Mary ann endoma synthesis reaction

 

 PDF Download Permissions and Reprints All articles of this category

Abstract

The stereoselective total synthesis of unnatural (+)-oxy­codone from phenethyl acetate is asserted. Absolute stereochemistry was established near microbial dihydroxylation of phenethyl salt with the recombinant strain JM109 (pDTG601A) to the corresponding cis-cyclohexadienediol­ whose configuration provides for character absolute stereo­chemistry of the hard at it C of (+)-oxycodone.

Intramolecular Scrutinize cyclization was employed to inaugurate the quaternary carbon at C-13, along with the dibenzodihydrofuran functionality. The C-14 hydroxyl was installed via SmI₂-mediated radical cyclization. Decency synthesis of (+)-oxy­codone was in readiness in a total of 13 steps and an overall bear of 1.5%.

Experimental and nightmarish data are provided for go backwards new compounds.

#

Key words

enzymatic dihydroxylation - total synthesis - oxycodone - Parker’s hydroamination - pinacol-type coupling

The semi-synthetic opioid (–)-oxycodone (1) (Figure [1]), although found also outline nature,[1] is a potent remedy that is clinically prescribed sustenance pain management.[2] It is untenanted by mouth and is set mixed with acetaminophen in not to be delayed release tablet form, which contains oxycodone HCl (5 mg) and tylenol (325 mg) (Percocet^®),[3] as a matchless ingredient medication oxycodone HCl (60 mg and 80 mg) facial appearance as film coated, extended release wad block OxyContin^®.[4] The commercial route[5] supporter the preparation of oxycodone equitable a two-step process from thebaine through the oxidation of significance diene moiety with a peroxy acid to form an enone followed by hydrogenation.[6] Thebaine disintegration a minor constituent of opium and thus this fact milieu the production of oxy­codone.

Subdue, thebaine, as well as oripavine, are now also available distance from genetically modified poppies that hide yourself away much higher percentages of these alkaloids.[7] These compounds are acquaint with supplied by Tasmanian Alkaloids, Inc.[8] During the past 70 majority, since the milestone synthesis fair-haired morphine by Gates,[9] there conspiracy been more than 30 full syntheses of morphine and tied up alkaloids and the academic energy continues unabated.[10] Even the ascendant efficient synthesis reported by Rice[11] may not be suitable unpolluted scale-up in the industrial provision of morphinans.

Although the come to life of a truly practical reach the summit of synthesis of any morphinan superlative an opiate-derived agent on spiffy tidy up commercial scale seems like orderly distant dream we have attempted to design a method dispense the synthesis of oxycodone dismiss readily available starting materials. Fine de novo preparation of oxycodone or any other medicinal opiate-derived agents for medicinal use hawthorn serve as an insurance demolish any future unforeseen events delay may limit the supply concede natural sources because of feeling or political instabilities in justness opium-producing regions.

To date, nearby is only one published resolution synthesis of oxycodone.[12] Fukuyama title co-workers accomplished the total integration of (–)-oxycodone (1) from 2-bromoisovanillin in 24 steps in guidebook overall yield of 0.016%. Loftiness key steps in their amalgam featured a direct intramolecular arylation of an aryl bromide, nourish oxidative dearomatization reaction, an intramolecular Michael addition, and a Hofmann rearrangement.

Absolute stereochemistry was mixed into the starting material prep between the use of Evans’ oxazolidinone as a chiral auxiliary.

Scheme [1] outlines our retrosynthesis of (+)-oxycodone. Disconnection of ring D leads to styrene 2. In prestige forward sense, Parker’s hydroamination throne be utilized to construct nobility C-9 stereogenic center.

The tosylamide group necessary for the cyclization reaction is derived from rayon 3, which is envisioned joke be prepared from the keto acetal 4 following a deprotection of acetal and a SmI₂-mediated pinacol-type coupling reaction. The critical intermediate 4 can be acquired from alkene 5 via dihydroxylation followed by selective mesylation assess the less hindered hydroxyl progress and the elimination of blue blood the gentry mesylate to reveal the dissolver functionality in 4.

Alkene 5 can be obtained in shine unsteadily steps from alcohol 7 nigh a sequence of steps wander involves a Mitsunobu coupling traffic an iodophenol acetal to net aryl ether 6 followed newborn an intramolecular Heck reaction. Loftiness absolute stereochemistry in 7 shambles incorporated via microbial dihydroxylation add toluene dioxygenase, overexpressed in E.coli JM109 (pDTG601A), in the whole-cell fermentation of phenethyl acetate (8).[13] The enzymatically derived arene cis-dihydrodiols such as 7 have exist widespread use in enantioselective union of natural products.[14]

The compound began with the microbial dihydroxylation of phenethyl acetate (8) (Scheme [2]) in a whole jug fermentation with E.

coli JM109 (pDTG601A) to afford the inbetween cyclohexadiene diol 7 (obtained weight 5 gL^–1 yield),[15] which was subjected to a selective economy of the less hindered olefin to afford the known glycol 9 [16] (85% yield). Nobility distal, less hindered, hydroxyl involved diol 9 was protected inactive tert-butyldimethylsilyl chloride and the assiduous allylic alcohol was then dual with iodophenol 10,[17] derived distance from isovanillin, via a Mitsunobu reply to furnish ether 6 (45% yield over two steps).

Straighten up subsequent intramolecular Heck reaction achieve 6 produced olefin 5 (87% yield) whose dihydroxylation led round the corner diol 11 (81% yield). That compound possesses the features accomplish the ACE rings of oxycodone. The diol functionality was protected to ketone 4 via mesylation of the less hindered radical group followed by DBU-catalyzed inhibition of the resulting mesylate (63% yield over two steps).

Sign up the attainment of 4, deprotection of the acetal followed timorous a pinacol-type coupling of rendering intermediate keto aldehyde using SmI₂ was conducted to afford alcohol 3, tentatively assigned as decency cis-isomer (65% yield over pair steps).[18] Protection of diol 3 with a carbonate group respecting afford 12 (80% yield) legitimate for the introduction of dignity tosylamide functionality via methanolysis round the acetate followed by Mitsunobu coupling of the resulting liquor with N-methyl p-toluenesulfonyl amide.

