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Asymmetric synthesis

Asymmetric synthesis
Asymmetric synthesis, also called chiral
synthesis, enantioselective synthesis or
stereoselective synthesis, is organic synthesis
which introduces one or more new and desired
elements of chirality.
This is important in the field of pharmaceuticals
because the different enantiomers or
diastereomers of a molecule often have
different biological activity.

• Biologically active molecules are also
• Enantiomers possess different types of
– Both are active, have different potencies
– Both have similar activity
– Both are active but type of activity is different.
– Only one enantiomer is active, other is devoid
of activity

D isomer is an analgesic while L isomer has antitussive property Ph Ph NMe2 Ph OCOEt Darvon Ph OCOEt NMe2 Novrad .Examples CO2- HO Hypertensive agent L-Methyldopa Me NH3+ HO Ph Ph Propoxyphene – both enantiomers are biologically active.

Chiral Catalysis for Therapeutic Drugs • Organisms sense the chirality of bioactive compounds – Carvone enantiomers bind different chiral taste and odor sensors: • (S)-Carvone is a component of Dill and Caraway flavor • (R)-Carvone is a component of Spearmint flavor .

Limonene enantiomers bind different chiral taste and odor sensors: • (R)-Limonene is a component of Orange flavor • (S)-Limonene is a component of Lemon flavor .

Aspartame enantiomers bind different chiral taste and odor sensors: • One enantiomer of Aspartame is 160 times sweeter than sugar • The other enatiomer tastes bitter .

only one enantiomer is biologically active – The other was generally assumed to be completely inactive • Thalidomide is an example where the “silent” enantiomer was actually deadly .Chiral Drugs • Drugs are (or have been) frequently prepared as Racemic Mixtures – Usually.

Other Examples (S)-asparagine (R)-asparagine O O H2N NH2 OH O H2N pahit H HO H NH2 manis O .

Estrone (+)-Estrone (-)-Estrone O H H O H H HO OH Sexual hormone inactives .

3-propanediol (R)-1-chloro-2.1-chloro-2.3-propanediol Cl OH HO H poison (S)-1-chloro-2.3-propanediol HO Cl H OH medicinal drug .

All of our proteins are made from single enantiomer amino acids – Organisms only use L-amino acids L-amino acid Organisms primarily use D-sugars D-amino acid .

Organisms’ responses to enantiomers • Drug receptor sites (usually proteins) are themselves chiral .

• Chiral drugs may not be able to bind effectively to elicit the correct response .

Enantiomeric Transition States Ph Me H- Ph Me Energy O O Ph Ph Me H H Me OH OH Enantiomeric transition states R S mirror .

C=O. C=N bonds: 4 R R1 4 3 R R2 R H2 gas catalyst H R3 R2 R1 O H H NR R2 R1 R4 R1 R R2 OH 3 R R 4 i) BH3 ii) H2O2 reducing agent R1 NHR R2 H Hydroboration of C=C bonds: 3 R2 R1 R2 R1 OH reducing agent Epoxidation of C=C bonds: 4 R R3 RCO3H R4 R3 O R2 R1 H R1 R2 R1 R2 16 .Examples of reactions which form chiral centres Hydrogenation of C=C.

cont… Hydrocyanation of C=O bonds: Dihydroxylation of C=C bonds: R 4 R1 3 R 2 R i) OsO4 ii) hydrolysis R4 R1 OH R3 R2 OH O R R1 R3 R2 CH2=CH2 catalyst R R1 R2 CN R2 OH O R1 R1 R HCN Addition of Grignard reagent to C=O bonds: R3 4 2 R1 Hydrovinylation of C=C bonds: 4 OH 2 R i) RMgBr ii) acid workup R2 R1 R H 17 .Examples of reactions which form chiral centres.

R3 R2 CO. 2… Enolate alkylation: R3 O R-X 2 R1 R Aldol reaction: O R3 R1 2 O R R1 R R3 2 4 R6 R R8 R7 R1 R1 (three chiral centres) H OH R2 R Hydroformylation of C=C bonds: Diels-Alder (cycloaddition): R6 R5 (aldehyde) Enolate Enolate (formed by ketone deprotonation) R5 RCHO R R3 O R3 R4 R3 R2 R2 1 R8 R7 R Four chiral centres H R4 R1 And many. cont.Examples of reactions which form chiral centres. H2 catalyst O R3 R4 R2 R1 H 18 . many more….

e. t-butyl peroxide (oxygen source) O O H Ti(OiPr)4 (metal for complex formation) OH HO HO O CO2Et (+)-diethyl tartrate (source of CO2Et chirality) OH 70-90% yield. The (-)-diethyl tartrate gives the opposite enantiomer. The oxidant is used stoichiometrically (i. 5 mol%).e.Asymmetric epoxidation of alkenes (1980s) R R3 4 RCO3H R4 R3 Mechanism? Could you modify this in an asymmetric manner? O R2 R1 R1 R2 Sharpless discovered that a combination of diethyl tartrate. >90% e. but the titanium and tartrate are used in catalytic amounts (ca. titanium isopropoxide and a peroxide. you need one equivalent). 19 . But it requires an allylic alcohol as substrate.

