N- -proline

Fig. 6. Reduced viscosity (C = 1%) of poly-n-proline at SCO as a function of [a]". —, data taken during forward mutarotation in glacial acetic acid A—Ai data taken during forward mutarotation in acetic acid-water (7 3 v/v) O—O, data taken during reverse mutarotation in acetic acid- -propanol (1 9 v/v) A, value in aqueous 12 M LiBr. (Prom Steinberg et al., 1960b. Reproduced with kind permission of the American Chemical Society.)...

An initial configurational change takes place in the pyrrolidine-rich portions of the gelatin chains, which nucleates the poly-n-proline H-type helix. This step goes to completion rapidly and is detected by the change from simple to complex collagenase kinetics. 

Bahmanyar, S., Houk, K. N. Proline-catalyzed direct asymmetric aldol reactions. Catalytic asymmetric synthesis of anti-1,2-diols. Chemtracts 2000,13, 904-911. 

It is well known that catalytic amounts of aldehyde can induce racemization of a-amino acids through the reversible formation of Schiff bases [571. Combination of this technology with a classic resolution leads to an elegant asymmetric transformation of L-proline to n-proline (Scheme 8) [58,59]. When i.-proline is heated with one equivalent of o-tartaric acid and a catalytic amount of -butyral-dehyde in butyric acid, it first racemizes due to the reversible formation of the proline-butyraldehyde Schiff base. The newly generated o-prolinc fonns an insoluble salt with D-tartaric acid and precipitates out of the solution, while the soluble L-proline is continuously being racemized. The net effect is the continuous transformation of the soluble L-proline to the insoluble D-proline-n-tartaric acid complex, resulting in near complete conversion. Treatment of the n-proline-D-tartaric acid complex with concentrated ammonia in methanol liberates the d-proline (16) (99% ee, with 80-90% overall yield from L-proline). This is a typical example of a dynamic resolution in which L-proline is completely converted to D-proline with simultaneous in situ racemization. As far as the process is concerned, this is an ideal case because no extra step is required for recycle and racemization of the undesired enantiomer, and a 100% chemical yield is achievable. The only drawback of this process is tlie use of stoichiometric amount of... 

NMR spectrum of the dragline silk of the C/ N-proline-enriched Argiope aurantia spider, which is rich in MaSp2. However, extensive spectral overlap between Pro and other amino acids, with the exception of the Pro C(x, compromises the extraction of exact chemical shift values. Hence, 13c 13c correlation NMR with a medium 50 ms DARR recoupling period was utilized to exploit the connectivity within the Pro residue to yield precise chemical shifts. A chemical shift difference of 5.1 ppm was found, which was indicative of a type II P-tum structure. This structural assignment was further confirmed by using HETCOR experi-... 

A salient feature of the SAMP and RAMP hydrazone auxiliaries is their ready availability. SAMP (150) can be synthesized from L-proline (163), either in four steps via a nitroso intermediate or more conveniently by Hoffmann degradation (165 150, Scheme 3.26) [96]. Its enantiomer, RAMP, can likewise be obtained from n-proline or alternatively, in six steps and 35 % overall yield from the cheaper starting material (R)-glutamic acid (166) [93]. 

Progress has been made toward enantioselective and highly regioselective Michael type alkylations of 2-cyclohexen-l -one using alkylcuprates with chiral auxiliary ligands, e. g., anions of either enantiomer of N-[2-(dimethylamino)ethyl]ephedrine (E. J. Corey, 1986), of (S)-2-(methoxymethyl)pyrrolidine (from L-proline R. K. EHeter, 1987) or of chiramt (= (R,R)-N-(l-phenylethyl)-7-[(l-phenylethyl)iinino]-l,3,5-cycloheptatrien-l-amine, a chiral aminotro-ponimine G. M. Villacorta, 1988). Enantioselectivities of up to 95% have been reported. 