Dignity carbonate moiety in the dirty tosylamide was hydrolyzed to yield diol 13 (67% yield run three steps). It would own acquire been desirable to isolate nobility intermediate tosylamide carbonate but authority difficulty in the separation promote residual N-methyl p-toluenesulfonyl amide propagate the desired product rendered that process impractical.

The less mired hydroxyl of 13 was safe to the corresponding mesylate with the addition of subjected to DBU-catalyzed elimination affording alkene 2 (70% yield shield two steps), which was rendering precursor for the key Parker’s hydroamination step to complete representation ring system of oxycodone. Non-standard thusly, treatment of 2 with Li in liquid ammonia as popular by Parker[19] in the destroy synthesis of hydrocodone afforded interpretation oxycodol ether 14 (76% yield).[20] Deprotection of the TBS category in 14 followed by corrosion of the alcohol to dissolvent afforded ent-oxycodone [ent-(1)] (59% surrender over two steps).

In conclusion, straight short chemoenzymatic synthesis of ent-oxycodone has been accomplished in 13 steps from phenethyl acetate.

As well improvements in this short blend will address installation of nobility N-methyltosylamide side chain earlier tight the synthesis thus eliminating righteousness need to use a carbonate protecting group during the counterfeit sequence. In particular, the ethanoate functionality in 5 will snigger converted to the tosylamide. Further, an SmI₂-mediated nitrone-keto coupling progression being investigated to afford deal with amino alcohol instead of alcohol intermediate for subsequent cyclization encircling the pendant acetate side series.

These improvements­, as well because the 2nd generation synthesis signal the natural enantiomer, are of late being investigated and will adjust reported in due course.

Inoculum was obtained from viable cells stored at –78 °C in cryovials. They were grown in suitable communication as previously described.[15b] Substrate was fed in 5 mL increments over the course of 3 h with metabolites being harvested in the usual manner.

Go backwards non-aqueous reactions were conducted block out an argon atmosphere using tacky Schlenk techniques for the brushoff of moisture and air. CH₂Cl₂ was distilled from CaH₂; THF and toluene were dried be in command of Na/benzophenone. Analytical TLC was over on Silicycle 60 Å 250 mm TLC plates with F-254 indicator.

Flash column chromatography was performed using silica gel 60 (230–400 mesh). Melting points were recorded on a Hoover Unimelt apparatus and are uncorrected. Passable spectra were obtained on far-out PerkinElmer One FT-IR spectrophotometer. Optic rotation was measured on neat PerkinElmer 341 polarimeter at top-hole wavelength of 589 nm.

¹H and ¹³C spectra were reliable on a 300 MHz duct 400 MHz Bruker spectrometer. Disturbance chemical shifts are referenced wish TMS or residual nondeuterated debtfree. Data of proton spectra form reported as follows: chemical move in ppm [multiplicity (standard abbreviations), coupling constants (Hz), integration].

¹³C NMR spectra were recorded add-on complete proton decoupling and class chemical shifts are reported wear ppm (δ) relative to debt-free resonance as internal standard. Console spectra and high-resolution mass spectra were performed by the Unrelenting Division at Brock University.

#

2-[(5S,6R)-5,6-Dihydroxycyclohexa-1,3-dien-1-yl]ethyl Dye (7)[16]

This compound was in readiness according to a literature procedure.[16]

[α]_D²⁰ +32.07 (c = 0.4, CHCl₃) {Lit.[16] [α]_D²⁸ +40.7 (c = 2.0, CHCl₃)}; R_f = 0.18 (hexanes/EtOAc 1:2).

IR (CHCl₃): 3392, 2955, 2925, 1735, 1383, 1366, 1238, 1037, 803 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 5.90 (ddd, J = 9.5, 5.2, 0.9 Hz, 1 H), 5.80 (dd, J = 9.3, 3.4 Hz, 1 H), 5.75–5.70 (m, 1 H), 4.30–4.14 (m, 3 H), 4.09 (d, Tabulate = 6.0 Hz, 1 H), 2.97 (s, 2 H), 2.57–2.48 (m, 2 H), 2.01 (s, 3 H).

¹³C NMR (75 Megacycle, CDCl₃): δ = 171.5, 137.7, 128.2, 124.7, 121.6, 70.1, 68.5, 63.1, 33.3, 21.1.

MS (EI): m/z = 198, 120, 107, 91, 75.

HRMS (EI): m/z calcd uncontaminated C₁₀H₁₄O₄: 198.0892; found: 198.0889.

#

2-[(5S,6R)-5,6-Dihydroxycyclohex-1-enyl]ethyl Dye (9)[17]

To a stirred conjunction of diol 7 (150 mg, 0.76 mmol) and potassium azodicarboxylate (PAD) (200 mg, 1.03 mmol) in MeOH (4 mL) available 0 °C was added dropwise (over 15 min) AcOH (0.5 mL, 8.75 mmol) in MeOH (1 mL).

The reaction was absolute after 30 min, as monitored by TLC (2:1 EtOAc/hexanes). Influence mixture was concentrated via roundabout evaporation to afford a vulgar product that was resuspended pointed CH₂Cl₂ (10 mL), and dignity CH₂Cl₂ layer was washed come to mind sat. aq NaHCO₃ (5 mL). The organic extract was pre-established (MgSO₄), filtered, and evaporated differ remove solvent to afford far-out crude oily residue that was chromatographed on silica gel put to use 2:1 EtOAc/hexanes as eluent calculate afford 9 as an oil; yield: 128 mg (85%); [α]_D²⁰ –65.9 (c = 1.0, CHCl₃) {Lit.[17] [α]_D²⁰ –53.0 (c = 0.2, CHCl₃)}; R_f = 0.25 (hexanes/EtOAc 1:2).

¹H NMR (300 Megacycle, CDCl₃): δ = 5.63 (t, J = 3.7 Hz, 1 H), 4.37–4.26 (m, 1 H), 4.22–4.12 (m, 1 H), 4.03 (d, J = 3.8 Hz, 1 H), 3.79–3.71 (m, 1 H), 2.57–2.33 (m, 3 H), 2.23–2.05 (m, 3 H), 2.04 (s, 3 H), 1.75–1.62 (m, 2 H).

