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Asymmetric synthesis

Mukund jha

Mpharm 2

nd

semester

Pharmaceutical chemistry

Introduction The direct synthesis of an optically active substance from optically inactive compound with or without the use of optically active reagent is called asymmetric synthesis. In asymmetric synthesis, the reactions are either highly enantioselective or enantiospecific (100%). Ph C O H

• HCN^ C^ Ph H CN H O ( R ) - ( + ) - m a n d e l o n i t r i l e m a n d e l o n i t r i l e l y a s e a s y m m e t r i c a l r e a c t i o n

Chiral pool synthesis refers to a synthetic process that employs a member of the chiral pool as a starting material (SM) in the synthesis of a target molecule (TM). Chiral Pool Synthesis Functional Group Interconversion Chiral pool synthesis of L-glyceraldehyde, the unnatural sugar, from the natural amino acid L-Serine.

NH 2 H O O OH NaNO (^2) HCl H 2 O (^) OH H O O OH O P

• TsOH (^) O O O OH BH 3 O PCC^ O^ OH O H^ O^ O 2 O AcOH OH H O O S - s e r i n e

N a t u r a l e n a n t i o m e r

( V e r y c h e a p )

L - g l y c e r a l d e h y d e

U n n a t u r a l e n a n t i o m e r

V e r y e x p e n s i v e

Asymmetrical synthesis using chiral auxillary A chiral auxiliary is a chiral molecular unit that can be temporarily incorporated in an achiral substrate to guide selective formation of one of a possible pair of enantiomers. Chiral auxiliaries are optically active compounds and introduce chirality in otherwise achiral starting materials. Examples of chiral auxiliaries used in the alkylation of enolates.

OH

Ph

NH

CH 3

CH 3

H N O

O

Asymmetric Enolate Alkylation Optically active carboxylic acids can be prepared with high enantiomeric excess based on the chiral auxiliary approach to asymmetric synthesis. O NH O ( 1 ) n -BuLi ( 2 ) Cl O CH 3 O O (^) N CH 3 O LDA O O (^) N CH 3 O Li H Z - E n o l a t e PhCH 2 I O O (^) N CH 3 O H (^) Ph LiOH H 2 O 2 O CH 3 Ph

+ H^ O

O (^) NH O ( R ) (^) - 2 - m e t h y l - 3 - p h e n y l p r o p a n o i c a c i d s

a. Needs to be available in both enantiomeric forms. b. Needs to be easy and quick to synthesize. c. Must be readily incorporated onto an achiral substrate. d. It should provide good levels of asymmetric induction. e. Needs to be selectively cleaved from the substrate under mild conditions. f. Must be recoverable and re-useable. Qualities of a Good Chiral Auxiliary

Catalytic asymmetric synthesis Catalytic asymmetric synthesis generally refers to asymmetric synthesis by the help of sub-stoichiometric chiral catalysts. Most commonly asymmetric reactions begins with a pro-chiral substrate in the presence of chiral catalyst, which are subjected to two diastereomeric reaction pathways with quite different activation energies. The catalyst role is to offer an alternative favourable in mechanism part. The production of fine chemicals and pharmaceuticals is basically a heterogeneous asymmetric catalysis method. It includes the utilisation of converted or rather the immobilized homogeneous asymmetric catalysts and even heterogeneous metal catalysts which are chirally modified, for enantioselective reaction.

EtO 2 C O EtO 2 C O O^ CO 2 Et O (^) CO 2 Et Ti Ti OiPr PrOi OiPr OiPr The tartrate and metal form a complex: O O^ CO 2 Et O (^) CO 2 Et Ti Ti O O O OH OH O O O^ CO 2 Et O (^) CO 2 Et Ti Ti O O O O OH OH 2 x iPrO ligands replace the departing product hence the catalyst is regenerated. The substrate and oxidant replace two OiPr ligands. product side-product The oxygen atom is directed to the alkene. The alkene is above the peroxide. Sharpless epoxidation

Enantiopure separation in stereochemistry is a process for the separation of racemic compounds into their enantiomers. It is an important tool in the production of optically active drugs. There are different method for enantiopure separation which include-  HPLC (High Performance Liquid Chromatography) -; Chiral batch HPLC is the simplest and quickest way to obtain small scale (mg to-multi g) samples using 1-10cm I.D. columns. Over 90% of racemic small molecules can be separated at this scale. One key advantage is that both enantiomers are isolated which allows both to be submitted for toxicology studies.  SFC (Supercritical Fluid Chromatography) -; SFC is relatively new technology. This is liquid chromatography using supercritical carbon dioxide as the solvent. Since supercritical liquid has both gas and liquid characters, the resultant low viscosity allows very high flow rate making it suitable for small to larger (-10kg) separation. Enantiopure separation

 SMB (Simulated Moving Bed) -; SMB technology is a continuous process using several columns to gain high productivity. Daicel group has several scales of SMB equipment which allows to separate from 10kg to 10s MT.

Dehydrohalogenation of 2-iodo-butane which yields 60% trans -2-butene and 20% cis - 2-butane.  (^) The addition of formic acid to norbornene is also stereospecific because the exo isomer is formed exclusively without any of the endo isomer.

Stereoselective synthesis of pinane-based 1,3,4- oxadiazole

Myrtenic acid was coupled with benzhydrazide in the

presence of CDI. Cyclodehydration of N,N0 -

diacylhydrazine with POCl3 at 80 ◦C furnished with

moderate yield. Dihydroxylation with OsO4/NMO

afforded in a highly diastereoselective reaction, similar to

1,2,4-oxadiazoles.

COOH

O

NHNH 2

Ph

C D I , D C M

4 0 h r , 4 2 %

O

NH

NH

O

Ph

POCl (^3) , 8 0 0 c 3 h r , 3 8 %

O

N

N

ph

OsO 4 , NMO,

THF, H 2 O

4 8 h r , 9 5 %

O

N

N

ph

OH

OH