A5038591449- Synthetic Organic Chemistry Methods
- Asymmetric Synthesis and Catalysis
- Chemical Synthesis and Analysis
- X-ray Diffraction in Crystallography
- Chemical Synthesis and Reactions
- Crystallization and Solubility Studies
- Crystallography and molecular interactions
- Asymmetric Hydrogenation and Catalysis
- Marine Sponges and Natural Products
- Catalytic C–H Functionalization Methods
- Microbial Natural Products and Biosynthesis
- Marine Toxins and Detection Methods
- Catalytic Cross-Coupling Reactions
- Sulfur-Based Synthesis Techniques
- Cyclopropane Reaction Mechanisms
- Radical Photochemical Reactions
- Oxidative Organic Chemistry Reactions
- Catalytic Alkyne Reactions
- Advanced Synthetic Organic Chemistry
- Synthesis and Catalytic Reactions
- Traditional and Medicinal Uses of Annonaceae
- Microtubule and mitosis dynamics
- Cancer Treatment and Pharmacology
- Carbohydrate Chemistry and Synthesis
- Axial and Atropisomeric Chirality Synthesis
Harvard University
2017-2024
Osaka University
2011-2024
Max-Planck-Institut für Kohlenforschung
2021-2023
Kingston University
2020
Harvard University Press
2019
Suita Municipal Hospital
2017
Tohoku University
2014
Cobalt-catalyzed Markovnikov-selective hydroamination of nonactivated olefins was developed. Hydrogen atom transfer from a catalytically generated cobalt(III)–hydride complex to the proceeded regioselectively, and nucleophilic addition benzotriazoles occurred selectively at their N2-positions. The synthetic utility obtained N2-alkylated as stable amine protecting groups under various reaction conditions demonstrated, products were also transformed into primary amines by zinc-mediated reduction.
Herein, we describe the generation of an organochromium-type carbanion species from a non-activated C-H bond and its nucleophilic addition to aldehydes. The catalytic occurred through formal deprotonation under mild conditions did not need prefunctionalization or anion stabilizing group. Carbon radical intermediates generated by decatungstate photocatalyst-mediated hydrogen abstraction were captured chromium salt with reductive radical-polar crossover reaction produce organochromium carbanions.
The dinoflagellate-derived polyether prorocentin is a co-metabolite of the archetypical serine/threonine phosphatase inhibitor okadaic acid. Whereas structural relationship cannot be missed and biosynthetic link was proposed, it currently unknown whether there any parallel in bioactivity profile these natural products. However, insinuated past that structure assigned to might need revised. Indeed, re-examination published spectra cast doubts as constitution fused/spirotricyclic BCD-ring...
Abstract A zirconium/nickel‐mediated one‐pot synthesis of ketones is reported. In the presence Zn or Mn, Cp 2 ZrCl was found to dramatically accelerate coupling and suppress side product formation via an I→SPy displacement at same time. Unlike Zn/Pd‐ Fe/Cu‐mediated ketone syntheses, new method effective for nucleophiles bearing OR equivalent functional groups α‐position. mechanism comprising a nickel catalytic cycle, zirconium Zr→Ni transmetalation proposed, and/or low‐valent Zr species are...
E7130 is a novel drug candidate with an exceedingly complex chemical structure of the halichondrin class, discovered by total synthesis approach through joint research between Kishi group at Harvard University and Eisai. Only 18 months after completion initial milligram-scale synthesis, ten-gram-scale was achieved, providing first good manufacturing practice (GMP) batch to supply clinical trials. This paper highlights challenges in developing from synthesis.
Process development of E7130 Drug Substance, which is a novel anticancer drug candidate, described. To accomplish rapid delivery such large and structurally complex substance for first-in-human (FIH) clinical trial, close collaboration among medicinal chemistry, process academia teams was required. The successful establishment suitable synthetic route in concise time frame while negotiating challenging chemical reactions (e.g., asymmetric catalytic Nozaki–Hiyama–Kishi (NHK) reaction...
Abstract Unified, efficient, and scalable syntheses of the halichondrin natural products are reported. A newly developed Zr/Ni‐mediated one‐pot ketone synthesis was used to couple two halves final product at a late stage in synthesis. With use slight excess left halves, desired ketones were isolated yields 80–90 %. The halichondrins obtained from these steps, namely desilylation [5,5]‐spiroketal formation. new synthetic route effective for total all members homohalichondrin subgroup....
Abstract Despite their outstanding antitumour activity in mice, the limited supply from natural sources has prevented drug discovery/development based on intact halichondrins. We achieved a total synthesis of C52-halichondrin-B amine (E7130) >10 g scale with >99.8% purity under GMP conditions. Interestingly, E7130 not only is novel microtubule dynamics inhibitor but can also increase intratumoural CD31-positive endothelial cells and reduce α-SMA-positive cancer-associated fibroblasts...
Abstract Guangnanmycin A is a recently discovered congener of the well‐known antitumor drug lead leinamycin; its macrolactam ring, however, even more strained than that parent compound. The first synthetic foray towards this challenging target reported, which relies on molybdenum‐catalyzed macrocyclization by ring closing alkyne metathesis (RCAM) followed ruthenium‐catalyzed redox isomerization propargyl alcohol thus formed; resulting enone enabled introduction yet missing exo ‐methylene...
Step saver: Carbonyl groups with lower reactivities can be transformed in the presence of more reactive ones by treatment PPh3 (or PEt3) and TMSOTf prior to reaction (see scheme; TMS=trimethylsilyl, Tf=trifluoromethanesulfonyl). This methodology applied reduction alkylation reactions, enabled short asymmetric total synthesis (+)-centrolobine highest overall yield reported date.
