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PubMed2005

Rh(I)-catalyzed cyclization of 1-arylprop-2-yn-1-ol derivatives utilizing rhodium 1,4-migration.

A highly useful method for the construction of cyclopentanone derivatives fused with aromatic ring based on hydrorhodation-1,4-rhodium migration sequence is achieved. Treatment of 1-aryl-prop-2-yn-1-ols, which are easily accessible via an addition of acetylides to the corresponding aryl aldehydes, with a catalytic amount of [Rh(cod)2]2(BF4) and P(p-tolyl)3 in the presence of a base gives cyclopentanone derivatives in moderate to good yield.

Journal Article↗
PubMed2005

Bergman cyclization of sterically hindered substrates and observation of phenyl-shifted products.

Heating 1,2-bis(phenylethynyl)benzene in the presence of 1,4-cyclohexadiene at temperatures ranging from 260 to 360 degrees C yielded the expected Bergman product, 2,3-diphenylnaphthalene, as only a minor product (<3%) under all reaction conditions studied. The major products, resulting from one or more phenyl shifts, were 1,3- and 1,4-diphenylnaphthalene which formed in up to 16% and 11% yield, respectively. Although somewhat less efficiently, 1-ethynyl-2-(phenylethynyl)benzene and (Z)-1,6-diphenylhex-3-ene-2,5-diyne also yielded products resulting from phenyl shifts. These results are explained through computations that point to the role of steric repulsion and benzyne stability in driving these isomerizations. The computed barriers for phenyl shifting are dramatically higher than those observed in the case of sp3 radicals. However, these transformations are relevant in solution chemistry as well as in more extreme environments such as those encountered during combustion, pyrolysis, and electric discharge heating.

Journal Article↗
PubMed2005

Asymmetric induction during Yang cyclization of alpha-oxoamides: the power of a covalently linked chiral auxiliary is enhanced in the crystalline state.

Gamma-hydrogen abstraction has been revealed to be the primary photoprocess in the crystalline state of alpha-oxoamides through photochemical and X-ray structural studies. The outstanding ability of a covalent chiral auxiliary in generating asymmetric induction in the photoproduct beta-lactam has been established with 10 examples. We have shown that the crystal lattice preorganizes the reactant molecules toward a single diastereomer of the beta-lactam and prevents large motions of the 1,4-diradical intermediate that would result in the loss of stereochemical memory. A rare single-crystal-to-single-crystal transformation path of one of the examples investigated establishes the direct correlation between the stereochemistries of the reactant and the product.

Journal Article↗
PubMed2004

Oxidative cyclizations: the asymmetric synthesis of (-)-alliacol A.

A tandem anodic coupling-Friedel-Crafts alkylation strategy has been used to rapidly complete the asymmetric synthesis of alliacol A. The anodic oxidation reaction allowed for the generation of a new bond between two nucleophiles. In the synthesis, the absolute stereochemistry of the final natural product is set relative to a methyl group that is incorporated early in the sequence using an asymmetric Michael reaction.

Agaricales↗
PubMed2004

Highly enantioselective catalytic carbon dioxide incorporation reaction: nickel-catalyzed asymmetric carboxylative cyclization of bis-1,3-dienes.

A method for nickel-catalyzed asymmetric carbon dioxide (CO2) incorporation via carbon-carbon bond formation was developed. In the presence of a catalytic amount of Ni(acac)2 and MeO-MOP, various bis-1,3-dienes reacted with CO2 (1 atm) and a diorganozinc reagent (Me2Zn or Ph2Zn) to afford cyclic carboxylic acids in good yields (71-100%) and with high enantioselectivities (90-96% ee).

Journal Article↗
PubMed2005

Theoretical studies of stereoselectivities of intramolecular aldol cyclizations catalyzed by amino acids.

The effects of different amino acid catalysts and substrate substituents on the stereoselectivity of the title reactions have been studied with the aid of density functional theory methods. Experimental data available in the literature have been compiled. B3LYP/6-31G(d) calculations match the general experimental trends and provide useful insights into the origins of the variations in stereoselectivities. Acyclic primary amino acids allow a greater conformational flexibility in the aldol transition states compared with proline. This makes them poorer enantioselective catalysts with triketone substrates with a methyl ketone side chain. The steric repulsion upon substitution at the terminal methyl group increases the energy difference between anti- and syn-chairs with primary amino acid catalysts and, consequently, the stereoselectivities. Proline, in contrast, is a poor catalyst for the latter reactions because the substituent's steric bulkiness raises the activation energy of the favored C-C bond-forming pathway.

