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The evolution of methods for carbonyl allylation and crotylation of alcohol proelectrophiles culminating in the design of iodide-bound ruthenium-JOSIPHOS catalysts is prefaced by a brief historical perspective on asymmetric carbonyl allylation and its relevance to polyketide construction. Using gaseous allene or butadiene as precursors to allyl- or crotylruthenium nucleophiles, respectively, new capabilities for carbonyl allylation and crotylation have been unlocked, including stereo- and site-selective methods for the allylation and crotylation of 1,3-diols and related polyols.1 Introduction and Historical Perspective2 Ruthenium-Catalyzed Conversion of Lower Alcohols into Higher Alcohols3 Conclusion and Future Outlook

In this Perspective, the use of methanol and ethanol as C1 and C2 feedstocks in metal-catalyzed C-C couplings to π-unsaturated pronucleophiles via hydrogen auto-transfer is surveyed. In these processes, alcohol oxidation to form an aldehyde electrophile is balanced by reduction of an π-unsaturated hydrocarbon to form a transient organometallic nucleophile. Mechanistically related reductive couplings of paraformaldehyde mediated by alcohol reductants or formic acid also are described. These processes encompass the first catalytic enantioselective C-C couplings of methanol and ethanol and, more broadly, illustrate how the native reducing ability of alcohols enable the departure from premetalated reagents in carbonyl addition.

ConspectusCyclometalated π-allyliridium

The first enantioselective ruthenium-catalyzed carbonyl vinylations via hydrogen auto-transfer are described. Using a ruthenium-JOSIPHOS catalyst, primary alcohols 2a-2m and 2-butyne 1a are converted to chiral allylic alcohols 3a-3m with excellent levels of absolute stereocontrol. Notably, 1°,2°-1,3-diols participate in site-selective C-C coupling occurs, enabling asymmetric carbonyl vinylation beyond premetalated reagents, exogenous reductants or hydroxyl protecting groups. Using 2-propanol as reductant, aldehydes dehydro-2a, 2l participate in highly enantioselective 2-butyne-mediated vinylation under otherwise identical reaction conditions. Regio-, stereo- and site-selective vinylations mediated by 2-pentyne 1b to form adducts 3n, 3o and epi-3o also are described. The tiglyl alcohol motif obtained upon butyne-mediated vinylation, which is itself found in diverse secondary metabolites, may be converted to commonly encountered polyketide stereodiads, -triads and -tetrads, as demonstrated by the formation of adducts 4a-4d. The collective mechanistic studies, including deuterium labelling experiments, corroborate a mechanism involving alcohol dehydrogenation to form a transient aldehyde and a ruthenium hydride, which engages in alkyne hydrometallation to form a nucleophilic vinylruthenium species that enacts carbonyl addition. A stereochemical model for carbonyl addition invoking formyl CH···I[Ru] and CH···O≡C[Ru] hydrogen bonds are proposed based on prior calculations and crystallographic data.

The mechanism of π-allyliridium C,O-benzoate-catalyzed allylic amination was studied by (a) reaction progress kinetic analysis (RPKA), (b) tandem ESI-MS analysis, and (c) computational studies involving density functional theory (DFT) calculations. Reaction progress kinetic analysis (RPKA) reveals a zero-order dependence on allyl acetate, first-order dependence on catalyst and fractional-order dependence on amine. These data corroborate rapid ionization of the allylic acetate followed by turnover limiting C-N bond formation. To illuminate the origins of the 0.4 kinetic order dependence on amine, ESI-MS analyses of quaternary ammonium-labelled piperazine with multistage collision induced dissociation (CID) were conducted that corroborate intervention of cesium-bridged amine dimers that dissociate to form monomeric cesium amide nucleophiles. Computational data align with RPKA and ESI-CID-MS analyses and suggest early transition states mitigate the impact of steric factors, thus enabling formation of highly substituted C-N bonds with complete levels of branched regioselectivity. Specifically, trans-effects of the iridium complex facilitate nucleophilic attack at the more substituted allyl terminus trans to phosphorus with enantioselectivity governed by steric repulsions between the chiral bisphosphine ligand and the π-allyl of a dominant diastereomer of the stereogenic-at-metal complex. Beyond defining aspects of the mechanism of π-allyliridium C,O-benzoate-catalyzed allylic amination, these data reveal that a key feature of cesium carbonate not only lies in its enhanced basicity, but also its capacity for Lewis-acid enhanced Brønsted acidification of amines.

