Efficient reductive etherification of carbonyl compounds with alkoxytrimethylsilanes

Hatakeyama, Susumi; Mori, Hidefumi; Kitano, Kaori; Yamada, Hidetoshi; Nishizawa, Masatoyo

doi:10.1016/s0040-4039(00)73357-0

Cited by 100 publications

(50 citation statements)

References 14 publications

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“…10 To our disappointment we did not obtain the desired product 21, but instead isolated spiroethers 2a and 2b. These products resulted from a cyclization that had been known for quite some The trans diastereomer 2a hydrochloride exhibited very high binding affinities to the NOP as well as the MOP receptors K i (hNOPr) = 0.3 nM (N = 4, SEM = 0.05 nM), K i (hMOPr) = 0.6 nM (N = 2, SEM = 0.14 nM), while the cis-diastereomer 2b was significantly less active (%Inh.…”

Section: Acs Medicinal Chemistry Lettersmentioning

confidence: 94%

Discovery of Spiro[cyclohexane-dihydropyrano[3,4-b]indole]-amines as Potent NOP and Opioid Receptor Agonists

Schunk¹,

Linz²,

Frormann³

et al. 2014

ACS Med. Chem. Lett.

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ABSTRACT:We report the discovery of spiro [cyclohexanepyrano[3,4-b]indole]-amines, as functional nociceptin/orphanin FQ peptide (NOP) and opioid receptor agonists with strong efficacy in preclinical models of acute and neuropathic pain. Utilizing 4-(dimethylamino)-4-phenylcyclo-hexanone 1 and tryptophol in an oxa-Pictet−Spengler reaction led to the formation of spiroether 2, representing a novel NOP and opioid peptide receptor agonistic chemotype. This finding initially stems from the systematic derivatization of 1, which resulted in alcohols 3−5, ethers 6 and 7, amines 8−10, 22−24, and 26−28, amides 11 and 25, and urea 12, many with low nanomolar binding affinities at the NOP and mu opioid peptide (MOP) receptors. KEYWORDS: NOP receptor agonist, MOP receptor agonist F or decades, opioid peptide receptors have been targeted for the treatment of pain, and the present day opioids remain the most effective clinically used drugs for the treatment of moderate to severe acute and chronic pain. However, opioids also carry the risk of severe side effects such as respiratory depression, nausea, vomiting, and constipation, and their use may lead to physical dependence and tolerance.1 The nociceptin receptor and its endogenous ligand nociceptin/ orphanin FQ (N/OFQ), a 17-amino acid neuropeptide, have been described almost 20 years ago.2,3 Because of its partial homology to the three opioid peptide receptor subtypes mu opioid peptide (MOP), kappa opioid peptide (KOP), and delta opioid peptide (DOP) and its insensitivity to opioid agonists (e.g., morphine) and antagonists (e.g., naloxone), the receptor was initially termed "opioid-receptor-like 1" (ORL 1). More recently, however, it was renamed after its endogenous ligand to nociceptin/orphanin FQ peptide (NOP) receptor. Despite its structural and functional homology to opioid receptors, the NOP receptor is not an opioid peptide receptor from a pharmacological perspective and, as such, is considered a nonopioid member of the opioid peptide receptor family. 4 NOP and MOP receptor agonists modulate pain and nociception via distinct yet related targets. Addressing both mechanisms may constitute a novel approach for the development of innovative analgesics. Indeed, recent publications indicate that concurrent activation of NOP and MOP receptors may potentiate opiate analgesia and at the same time lead to an improved side effect profile. 5,6 We therefore aimed at identifying highly potent, small molecule NOP and MOP receptor agonists.This endeavor started with a literature-to-lead approach based on cyclohexanone 1, which has previously been reported by Lednicer et al. as representing a novel class of analgesics. 7,8 As a starting point it was clear that, due to its size, compound 1 would lack key interactions within the binding pocket of both the NOP and MOP receptors and therefore would have only minimal receptor binding affinities (K i (NOP) = 1.5 μM; K i (MOP) = 1.7 μM). It was our strategy to utilize 1 as a core and its ketone moiety for functionalization. Thus, fixing the 4-...

