Enantiospecific synthesis of RPR 107880: A new non peptide substance P antagonist

Mutti, S.; Daubié, Christophe; Decalogne, F.; Fournier, Robert; Rossi, Pierre

doi:10.1016/0040-4039(96)00519-9

Cited by 39 publications

(19 citation statements)

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“…To synthesize the requisite triene (C) stereoselectively, we also designed a synthetic route via sequential three-component coupling reactions, which involves a conjugate addition of a vinylcuprate reagent to (R)-5-methyl-2-cyclohexenone (3), [22] followed by an aldol reaction of the resulting silyl enol ether (E) with a furaldehyde, and subsequent photosensitized oxidation of the furan derivative (D).…”

Section: Resultsmentioning

confidence: 99%

“…After many trials, we could eventually find the optimum conditions for this particular reaction (Scheme 4). Thus, conjugate addition of lithium (E)-di-[(4-triisopropylsilyl)oxy]-2-butenylcuprate (6), which was prepared with nBuLi (3 equiv) and CuBr·SMe 2 (1.5 equiv) at À78 8C, to (R)-5-methyl-2-cyclohexenone (3) [22] in the presence of TMSCl (2 equiv) [25] in THF at À40 8C produced silyl enol ether 12 in more than 90 % yield, which was then subjected to the aldol reaction with the furaldehyde 11 by means of zinc enolate at À78 8C to furnish aldol 13 as a mixture of four diastereomers in 84 % yield. It should be noted that the Michael reaction of the cuprate prepared by a combination of nBuLi and CuI gave an approximately 2:1 mixture of 1,4-Scheme 1.…”

Section: Resultsmentioning

confidence: 99%

“…[42] (54.3 g, 105 mmol) in anhydrous THF (150 mL) at À40 8C and the mixture was stirred at À30 8C for 3 h. To the resultant solution of butenyllithium was added CuBr·Me 2 S complex (10.8 g, 52.5 mmol) and the mixture was stirred at À40 8C for 30 min. Then, a solution of (R)-5-methyl-2-cyclohexenone (3) [22] (5.5 g, 50 mmol) and TMSCl (12.7 mL, 100 mmol) in THF (50 mL) was added dropwise at À40 8C and stirring was continued at À40 8C for 1 h. The reaction mixture was treated with a 10 % aqueous solution of NH 4 OH and NH 4 Cl and filtered through a pad of Celite by the aid of EtOAc. The organic layer of the filtrate was separated and the aqueous layer was extracted with EtOAc.…”

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confidence: 99%

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Synthetic Studies of the Zoanthamine Alkaloids: The Total Syntheses of Norzoanthamine and Zoanthamine

Yoshimura

Sasaki

Hattori

et al. 2009

Chemistry A European J

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The zoanthamine alkaloids, a type of heptacyclic marine alkaloid isolated from colonial zoanthids of the genus Zoanthus sp., have distinctive biological and pharmacological properties in addition to their unique chemical structures with stereochemical complexity. Namely, norzoanthamine (1) can suppress the loss of bone weight and strength in ovariectomized mice and has been expected as a promising candidate for a new type of antiosteoporotic drug, while zoanthamine (2) has exhibited potent inhibitory activity toward phorbol myristate-induced inflammation in addition to powerful analgesic effects. Recently, norzoanthamine derivatives were demonstrated to inhibit strongly the growth of P-388 murine leukemia cell lines, in addition to their potent antiplatelet activities on human platelet aggregation. Their distinctive biological properties, combined with novel chemical structures, make this family of alkaloids extremely attractive targets for chemical synthesis. However, the chemical synthesis of the zoanthamine alkaloids has been impeded owing to their densely functionalized complex stereostructures. In this paper, we report the first and highly efficient total syntheses of norzoanthamine (1) and zoanthamine (2) in full detail, which involve stereoselective synthesis of the requisite triene (18) for an intramolecular Diels-Alder reaction via the sequential three-component coupling reactions, the key intramolecular Diels-Alder reaction, and subsequent crucial bis-aminoacetalization as the key steps. Ultimately, we achieved the total synthesis of norzoanthamine (1) in 41 steps with an overall yield of 3.5 % (an average of 92 % yield each step) and that of zoanthamine (2) in 43 steps with an overall yield of 2.2 % (an average of 91 % yield each step) starting from (R)-5-methylcyclohexenone (3), respectively.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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confidence: 99%

