Proline isomers

The delicacy of the hitherto only synthetic pathway to the peptide alkaloids of lysergic acid is also underlined by the fact that other authors had failed to circumvent it (37). The main difficulty lies in the rapid epimerization of the L-proline containing intermediates to the d-proline isomers and the inherent instability of functionalized a-hydroxy-a-amino acid derivatives. 

Common Errors - One of the most common folding errors occurs via cis-trans isomerization of the amide bond adjacent to a proline residue (see here). Proline is the only amino acid in proteins that forms peptide bonds in which the trans isomer is only slightly favored (4 to 1 versus 1000 to 1 for other residues). Thus, during folding, there is a significant chance that the wrong proline isomer will form first. It appears that cells have enzymes to catalyze the cis-trans isomerization necessary to speed correct folding. 

L-proline isomer Actinomycin Radioactivity in peptide-bound imino acids ... 

Figure 6 Thermodynamic cycle for multi-substate free energy calculation. System A has n substates system B has m. The free energy difference between A and B is related to the substate free energy differences through Eq. (41). A numerical example is shown in the graph (from Ref. 39), where A and B are two isomers of a surface loop of staphylococcal nuclease, related by cis-trans isomerization of proline 117. The cis trans free energy calculation took into account 20 substates for each isomer only the six or seven most stable are included in the plot.

In the native protein these less stable ds-proline peptides are stabilized by the tertiary structure but in the unfolded state these constraints are relaxed and there is an equilibrium between ds- and trans-isomers at each peptide bond. When the protein is refolded a substantial fraction of the molecules have one or more proline-peptide bonds in the incorrect form and the greater the number of proline residues the greater the fraction of such molecules. Cis-trans isomerization of proline peptides is intrinsically a slow process and in vitro it is frequently the rate-limiting step in folding for those molecules that have been trapped in a folding intermediate with the wrong isomer. 

Thus the product in such cases can exist as two pairs of enantiomers. In a di-astereoselective process, one of the two pairs is formed exclusively or predominantly as a racemic mixture. Many such examples have been reported. In many of these cases, both the enolate and substrate can exist as (Z) or (E) isomers. With enolates derived from ketones or carboxylic esters, (E) enolates gave the syn pair of enantiomers (p. 146), while (Z) enolates gave the anti pair. Addition of chiral additives to the reaction, such as proline derivatives, or (—)-sparteine lead to product formation with good-to-excellent asynunetric induction. Ultrasound has also been used to promote asymmetric Michael reactions. Intramolecular versions of Michael addition are well known. ... 

A simple and rapid method of separating optical isomers of amino acids on a reversed-phase plate, without using impregnated plates or a chiral mobile phase, was described by Nagata et al. [27]. Amino acids were derivatized with /-fluoro-2,4-dinitrophenyl-5-L-alanine amide (FDAA or Marfey s reagent). Each FDAA amino acid can be separated from the others by two-dimensional elution. Separation of L- and D-serine was achieved with 30% of acetonitrile solvent. The enantiomers of threonine, proline, and alanine were separated with 35% of acetonitrile solvent and those of methionine, valine, phenylalanine, and leucine with 40% of acetonitrile solvent. The spots were scraped off the plate after the... 

As already discussed for aldol and Robinson annulation reactions, proline is also a catalyst for enantioselective Mannich reactions. Proline effectively catalyzes the reactions of aldehydes such as 3-methylbutanal and hexanal with /V-arylimines of ethyl glyoxalate.196 These reactions show 2,3-syn selectivity, although the products with small alkyl groups tend to isomerize to the anti isomer. 

The TS proposed for these proline-catalyzed reactions is very similar to that for the proline-catalyzed aldol addition (see p. 132). In the case of imines, however, the aldehyde substituent is directed toward the enamine double bond because of the dominant steric effect of the (V-aryl substituent. This leads to formation of syn isomers, whereas the aldol reaction leads to anti isomers. This is the TS found to be the most stable by B3LYP/6-31G computations.199 The proton transfer is essentially complete at the TS. As with the aldol addition TS, the enamine is oriented anti to the proline carboxy group in the most stable TS. 

