Designed asymmetric coordination helicates with bis-ß-diketonate ligands.

A new bis-(ß-diketone) ligand featuring built-up structural asymmetry yields non-symmetric Fe(iii) and Ga(iii) dinuclear, triple-stranded helicates by design. Their structural properties have been studied, both in solid state and in solution, and compared with their corresponding symmetric analogues. The robustness observed shows the potential of this synthetic strategy to develop non-symmetric helicoidal motifs with specific functional groups.

A Magneto-optical Molecular Device: Interplay of Spin Crossover, Luminescence, Photomagnetism, and Photochromism.

A bis(pyrazolylpyridyl) ligand, L, containing a central photochromic dithienylethene spacer predictably forms a ferrous [Fe2 L3 ]4+ helicate exhibiting spin crossover (SCO). In solution, the compound [Fe2 L3 ](ClO4 )4 (1) preserves the magnetic properties and is fluorescent. The structure of 1 is photo-switchable following the reversible ring closure/opening of the central dithienylethene via irradiation with UV/visible light. This photoisomerization switches on and off some emission bands of 1 and provides a means of externally manipulating the magnetic properties of the assembly.

Molecules Designed to Contain Two Weakly Coupled Spins with a Photoswitchable Spacer.

Controlling the charges and spins of molecules lies at the heart of spintronics. A photoswitchable molecule consisting of two independent spins separated by a photoswitchable moiety was designed in the form of new ligand H4 L, which features a dithienylethene photochromic unit and two lateral coordinating moieties, and yields molecules with [MM⋅⋅⋅MM] topology. Compounds [M4 L2 (py)6 ] (M=Cu, 1; Co, 2; Ni, 3; Zn, 4) were prepared and studied by single-crystal X-ray diffraction (SCXRD). Different metal centers can be selectively distributed among the two chemically distinct sites of the ligand, and this enables the preparation of many double-spin systems. Heterometallic [MM'⋅⋅⋅M'M] analogues with formulas [Cu2 Ni2 L2 (py)6 ] (5), [Co2 Ni2 L2 (py)6 ] (6), [Co2 Cu2 L2 (py)6 ] (7), [Cu2 Zn2 L2 (py)6 ] (8), and [Ni2 Zn2 L2 (py)6 ] (9) were prepared and analyzed by SCXRD. Their composition was established unambiguously. All complexes exhibit two weakly interacting [MM'] moieties, some of which embody two-level quantum systems. Compounds 5 and 8 each exhibit a pair of weakly coupled S=1/2 spins that show quantum coherence in pulsed Q-band EPR spectroscopy, as required for quantum computing, with good phase memory times (TM =3.59 and 6.03 µs at 7 K). Reversible photoswitching of all the molecules was confirmed in solution. DFT calculations on 5 indicate that the interaction between the two spins of the molecule can be switched on and off on photocyclization.

A Useful Allene for the Stereoselective Synthesis of Protected Quaternary 2-Amino-2-vinyl-1,3-diols.

Treatment of readily available allene 1 with Cy2BH followed by addition of an aldehyde led to quaternary protected 2-amino-2-vinyl-1,3-diols in high yield and excellent stereochemical purity. The choice of benzoyl as N-protecting group is critical since the observed N- to O-Bz transfer during the process prevents later undesired isomerizations in the adducts and keeps all heteroatoms protected.

Total synthesis of (-)-isoavenaciolide.

An enantioselective approach to (-)-isoavenaciolide was achieved starting from 1-undecyn-3-ol. The synthesis relied upon the preparation of a chiral 4-silyloxy-2-alkenylborane by hydroboration of a protected 2,3-allenol and subsequent stereoselective addition to 2-thiophenecarboxaldehyde.

Use of the SPhos ligand to suppress racemization in arylpinacolboronate ester Suzuki couplings involving alpha-amino acids. Synthesis of biaryl derivatives of 4-hydroxyphenylglycine, tyrosine, and tryptophan.

Alpha-amino acid derivatives, particularly those of phenylglycine, can suffer significant racemization in Suzuki couplings. When arylpinacolboronate esters are used as coupling partners this unwanted side reaction can be suppressed by the use of Pd(OAc)(2) as Pd(0) source, in the presence of Buchwald's SPhos ligand. The syntheses of biaryl amino acids of tyrosine, phenylglycine, and tryptophan, including Phg-Trp units similar to those found in the chloropeptin family of natural products, are reported.

Racemization in suzuki couplings: a quantitative study using 4-hydroxyphenylglycine and tyrosine derivatives as probe molecules.

Reaction conditions considered to be typical in Suzuki couplings can cause significant (up to 34% of the unwanted enantiomer) loss of optical purity in sensitive substrates such as hydroxyphenylglycine 1. This may be remedied using sodium succinate instead of sodium carbonate as base, but chemical yields are somewhat lower. Optically pure biaryl amino acids related to those found in the chloropeptins and vancomycin were synthesized by Suzuki coupling of 1 with indolylboronic acids 6-8 and with cyclic boronic acid 9.

Synthesis, conformational analysis, and cytotoxicity of conformationally constrained aplidine and tamandarin A analogues incorporating a spirolactam beta-turn mimetic.

