Nozaki-Hiyama-Kishi Reaction Research Articles

A Nickel-Catalyzed Nozaki–Hiyama–Kishi Reaction under Visible Light Photocatalysis

A Nickel-Catalyzed Nozaki–Hiyama–Kishi Reaction under Visible Light Photocatalysis

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.

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.

Cover Feature: A Photoredox Nozaki‐Hiyama Reaction Catalytic in Chromium (Eur. J. Org. Chem. 29/2022)

The Cover Feature celebrates Japanese chemists Prof. Hitosi Nozaki and Prof. Tamejiro Hiyama, who discovered the Cr-mediated allyl addition to aldehydes. This work reports a catalytic photoredox version of the Nozaki-Hiyama reaction, without any problem related to the use of stoichiometric Mn or Zn as reducing agents….Mondai arimasen! More information can be found in the Research Article by P. G. Cozzi et al.

Electroreductive Nozaki–Hiyama–Kishi Reaction

Electroreductive Nozaki–Hiyama–Kishi Reaction

Efficient Construction of (±)-epi-Costunolide through a Chromium(II)-Mediated Nozaki–Hiyama–Kishi Reaction

Abstract(±)-epi-Costunolide has been synthesized through a seven-step procedure starting from (E,E)-farnesol. The key step includes an intramolecular allylation of an aldehyde through a chromium(II)-mediated Nozaki–Hiyama–Kishi reaction, in which more than one equivalent of CrCl2 has been recognized as the most effective reagent to promote the conversion. An anti-inflammatory screen showed that epi-costunolide is a moderate inhibitor of B lymphocyte proliferation.

Chromium-Catalyzed Nozaki–Hiyama–Kishi Reaction

Chromium-Catalyzed Nozaki–Hiyama–Kishi Reaction

Total Synthesis of (+)-Cornexistin.

Herein, we describe the first total synthesis of (+)‐cornexistin as well as its 8‐epi‐isomer starting from malic acid. The robust and scalable route features a Nozaki–Hiyama–Kishi reaction, an auxiliary‐controlled syn‐Evans‐aldol reaction, and a highly efficient intramolecular alkylation to form the nine‐membered carbocycle. The delicate maleic anhydride moiety of the nonadride skeleton was constructed from a β‐keto nitrile. The developed route enabled the synthesis of 165 mg (+)‐cornexistin.

Total Synthesis of Conidiogenone Natural Products

Key words conidiogenones - quaternary centers - Heck reaction - reductive cyclization - Nozaki–Hiyama–Kishi reaction

Recent Advances in the Asymmetric Nozaki–Hiyama–Kishi Reaction

This review will survey recent developments in the area of the catalytic asymmetric Nozaki–Hiyama–Kishi reaction. The content will be classified according to reaction type as follows: asymmetric allylation, asymmetric propargylation, asymmetric alkynylation, asymmetric vinylation, and asymmetric alkylation. 1 Introduction 2 Asymmetric Allylation 3 Asymmetric Propargylation and Asymmetric Homoallenylation 4 Asymmetric Alkynylation 5 Asymmetric Vinylation and Arylation 6 Asymmetric Alkylation 7 Intramolecular Nozaki–Hiyama–Kishi Reaction 8 Conclusion and Perspectives

Total Syntheses of the Resorcylic Acid Lactones Paecilomycin F and Cochliomycin C Using an Intramolecular Loh-Type α-Allylation Reaction for Macrolide Formation.

Subjection of the resorcylic ester 16 to a Nozaki-Hiyama-Kishi reaction afforded the 12-membered lactone 17, while treatment of it under the Loh-type α-allylation conditions using indium metal gave the isomeric, 14-membered macrolide 18. Compound 18 was readily elaborated to the resorcylic acid lactone type natural products paecilomycin F and cochliomycin C.

