Conversion of lactones into ethers

Kraus, George A.; Frazier, Kevin; Roth, Bruce D.; Täschner, Michael; Neuenschwander, Kent

doi:10.1021/jo00324a050

Cited by 113 publications

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“…17-Deoxysalvinorin A (12) was synthesised by deoxygenation of known lactol 11 13c using Et 3 SiH and BF 3 •Et 2 O. 18 By 1 H NMR, the H-17 oxymethylene appeared as a doublet, δ 3.58, coupling to H-8 (COSY crosspeak). As with 1, irradiation of H-12 gave a strong nOe enhancement of H-20 rather than H-8, confirming the configuration at C-8.…”

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confidence: 99%

Studies toward the Pharmacophore of Salvinorin A, a Potent κ Opioid Receptor Agonist

et al. 2004

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Salvinorin A (1), from the sage Salvia divinorum, is a potent and selective kappa opioid receptor (KOR) agonist. We screened other salvinorins and derivatives for binding affinity and functional activity at opioid receptors. Our results suggest that the methyl ester and furan ring are required for activity, but that the lactone and ketone functionalities are not. Other salvinorins showed negligible binding affinity at the KOR. None of the compounds bound to mu or delta opioid receptors.Salvinorin A (1) 1 was isolated from Salvia divinorum, a traditional medicine of the Mazatec Indians of Oaxaca, Mexico. Infusions of the leaves induce visions, and 1 is a potent hallucinogen in humans. 2 1 is a selective agonist at the κ opioid receptor (KOR), 3 with comparable potency and efficacy to the synthetic KOR agonists U50488 and U69593. 4 KOR ligands appear to have therapeutic potential against a range of conditions, including pain, 5 nausea, 6 depression, 7 and HIV infection. 8 1 is the only non-nitrogenous KOR agonist known, with no structural similarity to other such compounds. 3 Given this, 1 represents a valuable lead for the development of more potent and selective KOR ligands. At present, little is known of the compound's structure-activity relationships. The deacetyl compound salvinorin B (2), also isolated from S. divinorum ,9 is inactive at the KOR, while substitution of more hindered esters at the 2-position reduces or abolishes activity. 4 To probe the importance of other functional groups in 1, we set out to test related compounds from this plant, as well as semisynthetic derivatives of 1, for binding affinity and functional activity at cloned opioid receptors.Salvinorins A (1), D (4), and E (5) were isolated as described previously. 10 Acetylation of 4 gave salvinorin C (6). 11 The known 1α-hydroxy derivative 8 9,12a and diacetate 9 11 were prepared by published procedures (Figure 1).A number of new derivatives of 1 were also synthesized, and the structures verified by NMR analysis, including DEPT, COSY, HMQC, HMBC and nOe experiments. As a preliminary step, 1 itself was reexamined using these techniques. This confirmed the original 1 H and 13 C assignments (based on decoupling experiments) 9 in all cases except the overlapping multiplets of H-6 and H-7. The HMQC spectrum showed crosspeaks from C-6 (δ 38.1 ppm) to multiplets *Corresponding author. Tel: +61-3-8344-6488. Fax: +61-3-9347-5180. E-mail: masr@unimelb.edu.au.. Supporting Information Available: Experimental procedures, characterization data, 1 H and 13 C NMR spectra, and IUPAC/NIST Chemical Identifiers (INChIs) of the target compounds (the spectra of 4 and 5 were published previously). 10 This material is available free of charge via the Internet at http://pubs.acs.org. Until recently, no satisfactory procedure for deacetylation of 1 had been published. Brown reported that KCN in refluxing MeOH/THF gave 2 in quantitative yield, 13a but in our hands 8-epi-2 was the major product. Additionally, the epimers were not resolved on silica using Br...

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Studies toward the Pharmacophore of Salvinorin A, a Potent κ Opioid Receptor Agonist

et al. 2004

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“…For the reduction of the free carboxylic group we used a protocol proposed by Ravid et al 35 For compounds 2a-e the isolated yields of the resulted lactone alcohols 5a-e were in a range of 68-77% (Scheme 3, Table 1). The most promising, according to us, is a method, described by Kraus et al 37 where DIBALH at -78ºC with Et 3 SiH and BF 3 ·Et 2 O in DCM is used. The latter conditions were applied to the starting material 5a, affording in the first attempt a low yield -<20% according to GC analysis.…”

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confidence: 99%

Synthesis of chiral tetrahydrofuran derivatives

Lopp¹,

Niidu²,

Paju³

et al. 2010

Arkivoc

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“…The organic solution was separated, washed with brine, and dried (Na 2 S0 4 ). Concentration followed by silica gel column chromatography (ethyl acetate/benzene = 1/9) gave diol 4 (5.49 g, (6). To a solution of erythro lactone 5 (0.14 g. 0.19 mmol) in toluene (l0 ml) was added diisobutylaluminum hydride (0.29 ml, 1 M in toluene, 0.29 mmol) at ~ 75°C under nitrogen gas.…”

Section: (3r4r5s)-5-[( Tert-butyldiphenylsilyl }Oxy]methyl-3-[(mentioning

confidence: 99%

“…Resulting erythro silyloxy lactone 5 was reduced to a hemiacetal by diisobutylaluminum hydride. Without purification, this hemiacetal was exposed to silane reduction under the influence of triethylsilane and a catalytic amount of boron trifluoride etherate in dichloromethane 6 ) at -20°C, reducing only the hemiacetal position to provide disilyloxy tetrahydrofuran 6 in a 28 % yield from erythro 5, with the hemiacetal being recovered. An increase of temperature to 2°C permitted both reduction of the hemiacetal position and of the benzylic position to provide silyloxy tetrahydrofuran 7 in a 71 % yield from a mixture of erythro/threo silyloxy lactone 5.…”

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confidence: 99%