With the aim of studying the contribution of the beta II turn conformation at the side chain of didemnins to the bioactive conformation responsible for their antitumoral activity, conformationally restricted analogues of aplidine and tamandarin A, where the side chain dipeptide Pro8-N-Me-d-Leu7 is replaced with the spirolactam beta II turn mimetic (5R)-7-[(1R)-1-carbonyl-3-methylbutyl]-6-oxo-1,7-diazaspiro[4.4]nonane, were prepared. Additionally, restricted analogues, where the aplidine (pyruvyl9) or tamandarin A [(S)-Lac9] acyl groups are replaced with the isobutyryl, Boc, and 2-methylacryloyl groups, were also prepared. These structural modifications were detrimental to cytotoxic activity, leading to a decrease of 1-2 orders of magnitude with respect to that exhibited by aplidine and tamandarin A. The conformational analysis of one of these spirolactam aplidine analogues, by NMR and molecular modeling methods, showed that the conformational restriction caused by the spirolactam does not produce significant changes in the overall conformation of aplidine, apart from preferentially stabilizing the trans rotamer at the pyruvyl9-spirolactam amide bond, whereas in aplidine both cis and trans rotamers at the pyruvyl9-Pro8 amide bond are more or less equally stabilized. These results seem to indicate a preference for the cis form at that amide bond in the bioactive conformation of aplidine. The significant influence of this cis/trans isomerism upon the cytotoxicity suggests a possible participation of a peptidylprolyl cis/trans isomerase in the mechanism of action of aplidine.

Arylboronic acids and arylpinacolboronate esters in Suzuki coupling reactions involving indoles. Partner role swapping and heterocycle protection.

Yields of Suzuki couplings involving indoles depended upon (i) whether arylboronic acids or arylpinacolboronate esters were used, (ii) whether the heterocycle was the aryl halide or the arylboron coupling partner, and (iii) whether the heterocycle was protected or not. Highest yields, which were unaffected by incorporating Boc or Tos protection at the heterocyclic nitrogen, were obtained when indole bromides were reacted with phenylboronic acids. When indolylboronic acids were reacted with phenyl bromides, yields were somewhat lower and depended on the nitrogen substituent, being highest in the absence of protection, lower in the presence of the Boc group, and lowest of all with the Tos group. Arylpinacolboronate esters were less reactive than arylboronic acids. They required considerably longer reaction times and furnished generally lower yields of biaryl. Furthermore, irrespective of whether the heterocycle was the aryl bromide or the arylpinacolboronate ester, these yields were highest when it was protected with the Tos group. Yields were lower with the Boc group, and unprotected heterocycles gave only traces of biaryl. Careful selection of arylboron reagent, of coupling partner roles, and of protecting groups are essential to ensuring optimum results in these Suzuki couplings. These results may also be relevant to couplings involving other substrates.

Analysis of conformational equilibria in aplidine using selective excitation 2D NMR spectroscopy and molecular mechanics/dynamics calculations.

Aplidine (dehydrodidemnin B), a natural product with potent antitumor activity currently in multicenter phase II clinical trials, exists in DMSO as a mixture of four slowly interconverting conformations in a ratio of 47:33:13:7. NMR spectroscopy shows that these arise as a consequence of cis/trans isomerization about the NMe-Leu(7)-Pro(8) and Pro(8)-Pyr amide bonds of the molecule's side chain. Two major conformations account for 47% and 33% of the total population, a ratio of 60:40 between the two. They correspond to the cis- and trans-isomers, respectively, about the Pro(8)-Pyr amide bond. Two minor conformers arise as a consequence of similar isomerism about the Pro(8)-Pyr amide bond, but in structures in which the NMe-Leu(7)-Pro(8) amide bond is cis rather than trans. These account for approximately 13% and 7% of the total population, corresponding to a ratio of 65:35 cis/trans, respectively. Molecular dynamics simulations show that the three-dimensional structures of all four conformational isomers are similar in the macrocycle and that all are essentially unchanged with respect to the macrocycle of didemnin B. Significant differences in the conformation of the molecule's side chain are, however, observed between major and minor pairs. Analysis of hydrogen-bonding patterns shows that each major conformer exhibits a beta-turn like structure and is stabilized by hydrogen bonding between a different carbonyl group of the pyruvyl unit of the molecule's side chain and the NH of the Thr(6) residue. The minor isomers have a cis-amide bond between the NMe-Leu(7) and Pro(8) residues that obliges the side chain to adopt an extended disposition where hydrogen bonding to the macrocycle is absent. These results suggest that the ability of the molecule's side chain to adopt a beta-turn-like conformation may not be a prerequisite for biological activity in the didemnins and that conformations having an extended side-chain may play a role in the biological activity of aplidine.

Total Synthesis of Dehydrodidemnin B. Use of Uronium and Phosphonium Salt Coupling Reagents in Peptide Synthesis in Solution.

New total syntheses of didemnin A and of dehydrodidemnin B are described. The latter didemnin has the highest antiproliferative activity of all members of this family of macrocyclic depsipeptides. It was produced on coupling the side chain Pyr-Pro-OH to didemnin A, which was itself synthesized by two novel routes. One of these was based on the elaboration of a linear heptadepsipeptide incorporating the first amino acid of the didemnin side chain, (R)-N(Me)-Leu. Deprotection of the amino and carboxyl terminii of this linear precursor followed by macrocyclization gave a protected derivative of didemnin A. The second route involved synthesis of the Boc-protected didemnin macrocycle from a linear hexadepsipeptide lacking (R)-N(Me)-Leu. Removal of the Boc group from the macrocycle followed by its coupling with Boc-(R)-N(Me)-Leu-OH then gave Boc-didemnin A. The overall yield was much higher for the second strategy (27% compared to 4% for the first synthesis), but both allowed synthetic didemnin A, identical with a natural sample, to be prepared. Extensive use was made of phosphonium and uronium salt-based coupling reagents, such as BOP, PyBrOP, PyAOP, HBTU, and HATU for the formation of both the secondary and tertiary amide bonds present in these complex depsipeptides.