Methyl Cation Affinities of Canonical Organic Functional Groups.

Methyl cation affinities are calculated for the canonical nucleophilic functional groups in organic chemistry. These methyl cation affinities, calculated with a solvation model (MCA*), give an emprical correlation with the NsN term from the Mayr equation under aprotic conditions when they are scaled to the Mayr reference cation (4-MeOC6H4)2CH+ (Mayr E = 0). Highly reactive anionic nucleophiles were found to give a separate correlation, while some ylides and phosphorus compounds were determined to give a poor correlation. MCA*s are estimated for a broad range of simple molecules representing the canonical functional groups in organic chemistry. On the basis of a linear correlation, we estimate the range of nucleophilicities of organic functional groups, ranging from a C-C bond to a hypothetical tert-butyl carbanion, toward the reference electrophile to be about 50 orders of magnitude.

Methyl Anion Affinities of the Canonical Organic Functional Groups.

Calculated methyl anion affinities are known to correlate with experimentally determined Mayr E parameters for individual organic functional group classes but not between neutral and cationic organic electrophiles. We demonstrate that methyl anion affinities calculated with a solvation model (MAA*) give a linear correlation with Mayr E parameters for a broad range of functional groups. Methyl anion affinities (MAA*), plotted on the log scale of Mayr E, provide insights into the full range of electrophilicity of organic functional groups. On the Mayr E scale, the electrophilicity toward the methyl anion spans 180 orders of magnitude.

Total Synthesis of (±)-Brazilin Using [4 + 1] Palladium-Catalyzed Carbenylative Annulation.

Palladium-catalyzed carbene insertion was utilized in a formal synthesis of (±)-picropodophyllone and a total synthesis of (±)-brazilin. All prior syntheses of brazilin have involved a Friedel-Crafts alkylation in the key carbon-carbon bond forming events. The palladium-catalyzed [4 + 1] reaction generates a 1-arylindane with all of the functionalities needed for formation of the indano[2,1-c]chroman ring system of brazilin. The synthesis of (±)-brazilin was achieved in 11 steps (longest linear sequence) with an overall 11% yield.

Enantioselective Palladium-Catalyzed Carbene Insertion into the N-H Bonds of Aromatic Heterocycles.

C3-substituted indoles and carbazoles react with α-aryl-α-diazoesters under palladium catalysis to form α-(N-indolyl)-α-arylesters and α-(N-carbazolyl)-α-arylesters. The products result from insertion of a palladium-carbene ligand into the N-H bond of the aromatic N-heterocycles. Enantioselection was achieved using a chiral bis(oxazoline) ligand, in many cases with high enantioselectivity (up to 99 % ee). The method was applied to synthesize the core of a bioactive carbazole derivative in a concise manner.

Rhodium(II)-Catalyzed Hinsberg Dearomatization Using Trimethylsilyldiazomethane.

Rhodium(II) catalyzes carbene transfer from trimethylsilyldiazomethane to arylmethyl thioethers, generating sulfonium ylides that undergo [2,3]-sigmatropic rearrangement, punching quaternary centers into aromatic rings. The reaction works well with naphthalene, indole, and benzofuran ring systems, but the reaction is unsuccessful with the monocyclic benzene homologue. For aryl thioethers, Rh2(OAc)4 gives good results. For alkyl thioethers, the yields improve with Rh2(cap)4. Surprisingly, thioesters and thiocarbamates are also competent substrates for the reaction.

Tandem Insertion/[3,3]-Sigmatropic Rearrangement Involving the Formation of Silyl Ketene Acetals by Insertion of Rhodium Carbenes into S-Si Bonds.

Allyl 2-diazo-2-phenylacetates are shown to react with trimethylsilyl thioethers in the presence of rhodium(II) catalysts to generate α-allyl-α-thio silyl esters. The transformation involves a tandem process involving formal rhodium-catalyzed insertion of the carbene group into the S-Si bond to generate a silyl ketene acetal, followed by a spontaneous Ireland-Claisen rearrangement. The silyl ester products were isolated as the corresponding carboxylic acids after aqueous workup. Intramolecular cyclopropanation of the allyl fragment generally competes with addition of the heteroatom to the carbene center. The reaction occurs under mild conditions and in high yield, allowing for rapid entry into rearrangement tetrasubstituted products. Propargyl esters were shown to generate the corresponding α-allenyl products.

Palladium-catalyzed insertion of alpha-diazoesters into vinyl halides to generate alpha,beta-unsaturated gamma-amino esters.

As easy as 1, 2, 3: A palladium-catalyzed three-component coupling generates alpha,beta-unsaturated gamma-amino acids in a single step (see scheme). The reaction is believed to involve migration of a vinyl substituent to a highly electrophilic palladium carbene. Unlike previous synthetic approaches, this synthesis provides access to gamma-amino acids with non-natural side chains.

