Protected lactam-bridged dipeptides for use as conformational constraints in peptides

Freidinger, Roger; Perlow, Debra S.; Veber, Daniel F.

doi:10.1021/jo00340a023

Cited by 223 publications

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“…[8] Along with this trend, oligomers containing periodic b-org-turn dipeptide mimetics have been shown to retain the intrinsic conformational properties of their monomeric units within the oligomer, thus displaying regular secondary structures. [6] Herein, we propose as trategy to generate novel folded architectures based on a-amino-g-lactam derivatives (Agl-AA x with AA x = amino acid), so-called Freidingers lactams, [9,10] widely used as type II b-turn inducers in relevant bioactive peptides. [11] This strategy has several advantages.…”

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confidence: 99%

Turning Peptide Sequences into Ribbon Foldamers by a Straightforward Multicyclization Reaction

et al. 2015

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The conformational control of molecular scaffolds allows the display of functional groups in defined spatial arrangement. This is of considerable interest for developing fundamental and applied systems in both the fields of biology and material sciences. Peptides afford a large diversity of functional groups, and peptide synthetic routes are very attractive and accessible. However, most short peptides do not possess well-defined secondary structures. Herein, we developed a simple strategy for converting peptide sequences into structured γ-lactam-containing oligomers while keeping the amino acids side chain diversity. We showed the propensity of these molecules to adopt ribbon-like secondary structures. The periodic distribution of the functional groups on both sides of the ribbon plane is encoded by the initial peptide sequence.

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Turning Peptide Sequences into Ribbon Foldamers by a Straightforward Multicyclization Reaction

et al. 2015

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“…The disappearance of 14 was monitored by TLC. The next day saturated NH 4 Cl solution (20 mL) was added and the solution color turned dark brown. The reaction mixture was concentrated under vacuum and the residue partitioned between brine and CH 2 Cl 2 (150 mL).…”

Section: General Procedures For Templates 2 and 3 3-[1-(4-methyl-26mentioning

confidence: 99%

“…The reaction was stirred at −78 °C for 30 min before the addition of allyl bromide (0.17 mL, 2 mmol). The next day 5 mL of saturated NH 4 Cl solution was added and the mixture extracted with CH 2 Cl 2 (2 × 25 mL). The organic layers were combined, dried over MgSO 4 and then concentrated under vacuum to give an oily residue.…”

Section: General Procedures For Alkylation Of Template 2 and 3 3-[3(rmentioning

confidence: 99%

Short Stereoselective Synthesis of α-Substituted γ-Lactams

Raghavan

Johnson

2006

J. Org. Chem.

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A concise, stereoselective synthesis of α-substituted γ-lactams is reported. γ-Lactam scaffolds 2 and 3 possessing an Evans' chiral auxiliary and two types of N-substituents were successfully alkylated with different electrophiles to give α-substituted γ-lactams with reasonable diastereoselectivities. The use of a masked carboxymethyl function off the lactam nitrogen provided a convergent means to α-substituted γ-lactam dipeptide isosteres.γ-Lactams, with their ψ angle constrained, are important constituents of β-turn peptidomimetics. Our ongoing research on the synthesis of unsubstituted 1,2 and substituted 3 γ-lactam peptide isosteres as Pro-Leu-Gly-NH 2 (PLG) mimics led us to reinvestigate the existing synthetic methodologies to this scaffold. Over the years, several approaches have been used for the synthesis of peptidomimetics containing lactam scaffolds. One method of obtaining the lactam is through a route established by Freidinger et al 4 , involving the formation of a sulfonium salt followed by subsequent intramolecular cyclization. Other widely used approaches are reductive amination followed by thermal cyclization 5 and an intramolecular Mitsunobu reaction. 6 For α-substituted γ-lactams, the stereoselective synthesis of α,α-dialkyl amino acids has to be achieved prior to their incorporation into the lactam by the above methods. 5,7,8 In short, the current methods for the synthesis of α-substituted γ-lactams are linear in their approach. Thus, there is a need for a more efficient and versatile approach for such syntheses.AUTHOR EMAIL ADDRESS johns022@umn.edu. SUPPORTING INFORMATION. Experimental procedures and spectral data for 2, 5, 7, 8, 11−13, and 15−18. X-ray structure data (ORTEP diagrams and CIF files) for 7a and 15a. This material is available free of charge via the Internet at http://pubs.acs.org. Recently, Palomo et al. 9 constructed α-substituted β-lactams in a stereoselective manner with template 1. We felt that such an approach could be adapted to the more commonly used γ-lactam scaffold, thereby providing a method for the stereoselective synthesis of highly desirable α-substituted γ-lactams. Such a method would greatly enhance the utility of the γ-lactam scaffold in peptidomimetic design. Since the synthetic approach used for template 1 was not deemed applicable for the γ-lactam system, compounds 2 and 3 were designed to serve as potential templates for the stereoselective synthesis of α-alkylated γ-lactams. NIH Public AccessIn 2, the 4-methoxy-benzyl moiety was incorporated as the lactam N-substituent in our initial studies because of its ready availability and its ease of removal. We recognized, however, that template 2 suffered from the same drawback as template 1 in that in order for both lactam templates to serve as useful synthetic dipeptide isosteres, the lactam N-substituent first needed to be removed and the lactam then N-alkylated with a suitable carboxymethyl derivative. We felt that the versatility of a template like 2 could be enhanced if the N-substituent was a masked...