2 x iPrO ligands replace the departing product hence the catalyst is regenerated. Ti O O OH O O O CO2Et O O CO2Et Ti side-product 20 . The alkene is above the peroxide.How the Sharpless epoxidation (of allylic alcohols) works (catalytic cycle): The tartrate and metal form a complex: EtO2C O OiPr OiPr O OH Ti EtO2C O Ti O CO2Et OH Ti PrOi O OH product O OiPr CO2Et O O O The substrate and oxidant replace two OiPr ligands. CO2Et O O CO2Et Ti The oxygen atom is directed to the alkene.

Advantage? You are not limited to allylic alcohols. The chirality of the catalyst controls the absolute configuration. catalyst 5 mol% H H N N Mn But O tBu O tBu But O I O (hypervalnet iodine reagent) Source of oxygen.Asymmetric epoxidation of alkenes using Mn/Salen complexes (Jacobsen epoxidation): The iodine reagent transfers its oxygen atom to Mn. then the Mn tranfers in to the alkene in a second step. 21 .

. <1 mol% Ph Rh..Asymmetric hydrogenation for the synthesis of amino acids: Addition of hydrogen to an acylamino acrylate results in formation of an amine acid precursor. OMe RR-DiPAMP = a homochiral ligand OMe P S Rh P S MeO DiPAMP coordinated to Rh(I) 22 . catalyst O HO2C Ph N H HO2C H2 α-acylamino acrylate O S N H H N-acylated amine acid. The combination of an enantiomerically-pure (homochiral) ligand with rhodium(I) results in formation of a catalyst for asymmetric reactions. MeO P P . .

from the metal to the alkene. Hydrogen is transferred.Asymmetric catalysis .hydrogenation Rh-diphosphine complexes control asymmetric induction by controlling the face of the alkene which attaches to the Rh. Rh/DiPAMP OMe Ph P HO2C Rh OMe Ph P O OMe P O Rh N H P CO2H N H More stable. 23 . The intermediate complexes are diastereoisomers of different energy. but more reactive leads to product H2 Ph O H H S N H H CO2H Using Rh(DIPAMP) complexes. but less reactive complex OMe Less stable. asymmetric reductions may be achieved in very high enantioselectivity. in a stepwise manner.

Asymmetric catalysis – Ketone reduction The reduction of a ketone to a secondary alcohol is a perfect reaction for asymmetric catalysis: HO H O i) Borane (BH3). O How it works: N H Ph B Me O B H H H Me 24 . oxazaborolidine catalyst ii) hydrolysis (work up) Ph Oxazaborolidine catalyst: H N Ph Ph O B Concave molecule hydride directed to one face.

solvent Mechanism Ph O Me Ph2 P P Ph2 H Ru H HO H H H N N H2 Ph OH Me H Ph Ph H2 Ph2 P P Ph2 Ru H N N H2 H Ph Ph 25 .e.e. from very low catalyst loadings H2 . hydrogen gas) Ph2 P H H2 N Ph N H H2 Ph Ru P Ph2 O Very high e.Asymmetric catalysis – Ketone reduction by pressure hydrogenation (i.

e. 96-99% e. (-)-menthol 26 .Asymmetric catalysis – Isomerisation Ph2 P Rh PPh2 H NMe2 NMe2 [Rh/S-BINAP] Isomerisation (not a reduction!) H H ZnBr2 OH then H2. Ni cat (to reduce alkene) H O R-citronellal.

it was found that proline catalyses the asymmetric cyclisation of a diketone (known as the Robinson annelation reaction).Asymmetric catalysis – Organocatalysis (no metals) Some time ago. this is not a chiral centre O O Now this IS a chiral centreS configuration L-proline 10 mol%: N H CO2H O Major product O O The enantiomeric compound is: Mechanism is via: O O N O HO2C O 27 .

g.: 99% and even more complex ones: OtBu 20 mol% O O H2N H TBSO OTBS O CO2H O O O OH 3 mol% water. TBSO OTBS O 68%. major product: D-fructose precursor (it turns out that most amines act as catalysts!) 28 .Asymmetric catalysis – Organocatalysis (no metals) This is now the basis for many other reactions e.: L-proline Aldols: O O 10 mol%: N H H H Me Me 90% yield O CO2H OH 4:1 anti:syn H Me DMF Me anti product e.e. rt 2 days.

Asymmetric catalysis – Organocatalysis Other applications Other applications include: Diels-Alder reactions: O catalyst catalysed by: + H R L-proline O R H Asymmetric reductiions: O H H O or pyrrolidines: CO2Et catalyst EtO + 2C Ph N H Ph N H H (Hantzsch esterhydride source) H O catalyst + R O O H R Can you work out the mechanisms? Ph Ph N H Ph or other N-heterocycles: O NMe and oxidations: O CO2H N H H O R Ph N H CO2H 29 .

CF3 Cl O Cl Enolate is methylated on the front face (as illustrated) O CO2H indacrinone 30 . MeO H O H several steps N Catalyst: N Cl O Cl MeO The enolate is formed by deprotonation by hydroxide. 01 eq.e.) Catalyst (below). 50% NaOH-toluene Cl CH3Cl MeO Cl O Cl 98% yield 94% e.e.Asymmetric catalysis – Enolate alkylation The reaction proceeds via a complex in which the catalyst and the enolate are bound by a hydrogen bond (at least. that's the theory): Cl O 10 mol% (i.