[Show abstract][Hide abstract] ABSTRACT: A simple and efficient protocol was developed for the synthesis of aryl azides directly from aryl carbinols using ZrCl4 as a Lewis acid catalyst. The azides were converted to novel triazoles under click reaction conditions, which were evaluated for their antimicrobial activity against various strains.
[Show abstract][Hide abstract] ABSTRACT: The present study is aimed at the design and synthesis of peptides with hybrid helix-turn-helix (HTH) motif and their conformational analysis (NMR, MD and CD studies). The requisite peptides with heterogeneous backbones were prepared from β-, γ- and δ-amino acids with carbohydrate side chains, and α-amino acid, L-Ala. The α/β-peptides were prepared from (S)- β-Caa(l) (C-linked carbo-β-amino acid with D-lyxo furanoside side chain) and L-Ala with a 1:1 alternation. The α/β-peptide with 'helix-turn' motif displayed a 11/9-helix nucleating a 13-atom H-bonding turn. The α/β-octapeptides showed the presence of HTH structures with bifurcated 11/15-H-bonded turn. Further, the α/β-hexapeptide with HT motif, independently on coupling with γ-α-γ-α- and δ-α-δ-α-tetrapeptides at the C-terminus provided access to the decapeptides with 'hybrid HTH' motifs. The decapeptide ('α-β-α-β-α-β-γ-α-γ-α') showed a hybrid HTH with '11/9/11/9/11/16/9/12/10' H-bonding, while, the decapeptide ('α-β-α-β-α-β-δ-α-δ-α') revealed the presence of a '11/9/11/9/11/17/9/13/11' helical pattern. The above peptides thus have shown compatibility between different types of helices and serendipitous bifurcated 11/16- and 11/17-turns. The present study thus provided the first opportunity for the design and study of 'hybrid HTH' motifs with more than one kind of helical structures in them.
The Journal of Organic Chemistry 09/2014; · 4.56 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A new three-residue turn in β peptides nucleated by a 12/10-mixed helix is presented. In this design, β peptides were derived from the 1:1 alternation of C-linked carbo-β-amino acid ester [BocNH-(R)-β-Caa(r) -OMe] (Boc=tert-butyloxycarbonyl), which consisted of a D-ribo furanoside side chain, and β-hGly residues. The hexapeptide with (R)-β-Caa(r) at the N terminus showed the 'turn' stabilized by a 14-membered NH(4)⋅⋅⋅CO(6) hydrogen bond at the C terminus nucleated by a robust 12/10-mixed helix, thus providing a 'helix-turn' (HT) motif. The turn and the helix were additionally stabilized by intraresidue electrostatic interaction between the furan oxygen in the carbohydrate side chain and NH in the backbone. However, the hexapeptide with a β-hGly residue at the N terminus demonstrated the presence of a 10/12 helix through its entire length, which again showed the intraresidue interaction between NH and furan oxygen. The intraresidue NH⋅⋅⋅OMe electrostatic interactions observed in the monomer, however, were absent in the peptides.
Chemistry - An Asian Journal 09/2014; · 4.57 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In α-peptides, the 8/10 helix is theoretically predicted to be energetically unstable and has not been experimentally observed so far. Based on our earlier studies on ‘helical induction’ and ‘hybrid helices’, we have adopted the ‘end-capping’ strategy to induce the 8/10 helix in α-peptides by using short α/β-peptides. Thus, α-peptides containing a regular string of α-amino acids with alternating chirality were end capped by α/β-peptides with 11/9-helical motifs at the termini. Extensive NMR spectroscopy studies of these peptides revealed the presence of a hitherto unknown 8/10-helical pattern; the H-bonds in the shorter pseudorings were rather weak. The approach of using short helical motifs to induce new mixed helices in α-peptides could provide avenues for more versatile design strategies.
Chemistry - A European Journal 07/2014; · 5.93 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Formal synthesis of ethisolide and iso-avenaciolide was achieved using furanoid glycal-vinyl radical intermediates. The vinyl radical cyclization by 5-exo-dig mode gave the cis-fused bicyclic systems with an efficient introduction of the exo-methylene group, besides helping in the inversion of the adjacent stereocentre. Further, the study describes the synthesis of cis-fused bicyclic systems from L-arabinose and D-xylose for the creation of diverse natural and synthetic products of this class.
[Show abstract][Hide abstract] ABSTRACT: A convergent synthesis of the protected C(1)-C(23) fragment 4 of the targeted natural product spirastrellolide B is described. The key step of the synthesis is cross metathesis (CM) and TBAF promoted oxa-Michael to construct tetrahydropyran moiety.
