The pyridinium reduction route to alkaloids: a synthesis of (±)-tashiromine

Bates, Roderick W.; Boonsombat, Jutatip

doi:10.1039/b100407g

Cited by 43 publications

(18 citation statements)

References 16 publications

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“…Lithium aluminium hydride reduction of crude 10 provided tashiromine (1) in 36% yield over the two steps. The spectral data were in accord with those reported in the literature [7][8][9][10][11][12][13][14][15][16][17] In summary, we have developed a six-step synthesis of tashiromine from succinimide (19% overall yield). The key finding in this synthesis is that olefin cross-metathesis is a useful route to nitrogen-containing functionalised allylsilanes.…”

Section: Methodssupporting

confidence: 84%

A Concise Synthesis of Tashiromine

McElhinney¹,

Marsden²

2005

Synlett

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A concise (six-step) synthesis of the indolizidine alkaloid tashiromine (1) has been achieved. Olefin cross-metathesis was used to prepare a key functionalised allylsilane, which subsequently underwent electrophile-induced ring-closure to establish the bicyclic framework with complete control of stereochemistry.Functionalised allylsilanes have been much used in the stereoselective construction of a variety of carbocyclic and heterocyclic structures. 1 Our own group 2,3 and others 4 have been interested in the use of olefin metathesis for the efficient construction of functionalised allylsilanes. To date our own studies have focused on the synthesis of oxygen-containing allylsilanes by ring-closing olefin metathesis 5 and the application of these entities in the stereocontrolled construction of tetrahydrofuran 2 and aryltetralin skeleta. 3 We now wish to report our first ventures into the synthesis of nitrogen containing allylsilanes by olefin cross-metathesis in the context of a short total synthesis of tashiromine (1). Figure 1Alkaloids containing the indolizidine skeleton have diverse biological activity and remain popular targets for synthetic chemists. 6 Tashiromine (1), 7 for example, has been the subject of ten different total syntheses to date (Figure 1). [8][9][10][11][12][13][14][15][16][17] We considered that 1 could be accessed from an intermediate 2 which would be prepared by the intramolecular trapping of an acyl iminium ion 3 by the pendant allylsilane (Scheme 1). In fact, reactions of this type have been developed by Hiemstra and Speckamp, 18 and cyclisation of allylsilane (Z)-4 has been shown to proceed with perfect stereocontrol for the formation of the required trans-stereochemistry. Hiemstra's synthesis of 4 involved alkylation of succinimide with allylsilane-containing mesylate 5a, prepared in four steps from commercially available iodomethyltrimethylsilane and 2-(4-pentynyloxy)tetrahydropyran. Compound 5a and the corresponding iodide 5b have been much employed (both as electrophiles and sources of nucleophiles) in the synthesis of functionalised allylsilanes, and can also be accessed by Wittig reactions using the Seyferth-Fleming phosphorane 19 and nickel-catalysed 1,2-metallate rearrangement of 2-dihydropyranyllithium. 20 We considered that a shorter, more economical 21 and convenient approach to 4 would involve the olefin cross-metathesis of (4-pentenyl)succinimide with the commercially available allyltrimethylsilane (6). 22 Such an approach would have broad applicability well beyond the current investigation and we therefore set about demonstrating its viability. We report herein the successful attainment of this goal. Scheme 1Alkylation of the sodium salt of succinimide with 4-pentenyl bromide gave our metathesis substrate 7 in 98% yield (Scheme 2). Olefin cross-metathesis of 7 with 6 mediated by Grubbs' second generation metathesis catalyst [(H 2 Imes)(Pcy 3 )Cl 2 Ru=CHPh] gave the desired allylsilane 8 in 73% yield as a 3:1 mixture of E-and Z-isomers.

