The Total Synthesis of Strychnine

Woodward, R. B.; Cava, Michael P.; Ollis, W. D.; Hunger, A.; Daeniker, H. U.; Schenker, K.

doi:10.1021/ja01647a088

Cited by 313 publications

(185 citation statements)

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“…Notably, this approach also constitutes the most concise synthesis of (−)-strychnine as the subject of many total syntheses (Bonjoch and Sole, 2000;Cannon and Overman, 2012) to date, with an overall yield of 6.4% in 12 steps starting from a commercially available compound. This compares to 2 × 10 −4 % overall and 29 steps in the landmark Woodward synthesis of the compound (Woodward et al, 1954). This collective synthesis approach for plant compounds has subsequently been taken up by others (Ghavimi and Magnus, 2014;Han et al, 2014;.…”

Section: Organic Synthesismentioning

confidence: 90%

Discovery and resupply of pharmacologically active plant-derived natural products: A review

2015

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Medicinal plants have historically proven their value as a source of molecules with therapeutic potential, and nowadays still represent an important pool for the identification of novel drug leads. In the past decades, pharmaceutical industry focused mainly on libraries of synthetic compounds as drug discovery source. They are comparably easy to produce and resupply, and demonstrate good compatibility with established high throughput screening (HTS) platforms. However, at the same time there has been a declining trend in the number of new drugs reaching the market, raising renewed scientific interest in drug discovery from natural sources, despite of its known challenges. In this survey, a brief outline of historical development is provided together with a comprehensive overview of used approaches and recent developments relevant to plant-derived natural product drug discovery. Associated challenges and major strengths of natural product- Europe PMC Funders Author ManuscriptsEurope PMC Funders Author Manuscripts based drug discovery are critically discussed. A snapshot of the advanced plant-derived natural products that are currently in actively recruiting clinical trials is also presented. Importantly, the transition of a natural compound from a "screening hit" through a "drug lead" to a "marketed drug" is associated with increasingly challenging demands for compound amount, which often cannot be met by re-isolation from the respective plant sources. In this regard, existing alternatives for resupply are also discussed, including different biotechnology approaches and total organic synthesis.While the intrinsic complexity of natural product-based drug discovery necessitates highly integrated interdisciplinary approaches, the reviewed scientific developments, recent technological advances, and research trends clearly indicate that natural products will be among the most important sources of new drugs also in the future.

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Section: Organic Synthesismentioning

confidence: 90%

Discovery and resupply of pharmacologically active plant-derived natural products: A review

2015

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“…45) The first total synthesis of (Ϫ)-strychnine was achieved by Woodward et al in 1954. 46) After that brilliant achievement, there were no other reports on the total synthesis of strychnine for about 40 years. However, tremendous progress has been made recently in synthetic organic chemistry using organometallic complexes, and the total syntheses of complicated natural products have been achieved using novel procedures.…”

Section: Total Synthesis Of (؊)-Strychninementioning

confidence: 99%

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

Mori

2005

CHEMICAL & PHARMACEUTICAL BULLETIN

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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...

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“…The first total synthesis of strychnine, one of the most significant achievements in the history of organic synthesis, was reported by Woodward in 1954. 37,38) Nearly 40 years after Woodward's pioneering work, a number of groups reported the total synthesis, [37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52] four of which culminated in an enantioselective synthesis of the natural enantiomer. 41,42,44,45,47,48,52) As summarized in Bonjoch's excellent review, 34) the major stumbling blocks in the synthesis are the generation of the spirocenter at C7 and the assembly of the bridged framework (CDE core ring).…”

Section: )mentioning

confidence: 99%

“…Finally, removal of the acetyl group provided the crude Wieland-Gumlich aldehyde, which was converted to (Ϫ)-strychnine (4) by the established method. [37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53] 2-2. Development of the Stable, Storable, and Reusable Asymmetric Catalyst La-O-linked-BINOL Complex for a Catalytic Asymmetric Michael Reaction [22][23][24] The ALB complex is a highly efficient catalyst for the Michael reaction of malonates to cyclic enones.…”

Section: )mentioning

confidence: 99%

Enantioselective Total Syntheses of Several Bioactive Natural Products Based on the Development of Practical Asymmetric Catalysis

Ohshima

2004

CHEMICAL & PHARMACEUTICAL BULLETIN

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I present herewith enantioselective total syntheses of several bioactive natural products, such as (؊)-strychnine, (؉)-decursin, (؊)-cryptocaryolone diacetate, (؊)-fluoxetine, and aeruginosin 298-A, based on practical asymmetric catalyses (Michael reaction, epoxidation, and phase-transfer reaction) that I developed with coworkers in Prof. Shibasaki's group over the past 5 years. In the first part of this review, I discuss the great improvement of catalyst efficiency in an ALB-catalyzed asymmetric Michael reaction of malonate and application to the pre-manufacturing scale (greater than kilogram scale) and enantioselective total synthesis of (؊)-strychnine with the development of novel domino cyclization. To broaden the substrate generality of the Michael reaction, we developed a highly stable, storable, and reusable La-O-linked-BINOL complex. Further extension of the reaction using b b-keto ester as a Michael donor was achieved with the development of a La-NR-linked-BINOL complex, thereby improving indole alkaloid syntheses. In the second section, I discuss enantioselective total synthesis of (؉)-decursin using catalytic asymmetric epoxidation. To achieve the synthesis, we developed a new La-BINOL-Ph 3 As‫؍‬O (1 : 1 : 1) complex catalyst system, which has much higher reactivity and broader substrate generality than the previously developed catalyst systems. This allowed us to achieve catalytic asymmetric epoxidation of a a,b b-unsaturated carboxylic acid derivatives with high enantioselectivity and broad substrate generality for the first time by changing the lanthanide metal and reaction conditions. Among them, catalytic asymmetric epoxidation of a a,b b-unsaturated morpholinyl amides is quite useful in terms of synthetic utility of the corresponding a a,b b-epoxy morpholinyl amides. Highly catalyst-controlled enantio-or diastereoselective epoxidation of the a a,b b-unsaturated morpholinyl amides, coupled with diastereoselective reduction of b b-hydroxy ketones, enabled the synthesis of all possible stereoisomers of 1,3-polyol arrays with successful enantioselective total synthesis of several 1,3-polyol natural products, such as (؊)-cryptocaryolone diacetate. In addition, the development of a new regioselective epoxide-opening reaction of a a,b b-epoxy amides to the corresponding a a-and b b-hydroxy amides enhanced the usefulness of the present epoxidation and was applied to the enantioselective total synthesis of (؊)-fluoxetine. In the final section, I report the development of a new asymmetric two-center organocatalyst (TaDiAS) and its application to the enantioselective synthesis of aeruginosin 298-A and its analogues. Because of the remarkable structural diversity of TaDiAS, a practical asymmetric phase-transfer reaction with broad substrate generality was achieved. As a result, we succeeded in developing a highly versatile synthetic method for aeruginosin 298-A and its analogues. Inhibitory activity studies of the compounds against the serine protease trypsin provided preliminary information about their str...

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The Total Synthesis of Strychnine

Cited by 313 publications

References 1 publication

Discovery and resupply of pharmacologically active plant-derived natural products: A review

Discovery and resupply of pharmacologically active plant-derived natural products: A review

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

Enantioselective Total Syntheses of Several Bioactive Natural Products Based on the Development of Practical Asymmetric Catalysis

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