the synthesis of dilantin also involves imines (expt 7):
TRANSCRIPT
The synthesis of Dilantin also involves imines (expt 7):
O
O
Ph
Ph
O
NH2
NH2
H+
H+ N
H
NH
OH
OH
O
Ph
Ph
H+
NH
N
OH
O
Ph
PhN
N
O
Ph
PhNH
NH
O
Ph
Ph
OH
NH
NH
O
Ph
Ph
O
+
Note the two +C's are adjacent
+
Dilantin
H+
Imines in putative prebiotic synthesis of histidine:
OH
H O
NH3
OH
HNH
NH
NH2
HOOC
+ 2 +
OH
H O
NH3
NHH
H NH
H H
O
H+
N
NH
OHH
+
N
NHN
NH
N
N
+ 2
+
-
tautomerize
N
N
OH
H
O
H
H+
NH
N
OH
H
ONH
NH
O
NH
NH
NHNH
N
NH2
H
NC
NH
N
NH2
H
HOOC
N
N
OH
H O H+
N
N
dehydration
NH3
Histidine
-
ALDOL- like
Imidazole (aromatic)
Strecker synthesis
• 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:• 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
b) 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,L-
aspartic 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:
• Rxn is diastereoselective but racemic
O
H
O
HNO2O OH
NO2
O
• Repeat with L-alanine as a catalyst:Cordova, A et al. Chem. Commun. 2005, 3586-3588
O
NH2 COOHN COOH
HNH COOH
H Ar
O
N COOH
Ar
OH
NH2 COOH
OH
Ar
O
+
IMINE
B
ENAMINE
TAUTOMERIZATION
H2O
(hydrolzye imine)
+
Catalyst recycled99% ee, 15:1 de
Chirality in the enamine is transferred to the new chiral centres in the aldol
Selectivity?
Mechanism:
Selectivity?
OH
N
OO
Ar
H
OH
Ar H
NCOOH
Ar
OH O
Proposed to occur via a 6-membered TS:
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 D-configuration & with enantioenrichment:
H
O
OBn
H
O
OBn
OH
OBn
O OH
OBn
OBn
BnO
BnOL-proline
2-4 days
+
95-99% ee >99% ee
hexose sugar
L-proline: a 2° amine; popular as an organocatalyst because it forms enamines readily
NH OH
O
L-proline
Cordova et al. Chem. Commun., 2005, 2047-2049
The Model:
Mechanism: enamine formation
H
O
OBnNH OH
ON
OH
O
OBn
H
NOH
O
OBn
H
O
OBnN
OH
O
OBn
OH
OBn
OBn
OH
OBn
O
+
+
+
1st aldol product (4C)
dilute
CO2H participates as acid
OBn
OH
OBn
ON
OH
O
OBnOBn
OH
OBn
OH O
OBn
OOH
OH
BnO
OBnBnO
O OH
OBn
OBn
BnO
BnO
+2nd proline-mediatedaldol reaction
benzyl protected allose
• Initially used 80% ee proline to catalyze reaction → >99% ee of allose
• Gradually decreased enatio-purity of proline– Found that optical purity of
sugar did not decrease until about 30% ee of proline!
– Non-linear relationship!
% ee of sugar vs % ee of AA
Enantioenrichment
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