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The synthesis of Dilantin also involves imines (expt 7):

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1 The synthesis of Dilantin also involves imines (expt 7):

2 Imines in putative prebiotic synthesis of histidine:

3 Strecker synthesis

4 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 15 N 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!

5 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, CaCO 3, (exception) displays surfaces that have a mirror relationship → “chiral-like”

6 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

7 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)

8 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 C 6 sugar Cluster also found to bind to PO 4 3- and some metals

9 Serine Octamers

10 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

11 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(PPh 3 ) 4, RuR 6, AlR 3,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

12 Repeat with L-alanine as a catalyst: Cordova, A et al. Chem. Commun. 2005, 3586-3588

13 Chirality in the enamine is transferred to the new chiral centres in the aldol Selectivity? Mechanism:

14 Selectivity? Proposed to occur via a 6-membered TS: Chirality in the enamine is transferred to the 2 new chiral centres in the aldol

15 An intriguing example of how chirally enriched amino acids in the prebiotic world can generate sugars with D- configuration & with enantioenrichment: L-proline: a 2° amine; popular as an organocatalyst because it forms enamines readily Cordova et al. Chem. Commun., 2005, 2047-2049 The Model:

16 Mechanism: enamine formation CO 2 H participates as acid

17

18 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

19  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


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