Asymmetric synthesis (As per new syllabus of PCI)
Methods of asymmetric synthesis using chiral pool
Chiral auxiliaries and catalytic asymmetric synthesis
Enantiopure seperation
Stereoselective synthesis
Recent advances
References
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Asymmetric synthesis
1. ASYMMETRIC
SYNTHESIS
Presented by -
Mr. Akshay Ramchandra Yadav
( Second year M.pharm).
Pharmaceutical chemistry Dept.
Rajarambapu college of pharmacy, Kasegaon..
2. ďAsymmetric synthesis
ďMethods of asymmetric synthesis using
chiral pool
ďChiral auxiliaries and catalytic
asymmetric synthesis
ďEnantiopure seperation
ď stereoselective synthesis
ďRecent advances
ďReferences
3. âThe direct synthesis of an optically active
substance from optically inactive compound
with or without the use of optically active
reagents is called asymmetric Synthesisâ.
4. ďąChiral pool synthesis
Chiral pool synthesis is used to build a part of the epothilone
molecule(an alternative to paclitaxel), from readily available
enantopure(-)pantolactone.
Enantiopure 2,3-butanediols used to synthesize chiraphos.
5. 1. Synthesis from enantioenriched chiral pool starting products-
The chiral pool is that collection of cheap,readily available pure
natural products,usually amino acids or sugars, from which pieces
containing the required chiral centres can be taken and incorporated into
the product.
2. Synthesis using enantioenriched chiral pool auxiliaries
the chiral auxiliary is temporiy incorpoated into an organic synthesis
which introduces chirality in otherwise racemic compounds.
3. Enantioselective catalysts
7. ďś A chiral compound Is temporarily incorporated into a molecule.
ďś First reported by Corey
CH3
CH3 CH3Ph
OH
Cl
CH2
O
AlCl3
AlCl3
CH3
CH3 CH3Ph
O
CH2
O
O O
Bno
OH
I
Bno
(-)-8-
phenylmenthol
Intermediate in
prostaglandin synthesis
8. â Evans oxazolidinone auxiliaries are the most well known chiral
auxiliaries
⢠Derive from amino acids
- Forms the (Z)-âboron enolates
â High stereoselectivity is attributed to the relatively short boronâoxygen
bond length
â Form a tight,six membered chair like transition state,Carbonyl is
opposed to the enolate oxygen dipole.
O N
O
CH3
O
Bn
CO2H
Ph
Me
OH
O NH
CH2
Bn
Bu2BOTf
O N
O O
Bn
Ph
OH
Me
LiOH,H2O2
Phcho
+
(4S)-4-benzyl-3-propanoyl-1,3-oxazolidin-2-one
(4S)-4-benzyl-3-[(2S,3S)-3-hydroxy-2-methyl-3-phenylpropanoyl]-1,3-oxazolidin-2-one
(4S)-4-benzyl-2-methylidene-1,3-oxazolidine
(a) (b)
(a)
(b)
9. 1.Selective crystallisation
2.Supercritical extraction
3.Fractional reaction extraction
4.Diastereomer seperation by distillation
5.Membrane assisted seperation
6.Chromatography and simulated moving bed
Enantiopure separation is a process of separating isomers in a
racemic mixture into their individual enantiomer.
10. ďś Selective crystallisation
This invention relates to a new and useful process of selective
crystallization, by which individual compounds may be separated
from a solution containing two or more crystallizable compounds.
it is an object of the present invention to provide means by which
compounds having 25 similar solubility characteristics may be
crystallized from solution and separated one from the other in a
simple, economical and effective manner.
13. The use of membranes in chiral separation can be divided into two
main categories, namely, adsorption-type enantioselective
membranes and membrane-assisted resolution with non-
enantioselective solid membranes
ďś Membrane assisted seperation
14. Stereoselective reactions â reactions where one
stereoisomer of product is formed predominantly because the
reaction has a choice of pathways, and one pathway is more
favourable than the other.
* *
CH3CH=CHCH3 + Br2 ď CH3CHCHCH3
Br Br
2-butene 2,3-dibromobutane
2 geometric isomers 3 stereoisomers
cis- and trans- (S,S)-, (R,R)-, and (R,S)-
meso-
15. CH3 CH3
H H
/ H Br Br H
C = C + Br2 ď +
/ Br H H Br
CH3 CH3
CH3 CH3
cis-2-butene
(S,S)- & (R,R)-2,3-dibromobutane
racemic modification only products
A reaction in which stereochemically different molecules react differently
is called a stereospecific reaction. In this case the cis- and trans-
stereoisomers give different products.
16. The fact that the addition of halogens to
alkenes is both stereoselective and
stereospecific gives us additional
information about the stereochemistry of
the addition and the mechanism for the
reaction.
17. ďCatalytic enantioselective oxidative coupling of
saturated ethers with carboxylic acids derivatives.
ďDual-catalytic transition metal systems for
functionalization of unreactive sites of molecules.
ďPyrrolidines and piperidines bearing chiral tertiary
alcohols by nickel-catalyzed enantioselective
reductive cycliztion of N-alkynones.
18. 1. Craner H, Groner E, Levy L, Agranat I. Trends in the development of chiral
drugs. Drug Discov Today 2004; 9: 105â110.
2. 2. Hutt AJ, Smith and Williams' Introduction to the principles of drug design
and action, 4th Edition, in Smith JH, Ed. (CRC Press LLC, Boca Raton, FL,
USA, 2006), pp 117â183.
3. 3. SimĂĄndi B, Keszei S, Fogassy E, KemĂŠny S, Sawinsky J. Separation of
enantiomers by supercritical fluid extraction. J Supercrit Fluids 1998; 13:
331-336.
4. Bauza R, RĂos A, Valcarcel M. Enantioselective supercritical fluid extraction
from racemic mixtures by use of chiral selectors. Separ Sci Technol 2004;
39:459-478.
5. SzĂŠkely E, SimĂĄndi B, IllĂŠs R, MolnĂĄr P, GebefĂźgi I, Kmecz I, et al.
Application of supercritical fluid extraction for fractionation of enantiomers.
J Supercrit Fluids 2004; 31: 33-40