Fmoc-leucine

For the synthesis of epopromycin B, precursor 47 was prepared via the addition of (S)-N-Fmoc-leucinal, 46, to HFIPA, 43, at -55 °C (Scheme 5.10) [67]. The reaction afforded, after methanolysis, two diastereoisomers the syn product 49 was obtained in 70% yield and in 99% ee, and the anti isomer 50 was obtained in 2% yield and in 99% ee. It should be noted that the hexafluoroisopropyl group was converted to the corresponding methyl ester in the alcoholysis step. The major syn isomer 49 was transformed to the epoxy end-product 51. 

Lammerhofer and Lindner reported on the enantiomer separation of derivatized amino acids and profens on a weak-anion-exchange(WAX)-type stationary phase based on chiral quinine carbamate selectors by p-CEC [54,55]. The separations were performed either under aqueous or [54] non-aqueous conditions [55]. The efficiency obtained in the p-CEC mode was about two to three time higher than with LC using an acetonitrile/buffer flow system [54], Very high resolutions and efficiencies were found for non-aqueous p-CEC. For example, the enantiomer separation of Fmoc-leucine was achieved in less than 10 min with a resolution Rs of 6.9 at about 100 000... 

DNZ-leucine, DNB-leucine, Fmoc-Leucine Silica based (Kromasil 100-5pm, Hypersil 120-3pm, Micra NPS-1.5pm) weak anion-exchange-type chiral stationary phases Acetonitrile or methanol-100 mA/MES (80 20) 335 mm x 75 or 100 pm i.d. 250 mm effective length, chiral separation... 

S. Hatekayama and co-workers developed a highly enantio- and stereocontrolled route to the key precursor of the novel plant cell Inhibitor epopromycin B, using a cinchona-alkaloid catalyzed Baylis-Hillman reaction of A/-Fmoc leucinal. ... 

The ring in oxadiazolinones 54 (R1 = 3-benzyloxyphenyl, CbzNH-L-leucine, R2 = H, Y = 0) in a reaction with hydrazine hydrate cleaved to afford product 55, which was then used in the syntheses of peptide mimetics <1998JME3923, 1999BMC599>. The reaction of oxadiazolinone 54 (R Fmoc, R2 = H, Y = 0) with primary... 

Hi. Lysine. Gamma radiolysis of aerated aqueous solution of lysine (94) has been shown, as inferred from iodometric measurements, to give rise to hydroperoxides in a similar yield to that observed for valine and leucine. However, attempts to isolate by HPLC the peroxidic derivatives using the post-column derivatization chemiluminescence detection approach were unsuccessful. This was assumed to be due to the instability of the lysine hydroperoxides under the conditions of HPLC analysis. Indirect evidence for the OH-mediated formation of hydroperoxides was provided by the isolation of four hydroxylated derivatives of lysine as 9-fluoromethyl chloroformate (FMOC) derivatives . Interestingly, NaBILj reduction of the irradiated lysine solutions before FMOC derivatization is accompanied by a notable increase in the yields of hydroxylysine isomers. Among the latter oxidized compounds, 3-hydroxy lysine was characterized by extensive H NMR and ESI-MS measurements whereas one diastereomer of 4-hydroxylysine and the two isomeric forms of 5-hydroxylysine were identified by comparison of their HPLC features as FMOC derivatives with those of authentic samples prepared by chemical synthesis. A reasonable mechanism for the formation of the four different hydroxylysines and, therefore, of related hydroperoxides 98-100, involves initial OH-mediated hydrogen abstraction followed by O2 addition to the carbon-centered radicals 95-97 thus formed and subsequent reduction of the resulting peroxyl radicals (equation 55). 

The group of Podlech has reported that trans-substituted (3-lactams (dr 70 30) can be prepared treating an Fmoc-protected leucine-derived diazoketone with a benzylidene-protected glycine ester in a photochemically induced Staudinger-type reaction [173]. Separation of the isomers, deprotection, and attachment of Fmoc-proline using the pentafluorphenyl ester activation protocol yielded the protected peptidomimetic in 93% yield, (Scheme 74). Deprotection and amidation resulted in formation of the /ram-substituted (3-lactam. 

In 2004, Podlech and coworkers have reported some further advances in the photochemical treatment of Fmoc-protected diazoketones A and B, (Scheme 76), derived from leucine and alanine, respectively, with /V-(benzylidene)glycine and leucine methyl ester to produce a mixture of the corresponding diastereomeric trans-substituted p-lactams [175],... 

Leucine oxidized with "OH produces a 5 -hydroperoxy derivative which is subjected to chemical reduction to yield (2S)-y-hydroxyleucine, (2S,4S)-8-hydroxy-leucine, (2S,4R)-8-hydroxyleucine. The S -hydroxyleucines have been confirmed to be the reduction products of the corresponding hydroperoxyleucines. 5 -Hydro-xylysines are natural products formed by lysyl oxidase and therefore are not useful markers of radical-mediated oxidation. The other hydroxylysines are useful markers, however, with HPLC analysis of 9-fluorenylmethyl chloroformate (FMOC)... 