[Show abstract][Hide abstract] ABSTRACT: (R,R)- and (S,S)-aminopyrancarboxylic acids (APyCs) were used in the design of mixed β- and α/β-peptides in alternation with β-hGly and L-Ala/D-Ala, respectively. The enantiomeric β- and α/β-tetrapeptides were then coupled in a 1:1 fashion to give octapeptides with 12/10- and 9/11-mixed helices, respectively. The structure of the helices, with their characteristic hydrogen-bonding patterns and an additional stabilizing interaction between peptide-bond NH groups and pyran-ring oxygen atoms, was investigated by NMR spectroscopy, molecular dynamics, and quantum chemical studies. The presence of equal parts of left- and right-handed helices was confirmed by the cancellation of their respective CD patterns. Despite the disruption of the hydrogen bonding in the transition region, the helical conformation was maintained in the octamers. This study demonstrates the possibility of accommodating helices of opposite handedness within the same peptide.
Annalen der Chemie und Pharmacie 06/2014; · 3.10 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: β-Dipeptides containing allyl groups at different positions on the peptide backbone were prepared. Ring-closing metathesis of these β-dipeptides with the use of a ruthenium catalyst led to medium-sized cyclic β-dipeptides and macrocyclic tetrapeptides, depending on the nature of the allylic substitution on the β-dipeptides.
[Show abstract][Hide abstract] ABSTRACT: The study describes the synthesis of new geminally disubstituted C-linked carbo-β(2,2)-amino acids (β(2,2)-Caas) with different carbohydrate side chains, and their use in the synthesis of β(2,2)-peptides. The study infers that the side chain has an influence on the synthesis of peptides and their conformational behaviour.
Carbohydrate research 02/2014; 388C:8-18. · 2.03 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The Borono-Mannich reaction of (Z)-1-alkene-1,2-diboronic esters proceeded regioselectively at the terminal C-B bond to afford (E)-γ-boronated unsaturated amino esters in good yields. These compounds were then subjected to Suzuki couplings for the creation of diversely substituted olefinic amino acid systems. Several other functional transformations were also carried out to illustrate the synthetic utility of the Petasis products.
The Journal of Organic Chemistry 12/2013; · 4.56 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: New fused cis- and trans-furano-pyran β-amino acids were synthesized. The cis-monomer was utilized for the synthesis of α/β-peptides (tetra-, penta-, hexa- and hepta-mers), to understand its impact on helix formation. Conformational analysis of the peptides with a “β-α-β” sequence at the C-terminus showed the presence of a left-handed 9/11-helix in which the nine-membered H-bond motif is found to be weak and contributes only a small amount of electrostatic interaction to helix stabilization. Peptides with an “α-β-α” sequence at the C-terminus revealed the presence of a left-handed 9/11-helix involving the central residues and display a clear 12-membered turn at the C-terminus. In both the cases, the 9/11-helix was stabilized by a seven-membered H-bond at the N-terminus.
Annalen der Chemie und Pharmacie 06/2013; 2013(17). · 3.10 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This study describes chirality- or template-mediated helical induction in achiral β-peptides for the first time. A strategy of end capping β-peptides derived from β-hGly (the smallest achiral β-amino acid) with a chiral β-amino acid that possesses a carbohydrate side chain (β-Caa; C-linked carbo β-amino acid) or a small, robust helical template derived from β-Caas, was adopted to investigate folding propensity. A single chiral (R)-β-Caa residue at the C- or N-terminus in these oligomers led to a preponderance of right-handed 12/10-helical folds, which was reiterated more strongly in peptides capped at both the C- and N-terminus. Likewise, the presence of a template (a 12/10-helical trimer) at both the C- and N-terminus resulted in a very robust helix. The propagation of the helical fold and its sustenance was found in a homo-oligomeric sequence with as many as seven β-hGly residues. In both cases, the induction of helicity was stronger from the N terminus, whereas an anchor at the C terminus resulted in reduced helical propensity. Although these oligomers have been theoretically predicted to favor a 12/10-mixed helix in apolar solvents, this study provides the first experimental evidence for their existence. Diastereotopicity was found in both the methylene groups of the β-hGly moieties due to chirality. Additionally, the β-hGly units have shown split behavior in the conformational space to accommodate the 12/10-helix. Thus, end capping to assist chiralty- or template-mediated helical induction and stabilization in achiral β-peptides is a very attractive strategy.
Chemistry - A European Journal 10/2012; · 5.93 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: C-linked carbo-β(2)-amino acids (β(2)-Caa), a new class of β-amino acid with a carbohydrate side chain having d-xylo configuration, were prepared from d-glucose. The main idea behind the design of the new β-amino acids was to move the steric strain of the bulky carbohydrate side chain from the Cβ- to the Cα-carbon atom and to explore its influence on the folding propensities in peptides with alternating (R)- and (S)-β(2)-Caas. The tetra- and hexapeptides derived were studied employing NMR (in CDCl(3)), CD, and molecular dynamics simulations. The β(2)-peptides of the present study form left-handed 12/10- and 10/12-mixed helices independent of the order of the alternating chiral amino acids in the sequence and result in a new motif. These results differ from earlier findings on β(3)-peptides of the same design, containing a carbohydrate side chain with d-xylo configuration, which form exclusively right-handed 12/10-mixed helices. Quantum chemical calculations employing ab initio MO theory suggest the side chain chirality as an important factor for the observed definite left- or right-handedness of the helices in the β(2)- and β(3)-peptides.
