BF3·OEt2-Catalyzed Unexpected Stereoselective Formation of 2,4-trans-Diallyl-2-methyl-6-aryltetrahydro-2H-pyrans with Quaternary Stereocenters.

The present manuscript describes a convenient, mild, and highly stereoselective method for the allylation of δ-hydroxy-α,ß-unsaturated ketones having a benzylic hydroxyl group at the δ-position using allyltrimethylsilane mediated by BF3·OEt2, leading to 2,4-diallyl-2-methyl-6-aryltetrahydro-2H-pyran ring systems with quaternary carbon stereogenic centers. This represents the first example of a tandem isomerization followed by one C-O and two C-C bond-forming reactions in one pot. The isolation of TMS-protected lactol as an intermediate from the reaction strongly supports the proposed mechanistic pathway.

Synthesis, structural studies, and cytotoxic evaluation of novel ursolic acid hybrids with capabilities to arrest breast cancer cells in mitosis.

Some novel chemically modified frameworks of ursolic acid have been designed and synthesized. The key step was the cycloaddition of azidopropyl-3ß-hydroxy-urs-12-en-28-oate with the appropriate C28 propargyl esters of ursolic, corosolic, asiatic, oleanolic, and betulinic acid under Click reaction conditions, and the products were obtained in 74-84% yields. In view of their intriguing structural diversity, they have been subjected to detailed 1D and 2D NMR studies and their structures are thoroughly assigned. The synthesized compounds were screened for their anticancer potential against two human breast cancer cell lines (MCF-7 & MDA-MB-231) using sulforhodamine B cell proliferation assay. The GI50 data revealed that the synthesized compounds exhibit highly potent activities against the two tested cell lines. Interestingly, the synthesized compounds showed selectivity and higher activity against MDA-MB-231 cell line than MCF-7. Among the tested compounds, compound 17 is the most potent one with GI50 value of 1.4 ± 0.1 µM and showed 2.9 times more activity than the standard doxorubicin against MDA-MB-231. In addition, 17 arrests cells in mitotic phase of cell cycle, resulting in a change in cell phenotype. In view of the selective and highly promising activity against breast cancer cell lines, these compounds can serve as promising leads for further development.

Formation of periodic γ-turns in α/ß-hybrid peptides: DFT and NMR experimental evidence.

Hybrid peptidic oligomers comprising natural and unnatural amino acid residues that can exhibit biomolecular folding and hydrogen-bonding mimicry have attracted considerable interest in recent years. While a variety of hybrid peptidic helices have been reported in the literature, other secondary structural patterns such as γ-turns and ribbons have not been well explored so far. The present work reports the design of novel periodic γ-turns in the oligomers of 1:1 natural-α/unnatural trans-ß-norborenene (TNAA) amino acid residues. Through DFT, NMR, and MD studies, it is convincingly shown that, in the mixed conformational pool, the heterogeneous backbone of the hybrid peptides preferentially adopt periodic 8-membered (pseudo γ-turn)/7-membered (inverse γ-turn) hydrogen bonds in both polar and non-polar solvent media. It is observed that the stereochemistry and local conformational preference of the ß-amino acid building blocks have a profound influence on accessing the specific secondary fold. These findings may be of significant relevance for the development of molecular scaffolds that facilitate desired positioning of functional side-chains.

A synthetic zipper peptide motif orchestrated via co-operative interplay of hydrogen bonding, aromatic stacking, and backbone chirality.

Here, we report on a new class of synthetic zipper peptide which assumes its three-dimensional zipper-like structure via a co-operative interplay of hydrogen bonding, aromatic stacking, and backbone chirality. Structural studies carried out in both solid- and solution-state confirmed the zipper-like structural architecture assumed by the synthetic peptide which makes use of unusually remote inter-residual hydrogen-bonding and aromatic stacking interactions to attain its shape. The effect of chirality modulation and the extent of noncovalent forces in the structure stabilization have also been comprehensively explored via single-crystal X-ray diffraction and solution-state NMR studies. The results highlight the utility of noncovalent forces in engineering complex synthetic molecules with intriguing structural architectures.

Total synthesis and stereochemical revision of acortatarins A and B.

A first total synthesis of acortatarins A, B, and an enantiomer of the proposed structure of acortatarin B is described by using readily available d-sugars. This convergent total synthesis revealed the revision of the absolute configuration of acortatarin A and structural revision of acortatarin B. The key steps involved are regioselective epoxide opening with deprotonated 2,5-disubstituted pyrrole and spiroketalization.

A novel acid-catalyzed C5-alkylation of oxindoles using alcohols.

A novel C5-alkylation of oxindoles using alcohols as alkylating agents under acid catalysis is described for the first time. The reactions of various benzylic, allylic and propargylic alcohols are studied to obtain the corresponding 5-substituted oxindoles in good yields.

Novel helical foldamers: organized heterogeneous backbone folding in 1 : 1 alpha/nucleoside-derived-beta-amino acid sequences.

Secondary structural conformation of hybrid oligo-peptides comprised of 1 : 1 alternating Nucleoside Derived beta-Amino acid (NDA) and l-amino acid residues has been reported. The studies reveal that the NDA residues organize the heterogeneous backbone featuring the surface properties of both nucleic acids and peptides, to adopt a novel 11/8-helical fold.

A flexible enantioselective total synthesis of diospongins A and B and their enantiomers using catalytic hetero-Diels-Alder/Rh-catalyzed 1,4-addition and asymmetric transfer hydrogenation reactions as key steps.

A unified enantioselective route to total synthesis of diospongins A and B and their enantiomers has been developed employing achiral starting materials. All three stereocenters were introduced by means of catalytic reactions.

RDC enhanced NMR spectroscopy in organic solvent media: the importance for the experimental determination of periodic hydrogen bonded secondary structures.

