Transcript Feb.6-8 - McMaster University

The synthesis of Dilantin also involves imines (expt 7):
+
H
Ph
+
H
OH
H2N
O
+
+
H
O
H2N
O
Ph
Ph
H
N
O
Ph
OH
N
H
Note the two +
C's are adjacent
+
H
H
N
Ph
Ph
Ph
O
N
H
Dilantin
N
H
OH
H
N
Ph
O
Ph
N
H
Ph
O
N
O
+
HO
Ph
N
O
Ph
N
Imines in putative prebiotic synthesis of histidine:
N
H
O
H
2 NH3
+
+
H
O
H2N
N
H
H
O
H
HOOC
+
H
O
H
O
+
H
H
NH
H
NH
2 NH3
O
H
OH
NH
+
N
N
H
+
H
N
N
H
N
N
tautomerize
NH
N
N
-
Imidazole (aromatic)
N
N
H
O
ALDOL- like
+
H
O
H
OH
OH
H
H
H
N
dehydration
H
O
O
O
N
N
N
H
N
H
N
+
H
NH3
H
H
N
HOOC
NH2
N
H
N
NC
NH2
N
H
Histidine
Strecker synthesis
H
N
NH
N
H
• Interestingly, AA’s have been detected in space:
Murchison Meteorite:
– Murchison, Australia (1969)
– Contained noble gases & insoluble material such as graphite &
silicates
– Also contained several organics:
– Dicarboxylic acids, alkanes & amino acids
• Contained gly, ala, glu & non-proteinegenic AA’s (isovaline → most
abundant)
• Components found in Urey-Miller Exp’t!!
– Origin in space?
• Isotopic distribution indicates amino acids were extraterrestrial in
origin
i.e., Natural abundance of 15N is 0.37%, however, meteorites were
found to have +50% to 93%
– Majority of AA’s were racemic, but some did show slight
enantiomeric excess (L) (1-15%)
–  there is enrichment!
There had to be a natural process that separated &
concentrated one enantiomer over the other → chiral
selection
Mechanism of enrichment?
a)
Circularly polarized light from stars:
•
•
•
b)
This CPL is in the UV & IR range & is chiral
 CPL can form or destroy the two enantiomers of an AA at
different rates → asymmetric photolysis
Could have led to enrichment of L-amino acids in meteorite
Selection by crystal faces:
•
•
Most minerals are centric → do not display handedness
Calcite, CaCO3, (exception) displays surfaces that have a
mirror relationship → “chiral-like”
• Hazen exp’t:
– Immersed large crystal of calcite in a dilute solution of 50:50 D,Laspartic acid
– GC analysis found that calcite absorbs different enantiomers on
different surfaces
•
Enantioenrichment?
–
If one face proceeds forward, while the other is chemically
inert, then we get enantioenrichment
i.e., one face is exposed to light or one face is immersed (by
chance) in water
**Does calcite promote amino acid chain formation?
•
Whatever the origin of homo-chirality, the ee was likely
low
However, once one AA is present in excess, then
enantioenrichment can occur:
•
•
Via Serine octamer
(Cooks et al,. Angew. Chem. Int. Ed., 2003, 42, 3521)
•
Enrichment by sublimation
(Feringa et al,. Chem. Commun., 2007, 2578)
i. Serine octamer
•
•
•
•
•
•
forms a non-covalent homochiral octamer in a mass
spectrometer via electrospray ionization
Octamer was found to be chiroselective—formed from
enantiopure samples, but not racemic ones!
 one L-serine selects to bind with 7 more L-enantiomers
Also found that they could incorporate more than one type of
AA—providing that all of the amino acids had the same
chirality
Additionally, octamer forms adducts enantioselectively with
D-glyceraldehyde → could help explain relationship between
L-amino acids in proteins & D-sugars as the dominant
species in nature!
Serine cluster also catalyzed dimerization of glyceraldehyde
giving a C6 sugar
Cluster also found to bind to PO43- and some metals
Serine Octamers
ii.
Enrichment by sublimation
•
•
•
•
Took mixtures of AA’s (leu, ala, phe, etc.) with low ee (~9%) &
partially sublimed sample
Results showed that in each case there was enrichment of the
enantiomer (20-80%)!
Indicates that a heat source may suffice for enantiomeric
enrichment:
Meteorites could be subjected to high temperatures that could
result in enrichment
Another mechanism for enantioenrichment:
organocatalysis via the aldol reaction
• Several years ago is was found that amino acids can
catalyze reactions
• Recently “re-invented” as organocatalysts (as opposed
to organometallic catalysts → Pd(PPh3)4, RuR6, AlR3,etc)
• Like the reactions we have seen already, it involves
imines & their enamine tautomers
• For example in the aldol reaction:
O
NO2
O
O
H
O
OH
H
NO2
• Rxn is diastereoselective but racemic
• Repeat with L-alanine as a catalyst:
Cordova, A et al. Chem. Commun. 2005, 3586-3588
Mechanism:
TAUTOMERIZATION
O
N
+
H2N
COOH
COOH
HN
H
IMINE
COOH
ENAMINE
O
B
H
O
H2N
COOH
+
OH
H2O
N
COOH
OH
Ar
Ar
(hydrolzye
imine)
Catalyst recycled
99% ee, 15:1 de
Chirality in the enamine is transferred to the new chiral centres in the aldol
Selectivity?
Ar
Selectivity?
Proposed to occur via a 6-membered TS:
N
Ar
O
H
N
H
O
O
COOH
OH
O
OH
Ar
Ar
H
Chirality in the enamine is transferred to the 2 new chiral centres in the aldol
• An intriguing example of how chirally enriched amino
acids in the prebiotic world can generate sugars with Dconfiguration & with enantioenrichment:
Cordova et al. Chem. Commun., 2005, 2047-2049
The Model:
O
L-proline
OH
O
H
H
OBn
BnO
2-4 days
O
OH
+
OBn OBn
BnO
OBn
OBn
95-99% ee
>99% ee
hexose sugar
L-proline: a 2° amine; popular as an
organocatalyst because it forms enamines
readily
O
N
H
L-proline
OH
Mechanism: enamine formation
O
+
H
OBn
O
+
N
O
OH
H
N
H
OH
OBn
dilute
O
OH
+
N
O
OH
OBn
OBn
O
H
OBn
N
OH
OBn
CO2H participates as acid
OH
OBn
O
OBn
1st aldol product
(4C)
OH
O
O
OH
N
O
OH
+
OBn
OH
OBn
2nd proline-mediated
aldol reaction
OBn
BnO
O
OBn
OBn
OH
OH
BnO
BnO
OBn
OBn
benzyl protected allose
BnO
OBn
O
OBn
OH
Enantioenrichment
% ee of sugar vs % ee of AA
• Initially used 80% ee proline to
catalyze reaction → >99% ee
of allose
• Gradually decreased enatiopurity of proline
– Found that optical purity of
sugar did not decrease until
about 30% ee of proline!
– Non-linear relationship!
•  chiral amplification
– % ee out >> % ee in!
• Suggests that initial chiral pool was composed of amino
acids
• Chirality was then transferred with amplification to
sugars → “kinetic resolution”
• Could this mechanism have led to different sugars
diastereomers?
• Sugars →→ RNA world →→ selects for L-amino acids?
• Alternative: small peptides