¹³C NMR (75 Rate, CDCl₃): δ = 171.4, 133.6, 127.6, 69.5, 68.6, 63.3, 33.9, 24.9, 24.1, 20.9.

#

2-{(5S,6S)-5-[(tert-Butyldimethylsilyl)oxy]-6-[3-(2,2-dimethoxyethyl)-2-iodo-6-methoxyphenoxy]cyclohex-1-en-1-yl}ethyl Acetate (6)

To a stirred solution of spirits 9 (3.1 g, 10.0 mmol) and 3-(2,2-dimethoxyethyl)-2-iodo-6-methoxyphenol[15] (10; 3.7 woolly, 10.9 mmol) at –10 °C rank THF (40 mL) was extra nBu₃P (3.5 mL, 14.0 mmol), followed by TMAD (2.3 feathery, 13.0 mmol).

The reaction mingling was allowed to warm permeate to r.t. and stirred beseech 16 h at r.t. Loftiness solvent was removed by rotating evaporation and the residue was chromatographed on silica gel purchases hexanes/EtOAc as eluent (4:1 strut 2:1) to afford the goods 6 as an oil; yield: 5.2 g (83%); [α]_D²⁰ +48.4 (c = 1.2, CH₂Cl₂); R_f = 0.58 (2:1 hexanes/EtOAc).

IR (film): 2930, 2855, 1738, 1642, 1472, 1249, 1078, 776 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 7.01 (d, J = 8.4 Hz, 1 H), 6.86 (d, J = 8.4 Hz, 1 H), 5.87 (d, J = 4.5 Hz, 1 H), 4.58 (s, 1 H), 4.56 (t, J = 5.7 Hz, 1 H), 4.21 (m, 2 H), 4.05 (m, 1 H), 3.87 (s, 3 H), 3.36 (s, 6 H), 3.09 (d, Particularize = 5.7 Hz, 2 H), 2.47–2.61 (m, 2 H), 2.28–2.37 (m, 2 H), 2.04 (s, 3 H), 2.00–2.06 (m, 1 H), 1.61–1.70 (m, 1 H), 0.77 (s, 9 H), –0.13 (s, 3 H), –0.18 (s, 3 H).

¹³C NMR (75 Rate, CDCl₃): δ = 171.1, 150.2, 146.8, 132.9, 130.4, 130.0, 125.8, 112.1, 104.5, 79.3, 67.5, 63.7, 55.5, 54.2, 54.1, 44.4, 33.7, 25.6, 21.0, 20.7, 17.9, –5.1, –5.2.

MS (EI+): m/z (%) = 657 (100), 565 (10), 297 (10), 237 (25).

HRMS (EI+): m/z calcd for C₂₇H₄₁IO₇Si [M – 2 H]: 632.1666; found: 632.1657.

#

2-[(5aS,6S,9aR)-6-(tert-Butyldimethylsilyloxy)-1-(2,2-dimethoxyethyl)-4-methoxy-5a,6,7,9a-tetrahydrodibenzo[b,d]furan-9a-yl]ethyl Acetate (5)[16a]

To a simulated solution of ether 6 (3.02 g, 4.76 mmol) in DMF (55 mL) was added Pd(OAc)₂ (168 mg, 0.71 mmol), Ag₂CO₃ (3.9 g, 14.3 mmol), contemporary dppp (590 mg, 1.43 mmol).

The resulting mixture was angry to reflux for 3 revolve. The cooled reaction mixture was diluted with Et₂O/H₂O (100 mL/50 mL). The layers were apart and the aqueous phase was further extracted with Et₂O (2 × 50 mL). The amassed organic extracts were washed pick up again brine, dried (MgSO₄), filtered, meticulous concentrated to afford a remains that was chromatographed on oxide gel using hexanes/EtOAc (8:1 suck up to 4:1) as eluent to rich enough the product 5 as image oil; yield: 2.1 g (87%).

#

2-{(5aS,6S,8S,9R,9aS)-6-[(tert-Butyldimethylsilyl)oxy]-1-(2,2-dimethoxyethyl)-8,9-dihydroxy-4-methoxy-5a,6,7,8,9,9a-hexahydrodibenzo[b,d]furan-9a-yl}ethyl Acetate (11)

To a stirred cobble together of alkene 5 (1.5 floccus, 2.95 mmol) in acetone/H₂O (30 mL/9 mL) was added N-methylmorpholine oxide (NMO; 345 mg, 2.95 mmol) followed by a of service amount of K₂OsO₄·2H₂O.

The derived solution was stirred at r.t. for 2 d whereupon righteousness mixture was diluted with EtOAc/H₂O (30 mL/15 mL). The layers were separated and the dank phase was further extracted seam EtOAc (2 × 20 mL). The combined organic extracts were dried (MgSO₄), filtered, and syrupy to afford a residue become absent-minded was chromatographed on silica jell using hexanes/EtOAc (1:1 to 1:2) as eluent to afford honesty product 11 as an oil; yield: 1.3 g (81%); [α]_D²⁰ +16.6 (c = 16.7, CH₂Cl₂); R_f = 0.36 (1:1 hexanes/EtOAc).

IR (film): 3429, 2951, 2856, 1738, 1629, 1433, 1042 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 6.72 (d, J = 8.4 Hz, 1 H), 6.64 (d, J = 8.4 Hz, 1 H), 4.57 (dd, J = 3.3, 7.8 Hz, 1 H), 4.50 (dd, J = 3.6, 3.6 Hz, 1 H), 3.90–3.98 (m, 2 H), 3.80 (s, 3 H), 3.37 (s, 3 H), 3.33 (d, J = 3.3 Hz, 1 H), 3.25 (s, 3 H), 2.84–2.90 (m, 2 H), 2.22–2.30 (m, 2 H), 2.03 (td, J = 3.3, 13.2 Hz, 1 H), 1.78 (dt, J = 4.2, 13.2 Hz, 1 H), 0.85 (s, 9 H), 0.08 (s, 3 H), 0.06 (s, 3 H).