Aldehydes↗
PubMed2005

1,2-Didehydro[10]annulenes: structures, aromaticity, and cyclizations.

The conformational space of C(10)H(8) 1,2-didehydro[10]annulenes, along with their unimolecular conversion to isonaphthalenes (cyclic allenes), has been studied computationally using DFT (B3LYP), single-reference [CCSD(T)], and multireference (MCQDPT2) post-HF methods. The introduction of the linear alkynyl moiety releases enough angle strain to make a nearly planar "heart" aromatic form the preferred conformer by more than 6 kcal/mol [CCSD(T)] over a localized C(2) "twist" structure, as opposed to the closely related C(10)H(10) [10]annulene system. Computations also show that electrocyclic ring-opening of isonaphthalenes to the heart C(10)H(8) annulene takes place through a low barrier of 15 kcal/mol, and this should be considered the working mechanism for the reported isomerizations during dehydro Diels-Alder reactions of phenylacetylenes.

Journal Article↗
PubMed2005

Organomediated Morita-Baylis-Hillman cyclization reactions.

We have developed the Morita-Baylis-Hillman reaction to include, for the first time in a completely organomediated process, intramolecular examples bearing allylic leaving groups as the electrophilic partner providing a facile, high yielding, straightforward synthesis of densely functionalized cyclic molecules.

Journal Article↗
PubMed2006

Tandem Nazarov cyclization-michael addition sequence catalyzed by an Ir(III) complex.

The first examples of a tandem Nazarov cyclization/Michael addition process are described. The sequence is efficiently catalyzed by Ir[Me(CO)(dppe)(DIB)]2+ and occurs with high diastereoselectivity, creating three contiguous stereocenters. The mechanistic factors controlling the reactivity and diastereoselectivity are discussed.

Journal Article↗
PubMed1994

Design, synthesis, and biological properties of highly potent cyclic dynorphin A analogues. Analogues cyclized between positions 5 and 11.

We have recently reported the synthesis of several cyclic disulfide bridge-containing peptide analogues of dynorphin A (Dyn A), which were conformationally constrained in the putative address segment of the opioid ligand. Several of these analogues, bridged between positions 5 and 11 of Dyn A1-11-NH2, exhibited unexpected selectivities for the kappa and mu receptors of the central over the peripheral nervous systems. In order to further investigate the conformational and topographical requirements for the residues in positions 5 and 11 of these analogues, we have synthesized a systematic series of Dyn A1-11-NH2 analogues incorporating the sulfydryl containing amino acids L- and D-Cys and L- and D-Pen in positions 5 and 11, thus producing 16 cyclic peptides. In addition, Dyn A1-11-NH2, [D-Leu5]Dyn A1-11-NH2, and [D-Lys11]Dyn A1-11-NH2 were synthesized as standards. Several of these cyclic analogues, especially c[Cys5,D-Cys11] Dyn A1-11-NH2, c[Cys5, L- or D-Pen11]Dyn A1-11-NH2, c[Pen5, L-Pen11]Dyn A1-11-NH2 and c[Pen5, L- or D-Cys11]Dyn A1-11-NH2, retained the same affinity and selectivity (vs the mu and delta receptors) as the parent compound Dyn A1-11-NH2 in the guinea pig brain (GPB). These same analogues and most others exhibited a much lower activity in the guinea pig ileum (GPI), thus leading to centrally vs peripherally selective peptides, but showed a different structure-activity relationship than found previously. In a wider scope, this series of analogues also provided new insights into which amino acids (and their configurations) may be used in positions 5 and 11 of Dyn A analogues for high potency and good selectivity at kappa opioid receptors. The results obtained in the GPB suggest that requirements for binding are not the same for the kappa, mu, or delta central receptors.

