Nozaki-Hiyama-Kishi Research Articles

Cobalt-Catalyzed Asymmetric Migratory Nozaki-Hiyama-Kishi Coupling.

Selective functionalization of ubiquitous C-H bonds based on 1,n-metal migration provides an attractive and sustainable route to access complex molecules from readily available precursors. Herein, we report a Co-catalyzed asymmetric reductive migratory Nozaki-Hiyama-Kishi (NHK) coupling between two readily available electrophiles, aryl (pseudo)halides and aldehydes, via an unprecedented through-space aryl-to-alkenyl 1,4-cobalt/hydride shift. The judicious choice of ligands is crucial for selectivity, leading to either ipso- or migratory NHK products with exquisite control of regio-, E/Z-, and enantioselectivity. Enabled by a ligand relay catalytic strategy, this platform has been further extended to aryl-to-aryl asymmetric migratory NHK coupling. These high-value NHK adducts, including α-chiral allylic alcohols and benzyl alcohols, are readily convertible to a variety of useful synthons.

Chromium- and Metal-Reductant-Free Asymmetric Nozaki-Hiyama-Kishi (NHK) Reaction Enabled by Metallaphotoredox Catalysis.

Chiral allylic alcohols are highly prized in synthetic chemistry due to their versatile reactivity stemming from both alkenyl and hydroxyl functionalities. While the Nozaki-Hiyama-Kishi (NHK) reaction is a widely used method for the synthesis of allylic alcohols, it suffers from drawbacks such as the use of toxic chromium salts, high amounts of metal reductants, and poor enantiocontrol. To address these limitations, we present a novel approach involving a metallaphotoredox-catalyzed asymmetric NHK reaction for the production of chiral allylic alcohols. This method marries alkenyl (pseudo)halides with aldehydes, leveraging a synergistic blend of a chiral nickel catalyst and a photocatalyst. This innovative technique enables both oxidative addition and insertion just using nickel, diverging significantly from the conventional NHK reaction pathway mediated by nickel and chromium salts. The adoption of this methodology holds immense promise for crafting a spectrum of intricate compounds, particularly those of significance in pharmaceuticals. Detailed experimental investigations have shed light on the metallaphotoredox process, further enhancing our understanding and enabling further advancements.

Chromium‐ and Metal‐Reductant‐Free Asymmetric Nozaki–Hiyama–Kishi (NHK) Reaction Enabled by Metallaphotoredox Catalysis

AbstractChiral allylic alcohols are highly prized in synthetic chemistry due to their versatile reactivity stemming from both alkenyl and hydroxyl functionalities. While the Nozaki–Hiyama–Kishi (NHK) reaction is a widely used method for the synthesis of allylic alcohols, it suffers from drawbacks such as the use of toxic chromium salts, high amounts of metal reductants, and poor enantiocontrol. To address these limitations, we present a novel approach involving a metallaphotoredox‐catalyzed asymmetric NHK reaction for the production of chiral allylic alcohols. This method marries alkenyl (pseudo)halides with aldehydes, leveraging a synergistic blend of a chiral nickel catalyst and a photocatalyst. This innovative technique enables both oxidative addition and insertion just using nickel, diverging significantly from the conventional NHK reaction pathway mediated by nickel and chromium salts. The adoption of this methodology holds immense promise for crafting a spectrum of intricate compounds, particularly those of significance in pharmaceuticals. Detailed experimental investigations have shed light on the metallaphotoredox process, further enhancing our understanding and enabling further advancements.

Redox-Neutral 1,2-Dicarbofunctionalization of Buta-1,3-diene by Merging Decatungstate and Chromium Catalysis

AbstractHomoallylic alcohol is a significantly useful intermediate in organic synthesis. Here we establish a three-component Nozaki–Hiyama–Kishi (NHK) type reaction of buta-1,3-diene, aldehydes, and aliphatic C–H partners by merging decatungstate and chromium catalysis, enabling a modular, redox-neutral, and atom-economic strategy to access a diverse range of homoallylic alcohols.

Collective Synthesis of Highly Oxygenated (Furano)germacranolides Derived from Elephantopus mollis and Elephantopus tomentosus.