Precise NMR structural determination of distinct hydrogen-bonded secondary folds in unnatural peptides is demonstrated by using residual dipolar couplings (RDCs), measured in organic solvent media. The results show that the conventional constraints, (3)J(HH) and NOE-derived distances alone do not allow the accurate structural elucidation even for rigid foldamers and emphasize the need of RDC-based structure validation and refinement for unnatural peptides in particular and small organic molecules in general.

Enantiopure cycloalkane fused tetrahydropyrans through domino Michael-ketalizations with organocatalysis.

Enantiopure cyclohexane fused tetrahydropyrans have been synthesized using domino Michael-ketalization under organocatalysis.

Total synthesis of azumamide E and sugar amino acid-containing analogue.

An efficient and practical total synthesis of marine cyclic tetrapeptide, natural product azumamide E (1) is achieved via high-yielding reactions. The strategy also allowed us to synthesize the azumamide E-SAA (sugar amino acid) analogue (2), whose solution-phase NMR and biological activity studies were also carried out.

Beta-sugar aminoxy peptides as rigid secondary structural scaffolds.

Short homo-oligomers of a new building block, cis-beta(2,3)-furanoid sugar aminoxy acid, are designed, characterized, and found to exhibit rigid ribbon-like secondary structures composed of 5/7 bifurcated intramolecular hydrogen bonds.

Formation of left-handed helices in hybrid peptide oligomers with cis beta-sugar amino acid and L-Ala as building blocks.

Residue based control of specific helical folding is explored in hybrid peptide oligomers consisting of alternating L-Ala and cis-beta-furanoid sugar amino acid (FSAA) residues as building blocks; two series of these hybrid oligomers are designed, synthesized and extensively characterized by using NMR, CD, FT-IR and MD simulation studies; results show the co-existence of left-handed 11- and 14/15-helical conformations in these short oligomers of Boc-(alpha/beta) and Boc-(beta/alpha) series.

Oligomers of cis-beta-norbornene amino acid: formation of beta-strand mimetics.

The oligomers of constrained cis-exo-beta-norbornene amino acid were synthesised and characterised by extensive NMR, CD, IR and MD studies. The results showed the formation of both right and left handed consecutive 6-membered hydrogen-bonded strands for [2S,3R] and [2R,3S] enantiomers, respectively.

Self-assembly of cyclic homo- and hetero-beta-peptides with cis- furanoid sugar amino acid and beta-hGly as building blocks.

The design, synthesis and characterization of a new class of peptide nanotubes, self-assembled from cyclic homo- and hetero-beta-peptides based on cis-furanoid sugar amino acid and beta-hGly residues are described; these results represent the expansion of the conformational pool of cis beta-sugar amino acids in the design of peptide nanotubes.

Expanding the conformational pool of cis-beta-sugar amino acid: accommodation of beta-hGly motif in robust 14-helix.

Tendencies of forming stable helices of heterooligomers composed of alternating rigid cis-beta-sugar amino acid and flexible beta-hGly motifs have been investigated, using a combination of molecular mechanics, CD, FT-IR, and NMR techniques. The results show that the solution structures of these oligomers exist as robust right-handed 14-helices. Here, we examine the role of conformationally rigid cis-beta-sugar amino acid in preorganizing the conformation of beta-hGly to form the 14-helix. Our findings also show that a right-handed 14-helix can be formed with as few as four properly sequenced heterogeneous residues. These results represent the expansion of the conformational pool of sugar amino acid in the design of well-folded 14-helices, which can be used to develop beta-peptides endowed with biological activity.

Morphology and chain dynamics during collapse transition of PNIPAM gels studied by combined imaging, relaxometry and 129Xe spectroscopy techniques.

The temperature-induced shape transition of poly(N-isopropylacrylamide) gels of different cross-link densities was investigated by a combination of NMR techniques allowing the characterization of both the macroscopic collapse as well as the changes on a molecular scale related to the expulsion of water from the gel network. The proton-containing gel phase was visualized by swelling in heavy water, and the volume change was monitored by proton imaging for cross-link densities between 0.5% and 2.5%. Above the transition temperature of 35 degrees C, gel collapse led to a volume change of up to a factor of 17 for the gel of smallest cross-link density. Two spectral lines of 129Xe are found in the gel state and are assigned to the hydrophobic and hydrophilic parts of the network. In the collapsed state, the hydrophobic peak shows a strong shift while the hydrophilic peak disappears. A considerable shortening of both T1 and T2 of the gel protons upon collapse was found at a field of 4.7 T. At lower fields, the effect becomes more pronounced and qualitatively different dispersion behaviors between the swollen and the collapsed states are observed.

Biflavonoids from Cycas beddomei.

Chemical investigation on the constituents of the cones of Cycas beddomei has resulted in the isolation of a new biflavonoid, 2,3-dihydro-4'''-O-methyl amentoflavone, along with 2,3,2'',3''-tetrahydro hinokiflavone, 2,3,2'',3''-tetrahydro amentoflavone, 2,3-dihydro amentoflavone. The last two compounds were not reported earlier from this plant. The structure of the new compound was established by detailed analysis of its spectral (mainly 1D and 2D NMR) data.

Formation of a stable 14-helix in short oligomers of furanoid cis-beta-sugar-amino acid.

Oligomers of a new class of sugar amino acids (SAA) using a xylofuranoic acid has been shown to generate a robust 14-helix. The design involved the use of xylofuranose with a cis arrangement between the amine and carboxyl groups to promote the adoption of a 14-helix instead of a mixed 12/10-helix observed in a sugar oligomer using a ribofuranoic acid and beta-Ala. The observation of a stable right-handed 14-helix in a cis-SAA is unprecedented.