Redox‐Triggered C?C Coupling of Diols and Alkynes: Synthesis of β,γ‐Unsaturated α‐Hydroxyketones and Furans by Ruthenium‐Catalyzed Hydrohydroxyalkylation

Direct ruthenium‐catalyzed C C coupling of alkynes and vicinal diols to form β,γ‐unsaturated ketones occurs with complete levels of regioselectivity and good to complete control over the alkene geometry. Exposure of the reaction products to substoichiometric quantities of p‐toluenesulfonic acid induces cyclodehydration to form tetrasubstituted furans. These alkyne‐diol hydrohydroxyalkylations contribute to a growing body of merged redox‐construction events that bypass the use of premetalated reagents and, hence, stoichiometric quantities of metallic by‐products.     

Enantioselective Palladium‐Catalyzed Insertion of α‐Aryl‐α‐diazoacetates into the O?H Bonds of Phenols

A palladium‐catalyzed asymmetric O H insertion reaction was developed. Palladium complexes with chiral spiro bisoxazoline ligands promoted the insertion of α‐aryl‐α‐diazoacetates into the O H bond of phenols with high yield and excellent enantioselectivity under mild reaction conditions. This palladium‐catalyzed asymmetric O H insertion reaction provided an efficient and highly enantioselective method for the preparation of synthetically useful optically active α‐aryl‐α‐aryloxyacetates.     

Rhodium‐catalyzed coupling reactions of β‐ or α,β‐substituted vinylpyridines with alkenes via C?H bond activation

β‐ or α,β‐Substituted vinylpyridines react with 3,3‐dimethylbut‐1‐ene in the presence of Wilkinson catalyst [RhCl(PPh₃)₃] to give the corresponding alkylated products along with unusually isomerized products. © 2002 Wiley Periodicals, Inc. Heteroatom Chem 13:346–350, 2002; Published online in Wiley Interscience (www.interscience.wiley.com). DOI 10.1002/hc.10045     

Note: Helix or No Helix of β‐Peptides Containing β3hAla(αF) Residues?

A remote ⁴J(F,H) coupling (F? C(α)? C(O)? N? H) of up to 4.2 Hz in α‐fluoro amides with antiperiplanar arrangement of the C? F and the C?O bonds (dihedral angle F? C? C?O ca. 180°) confirms that previous NMR determinations, using the XPLOR‐NIH procedure, of the secondary structures of β‐peptides containing β³hAla(αF) and β³hAla(αF₂) residues were correct. In contrast, molecular‐dynamics (MD) simulations, using the GROMOS program with the 45A3 force field, led to an incorrect conclusion about the relative stability of secondary structures of these β‐peptides. The problems encountered in NMR analyses and computations of the structures of backbone‐F‐substituted peptides are briefly discussed.     

Conformationally Biased Mimics of Mannopyranosylamines: Inhibitors of β‐Mannosidases?

The enol ether 7 was prepared by cleavage of the N−O bond of the known isoxazolidine 3 , followed by N‐alkylation to 4 , silylation and oxidation to the N‐oxide 6 , and Cope elimination. Cu‐Catalysed cyclopropanation of 7 led to the diastereoisomeric cyclopropanes 8 and 9 , which were subjected to a Curtius degradation. The resulting carbamates 12 and 16 were deprotected to the ammonium salts 14 and 18 , respectively. Both salts adopt a B_1,4 conformation, similarly as the ester 8 , while the isomeric ester 9 exists in a ca. 6 : 4 equilibrium of the ⁴C₁ and B_1,4 conformers. The β‐mannoside mimic 14 does not inhibit snail β‐mannosidase at 10 mM , but the α‐mannoside mimic 18 inhibits Jack bean α‐mannosidase (IC₅₀=80 μM ). These results are in keeping with the postulate that glycoside cleavage of β‐D ‐glycopyranosides requires a conformational change in agreement with the principle of stereoelectronic control.     

Synthesis of Perfluoroalkyl‐Substituted γ‐Lactones and 4,5‐Dihydropyridazin‐3(2H)‐ones via Donor?Acceptor Cyclopropanes

Rh₂(OAc)₄‐Catalyzed decomposition of diazo esters in the presence of perfluoroalkyl‐ or perfluoroaryl‐substituted silyl enol ethers smoothly provided the corresponding alkyl 2‐siloxycyclopropanecarboxylates in very good yields. The generated donor? acceptor cyclopropanes are equivalents of γ‐oxo esters, which we demonstrated by their one‐pot transformations to yield fluorine‐containing heterocycles. A reductive procedure selectively afforded perfluoroalkyl‐substituted γ‐hydroxy esters or γ‐lactones. The treatment of the donor? acceptor cyclopropanes with hydrazine or phenylhydrazine afforded a series of perfluoroalkyl‐ and perfluoroaryl‐substituted 4,5‐dihydropyridazin‐3(2H)‐ones.     