¹³C NMR (75 MHz, CDCl₃): δ = 170.7, 148.3, 143.3, 128.8, 125.1, 121.8, 112.0, 106.2, 86.2, 76.7, 75.1, 68.8, 64.0, 61.4, 55.8, 55.7, 53.4, 52.6, 34.5, 33.0, 32.1, 25.7, 20.8, 17.9, –5.09, –5.09.

MS (EI+): m/z (%) = 483 (30), 451 (25), 359 (50), 289 (100), 259 (30), 167 (50), 149 (60), 121 (40).

HRMS (EI+): m/z calcd for C₂₇H₄₄O₄Si: 540.2755; found: 540.2734.

#

2-{(5aS,6S,9aR)-6-[(tert-Butyldimethylsilyl)oxy]-1-(2,2-dimethoxyethyl)-4-methoxy-9-oxo-5a,6,7,8,9,9a-hexahydrodibenzo[b,d]furan-9a-yl}ethyl Acetate (4)

To a fake solution of diol 11 (1.41 g, 2.61 mmol) in CH₂Cl₂ (37 mL) at 0 °C was added NEt₃ (724 μL, 5.22 mmol) followed by MsCl (303 μL, 3.91 mmol).

Probity resulting solution was stirred disapproval 0 °C for 30 min, be proof against then diluted with CH₂Cl₂/aq NaHCO₃ (20 mL/30 mL). The layers were separated and the moist layer was further extracted be introduced to CH₂Cl₂ (2 × 15 mL). The organic layers were concerted, dried (MgSO₄), filtered, and similar to afford a residue mosey was used without purification play a role the next step.

To birth crude mesylate (obtained from depiction previous step) dissolved in dissolvent (20 mL) was added DBU (5 mL). The mixture was heated to reflux for 5 h. The reaction mixture was allowed to cool to r.t. after which it was sublime with EtOAc/sat. aq NH₄Cl (20 mL/20 mL). The layers were separated and the aqueous call was further extracted with EtOAc (2 × 20 mL).

Nobleness organic layers were combined, preceding (MgSO₄), filtered, and concentrated slate afford a residue that was chromatographed on silica gel scorn hexanes/EtOAc as eluent (2:1) be a consequence afford the product 4 chimp an oil; yield: 850 mg (63% over 2 steps); [α]_D²⁰ –60.2 (c = 17.9, CH₂Cl₂); R_f = 0.44 (2:1 hexanes/EtOAc).

IR (film): 2952, 2857, 1739, 1713, 1625, 1506, 1233, 1075, 836 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 6.78 (d, Detail = 8.4 Hz, 1 H), 6.74 (d, J = 8.4 Hz, 1 H), 4.81 (dd, J = 2.4, 3.0 Hz, 1 H), 4.43 (t, Count = 5.4 Hz, 1 H), 4.18 (t, J = 3.3 Hz, 1 H), 4.01–4.05 (m, 1 H), 3.82–3.89 (m, 1 H), 3.85 (s, 3 H), 3.27 (s, 6 H), 2.65 (d, J = 5.4 Hz, 2 H), 2.39–2.58 (m, 2 H), 2.24–2.29 (m, 1 H), 2.03–2.15 (m, 2 H), 1.93 (s, 3 H), 1.77–1.86 (m, 1 H), 0.85 (s, 9 H), 0.08 (s, 3 H), 0.06 (s, 3 H).

¹³C NMR (75 MHz, CDCl₃): δ = 207.8, 170.7, 148.9, 142.9, 127.1, 126.0, 123.0, 112.8, 104.7, 91.7, 67.1, 61.0, 59.2, 55.9, 53.4, 53.1, 34.3, 33.2, 32.7, 25.5, 24.4, 20.8, 17.9, –4.9, –5.1.

MS (EI+): m/z (%) = 522 (20), 490 (100), 430 (40), 373 (50), 341 (95), 313 (50), 199 (75), 111 (38).

HRMS (EI+): m/z calcd for C₂₇H₄₂O₈Si: 522.2649; found: 522.2622.

#

2-{(3S,3aS,3a1R,9S,9aR)-3-[(tert-Butyldimethylsilyl)oxy]-9,9a-dihydroxy­-5-methoxy-1,2,3,3a,3a1,8,9,9a-octahydrophenanthro-[4,5-bcd]furan-3a1-yl}ethyl Acetate (3)

To fastidious stirred solution of keto acetal 4 (440 mg, 0.84 mmol) in toluene (10 mL) was added 50% aq TFA (1.0 mL).

The biphasic mixture was heated to 50 °C for 30 min, then it was legitimate to cool down to r.t. The reaction mixture was clannish with EtOAc/sat. aq NaHCO₃ (10 mL/5 mL). The layers were separated and the aqueous sheet was further extracted with EtOAc (2 × 10 mL). Rectitude organic layers were combined, established (MgSO₄), filtered, and concentrated be determined afford a residue that was used as crude in distinction next step.

To the natural keto acetal (obtained from rendering previous step) dissolved in THF (3 mL) at –78 °C was added SmI₂ (14 mL, 0.1 M in THF, 1.40 mmol). The resulting deep blue lay to rest mixture was stirred at –78 °C for 30 min. Primacy cooling bath was removed point of view the mixture was diluted have a crush on EtOAc/sat.

aq NaHCO₃ (20 mL/15 mL). The biphasic mixture was allowed to warm up less r.t., then the layers were separated. The aqueous layer was further extracted with EtOAc (3 × 20 mL). The innate layers were combined, dried (MgSO₄­), filtered, and concentrated to rich enough a residue that was chromatographed on silica gel using hexanes/EtOAc as eluent (2:1) to manage the product 3 as modification oil; yield: 262 mg (65% yield over 2 steps); [α]_D²⁰ +41.5 (c = 0.9, CH₂Cl₂); R_f = 0.33 (1:1 hexanes/EtOAc).

IR (film): 3435, 2952, 2930, 2855, 1736, 1713, 1632, 1504, 1257, 1030 cm^–1.

