Vinyltriarylbismuthonium Salts: Powerful Vehicles for α-Vinylation of Carbonyl Compounds.

α-Vinyl-carbonyl compounds are a class of orthogonally functionalized molecules, wherein the intrinsic C═O and C═C bonds can be used to unlock distinctly different reactivities. In this report, we present a simple method for the direct α-vinylation of carbonyl compounds utilizing vinyltriarylbismuthonium ("Vinyl-Bis") salts, which are stable and readily preparable on a decagram scale. This transformation is accomplished efficiently through the reaction of an in situ generated Li-enolate intermediate with a Vinyl-Bis reagent, leading to the formation of α-vinylated carbonyl compounds in good to excellent yields and with a remarkably broad substrate scope. Critically, this vinylation method is effective for enolates generated via numerous methods, enabling the sequencing of reactions that generate enolates with the vinylation step and the ready synthesis of diversely functionalized compounds, thereby underscoring the versatility and practicality of this method. Analogous reactions of discrete Li-enolates with other vinyl units and with aryl groups are also demonstrated.

Rapid Access to 2,2-Disubstituted Indolines via Dearomative Indolic-Claisen Rearrangement: Concise, Enantioselective Total Synthesis of (+)-Hinckdentine A.

The construction of 2,2-disubstituted indolines has long presented a synthetic challenge without any general solutions. Herein, we report a robust protocol for the dearomative Meerwein-Eschenmoser-Claisen rearrangement of 3-indolyl alcohols that provides efficient access to 2-substituted and 2,2-disubstituted indolines. These versatile subunits are useful for natural product synthesis and medicinal chemistry. The title [3,3] sigmatropic rearrangement proceeds in generally excellent yield and transfers the C3-indolic alcohol chirality to the C2 position with high fidelity, thus providing a reliable method for the construction of enantioenriched 2,2-disubstituted indolines. The power of this methodology is demonstrated through the concise and strategically unique total synthesis of the marine natural product hinckdentine A, which features a dearomative Claisen rearrangement, a diastereocontrolled hydrogenation of the alkene product, a one-pot amide-to-oxime conversion using Vaska's complex, and a regioselective late-stage tribromination.

Total Synthesis of the Chlorinated Pentacyclic Indole Alkaloid (+)-Ambiguine G.

Reported herein is the total synthesis of (+)-ambiguine G, the first member of the chlorinated pentacyclic ambiguines to yield to chemical synthesis. The synthesis is accomplished through a convergent strategy that proceeds in 10 steps from (S)-carvone oxide. Pivotal to the concise route is the successful realization of a [4+3] cycloaddition that conjoins two easily synthesized components of the carbon framework of the natural product. Also featured in the synthesis is the efficient, diastereoselective construction of a key vinylated chloro ketone and the unprecedented, one-pot reduction-elimination-oxidation sequence that transforms an enone to an advanced hydroxylated-diene intermediate.

Enantioselective Total Synthesis of (+)-Heilonine.

Chemical transformations that rapidly and efficiently construct a high level of molecular complexity in a single step are perhaps the most valuable in total synthesis. Among such transformations is the transition metal catalyzed [2 + 2 + 2] cycloisomerization reaction, which forges three new C-C bonds and one or more rings in a single synthetic operation. We report here a strategy that leverages this transformation to open de novo access to the Veratrum family of alkaloids. The highly convergent approach described herein includes (i) the enantioselective synthesis of a diyne fragment containing the steroidal A/B rings, (ii) the asymmetric synthesis of a propargyl-substituted piperidinone (F ring) unit, (iii) the high-yielding union of the above fragments, and (iv) the intramolecular [2 + 2 + 2] cycloisomerization reaction of the resulting carbon framework to construct in a single step the remaining three rings (C/D/E) of the hexacyclic cevanine skeleton. Efficient late-stage maneuvers culminated in the first total synthesis of heilonine (1), achieved in 21 steps starting from ethyl vinyl ketone.

Total Synthesis of (-)-Ambiguine P.

Described is a concise total synthesis of (-)-ambiguine P, a cycloheptane-containing member of the hapalindole alkaloids. The challenging pentacyclic framework of the natural product was assembled rapidly via a [4 + 3] cycloaddition reaction-inspired strategy, and the tertiary hydroxy group was introduced by an NBS-mediated bromination-nucleophilic substitution sequence.

Rapid construction of tetrahydropyridine scaffolds via formal imino Diels-Alder reactions of Schiff bases and Nazarov reagents.

Described is a one-flask, two-step method for the synthesis of highly functionalized piperidines. The process involves formal [4 + 2] cycloadditions of Schiff bases and Nazarov reagents, followed by facile elaborations of the initial cycloadducts. Notably, these aza-annulations are facilitated by protic solvents and proceed smoothly under ambient conditions, without other additives. The synthetic utility of this annulation protocol is further showcased through a concise, convergent synthesis of (±)-tetrabenazine.

