Palladium-Catalyzed Double Allylation of Sugar-Imines by Employing Tamaru-Kimura's Protocol: Access to Unnatural Iminosugars.

Conversion of vinyl pyranosylamine and vinyl furanosylamines to 2,6- and 2,5-disubstituted pyrrolidine and piperidine iminosugars, respectively, in one pot was developed using Kimura and Tamaru's procedure, where a Pd salt in the presence of Et2Zn was used for the domino reaction. In this procedure, double allylation, which involves nucleophilic allylation-heterocyclization, took place to give desired nitrogen heterocycles. This strategy was further elaborated to synthesize some unnatural deoxycalystegines, hydroxylated pyrrolidines, piperidines, and indolizidine analogues.

Total Synthesis of the Proposed Structure of Maltepolide C.

The first total synthesis of the proposed structure of cytotoxic macrolide maltepolide C has been achieved via an E-selective intramolecular Heck cyclization as a key step. Other key features of the synthesis are Z-selective Wittig olefination, Sharpless asymmetric dihydroxylation followed by Williamson-type cyclo-etherification, Brown asymmetric allylation, and Noyori reduction of an alkynone. Detailed NMR study confirms the structure and stereochemistry of the synthetic maltepolide C unambiguously. However, the deviation of the spectra of the synthetic maltepolide C from those of the natural maltepolide C indicates a possible error in the original structural assignment.

A novel domino cyclization for the stereoselective synthesis of indeno[2,1-c]pyran and cyclopenta[c]pyran derivatives.

A novel bicyclization of 2-(2-(hydroxymethyl)-1-methylene-2,3-dihydro-1H-inden-2-yl)ethanol with aldehydes in the presence of 10 mol% BF3·OEt2 in dichloromethane at 0-25 °C affords the biologically relevant indeno[2,1-c]pyran scaffolds in good yields with high selectivity. Similarly the bicyclization of 2-(1-(hydroxymethyl)-2-methylenecyclopentyl)ethanol with aldehydes generates the corresponding cyclopenta[c]pyran derivatives under similar conditions. This method is very useful to produce hematoxylin and brazilin like scaffolds.

A novel Prins cascade process for the stereoselective synthesis of oxa-bicycles.

E- and Z-9-Methyldeca-3,8-dien-1-ols undergo smooth cyclization with aldehydes in the presence of 20 mol% AgSbF6 under extremely mild conditions to generate the corresponding oxa-bicycles in good yields with excellent selectivity. In fact, E-olefin affords the trans-product exclusively, whereas the Z-olefin gives the cis-product predominantly. In the case of E- or Z-8-methylnona-3,8-dien-1-ol, the product is formed via the termination of Prins cyclization with an allylic C-H bond through olefin migration. The termination of Prins cyclization with tethered olefin is an unprecedented reaction, which provides a useful motif of various natural products.

Thia-prins bicyclization approach for the stereoselective synthesis of dithia- and azathia-bicycles.

A novel thia-Prins bicyclization approach has been developed for the first time for the synthesis of hexahydro-2H-thieno[3,2-c]thiopyran derivatives from the coupling of homoallylic mercaptans such as hex-3-ene-1,6-dithiol with various aldehydes using 10 mol % InBr3 in dichloromethane with high selectivity. In addition, the coupling of (E)-N-(6-mercaptohex-3-enyl)-4-methylbenzenesulfonamide with aldedydes affords the corresponding N-tosyloctahydrothiopyrano[4,3-b]pyrrole derivatives in good yields. This reaction is a stereoselective affording trans-fused product from E-homoallyllic mercaptan and cis-fused product from Z-homoallyllic mercaptan.

The stereoselective synthesis of cis-/trans-fused hexahydropyrano[4,3-b]chromenes via Prins cyclization trapping by a tethered nucleophile.

A novel intramolecular Prins cyclization of (Z)-2-(5-hydroxypent-2-enyl)phenol with various aldehydes has been achieved using 10 mol% In(OTf)(3) and 30 mol% TsOH to produce the cis-fused hexahydropyrano[4,3-b]chromene derivatives in good yields, while the coupling of (E)-2-(5-hydroxypent-2-enyl)phenol with aldehydes under similar conditions affords the corresponding trans-fused hexahydropyrano[4,3-b]chromene derivatives.

