Showing papers by "Padmanabhan Balaram published in 1981"

Asymmetric Total Synthesis of Erythromycin. 1. Synthesis of an Erythronolide A Seco Acid Derivative via Asymmetric Induction

Abstract: 3210-3213 The specific incorporation per C4 unit, 3.3%, calculated from 13C NMR data (Table I), is identical with that obtained from I4C radioactivity measurements. The signals due to the I3C-enriched carbon atoms in the proton decoupled I3C NMR spectrum of labeled retronecine appear as multiplets (Table

Alamethicin, a Transmembrane Channel

Abstract: Peptides possessing antibiotic activity, isolated from microbial sources, have been the subject of intensive structural and biological investigation over the past two decades.

Asymmetric total synthesis of erythromycin. 3. Total synthesis of erythromycin

Abstract: In the preceding paper' we described the preparation of the key lactone intermediate la in optically active form. In this paper we report the synthesis of erythromycin (2) from la. In essence,this transformation involves the glycosidation of a suitable derivative of la with L-cladinose and D-desosamine and the generation of the C-9 ketone functionality.

Asymmetric total synthesis of erythromycin. 2. Synthesis of an erythronolide A lactone system

Abstract: In reporting a total synthesis of erythromycin (la) we described in the preceding paper1 the synthesis of the erythronolide A seco acid derivative 2 in optically active form. In this paper we wish to report a successful transformation of 2 to 12 (synthetically equivalent to erythronolide A) via lactonization and also demonstrate that the proper functionalization of a substrate is critical for the successful lactonization.

Conformations of synthetic alamethicin fragments. Evidence for 310 helical folding from 270-MHz hydrogen-1 nuclear magnetic resonance and circular dichroism studies

Abstract: IH NMR studies at 270 MHz on the synthetic alamethicin fragments Z-Aib-Pro-Aib-Ala-Aib-Ala-OMe (1-6), Boc-Gln-Aib-Val-Aib-Gly-Leu-Aib-OMe (7-1 3), Boc-Leu-Aib-Pro-Val-Aib-OMe (1 2-16), and Boc-Gly-Leu- Aib-Pro-Val-Aib-OMe (1 1-16) have been carried out in CDC13 and (CD3)2S0. The intramolecularly hydrogen bonded amide hydrogens in these peptides have been delineated by using solvent titration experiments and temperature coefficientsof NH chemical shifts in (CD3)+30. All the peptides adopt highly folded structures, characterized by intramolecular 4 - 1 hydrogen bonds. The 1-6 fragment adopts a 310 helical conformation with four hydrogen bonds, in agreement with earlier studies (Rao, Ch. P., Nagaraj, R., Rao, C. N. R., & Balaram, P. (1980) Biochemistry 19, 425-4311. The 7-13

X-Pro Peptides: Solution and Solid-state Conformation of $Benzyloxycarbonyl-{(Aib-Pro)}_2-methyl Ester$, a Type I \beta-Turn

Abstract: The synthesis of the tetrapeptide $benzyloxycarbonyl{(\alpha-aminoisobutyryl-L-prolyl)}_2-methyl ester$ $(Z-{(Aib-Pro)}_2-OMe)$ and an analysis of its conformation in solution and the solid state are reported. Stepwise synthesis using dicyclohexylcarbodiimide leads to racemization at Pro(2). Evidence for the presence of diastereomeric tetrapeptides is obtained from 270-${MHz}^1H-nmr$ and 67.89-MHz 13C-nmr. The all-L tetrapeptide is obtained by fractional crystallization from ethyl acetate. The NH of Aib(3) is shown to be involved in an intramolecular hydrogen bond by variable-temperature 1H-nmr and the solvent dependence of NH chemical shifts. The results are consistent with a \beta-turn conformation with Aib(1) and Pro(2) at the corners stabilized by a 4 \rightarrow 1 hydrogen bond. The molecule crystallizes in the space group ${P2}_12_12_1$, with a = 8.839, b = 14.938, and c = 22.015 A. The structure has been refined to an R value of 0.051. The peptide backbone is all-trans, and a 4 \rightarrow 1 hydrogen bond, between the CO group of the urethane moiety and Aib(3) NH, is observed. Aib(1) and Pro(2) occupy the corner positions of a type I \beta-turn with \phi = -55.4 deg, \psi = -31.3 deg for Aib(1) and \phi = -71.6 deg, \psi = -38 deg for Pro(2). The tertiary amide unit linking Pro(2) and Aib(3) is significantly distorted from planarity (${\Delta}_{\omega}$ = 14.3 deg).

X‐Pro peptides: Synthesis and solution conformation of benzyloxycarbonyl‐(Aib‐Pro)4methyl ester. Evidence for a novel helical structure

Abstract: The synthesis of the octapeptide, benzyloxycarbonyl-(-aminoisobutyryl-L-prolyl)4-methyl ester [Z-(Aib-Pro)4-OMe] and an analysis of its solution conformation is reported. The octapeptide is shown to possess three strong intramolecular hydrogen bonds on the basis of studies of the solvent and temperature dependence of NH chemical shifts and rates of hydrogen-deuterium exchange. 13C studies are consistent with a structure involving only trans Aib-Pro bonds, while ir experiments support a hydrogen-bonded conformation. The Aib 3, 5, and 7 NH groups are shown to participate in hydrogen bonding. A 310 helical conformation compatible with the spectroscopic data is suggested. The proposed conformation consists of three type III -turns with Aib and Pro at the corners and stabilized by 4 1 intramolecular hydrogen bonds.