Germacranolides, secondary metabolites produced by plants, have garnered academic and industrial interest due to their diverse and complex topology as well as a wide array of pharmacological activities. Molephantin, a highly oxygenated germacranolide isolated from medicinal plants, Elephantopus mollis and Elephantopus tomentosus, has exhibited antitumor, inflammatory, and leishmanicidal activities. Its chemical structure is based on a highly strained ten-membered macrocyclic backbone with an (E,Z)-dienone moiety, which is fused with an α-methylene-γ-butyrolactone and adorned with four successive stereogenic centers. Herein, we report the first synthesis of molephantin in 12 steps starting from readily available building blocks. The synthesis features the highly diastereoselective intermolecular Barbier allylation of the β,γ-unsaturated aldehyde with optically active 3-bromomethyl-5H-furan-2-one intermediate and ensuing Nozaki-Hiyama-Kishi (NHK) macrocyclization for the construction of the highly oxygenated ten-membered macrocyclic framework. This synthetic route enabled access to another germacranolide congener, tomenphantopin F. Furthermore, cycloisomerization of molephantin into 2-deethoxy-2β-hydroxyphantomolin could be facilitated by irradiation with ultraviolet A light (λmax=370 nm), which opened a versatile and concise access to the related furanogermacranolides such as EM-2, phantomolin, 2-O-demethyltomenphantopin C, and tomenphantopin C.

Collective Synthesis of Highly Oxygenated (Furano)germacranolides Derived from Elephantopus mollis and Elephantopus tomentosus

AbstractGermacranolides, secondary metabolites produced by plants, have garnered academic and industrial interest due to their diverse and complex topology as well as a wide array of pharmacological activities. Molephantin, a highly oxygenated germacranolide isolated from medicinal plants, Elephantopus mollis and Elephantopus tomentosus, has exhibited antitumor, inflammatory, and leishmanicidal activities. Its chemical structure is based on a highly strained ten‐membered macrocyclic backbone with an (E,Z)‐dienone moiety, which is fused with an α‐methylene‐γ‐butyrolactone and adorned with four successive stereogenic centers. Herein, we report the first synthesis of molephantin in 12 steps starting from readily available building blocks. The synthesis features the highly diastereoselective intermolecular Barbier allylation of the β,γ‐unsaturated aldehyde with optically active 3‐bromomethyl‐5H‐furan‐2‐one intermediate and ensuing Nozaki–Hiyama–Kishi (NHK) macrocyclization for the construction of the highly oxygenated ten‐membered macrocyclic framework. This synthetic route enabled access to another germacranolide congener, tomenphantopin F. Furthermore, cycloisomerization of molephantin into 2‐deethoxy‐2β‐hydroxyphantomolin could be facilitated by irradiation with ultraviolet A light (λmax=370 nm), which opened a versatile and concise access to the related furanogermacranolides such as EM‐2, phantomolin, 2‐O‐demethyltomenphantopin C, and tomenphantopin C.

Cobalt‐Catalyzed Asymmetric Aza‐Nozaki–Hiyama–Kishi (NHK) Reaction of α‐Imino Esters with Alkenyl Halides

AbstractChromium‐catalyzed enantioselective Nozaki–Hiyama–Kishi (NHK) reaction represents one of the most powerful approaches for the formation of chiral carbon‐heteroatom bond. However, the construction of sterically encumbered tetrasubstituted stereocenter through NHK reaction still posts a significant challenge. Herein, we disclose a cobalt‐catalyzed aza‐NHK reaction of ketimine with alkenyl halide to provide a convenient synthetic approach for the manufacture of enantioenriched tetrasubstituted α‐vinylic amino acid. This protocol exhibits excellent functional group tolerance with excellent 99 % ee in most cases. Additionally, this asymmetric reductive method is also applicable to the aldimine to access the trisubstituted stereogenic centers.

Cobalt-Catalyzed Asymmetric Aza-Nozaki-Hiyama-Kishi (NHK) Reaction of α-Imino Esters with Alkenyl Halides.

Chromium-catalyzed enantioselective Nozaki-Hiyama-Kishi (NHK) reaction represents one of the most powerful approaches for the formation of chiral carbon-heteroatom bond. However, the construction of sterically encumbered tetrasubstituted stereocenter through NHK reaction still posts a significant challenge. Herein, we disclose a cobalt-catalyzed aza-NHK reaction of ketimine with alkenyl halide to provide a convenient synthetic approach for the manufacture of enantioenriched tetrasubstituted α-vinylic amino acid. This protocol exhibits excellent functional group tolerance with excellent 99 % ee in most cases. Additionally, this asymmetric reductive method is also applicable to the aldimine to access the trisubstituted stereogenic centers.

Asymmetric total synthesis of humulane sesquiterpenoids alashanoids B, C, E, and F and 2,9-humuladien-6-ol-8-one.

Naturally occurring sesquiterpenes having humulane frameworks are structurally intriguing and possess significant biological profiles. Asymmetric synthesis of the alashanoids B, C, E, and F and 2,9-humuladien-6-ol-8-one is achieved for the first time through a linear synthetic strategy. Intramolecular late-stage Nozaki-Hiyama-Kishi (NHK) coupling is employed to access the eleven-membered macrocyclic core present in the target molecules. The NHK precursors are accessed using the Evans and non-Evans syn and anti-aldol reaction as a key transformation. X-ray and ECD analysis reconfirmed the synthesized compounds' structures and chirotopical properties.