Is δ‐Aminolevulinic Acid Dehydratase Rate Limiting in Heme Biosynthesis Following Exposure of Cells to δ‐Aminolevulinic Acid?¶

Understanding the regulation and control of heme/porphyrin biosynthesis is critical for the optimization of the delta-aminolevulinic-acid (ALA)-mediated photodynamic therapy of cancer, in which endogenously produced protoporphyrin IX (PPIX) is the photosensitizer. The human breast cancer cell line MCF-7, the rat mammary adenocarcinoma cell line R3230AC, the mouse mammary tumor cell line EMT-6 and the human mesothelioma cell line H-MESO-1 were used to study ALA-induced PPIX levels and their relationship to delta-aminolevulinic acid dehydratase (ALA-D) activity in vitro. Incubation of these cell lines with 0.5 mM ALA for 3 h resulted in a significant increase in PPIX accumulation, compared with control cells, but there was no significant change in ALA-D activity. Exposure of cells incubated with ALA to 30 mJ/cm2 of fluorescent light, a dose that would cause a 50% reduction in cell proliferation, did not significantly alter the activity of ALA-D. Increasing the activity of porphobilinogen deaminase (PBGD), the enzyme immediately subsequent to ALA-D, by four- to seven-fold via transfection of cells with PBGD complementary DNA did not alter the activity of ALA-D. However, incubation of cells with various concentrations of succinyl acetone, a potent inhibitor of ALA-D, caused a concomitant decline in both PPIX accumulation and ALA-D activity. These data imply that when cells are exposed to exogenous ALA, ALA-D is an important early-control step in heme/porphyrin biosynthesis and that regulation of PPIX synthesis by this dehydratase may impact the effectiveness of ALA-mediated photosensitization.     

Oligomers of β2- and of β3-Homoproline: What are the Secondary Structures of β-Peptides Lacking H-Bonds?

To study the role of H-bonds in stabilizing β-peptidic secondary structures, we have synthesized β-oligopeptides (up to the octadecamer 12 ) consisting of β²- and β³-homoproline, i.e., β-peptides lacking amide protons. The enantiomer purity of the building block β²-homoproline (nipecotic acid, 4 ) was determined by HPLC analysis of the N-(2,4-dinitrophenyl) derivative 5 on a Chiralcel-OD column (cf. Fig. 2). The CD spectra of the all-(S)-β²- and all-(S)-β³-HPro-containing β-peptides display novel and intensive CD patterns which may be indicative of a secondary structure (cf. Fig. 3). It is noteworthy that a distinct CD pattern was observed with the β³-HPro derivatives containing as few as three residues ( 7a ). The crystal structure of a N-deprotected β³-HPro-tripeptide 7c is presented (cf. Figs. 4 and 5), and a model for the structure of β-peptides consisting of β³-HPro is discussed (cf. Figs. 6 and 7).     

How Strong Are Hydrogen Bonds in Metalla‐β‐diketones?

The energies of the kinetically inert, electronically saturated Lukehart-type metalla-beta-diketone [Re{(COMe)2H}(CO)4] (9 a) and of the kinetically labile, electronically unsaturated platina-beta-diketones [Pt{(COMe)2H}Cl2]- (10 a), [Pt2{(COMe)2H}2(micro-Cl)2] (11 a), and [Pt{(COMe)2H}(bpy)]+ (12 a) have been calculated by DFT at the B3LYP/6-311++G(d,p) level using effective core potentials with consideration of relativistic effects for the transition metals. Analogously, energies of the requisite open (non-hydrogen-bonded) equilibrium conformers (9 b, 10 c, 11 b, 12 b) and energies which were obtained from the hydrogen-bonded conformers by rigid rotation of the OH group around the C--O bond by 180 degrees followed by relaxation of all bond lengths and angles (9 c, 10 d, 11 c, 12 d) have been calculated. These energies were found to be higher by 14.7/27.2 (9 b/9 c), 20.7/27.2 (10 c/10 d), 19.2/25.7 (11 b/11 c), and 9.4/19.6 kcal mol(-1) (12 b/12 d) than those of the intramolecularly O--HO hydrogen-bonded metalla-beta-diketones 9 a, 10 a, 11 a, and 12 a, respectively. In acetylacetone (Hacac), the generic organic analogue of metalla-beta-diketones, the energies of the most stable non-hydrogen-bonded enol isomer (6 b) and of the conformer derived from the H-bonded form by rigid rotation of the OH group by 180 degrees followed by subsequent relaxation of all bond lengths and angles (6 k) were found to be 10.9/16.1 kcal mol(-1) (6 b/6 k) higher compared to the intramolecularly O--HO bonded isomer 6 a. Thus, the hydrogen bonds in metalla-beta- diketones must be regarded as strong and were found to be up to twice as strong as that in acetylacetone. A linear relationship was found between the hydrogen-bond energies based on the rigidly rotated structures and the OO separation in the hydrogen-bonded structures. Furthermore, these energies were also found to be correlated with the electron densities at the OH bond critical points (rhobcp) in the O--HO bonds of metalla-beta-diketones 9 a, 10 a, 11 a, and 12 a (calculated using the AIM theory). The comparison of the energies of the doubly intermolecularly hydrogen-bonded dinuclear platina-beta-diketone [{Pt{(COMe)2H}(bpy)}2]2+ (14) with that of the mononuclear intramolecularly hydrogen-bonded cation [Pt{(COMe)2H}(bpy)]+ (12 a) showed that the intermolecular hydrogen bonds in 14 are weaker than the intramolecular hydrogen bond in 12.     