Grainger s group has developed an asymmetric route to (-)-cuparene (5-83) [22] using another photoinduced generation of a biradical (Scheme 5.16) [23]. Thus, irradiation of (S)-proline-derived 5-80 resulted initially in the formation of 5-81, which subsequently cyclizes in almost quantitative yield to afford a mixture of the four possible diastereomers 5-82a-d in an approximate 10 5 2 1 ratio. The two major isomers could be separated by column chromatography to provide 5-82a in 36% yield and the desired 5-82b in 55 %, which was converted into the natural product 5-83 in 24% yield over three steps. 

This reaction was applied to L-proline ethyl ester (R = H), and two diastere-omers were isolated, each diastereomer being a mixture of stereoisomers (E/Z) related to the oximino group. Attempts to completely separate these isomers failed. The oximino group of the product (462a) was removed by a CH2O/HCI mixture. As a result, hydrated aldehyde hydrochloride (463a) was obtained. It... 

The reaction of the aldehyde 256 with proline gave a product which was not the expected dihydiodibenz[r,f ]azepinc 257. Spectroscopic analysis revealed that this new product was an oxazolidine 259 (obtained as a single isomer) resulting from the 1,3-cycloaddition of the azomethine ylide 258 to the precursor aldehyde 256 (Scheme 38) <1999J(P1)2605>. 

Reactions of the sulfonylsulfines 56 (e.g. R1 = R2 = Bn R1 — Me, R2 — Ph R1 — CPh3, R2 = ph etc.) derived from (S)-proline with 2,3-dimethyl-l,3-butadiene afford dihy-drothiopyran S-oxides 57 with asymmetric induction of up to 40% (equation 38)34. Methyl cyanodithioformate 58 is a very reactive dienophile with cyclopentadiene it forms a mixture of 40 parts of the endo-adduct 59 and 60 parts of the exo-isomer 60 (equation 39)35. 

Isomer shift data, Fe,S4 clusters, 38 20, 50 Isomorphic substitution, 39 179, 186 p-Isonicotinamide complexes, osmium, 37 307 p-lsonicotinamidepoly(proline) complexes, osmium, 37 307 Isonitrile complexes osmium, 37 245 technetium(I), 41 13-14 technetium(II), 41 31 technetium(IIl), 41 45 Isopolymolybdates, 19 239ff 19 265-280 crystallization from aqueous solution, 19 265-269... 

Conformational results on proline analogs have also been reported. N-Acetyl-2,3-dehydroproline (91) shows an equilibrium of the two conformers in almost equimolecular amounts (82MI3). The equilibrium is shifted by different acidic conditions, while the energy barrier for rotation around the amide bond ( 63 kJ mol" ) is lower than in proline, owing to the presence of the unsaturated bond. Only the s-trans isomer was observed (82M13) in the case of N-acetyl-5-oxo-L-proline (92), and apparently no effect is found on changing the pH of the solution. 

In one synthesis of this drug, L-proline (11-2) is acylated with the acid chloride (11-1) obtained from the addition of hydrogen chloride to the double bond in methacrylic acid followed by reaction with thionyl chloride to give amide (11-3) as a mixture of diastereomers. The pure 2S isomer is then isolated from the mixture by fractionation as the dicyclohexylamine salt. Treatment of that compound with ammonium hydrosulfide leads to the displacement of chlorine by a thiol group and the formation of captopril (11-4) [13]. 

This approach requires no additional synthetic steps for catalyst modification and overcomes proline s main shortcomings of moderate yield and enantioselectivity. In some cases, an even better combination of yield and enantioselectivity could be achieved using just 0.5 mol% of (R)-BINOL, but in general both isomers of BINOL were almost equally effective. However BINOL is unlikely to be readily biodegradable, biorenewable/biodegradable alternatives could further improve the environmental profile of this co-catalytic process. Although the cocatalyst loading of just... 

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