1228577-03-4Relevant articles and documents
Synthesis of Fmoc-protected trans-4-methylproline
Nevalainen,Kauppinen,Koskinen
, p. 2061 - 2066 (2001)
Fmoc-protected trans-4-methylproline was synthesized starting from D-serine. The chiral scaffold of serine in the form of olefinated Garner's aldehyde 3 was used to control the diastereoselective formation of the new stereocenter on the hydrogenation of allylic alcohol 4. The diastereoselectivity (syn/anti ratio) of the process was 86:14, attained with Raney nickel. Hydrogen migration seems not to be the sole factor lowering the diastereoselectivity, as nickel is known not to promote doublebond migration. Instead, the moderate stereocontrol is attributed to the mobility of the side chain of 4, which allows the attack of hydrogen on both faces of the olefin (open transition state). A series of transformations led to ring precursor 8, which after recrystallization afforded the syn diastereoisomer in dr = 95:5. Protected trans-4-methylproline 11 was obtained from 8 in a straightforward fashion.
A one-pot chemoenzymatic synthesis of (2S, 4R)-4-methylproline enables the first total synthesis of antiviral lipopeptide cavinafungin B
Zwick, Christian R.,Renata, Hans
, p. 6469 - 6473 (2018)
We report an efficient ten-step (longest linear sequence) synthesis of antiviral natural product cavinafungin B in 37% overall yield. By leveraging a one-pot chemoenzymatic synthesis of (2S,4R)-4-methylproline and oxazolidine-tethered (AT (Boc)G-Rink resin) SPPS methodology, the assembly of our molecular target could be conducted in an efficient manner. This general strategy could prove amenable to the construction of other natural and unnatural linear lipopeptides. The value of incorporating biocatalytic steps in complex molecule synthesis is highlighted by this work.
Total Synthesis of Malacidin A by β-Hydroxyaspartic Acid Ligation-Mediated Cyclization and Absolute Structure Establishment
Brady, Sean F.,Chen, Sheng,Forelli, Nicholas,Li, Xuechen,Po, Kathy Hiu Laam,Shang, Zhuo,Sun, Zhenquan
supporting information, p. 19868 - 19872 (2020/09/02)
The development of novel antibiotics is critical to combating the growing emergence of drug-resistant pathogens. Malacidin A is a new member of the calcium-dependent antibiotic (CDAs) family with activity against antibiotic-resistant pathogens. Its mode of action is distinct from classical CDAs. However, the absolute structure of malacidin A has not been established. Herein, the total syntheses of malacidin A and its analogues are reported by a combination of Fmoc-based solid-phase peptide synthesis (SPPS) and β-hydroxyaspartic acid ligation-mediated peptide cyclization. The total synthesis enabled us to establish the absolute configuration of malacidin A, which is in agreement with those for natural malacidin A confirmed by advanced Marfey's analysis in our study.
A lanthanide(III) triflate mediated macrolactonization/solid-phase synthesis approach for depsipeptide synthesis
Goodreid, Jordan D.,Dos Santos Da Silveira, Eduardo,Batey, Robert A.
supporting information, p. 2182 - 2185 (2015/05/13)
The effect of dysprosium(III) triflate on macrolactonization reactions to form depsipeptides using MNBA (Shiina's reagent) is reported. Improved yields were obtained for the formation of 16-membered depsipeptides using lanthanide triflate additives. The use of a macrocyclization strategy permits the use of a semiautomated solid-phase synthesis approach for the rapid synthesis of analogues of the antibacterial A54556 acyldepsipeptides in only two physical operations, requiring only final product purification after cyclization.
Conformational ensembles of flexible β-turn mimetics in DMSO-d 6
Koivisto, Jari J.,Kumpulainen, Esa T. T.,Koskinen, Ari M. P.
supporting information; experimental part, p. 2103 - 2116 (2010/07/04)
β-Turns play an important role in peptide and protein chemistry, biophysics, and bioinformatics. The aim of this research was to study short linear peptides that have a high propensity to form β-turn structures in solution. In particular, we examined conformational ensembles of β-turn forming peptides with a general sequence CBz-L-Ala-L-Xaa-Gly-L-Ala-OtBu. These tetrapeptides, APGA, A(4R)MePGA, and A(4S)MePGA, incorporate proline, (4R)-methylproline, and (4S)-methylproline, respectively, at the Xaa position. To determine the influence of the 4-methyl substituted prolines on the β-turn populations, the NAMFIS (NMR analysis of molecular flexibility in solution) deconvolution analysis for these three peptides were performed in DMSO-d6 solution. The NBO (natural bond orbital) method was employed to gain further insight into the results obtained from the NAMFIS analysis. The emphasis in the NBO analysis was to characterize remote intramolecular interactions that could influence the backbone-backbone interactions contributing to β-turn stability. NAMFIS results indicate that the enantiospecific incorporation of the methyl substituent at the C γ (C4) position of the proline residue can be used to selectively control the pyrrolidine ring puckering propensities and, consequently, the preferred ,ψ angles associated with the proline residue in β-turn forming peptides. The NAMFIS analyses show that the presence of (4S)-methylproline in A(4S)MePGA considerably increased the type II β-turn population with respect to APGA and A(4R)MePGA. The NBO calculations suggest that this observation can be rationalized based on an n→π* interaction between the N-terminus alanine carbonyl oxygen and the proline carbonyl group. Several other interactions between remote orbitals in these peptides provide a more detailed explanation for the observed population distributions.
Collagen mimics
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Page/Page column 5; sheet 3, (2008/06/13)
Novel collagen mimics are disclosed with a tripeptide unit having the formula (Xaa-Yaa-Gly)n, where one of the positions Xaa or Yaa is a bulky, non-electron withdrawing proline derivative. By substituting a proline derivative at either the Xaa or Yaa position in the native collagen helix, the stability of the helix is increased due solely to steric effects relative to prior known collagen-related triple helices. Methods are also disclosed for making the novel collagen mimics.
Reciprocity of steric and stereoelectronic effects in the collagen triple helix
Shoulders, Matthew D.,Hodges, Jonathan A.,Raines, Ronald T.
, p. 8112 - 8113 (2007/10/03)
In previous work, we demonstrated that 4-fluoroproline residues can contribute greatly to the conformational stability of the collagen triple helix, and that this stability arises from stereoelectronic effects that fix the pucker of the pyrrolidine ring and thereby preorganize the backbone properly for triple-helix formation. Here, we take a reciprocal approach, demonstrating that the steric effect of a 4-methyl group confers stability similar to that from a 4-fluoro group in the opposite configuration. Such fundamental interplay between steric and stereoelectronic effects is heretofore unknown in proteinsnatural or syntheticand provides a new means to modulate conformational stability. Copyright
Total synthesis, NMR solution structure, and binding model of the potent histone deacetylase inhibitor FR235222
Rodriquez, Manuela,Terracciano, Stefania,Cini, Elena,Settembrini, Giulia,Bruno, Ines,Bifulco, Giuseppe,Taddei, Maurizio,Gomez-Paloma, Luigi
, p. 423 - 427 (2007/10/03)
An alternative route: The fungal metabolite FR235222, a potent inhibitor of mammalian histone deacetylase (HDAC), has been synthesized. Key steps are the preparation of unusual amino acids Ahoda and (2R,4S)-MePro. A 3D model for cyclopeptide inhibitor int