Ruthenium-catalyzed hydrogen auto-transfer reactions for the direct enantioselective conversion of lower alcohols to higher alcohols are surveyed. These processes enable completely atom-efficient carbonyl addition from alcohol proelectrophiles in the absence of premetalated reagents or metallic reductants. Applications in target-oriented synthesis are highlighted, and a brief historical perspective on ruthenium-catalyzed hydrogen transfer processes is given.

Robust air-stable cyclometallated π-allyliridium C,O-benzoates modified by (S)-tol-BINAP catalyze the reaction of secondary aliphatic amines with racemic alkyl-substituted allylic acetates to furnish products of allylic amination with high levels of enantioselectivity. Complete branched regioselectivities are observed despite formation of more highly substituted C-N bonds. [Image: see text]

Crystallographic characterization of RuX(CO)(η(3)-C(3)H(5))(JOSIPHOS), where X = Cl, Br, I, reveals a halide-dependent diastereomeric preference that defines metal-centered stereogenicity and, therefrom, the enantioselectivity of C-C coupling in ruthenium-catalyzed anti-diastereo- and enantioselective C-C couplings of primary alcohols with 1-aryl-1-propynes to form products of carbonyl anti-(α-aryl)allylation. Computational studies reveal a non-classical hydrogen bond between iodide and the aldehyde formyl CH bond stabilizes the favored transition state for carbonyl addition. An improved catalytic system enabling previously unattainable transformations was developed that employs an iodide-containing precatalyst RuI(CO)(3)(η(3)-C(3)H(5)) in combination with trifluoroethanol (TFE), as illustrated by the first enantioselective ruthenium-catalyzed C-C couplings of ethanol to form higher alcohols.

Neaumycin B is a femtomolar inhibitor of U87 human glioblastoma. Using a newly developed anti-diastereoselective ruthenium-catalyzed butadiene-mediated crotylation of primary alcohol proelectrophiles via hydrogen auto-transfer, as well as a novel variant of the catalytic asymmetric vinylogous Mukaiyama aldol (VMA) reaction applicable to linear aliphatic aldehydes and terminally methylated dienyl ketene acetals, preparation of the key C1-C19 and C23-C35 substructures of neaumycin B is achieved in 12 and 7 steps (LLS), respectively.

Iodide-bound ruthenium-JOSIPHOS complexes catalyze the redox-neutral C-C coupling of primary alcohols with methylallene (1,2-butadiene) or 1,3-butadiene to form products of anti-crotylation with good to excellent levels of diastereo- and enantioselectivity. Distinct from other methods, direct crotylation of primary alcohols in the presence of unprotected secondary alcohols is possible, enabling generation of spirastrellolide B (C9-C15) and leucascandrolide A (C9-C15) substructures in significantly fewer steps than previously possible.

[Image: see text] Total Synthesis Fueled by Alcohol. The potent spliceosome modulator pladienolide B, which bears 10 stereogenic centers, is prepared in 10 steps (LLS). Asymmetric alcohol-mediated carbonyl crotylations catalyzed by ruthenium and iridium that occur with syn- and anti-diastereoselectivity, respectively, were used to form the C20-C21 and C10-C11 C-C bonds.