New Demethylated Derivatives of Carolacton and Structure–Activity Relationship (SAR) Studies on Their Biofilm Inhibitory Properties

AbstractThe total synthesis of a series of new carolacton derivatives that mainly lack selected methyl substituents along the polyketide backbone is reported. Their inhibitory activity towards bacterial biofilms revealed that selective removal of the methyl group at C10 does not have a major effect on biological activity, whereas additional removal of the methyl group at C14 in carolacton results in a large decrease in antibacterial activity. A key new feature of this work is the replacement of the Nozaki–Hiyama–Kishi (NHK) vinylation with a titanium-mediated protocol for the fusion of the two main fragments.

Strategies to access the [5-8] bicyclic core encountered in the sesquiterpene, diterpene and sesterterpene series.

Terpene compounds probably represent the most diversified class of secondary metabolites. Some classes of terpenes, mainly diterpenes (C20) and sesterterpenes (C25) and to a lesser extent sesquiterpenes (C15), share a common bicyclo[3.6.0]undecane core which is characterized by the presence of a cyclooctane ring fused to a cyclopentane ring, i.e., a [5-8] bicyclic ring system. This review focuses on the different strategies elaborated to construct this [5-8] bicyclic ring system and their application in the total synthesis of terpenes over the last two decades. The overall approaches involve the construction of the 8-membered ring from an appropriate cyclopentane precursor. The proposed strategies include metathesis, Nozaki-Hiyama-Kishi (NHK) cyclization, Pd-mediated cyclization, radical cyclization, Pauson-Khand reaction, Lewis acid-promoted cyclization, rearrangement, cycloaddition and biocatalysis.

Enantioselective Metal-Catalyzed Reductive Coupling of Alkynes with Carbonyl Compounds and Imines: Convergent Construction of Allylic Alcohols and Amines.

The use of alkynes as vinylmetal pronucleophiles in intermolecular enantioselective metal-catalyzed carbonyl and imine reductive couplings to form allylic alcohols and amines is surveyed. Related hydrogen auto-transfer processes, wherein alcohols or amines serve dually as reductants and carbonyl or imine proelectrophiles, also are cataloged, as are applications in target-oriented synthesis. These processes represent an emerging alternative to the use of stoichiometric vinylmetal reagents or Nozaki-Hiyama-Kishi (NHK) reactions in carbonyl and imine alkenylation.

Mechanistic Diversity of Low-Valent Chromium Catalysis: Cross-Coupling and Hydrofunctionalization

ConspectusTransition-metal catalysis has traditionally been dominated by precious metals because of their high reactivity toward chemical transformations. As a cost-effective alternative, catalysis by earth-abundant group 6 metal chromium is underdeveloped, and its reactivity remains largely unexplored, although the industrially important Phillips catalyst, which is composed of Cr as the active metal, is currently used to supply almost 40% of the total world demand for high-density polyethylene. Cr has traditionally served in organoreagents with high-valent states (≥2+), which are typified by reactions involving Nozaki-Hiyama-Kishi (NHK) and Takai-Utimoto one-electron transfer processes. Given that low-valent metals usually facilitate the process of oxidative addition (OA), studying the catalysis of Cr in the low-valent state provides the opportunity to develop new transformations. However, probably because of the low stability of reactive low-valent Cr or the lack of catalytic activity of structurally stable complexes, there has been limited success with respect to developing catalysis promoted by low-valent Cr. In recent years, our group has probed the reactivity of low-valent Cr in catalysis by adopting a strategy of forming reactive Cr in situ. In this Account, we detail our efforts to study the catalytic behavior and mechanism of low-valent Cr in challenging transformations, such as the cleavage of chemically inert bonds for the cross-coupling and hydrofunctionalization of arenes and nitro motifs, by developing strategies to address the prominent selectivity issues. We highlight the finding that low-valent Cr, being formed in situ, possesses the intriguing ability to promote the catalytic cleavage of unactivated C-O, C-N, and C-H bonds to achieve the Kumada couplings and even to enable challenging cross-coupling between two unactivated C(aryl)-O/C(aryl)-N bonds. During these catalytic processes, Cr usually adopts a high-spin state to interact with chemicals, allowing for insertion into unactivated σ-bonds. The OA catalytic model involving a two-electron process for the cleavage of unactivated bonds has rarely been considered for Cr. We highlight the finding that Cr allows for the breakage of two chemically inert bonds in one catalytic cycle. This ability is intriguing because most transition metals are suitable only for the cleavage of one unactivated bond in catalysis. Mechanisms involving two-electron OA for Cr are unusual, with processes involving one-electron transfer more often proposed, as exemplified in the NHK reactions. These reactions provide efficient strategies for forming functionalized benzaldehydes, amides, anilines, and amines, usually with high levels of selectivity. We hope that this account will extend the scope of cognition to Cr catalysis.