Oxidative Prins and Prins/Friedel-Crafts cyclizations for the stereoselective synthesis of dioxabicycles and hexahydro-1H-benzo[f]isochromenes via the benzylic C-H activation.

1-Benzyl ethers of (E)- and (Z)-hex-3-en-1,6-diols and hept-3-en-1,7-diols undergo a smooth oxidative cyclization with DDQ in the presence of In(OTf)(3) through a sequential C-H bond activation and an intramolecular Prins cyclization to afford the corresponding trans- and cis-fused hexahydro-2H-furo[3,2-c]pyrans and octahydropyrano[4,3-b]pyrans respectively in good yields with an excellent stereoselectivity. Aryl tethered homoallylbenzyl ethers such as benzyl ethers of (E)- and (Z)-6-arylhex-3-enyl alcohols undergo a tandem Prins/Friedel-Crafts cyclization in the presence of stoichiometric amounts of DDQ and SnCl(4)via the benzylic C-H bond activation to furnish the corresponding trans- and cis-fused hexahydro-1H-benzo[f]isochromenes in good yields with complete stereoselectivity.

Differentiation of three pairs of Boc-beta,gamma- and gamma,beta-hybrid peptides by electrospray ionization tandem mass spectrometry.

A new series of Boc-N-beta(3), gamma(4)-/gamma(4), beta(3)-isomeric hybrid peptides (containing repeats of beta(3)-Caa and gamma(4)-Caa's, Caa = C-linked carbo beta(3)-/gamma(4)-amino acids derived from D-xylose) have been differentiated by both positive and negative ion electrospray ionization (ESI) ion-trap and high resolution quadrupole time-of-flight/tandem mass spectrometry (Q-TOF MS/MS). MS(n) of protonated isomeric peptides and [M+H-Boc+H](+) produce characteristic fragmentation involving the peptide backbone, the Boc-group, and the side chain. The positional isomers are differentiated from one another by the presence of y(n)(+), b(n)(+), and other fragment ions of different m/z values. It is observed that the peptides with beta-Caa at the N-terminus produce extensive fragmentation, whereas gamma-Caa gave rise to much less fragmentation. Peptides with gamma-Caa at the N-terminus lose NH(3), whereas this process is absent for the carbopeptides with beta-Caa at the N-terminus. Two pairs of dipeptide diastereomers are clearly differentiated by the collision-induced dissociation (CID) of their protonated molecules. The loss of 2-methylprop-1-ene is more pronounced for Boc-NH-(R)-beta-Caa-(R)-gamma-Caa-OCH(3) (6) and Boc-NH-(R)-gamma-Caa-(R)-beta-Caa-OCH(3) (12), whereas it is insignificant or totally absent for its protonated diastereomeric pair Boc-NH-(S)-beta-Caa-(S)-gamma-Caa-OCH(3) (1) and Boc-NH-(S)-gamma-Caa-(S)-beta-Caa-OCH(3) (7). Further, ESI negative ion tandem mass spectrometry has also been found to be useful for differentiating these isomeric peptide acids.

Differentiation of three pairs of positional isomers of hybrid peptides with repeats of phenylalanine-beta3-h-valine/beta3-valine-phenylalanine by electrospray ionization tandem mass spectrometry.

Electrospray ionization ion trap mass spectrometry has been used to distinguish three pairs of positional isomers of a new series of N-blocked hybrid peptides derived from repeats of phenylalanine(D)-beta3-h-valine/beta3-h-valine-phenylalanine(D) (FbetaV/betaVF) non-natural amino acids. MSn of protonated isomeric peptides produces characteristic fragmentation involving the peptide backbone, the Boc group and the side chain. FbetaV-peptides can be distinguished from betaVF-peptides by the loss of R-OH from [M+H-Boc+H]+, which is either of relatively low abundance or totally absent for the latter peptides. In contrast, betaVF-peptides show abundant Mannich base characteristic ions by the elimination of ammonia, and imine due to a retro-Mannich cleavage. This fragmentation is absent for FbetaV-peptides. When beta-valine is at the C-terminus, abundant b+(n-1) ions are produced. This is ascribed to the probable formation of a stable diketopiperazine structure, and this has been supported by the loss of H2O and CO in the CID spectra of b+(n-1) ions. The hybrid dipeptide acids have also been distinguished in negative ion mass spectrometry.

Furanoid sugar amino acids as dipeptide mimics in design of analogs of vasoactive intestinal peptide receptor binding inhibitor.