Atom-efficient processes that occur via addition, redistribution or removal of hydrogen underlie many large volume industrial processes and pervade all segments of chemical industry. Although carbonyl addition is one of the oldest and most broadly utilized methods for C-C bond formation, the delivery of non-stabilized carbanions to carbonyl compounds has relied on premetalated reagents or metallic/organometallic reductants, which pose issues of safety and challenges vis-à-vis large volume implementation. Catalytic carbonyl reductive couplings promoted via hydrogenation, transfer hydrogenation and hydrogen auto-transfer allow abundant unsaturated hydrocarbons to serve as substitutes to organometallic reagents, enabling C-C bond formation in the absence of stoichiometric metals. This perspective (a) highlights past milestones in catalytic hydrogenation, hydrogen transfer and hydrogen auto-transfer, (b) summarizes current methods for catalytic enantioselective carbonyl reductive couplings, and (c) describes future opportunities based on the patterns of reactivity that animate transformations of this type.

[Image: see text] Maize to Medicine. With annual production at >85 million tons/year, ethanol is the world’s largest-volume renewable small molecule carbon source, yet its use as a C2-feedstock in enantioselective C-C coupling is unknown. Here, the first catalytic enantioselective C-C couplings of ethanol are demonstrated in reactions with structurally complex, nitrogen-rich allylic acetates incorporating the top 10 N-heterocycles found in FDA-approved drugs.

Ruthenium-catalyzed cycloadditions to form five-, six-, and seven-membered rings are summarized, including applications in natural product total synthesis. Content is organized by ring size and reaction type. Coverage is limited to processes that involve formation of at least one C-C bond. Processes that are stoichiometric in ruthenium or exploit ruthenium as a Lewis acid (without intervention of organometallic intermediates), ring formations that occur through dehydrogenative condensation-reduction, σ-bond activation-initiated annulations that do not result in net reduction of bond multiplicity, and photochemically promoted ruthenium-catalyzed cycloadditions are not covered.

Highly tractable 1-aryl-1-propynes, which are readily accessible via Sonogashira coupling, serve as chiral allylmetal pronucleophiles in ruthenium-JOSIPHOS-catalyzed anti-diastereo- and enantiosele...

The first application of ruthenium(0)-catalyzed 1,2-dione-diyne [2+2+2] cycloaddition to PAH construction is achieved by the precision synthesis of soluble diindenoperylenes (DIPs), the electronic structures of which were investigated using steady-state absorption and emission, transient absorption, cyclic voltammetry and time-dependent density functional theory.

Catalytic reductive coupling of enone, acrylate or vinyl heteroaromatic pronucleophiles with carbonyl or imine partners offers an alternative to base-mediated enolization in aldol and Mannich type reactions. In this monograph, direct catalytic reductive aldol and Mannich reactions are exhaustively catalogued on the basis of metal or organocatalyst. Step-wise processes involving enone conjugate reduction to form discrete enol or (metallo)enolate derivatives followed by introduction of carbonyl or imine electrophiles and aldol reactions initiated via enone conjugate addition are not covered.

Iridium-tol-BINAP-catalyzed reductive coupling of allylic acetates with oxetanones and azetidinones mediated by 2-propanol provides chiral α-stereogenic oxetanols and azetidinols. As illustrated in 50 examples, complex, nitrogen-rich substituents that incorporate the top 10 N-heterocycles found in FDA-approved drugs are tolerated. In addition to 2-propanol-mediated reductive couplings, oxetanols and azetidinols may serve dually as reductant and ketone proelectrophiles in redox-neutral C-C couplings via hydrogen auto-transfer, as demonstrated by the conversion of dihydro-1a and dihydro-1b to adducts 3a and 4a, respectively. The present method delivers hitherto inaccessible chiral oxetanols and azetidinols, which are important bioisosteres.

Cyclometallated iridium-PhanePhos complexes catalyze 2-propanol-mediated reductive couplings of 2-substituted dienes with oxetanone and N-acyl-azetidinones to form branched homoallylic oxetanols and azetidinols with excellent control of regio- and enantioselectivity without C-C cleavage of the strained ring. This work represents the first systematic study of enantioselective additions to symmetric ketones.

The total synthesis of soraphen A, a myxobacterial metabolite and inhibitor of acetyl CoA carboxylase, was completed in 11 steps (longest linear sequence), less than half the steps previously required. Seven metal-catalyzed processes were deployed to unlock step-economy (comprising five asymmetric processes and four C-C bond formations). The present route does not utilize chiral auxiliaries, and four of five C-C bond formations exploit non-premetalated partners. To maximize convergency, an asymmetric Tsuji reduction was developed using a Pd-AntPhos catalyst that allows a metathesis-inactive allylic carbonate to serve as a masked terminal olefin, thereby enabling successive olefin metathesis events.