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Section: Acs Medicinal Chemistry Lettersmentioning

confidence: 94%

Discovery of Spiro[cyclohexane-dihydropyrano[3,4-b]indole]-amines as Potent NOP and Opioid Receptor Agonists

Schunk¹,

Linz²,

Frormann³

et al. 2014

ACS Med. Chem. Lett.

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“…A number of other reaction conditions led to the formation of mixtures of regioisomeric benzyl ethers. For example, the use of BH 3 .NHMe 2 in DCM, which is the conventional solvent for this reagent, 30 gave a mixture of products .Glycosyl donor 4 31 and fatty acids 6 ,26 7 and 8 32,33 were prepared by reported procedures.…”

Section: Chemical Synthesismentioning

confidence: 99%

Agonistic and antagonistic properties of a Rhizobium sin-1 lipid A modified by an ether-linked lipid

2007

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LPS from Rhizobium sin-1 (R. sin-1) can antagonize the production of tumor necrosis factor alpha (TNF-α) by E. coli LPS in human monocytic cells. Therefore these compounds provide interesting leads for the development of therapeutics for the prevention or treatment of septic shock. Detailed structure activity relationship studies have, however, been hampered by the propensity of these compounds to undergo β-elimination to give biological inactive enone derivatives. To address this problem, we have chemically synthesized in a convergent manner a R. sin-1 lipid A derivative in which the β-hydroxy ester at C-3 of the proximal sugar unit has been replaced by an ether linked moiety. As expected, this derivative exhibited a much-improved chemical stability. Furthermore, its ability to antagonize TNF-α production induced by enteric LPS was only slightly smaller than that of the parent ester modified derivative demonstrating that the ether-linked lipids affect biological activities only marginally. Furthermore, it has been shown for the first time that R. sin-1 LPS and the ether modified lipid A are also able to antagonize the production of the cytokine interferoninducible protein 10, which arises from the TRIF-dependent pathway. The latter pathway was somewhat more potently inhibited than the MyD88-dependent pathway. Furthermore, it was observed that the natural LPS possesses much greater activity than the synthetic and isolated lipid As, which indicates that di-KDO moiety is important for optimal biological activity. It has also been found that isolated R. sin-1 LPS and lipid A agonize a mouse macrophage cell line to induce the production of TNF-α and interferon beta in a Toll-like receptor 4-dependent manner demonstrating species specific properties.

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“…[5] Acetal formation, regioselective reductive opening of arylidene acetals or reductive etherification, and acylation are reactions widely used on carbohydrate templates that can all be readily catalyzed by triflate salts or trimethylsilyl triflate (TMSOTf). [6][7][8][9] The possibility then emerges that these reactions could be programmed in tandem. [5] This intriguing approach would, however, require an absolute fine-tuning of the experimental conditions that would be compatible with all three reactions conducted in the same vessel.…”

mentioning

confidence: 99%

Tandem Catalysis for a One‐Pot Regioselective Protection of Carbohydrates: The Example of Glucose

2007

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Efficient reductive etherification of carbonyl compounds with alkoxytrimethylsilanes

Cited by 100 publications

References 14 publications

Discovery of Spiro[cyclohexane-dihydropyrano[3,4-b]indole]-amines as Potent NOP and Opioid Receptor Agonists

Discovery of Spiro[cyclohexane-dihydropyrano[3,4-b]indole]-amines as Potent NOP and Opioid Receptor Agonists

Agonistic and antagonistic properties of a Rhizobium sin-1 lipid A modified by an ether-linked lipid

Tandem Catalysis for a One‐Pot Regioselective Protection of Carbohydrates: The Example of Glucose

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