Membrane channel forming polypeptides. 270-MHz proton magnetic resonance studies of the aggregation of the 11-21 fragment of suzukacillin in organic solvents.

Abstract: 270-MHz 1H NMR studies of the 11-21 suzukacillin fragment Boc-Gln-Aib-Leu-Aib-Gly-Leu-Aib-Val-Aib-Aib-OMe (11-G) and its analogue Boc-Ala-Aib-Leu-Aib-Gly-Leu-Aib-Pro-Val-Aib-Aib-OMe (11-A) have been carried out in $CD{Cl}_3$ and ${({CD}_3)}_2SO$. The NH chemical shifts and their temperature coefficients have been measured as a function of peptide concentration in both solvents. It is established that replacement of Gln by Ala is without effect on backbone conformation. Both peptides adopt highly folded $3_{10}$ helical conformations stabilized by seven intramolecular 4 \rightarrow 1 hydrogen bonds. Nonlinear temperature dependences are demonstrated for free NH groups in the Gln(1) peptide. Aggregation is mediated by intermolecular hydrogen bonds formed by solvent-exposed NH groups. A major role for the Gln side chain in peptide association is suggested by differences in the NMR behavior of the Gln(1) and Ala(1) peptides. For the Gln(1) peptide in $CD{Cl}_3$, the carboxamide side chain carbonyl group forms an intramolecular hydrogen bond to the peptide backbone, while the trans side chain NH shows evidence for intermolecular interactions. In ${({CD}_3)}_2SO$, the cis carboxamide NH is involved in intermolecular hydrogen bonding. The possible role of the central Gln residue in sta-bilizing aggregates of peptide channel formers is discussed, and a model for hexameric association is postulated.

Membrane Channel Forming Polypeptides. 270-MHz Hydrogen-1 Nuclear Magnetic Resonance Studies on the Conformation of the 11-21 Fragment of Suzukacillin

Abstract: 270-MHz 1H NMR studies on the synthetic suzukacillin fragments Boc-Leu-Aib-Gly-Leu-Aib-OMe (13-17), Boc-Gln-Aib-Leu-Aib-Gly-Leu-Aib-OBz (11-17), Boc-Leu-Aib-Gly-Leu-Aib-Pro-Val-Aib-Aib-OMe (13-21), and Boc-Gln-Aib-Leu- Aib-Gly-Leu-Aib-Pro-Val-Aib-Aib-OMe (11-21) have been carried out in $CD{Cl}_3$ and ${({CD}_3)}_2SO$. The intramolecularly hydrogen-bonded amide hydrogens in these peptides have been identified by using solvent titration experiments and temperature coefficients of NH chemical shifts in ${({CD}_3)}_2SO$. The peptides are shown to favor conformations stabilized by intramolecular 4 \rightarrow 1 hydrogen bonds. The 11-21 fragment adopts a highly folded, largely $3_{10}$ helical conformation stabilized by seven intramolecular hydrogen bonds. An eighth NH group [Gly(5)] appears to be involved in a weaker interaction. Evidence for the possible participation of the Gln side-chain carboxamide group in hydrogen bonding to the peptide backbone is also presented.

Temperature dependence of peptide NH chemical shifts in benzene: Delineation of solvent‐shielded and exposed amide protons

Abstract: 1H-nmr is one of the most widely used techniques for the study of intramolecular hydrogen-bonded conformations of peptides in solution. The parameters used to delineate solvent-shielded amide NH groups include rates of hydrogen-deuterium exchange: solvent shifts paramagnetic radical-induced broadening: transfer of saturation from exchangeable solvent protons, and temperature coefficients (d\delta / dT) of NH chemical shifts, in strongly hydrogen-bond-accepting solvents like ${({CD}_3)}_2SO$. Of these, the use of temperature coefficients is probably the most widespread. In general, values 0.004 ppm/deg C have been assigned to exposed groups. The model compound, N-methylacetamide ${CH}_3CONH{CH}_3$ yields a value of 0.006 ppm/deg C in ${({CD}_3)}_2SO$. The large temperature coefficients for exposed NH protons presumably arise by the breaking of solute-solvent hydrogen bonds on increasing the temperature. Peptides dissolved in $CD{Cl}_3$ show low temperature coefficients for both solvent-shielded and exposed amide hydrogens, a reflection of the poor hydrogen-bonding capability of this solvent. We describe in this report the use of temperature coefficients of peptide NH groups in benzene $(C_6D_6)$, as a sensitive parameter for the determination of the degree of solvent exposure.

Internal water bridge and antiparallel sheet in the structure of benzyloxycarbonyl‐l‐alanyl‐d‐phenylalanyl‐l‐proline monohydrate

Abstract: Benzyloxycarbonyl-L-alanyl-o-phenylalanyl-L-proline monohydrate, $C_{25}H_{29}N_3O_6. H_2O$, crystallizes in the orthorhombic space group ${P2}_12_12_1$ with four molecules in a unit cell of dimensions a = 9.594 (9), b = 9.705 (4) and c = 27.9 17 (12) A. The structure has been refined to an R value of 0.067 for 2046 observed reflections. All the peptide units in the molecule are trans and the prolyl residue is in the $C_2-C^{\gamma}-exo-C^{\beta}-endo$ conformation. The lone water molecule in the structure is hydrogen bonded to the carbonyl O atom in the benzyloxycarbonyl group and to one of the O atoms in the terminal carboxyl group. This internal water bridge, observed for the first time in a linear peptide, provides a model for water-mediated chain-reversal. An interesting feature of the crystal structure is the presence of an antiparallel sheet involving the alanyl and the phenyl-alanyl residues.