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Transcript
Lecture 1c
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)
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
• (*) These drugs are isomerized in vivo
O
N
O
O
*
NH
O
COOH
O
HO
OH
NH2
HO
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
OCH3
P
P
(R,R)-DIPAMP
OCH3
History of Asymmetric Synthesis II
• 1980: T. Katsuki and K.B. Sharpless develop chiral epoxidation of
allylic alcohols (90 % e.e., but moderate yields!)
H
geraniol
OH
1. (+)-DET,
Ti(iOPr)4
O
2. TBHP
H
(2S, 3S)
major
OH +
O
H
OH
(2R, 3R)
minor
• They attribute the high selectivity to the in-situ
formation of a chiral, dinuclear Ti-complexes
E
R
R
iPr O
O
OiPr
O
Ti
E O
Ti
O
• The alkene is tied to the reaction center by the allylic O
EO
O
hydroxyl function
O
Bu
• This places the peroxide function in close proximity EtO
E=COOEt
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
t
R
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
•
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‡)
Difference of Activation Energy required vs. the Ratio of Enantiomers
K
16000
 DDG‡
e RT
14000
DDG‡ (J/mol)
12000
173
10000
273
8000
298
6000
373
4000
2000
T\DDG‡
173
16.1
273
5.8
298
5.0
373
3.6
0
0
10
20
30
40
50
60
70
80
90
4000 J
100
K
• 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
Chiral Reagent
• Example: Enantioselective reduction of aromatic ketones using
BINAL-H
H
(n-C H )
78% yield, 100 % e.e.
AL3
N
-BI
(R)
HO
H
7
(R)
(n-C3H7)
O
(S)
-BI
NA
L-H
(n-C3H7)
64% yield, 100 % e.e.
H OH (S)
• 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
Chiral Auxiliary I
Front view
• Evans (1982): Oxazolidinones for chiral alkylations
O
O
O
Cl
NH
O
O
N
(4S)-(-)-4-isopropyl2-oxazolidine
•
•
O
O
1. Li(N(i-C3H7)2) O
2. PhCH2Br
O
O
LiOCH2Ph
N
CH2Ph
PhH2CO
CH2Ph
>99% e.e.
92% yield
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
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
Chiral Catalyst
• In Chem 30CL, a chiral catalyst is used to form a
specific enantiomer of an epoxide
NH 2 HOOC
R1
OH
O
R2
+
NH 2 HOOC
R3
OH
R4
NaOCl
H 2O/AcOH
NH 3
NH 3
+
-
+
-
OO C
OO C
OH
OH
N
R3
R4
N
O
1. Mn(OAc)2*4 H2O
2 K2CO3
2
R2
OH
OH
CHO
R1
N
OH
2 Air
3. LiCl
Mn
N
Cl
O