Covalent assemblies of conjugated organic chromophores provide the opportunity to engineer new excited states with novel properties. In this work, a newly developed triple-stranded cage architecture, in which meta-substituted aromatic caps serve as covalent linking groups that attach to both top and bottom of the conjugated molecule walls, is used to tune the properties of thiophene oligomer assemblies. Benzene-capped and triazine-capped 5,5'-(2,2-bithiophene)-containing arylene cages are synthesized and characterized using steady-state and time-resolved spectroscopic methods. The conformational freedom and electronic states are analyzed using time-dependent density functional theory. The benzene cap acts as a passive spacer whose electronic states do not mix with those of the chromophore walls. The excited state properties are dominated by through-space interactions between the chromophore subunits, generating a neutral Frenkel H-type exciton state. This excitonic state undergoes intersystem crossing on a 200 ps time scale while the fluorescence output is suppressed by a factor of 2 due to a decreased radiative rate. Switching to a triazine cap enables electron transfer from the chromophore-linker after the initial excitation to the exciton state, leading to the formation of a charge-transfer state within 10 ps. This state can avoid intersystem crossing and exhibits red-shifted fluorescence with enhanced quantum yield. The ability to interchange structural modules with different electronic properties while retaining the overall cage morphology provides a new approach for tuning the properties of discrete chromophore assemblies.

Alkyne-Directed Chemo- and Enantioselectivity. Highly enantioselective catalytic reductive coupling of allyl acetate with acetylenic ketones occurs in a chemoselective manner in the presence of aliphatic or aromatic ketones. This method was used to construct C14-C23 of pladienolide D in half the steps previously required.

Cyclometalation of a triple helical N-doped phenylene cage prepared by ruthenium(0)-catalyzed diol-diene benzannulation delivers a chiral, conformationally constrained Ir(ppy)3 analogue. Like the parent complex, fac-Ir(ppy)3 , the iridium-containing PAH-cage is phosphorescent, but displays enhanced resistance to oxygen quenching.

The first examples of rhodium-catalyzed carbonyl addition via hydrogen autotransfer are described, as illustrated in tandem butadiene-mediated carbonyl addition-redox isomerizations that directly convert primary alcohols to isobutyl ketones. Related reductive coupling-redox isomerizations of aldehyde reactants mediated by sodium formate also are reported. A double-labeling crossover experiment reveals that the rhodium alkoxide obtained upon carbonyl addition enacts redox isomerization without dissociation of rhodium at any intervening stage.

Two catalytic systems for the formate-mediated cross-electrophile reductive coupling of 4-iodoansiole with 6-bromopyridines are described. Using homogenous rhodium or heterogeneous palladium catalysts, the product of reductive biaryl cross-coupling could be formed in moderate yield with excellent levels of chemoselectivity.

The use of allenes and 1,3-dienes as chiral allylmetal pronucleophiles in intermolecular catalytic enantioselective reductive additions to aldehydes, ketones, imines, carbon dioxide and other C=X electrophiles is exhaustively catalogued together with redox-neutral hydrogen auto-transfer processes. Coverage is limited to processes that result in both C-H and C-C bond formation. The use of alkynes as latent allylmetal pronucleophiles and multicomponent C=X allylations involving allenes and dienes is not covered. As illustrated in this review, the ability of allenes and 1,3-dienes to serve as tractable non-metallic pronucleophiles has evoked many useful transformations that have no counterpart in traditional allylmetal chemistry.

The total synthesis of leiodermatolide A was accomplished in 13 steps (LLS). Transfer hydrogenative variants of three carbonyl additions that traditionally rely on premetalated reagents (allylation, crotylation, and propargylation) are deployed together in one total synthesis.