Development of Chiral, Bifunctional Thiosquaramides: Enantioselective Michael Additions of Barbituric Acids to Nitroalkenes.

We report a general method for the synthesis of chiral thiosquaramides, a class of bifunctional catalysts not previously described in the literature. Thiosquaramides are found to be more acidic and significantly more soluble in nonpolar solvents than their oxosquaramide counterparts, and they are excellent catalysts for the unreported, enantioselective conjugate addition reaction of the barbituric acid pharmacaphore to nitroalkenes, delivering the chiral barbiturate derivatives in high yields and high enantioselectivities, even with catalyst loadings as low as 0.05 mol%.

Total Synthesis of (-)-N-Methylwelwitindolinone†B Isothiocyanate.

The asymmetric synthesis of (-)-N-methylwelwitindolinone B isothiocyanate is reported. Critical challenges overcome through these studies include the stereoselective installation of the sterically congested C13 alkyl chloride and control of the wayward reactivity of the indole unit to standard oxidants. A Pt-catalyzed hydrosilylation helped stymie unwanted rearrangements facilitated by vinyl group participation during the chloride installation step, and a new FeII -catalyzed oxidation accomplished the problematic conversion of indole into 2-indolinone.

EPR Imaging Spin Probe Trityl Radical OX063: A Method for Its Isolation from Animal Effluent, Redox Chemistry of Its Quinone Methide Oxidation Product, and in Vivo Application in a Mouse.

We report herein a method for the recovery, purification, and application of OX063, a costly, commercially available nontoxic spin probe widely used for electron paramagnetic resonance (EPR) imaging, as well as its corresponding quinone methide (QM) form. This precious probe can be successfully recovered after use in animal model experiments (25-47% recovery from crude lyophilizate with 98.5% purity), even from samples that are >2 years old. Significantly, the recovered trityl can be reused in further animal model EPR imaging experiments. The work also describes support for the observed formation of an air-sensitive radical derived from the QM under reducing conditions.

Studies Directed toward the Synthesis of Aspidophytine: Construction of Its Perhydroquinoline Core.

We have developed an efficient route for the synthesis of the perhydroquinoline core of the indole alkaloid aspidophytine (2), starting from commercially available and inexpensive 3-acetylpyridine. This densely functionalized perhydroquinoline core displays four contiguous stereocenters including an all-carbon quaternary center. The synthetic sequence features a highly effective Diels-Alder reaction using a carbamate-substituted siloxy diene accompanied by a spontaneous intramolecular substitution of the newly formed 3°-alkyl bromide with a carbamate group. The installation of the electron-rich aniline moiety was accomplished via a TBSOTf-mediated intramolecular aza-Michael reaction, and the relative stereochemistry of the aza-Michael product (30) was confirmed by X-ray crystallographic analysis. Among the useful transformations that were developed through this study is a highly enantioselective Diels-Alder reaction of a versatile cyclic carbamate siloxy diene.

Reductive Chlorination and Bromination of Ketones via Trityl Hydrazones.

A method is presented for the direct transformation of a ketone to the corresponding reduced alkyl chloride or bromide. The process involves the reaction of a ketone trityl hydrazone with tBuOCl to give a diazene which readily collapses to the α-chlorocarbinyl radical, reduction of which by a hydrogen atom source gives the alkyl chloride product. The use of N-bromosuccinimide provides the corresponding alkyl bromide. This unique transformation provides a reductive halogenation that complements Barton's redox-neutral vinyl halide synthesis.

Access to Spirocyclized Oxindoles and Indolenines via Palladium-Catalyzed Cascade Reactions of Propargyl Carbonates with 2-Oxotryptamines and Tryptamines.

Reported here are methods for the direct construction of a range of spirocyclized oxindoles and indolenines in good to excellent yields. Specifically, we report the palladium-catalyzed reactions of oxindoles and indoles, both functioning as bis-nucleophiles, with propargyl carbonates to afford spirocyclic products having an exocyclic double bond on the newly formed ring. The reaction proceeds through a process wherein the first nucleophilic unit on the oxindole or indole reacts with an allenyl-palladium species, formed from oxidative addition of Pd(0) to propargyl carbonates, to generate a π-allyl palladium intermediate that then reacts further with the second nucleophilic component of the oxindole or indole. The cascade process forges two bonds en route to spirocyclized oxindole and indolenine products. The use of chiral phosphines renders the cyclization sequence enantioselective, providing spirocyclic products with modest to good enantioselectivities.

Synthesis of α-amino acid derivatives and peptides via enantioselective addition of masked acyl cyanides to imines.

