Heteroatom directed photoarylation: synthesis of a tetracyclic morphine structural analogue

Schultz, Arthur G.; Lucci, Robert D.

doi:10.1039/c39760000925

Cited by 19 publications

(3 citation statements)

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“…The unexpected formation of cis-dihydro 17 rather than 16 may be a result of the relative instability calculated for 16 compared to 17 (∼6 kcal/mol). Perhaps another mechanism for hydrogen atom transfer in zwitterion 19 competes with the expected suprafacial 1,5-hydrogen migration to give the more stable product . It is noteworthy that thiophenol was found to be an effective additive to avert the formation of 20 .…”

Section: Resultsmentioning

confidence: 98%

The First Asymmetric Total Syntheses of (+)-Lycorine and (+)-1-Deoxylycorine

1996

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The first asymmetric total syntheses of (+)-1-deoxylycorine (2a) and (+)-lycorine (2b), the unnatural enantiomer of lycorine (1), are described. Construction of lactam 12, a key intermediate in the synthesis of both 2a and 2b, began by Birch reduction-alkylation of the chiral benzamide 3 with 2-bromoethyl acetate followed by ester saponification to give the 6-(2-hydroxyethyl)-1-methoxy-1,4-cyclohexadiene 6a in 96% yield as a single diastereomer. This material was converted to the radical cyclization substrates 11a and 11b. Both 11a and 11b gave 12 and the reduced enamide 11c on treatment with AIBN and Bu 3 SnH in refluxing benzene solution. Lactam 12 also was obtained by photocyclization of enamide 11c. The allylic alcohol unit characteristic of the C ring of the lycorine alkaloids was fashioned by a radical induced decarboxylation-epoxide fragmentation of the N-hydroxy-2-thiazoline ester 21b. The resulting (+)-2-epi-deoxylycorine (22) was subjected to Mitsunobu inversion followed by LiAlH 4 reduction to give (+)-1-deoxylycorine (2a). The synthesis of (+)-lycorine (2b) involved the conversion of 12 to allylic alcohol 32 followed by a Torssell rearrangement of 32 to give the rearranged allylic acetate 35. Epoxidation of 35 with dimethyldioxirane gave 36a, which set the stage for a decarboxylation-epoxide fragmentation of carboxylic acid 36b to give 37 by photolysis of 36b in the presence of acridine and tert-BuSH. Reduction of 37 with LiAlH 4 gave (+)-lycorine (2b). Lycorine (1) is the most abundant alkaloid in plants of theAmaryllidaceae. It is said that as much as 1% of the dry weight of daffodil bulbs may consist of lycorine. 1 From the time of its initial isolation in 1877 lycorine was recognized as a potent emetic; 2 more recent studies have shown that lycorine inhibits protein and DNA synthesis in murine cells and in ViVo growth of a murine transplantable ascite tumor. 3 Lycorine is a powerful inhibitor of growth and cell division in higher plants, algae, and yeast 4 and has antiviral activity. 5Much of the determination of structure for lycorine was accomplished by Kondo and co-workers 2,6 by utilization of classical chemical studies; proof of structure was provided by X-ray crystallographic analysis of dihydrolycorine hydrobromide. 7 Although several syntheses of racemic lycorine alkaloids have been developed, 8 an asymmetric synthesis had not been reported until we communicated the first asymmetric synthesis of (+)-1-deoxylycorine (2a). 9 Herein we report the details of the synthesis of 2a along with the first asymmetric synthesis of (+)-lycorine (2b), the unnatural enantiomer of 1.