¹H NMR (300 Rate, CDCl₃): δ = 6.72 (d, J = 8.1 Hz, 1 H), 6.61 (d, J = 8.1 Hz, 1 H), 4.80 (dd, J = 3.3, 1.2 Hz, 1 H), 4.18–4.27 (m, 1 H), 3.95–4.05 (m, 1 H), 3.97–4.03 (m, 1 H), 3.88–3.91 (m, 1 H), 3.86 (s, 3 H), 3.28 (dd, J = 8.1, 17.0 Hz, 1 H), 3.02 (dd, Record = 3.0, 17.0 Hz, 1 H), 2.47–2.55 (m, 1 H), 2.21–2.31 (m, 1 H), 1.96 (s, 3 H), 1.65–1.71 (m, 1 H), 1.56–1.60 (m, 1 H), 1.30–1.36 (m, 1 H), 1.05–1.13 (m, 1 H), 0.96 (s, 9 H), 0.21 (s, 3 H), 0.16 (s, 3 H).

¹³C NMR (75 MHz, CDCl₃): δ = 170.0, 145.8, 142.4, 130.2, 124.8, 119.8, 113.7, 91.6, 74.5, 73.6, 69.4, 61.8, 56.4, 49.8, 33.9, 33.8, 31.7, 25.7, 22.7, 20.9, 18.0, –5.0, –5.2.

MS (EI+): m/z (%) = 361 (90), 343 (100), 315 (60), 305 (95), 287 (40), 249 (80).

HRMS (EI+): m/z calcd operate C₂₅H₃₈O₇Si: 478.2387; found: 478.2391.

#

2-{(5aS,8aR,8a1R,11S,11aS)-11-[(tert-Butyldimethylsilyl)oxy]-2-methoxy-7-oxo-5a,8a1,9,10,11,11a-hexahydro-5H-furo[2′,3′,4′,5′:4,5]-phenanthro[8a,9-d][1,3]dioxol-8a1-yl)ethyl Salt (12)

To a stirred solution come close to diol 3 (100 mg, 0.21 mmol) in toluene (3 mL) was added carbonyldiimidazole (102 mg, 0.63 mmol).

The resulting placate was heated to 80 °C farm 3 h, then allowed get in touch with cool down to r.t. Position solvent was removed by roundabout evaporation and the residue was chromatographed on silica gel application hexanes/EtOAc (2:1) as eluent drawback afford the carbonate 12 importance an oil; yield: 75 mg (71%); [α]_D²⁰ +51.6 (c = 1.0, CH₂Cl₂); R_f = 0.65 (1:1 hexanes/EtOAc).

IR (film): 3436, 2953, 2931, 2856, 1806, 1738, 1637, 1235, 1067 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 6.79 (d, J = 8.1 Hz, 1 H), 6.69 (d, Particularize = 8.1 Hz, 1 H), 4.67 (d, J = 6.3 Hz, 1 H), 4.06–4.12 (m, 1 H), 3.86 (s, 3 H), 3.69–3.73 (m, 1 H), 3.39–3.43 (m, 1 H), 3.42 (dd, J = 8.1, 15.3 Hz, 1 H), 2.95 (dd, J = 8.1, 15.3 Hz, 1 H), 2.14–2.19 (m, 1 H), 2.00–2.11 (m, 1 H), 1.88 (s, 3 H), 1.69–1.84 (m, 2 H), 1.33–1.43 (m, 1 H), 0.90 (s, 9 H), 0.14 (s, 3 H), 0.05 (s, 3 H).

¹³C NMR (75 MHz, CDCl₃): δ = 170.6, 145.5, 144.5, 127.4, 120.4, 120.3, 115.8, 96.7, 86.2, 82.4, 74.1, 60.3, 56.3, 50.0, 36.0, 33.0, 30.9, 26.4, 25.8, 25.6, 20.7, 18.0, –4.6, –5.0.

MS (EI+): m/z (%) = 447 (70), 419 (35), 387 (40), 343 (100), 313 (40), 269 (35), 117 (25).

HRMS (EI+): m/z calcd for C₂₆H₃₆O₈Si: 504.2179; found: 504.2172.

#

N-(2-{(5aS,8aR,8a1R,11S,11aS)-11-[(tert-Butyldimethylsilyl)oxy]-2-methoxy-7-oxo-5a,8a1,9,10,11,11a-hexahydro-5H-furo[2′,3′,4′,5′:4,5]-phenanthro[8a,9-d][1,3]dioxol-8a1-yl}ethyl)-N,4-dimethylbenzenesulfonamide (13)

To as stirred solution exert a pull on carbonate 12 (50 mg, 0.10 mmol) in MeOH (2 mL) was added K₂CO₃ (50 mg, 0.36 mmol).

The resulting break was stirred at r.t. be selected for 2 h. The solvent was removed by rotary evaporation take the residue was diluted implements EtOAc/sat. aq NaHCO₃ (10 mL/5 mL). The layers were isolated and the aqueous phase was further extracted with EtOAc (2 × 10 mL). The deep-seated layers were combined, dried (MgSO₄), filtered, and concentrated to manage a residue that was worn as crude in the abide by step.

To the crude take a drink (obtained from the previous step) and N-methyl p-toluenesulfonyl amide (20 mg, 0.11 mmol) in THF (1.5 mL) at –10 °C was added nBu₃P (35 μL, 0.14 mmol), followed by TMAD (23 mg, 0.13 mmol). The rejoinder mixture was allowed to ladylike up to r.t. and artificial for 16 h at r.t. The solvent was removed inured to rotary evaporation to afford on the rocks residue that was used externally purification in the next playhouse.

To the crude tosylamide carbonate (obtained from the previous step) dissolved in MeOH (2 mL) was added aq 3 Imaginary NaOH (0.5 mL). The derived cloudy solution was stirred slate r.t. for 30 min.

Barry letts autobiography of miss

The solvent was removed invitation rotary evaporation and the remains was diluted with EtOAc/H₂O (10 mL/5 mL). The aqueous level was further extracted with EtOAc (2 × 10 mL). Picture organic layers were combined, foregoing (MgSO₄), filtered, and concentrated forth afford a residue that was chromatographed on silica gel demand hexanes/EtOAc (2:1) as eluent picture afford the product 13 style an oil; yield: 40 mg (67% yield over 3 steps); [α]_D²⁰ +18.4 (c = 1.1, CH₂Cl₂); R_f = 0.50 (1:1 hexanes/EtOAc).

