A Short Intramolecular Diels−Alder Route to Himbacine Derivatives

Hofman, Sven; Gao, Ling‐Jie; Dingenen, Hilde Van; Hosten, N.; Haver, Dirk Van; Clercq, Pierre J. De; Milanesio, Marco; Viterbo, D.

doi:10.1002/1099-0690(200108)2001:15<2851::aid-ejoc2851>3.0.co;2-u

Cited by 28 publications

(11 citation statements)

References 15 publications

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“…The aqueous solution was extracted four times with EtOAc and then the combined organic extracts were washed with brine, dried, and the solvent removed under vacuum. The residue was recrystallized from acetone/petroleum spirit to afford white crystals of 13 (26 g, 80%), mp 184 • C, dec. (19) Sodium hydride (60% in paraffin oil, 15 g, 375 mmol) was washed with petroleum spirit, suspended in THF (500 mL), and the solution cooled to 0 • C. The ketone prepared above (10 g, 36 mmol) was dissolved in THF (100 mL) and this solution was added slowly to the sodium hydride suspension. After stirring for 5 min, ethyl formate (25 mL, 310 mmol) was added and the solution stirred a further 1 h at 0 • C. The cooling bath was removed and the solution stirred at room temperature for 16 h. Methanol (20 mL) was added to quench the excess sodium hydride and the solution was diluted with water and acidified to pH 1 with dilute HCl (2 M).…”

Section: (5rs9sr)-5678910-hexahydro-5-hydroxy-2-methoxy-8-oxo-5mentioning

confidence: 99%

“…This was extracted with ethyl acetate, the organic layers were then combined and washed with water and brine, and then dried and evaporated under vacuum to give an oily residue. This was purified by column chromatography (ethyl acetate/petroleum spirit, 1/1) to give the pure α,β-enone 41 as an oil that solidified on standing (100 mg, 55% 135 (18), 110 (100), 91 (24), 67 (19)…”

Section: (6asr7sr13rs13asr13brs)-23466a712 1313a13b-decamentioning

confidence: 99%

“…However, this increased level of acetylcholine is offset by increased inhibition of post-synaptic M 1 receptors and thus, numerous analogues of himbacine have been produced to try to reverse this selectivity and increase potency. As a consequence, seven total syntheses of himbacine have been reported to date [6,[10][11][12][13][14][15][16][17][18][19][20][21][22][23] and screening of related compounds has led to the synthetic analogue 8 (Fig. 3) that has been shown to be a potent thrombin receptor (PAR-1) antagonist and is presently undergoing phase 3 clinical trials for the treatment of acute coronary syndrome and for secondary prevention in patients who have had a prior myocardial infarct or stroke.…”

Section: Introductionmentioning

confidence: 99%

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The Total Synthesis of the Galbulimima Alkaloid GB 13

Mander

McLachlan

2003

J. Am. Chem. Soc.

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This contribution describes a synthetic approach to alkaloid GB 13, previously isolated from the North Australian and Papua New Guinean rain forest tree Galbulimima belgraveana. A Birch reductive alkylation of 2,5-dimethoxybenzoic acid by 3-methoxybenzyl bromide, followed by an acid-catalyzed cyclization was used to synthesize the [3.3.1]bicyclononane 8. A ring contraction performed on the diazo derivative 9 of the [3.3.1]bicyclononane led to [3.2.1]bicyclooctane 10. This [3.2.1]bicyclooctane was converted into a dienophile and subjected to a Diels-Alder reaction to generate a pentacyclic intermediate 13 with a carbon skeleton closely resembling the target alkaloid. The surplus substituent, required for activation and regioselectivity in the Diels-Alder reaction, was removed using Birch reductive conditions to effect a decyanation. It was discovered that a Birch reduction of the aromatic ring also present in the molecule could be performed at the same time to give the enone 15, which was cleaved by means of an Eschenmoser fragmentation. The piperidine ring found in the natural product was formed by reductive cyclization of the bis-oxime 18 derived from the alkynyl ketone 17 and the resulting material further elaborated to GB 13 (1) via ketone 20.

