Chem 125 Lecture 28 11/10/08 This material is for the exclusive use of Chem 125 students at Yale and may not be copied or distributed further. It is not readily understood without reference to notes or the wiki from the lecture.

N N O O O S T E R E O B I N O C U L A R S T E R E O N N O O O Exam Review: 9-11pm Wednesday 211 Mason Lab

Dr. Ridker, a co-inventor of a CRP test, said he first sought federal financing for the study and was turned down. He and the other scientists interviewed for this article, except for Dr. Nabel, Dr. Gardner and Dr. Wolfe, have consulted for or received research money from stain makers. Like many clinical trials, the Jupiter study was sponsored by a pharmaceutical company, in this case AstraZeneca. It makes the drug in the trial, rosuvastatin, which is sold as Crestor.

Tartaric Acid Isomers Configurational Nomenclature Defined as “D”-glyceraldehyde (Fischer’s Guess) m.p. [  ] D 140°C 0° 170°C +13° 170°C -13° (meso) (d extro +) (l aevo - ) Phenomenological Multi-Step Synthesis D-Tartaric Acid Why not? Genealogical (Fischer, 1891) d-(+)-glyceraldehyde HOCH 2 CH(OH)CHO Relative (by synthesis) to ? D/L designation is ambiguous without having a detailed synthesis recipe or a convention. ?

Absolute Configuration J. M. Bijvoet van't Hoff Laboratory, Univ. Utrecht ( ) Na Rb d-(L)-Tartrate X-ray anomalous dispersion 60 year old Fischer Guess for (L)-Tartrate “The question of nomenclature is beyond the scope of our investigation... The problem of nomenclature now concerns given configurations, and requires a notation which denotes these configurations in an unambiguous and if possible self- explanatory way.” (Bijvoet, 1951)

Naming Double Bond Configuration Malic Acid (HO 2 C)CH(OH).CH 2. (CO 2 H) Maleic & Fumaric Acids (HO 2 C)HC=CH(CO 2 H)  cis (on this side of) trans (across) cis or trans? Absolute nomenclature is hard to generalize O O O + H 2 O cis trans (though relative is fine) 

Double Bond Configuration Assign groups at either end "priority" by atomic number (or weight for isotopes) at first difference O O (E) ntgegen (Opposed) (Z) usammen (Together) The names trans and cis are "polluted" by previous usage.

In Assigning Priority Proceed One "Shell" at a Time (respecting previous decisions) Tie Win Tie Win Cl is high in priority, but irrelevant; the decision is already made. Cl

Robinson: "Hello Katchalsky. What are you doing here in Zurich?" from V. Prelog, My 132 semesters of chemistry studies (1981) The 1950s "CIP" Priority Scheme is Conventional R. S. Cahn C. K. Ingold V. Prelog Robinson: "Well then, if it is not wrong, it is absolutely unnecessary." Robinson: "You know, Prelog, your and Ingold's configurational notation is all wrong." Prelog: "Excuse me, Sir Robert, I am only Prelog, and I live here." Prelog: "Sir Robert, it can't be wrong. It is just a convention. You either accept it or not." R. RobinsonR. B.Woodward by permission J. D. Roberts

Exercise for Wednesday: Eadfrith’s Error (Click here & create your very own chiral conventions) (Click here & create your very own chiral conventions)

CIP (R/S) Nomenclature for Stereogenic Centers (S) inister (left) (2R,3R)- 2,3-dihydroxy butanedioic acid right turn H (R) ectus (right) H H left turn H CH 3 HO D H H D

Bloomer Gate

Organic

:B:B Racemization HOMO  * LUMO (R) (RS) easy harder (occasional) dianion very rare planar achiral! (R)-Lactic Acid H COOH CH 3 HO (S)-Lactic Acid COOH H CH 3 HO H H COO CH 3 HO

Epimerization (R,R)-Tartaric Acidmeso-Tartaric Acid (R,R) (R,S) Change at One Center of Two (or many) 

Racemization (R) (RS)Resolution (S)+ 1) Pasteur “Conglomerate” Chiral-Resolved Seeding Chiral-Resolved Poison

Crystal in Equilibrium with Saturated Solution Crystal at Equilibrium Interior Molecules more stable than in solution Surface Molecules less stable than in solution Average Molecule same as solution Lengthening Rate Depends on Width Metastable (in  solution) Average molecule less stable than in solution “Critical” Nucleus Average molecule more stable than in solution

Resolution(R) (RS) (S) + 1) Pasteur Conglomerate Chiral-Resolved Seeding Chiral-Resolved Poison 2) Temporary Diastereomers Chromatography with Chiral-Resolved Support Compound with Chiral-Resolved Mate cont. Influence nucleation

van’t Hoff Prediction 1874

Brucine Kohler Walker Tishler 1935 “Alkaloids” organic bases isolated from plants used to make diastereomeric salts with racemic acids

Kohler Walker Tishler 1935 Levo °C [  ] D -28.4° mixed mp 195°C Mole ratio brucine/acid % yield

End of Lecture 28 Nov. 10, 2008