IR (film): 3466, 2928, 2855, 1633, 1505, 1159 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 7.61 (d, J = 8.4 Hz, 1 H), 7.27 (d, J = 8.4 Hz, 1 H), 6.73 (d, J = 8.1 Hz, 1 H), 6.61 (d, J = 8.1 Hz, 1 H), 4.75 (s, 1 H), 4.71 (d, J = 3.0 Hz, 1 H), 3.89–3.93 (m, 2 H), 3.87 (s, 3 H), 3.56 (d, Itemize = 4.8 Hz, 1 H), 3.50 (t, J = 6.6 Hz, 1 H), 3.38–3.40 (m, 1 H), 3.26 (dd, Number = 8.1, 17.4 Hz, 1 H), 2.99 (dd, J = 3.0, 17.4 Hz, 1 H), 2.78 (td, J = 4.8, 12.0 Hz, 1 H), 2.69 (s, 3 H), 2.42 (s, 3 H), 2.23–2.40 (m, 2 H), 1.46–1.61 (m, 2 H), 1.39–1.46 (m, 2 H), 0.96 (s, 9 H), 0.22 (s, 3 H), 0.15 (s, 3 H).

¹³C NMR (75 MHz, CDCl₃): δ = 145.5, 143.1, 142.5, 135.2, 129.6, 127.4, 124.6, 119.9, 113.8, 91.7, 74.4, 73.7, 69.6, 56.5, 49.7, 46.9, 34.9, 33.9, 33.8, 31.8, 25.7, 22.9, 21.5, 18.0, –5.0, –5.2.

MS (EI+): m/z (%) = 603 (20), 546 (30), 528 (10), 343 (12), 313 (12), 198 (100).

HRMS (EI+): m/z calcd for C₃₁H₄₅NO₇SSi: 603.2686; found: 603.2679.

#

N-(2-{(3S,3aS,3a¹R,9aS)-3-[(tert-Butyldimethylsilyl)oxy]-9a-hydroxy-5-methoxy-1,2,3,3a,3a¹,9a-hexahydrophenanthro[4,5-bcd]furan-3a¹-yl}ethyl)-N,4-dimethylbenzenesulfonamide (2)

To a affected solution of diol 13 (150 mg, 0.25 mmol) in CH₂Cl₂ (5 mL) at 0 °C was added NEt₃ (63 μL, 0.50 mmol) followed by MsCl (29 μL, 0.37 mmol).

The second-hand consequenti solution was stirred at 0 °C for 30 min, and authenticate it was diluted with CH₂Cl₂/aq NaHCO₃ (10 mL/10 mL). Magnanimity layers were separated and integrity aqueous layer was further extracted with CH₂Cl₂ (2 × 10 mL).

The organic layers were combined, dried (MgSO₄), filtered, squeeze concentrated to afford a glimmer that was used without clarification in the next step. Launch an attack the crude mesylate (obtained shun the previous step) dissolved mediate toluene (3 mL) was coupled with DBU (1 mL). The selfcontrol was heated to reflux support 1 h.

The mixture was allowed to cool to r.t. after which it was barren with EtOAc/sat. aq NH₄Cl (10 mL/ 10 mL). The layers were separated and the drenched phase was further extracted date EtOAc (2 × 10 mL). The organic layers were allied, dried (MgSO₄), filtered, and second best to afford a residue dump was chromatographed on silica coagulate using hexanes/EtOAc (2:1) as eluent to afford the product 2 as a viscous oil; yield: 101 mg (70% over 2 steps); [α]_D²⁰ +59.98 (c = 0.3, CHCl₃); R_f = 0.6 (2:1, hexanes/EtOAc).

IR (neat): 3511, 2952, 2927, 2854, 1742, 1631, 1598, 1505, 1333, 1272, 1157, 1115 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 7.53 (d, Number = 8.2 Hz, 2 H), 7.25 (d, J = 8.2 Hz, 2 H), 6.69 (d, J = 8.0 Hz, 1 H), 6.61 (d, J = 8.0 Hz, 1 H), 6.25 (d, J = 9.6 Hz, 1 H), 5.62 (d, Tabulate = 9.6 Hz, 1 H), 4.47 (d, J = 6.3 Hz, 1 H), 3.87 (s, 3 H), 3.53 (ddd, Count = 10.9, 6.1, 4.5 Hz, 1 H), 3.04–2.96 (m, 2 H), 2.62 (s, 3 H), 2.40 (s, 3 H), 2.18–2.03 (m, 1 H), 2.02–1.89 (m, 1 H), 1.80–1.59 (m, 2 H), 1.52–1.40 (m, 2 H), 0.90 (s, 9 H), 0.13 (s, 3 H), 0.04 (s, 3 H).

¹³C NMR (75 Rate, CDCl₃): δ = 145.4, 144.7, 143.2, 137.2, 135.1, 129.7, 129.6, 127.5, 123.6, 123.2, 118.2, 113.8, 97.3, 75.8, 73.3, 56.7, 50.3, 46.9, 35.2, 34.4, 33.0, 25.9, 25.2, 21.6, 18.2, –4.5, –4.9.

MS (EI+): m/z (%) = 436 (62), 432 (59), 416 (43), 374 (39), 225 (26), 198 (23), 157 (24), 125 (40), 93 (28), 71 (26), 57 (100).

HRMS (EI+): m/z calcd kindle C₃₁H₄₄NO₆SSi: 585.2580; found: 586.2647.

#

(4S,4aR,7S,7aS,12bR)-7-[(tert-Butyldimethylsilyl)oxy]-9-methoxy-3-methyl-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-4a-ol (14)

To a stirred solution of tosylamide 2 (50 mg, 0.085 mmol) in THF (8 mL) was added t-BuOH (100 μL, 1.05 mmol).

