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Assigned Reading• Hanson, J. J. Chem. Educ. 2001, 78(9), 1266 (including supplemental
material).• Larrow, J.F.; Jacobsen, E.N. Org. Synth. 1998, 75, 1. • Cepanec, I. et al. Synth. Commun. 2001, 31(19), 2913.• Flessner, T.; Doye, S. J. Prakt. Chem. 1999, 341, 436. • McGarrigle, E.M.; Gilheany, D.G. Chem. Rev. 2005, 105(5), 1563.• Schurig, V.; Nowotny, H.P. Angew. Chem. Int. Ed. Engl. 1990, 29(9), 939. • Sharpless, B. Angew. Chem. Int. Ed. Engl. 2002, 41, 2024.• Katsuki, T. Coord. Chem. Rev. 1995, 140, 189.• Kunkely, H.; Vogler, A. Inorg. Chem. Comm. 2001, 4, 692.• Trost, B. PNAS 2004, 101, 5348• Yoon, J.W.; Soon, W.L.; Shin, W. Acta Cryst .1997, C53, 1685.• Yoon, J.W.; Yoon, T.; Soon, W.L.; Shin, W. Acta Cryst. 1999, C55, 1766.
Why Asymmetric Synthesis?• Chirality plays a key role in many biological systems i.e.,
DNA, amino acids, sugars, terpenes, etc.• Many commercial drugs are sold as single enantiomer
drugs because often only one enantiomer (eutomer) exhibits the desired pharmaceutical activity while the other enantiomer is inactive or in many cases even harmful (distomer)
• (*) These drugs are isomerized in vivo
Drug R-enantiomer S-enantiomer
Thalidomide Morning sickness Teratogenic*
Ibuprofen Slow acting Fast acting*
Prozac Anti-depressant Helps against migraine
Naproxen Liver poison Arthritis treatment
Methadone Opioid analgesic NMDA antagonist
Dopa Biologically inactive Parkinson’s disease
N
O
O
* NHO
O
COOH
HO
HO
NH2
OH
O
L-DOPA
History of Asymmetric Synthesis I• 1848: Louis Pasteur discovers the chirality of sodium
ammonium tartrate • 1894: Hermann Emil Fischer outlined the concept of
asymmetric induction• 1912: G. Bredig and P.S. Fiske conducted one of the
first well documented enantioselective reactions (addition of hydrogen cyanide to benzaldehyde in the presence of quinine with 10 % e.e.)
• 1960ties: Monsanto uses transition metal complexes for catalytic hydrogenations i.e., Rh-DIPAMP for L-dopa (Parkinson disease, 95 % e.e.)
• 1980ties : R. Noyori developed hydrogenation catalyst using rhodium or ruthenium complexes of the BINAP ligand
PP
OCH3
OCH3
(R,R)-DIPAMP
(R)
PPh2
PPh2
(R)-BINAP
History of Asymmetric Synthesis II• 1980: T. Katsuki and K.B. Sharpless develop chiral epoxidation of allylic
alcohols (90 % e.e., but moderate yields!)
• They attribute the high selectivity to the in-situ formation of a chiral, dinuclear Ti-complexes• The alkene is tied to the reaction center by the allylic
hydroxyl function• This places the peroxide function in close proximity
to the alkene function• The reaction is usually carried out at low temperatures (-20 oC),
is very sensitive towards water and require up to 18 hours to complete• The yields are moderate (77 % for the reaction above) due to the increased water
solubility of the products
HOH
HOH
1. (+)-DET,Ti(iOPr)4
2. TBHP
O
HOH
O+
geraniol (2S, 3S)major
(2R, 3R)minor
O OTi
OiPr
E
OTi
O
E
O
O
O
tBu
RR
R
EiPr O
E=COOEt
OEtO
History of Asymmetric Synthesis III
• Example: Sharpless epoxidation is used to prepare (+)-disparlure, a sex pheromone, that has been used to fight Gypsy moths through mating disruption (note that the (-) enantiomer is a deterrent and reduces trap captures)
• The Sharpless epoxidation is also used to obtain intermediates in the preparation of methymycin and erythromycin (both macrolide antibiotic)
• The Nobel Prize in Chemistry in 2001 was awarded to three of the pioneers in the field: K. B. Sharpless, R. Noyori, W. S. Knowles
OH1. (+)-DETTi(OiPr)42. TBHP
OHO
> 98% ee
O
(+)-disparlure
O
H3C
OH
HO
CH3
OH
CH3
CH3
O
H3C
H3CH2C
H3C
O
O O
OHO
N(CH3)2
CH3
O
OCH3
CH3OH
CH3
How do Chemists control Chirality?