Several alternative procedures have been proposed to address this serious problem, a very simple one being changes in the reaction conditions. In fact, the amount of side product is substantially reduced when a slight excess of amino acid over acylating agent (1.25 equiv) and sodium carbonate (4 equiv) are used with a minimum amount of dioxane and with vigorous stirring at room temperature. This procedure, however, cannot be applied with hydrophobic amino acids such as leucine or vahne.t l Acylation of amino acids with 9-fluorenylmethyl azidoformate (Fmoc-N3, 18, prepared from Fmoc-Cl and pre-... 

CD9 Dansyl-methione, dansyl-phenylalanine, dansyl-alanine, dansyl-leucine, dansyl-norvaline, dansyl-tryptophan, dansyl-glutamic acid, dansyl-aspartic acid, dansyl-threonine, l,l -binaphthyl-2,2 -diylhydrogenphosphate, carvedUol, erythro-mefloquine, clidinum bromide, FMOC-phenylalanine, FMOC-tryptophane, FMOC-alanine, narigin, hespesperetin, neohesperidin, neoeriocitrin 29... 

The reaction of A -Fmoc-L-leudnal (139) with l,l,l>3,3>3-hexafluoroisopropyl acrylate (140) proceeded smoothly in the presence of a stoichiometric amount of cinchona alkaloid 141, even at very low temperature, to give a 6 1 mixture of j yw-ester 142 and dioxane derivative 143 (Scheme 1.62). However, the same reaction with N-Fmoc-o-leucinal (ent-139) turned out to be sluggish and only a mixture of dioxanones 143 was obtained in low yield. Thus, it can be concluded that the (/ )-selectivity of the chiral amine catalyst matches well with L-config-uration of the substrate, leading to high yn-selectivity. ... 

On the basis of this work, Hatakeyama et al. have investigated the p-ICD-catalyzed MBH reaction of chiral iV-Boc-oi-amino aldehydes 140 and HFIPA (Scheme 2.67). The reaction proceeded smoothly without racemization and exhibited the match-mismatch relationship between the substrate and the catalyst, which was similar to that of the synthesis of epopromycin B from iV-Fmoc-L-leucinal with HFIPA. In the case of acyclic amino aldehydes. 

In 2010, de Lera et al. synthesized the heterodimeric diketopiperazine (+)-pestalazine B (658) (416). With this material in hand, they were able to revise the earlier proposed structure 659 for the natural product. These investigators utilized a convergent synthesis strategy, starting with the condensation of L-trypto-phan methyl ester (616) and IV-Fmoc-o-phenylalanine (652), to give diketopiperazine derivative 653 after Fmoc-deprotection (Scheme 10.6). This was reacted with 3a-bromopyrrolidinoindoline 654 (417) to furnish the dimeric product 655. Boc-deprotection ( 656), coupling with iV-Fmoc-o-leucine ( 657), and Fmoc-deprotection finally led to compotmd 658 for which the spectroscopic data matched those of the natural product. 

Scheme 10.6 Total synthesis of (+)-pestalazine B (658) and proposed stmctine 659 for (+)-pestalazine B. Reagents and crmditions a) EDC, CH2O2, it, overnight then Et2NH, MeOH, It, ovOTiight, 68% ovct two steps b) /-BuOK, MeCN, 12°C, 30% c) TMSCl, MeCN, 0°C, 85% d) N-Fmoc-D-leucine, HATU, Et3N, DMF, 0°C to rt then Et2NH, MeOH, it, 57% over two steps...

L-Leucine benzyl ester (1207) was coupled with Boc-o-leucine, which after Boc-deprotection gave dipeptide 1208. This was cruiverted into tripeptide 1209 by condensation with Fmoc-L-vaUne and hydrogenolytic removal of the benzyl ester. Furthermore, another dipeptide 1212 was prepared starting from commercially available Fmoc-D-S-tritylcysteine (1210), which was first cruiverted into its allyl ester, subsequently freed of the Fmtx group (—> 1211), and then coupled with another equivalent of Fmoc-o-S-tritylcysteine (1210), followed by Fmoc deprotection - 1212). Tripeptide 1209 and dipeptide 1212 were afterwards coupled to... 

Table 2.2, entry 4 is a system based on subtilisin and thermolysin [33]. The protease thermolysin acts as the stimulus for assembly, operating to form dipeptide derivatives from Fmoc-threonine and either a leucine or a phenylalanine methyl ester (Figure 2.8c). The dipeptide derivatives formed give rise to self assembled nanofibrous hydrogels. The hydrogel can be dissolved by employing a second enzyme, subtilisin, which cleaves the methyl ester to leave a soluble Fmoc-dipeptide. This system could be used to entrap cells in a network using one enzyme, and release them upon application of the other. 

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