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.
Chirality
• When we talk about chirality, we usually refer to asymmetrically
substituted carbon atoms
• However, other atoms can also act as chiral centers i.e., nitrogen,
phosphorus, sulfur, etc.
Cyclanoline
VX (nerve agent) Esomeprazole (Nexium)
• Chirality is not limited to the presence of stereogenic atoms but also can be
caused by hindered rotations (atropisomerism)
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: Georg 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.), which is one of
the first examples of organocatalysis
• 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?
• By manipulating the energy differences in transition states (DDG‡)
Difference of Activation Energy needed for a Specific Product Ratio
K
DDG‡ (J/mol)
16000
 DDG‡
e RT
14000
373
T\DDG‡
12000
298
10000
8000
4000 J
6000 J
373
3.6
6.9
273
298
5.0
11.3
173
273
5.8
14.1
173
16.1
64.8
6000
4000
2000
0
0
10
20
30
40
50
60
70
80
90
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
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
Chiral Reagent
• Example: Enantioselective reduction of aromatic ketones using
BINAL-H
H
(n-C H )
78% yield, 100 % e.e.
ALN
-BI
(R)
3
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
• Evans (1982): Oxazolidinones for chiral alkylations
O
O
O
Cl
NH
(4S)-(-)-4-isopropyl2-oxazolidine
O
O
O
O
N
Front view
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)
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 Auxiliary III
• Chiral Auxiliaries (Summary)
• The desired enantiomer should be obtained in high purity and high
chemical yield, preferably without extended purification required.
It should ideally be available in both enantiomeric forms.
• The chiral auxiliary should be close to the reacting center, but not
adversely affect the rate of reaction. If the directing group is too large,
it will slow down the reaction too much or even can cause changes in
conformation in the substrate, which is highly undesirable.
• The final product must be readily separable from any chiral auxiliary.
• The incorporation and removal of any chiral auxiliary should be
chemically efficient and achieved without loss of optical activity
of the product and the auxiliary (recovery).
• For catalytic processes, the turnover number has to be high.
Chiral Catalyst I
• Hajos-Parrish-Eder-Sauer-Wiechert Reaction (1971):
intramolecular asymmetric aldol reaction that is used to
synthesize Wieland-Miescher ketone, which is used as
synthon in the synthesis of more than 50 natural compounds
(i.e., Taxol, steroids, diterpenes)
• List (2000): intermolecular asymmetric aldol reaction
Chiral Catalyst II
• 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