In this study we describe the development of peptidomimetic analogs of the potent vasoactive intestinal peptide receptor binding inhibitor, Leu(1) -Met(2) -Tyr(3) -Pro(4) -Thr(5) -Tyr(6) -Leu(7) -Lys(8) -OH 1, by incorporating furanoid sugar amino acids (SAAs) 2-4 into the molecule. The furanoid SAAs 2-4 were used as dipeptide isosteres to replace Tyr(3) -Pro(4) or Pro(4) -Thr(5) in sequence 1. The resulting analogs 5-9 were tested for their anti-cancer activities in vitro, following the standard MTT assay on a panel of human cancer cell lines. One of the potent analogs, 6a was tested in vivo for tumor regression on primary colon tumor xenografted nude mice. Our experimental results suggest that many of these analogs show either retention or enhancement of biological activity.

Conformational studies of peptides containing cis-3-hydroxy-D-proline.

Conformational analysis of peptides containing cis-3-hydroxy-d-proline (d-cis-3-Hyp) by NMR studies revealed that the 3-hydroxyl group in this amino acid plays a significant role in the overall three-dimensional structures of the peptides. When the d-cis-3-Hyp had its 3-hydroxyl group protected as the benzyl (Bn) ether, the peptide displayed a beta-hairpin structure in both CDCl(3) and DMSO-d(6). Even after the removal of the Bn group, the resulting deprotected compound retained the same structure as in the protected version in CDCl(3). However, in polar solvent DMSO-d(6), the C-terminal strand of the hydroxyl-deprotected peptide flipped to the side of the hydroxyl group, breaking the hairpin to form a pseudo beta-turn-like nine-membered ring structure involving an intramolecular hydrogen bond between LeuNH --> HypC3-OH.

Synthesis and conformational studies of novel cyclic peptides constrained into a 3 10 helical structure by a heterochiral D-pro-L-pro dipeptide template.

An acyclic tripeptide based on a heterochiral D-pro-L-pro template shows a propensity to exist as a 3(10) helical conformation and can be cyclized, via ring-closing metathesis, to the corresponding cyclic tetrapeptides without disrupting the helical conformations in CDCl(3) as well as in DMSO-d(6) solutions. The detailed conformational studies were carried out by using NMR spectroscopy, X-ray crystallography, molecular dynamic simulations, and circular dichroism spectroscopy.

Robust mixed 10/12 helices promoted by "alternating chirality" in a new family of C-linked carbo-beta-peptides.

The C-linked carbo-beta-peptides, oligomers of a new class of C-linked carbo-beta3-amino acids, have been shown to generate mixed 12/10 and 10/12 helices. The design involves use of "alternating chirality" of the epimeric (at the amine center) monomers to control the stability of these helices. The observation of stable 12/10 helix in a tripeptide and 10/12 helix in a tetrapeptide is unprecedented.

Cyclic homooligomers of furanoid sugar amino acids.

Cyclic homooligomers of mannose-derived furanoid sugar amino acid 1 [H-Maa(Bn(2))-OH] were synthesized by using BOP reagent in the presence of DIPEA under dilute conditions that converted the sugar amino acid monomer directly into its cyclic homooligomers 3a and 4a. The glucose-based sugar amino acid 2 [H-Gaa(Bn(2))-OH] under the same reaction conditions gave a bicyclic lactam 5a as the major product. Cyclic homooligomers of 2 were prepared by cyclizing their linear precursors 6 and 7 leading to the formation of cyclic peptides 8a and 9a, respectively. Conformational analysis by NMR and constrained MD studies revealed that all the cyclic products, 3, 4, 8, and 9, had symmetrical structures. The deprotected cyclic trimer of Maa 3b displayed a conformation in which all the C=O and the N-H bonds of the molecule point in opposite directions. In the deprotected cyclic tetramer of Maa 4b, the COs and NHs were in the plane of the ring with the former pointing to outside and the latter inside the ring. The structure of the cyclic Gaa dimer 8b displayed an unusual six-membered intramolecular hydrogen bond between NH(i)() --> C3-O(i)()(-)(1) and a syn orientation between the C2-H and CO. In this molecule, the C2-hydrogens and the COs can be seen on one side of the ring while the NHs point to the other side. Addition of the bicyclic lactam 5b resulted in the influx of Na(+) ions across the lipid bilayer leading to the dissipation of valinomycin-mediated K(+) diffusion potential.