[Show abstract][Hide abstract] ABSTRACT: The first total synthesis of dinemasone A, a bioactive metabolite with a spiroketal moiety, is described. The main strategy for the construction of the spiroketal unit involves a double intramolecular hetero-Michael addition (DIHMA) of an ynone moiety. The thus obtained axial-equatorial mono anomeric spiroketal, on spiroepimerization with ZnBr(2), was converted into the requisite axial-axial double anomeric spiroketal. The ynone moiety with four stereocentres, was prepared from a chiral propargylic alcohol (C5-C11 fragment) and a dihydroxy aldehyde (C1-C4 fragment), which in turn were obtained from d-mannitol and crotyl alcohol respectively.
[Show abstract][Hide abstract] ABSTRACT: A new C-linked carbo-β-amino acid, (R)-β-Caa((r)), having a carbohydrate side chain with D-ribo configuration, was prepared from D-glucose by inverting the C-3 stereocenter to introduce constraints/interactions. From the NMR studies it was inferred that the new monomer may participate in additional electrostatic interactions, facilitating and enhancing novel folds in oligomeric peptides derived from it. The α/β-peptides, synthesized from alternating L-Ala and (R)-β-Caa((r)), have shown the presence of 14/15-helix by NMR (in CDCl(3), methanol-d(3) and CD(3)CN), CD and MD calculations. The hybrid peptides showed the presence of electrostatic interactions involving the intraresidue amide proton and the C3-OMe, which helped in the stabilization of the NH(i)···CO(i-4) H-bonds and adoption of 14/15-helix. The importance of such additional interactions has been well defined in recent times to stabilize the folding in a variety of peptidic foldamers. These observations suggest and emphasize that the side chain-backbone interactions are crucial in the stabilization of the desired folding propensity. The designed monomer thus enlarges the opportunities for the synthesis of peptides with novel conformations and expands the repertoire of the foldamers.
The Journal of Organic Chemistry 07/2012; 77(16):6834-48. · 4.56 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The study describes the synthesis of new β2,2-peptides made from geminally disubstituted β2,2-amino acid and their folding propensities. The (R)-C-linked carbo-β2,2-amino acid [(R)-β2,2-Caa] was prepared from d-glucose and converted into the homo-oligomeric di-, tetra-, and hexapeptides. The conformational studies were carried out using NMR (in CDCl3), CD, IR, and MD calculations. These β2,2-peptides were interestingly stabilized by five-membered (mr) inter-residue H-bonds NH(i)⋯O(i-1) (furanoside) and a 6-mr intra-residue H-bond between amide proton (NH(i)) and the oxygen of –OMe(i) at the C3 carbon of the carbohydrate side chain. These results amply demonstrate that the ‘epimerization’ at the spiro carbon center has an effect on the conformational behavior of these peptides. Finding of these, H-bonding patterns, which are not so common to stabilize the folds in this class of β2,2-Caa derived peptides would further facilitate augmentation in the domain of foldamer.
[Show abstract][Hide abstract] ABSTRACT: The synthesis of the macrolactone core of (+)-neopeltolide has been achieved. The key synthetic strategy involves the highly diastereoselective synthesis of the 2,6-cis-disubstituted tetrahydropyran ring by a transannular cyclization of δ-hydroxy alkene using mercuric trifluoroacetate. Two of the six stereocenters C-5 and C-11 were realized from L-malic acid, while the remaining stereocenters C-3 (Sharpless asymmetric epoxidation), C-7 (transannular cyclization), C-9 (regioselective epoxide opening) and C-13 (chelation controlled reduction) were derived by asymmetric synthesis. The macrolactone ring was synthesized by macrocyclization using a RCM protocol.
[Show abstract][Hide abstract] ABSTRACT: The total synthesis of macrosphelide M is described. The key steps include the preparation of the acid and alcohol fragments from diacetone glucose and (S)-malic acid, respectively, followed by Yamaguchi esterification and macrocyclization of the tris-olefin by ring-closing metathesis. Finally, one-pot deprotection of the PMB and TBS groups with TiCl4 results in the target. The C-3/C-4 stereocenters of diacetone glucose are used for the introduction of four stereocenters, whereas the fifth stereocenter is realized from (S)-malic acid.
Annalen der Chemie und Pharmacie 04/2012; 2012(12). · 3.10 Impact Factor