Proline analog

Fluorous Synthesis of Biaryl-Subshtuted Proline Analogs. 112... 

Fluorous Synthesis of Biaryl-Substituted Proline Analogs... 

Fig. 30 Microwave-promoted fluorous synthesis of biaryl-subshtuted proline analogs. Reagents and condihons a EtaN, DMF, MW 150 °C, 15 min, 40-75%, closed vials b R""PhB(OH)2, Pd(dppf)Cl2, K3PO4, toluene Acetone H2O, MW 120 °C, 12 min, sealed vial system, 19-79%. R=Me, Et R = Me, 1 - Pr R" = H, 3-MeO R" =Me, Et R""= 4-MeO, 3-Cl, 4-Ac,3,4-diCl,3,4-methylenedioxy...

Proline analogs, biaryl-substituted, fluorous synthesis 112 PS-anthracene, dienophiles 151 PS-carbodiimide 136 Pimine C-2, nucleophilic displacement 119... 

Proline analogs can carbamates. be obtained by cyclization of 8-hydroxyalkylamino acid... 

The optically active //-amino alcohol (1 / . 3 R. 5 / )-3-(di phenyl hydroxymethyl )-2-azabicyclo[3.3.0]octane [(li ,3i ,5i )-121], can be derived from a bicyclic proline analog. It catalyzes the enantioselective addition of diethylzinc to various aldehydes. Under mild conditions, the resulting chiral secondary alcohols are obtained in optical yields up to 100%. The bicyclic catalyst gives much better results than the corresponding (S )-proline derivative (S )-122 (Scheme 2-47).114... 

List/Barbas III (2000) proline and proline analogs iminuim Cataiysis... 

Proline analogs can be obtained by cylization of <5-hydroxyalkylamino acid carbamates. 

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. 

A study of a Philippines Dysidea sp. has yielded the novel proline analogs of dysidenin, dysideaprolines A-F (950-955) and barbaleucamides A (956) and B (957), which are reminiscent of barbamide (995). Also from the Philippines was isolated the novel pyrrolidone 958 from the nudibranch Asteronotus cespitosus (996), which is the first example of a Dysidea-type polychlorinated metabolite found in a carnivorous mollusc. An Indonesian collection of Dysidea sp. has furnished dysithiazolamide (959), having the suggested absolute configuration shown (997). 

The preparation of chiral, non-racemic pyrrolidines from enantiomerically-enriched vinyl epoxides has been reported <02SL731, 02JOC7774> (Scheme 14). In like fashion, the addition of allylamine to the enantiomerically-enriched epoxide 22 gives diol 23 which can be transformed into the proline analog 24 by a sequence of steps including RCM <02JOC6896>. 

Proline analogs, (2S,4R)-4-methylproline (/ra .s-4-methyl-l-proline) and (2S, 4S)-4-methylproline (ris-4-methyl-l-proline), derive from reduction of their corresponding cyclic Schiff bases (F22) (Fig. 3). 

Sunoj also predicted the enantioselectivity offered by a series of bicyclic proline analogs in the aldol reaction of acetone with p-nitrobenzaldehyde. The two best performing catalysts are 59 and 60 both are predicted to give an ee greater than 90 percent, which exceeds the selectivity afforded by proline itself. The TS geometries all display the Houk-List characteristics. 

Manfre, F., Kern, J.-M., and Bielhnan, J.-F. 1992. Syntheses of proline analogs as potential mechanism-based inhibitors of proline dehydrogenase 4-methylene-1-, (e)- and (z)-4-(fluoromethylene)-l-, cis- and fraf s-5-ethynyl-( )-, and cis- and fraf s-5-vinyl-l-proline. J Org Chem 57, 2060-2065. 

Synthesis of Unnatural (S)-Proline Derivatives. The condensation of pivaladehyde with (S)-proline yields stereoselec-tively, after lithiation and reaction with an electrophile, the hi-cyclic compound (28), which is a versatile educt for the synthesis of many a-suhstituted proline analogs (29) (eq 12). The reactions proceed via the formation of a chiral lithium enolate without the use of a chiral auxiliary (self-reproduction of chirality). The reaction with a variety of electrophiles cis to the t-Bu group yields a plethora of a-substituted (5)-proline derivatives (29). A limitation of this strategy is the acetal cleavage of some substituted products (28). ... 

Extensive mapping of the conformational surface of c[Pro-pro-Pro-pro] with DFT calculations by Che and Marshall (124) showed that a set of eight distinct amide-bond conformers and their interconversions (Fig. 9) based on the number and location of cis- or tmns-amide bonds tttt, or all trans cccc, or all cis tctc ctct, tccc, cttt, ttcc, and cctt) were accessible. Individual conformers could be selectively stabilized by use of azaproline in which the alpha carbon of proline was replaced by nitrogen and other proline analogs. 

Among other proline analogs such as 13-17 shown in Fig. 11.4, NMR analysis of the N-acetyl derivatives of 13-16 in neutral solutions did not reveal any significant difference in the trans/cis ratio compared with N-acetyl-proline except for 5-oxo-proline (15) which exhibits an exclusive trans-amide conformation [63]. However, when replacing proline in Ala-Pro-pNA with Aze (13) and Pip (14) the cis-amide content was 20% and 13%, respectively, compared with 6% for the Pro-peptide. Rates of CTI were accelerated 14.5- and 49-fold relative to the Pro-peptide [64]. 

The different propensities of the alkylated proline analogs Tbp and Dmp for the cis conformation were recently exploited to modulate the activation of 5-hydroxy-tryptamine type 3 receptor upon site-specific incorporation of these residues at the place of a critical proline residue. A direct comparison of Pro, Pip, Aze, Tbp, and Dmp at a defined position of the loop between the second and third transmembrane helices allowed to correlate directly the intrinsic ds-to-trans energy gap of these residues with the activation of the channel [81]. 

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