A general, asymmetric synthesis of amino acid derivatives is reported. Masked acyl cyanide (MAC) reagents are shown to be effective umpolung synthons for enantioselective additions to N-Boc-aldimines. The reactions are catalyzed by a modified cinchona alkaloid, which can function as a bifunctional, hydrogen bonding catalyst, and afford adducts in excellent yields (90-98%) and high enantioselectivities (up to 97.5:2.5 er). Unmasking the addition products gives acyl cyanide intermediates that are intercepted by a variety of nucleophiles to afford α-amino acid derivatives. Notably, the methodology provides an alternative method for peptide bond formation.

Salen promoted enantioselective Nazarov cyclizations of activated and unactivated dienones.

A novel class of chiral 5,5'-di(2,4,6-trialkyl)aryl salen-metal complexes have been developed and shown to catalyze highly enantioselective Nazarov cyclization reactions, giving rise to cyclopentenoids in 90:10-98:2 er. Significantly, the catalysts also promote, for the first time, highly enantioselective Nazarov reactions of "unactivated" dienones, producing hydrindenone products having in place three contiguous chiral centers.

Squaramide-catalyzed enantioselective Michael addition of masked acyl cyanides to substituted enones.

Masked acyl cyanide (MAC) reagents are shown to be effective umpolung synthons for enantioselective Michael addition to substituted enones. The reactions are catalyzed by chiral squaramides and afford adducts in high yields (90-99%) and with excellent enantioselectivities (85-98%). The addition products are unmasked to produce dicyanohydrins that, upon treatment with a variety of nucleophiles, provide γ-keto acids, esters, and amides. The use of this umpolung synthon has enabled, in enantiomerically enriched form, the first total synthesis of the prenylated phenol (+)-fornicin C.

Inhibition of eukaryotic translation elongation by the antitumor natural product Mycalamide B.

Mycalamide B (MycB) is a marine sponge-derived natural product with potent antitumor activity. Although it has been shown to inhibit protein synthesis, the molecular mechanism of action by MycB remains incompletely understood. We verified the inhibition of translation elongation by in vitro HCV IRES dual luciferase assays, ribosome assembly, and in vivo [(35)S]methinione labeling experiments. Similar to cycloheximide (CHX), MycB inhibits translation elongation through blockade of eEF2-mediated translocation without affecting the eEF1A-mediated loading of tRNA onto the ribosome, AUG recognition, or dipeptide synthesis. Using chemical footprinting, we identified the MycB binding site proximal to the C3993 28S rRNA residue on the large ribosomal subunit. However, there are also subtle, but significant differences in the detailed mechanisms of action of MycB and CHX. First, MycB arrests the ribosome on the mRNA one codon ahead of CHX. Second, MycB specifically blocked tRNA binding to the E-site of the large ribosomal subunit. Moreover, they display different polysome profiles in vivo. Together, these observations shed new light on the mechanism of inhibition of translation elongation by MycB.

Exploring the potential of diarylacetylenediols as hydrogen bonding catalysts.

In the course of a search for new classes of hydrogen bonding catalysts, we have examined diarylacetylenediols as potential catalysts for the Diels-Alder reaction. General and efficient methods have been developed for the preparation of these diols. Their structures were systematically modified, and increased activity was observed for those possessing an electron-withdrawing group on the aryl groups. The electron-deficient diarylacetylenediol catalysts, while more active, undergo spontaneous cyclization to the corresponding benzo[b]furans. A mechanism is postulated to explain this facile transformation. Computational studies performed on 2-ethynylphenol help to explain the effect of the alkyne on the conformation and hydrogen bond donating ability of the adjacent OH group. Finally, the crystal structure of one of the diols is reported, and it displays an intricate network of intermolecular hydrogen bonds.

Stacks and clips: Uncanny similarities in the modes of self-assembly in tenary Ag(I) complexes with 1,2-diazines and chelating heteroarenes.

The first synthesis and structural elucidation of Ag(I) ternary complexes with 1,2-diazines and chelating heteroarenes have been described. Conserved modes of inter-cation Ag+⋯π and π⋯π stacking interactions result in near identical patterns of cation self-assembly in these ternary complexes.

[2+2+2] Cycloadditions of siloxy alkynes with 1,2-diazines: from reaction discovery to identification of an antiglycolytic chemotype.

Cycloaddition uncovered: The title reaction produces novel polycyclic compounds with high efficiency and excellent diastereoselectivity under mild reaction conditions. A small-molecule library, synthesized using this reaction, yielded a novel chemotype which inhibited glycolytic ATP production by blocking glucose uptake in CHO-K1 cells. DMF=N,N-dimethylformamide, Tf=trifluoromethanesulfonyl, TIPS=triisopropylsilyl.

Palladium-catalyzed C3-benzylation of indoles.

A general method for regioselective C3-benzylation of indoles has been developed. Various 3-substituted indoles and benzyl methyl carbonates with different electronic properties react under mild conditions to afford a diverse range of 3-benzylindolenine products in good yields.