Can Twisted Double Bonds Facilitate Stepwise [2 + 2] Cycloadditions?

Computational studies for a series of low to high strain anti-Bredt alkenes suggest that those with highly twisted bridgehead double bonds and a small singlet-triplet energy gap may undergo facile stepwise [2 + 2] cycloadditions to furnish four membered rings. A selection of reaction substrates, including ethylene, acetylene, perfluoroethylene, and cyclooctyne are considered.

Photoactivation of Hydrazones for the Synthesis of Diarylalkanes and Trialkylmethylboronates: The Key Role Played by Soluble Base.

The synthesis of diaryl alkanes and tertiary organoboronates via Barluenga coupling at room temperature occurred via photoactivated conversion of aryl sulfonyl hydrazones to diazo compounds in the presence of soluble bases. The combination of arylsulfonyl hydrazone and a soluble base is necessary to provide a near-UV chromophore. Using aromatic hydrazones and aromatic boronic acids resulted in rapid deboronation because of the instability of dibenzylic boron intermediates. Alkyl hydrazones allowed the isolation of derivatives of the tertiary boronate.

Regio- and enantioselective synthesis of acyclic quaternary carbons via organocatalytic addition of organoborates to (Z)-Enediketones.

The chemical synthesis of molecules with closely packed atoms having their bond coordination saturated is a challenge to synthetic chemists, especially when three-dimensional control is required. The organocatalyzed asymmetric synthesis of acyclic alkenylated, alkynylated and heteroarylated quaternary carbon stereocenters via 1,4-conjugate addition is here catalyzed by 3,3´-bisperfluorotoluyl-BINOL. The highly useful products (31 examples) are produced in up to 99% yield and 97:3 er using enediketone substrates and potassium trifluoroorganoborate nucleophiles. In addition, mechanistic experiments show that the (Z)-isomer is the reactive form, ketone rotation at the site of bond formation is needed for enantioselectivity, and quaternary carbon formation is favored over tertiary. Density functional theory-based calculations show that reactivity and selectivity depend on a key n→π* donation by the unbound ketone's oxygen lone pair to the boronate-coordinated ketone in a 5-exo-trig cyclic ouroboros transition state. Transformations of the conjugate addition products to key quaternary carbon-bearing synthetic building blocks proceed in good yield.

Enantioselective Total Synthesis of Cannabinoids via a Tandem Conjugate Addition/Enolate Alkylation Annulation with Ambiphilic Organoboronates.

Cannabinoid research depends on synthesizing derivatives for structure-activity relationship studies. (-)-Δ9-Tetrahydrocannabinol and cannabidiol were synthesized via a tandem enantioselective conjugate addition/enolate alkylation annulation with a novel ambiphilic trifluoroborate in seven steps. A new class of alkenyl and aryl ambiphilic trifluoroborates were synthesized and showed great compatibility with various functional groups, high yields, and excellent enantio- and diastereoselectivity. A novel benzo-fused cannabinoid analogue and tandem quaternary stereocenter-containing reaction products were synthesized with good to excellent enantioselectivity.

Quaternary and Tertiary Carbon Centers Synthesized via Gallium-Catalyzed Direct Substitution of Unfunctionalized Propargylic Alcohols with Boronic Acids.

(IPr)GaCl3/AgSbF6, AgSbF6, and GaCl3 catalyzed substitution of the hydroxyl of secondary and tertiary propargylic alcohols with organoboronic acids via C-C bond formation, and GaCl3 effectively synthesized all-carbon quaternary propargylic centers. These catalysts performed the substitution at carbons bearing alkyl substituents, which has been problematic for other systems. Highly hindered carbon stereocenters were thus produced, including quaternary centers bearing doubly ortho-substituted aryl rings, that are difficult to access with traditional methods.

Enantioselective Organocatalytic Conjugate Addition in a Tandem Synthesis of δ-Substituted Cyclohexenones and Four-Step Total Synthesis of Penienone.

A bisperfluorotoluyl-BINOL catalyzed conjugate addition of trifluoroborate salts to doubly vinylogous esters and aldol condensation synthesized chiral δ-substituted cyclohexenones with high yields and enantioselectivities (10 examples, up to 89% yield, 89-98% ee). Stepwise and single-pot sequences were developed, with the former also providing ß-substituted masked ketoaldehydes containing a vinyl ether. The transformation was used in a four-step total synthesis of penienone (24% overall yield), ≤ half the steps as in previous syntheses.

Experimental and Computational Mechanistic Study of Carbonazidate-Initiated Cascade Reactions.

A variety of Huisgen cyclization or nitrene/carbene alkyne cascade reactions with different types of termination were investigated. Accessible nitrene precursors were assessed, and carbonazidates were found to be the only effective initiators. Solvents, terminal alkynyl substituents, and catalysts can all impact the reaction outcome. Study of the mechanism both computationally (by density functional theory) and experimentally revealed relevant intermediates and plausible reaction pathways.

