Asymmetric Synthesis: Basics

Enantiomers and Enantioselective Reaction

OH OH 1 Chiral RCHO + (R )2Zn 1 Ligand RR1 RR

70% Yield 30% Yield [R] - [ S] [70 ] - [ 30 ] %ee = x 100 x 100 = 40% [R + S ] [100]

Stereospecific Reaction: Enantiospecific Reaction Ph H Ph O O (0.1 equiv.) HO H N B H

BH3:THF (1.0 equiv.), THF, 23 °C

100%, 99% ee Asymmetric Synthesis: Basics

Racemates : An equal mixture of enantiomers (50% of each)

Racemization :The conversion of enantioenriched compounds to racemic materials

Epimers : Diastereomers that differ in configuration at one of two or more stereogenic units

Epimerization : The interconversion of epimers Asymmetric Synthesis: Enantiomeric Purity Analysis

NMR Chiral Shift Reagents Chiral Solvating Agents

GC or Chiral Stationary Phase HPLC

Chemical Formation of diastereomeric molecules Methods Mosher ester analysis Conversion to known compounds and measurement of optical rotation

Optical Optical Rotation Methods Asymmetric Synthesis: Basics

Diastereomers and Diastereomeric Excess

O O O O OH O O OH Bu2BOTf O N O N R1 O N R1 Et 3N, R 1CHO CH CH R R 3 R 3 96 4

[D1] - [ D2] %de = x 100 = 92% [D1] + [ D2] Methods of Asymmetric Synthesis

Resolution: A useful method for separation of enantiomeric compounds by preparation of diastereomeric molecules. Chemical, biochemical, or analytical

Asymmetric induction: The preferential formation of one enantiomer or diastereomer over the other with the assistance of a stereogenic element in the substrate, reagent, catalyst, or environment. Asymmetric Synthesis: Commonly used Chiral Auxiliaries

O O O Me2N O NH O NH O NH Ph N R Ph CH3 Ph t-BuO R = CH(CH 3)2 R = CH 2Ph R = Ph

H N O Ph RO2CCO2R N OH NH O N R OMe HO OH H NH S 2 O O

A chiral element which is attached to the substrate covalently A stereoselective or stereospecific reaction is carried out The chiral element is removed Chiral Auxiliary Controlled Conjugate Addition to Enoates: Remot e Induction O H O H

O Nucleophile O

R R1 R Re Note Nucleophile R %Yield %de prefered s-trans ester πππ geometry and -stacking PhCuBF3 Me 76 >99

(E)-Enoates give higher n-BuCuBF3 Me 75 >99 selectivity MeCuP(n-Bu)3BF3 n-Bu 96 93 Additions to di- and trisubstituted double bonds are not very successful si face

R SO2Ph R O t-Bu Oppolzer N Helmchen O O

H O H O Oppolzer, W.; Loher, H. J. Helv. Chim. Acta 1981 , 64 , 2808-2811 Helmchen, G.; Wegner, G. Tetrahedron Lett. 1985 , 26 , 6051-6054. Asymmetric Synthesis: Catalysis

A process in which an additive enhances the rate of a reaction without undergoing any changes itself

Advantages: Lesser amount of reagents No need to covalently attach chiral information to substrate No need to detach the chiral information after completion of the reaction Easier variation of Lewis acid and the ligand combination to do chiral Lewis acid reactions

Disadvantages: Difficult to enhance enantioselectivity in moderately selective reactions by simple methods