Unified synthesis and assessment of tumor cell migration inhibitory activity of optically active UTKO1, originally designed moverastin analog.

UTKO1 is a synthetic analog of a natural tumor cell migration inhibitor, moverastin, isolated from microbial extracts of Aspergillus sp. 7720. UTKO1 was initially developed as a mixture of the stereoisomers. In this study, a concise and unified synthesis of the 4 optically active stereoisomers of UTKO1 was achieved from a known optically pure dihydro-α-ionone through a 5-step sequence. The key transformation in the synthesis was a Nozaki-Hiyama-Kishi (NHK) reaction between an optically active enoltriflate and a known aldehyde to install the chiral allylic hydroxy group at C2'. Simple chromatographic separation of the 2 diastereomers with regard to the allylic hydroxy group was possible by the derivatization into the corresponding acetals with Nemoto's optical resolution reagent, (S)- or (R)-5-allyl-2-oxabicyclo[3.3.0]octene (ALBO). All 4 synthetic stereoisomers of UTKO1 exhibited comparable tumor cell migration inhibitory activity.

A chiral oxazoline for catalytic enantioselective Nozaki-Hiyama-Kishi allylation and vinylation of aldehydes

Asymmetric allylation and vinylation of aldehydes with allyl halides and vinyl halides have been achieved using the chromium(II)-oxazoline catalyst. The catalyst promotes the highly efficient enantioselective Nozaki–Hiyama-Kishi (NHK) allylation of aldehydes using allyl bromide, producing the corresponding homoallylic alcohols in good yields (up to 84%) and a high level of enantioselectivity (up to 98% ee). Meanwhile, the NHK vinylation of aldehydes produce desired allylic alcohols in satisfactory yields (up to 88%) and a high level of enantioselectivity (up to 97% ee). We developed a reliable and milder protocol for preparing chiral homoallylic and allylic alcohols.

Total synthesis of PGF2α and 6,15-diketo-PGF1α and formal synthesis of 6-keto-PGF1α via three-component coupling

The asymmetric total synthesis of PGF2α and 6,15-diketo-PGF1α and formal synthesis of 6-keto-PGF1α from a common key intermediate are described. The key intermediate, which has a chiral cyclopentane backbone possessing suitable functional groups with required stereochemistry for both side chains, was prepared from (R)-4-silyloxy-2-cyclopentenone through a three-component coupling reaction. The Wittig reaction, Nozaki-Hiyama-Kishi (NHK) coupling and cross metathesis completed the synthesis of PGF2α, 6,15-diketo-PGF1α and 6-keto-PGF1α.

Toward the Stereoselective Synthesis of Arthrobotrisin A: Fragment Synthesis and Coupling Studies

A route towards the stereocontrolled synthesis of arthrobotrisin A based on a Nozaki–Hiyama–Kishi (NHK) coupling strategy was developed. Highlights of the fragment synthesis include enzyme-catalyzed kinetic resolution, Negishi carbometalation–iodination, quinone formation through oxidation with hypervalent iodine, chiral oxazaborolidine-catalyzed asymmetric Diels–Alder reaction with cyclopentadiene, regio- and stereoselective epoxidation, Noyori reduction, retro-Diels–Alder reaction, diastereoselective Luche reduction, and, finally, a Nozaki–Hiyama–Kishi (NHK) coupling of the vinyl iodide fragment.

Tamejiro Hiyama

Tamejiro Hiyama

ChemInform Abstract: Total Synthesis of Sacrolide A by Following a Nozaki—Hiyama—Kishi Macrocyclization Strategy.

AbstractThe title compound is obtained through a Jacobsen hydrolytic kinetic resolution, Sharpless asymmetric epoxidation, Yamaguchi esterification, and intramolecular Nozaki—Hiyama—Kishi (NHK) macrocyclization as key steps.

Synthesis of the C22-C40 Domain of the Azaspiracids.

An efficient synthesis of the C22-C40 domain of the azaspiracids is described. The synthetic route features a Nozaki-Hiyama-Kishi (NHK) coupling and chelation controlled Mukaiyama aldol reaction to access an acyclic intermediate and a double-intramolecular-hetero-Michael addition (DIHMA) to provide the FG-ring system bridged ketal.