Author Topic: Synthesis of deuterium labeled Salvinorin A  (Read 1250 times)

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Lego

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Synthesis of deuterium labeled Salvinorin A
« on: September 16, 2004, 06:42:00 PM »
Not a total synthesis but nonetheless interesting.
See also

Post 492481 (missing)

(Rhodium: "Salvinorin A and its Analogs in the Literature", General Discourse)





A facile method for the preparation of deuterium labeled salvinorin A: synthesis of [2,2,2-2H3]-salvinorin A
Kevin Tidgewell, Wayne W. Harding, Mark Schmidt, Kenneth G. Holden, Daryl J. Murry and Thomas E. Prisinzano
Bioorg. Med. Chem., 2004, 14(20), 5099-5102
DOI:

10.1016/j.bmcl.2004.07.081




Abstract: Salvinorin A is a novel hallucinogen isolated from the widely available leaves of Salvia divinorum. Based on its mechanism of action, salvinorin A has shown potential as a stimulant abuse therapeutic. However, there are no methods for the detection of salvinorin A or its metabolites in biological fluids. In order to begin developing salvinorin A as a potential therapeutic, an understanding of its metabolism is needed. Here, a straightforward synthesis of a deuterium labeled analog of salvinorin A and its utility as an internal standard for the detection of salvinorin A and its metabolites in biological fluids by LC–MS is described.

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Rather than begin a lengthy total synthesis of salvinorin A, we initially focused on extracting salvinorin A from the dried leaves of S. divinorum. Commercially available leaves were extracted as previously described1, 2, and 17 and afforded salvinorin A. However, we then set out to further improve the bioyield of salvinorin A. Modification of extraction procedure18 resulted in the isolation of 7.5 g of salvinorin A from 1.5 kg of dried leaves. This process has resulted in an improved bioyield of salvinorin A compared to previously described methodology. Efforts were then shifted to the preparation of salvinorin B. Basic hydrolysis of the C-2 acetate using sodium carbonate in MeOH afforded salvinorin B in 77% yield.19 Curiously, these conditions do not result in the cleavage of the C-18 methyl ester as noted by the presence of a methyl singlet at 3.7 ppm in the 1H NMR spectrum. This is likely due to the C-18 position being more sterically hindered than the C-2 position. More vigorous conditions, such as heat and NaOH, are required for the cleavage of this group. However, this leads to the opening of the lactone ring, as well as epimerization of the 8-position. Reacetylation of salvinorin B using d6-acetic anhydride in the presence of a catalytic amount of DMAP afforded [2,2,2-2H3]-salvinorin A (5) in 80% yield.20

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Scheme 1. Reagents and conditions: (a) Na2CO3, MeOH, 77%; (b) (Cd3CO2)2O, DMAP, CH2Cl2, 80%.

[...]

References

1. A. Ortega, J.F. Blount and P.S. Manchand, J. Chem. Soc., Perkin Trans. 1 (1982), pp. 2505-2508.
2. L.J. Valdes III, W.M. Butler, G.M. Hatfield, A.G. Paul and M. Koreeda, J. Org. Chem. 49 (1984), pp. 4716-4720;

Post 435658

(pHarmacist: "Salvinorin A", Methods Discourse)

[...]
17.

T.A. Munro and M.A. Rizzacasa, J. Nat. Prod. 66 (2003), pp. 703-705

(https://www.thevespiary.org/rhodium/Rhodium/pdf/salvinorin-d-f.pdf)

18. Dried Salvia divinorum leaves (1.5 kg) were ground to a fine powder and percolated with acetone (5 × 4 L). The acetone extract was concentrated under reduced pressure to afford a crude green gum (93 g), which was subjected to column chromatography on silica gel with elution in n-hexanes containing increasing amounts EtOAc. Fractions eluting in 20% n-hexanes/EtOAc contained salvinorin A (TLC) and other minor diterpenes and some pigmented material. These fractions were pooled and concentrated in vacuo to give a green gum (24 g). A mixture of the crude green gum, acetic anhydride (50 mL, 530 mmol) and DMAP (0.2 g) in CH2Cl2 (250 mL) was stirred at rt overnight. The CH2Cl2 solution was washed sequentially with 1 N HCl (2 × 500 mL), 2 N NaOH (100 mL), and H2O (2 × 100 mL). The CH2Cl2 solution was dried (Na2SO4) and the solvent was removed under reduced pressure to afford a yellow-green gum (23 g). The resulting gum was subjected to column chromatography on silica gel. Elution was performed in 1000 mL aliquots of a mixture of n-hexanes/EtOAc in increments of 10% EtOAc with the final elution in neat EtOAc. Fractions eluting in 30% n-hexanes/EtOAc and subsequent fractions were pooled and the solvent was removed under reduced pressure affording salvinorin A (7.5 g, 0.5%) as a green powder, mp 235–238 °C (lit1,2 240–242 °C)

19. A mixture of 1a (3.5 g, 8.0 mmol) and Na2CO3 (3.4 g, 32.2 mmol) in absolute MeOH (150 mL) was stirred at room temperature for 4 h. The solvent was removed under reduced pressure and CH2Cl2 (500 mL) was added to the crude residue. The organic extract was washed successively with 2 N HCl (50 mL) and saturated NaCl (50 mL) and dried (Na2SO4). The solvent was removed under reduced pressure and MeOH (100 mL) was added to the residue. The resulting solid was collected by filtration and dried to afford 2.4 g (77%) of 1b as a white solid, mp 211–214 °C (lit.2 213–216 °C)

20. A solution of 1b (0.1 g, 0.3 mmol), d6-acetic anhydride (0.1 g, 1.3 mmol) and a catalytic amount of DMAP in CH2 Cl2 (20 mL) was stirred at room temperature for 2 h. Absolute MeOH (15 mL) was added and the solvent was removed under reduced pressure. CH2Cl2 (25 mL) was added to the residue and the solution was washed with 10% HCl (3 × 20 mL) and saturated NaCl (3 × 20 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure afforded 0.09 g (80%) of 5 as a white solid, mp 237–240 °C.

[...]


java

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Salvinorin A....related
« Reply #1 on: September 16, 2004, 11:20:00 PM »
There is some synthesis attempt here.......java

http://www.pervertedlogic.com/lucifer_m/chemistry.htm