Engineering Escherichia coli for anaerobic alkane activation: Biosynthesis of (1-methylalkyl)succinates.

In anoxic environments, microbial activation of alkanes for subsequent metabolism occurs most commonly through the addition of fumarate to a subterminal carbon, producing an alkylsuccinate. Alkylsuccinate synthases are complex, multi-subunit enzymes that utilize a catalytic glycyl radical and require a partner, activating enzyme for hydrogen abstraction. While many genes encoding putative alkylsuccinate synthases have been identified, primarily from nitrate- and sulfate-reducing bacteria, few have been characterized and none have been reported to be functionally expressed in a heterologous host. Here, we describe the functional expression of the (1-methylalkyl)succinate synthase (Mas) system from Azoarcus sp. strain HxN1 in recombinant Escherichia coli. Mass spectrometry confirms anaerobic biosynthesis of the expected products of fumarate addition to hexane, butane, and propane. Maximum production of (1-methylpentyl)succinate is observed when masC, masD, masE, masB, and masG are all present on the expression plasmid; omitting masC reduces production by 66% while omitting any other gene eliminates production. Meanwhile, deleting iscR (encoding the repressor of the E. coli iron-sulfur cluster operon) improves product titer, as does performing the biotransformation at reduced temperature (18°C), both suggesting alkylsuccinate biosynthesis is largely limited by functional expression of this enzyme system.

Rate Dependence on Inductive and Resonance Effects for the Organocatalyzed Enantioselective Conjugate Addition of Alkenyl and Alkynyl Boronic Acids to ß-Indolyl Enones and ß-Pyrrolyl Enones.

Two key factors bear on reaction rates for the conjugate addition of alkenyl boronic acids to heteroaryl-appended enones: the proximity of inductively electron-withdrawing heteroatoms to the site of bond formation and the resonance contribution of available heteroatom lone pairs to stabilize the developing positive charge at the enone ß-position. For the former, the closer the heteroatom is to the enone ß-carbon, the faster the reaction. For the latter, greater resonance stabilization of the benzylic cationic charge accelerates the reaction. Thus, reaction rates are increased by the closer proximity of inductive electron-withdrawing elements, but if resonance effects are involved, then increased rates are observed with electron-donating ability. Evidence for these trends in isomeric substrates is presented, and the application of these insights has allowed for reaction conditions that provide improved reactivity with previously problematic substrates.

Formation of ß-Oxo-N-vinylimidates via Intermolecular Ester Incorporation in Huisgen Cyclization/Carbene Cascade Reactions.

Unusual intermolecular trapping of esters by carbenes generated via a Huisgen cyclization/retroelectrocyclization/dediazotization cascade reaction is presented. ß-Oxo-N-vinylimidates could be obtained in one step from propargyl carbonazidates. Mechanistic control experiments suggested reversible dipole formation by ester addition to the carbene, and nitrogen attack to the ester carbonyl was irreversibly followed by stereoselective decarboxylative elimination to give the Z-vinyl imidate. The cross-conjugated enone, imidate, and enamine functional groups in the ß-oxo-N-vinylimidates offer novel syntheses of functionalized oxazoles.

Synthesis of Bridged Azacycles and Propellanes via Nitrene/Alkyne Cascades.

A nitrene/alkyne cascade reaction terminating in C-H bond insertion to form functionalized bridged azacycles from carbonazidates is presented. Due to an initial Huisgen cyclization, all carbonazidates reacted with the alkyne in an exo mode in contrast to the use of sulfamate esters, which react predominately in an endo mode. Substrates with different ring sizes as well as different aryl and heteroaryl groups were also explored. Variation of the nitrene tether showed that 7-membered rings were the maximum ring size to be formed by nitrene attack on the alkyne. Examples incorporating stereocenters on the carbonazidate's tether induced diasteroselectivity in the formation of the bridged ring and two new stereocenters. Additionally, propellanes containing aminals, hemiaminals, and thioaminals formed from the bridged azacycles in the same reaction via an acid-promoted rearrangement.

Relay Catalysis To Synthesize ß-Substituted Enones: Organocatalytic Substitution of Vinylogous Esters and Amides with Organoboronates.

Organocatalysis was shown to facilitate conjugate additions to vinylogous esters and amides for the first time. Subsequent elimination of a ß-alcohol or amine provided π-conjugated ß-substituted enones. Remarkably, nucleophile addition to the electron-rich vinylogous substrates is more rapid than classical enones, forming monosubstituted products. A doubly organocatalytic (organic diol and methyl aniline) conjugate addition synthesized the products directly from alkynyl ketones. Both of these catalytic transformations are orthogonal to transition metal catalysis, allowing for good yields, easily accessible or commercially available reagents, high selectivity, reagent recovery and recyclability, facile scalability, and exceptional functional group tolerance.

Oxyallyl Cation Capture via Electrophilic Deborylation of Organoboronates: Access to α,α'-Substituted Cyclic Ketones.