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Section: Resultsmentioning

confidence: 98%

The First Asymmetric Total Syntheses of (+)-Lycorine and (+)-1-Deoxylycorine

1996

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“…Anal. (C2oHi9N03) C, , N. 4-[2-(Phenylmethoxy)-3-methoxyphenyl]pyridine-3carboxaldehyde (8). To a solution of alcohol 7 (11.9 g, 37.0 mmol) in CH2C12 (150 mL) was added Mn02 (20.9 g, 240 mmol).…”

Section: Methodsmentioning

confidence: 99%

“…Among the reported syntheses of the ACNO system of morphine with functionalized C-ring,8-10 the one reported by Weller et al10 was adopted for the preparation of our 7-keto analogs of 1 (Scheme 2). The key intermediate 4-[2-(phenylmethoxy)-3-methoxyphenyl]pyridine-3-carboxaldehyde (8) was synthesized by a new route (Scheme l).11 The starting 7-methoxy [ 1 ]benzopyrano [3,4-c]pyridin-5(2H)-one ( 5)12 was treated with sodium methoxide followed by benzyl bromide to give 4-arylnicotinate 6. Dibal reduction of 6 followed by oxidation of the resulting alcohol 7 with active manganese dioxide provided aldehyde 8, which was converted by literature proce-dures10 to give ester 9 in 58% overall yield from 5. The conversion of 9 to the desired 7-keto analogs of 1, namely 4a-c, essentially followed the published se-0022-2623/94/1837-3121$04.50/0 © 1994 American Chemical Society…”

Section: Chemistrymentioning

confidence: 99%

Synthesis and Opioid Activity of 7-Oxygenated 2,3,4,4a,5,6,7,7a-octahydro-1H-benzofuro[3,2-e]isoquinolinols

Cheng

Hsin²,

Tsai³

et al. 1994

J. Med. Chem.

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3-(Cyclopropylmethyl)-9-hydroxy-7-oxo-2,3,4,4a alpha,5,6,7,7a alpha- octahydro-1H-benzofuro[3,2-e]isoquinoline (4b) containing the ACNO ring system of morphine and a 7-keto function on ring C has been synthesized and found to possess potent PQW (ED50 = 0.15 mg/kg sc) and anti-Straub tail (ED50 = 0.02 mg/kg sc) activity. As compared to its 7-deoxy analog 1b, introduction of the 7-keto group did not significantly affect binding to any of the three opioid receptors (mu, kappa, and delta), but caused a 34-fold reduction in sigma-binding, suggesting reduced propensity to induce psychotomimetic effects. The C/D cis isomer of 4b (4c) was much less potent at the three opioid receptors, while displaying a slight increase in sigma affinity. Both 7-hydroxy derivatives 4e and 4f were active in anti-Straub tail assay (ED50 < or = 0.8 mg/kg sc), but only the alpha-isomer 4e demonstrated analgesic activity (PQW ED50 = 0.37 mg/kg sc) in the dose range tested. In guinea pig ileum preparations, 4e was characterized as a selective full agonist at the kappa opioid receptor (IC50 = 2.8 nM); while its beta-isomer 4f was a partial agonist (78% at 1 microM), with antagonist activity observed at both mu- and kappa-opioid receptors.

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ChemInform Abstract: HETEROATOM DIRECTED PHOTOARYLATION‐ SYNTHESIS OF A TETRACYCLIC MORPHINE STRUCTURAL ANALOG

Schultz¹,

Lucci²

1977

Chemischer Informationsdienst

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Heteroatom directed photoarylation: synthesis of a tetracyclic morphine structural analogue

Abstract: The tetracyclic structural analogue (7) of morphine is prepared in high yield by photocyclizationrearrangement of the aryloxyenone (4).WE describe our approach towards a total synthesis of morphine (la) and codeine (lb). The key step involves

Cited by 19 publications

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The First Asymmetric Total Syntheses of (+)-Lycorine and (+)-1-Deoxylycorine

The First Asymmetric Total Syntheses of (+)-Lycorine and (+)-1-Deoxylycorine

Synthesis and Opioid Activity of 7-Oxygenated 2,3,4,4a,5,6,7,7a-octahydro-1H-benzofuro[3,2-e]isoquinolinols

ChemInform Abstract: HETEROATOM DIRECTED PHOTOARYLATION‐ SYNTHESIS OF A TETRACYCLIC MORPHINE STRUCTURAL ANALOG

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