Rule 2 ● When a priority cannot be assigned on the basis of the atomic number of the atoms that are directly attached to the chirality center, then the next set of atoms in the unassigned groups is examined. This process is continued until a decision can be made. Ch. 5 - 29 Rule 3 ● Visualize the molecule so that the lowest priority group is directed away from you, then trace a path from highest to lowest priority. If the path is a clockwise motion, then the configuration at the asymmetric carbon is (R). If the path is a counter-clockwise motion, then the configuration is (S) Ch. 5 - 30 H Example HO (2-Butanol) ① ④ O H Step 1: C C ② or ③ ② or ③ ① ④ O H ③ C ② Step 2: CH3 H3C C H2 (H, H, H) (C, H, H) Ch. 5 - 31 ① OH OH ④ H ③ ② Me Et Et Me OH OH HO H = H Me Et Me Et Et Arrows are clockwise Me (R)-2-Butanol Ch. 5 - 32 Other examples ① Cl Cl Counter- clockwise ④ H ③ CH3 HO CH3 (S) HO ② Clockwise ② OCH3 OCH3 ④ (R) ③ H3C CH2CH3 Br CH2CH3 Br ① Ch. 5 - 33 Other examples ● Rotate C–Cl bond such that H is pointed to the back ② Cl Cl ④ ③ Br H H OH HO Br ① Cl Clockwise Br OH (R) Ch. 5 - 34 Other examples ● Rotate C–CH3 bond such that H is pointed to the back ② H OCH3 ④ I H ① OCH3 I H3C H3C ③ Counter-clockwise OCH3 H3C I (S) Ch. 5 - 35 Rule 4 ● For groups containing double or triple bonds, assign priorities as if both atoms were duplicated or triplicated e.g. C O as C O O C C C as C C C C C C C C as C C C C Ch. 5 - 36 Example ③ CH3 ④ (S) H ② CH=CH2 HO ① Compare CH3 & CH CH2 : H H CH CH2 equivalent to C C H C C Thus, CH3 ⇒ (H, H, H) CH CH2 ⇒ (C, C, H) Ch. 5 - 37 Other examples ② (R) OH ④ CH H ③ 3 Cl ① O ③ OH H2C ④ CH ② C ⇒ (O, O, C) H ② 3 Cl ① O (S) ③ C ⇒ (O, H, H) Ch. 5 - 38 8. Properties of Enantiomers: Optical Activity Enantiomers ● Mirror images that are not superposable H H * * Cl Cl CH3 H3C H3CH2C CH2CH3 mirror Ch. 5 - 39 Enantiomers have identical physical properties (e.g. melting point, boiling point, refractive index, solubility etc.) Compound bp (oC) mp (oC) (R)-2-Butanol 99.5 (S)-2-Butanol 99.5 (+)-(R,R)-Tartaric Acid 168 – 170 (–)-(S,S)-Tartaric Acid 168 – 170 (+/–)-Tartaric Acid 210 – 212 Ch. 5 - 40 Enantiomers ● Have the same chemical properties (except reaction/interactions with chiral substances) ● Show different behavior only when they interact with other chiral substances ● Turn plane-polarized light on opposite direction Ch. 5 - 41 Optical activity ● The property possessed by chiral substances of rotating the plane of polarization of plane-polarized light Ch. 5 - 42 8A. Plane-Polarized Light The electric field (like the magnetic field) of light is oscillating in all possible planes When this light passes through a polarizer (Polaroid lens), we get plane- polarized light (oscillating in only one plane) Polaroid lens Ch. 5 - 43 8B. The Polarimeter A device for measuring the optical activity of a chiral compound α =observed optical rotation Ch. 5 - 44 8C. Specific Rotation observed temperature rotation 25 α [α] = D c x ℓ wavelength concentration length of cell of light of sample in dm (e.g. D-line solution (1 dm = 10 cm) of Na lamp, in g/mL λ=589.6 nm) Ch. 5 - 45 The value of α depends on the particular experiment (since there are different concentrations with each run) ● But specific rotation [α] should be the same regardless of the concentration Ch.
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  • Highly Enantioselective Synthesis of Γ-, Δ-, and E-Chiral 1-Alkanols Via Zr-Catalyzed Asymmetric Carboalumination of Alkenes (ZACA)–Cu- Or Pd-Catalyzed Cross-Coupling