An umpolung strategy to synthesize α,α'-substituted cyclic ketones through the nucleophilic addition of organoboronates to α-hydroxyl silyl enol ethers is described. The reaction proceeds via the trapping of in situ generated oxyallyl cations via the electrophilic deborylation of C(sp2) and C(sp) borates. This efficient and straightforward method provides direct access to α-substituted silyl enol ethers in high yield with complete regioselectivity. Desilylation in a one-pot procedure provides the corresponding α,α'-disubstituted ketones with high diastereoselectivity.

Chiral Diol-Based Organocatalysts in Enantioselective Reactions.

Organocatalysis has emerged as a powerful synthetic tool in organic chemistry in the last few decades. Among various classes of organocatalysis, chiral diol-based scaffolds, such as BINOLs, VANOLs, and tartaric acid derivatives, have been widely used to induce enantioselectivity due to the ability of the hydroxyls to coordinate with the Lewis acidic sites of reagents or substrates and create a chiral environment for the transformation. In this review, we will discuss the applications of these diol-based catalysts in different types of reactions, including the scopes of reactions and the modes of catalyst activation. In general, the axially chiral aryl diol BINOL and VANOL derivatives serve as the most competent catalyst for most examples, but examples of exclusive success using other scaffolds, herein, suggests that they should not be overlooked. Lastly, the examples, to date, are mainly from tartrate and biaryl diol catalysts, suggesting that innovation may be available from new diol scaffolds.

Branched Amine Synthesis via Aziridine or Azetidine Opening with Organotrifluoroborates by Cooperative Brønsted/Lewis Acid Catalysis: An Acid-Dependent Divergent Mechanism.

A practical catalytic method to synthesize ß,ß- and γ,γ-substituted amines by opening aziridines and azetidines, respectively, using alkenyl, alkynyl, or aryl/heteroaryl trifluoroborate salts is described. This reaction features simple open-flask reaction conditions, the use of transition-metal-free catalysis, complete regioselectivity, and high diastereoselectivity. Preliminary mechanistic studies suggest that carbocation formation is disfavored. Stereoretentive addition is favored with Brønsted acid present, while stereoinversion is favored in its absence, indicating divergent mechanisms.

Tertiary and Quaternary Carbon Formation via Gallium-Catalyzed Nucleophilic Addition of Organoboronates to Cyclopropanes.

GaCl3 and (IPr)GaCl3/AgSbF6 formed γ-tertiary and γ-quaternary carbons via homoconjugate addition of organoboron nucleophiles to diester- and ketone-functionalized cyclopropanes. Electron donor group cyclopropane substituents were not needed, allowing electron-deficient aryl, alkenyl, alkyl, and hydrogen-substituted cyclopropanes to be used. The catalytic conditions were compatible with alkenyl, alkynyl, and aryl nucleophiles, including ortho-substituted aromatics, to synthesize highly hindered quaternary carbons. Alkynyl nucleophiles formed substituted cyclopentenes. A control experiment supports an intermediate carbocation in quaternary carbon center formation.

Synthesis of azasilacyclopentenes and silanols via Huisgen cycloaddition-initiated C-H bond insertion cascades.

An unusual transition metal-free cascade reaction of alkynyl carbonazidates was discovered to form azasilacyclopentenes. Mild thermolysis afforded the products via a series of cyclizations, rearrangements, and an α-silyl C-H bond insertion (rather than the more common Wolff rearrangement, 1,2-shift, or ß-silyl C-H insertion) to form silacyclopropanes. A mechanistic proposal for the sequence was informed by control experiments and the characterization of reaction intermediates. The substrate scope and post-cascade transformations were also explored.

Brønsted Acid Catalyzed Homoconjugate Addition of Organotrifluoroborates to Arylated Cyclopropyl Ketones.

A novel and practical homoconjugate addition of alkenyl, alkynyl, heteroaryl, and aryl trifluoroborates to arylated cyclopropyl ketones to synthesize γ,γ-disubstituted ketones is reported. A preliminary mechanistic proposal involving ketone protonation, an intermediary carbocation, and intermolecular nucleophile addition has been made based on control studies.

The synthesis of functionalized bridged polycycles via C-H bond insertion.

This review presents examples from the chemical literature of syntheses of bridged-polycyclic products via C-H bond insertion by carbenes and nitrenes. Applications to natural product synthesis, a description of the essential elements in substrate-controlled reactions, and mechanistic details of transformations are presented. Overall, these transformations allow the construction of important ring systems rapidly and efficiently, though additional catalyst development is needed.

Hydrazone-initiated carbene/alkyne cascades to form polycyclic products: ring-fused cyclopropenes as mechanistic intermediates.

A hydrazone-based carbene/alkyne cascade produced a variety of bridged and fused polycyclic products. NaOSiMe3 is a superior base for conversion of hydrazones to diazoalkanes. A key mechanistic intermediate, a ring-fused cyclopropene, has been isolated and characterized.