Application of a Rotor–Stator High-Shear System for Cr/Mn-Mediated Reactions in Eribulin Mesylate Synthesis

Potential issues associated with the scale up of a catalytic Nozaki–Hiyama–Kishi reaction and a Cr/Mn-mediated desulfonylation used in eribulin mesylate synthesis were evaluated, and countermeasures were investigated. When stir bar agitation, which is typically used for laboratory-scale reactions, was changed to impeller-type agitation upon scale up of these reactions, the conversion rate and yield decreased considerably. Traditional methods for overcoming such decreases, such as preactivation of the Mn or the use of fine particles of Mn, did not improve the conversion rate sufficiently, whereas a physical shearing approach was effective. Specifically, we found that the use of a rotor–stator high-shear system as a stirring device afforded the same conversion rate as that observed with a stir bar.

Convenient In-Flow Preparation of Cr(II) Chloride for Nozaki–Hiyama–Kishi Reaction

A flow preparation of chromous chloride has been introduced as a viable alternative to the batch protocol. Activity of the prepared reagent has been demonstrated in the traditional Nozaki–Hiyama–Kishi reaction.

Total Synthesis of Solandelactones A and B

AbstractThe total synthesis of solandelactones A and B is presented. The eastern cyclopropyl moiety was prepared following an exceptionally short chemoenzymatic approach whereas enantioselective synthesis of the western side‐chain relied on the application of diastereomerically pure allyl boronates. The natural products solandelactones A and B were isolated in good overall yields following convergence of each eastern and western element by application of the Nozaki–Hiyama–Kishi reaction.

ChemInform Abstract: Addition of Vinylmetallic Reagents to Chiral 2‐Formyltetrahydrofuran.

AbstractA carboaluminum reaction, a Nozaki—Hiyama—Kishi reaction, and a chelation‐controlled organometallic addition are investigated for the introduction of a side chain to aldehydes (III) and (VI).

Total Synthesis and Structure Revision of Didemnaketal B

Didemnaketal B, a structurally complex spiroacetal that exhibits potent HIV-1 protease inhibitory activity, was originally discovered by Faulkner and his colleagues from the ascidian Didemnum sp. collected at Palau. Its absolute configuration was proposed on the basis of degradation/derivatization experiments of the authentic sample. However, our total synthesis of the proposed structure of didemnaketal B questioned the stereochemical assignment made by Faulkner et al. Here we describe in detail our first total synthesis of the proposed structure 2 of didemnaketal B, which features 1) a convergent synthesis of the C7-C21 spiroacetal domain by means of a strategy exploiting Suzuki-Miyaura coupling, 2) an Evans syn-aldol reaction and a vinylogous Mukaiyama aldol reaction for the assembly of the C1-C7 acyclic domain, and 3) a Nozaki-Hiyama-Kishi reaction for the construction of the C21-C28 side chain domain. The NMR spectroscopic discrepancies observed between synthetic 2 and the authentic sample as well as careful inspection of the Faulkner's stereochemical assignment led us to postulate that the absolute configuration of the C10-C20 domain of 2 has been erroneously assigned. Accordingly, the total synthesis of the revised structure 65 was achieved to show that the NMR spectroscopic properties of synthetic 65 were in good agreement with those of the authentic sample. Furthermore, application of the phenylglycine methyl ester (PGME) method to the C7-C21 spiroacetal domain enabled us to establish the absolute configuration of didemnaketal B.

The protecting-group directed diastereoselective Nozaki-Hiyama-Kishi (NHK) reaction: total synthesis and biological evaluation of zeaenol, 7-epi-zeaenol and its analogues.

The stereoselective total synthesis of zeaenol and 7-epi-zeaenol is achieved in a convergent manner using Julia-Kocienski olefination, protecting group-directed intermolecular diastereoselective Nozaki-Hiyama-Kishi (NHK) reaction, De Brabander's lactonization reaction and CBS reduction as the key steps. In this article, we have observed the most suitable protecting groups with respect to selectivity during the protecting group directed intermolecular asymmetric Nozaki-Hiyama-Kishi reaction. The zeaenol, 7-epi-zeaenol and its derivatives were analyzed for their biological activity and screened in four cancer cell lines.

ChemInform Abstract: From Micrograms to Grams. Scale‐up Synthesis of Eribulin Mesylate

AbstractReview: 16 refs.