The first systematic study of simple nitronate nucleophiles in iridium-catalyzed allylic alkylation are described. Using a tol-BINAP-modified π-allyliridium C,O-benzoate catalyst, α,α-disubstituted nitronates substitute racemic branched alkyl-substituted allylic acetates, thus providing entry to β-stereogenic α-quaternary primary amines. DFT calculations reveal early transition states that render the reaction less sensitive to steric effects and distinct trans-effects of diastereomeric chiral-at-iridium π-allyl complexes that facilitate formation of congested tertiary-quaternary C-C bonds.

The first catalytic enantioselective ruthenium-catalyzed carbonyl reductive couplings of allene pronucleophiles is described. Using an iodide-modified ruthenium-BINAP-catalyst and O-benzhydryl alkoxyallene 1a, carbonyl (α-alkoxy)allylation occurs from the alcohol or aldehyde oxidation level to form enantiomerically enriched syn-sec,tert-diols. Internal chelation directs intervention of (Z)-σ-alkoxyallylruthenium isomers, which engage in stereospecific carbonyl addition.

Ruthenium-catalyzed butadiene-mediated benzannulation enabled the first synthesis of 3,10-(di-tert-butyl)rubicene and its N-doped derivatives as well as preliminary studies on their photophysical properties. Unlike the parent rubicene and 3,10-(di-tert-butyl)rubicene, which adopt classical herringbone-type packing motifs in the solid state, the N-doped congener 7 b displayed columnar packing with an alternating co-facial arrangement of aromatic and heteroaromatic substructures.

Alcohol-mediated carbonyl addition has enabled catalytic enantioselective syntheses of diverse fluorine-containing compounds without the need for stoichiometric metals or discrete redox manipulations. Reactions of this type may be separated into two broad categories: redox-neutral hydrogen autotransfer reactions, wherein lower alcohols and π-unsaturated pronucleophiles are converted to higher alcohols, and corresponding 2-propanol-mediated carbonyl reductive couplings.

[Image: see text] King of Bitters. An enantioselective total synthesis of the labdane diterpenoid andrographolide, the bitter principle of the medicinal herb Andrographis paniculata (known as “King of Bitters”), is accomplished in 14 steps (LLS) - 10 steps shorter than the prior total synthesis. Key transformations include iridium-catalyzed carbonyl reductive coupling to form the quaternary carbon stereocenter at C4, diastereoselective alkene reduction to establish the trans-decalin ring, and carbonylative lactonization to install the α-alkylidene-γ-butyrolactone.

Successive nucleophilic and electrophilic allylation mediated by the bis-Boc-carbonate derived from 2-methylene−1,3-propane diol enables formation of enantiomerically enriched 2,4-disubstituted pyrrolidines. An initial enantioselective iridium-catalyzed transfer hydrogenative carbonyl C-allylation is followed by Tsuji-Trost N-allylation using 2-nitrobenzenesulfonamide. Subsequent Mitsunobu cyclization provides the N-protected 2,4-disubstituted pyrrolidines.

Iridium complexes modified by PhanePhos catalyze the 2-propanol-mediated reductive coupling of diverse 1,1-disubstituted allenes 1a-1u with fluoral hydrate 2a to form CF(3)-substituted secondary alcohols 3a-3u that incorporate acyclic quaternary carbon-containing stereodiads. By exploiting concentration-dependent stereoselectivity effects related to the interconversion of kinetic (Z)- and thermodynamic (E)-σ-allyliridium isomers, adducts 3a-3u are formed with complete levels of branched regioselectivity and high levels of anti-diastereo- and enantioselectivity. The utility of this method for construction of CF(3)-oxetanes and CF(3)-azetidines is illustrated by the formation of 4a and 6a, respectively. Studies of the reaction mechanism aimed at illuminating the singular effectiveness of PhanePhos as a supporting ligand in this and related transformations have led to the identification of a chromatographically stable cyclometallated iridium-(R)-PhanePhos complex Ir-PP-I that is catalytically competent for allene-fluoral reductive coupling and previously reported transfer hydrogenative C-C couplings of dienes or CF(3)-allenes with methanol. Deuterium labelling studies, reaction progress kinetic analysis (RPKA) and computational studies corroborate a catalytic mechanism involving rapid allene hydrometalation followed by turnover-limiting carbonyl addition. A computationally determined stereochemical model shows the ortho-CH(2) group of the cyclometallated iridium-PhanePhos complex plays a key role in directing diastereo- and enantioselectivity. The collective data provide key insights into the structural-interactional features of allyliridium complexes required to enforce nucleophilic character, which should inform the design of related cyclometallated catalysts for umpoled allylation.