L-tyrosine D-tyrosine DL-tyrosine Heterogclic proline [60-18 ] [556-02-5] [556-03-6] [7005-20-1 ] Pro 2-pyrrobdine-carboxyb c acid N COOH 115.13... 

Fig. 10. Sequences (see Table 1) of betabeUins. In each case, only one-half of the P-sandwich is shown. The dimer is formed from identical monomeric sets of four P-strands. In the pattern sequence, e is for end, p is for polar residue, n is for nonpolar residue, and t and r are for turn residues. Lower case f is iodophenyialanine lower case a, d, k, and p are the D-amino acid forms of alanine, aspartic acid, lysine, and proline, respectively B is P-alanine (2,53,60,61).

Alkyldithio carbamates are prepared from the acid chloride (Et N, EtOAc, 0°) and amino acid, either free or as the O-silyl derivatives (70-88% yield). The N- i-propyldithio) carbamate has been used in the protection of proline during peptide synthesis. Alkyldithio carbamates can be cleaved with thiols, NaOH, Ph P/TsOH. They are stable to acid. Cleavage rates are a function of the size of the alkyl group as illustrated in the table below. 

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.

Figure 6.9 (a) Peptide units can adopt two different conformations, trans and cis. In the trans-form the C=0 and the N-H groups point in opposite directions whereas in the c/s-form they point in the same direction. For most peptides the trans-form is about 1000 times more stable than the c/s-form. (b) When the second residue in a peptide is proline the trans-form is only about four times more stable than the c/s-form. C/s-proline peptides are found in many proteins. 

The nonpolar amino acids (Figure 4.3a) include all those with alkyl chain R groups (alanine, valine, leucine, and isoleucine), as well as proline (with its unusual cyclic structure), methionine (one of the two sulfur-containing amino acids), and two aromatic amino acids, phenylalanine and tryptophan. Tryptophan is sometimes considered a borderline member of this group because it can interact favorably with water via the N-H moiety of the indole ring. Proline, strictly speaking, is not an amino acid but rather an a-imino acid. 

The tendencies of the amino acids to stabilize or destabilize a-helices are different in typical proteins than in polyamino acids. The occurrence of the common amino acids in helices is summarized in Table 6.1. Notably, proline (and hydroxyproline) act as helix breakers due to their unique structure, which fixes the value of the —N—C bond angle. Helices can be formed from either... 

This group was developed for the protection of amino acids. It is formed from 4-ethoxy-l,l,l-trifluoro-3-buten-2-one in aqueous sodium hydroxide (70-94% yield). Primary amino acids form the Z-enamines, whereas secondary amines such as proline form the -enamines. Deprotection is achieved with 1-6 N aqueous HCl in dioxane at rt. ... 

Spirapril (37) is a clinically active antihypertensive agent closely related structurally and mechanistically to enalapril. Various syntheses are reported with the synthesis of the substituted proline portion being the key to the methods. This is prepared fkim l-carbobenzyloxy-4-oxopro-line methyl ester (33) by reaction with ethanedithiol and catalytic tosic acid. The product (34) is deprotected with 20% HBr to methyl l,4-dithia-7-azospiro[4.4 nonane-8-carboxylate (35), Condensation of this with N-carbobenzyloxy-L-alanyl-N-hydroxysuccinate leads to the dipeptide ester which is deblocked to 36 by hydrolysis with NaOH and then treatment with 20% HBr. The conclusion of the synthesis of spirapril (37) follows with the standard reductive alkylation [11]. 

The first step is the manufacture of L-proline tert-butyl ester. L-proline (230 g) is dissolved in a mixture of water (1 ) and 5N sodium hydroxide (400 ml). The solution is chilled in an ice bath, and under vigorous stirring, 5 N sodium hydroxide (460 ml) and benzyloxycarbonyl chloride (340 ml) are added in five equal aliquots during a half-hour period. After one hour stirring at room temperature, the mixture is extracted twice with ether and acidified with concentrated hydrochloric acid. The precipitate Is filtered and dried. Yield is 442 g MP 78°C to 80°C. 

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