Amino Acid Sequence↗
PubMed2004

Synthesis and opioid activity of side-chain-to-side-chain cyclic dynorphin A-(1-11) amide analogues cyclized between positions 2 and 5. 1. Substitutions in position 3.

cyclo[d-Asp(2),Dap(5)]Dyn A-(1-13)NH(2) (Dap, 2,3-diaminopropionic acid; Dyn A, dynorphin A), synthesized previously in our laboratory, showed sub-nanomolar affinity for kappa opioid receptors and potent agonist activity in the guinea pig ileum assay (Arttamangkul et al., J. Med. Chem. 1995, 38, 2410-2417). Various modifications were made in position 3 of cyclo[d-Asp(2),Dap(5)]Dyn A-(1-11)NH(2) that could influence the opioid receptor affinity, selectivity, and/or efficacy of this peptide. An optimized orthogonal synthetic strategy was developed for the synthesis of these cyclic peptides in which the final peptides could be cleaved from the solid support with trifluoroacetic acid. Substitutions of Gly(3) by Ala, d-Ala, Trp, and d-Trp in cyclo[d-Asp(2),Dap(5)]Dyn A-(1-11)NH(2) and its linear counterpart [d-Asp(2),Dap(5)]Dyn A-(1-11)NH(2) were generally well tolerated by both kappa and micro opioid receptors. Despite differences in the size and stereochemistry of the substitutions, most of the peptides (except for cyclo[d-Asp(2),Pro(3),Dap(5)]Dyn A-(1-11)NH(2) and [d-Asp(2),d-Ala(3), Dap(5)]Dyn A-(1-11)NH(2)) exhibited low nanomolar affinity for both kappa (K(i) = 0.21 to 2.2 nM) and micro (K(i) = 0.22 to 7.27 nM) opioid receptors. All of the 3-substituted cyclic and linear analogues synthesized showed reduced affinity for delta opioid receptors. Incorporation of d-Ala at position 3 of cyclo[d-Asp(2),Dap(5)]Dyn A-(1-11)NH(2) exhibited 2-fold higher kappa opioid receptor affinity and 16-fold higher selectivity for kappa over micro opioid receptors than the parent cyclic peptide. In contrast, substitution of Ala at position 3 resulted in an analogue with 2.4-fold lower affinity and very low preference for kappa over micro opioid receptors. The Trp and d-Trp cyclic and linear analogues exhibited similar nanomolar affinities for kappa opioid receptors. cyclo[d-Asp(2),Pro(3),Dap(5)]Dyn A-(1-11)NH(2) showed the largest decreases in affinity for all three opioid receptors compared to the parent cyclic peptide. Except for cyclo[d-Asp(2), Pro(3),Dap(5)]Dyn A-(1-11)NH(2), which was a partial agonist, all of the cyclic peptides exhibited full agonist activity in the adenylyl cyclase assay using cloned kappa opioid receptors.

Adenylyl Cyclases↗
PubMed2005

Imaging of melanoma using 64Cu- and 86Y-DOTA-ReCCMSH(Arg11), a cyclized peptide analogue of alpha-MSH.

Early detection of melanoma is essential, since a patient's prognosis with metastatic melanoma is poor. Previous studies showed that (111)In-DOTA-ReCCMSH(Arg(11)), a cyclic analogue of alpha-melanocyte stimulating hormone (alpha-MSH), exhibited high tumor concentration and rapid clearance from nontarget tissue. The goal of this current study was to label DOTA-ReCCMSH(Arg(11)) with beta(+)-emitting radionuclides, to determine if the high sensitivity of positron emission tomography (PET) imaging would aid in the detection of malignant melanoma. DOTA-ReCCMSH(Arg(11)) was labeled with (64)Cu and (86)Y. Biodistribution and small animal PET imaging were carried out in mice implanted with B16/F1 murine melanoma tumor and compared with data obtained in the same animal model with [(18)F]FDG. In both cases a subset of animals were co-injected with 20 microg of DOTA-ReCCMSH(Arg(11)) to determine if tumor concentration was receptor mediated. Tumor concentration for both the (86)Y- and (64)Cu-complexes reached a maximum at 30 min, while coadministering 20 microg of unlabeled complex reduced tumor uptake significantly. Nontarget organ concentration was considerably lower with (86)Y-DOTA-ReCCMSH(Arg(11)) than its (64)Cu analogue, except in the kidneys, where the (64)Cu complex had lower accumulation at all time points. Small animal PET images for both complexes showed the tumor could be visualized after 30 min, with the standardized uptake value (SUV) analysis following a similar trend as the biodistribution data. The data obtained suggests that DOTA-ReCCMSH(Arg(11)), when labeled with beta(+)-emitting radionuclides, has the potential for early detection of malignant melanoma by exploiting the sensitivity and high resolution of PET.

Animals↗