Synthesis of a novel cis-proline-derived cyclic type VI beta-turn mimic via ring-closing metathesis.

A cis-proline derived cyclic mimic of a type VI beta-turn is synthesized via a ring-closing metathesis reaction. The solution NMR conformational study indicates that the major conformer of the cyclic peptide adopts a type VIa beta-turn in CDCl(3) and a type VIb beta-turn in DMSO-d(6).

Reverse turn induced pi-facial selectivity during polyaniline-supported cobalt(II) salen catalyzed aerobic epoxidation of N-cinnamoyl L-proline derived peptides.

A novel chemo- and diastereoselective aerobic epoxidation of the N-cinnamoyl peptides catalyzed by polyaniline-supported cobalt(II) salen (PASCOS) is described. The N-cinnamoyl proline derived peptides 1 show a high pi-facial selectivity during these epoxidations. The origin of this diastereoselectivity in 1 has been attributed to (i) the propensity of the N-cinnamoyl proline amide to exist predominantly as trans rotamer in CDCl3, DMSO-d6, and CH3CN medium and (ii) existence of these peptides as organized structures (gamma- and beta-turns) due to the presence of intramolecular hydrogen bonds. An extensive solution NMR and MD simulation study on 1d and 1f indicates that the origin of the high pi-facial selectivity is due to the well-defined gamma- and beta-turns which result in the hindrance of one face of the cinnamoyl double bond in the transition state of the epoxidation reaction.

Unusual cyclo-tetra and hexa peptidation of bis-boc-cystine with cystine-di-OMe: one step preparation of the novel 32- and 48-membered cyclotetracystine and cyclohexacystine.

The unprecedented formation of 32- and 48-membered macrocycles that inscribe 4 and 6 cystine units, in the peptidation of bis-Boc-cystine with cystine di-OMe is reported.

Studies on novel peptidomimetics having bi-directional dispositions of hydroxylated D-Pro-Gly motifs anchored on a C(2)-symmetric iminosugar-based foundation.

A rigid pyrrolidine based scaffold comprising of 2,5-dideoxy-2,5-imino-D-idaric acid (1) is developed. Attachment of peptide strands to the carboxylic groups at both ends of this novel template led to the peptidomimetics 2 and 3. Conformational analysis by NMR studies revealed that compounds 2b, 3b and 2c, 3c take interesting turn structures (C(2) symmetric for 2c and 3c) in DMSO-d(6) consisting of identical intramolecular hydrogen bonds at two ends between LeuNH --> sugar-OH as depicted in structure A, whereas 2a and 3a display structures with regular beta-turns with hydrogen bonds between LeuNH --> Boc-C=O in one-half of their molecular frameworks (structure B), characteristic of the turn structures commonly observed in "D-Pro-Gly"-containing peptides. These results suggest that a cis hydroxyl group at the 3-position of the proline residue favors a pseudo beta-turn-like nine-membered ring structure in hydroxyproline-containing peptides involving an intramolecular hydrogen bond between the hydroxyl and the i + 2 backbone amide.

NMR study of cyclic peptides with renin inhibitor activity.

Several cyclic analogues of renin inhibitors, based on Glu-D-Phe-Lys motif have been investigated by NMR spectroscopy and molecular dynamics calculations (MD). The 15 membered macrocycle, resulting from Glu and Lys side-chain cyclization, exhibits conformational preference. The structural evidence from NMR shows the presence of hydrogen bond between Lys NH and Glu side-chain carbonyl, resulting in a 10 membered pseudo beta-turn-like structure. The structure of the cyclic moiety is similar in all the peptides, which takes at least two conformations around Calpha-Cbeta in Glu side chain. The restrained MD calculations further support such observations and show that the macrocycle is fairly rigid, with two conformations about the Glu Calpha-Cbeta bond. The linear peptide appendages, which are essential for activity in cyclic peptides, show an extended structure in the beta-region of Ramchandran plot. These calculations also demonstrate that for the most active peptide, two major conformers each exist about the Calpha-CO bond of the Lys, D-Trp and Leu residues. In this peptide, the cyclic moiety presents a negatively charged surface formed due to the carbonyl oxygens, which are thus available to form hydrogen bonds with the receptor. The linear fragment presents further binding sites with a surface which has the hydrophobic side chains of D-Trp, Leu and D-Met on one side and carbonyls on the other side.