Development of a Novel Synthetic Method for Ring Construction Using Organometallic Complexes and Its Application to the Total Syntheses of Natural Products

Abstract

Organometallic complexes are useful tools in synthetic organic chemistry. In particular, they play an important role in carbon-carbon bond formation. A metalacycle, i.e., a ring compound containing a transition metal, is a useful intermediate in synthetic organic chemistry. Oxidative cyclization of unsaturated hydrocarbons, such as alkene, alkyne, carbonyl compounds, or nitrile, using a low-valent transition metal is a useful reaction for synthesis of metalacycles. It is known that a metalacycle formed from a late transition metal and unsaturated hydrocarbons is not stable and is easily converted into the reductive elimination product or b-hydrogen elimination product (Eq. 1). Since the low-valent metal complex is regenerated in this reaction, the reaction proceeds with a catalytic amount of the transition metal. On the other hand, the metalacycle formed from an early transition metal and unsaturated hydrocarbons is fairly stable and can be converted into various compounds with functional groups by treatment with various agents (Eq. 2). Therefore a stoichiometric amount of the metal complex is required in this reaction.(1) (2) Negishi et al.2) and Nugent and Calabrese 3) reported the syntheses of zirconacycles 2 from diene, enyne, and diyne 1 using zirconocene (Cp 2 Zr). Hydrolysis of zirconacycle afforded the cyclized compound 3 (Chart 1).Negishi et al. also found a synthetic method of dibutylzirconocene (Cp 2 ZrBu 2 ) from zirconocenedichloride (Cp 2 ZrCl 2 ) and butyl lithium, and dibutylzirconocene is easily converted into zirconocene coordinated by a butene ligand in situ at room temperature 4) (Eq. 3).This was a great discovery in zirconium chemistry because it is difficult to isolate zirconocene with no ligand. We were interested in those results and attempted to form carbon-carbon bonds between the unsaturated hydrocarbons, such as enyne and diene, using zirconocene. Synthesis of Heterocycles Using Zirconium-Mediated Cyclization and Total Synthesis of (؊)-DendrobineThe zirconacycles 2 were easily synthesized in situ from Cp 2 ZrCl 2 and diene, enyne, or diyne 1. To a THF solution of Cp 2 ZrCl 2 and unsaturated hydrocarbon 1 was added BuLi at Ϫ78°C under argon gas, and the solution was stirred at room Organometallic complexes are useful tools in synthetic organic chemistry. We investigated a novel synthetic method for ring construction using organometallic complexes and synthesized natural products and biologically active substances using these methods. Metalacycles formed from an early transition metal and diene, enyne, and diyne are stable under the reaction conditions and they are easily converted into compounds with functional groups by the addition of various agents. We have developed a novel synthetic method of heterocycles from enyne and diene using Cp 2 ZrBu 2 . The total syntheses of (؊)-dendrobine, (؎)-mecembrane, and (؎)-mecembrine were achieved using this procedure. To synthesize these natural products as a chiral form, a novel palladium-catalyzed asymmetric allylic amination was developed, an...

Methods Utilizing First-Row Transition Metals in Natural Product Total Synthesis

“…Broadly speaking, first-row transition metal analogues of classical Pd-catalyzed reactions have been less frequently employed in natural product synthesis. − , In Hu and co-workers’ total synthesis of the fungal macrolide recifeiolide ( 24 - 6 ), a nickel-catalyzed Suzuki–Miyaura coupling was used to synthesize esterification precursor 24 - 5 (Scheme ). The researchers began by performing a hydroboration of alkyne 24 - 1 .…”

“…The metals that deviate positively from the linear correlation are suspected to be overutilized in total synthesis relative to other fields, while those that deviate from linearity in a negative fashion are thought to be underutilized. It is unsurprising that Ru, − Os, Rh, − Ir, − and Pd − have a disproportionate occurrence with “total synthesis” given the dramatic impact that these metals have had on organic synthesis. , The remarkable occurrence of Pd in articles on total synthesis contrasts sharply with the abundance and deviation from linearity seen with Fe, and to a lesser extent the other first-row transition metals, with Cu being an exception.…”