In recent years, London dispersion interactions, which are the attractive component of van der Waals potential, have been found to play an important role in controlling regio- and/or stereoselectivity various reactions. Particularly, interactions between substrates and catalysts (or ligands) dominant selective catalyzes. contrast, repulsive steric rather than bulky substituents predominant most noncatalytic Herein, we demonstrate first example dispersion-controlled (2 + 2) cyclodimerization...
Enones selectively react with a combination of PPh3 and TMSOTf to produce phosphonium silyl enol ethers, which work as protective groups enones during the reduction other carbonyl functions can be easily deprotected regenerate parent at workup. Furthermore, first ketone selective alkylations in presence were also accomplished. This situ protection method was applied concise asymmetric total syntheses decytospolides A B.
The structure and electronic nature of the phosphine have a significant influence on not only formation, but also subsequent transformation O,P-acetals. O,P-acetals generated from tris(o-tolyl)phosphine [(o-tol)3P] underwent efficient substitution reactions with various nucleophiles.
An Fe/Cu-mediated one-pot ketone synthesis was reported. Unlike Ni- and Pd-mediated syntheses, the reported method allowed selective activation coupling of alkyl iodides over vinyl iodides. The newly developed applied to a iodide/ketone 13, left half halichondrin B, as well 8a, C20–C26 building block halichondrins.
A concise and unified strategy for the synthesis of C1–C18 macrolactone fragments FD-891 FD-892 as well their analogues is reported. The includes a stereoselective vinylogous Mukaiyama aldol reaction (VMAR) using chiral silyl ketene N,O-acetal to construct C6–C7 stereocenters, an E-selective ring closing metathesis C12–C13 olefin, stereodivergent construction C8–C9 epoxide.
The regiocontrolled protection of unsymmetrical 1,2- and 1,3-diols has been developed. Different types protected diols are available from the methylene acetal in a one-pot procedure. Highly regioselective with silyl group at less hindered hydroxy as well MOM more one were achieved. reaction conditions mild without affecting other functional groups including acid-labile function.
Abstract Mild substitution reactions of acetals with carbon nucleophiles via the pyridinium‐type salts generated by treatment TESOTf‐2,4,6‐collidine or 2,2′‐bipyridyl have been developed. Various nucleophiles, such as organocuprates, silyl enol ethers, enamines, etc., reacted to give corresponding substituted products in good yields. The proceeded under very mild conditions (non‐acidic conditions) and thus acid‐sensitive functional groups can be tolerated during reaction. In addition, only...
A methodology for selective transformations of ketones, esters, Weinreb amides, and nitriles in the presence aldehydes has been developed. The use a combination PPh3-trimethylsilyl trifluoromethanesulfonate (TMSOTf) promotes transformation to their corresponding, temporarily protected, O,P-acetal type phosphonium salts. Because, hydrolytic work-up following ensuing reactions other carbonyl moieties substrates liberates aldehyde moiety, sequence involving protection, groups, deprotection can...
After a recent total synthesis had resolved all issues surrounding the constitution and stereostructure of prorocentin, it was possible to devise new approach aiming at an improved supply this scarce marine natural product; compound is cometabolite prototypical phosphatase inhibitor okadaic acid but still awaits detailed biological profiling. The revised entry starts from 2-deoxy-d-glucose; keys success were telescoped hemiacetal reduction/acetal cleavage exquisitely selective gold/Brønsted...
A stereocontrolled synthesis of the left halves halichondrins was reported. An intramolecular oxy-Michael reaction under basic conditions used to construct [6,6]-spiroketal in a manner. With this approach, halichondrins, homohalichondrins, and norhalichondrins were synthesized.
Herein, we describe a novel synthetic method for 2,5-disubstituted tetrazoles from 5-substituted using cobalt-catalyzed intermolecular hydroamination reaction of nonactivated olefins. Owing to its mild conditions, the enabled use substrates having acid-labile functional groups, such as silyloxy and methoxymethyloxy groups. By optically active cobalt complexes, asymmetric olefins, longstanding challenge in organic chemistry, was developed produce disubstituted tetrazoles.
The facile deprotection of methylene acetal protection diols under mild conditions is established. combination trimethylsilyl triflate (TMSOTf) and 2,2′-bipyridyl followed by a weakly acidic hydrolysis was effective the substrates having acid sensitive functional groups can be tolerated stated conditions. selective between benzophenone ketal achieved.
The right halves of halichondrins A-C were synthesized by coupling the common C20-C37 building block 9 with C1-C19 blocks 10a-c, respectively. Catalytic, asymmetric Ni/Cr-mediated was used for three C-C bond formations. For all cases, stereochemistry controlled Cr catalyst prepared from chiral sulfonamide identified via toolbox approach. (3 + 4)-, (6 7)-, and (9 10)-couplings, stereoselectivity 28:1, >40:1, ∼20:1 achieved catalysts (S)-H, (S)-I, (R)-L, Unlike first second couplings, third...
Abstract Guangnanmycin A is a recently discovered congener of the well‐known antitumor drug lead leinamycin; its macrolactam ring, however, even more strained than that parent compound. The first synthetic foray towards this challenging target reported, which relies on molybdenum‐catalyzed macrocyclization by ring closing alkyne metathesis (RCAM) followed ruthenium‐catalyzed redox isomerization propargyl alcohol thus formed; resulting enone enabled introduction yet missing exo ‐methylene...