The air- and water-stable π-allyliridium C,O-benzoate modified by ( S)-tol-BINAP, ( S)-Ir-II, catalyzes highly regio- and enantioselective Tsuji-Trost-type aminations of racemic branched alkyl-substituted allylic acetates using primary or secondary (hetero)aromatic amines. Specifically, in the presence of ( S)-Ir-II (5 mol%) in DME solvent at 60-70 °C, α-methyl allyl acetate 1a (100 mol%) reacts with primary (hetero)aromatic amines 2a-2l (200 mol%) or secondary (hetero)aromatic amines 3a-3l (200 mol%) to form the branched products of allylic amination 4a-4l and 5a-5l, respectively, as single regioisomers in good to excellent yield with uniformly high levels of enantioselectivity. As illustrated by the conversion of heteroaromatic amine 3m to adducts 6a-6g, excellent levels of regio- and enantioselectivity are retained across diverse branched allylic acetates bearing normal alkyl or secondary alkyl substituents. For reactants 3n-3p, which incorporate both primary and secondary aryl amine moieties, regio- and enantioselective amination occurs with complete site-selectivity to furnish adducts 7a-7c. Mechanistic studies involving amination of the enantiomerically enriched, deuterium-labeled acetate 1h corroborate C-N bond formation via outer-sphere addition.

Natural products and their derivatives continue to be wellsprings of nascent therapeutic potential. However, many laboratories have limited resources for biological evaluation, leaving their previously isolated or synthesized compounds largely or completely untested. To address this issue, the Canvass library of natural products was assembled, in collaboration with academic and industry researchers, for quantitative high-throughput screening (qHTS) across a diverse set of cell-based and biochemical assays. Characterization of the library in terms of physicochemical properties, structural diversity, and similarity to compounds in publicly available libraries indicates that the Canvass library contains many structural elements in common with approved drugs. The assay data generated were analyzed using a variety of quality control metrics, and the resultant assay profiles were explored using statistical methods, such as clustering and compound promiscuity analyses. Individual compounds were then sorted by structural class and activity profiles. Differential behavior based on these classifications, as well as noteworthy activities, are outlined herein. One such highlight is the activity of (−)-2(S)-cathafoline, which was found to stabilize calcium levels in the endoplasmic reticulum. The workflow described here illustrates a pilot effort to broadly survey the biological potential of natural products by utilizing the power of automation and high-throughput screening., Canvass, a crowd-sourced library of natural products, was evaluated through HTS in a spectrum of disease-relevant assays to survey the broad biological potential of natural products in drug discovery.

Chiral metal complexes catalyze enantioselective carbonyl propargylation via reductive coupling or as hydrogen auto-transfer processes, in which reactant alcohols serve dually as reductant and carbonyl proelectrophile. Unlike classical propargylation protocols, which rely on allenylmetal reagents or metallic reductants (e.g. NHK reactions), reductive protocols for carbonyl propargylation can occur in the absence of stoichiometric metals, precluding generation of metallic byproducts. Propargylations of this type exploit both enyne and propargyl halide pronucleophiles. [Image: see text]

In the presence of a neutral dppf-modified iridium catalyst and Cs(2)CO(3), linear allylic acetates react with primary amines to form products of hydroamination with complete 1,3-regioselectivity. The collective data, including deuterium labeling studies, corroborate a catalytic mechanism involving rapid, reversible acetate-directed aminoiridation with inner-sphere/outer-sphere crossover followed by turn-over limiting protodemetalation mediated by amine.