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“…Replacement or modification of the peptide backbone function can lead to enzymatically resistant biologically active analogs. Among the factors contributing to altered chemical and biochemical parameters are changes in electronic properties, differences in solubility characteristics, resistance to proteolytic processes, and, perhaps most important, conformational restrictions and changes that can modify receptor recognition (Spatola, 1983).In particular, we have recently undertaken the synthesis of a series of conformationally constrained analogs of the neuroactive tripeptide H-L-Pro-L-LeuGIy-NH 2 (Johnson, Yu, Taraporewala, Mishra & Rajakumar, 1985;Yu, Rajakumar, Srivastava, Mishra & Johnson, 1988) in which the y-and fi-lactam residues developed by Freidinger, Perlow & Veber (1982)have replaced either the leucyl or glycinamide residues. These compounds were synthesized in an attempt to determine whether the trans amide bond and the fl-bend 0108-2701/89/020215-04503.00…”

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confidence: 99%

“…In particular, we have recently undertaken the synthesis of a series of conformationally constrained analogs of the neuroactive tripeptide H-L-Pro-L-LeuGIy-NH 2 (Johnson, Yu, Taraporewala, Mishra & Rajakumar, 1985;Yu, Rajakumar, Srivastava, Mishra & Johnson, 1988) in which the y-and fi-lactam residues developed by Freidinger, Perlow & Veber (1982)have replaced either the leucyl or glycinamide residues. These compounds were synthesized in an attempt to determine whether the trans amide bond and the fl-bend 0108-2701/89/020215-04503.00…”

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confidence: 99%

Structure of (3S)-3-tert-butyloxycarbonylamino-2-piperidone

Valle¹,

Crisma²,

Toniolo³

et al. 1989

Acta Crystallogr C

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Abstract. CIoHIaN203, monoclinic, P2 l, a= 15.515(2), b=6.730(1), c= 12.541(2)A, fl= 113.6 (2) °, V = 1200.0/1,3, Z = 4, D x = 1.186 gcm -3, ,t(Mo Ka) = 0.71069 A, g = 0.54 cm -~, F(000) = 464, T= 295 K. The final R value for 1611 observed (3139 unique) reflections is 0.055. In both the independent molecules A and B of the asymmetric unit of the title compound, the conformation of the urethane moiety is trans. The lactam group of molecule A is non-planar, the C(9)-N(2)-C(10)-C(6) torsion angle being 12.4 (14) °. One main difference between molecules A and B is in the value of the ¢[C(5)-N(1)-C(6)-C(10)] torsion angle [52.3(11) ° for molecule A while -86.5 (10) ° for molecule B] as a consequence of a rotation of the ring relative to the tert-butyloxycarbonylamino substituent. A second major difference is the 6-1actam ring conformation which is approximate half-chair for molecule A while boat for molecule B.Introduction. Replacement or modification of the peptide backbone function can lead to enzymatically resistant biologically active analogs. Among the factors contributing to altered chemical and biochemical parameters are changes in electronic properties, differences in solubility characteristics, resistance to proteolytic processes, and, perhaps most important, conformational restrictions and changes that can modify receptor recognition (Spatola, 1983).In particular, we have recently undertaken the synthesis of a series of conformationally constrained analogs of the neuroactive tripeptide H-L-Pro-L-LeuGIy-NH 2 (Johnson, Yu, Taraporewala, Mishra & Rajakumar, 1985;Yu, Rajakumar, Srivastava, Mishra & Johnson, 1988) in which the y-and fi-lactam residues developed by Freidinger, Perlow & Veber (1982)have replaced either the leucyl or glycinamide residues. These compounds were synthesized in an attempt to determine whether the trans amide bond and the fl-bend 0108-2701/89/020215-04503.00© 1989 International Union of Crystallography 216 (3S)-3-tert-BUTYLOXYCARBONYLAMINO-2-PIPERIDONE MULTAN80 (Main, Fiske, Hull, Lessinger, Germain, Declercq & Woolfson, 1980) and refined by blockdiagonal least squares (based on /7) with anisotropic thermal parameters for all non-H atoms (w = 1). Some of the H atoms were located on the difference Fourier map but not refined and some were calculated. All calculations were performed with atomic scattering values of Sheldrick (1976). Parameters refined 271; R = 0.055; ratio of maximum least-squares shift to e.s.d, in final refinement cycle 0.8; maximum and minimum height in final difference Fourier synthesis 0.25 and -0.20 e/k-3; S = 0.66. Table 1 gives the final atomic coordinates and equivalent isotropic thermal parameters for the non-H atoms.* at the -Leu-Gly-sequence that characterize the crystal structure of H-L-Pro-L-Leu-Gly-NH2 (Reed & Johnson, 1973) are also characteristic of the biologically active conformation of the neuropeptide.Here we describe the structural characterization by X-ray diffraction of (3 S)-3-tert-butyloxycarbonylamino- Experimental.Colorless prismatic cryst...

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Protected lactam-bridged dipeptides for use as conformational constraints in peptides

Cited by 223 publications

References 0 publications

Turning Peptide Sequences into Ribbon Foldamers by a Straightforward Multicyclization Reaction

Turning Peptide Sequences into Ribbon Foldamers by a Straightforward Multicyclization Reaction

Short Stereoselective Synthesis of α-Substituted γ-Lactams

Structure of (3S)-3-tert-butyloxycarbonylamino-2-piperidone

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