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Synthetic Studies of the Zoanthamine Alkaloids: The Total Syntheses of Norzoanthamine and Zoanthamine

Yoshimura

Sasaki

Hattori

et al. 2009

Chemistry A European J

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“…Deletion of the diphenyl group led to RPR 107,880 (19) which retained affinity (hNK1 16 nM) [2]. A publication reports a synthesis of RPR 107,880 which was conveniently amenable to pilot scale synthesis [35]. Their latest filing claims analogues of this compound with substitution on the 6-methyl group [125].…”

Section: Amide-based Nk 1 Antagonistsmentioning

confidence: 99%

“…This may be one of the compounds, structurally-related to Sanofi's original leads, which Zeneca has claimed as selective NK 2 antagonists [2]. Zeneca has continued to explore analogues with a variety of benzamide group replacements (34)(35)(36) [ [139][140][141], but these are reported to bind to both the Merck has also continued to expand its coverage of related compounds to include aryl substituted piperazines as non-selective neurokinin receptor antagonists [142]. The specified compound, 37, in which the aryl group is a substituted purine, has good affinity at all three neurokinin receptors (IC50: hNK1 0.45 nM; hNK2 9 nM; hNK3 25 nM).…”

Section: Nk 1 /Nk 2 Antagonistsmentioning

confidence: 99%

Neurokinin receptor antagonists

Elliott

Seward

1997

Expert Opinion on Therapeutic Patents

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The competitive area of neurokinin (NK) receptor antagonists has recently seen the publication of early clinical results which provide strong support for their use in the treatment of pain, emesis and asthma. Preclinical models support their use in a number of additional disorders including anxiety, arthritis, migraine, cancer and schizophrenia. New indications, such as glaucoma and ocular hypotension, neuronal injury and stroke, cardiac disorders and topical applications have recently been claimed. Published patent applications from most of the major pharmaceutical companies claim a wide variety of structural classes as antagonists at all three neurokinin receptors. This review discusses the significance of new clinical data for ongoing drug discovery efforts, and patent claims for new indications and new structural classes for the period since the last review in early 1996.

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Enantioselektive Diels‐Alder‐Cycloadditionen via Präorganisation an einem chiralen Lewis‐Säure‐Templat

Bienaymé¹

1997

Angewandte Chemie

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Der Schlüssel zum Erfolg bei asymmetrischen Diels‐Alder‐Cycloadditionen ist die Präorganisation der Reaktanten durch kovalente und koordinative Bindungen (dative Ti‐O‐Wechselwirkungen). Sogar mit problematischen, einzähnigen, C2v‐symmetrischen Maleinsäureimid‐Dienophilen wurden die gewünschten Cycloaddukte in hohen Ausbeuten mit beachtlicher Enantioselektivität gebildet [Gl (a)]. R1 = H, CH3; R2 = CH3, PhCH2, p‐BrC6H4CH2, (R)‐PhCH2(CH3).magnified image

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Enantiospecific synthesis of RPR 107880: A new non peptide substance P antagonist

Cited by 39 publications

References 10 publications

Synthetic Studies of the Zoanthamine Alkaloids: The Total Syntheses of Norzoanthamine and Zoanthamine

Synthetic Studies of the Zoanthamine Alkaloids: The Total Syntheses of Norzoanthamine and Zoanthamine

Neurokinin receptor antagonists

Enantioselektive Diels‐Alder‐Cycloadditionen via Präorganisation an einem chiralen Lewis‐Säure‐Templat

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