CD Spectra in Methanol of β‐Oligopeptides Consisting of β‐Amino Acids with Functionalized Side Chains,with Alternating Configuration,and with Geminal Backbone Substituents – Fingerprints of New Secondary Structures?

β‐Hexa‐, β‐hepta‐, and β‐nonapeptides, 1 – 6 , which carry functionalized side chains (CO₂R, CO, (CH₂)₄NH, CH₂−CH=CH₂) consisting of β³‐amino‐acid residues of alternating configuration, or which carry geminal substituents in the 2‐ or 3‐positions of all residues, have been synthesized (Schemes 1 – 3), and their CD spectra in MeOH are reported (Figs. 2 – 6). Strong Cotton effects (Θ>10⁵) are indicative of the presence of chiral secondary structures. It is suggested by simple modelling (Fig. 1) that the new β‐peptides should not be able to fold to the familiar 3₁₄‐helical structures. Still, three of them ( 3 , 4 , and 5 ) give rise to CD spectra matching those of β‐peptides that are known to be present as (M)‐ or (P)‐3₁₄‐helices in MeOH solution. While possible folding motifs (Figs. 3,b, and 7) of the new β‐peptides have been identified in crystal structures, an interpretation of the CD spectra has to be postponed until NMR solution structures become available. A list of all β‐peptides giving rise to CD spectra with a minimum near 215 nm is included (Table).     

Is the μ‐Oxo‐μ‐Peroxodiiron Intermediate of a Ribonucleotide Reductase Biomimetic a Possible Oxidant of Epoxidation Reactions?

Density functional calculations on a mu-oxo-mu-peroxodiiron complex (1) with a tetrapodal ligand BPP (BPP=N,N-bis(2-pyridylmethyl)-3-aminopropionate) are presented that is a biomimetic of the active site region of ribonucleotide reductase (RNR). We have studied all low-lying electronic states and show that it has close-lying broken-shell singlet and undecaplet (S=0, 5) ground states with essentially two sextet spin iron atoms. In strongly distorted electronic systems in which the two iron atoms have different spin states, the peroxo group moves considerably out of the plane of the mu-oxodiiron group due to orbital rearrangements. The calculated absorption spectra of (1,11)1 are in good agreement with experimental studies on biomimetics and RNR enzyme systems. Moreover, vibrational shifts in the spectrum due to (18)O(2) substitution of the oxygen atoms in the peroxo group follow similar trends as experimental observations. To identify whether the mu-oxo-mu-1,2-peroxodiiron or the mu-oxo-mu-1,1-peroxodiiron complexes are able to epoxidize substrates, we studied the reactivity patterns versus propene. Generally, the reactions are stepwise via radical intermediates and proceed by two-state reactivity patterns on competing singlet and undecaplet spin state surfaces. However, both the mu-oxo-mu-1,2-peroxodiiron and mu-oxo-mu-1,1-peroxodiiron complex are sluggish oxidants with high epoxidation barriers. The epoxidation barriers for the mu-oxo-mu-1,1-peroxodiiron complex are significantly lower than the ones for the mu-oxo-mu-1,2-peroxodiiron complex but still are too high to be considered for catalytic properties. Thus, theory has ruled out two possible peroxodiiron catalysts as oxidants in RNR enzymes and biomimetics and the quest to find the actual oxidant in the enzyme mechanism continues.     

Temperature-Dependent NMR and CD Spectra of β-Peptides: On the Thermal Stability of β-Peptide Helices – Is the Folding Process of β-Peptides Non-cooperative?