Total Synthesis of (±)-Pestalachloride C and (±)-Pestalachloride D through a Biomimetic Knoevenagel/Hetero-Diels-Alder Cascade.

A concise total synthesis of (±)-pestalachloride C and (±)-pestalachloride D was achieved through a Knoevenagel/hetero-Diels-Alder cascade reaction to test the nonenzymatic biosynthetic hypothesis of Shao, Wang, and co-workers. The cascade reaction generates a mixture of racemic indano[2,1- c]chromans like those found in the natural products.

Palladium-catalyzed carbene insertion and trapping with carbon nucleophiles.

Palladium catalysts are shown to catalyze the three-component coupling of vinyl halides, trimethylsilyldiazomethane, and stabilized carbon nucleophiles. The reaction is believed to proceed through a palladium-carbene intermediate LX(R)PdCHSiMe 3 that undergoes migration of the vinyl substituent to the electrophilic carbene center to generate an eta 3-allylpalladium intermediate. The allylpalladium intermediate is attacked by the carbon nucleophile to generate a vinylsilane product.

Synthesis, screening, and sequencing of cysteine-rich one-bead one-compound peptide libraries.

Cysteine-rich peptides are valued as tags for biarsenical fluorophores and as environmentally important reagents for binding toxic heavy metals. Due to the inherent difficulties created by cysteine, the power of one-bead one-compound (OBOC) libraries has never been applied to the discovery of short cysteine-rich peptides. We have developed the first method for the synthesis, screening, and sequencing of cysteine-rich OBOC peptide libraries. First, we synthesized a heavily biased cysteine-rich OBOC library, incorporating 50% cysteine at each position (Ac-X8-KM-TentaGel). Then, we developed conditions for cysteine alkylation, cyanogen bromide cleavage, and direct MS/MS sequencing of that library at the single bead level. The sequencing efficiency of this library was comparable to a traditional cysteine-free library. To validate screening of cysteine-rich OBOC libraries, we reacted a library with the biarsenical FlAsH and identified beads bearing the known biarsenical-binding motif (CCXXCC). These results enable OBOC libraries to be used in high-throughput discovery of cysteine-rich peptides for protein tagging, environmental remediation of metal contaminants, or cysteine-rich pharmaceuticals.

Palladium-catalyzed carbene insertion into vinyl halides and trapping with amines.

Palladium is shown to catalyze the three-component coupling of vinyl halides, trimethylsilyldiazomethane, and amines to generate allylamines. The mechanism is believed to involve formation of an R-Pd=CHSiMe3 intermediate that undergoes migration of the vinyl ligand to the empty p-orbital of the carbene ligand. The resulting eta1-allylpalladium species forms an eta3-allylpalladium intermediate that is trapped by the amine nucleophile. Under the conditions tested, cyclic secondary amines and terminal vinyl iodides give the best results.

Potent Antifungal Synergy of Phthalazinone and Isoquinolones with Azoles Against Candida albicans.

Four phthalazinones (CIDs 22334057, 22333974, 22334032, 22334012) and one isoquinolone (CID 5224943) were previously shown to be potent enhancers of antifungal activity of fluconazole against Candida albicans. Several even more potent analogues of these compounds were identified, some with EC50 as low as 1 nM, against C. albicans. The compounds exhibited pharmacological synergy (FIC < 0.5) with fluconazole. The compounds were also shown to enhance the antifungal activity of isavuconazole, a recently FDA approved azole antifungal. Isoquinolone 15 and phthalazinone 24 were shown to be active against several resistant clinical isolates of C. albicans.

DNA sequence recognition by the indolocarbazole antitumor antibiotic AT2433-B1 and its diastereoisomer.

The antibiotic AT2433-B1 belongs to a therapeutically important class of antitumor agents. This natural product contains an indolocarbazole aglycone connected to a unique disaccharide consisting of a methoxyglucose and an amino sugar subunit, 2,4-dideoxy-4-methylamino-L-xylose. The configuration of the amino sugar distinguishes AT2433-B1 from its diastereoisomer iso-AT2433-B1. Here we have investigated the interaction of these two disaccharide indolocarbazole derivatives with different DNA sequences by means of DNase I footprinting and surface plasmon resonance (SPR). Accurate binding measurements performed at 4 and 25 degrees C using the BIAcore SPR method revealed that AT2433-B1 binds considerably more tightly to a hairpin oligomer containing a [CG](4) block than to an oligomer with a central [AT](4) tract. The kinetic analysis shows that the antibiotic dissociates much more slowly from the GC sequence compared to the AT one. Preferential binding of AT2433-B1 to GC-rich sequences in DNA was independently confirmed by DNase I footprinting experiments performed with a 117 bp DNA restriction fragment. The specific binding sequence 5'-AACGCCAG identified from the footprints was then converted into a biotin-labeled DNA hairpin duplex and compound interactions with this specific sequence were characterized by high resolution BIAcore SPR experiments. Such a combined approach provided a detailed understanding of the molecular basis of DNA recognition. The discovery that the glycosyl antibiotic AT2433-B1 preferentially recognizes defined sequences offers novel opportunities for the future design of sequence-specific DNA-reading small molecules.

