Glycine → L-Phenylalanine, methyl ester

HRID 1048859Notes

Reaction equation

HRID 1048859 reaction equation
[NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].N[C@H:10]([C:18](O)=O)[CH2:11][C:12]1C=CC=C[CH:13]=1.N[C@H:22]([C:31](O)=O)[CH2:23][C:24]1C=CC(O)=C[CH:25]=1.N[C@H:35]([C:37](O)=O)[CH3:36].N[CH2:41]C(O)=O.N[C@H](C(O)=O)CC[S:49]C.N[C@H](C(O)=O)CC1C2C(=CC=CC=2)NC=1.[NH:69]([C:87]([O:89][CH2:90][C:91]1[CH:96]=[CH:95][CH:94]=[CH:93][CH:92]=1)=[O:88])[CH2:70][C:71]([NH:73][C@H:74]([C:83]([O:85]C)=O)CC1C=CC(O)=CC=1)=[O:72]>>[NH:69]([C:87]([O:89][CH2:90][C:91]1[CH:92]=[CH:93][CH:94]=[CH:95][CH:96]=1)=[O:88])[CH2:70][C:71]([NH:1][C@H:2]([C:6]([O:8][CH3:22])=[O:7])[CH2:3][C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:18]=1)=[O:72].[NH:73]([C:71]([O:8][CH2:6][C:2]1[CH:3]=[CH:5][CH:37]=[CH:35][CH:36]=1)=[O:72])[CH2:74][C:83]([SH:49])=[O:85].[NH2:1][C@H:2]([C:6]([O:8][CH3:41])=[O:7])[CH2:3][C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:31]=1

Participants

11

Reactant 8

HCID 750GlycineHCID 5950L-AlanineHCID 6057L-TyrosineHCID 6137L-MethionineHCID 6140L-PhenylalanineHCID 6287L-Valine2×HCID 6305L-TryptophanHCID 15838975HCID 15838975, compound

Product 3

HCID 736234L-Phenylalanine, methyl esterHCID 11523571HCID 11523571, compoundHCID 71350322{[(Benzyloxy)carbonyl]amino}ethanethioic S-acid

Procedure

Peptide bond formation was also easily accomplished using the silylative activation of N-protected α-amino thiol acids (FIG. 5). The peptidic thiol acids were generated from the corresponding 9-fluorenylmethyl thiol esters by the method of Crich et al., Org. Lett. 2007, 9, 4423-4426, hereby incorporated by reference in entirety, and used without further purification. As shown in FIG. 5, Gly, Met, Phe, Glu, and Pro thiol acid residues reacted smoothly to give the corresponding dipeptides (entries 1-9). It is noteworthy that sterically hindered α-amino thiol acids like Val (entries 10 and 11) and even 2-aminoisobutyric thiol acid (entry 12) are effectively coupled using this method, although longer reaction times were required to achieve acceptable yields. The amino acids, Phe, Tyr, Val, Ala, Gly, Met, Trp and Pro were all equally effective as N-terminal coupling partners (entries 1-15). The formation of Cbz-Gly-L-Tyr-OMe indicates that phenolic residues do not interfere with the coupling reaction (entry 2). Cbz-Gly-L-Phe-OMe, which is formed as a single dipeptide in 78% yield from Cbz-Gly-SH and L-Phe-OMe under the general coupling conditions (entry 1), is generated in almost an identical isolated yield (71%) when an equimolar amount of Cbz-L-Arg-OH is added to the reaction mixture. This simple experiment confirms the compatibility of this method with both carboxylic acid and guanidine functionalities.

Workup

  1. customalthough longer reaction times
  2. customdo not interfere with the coupling reaction (entry 2)

Sources & evidence

ORD record
ord-b84fcead0fde4f0a8a957cd6db8577e2
Source dataset
uspto-grants-2016_07
Patent number
US09382193B2

Reaction notes

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