Temperature-dependent NMR and CD spectra of methanol solutions of a β-hexapeptide and of a β-heptapeptide at temperatures between 298 and 393 K are reported. They establish the fact that the 3₁₄-helical secondary structures of the two β-peptides, 1 and 2 , do not `melt' in the temperature range investigated. This is in sharp contrast to the behavior of the helices of α-peptides and proteins which undergo cooperative unfolding (`denaturing') upon heating. A non-cooperative mechanism is proposed, with a stepwise, rather than an `un-zipping' opening of H-bonded rings (cf. Fig. 6). The experimental results are regarded as evidence that, of the three effects which have been identified as contributing to the stability of β-peptide helices, i.e., H-bonding, hydrophobic interactions, and ethane staggering, the latter one is predominant.     

Can Helical Peptides Unwind One Turn at a Time? ‐ Controlled Conformational Transitions in α,β2,3‐Hybrid Peptides

Unfolding of helical trans‐β^2,3‐hybrid peptides with (α–β)_nα composition, when executed by increasing solvent polarity or temperature, proceeded in a systematic manner with the turns unwinding sequentially; C‐terminal region of these peptides were first to unwind and the process propagated towards N terminus with more and more β residues equilibrating from the gauche to the anti rotameric state across C_α?C_β. This is evidenced by clear change in their C_βH signal splitting, ³J_CαH–CβH values, and sequential disappearance of i,i+2 NOEs.     

Nucleophilic Attack of α‐Aminoalkyl Radicals on Carbon?Nitrogen Triple Bonds to Construct α‐Amino Nitriles: An Experimental and Computational Study

A new reactivity pattern of α‐aminoalkyl radicals, involving nucleophilic attack on C?N triple bonds under thermal conditions, has been developed to construct α‐amino nitriles. In contrast to previous C? H functionalization of tertiary amines involving α‐aminoalkyl radicals, this methodology does not require the use of photocatalytic conditions or a transition‐metal catalyst. Inexpensive and nontoxic phenylacetonitrile was chosen as cyano source for this α‐aminonitrile forming reaction. A plausible mechanism is proposed based upon experimental and computational results. An α‐aminoalkyl radical intermediate and benzoyl cyanide have been shown to be key intermediates in this green and mild radical process. Nucleophilic attack of the α‐aminoalkyl radical on the C?N bond of PhCOCN followed by an elimination step forms the desired α‐aminonitrile and an acyl radical.     

Electrophilic Arene Hydroxylation and Phenol O?H Oxidations Performed by an Unsymmetric μ‐η1:η1‐O2‐Peroxo Dicopper(II) Complex

Reactions of the unsymmetric dicopper(II) peroxide complex [Cu^II₂(μ‐η¹:η¹‐O₂)(m‐XYL^N3N4)]²⁺ ( 1 O₂ , where m‐XYL is a heptadentate N‐based ligand), with phenolates and phenols are described. Complex 1 O₂ reacts with p‐X‐PhONa (X=MeO, Cl, H, or Me) at ?90 °C performing tyrosinase‐like ortho‐hydroxylation of the aromatic ring to afford the corresponding catechol products. Mechanistic studies demonstrate that reactions occur through initial reversible formation of metastable association complexes [Cu^II₂(μ‐η¹:η¹‐O₂)(p‐X‐PhO)(m‐XYL^N3N4)]⁺ ( 1 O₂ ?X‐PhO) that then undergo ortho‐hydroxylation of the aromatic ring by the peroxide moiety. Complex 1 O₂ also reacts with 4‐X‐substituted phenols p‐X‐PhOH (X=MeO, Me, F, H, or Cl) and with 2,4‐di‐tert‐butylphenol at ?90 °C causing rapid decay of 1 O₂ and affording biphenol coupling products, which is indicative that reactions occur through formation of phenoxyl radicals that then undergo radical C? C coupling. Spectroscopic UV/Vis monitoring and kinetic analysis show that reactions take place through reversible formation of ground‐state association complexes [Cu^II₂(μ‐η¹:η¹‐O₂)(X‐PhOH)(m‐XYL^N3N4)]²⁺ ( 1 O₂ ?X‐PhOH) that then evolve through an irreversible rate‐determining step. Mechanistic studies indicate that 1 O₂ reacts with phenols through initial phenol binding to the Cu₂O₂ core, followed by a proton‐coupled electron transfer (PCET) at the rate‐determining step. Results disclosed in this work provide experimental evidence that the unsymmetric 1 O₂ complex can mediate electrophilic arene hydroxylation and PCET reactions commonly associated with electrophilic Cu₂O₂ cores, and strongly suggest that the ability to form substrate?Cu₂O₂ association complexes may provide paths to overcome the inherent reactivity of the O₂‐binding mode. This work provides experimental evidence that the presence of a H⁺ completely determines the fate of the association complex [Cu^II₂(μ‐η¹:η¹‐O₂)(X‐PhO(H))(m‐XYL^N3N4)]ⁿ⁺ between a PCET and an arene hydroxylation reaction, and may provide clues to help understand enzymatic reactions at dicopper sites.