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Section: Methodssupporting

confidence: 84%

A Concise Synthesis of Tashiromine

McElhinney¹,

Marsden²

2005

Synlett

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“…This was done by taking advantage of the higher reactivity of the trans halogen in the 1,1-dihaloalkene 2. 144 50 The vinyl zirconium species was coupled with a vinyl bromide 2.153 that was the product of a Negishi coupling of a 1,2-dihaloalkene 2.151 with a diynyl zinc reagent 2.152. After desilylation, the syntheses were completed by Sonogashira reactions with either cis or trans 3-iodoallyl alcohol.…”

Section: Aluminium and Zirconiummentioning

confidence: 99%

“…A Sonogashira coupling of a chloropyridine 2.390 using a heterogeneous catalyst was a key step in a synthesis of the indolizidine alkaloid, tashiromine 2.394 (Scheme 2.122). 144 After alkyne reduction and removal of the THP protecting group, activation of the alcohol 2.392 as a mesylate led directly to the bicyclic pyridinium ion 2.393. Stereoelectronically controlled reduction of this ion, followed by reduction of the ester, gave tashiromine 2.394.…”

Section: Scheme 2120mentioning

confidence: 99%

Coupling Reactions

2012

Organic Synthesis Using Transition Metals

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The coupling of an organometallic and an organic halide should be a useful way of forming a C-C single bond. The reaction is, however, not general, but restricted to special cases. Grignard reagents will react efficiently with some halides, such as allyl halides, while copper reagents can be used in this type of reaction with a wider range of substrates. Even so, that range is not great and copper reagents are thermally unstable, as well as sensitive to air and moisture.A useful method would not require special conditions, be quite general and use easily prepared starting materials. This can be done with transition-metal catalysis (Scheme 2.1). By far the most widely used metal is palladium, but other metals, especially nickel and, more recently, iron, have also been employed. 1 The main variables to consider are the "R" and "R " groups that can be employed, the main group metals "M" that can be used, the nature of the leaving group "X" and the identity and quantity of the ligand "L". The basic mechanism for palladium-catalysed coupling is a simple combination of oxidative addition, transmetallation and reductive elimination (Scheme 2.2).A coordinatively unsaturated palladium(0) complex 2.1, which is the catalytic species, is generated from an 18-electron palladium(0) complex by reversible ligand dissociation. Alternatively, it can be generated by reduction of a palladium(II) complex. Both the L 4 Pd and the L 2 PdX 2 should be regarded as "pre-catalysts". The catalyst or pre-catalyst complex may be assembled in situ from a mixture of a palladium source, such as a palladium(II) salt, Pd 2 (dba) 3 or even, in a few cases, palladium on carbon, and the ligand. This avoids the need to preform a palladium complex.If a palladium(II) pre-catalyst is employed, then there must be a reduction step prior to the start of the catalytic process. This has sometimes been done by the addition of a reducing agent, but more commonly, the palladium(II) is reduced by homocoupling of the organometallic partner, RM (Scheme 2.3). This homocoupling reaction is of occasional synthetic use itself (see Section 2.10).So how do we know which catalyst to employ? It is determined by looking for precedent and by doing experiments. Key variables are the ligand to metal ratio, and the identity of the ligand. Historically, Ph 3 P has been the most widely used, but that doesn't mean it is best (although it is cheapest). A less widely explored variable is the metal.

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“…96 After reduction of the alkyne and removal of the THP protecting group, the alcohol 212 was treated with methanesulfonyl chloride. 96 After reduction of the alkyne and removal of the THP protecting group, the alcohol 212 was treated with methanesulfonyl chloride.…”

Section: Synthesis and Other Chemical Studiesmentioning

confidence: 99%

Indolizidine and quinolizidine alkaloids

Michael

2002

Nat. Prod. Rep.

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This review covers the isolation, structure determination, synthesis and biological activity of indolizidine and quinolizidine alkaloids from microbial, plant and animal sources. Included in the review are slaframine; hydroxylated indolizidines and their analogues; alkaloids from ants and amphibians; metabolites of the genera Prosopis, Streptomyces and Nuphar and the Lythraceae; phenanthroindolizidines and related alkaloids; lupin alkaloids; and alkaloids from sponges. tunicates and coccinellid beetles. The literature from July 2000 to June 2001 is reviewed, and 172 references are cited.

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The pyridinium reduction route to alkaloids: a synthesis of (±)-tashiromine

Cited by 43 publications

References 16 publications

A Concise Synthesis of Tashiromine

A Concise Synthesis of Tashiromine

Coupling Reactions

Indolizidine and quinolizidine alkaloids

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