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Section: (5rs9sr)-5678910-hexahydro-5-hydroxy-2-methoxy-8-oxo-5mentioning

confidence: 99%

Section: (6asr7sr13rs13asr13brs)-23466a712 1313a13b-decamentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Total Synthesis of the Galbulimima Alkaloid GB 13

Mander

McLachlan

2003

J. Am. Chem. Soc.

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“…25,26,27,28 Among the six different bond construction sets that one may distinguish following this particular cycloaddition strategy, two sets correspond to the intermolecular reaction mode, one of which has been realized in practice, 27 and the four remaining construction sets correspond to intramolecular versions of this popular construction reaction (IMDA). 29 Symptomatic of how pervasive this reaction type has become in terms of cyclic skeleton construction, especially when involving stereochemical constraints, is the observation that the three synthetic approaches that were first reported almost simultaneously in 1995, involved pathway i (Scheme 1).…”

Section: Figurementioning

confidence: 99%

“…The synthesis of vinylstannane 26 proceeded by reaction of a higher order tributyltincuprate derivative, obtained from copper(I) cyanide, n-butyllithium and tributyltinhydride, 44 with the known terminal alkyne 27 (80% yield). 28 The Sonogashira coupling involved reaction of the same bromides 25a and 25b with alkyne 27 (bis(triphenylphosphine)palladium(II) acetate, triethylamine in acetonitrile) and afforded enynes 29a (76% yield) and 29b (73% yield), respectively. 45 It is worth noting that the above conditions are the result of thorough experimentation.…”

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Synthesis and binding affinity studies of muscarinic receptor antagonists related to dehydrohimbacine

Gao¹,

Cauwenberge²,

Hosten³

et al. 2003

Arkivoc

Self Cite

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The intramolecular Diels−Alder reaction of bromo-substituted nonatrienoate 24 leads to a mixture of the anti-adducts 25a and 25b, in which the trans-fused lactone 25b, the result of an expected exo-addition, predominates (6.2:1 stereoselectivity). Further introduction of a 2,6-transdisubstituted piperidine ring (26 and 27) via palladium catalyzed cross-coupling reactions (Stille and Sonogashira) affords intermediates that are easily transformed into dehydrohimbacine derivatives 14a, 14b, 15a, and 15b. Binding affinity studies for the muscarine receptors M 1 , M 2 , M 3 , and M 4 show that 15a possesses a 18-fold selectivity for the M 2 relative to the M 1 receptor, but with concomittant loss in affinity compared to the naturally occurring (+)-himbacine (1), a recognized muscarinic receptor antagonist.

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Hydrozirconation of Alkynes

Milligan,

Hammill,

Crocker

et al. 2023

Organic Reactions

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Since the first preparation of organozirconocenes from alkenes and alkynes in 1972, hydrozirconation has become one of the most commonly used stoichiometric methods to convert readily available starting materials into reactive but stable organometallic intermediates. A broad range of subsequent transformations may be employed to convert organozirconocenes in situ into high‐value functionalized products, often with the strategic formation of one (or several) new carbon–carbon bonds. This chapter focuses on the hydrozirconation of terminal and internal alkynes, and the subsequent synthetic transformations of the resulting alkenylzirconocenes. Zirconocene hydrochloride, Cp 2 Zr(H)Cl, is most frequently employed for the hydrozirconation step and can be used as a reagent or prepared in situ. Subsequent reactions of alkenylzirconocenes include additions to inorganic electrophiles such as halogens, as well as in situ ligand transfers to other metals, such as palladium and zinc, that further expand the range of accessible bond formations. The initial discussion focuses on the mechanism and stereochemical considerations, and on the steric and electronic factors that determine the regiochemistry of the either kinetically or thermodynamically controlled hydrozirconation. The “Scope and Limitations” section presents information on functional group compatibilities and is organized by the type of synthetic transformation of alkenylzirconocenes. Representative applications of the hydrozirconation of alkynes are showcased in syntheses of natural products, comparisons to alternative methods for the hydrometallation of alkynes. The goal of this chapter is to demonstrate the significance of hydrozirconation in organic synthesis, including the utility of the stoichiometric zirconium organometallics obtained from alkyne substrates, and to provide inspiration for the future development of new synthetic methods and strategies.

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A Short Intramolecular Diels−Alder Route to Himbacine Derivatives

Abstract: The intramolecular cycloaddition of 5 yields the unsaturated lactones 17a, 17b, and 17c as three major isomeric adducts. These were further reduced to the corresponding derivatives 21a, 21b, and 21c, which are intermediates for the synthesis

Cited by 28 publications

References 15 publications

The Total Synthesis of the Galbulimima Alkaloid GB 13

The Total Synthesis of the Galbulimima Alkaloid GB 13

Synthesis and binding affinity studies of muscarinic receptor antagonists related to dehydrohimbacine

Hydrozirconation of Alkynes

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