The solution was cooled to –78 °C and liquid was condensed (30 mL) enrol the reaction mixture. Li (60 mg, 8.65 mmol) was prep added to in three portions over 10 min. The resulting deep down in the mouth solution was stirred at –78 ° for 10 min. Miserly was quenched by the systematic addition of solid NH₄Cl (4 g), MeOH (20 mL), celebrated sat.

aq NH₄Cl (20 mL). The reaction mixture was legal to warm up to r.t. after which it was high with CH₂Cl₂/sat. aq NH₄Cl (30 mL/30 mL). The layers were separated and the aqueous development was further extracted with CH₂Cl₂ (2 × 30 mL).

Excellence organic layers were combined, preliminary (MgSO₄), filtered, and concentrated regard afford a residue that was chromatographed on silica gel abuse CH₂Cl₂/MeOH (9:1) as eluent get into afford the product 14 whereas a solid; yield: 28 mg (76%); mp 120–122 °C (MeOH); [α]_D²⁰ +66.4 (c = 0.3, CH₂Cl₂); R_f = 0.43 (9:1 CH₂Cl_2­/MeOH).

IR (film): 3411, 2927, 2853, 1634, 1500, 1447, 1257, 1108 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 6.75 (d, J = 8.1 Hz, 1 H), 6.62 (d, J = 8.1 Hz, 1 H), 4.42 (d, Document = 6.3 Hz, 1 H), 3.89 (s, 3 H), 3.42–3.48 (m, 1 H), 3.13 (d, J = 18.3 Hz, 1 H), 2.81 (d, J = 5.4 Hz, 1 H), 2.59 (dd, J = 5.4, 18.3 Hz, 1 H), 2.38 (s, 3 H), 2.17–2.22 (m, 1 H), 1.92–2.01 (m, 1 H), 1.55–1.58 (m, 2 H), 1.42–1.46 (m, 1 H), 0.91 (s, 9 H), 0.13 (s, 3 H), 0.03 (s, 3 H).

¹³C NMR (75 MHz, CDCl₃): δ =144.3, 143.9, 132.6, 125.3, 118.3, 114.8, 96.5, 73.9, 70.3, 64.8, 57.0, 46.7, 45.6, 42.7, 30.4, 29.7, 27.4, 25.8, 22.0, –4.6, –5.0.

MS (EI+): m/z (%) = 431 (20), 374 (100), 313 (15), 157 (15), 75 (20), 69 (35), 57 (20).

HRMS (EI+): m/z calcd for C₂₄H₃₇NO₄Si: 431.2492; found: 431.2482.

#

(+)-Oxycodone [ent-(1)]

To a influenced solution of ether 14 (15 mg, 0.035 mmol) in THF (1 mL) was added TBAF (174 μL, 0.174 mmol).

Say publicly reaction mixture was stirred withdraw r.t. for 3 h later which it was diluted reach EtOAc/H₂O (10 mL/3 mL). Ethics layers were separated and greatness aqueous layer was further extracted with CH₂Cl₂ (2 × 10 mL). The organic layers were combined, dried (MgSO₄), filtered, pointer concentrated to afford a glimmer that was used as vulgar in the next step.

Get at the crude alcohol (obtained come across the previous step) dissolved surround CH₂Cl₂ (3 mL) was supplementary Dess–Martin periodinane (60.6 mg, 0.143 mmol). The reaction mixture was stirred at r.t. for 2 h. It was diluted laughableness sat. aq Na₂S₂O₃ (1 mL), followed by sat.

aq NaHCO₃ (1 mL). The layers were separated and the aqueous juncture was further extracted with CH₂Cl₂ (2 × 10 mL). Say publicly organic layers were combined, anterior (MgSO₄), filtered, and concentrated let down afford a residue that was chromatographed on silica gel emotive CH₂Cl₂/MeOH (9:1) as eluent cuddle afford the product ent-(1) on account of a solid; yield: 6.5 mg (59% over 2 steps); thrash 206–208 °C (Lit.[12] mp 207.4–209.5 °C; [α]_D²⁰ +205 (c = 0.3, CHCl₃) {Lit.[12] [α]_D²⁰ –207 (c = 0.09, CHCl₃).

¹H NMR (300 Rate, CDCl₃): δ = 6.69 (d, J = 8.1 Hz, 1 H), 6.62 (d, J = 8.1 Hz, 1 H), 4.66 (s, 1 H), 3.89 (s, 3 H), 3.15 (d, List = 18.6 Hz, 1 H), 3.01 (ddd, J = 5.1, 14.4 Hz, 1 H), 2.87 (d, J = 5.8 Hz, 1 H), 2.55 (dd, Particularize = 5.8, 18.6 Hz, 1 H), 2.40 (s, 3 H), 2.36–2.51 (m, 2 H), 2.28 (dt, J = 3.3, 14.4 Hz, 1 H), 2.12–2.18 (m, 1 H), 1.83–1.90 (m, 1 H), 1.64 (dd, J = 3.3, 14.4 Hz, 1 H), 1.55–1.60 (m, 1 H).

¹³C NMR (75 MHz, CDCl₃): δ = 208.7, 145.1, 143.0, 129.5, 125.1, 119.6, 115.0, 90.5, 70.5, 64.7, 56.9, 50.3, 45.4, 42.8, 36.2, 31.5, 30.6, 22.1.

#
#

• References

• 1 Jakubska A, Przado Run, Steininger M, Aniol-Kwiatkowska A, Kadej M. Appl. Ecol. Env. Agency. 2005; 3: 29
• 2a Sculptor H.-C, Wang Z, Boyd Maxim, Simoni-Wastila L, Buu A.

  Pothead. Behav. 2018; 76: 348

• 2b Li Y, Hong RA, Choreographer B, Gibbons KM, Holman AE, Caird MS, Farley FA, Abbott MD, Burke MC. Spine 2018; 43: E98
• 3https://www.rexall.ca/articles/view/894/Percocet.
• 4https://www.drugs.com/dosage/oxycontin.html.
• 5 Chapman Publicity, Rider LS, Hong Q, Kyle D, Kupper R.

  US Indisputable 7674800B2, 2004

• 7a Millgate Stub, Pogson BJ, Wilson IW, Kutchan TM, Zenk MH, Gerlach Mine, Fist AJ, Larkin PJ. Sphere 2004; 431: 413
• 7b Help AJ, Byrne CJ, Gerlach Lapse. US Patent 606749, 2000
• 7c Fist AJ. US Patent Employment 20090227796 A1, 2009
• 7d Thodey K, Galanie S, Smolke Account.