• Chiral pool: optically active compounds that can be isolated from natural sources (i.e., amino acids, monosaccharides, terpenes, etc.) and can be used as reactants or as part of a chiral catalyst or a chiral auxiliary• The TADDOL, DIOP and the Chiraphos ligand have tartaric acid as
chiral backbone
• Enzymatic process: very high selectivity, but it needs suitable substrates and well controlled conditions• The Lipitor synthesis requires halohydrin dehalogenase, nitrilase, aldolase• The reduction of benzil using cryptococcus macerans leads to the formation of
(R,R)-hydrobenzoin (dl:meso=95:5, 99 % e.e.)
• Chiral reagent: it exploits differences in activation energies for alternative pathways
• Chiral auxiliary: it is a chiral fragment that is temporarily added to the molecule to provide control during the key step of the reaction and is later removed from product
How do Chemists control Chirality?
• By manipulating the energy differences in transition states (DDG‡)
• Bottom line• The higher the energy difference in the transition states is the higher
the selectivity will be at a given temperature• The lower the temperature, the more selective the reaction will be at
a given difference in transition energy
0 10 20 30 40 50 60 70 80 90 1000
2000
4000
6000
8000
10000
12000
14000
16000
Difference of Activation Energy required vs. the Ratio of Enantiomers
173
273
298
373
K
‡ (
/)
DDG
Jmol
RT
G
eK
‡
T\DDG‡
4000 J
173 16.1
273 5.8
298 5.0
373 3.6
Chiral Reagent
• Example: Enantioselective reduction of aromatic ketones using BINAL-H
• The enantioselectivity for the reaction increases from R=Me (95 %) to R=n-Bu (100 %) but decreases for R=iso-Pr (71 %) and R=tert.-Bu (44 %) due to increased 1,3-diaxial interactions in the six-membered transition state
O
OAl
H
OEt LiAl
EtO Li OH
R
Runsat.
O
O
(R)-BINAL-H Transition state ofBINAL reduction
(n-C3H7)
O
(n-C3H7)
HO H (R)
78% yield, 100 % e.e.
(n-C3H7)
H OH
64% yield, 100 % e.e.
(S)
Chiral Auxiliary I• Evans (1982): Oxazolidinones for chiral alkylations
• The oxazolidinone is obtained from L-valine (via a reduction to form L-valinol, which is reacted with either urea or diethyl carbonate under MW conditions)
• The iso-propyl group in the auxiliary generates steric hindrance for the approach from the same side in the enolate (the high-lighted atom is the one which is deprotonated)
• Chiral auxiliaries• The auxiliary has to be close to reaction center, but not slow down the
reaction significantly or change the structure in the transition state• The auxiliary should be easily removed without loss of chirality• It should be readily available for both enantiomers
ON
OO 1. Li(N(i-C3H7)2)
2. PhCH2Br
ON
OO
ONH
O
Cl
O
CH2PhPhH2CO
O
CH2Ph
(4S)-(-)-4-isopropyl-2-oxazolidine
>99% e.e.92% yield
LiOCH2Ph
Front view
Side view
Chiral Auxiliary II
• In 1976, E. J. Corey and D. Enders developed the SAMP and RAMP approach that uses cyclic amino acid derivatives ((S)-proline for SAMP, (R)-glutamic acid for RAMP) and hydrazones to control the stereochemistry of the product.
• Below is an example for the use of SAMP in an asymmetric alkylation reaction. • The condensation of SAMP with a ketone affords an E-hydrazone• The deprotonation with LDA leads to the enolate ion that undergoes
alkylation from the backside • The chiral auxiliary is removed by ozonolysis
R'R''
O N
OCH3
NH2 R'R''
NN
OCH3 R'R''
NN
OCH3
R
1. LDA2. RX R'
R''
O
R
O3
"SAMP"