    Highly Enantioselective Synthesis of Γ-, Δ-, and E-Chiral 1-Alkanols Via Zr-Catalyzed Asymmetric Carboalumination of Alkenes (ZACA)–Cu- Or Pd-Catalyzed Cross-Coupling

    Highly enantioselective synthesis of γ-, δ-, and e-chiral 1-alkanols via Zr-catalyzed asymmetric carboalumination of alkenes (ZACA)–Cu- or Pd-catalyzed cross-coupling Shiqing Xu, Akimichi Oda, Hirofumi Kamada, and Ei-ichi Negishi1 Department of Chemistry, Purdue University, West Lafayette, IN 47907 Edited by Chi-Huey Wong, Academia Sinica, Taipei, Taiwan, and approved May 2, 2014 (received for review January 21, 2014) Despite recent advances of asymmetric synthesis, the preparation shown in Schemes 1 and 2 illustrate the versatility of ZACA of enantiomerically pure (≥99% ee) compounds remains a chal- represented by the organoaluminum functionality of the ini- lenge in modern organic chemistry. We report here a strategy tially formed ZACA products. Introduction of the OH group for a highly enantioselective (≥99% ee) and catalytic synthesis by oxidation of initially formed alkylalane intermediates in of various γ- and more-remotely chiral alcohols from terminal Scheme 2 is based on two considerations: (i) the proximity of the alkenes via Zr-catalyzed asymmetric carboalumination of alkenes OH group to a stereogenic carbon center is highly desirable for (ZACA reaction)–Cu- or Pd-catalyzed cross-coupling. ZACA–in situ lipase-catalyzed acetylation to provide ultrapure (≥99% ee) di- oxidation of tert-butyldimethylsilyl (TBS)-protected ω-alkene-1-ols functional intermediates, and (ii) the versatile OH group can R S α ω produced both ( )- and ( )- , -dioxyfunctional intermediates (3) be further transformed to a wide range of carbon groups by – ee ≥ ee in 80 88% , which were readily purified to the 99% level tosylation or iodination followed by Cu- or Pd-catalyzed cross- by lipase-catalyzed acetylation through exploitation of their high α ω coupling.
  • Catalytic Asymmetric Synthesis

    Catalytic Asymmetric Synthesis

    Catalytic Asymmetric Synthesis Dr Alan Armstrong Rm 313 (RCS1), ext. 45876; [email protected] 7 lectures Recommended texts: “Catalytic Asymmetric Synthesis, 2nd edition”, ed. I Ojima, Wiley-VCH, 2000 (or 1st ed., 1993, which contains most of the lecture material) “Asymmetric Synthesis”, G Procter, Oxford, 1996 Aims of course: To give students an understanding of the basic principles of asymmetric catalysis, and to demonstrate these in the context of state-of-the-art catalytic asymmetric processes for C-C bond formation and redox processes. Course objectives: At the end of this course you should be able to: • Recognise the types of functional groups which can be prepared by catalytic asymmetric methods discussed in the course; • Use this knowledge in planning the synthesis of enantiomerically enriched compounds from given prochiral starting materials; • Outline the scope and limitations of any methods you propose, with respect to parameters such as turnover, substrate and functional group tolerance, availability of catalysts and/or ligands etc Course content (by lecture, approximately): 1. Introduction and general principles of asymmetric catalysis. Oxidation of functionalised olefins: asymmetric epoxidation of allylic alcohols and enones 2. Oxidation of unfunctionalised olefins: epoxidation, dihydroxylation and aminohydroxylation. 3. Reduction of olefins: asymmetric hydrogenation. 4. Reduction of ketones and imines 5. Asymmetric C-C bond formation: nucleophilic attack on carbonyls, imines and enones 6. Asymmetric transition metal catalysis in C-C bond forming reactions (cross-couplings, Heck reactions, allylic substitution, carbenoid reactions) 7. Chiral Lewis acid catalysis (aldol reactions, cycloadditions, Mannich reactions, allylations) 1 Catalytic Asymmetric Synthesis - Lecture 1 Background and general principles • Why asymmetric synthesis? The need to prepare pharmaceuticals and other fine chemicals as single enantiomers drives the field of asymmetric synthesis.