Polychlorinated biphenyls inhibit amyloid fibril formation.

In this issue of Chemistry & Biology, Purkey et al. [1] compare the binding of PCBs and hydroxylated PCBs (polychlorinated biphenyls) with the human serum protein transthyretin. Hydroxylated PCBs appear to bind with higher selectivity to transthyretin relative to other serum proteins and in so doing inhibit amyloid fibril formation.

Carbenylative Amination and Alkylation of Vinyl Iodides via Palladium Alkylidene Intermediates.

Most palladium-catalyzed reactions involving insertion of alkylidenes with α-hydrogens undergo ß-hydride elimination from alkylpalladium(II) intermediates to form alkenes. Vinyl iodides were shown to generate η(3)-allylpalladium intermediates that resist ß-hydride elimination, preserving the sp(3) center adjacent to the carbene moiety. Acyclic stereocontrol (syn/anti) for carbenylative amination and alkylation reactions was low, suggesting a lack of control in the migratory insertion step. Highly hindered carbene precursors inexplicably led to formation of Z-alkenes with high levels of stereocontrol.

Potent Synergy between Spirocyclic Pyrrolidinoindolinones and Fluconazole against Candida albicans.

A spiroindolinone, (1S,3R,3aR,6aS)-1-benzyl-6'-chloro-5-(4-fluorophenyl)-7'-methylspiro[1,2,3a,6a-tetrahydropyrrolo[3,4-c]pyrrole-3,3'-1H-indole]-2',4,6-trione, was previously reported to enhance the antifungal effect of fluconazole against Candida albicans. A diastereomer of this compound was synthesized, along with various analogues. Many of the compounds were shown to enhance the antifungal effect of fluconazole against C. albicans, some with exquisite potency. One spirocyclic piperazine derivative, which we have named synazo-1, was found to enhance the effect of fluconazole with an EC50 value of 300 pM against a susceptible strain of C. albicans and going as low as 2 nM against some resistant strains. Synazo-1 exhibits true synergy with fluconazole, with an FIC index below 0.5 in the strains tested. Synazo-1 exhibited low toxicity in mammalian cells relative to the concentrations required for antifungal synergy.

Synthesis of dityrosine cross-linked peptide dimers using the Miyaura-Suzuki reaction.

[reaction: see text] Since peroxidase-catalyzed dityrosine formation is inefficient for peptides, we have developed alternative conditions for intermolecular dityrosine formation using the Miyaura-Suzuki reaction. A one-pot reaction is effective for cross-linking short peptides, but longer peptides inhibit the Suzuki step, mandating a traditional two-step procedure using potassium acetate for the Miyaura reaction and potassium carbonate for the Suzuki coupling. These palladium-based methods are complementary to the well-established peroxidase-catalyzed oxidative phenolic coupling of full-length proteins.

Synthesis of phakellistatin 13 and oxidation to phakellistatin 3 and isophakellistatin 3.

The natural product phakellistatin 13 cyclo-(TrpProPheGlyProThrLeu) was synthesized. Photosensitized oxidation of phakellistatin 13 gave the natural products phakellistatin 3 and isophakellistatin 3, demonstrating for the first time that a tryptophan residue can be directly converted to the corresponding 3a-hydroxypyrrolo[2,3-b]indoline in a full length peptide. Competitive oxidation of the indoline product was identified as the cause of low mass balance and is probably the source of low mass balance in the oxidative cyclization of all tryptamine derivatives. [reaction--see text]

Synthesis of (+/-)-madindolines and chemical models. Studies of chemical reactivity.

[reaction: see text] The madindolines are believed to inhibit cytokine signaling through the gp130 receptor. Model compounds of madindolines were synthesized and tested for thiol reactivity. The heterocyclic moiety of madindoline was shown to form thiol adducts via the Savige-Fontana reaction. The enedione moiety was found to be unreactive toward simple thiols unless the quaternary center was removed. Using the powerful Moore reaction, we have synthesized (+/-)-madindoline A and B in 11 steps.

Conformational Control in the Rebeccamycin Class of Indolocarbazole Glycosides.

Indolocarbazole glycosides are balanced between two conformations: a "closed" conformation containing a cyclic hydrogen bond between the indolocarbazole NH and the pyranose oxygen and an "open" conformation in which the indolocarbazole NH is hydrogen bonded to solvent. The open conformation never has a commanding advantage, even in DMSO, but in nonpolar environments the cyclic conformation predominates.