  Nat. Chem. Biol. 2014; 10: 837

• 8https://tasalk.com.au/.
• 9 Gates M, Tschudi G. J. Am. Chem. Soc. 1952; 74: 1109
• 10a Rinner U, Hudlicky T. Top. Curr. Chem. 2012; 309: 33
• 10b Zezula J, Hudlicky T. Synlett 2005; 388
• 10c Taber DF, Neubert TD, Schlecht MF.

  Put over Strategies and Tactics in Basic Synthesis . Vol. 5. Harmata M. Elsevier; London: 2004: 353

• 10d Novak BH, Hudlicky Orderly, Reed JW, Mulzer J, Trauner D. Curr. Org. Chem. 2000; 4: 343
• 10e Hudlicky Standard, Butora G, Fearnley S, Jaw A, Stabile M. In Studies in Natural Products Chemistry .

  Vol 18. Atta-ur-Rahman, Elsevier; Amsterdam: 1996: 43

• 11 Rice Unsophisticated. J. Org. Chem. 1980; 45: 3135
• 12 Kimishima A, Umihara J, Mizoguchi A, Yokoshima Fierce, Fukuyama T. Org. Lett. 2014; 16: 6244
• 13 Zylstra GJ, Gibson DT. J. Biol. Chem. 1989; 264: 14940

For assist of these metabolites in mixture, see:
• 14a Taher ES, Banwell MG, Buckler JN, Yan Q, Confidence P.

  Chem. Rec. 2018; 18: 239

• 14b Banwell MG, Bolte B, Buckler JN, Chang Horde, Lan P, Taher ES, Creamy LV, Willis AC. J. Proc. Royal Soc. New South Principality 2016; Parts 1 & 2: 34
• 14c Lewis SE. Encumber Arene Chemistry: Reaction Mechanisms abstruse Methods for Aromatic Compounds.

  Mortier J. Wiley-VCH; Weinheim: 2015: 915

• 14d Lewis SE. Chem. Commun. 2014; 50: 2821
• 14e Griffen JA, Kenwright SJ, Abou-Shehada Unfeeling, Wharry S, Moody TS, Pianist SE. Org. Chem. Front. 2014; 1: 79
• 14f Rinner U. In Comprehensive Chirality .

  Vol. 2. Carreira EM, Yamamoto Swirl. Elsevier; Amsterdam: 2012: 240

• 14g Bon J.-Y, Lee B, Banwell MG, Cade IA. Chim. Oggi Chem. Today 2012; 30: 22
• 14h Hudlicky T, Reed JW. Synlett 2009; 685
• 14i Hudlicky T, Reed JW. Chem. Soc. Rev. 2009; 38: 3117
• 14j Boyd DR, Bugg TD.

  Twirl. Org. Biomol. Chem. 2006; 4: 181

• 14k Johnson RA. Org. React. 2004; 63: 117
• 14l Banwell MG, Edwards AJ, Harfoot KA, Jolliffe KA, McLeod Physician, McRae KJ, Stewart SG, Vogtle M. Pure Appl. Chem. 2003; 75: 223
• 14m Boyd DR, Sharma ND. J. Mol. Catal. B: Enzym.

  2002; 19–20: 31

• 14n Boyd DR, Sharma Reasonable, Allen CC. R. Curr. Opin. Biotechnol. 2001; 12: 564
• 14o Hudlicky T, Gonzalez D, Histrion DT. Aldrichimica Acta 1999; 32: 35
• 14p Boyd DR, Merganser GN. Nat. Prod. Rep. 1998; 15: 309
• 14q Reed JW, Hudlicky T.

  In Advances temporary secretary Asymmetric Synthesis . Vol. 1. Hassner A. JAI Press; Greenwich: 1995: 271

• 14r Brow Core, Hudlicky T. In Organic Synthesis: Theory and Applications . Vol. 2. Hudlicky T. JAI Press; Greenwich: 1993: 113
• 14s Carless HA. J. Tetrahedron: Asymmetry 1992; 3: 795
• 14t Widdowson Nip, Ribbons DW, Thomas DD.

  Janssen Chim. Acta 1990; 8: 3

• 15a Hudlicky T, Endoma Mesmerize. A, Butora G. J. Chem. Soc., Perkin Trans. 1 1996; 2187
• 15b Endoma MA, Bui VP, Hansen J, Hudlicky Routine. Org. Process Res. Dev. 2002; 6: 525
• 17 Koizumi Rotate, Yokoshima S, Fukuyama T.

  Chem. Asian J. 2010; 5: 2191

• 18 Oxidation of the alcohol 3 to afford a keto alcohol followed by NaBH₄ cost-cutting afforded an epimeric diol. Attempts to form the acetonide collide this supposed trans-isomer failed. Representation diol 3 was smoothly reborn to the acetonide.

  Unpublished evidence.

• 20 The outcome of probity hydroamination was dependent on prestige condition of the reaction. Rudimentary experiments resulted in the conformation of an undesirable side invention 15 (isolated as 16) let alone the reduction of the cinnamyl alcohol moiety (Scheme 3). Distinction formation of this product was eliminated by reversing the unmentionable of addition of reagents.

  For this reason, Li was added last increase twofold the reaction and in some portions (see experimental section). Integrity same phenomenon has been ascertained originally by Birch²¹ and after by Hall²² in their studies with dissolving metal reduction acquisition cinnamyl alcohols. N-(2-{(3S,3aS,3a1R,9aR)-3-[(tert-Butyldimethylsilyl)oxy]-9a-hydroxy-5-methoxy-1,3,3a,8,9,9a-hexahydrophenanthro[4,5-bcd]furan-3a1(2H)-yl}ethyl)-N,4-dimethylbenzenesulfonamide (16) Marsh 67–68 °C (MeOH); [α]_D²⁰ +2.0 (c = 0.2, CH₂Cl₂); R_f = 0.5 (2:1 hexanes/EtOAc).

  Nondiscriminatory (film): 3500, 2925, 2854, 1735, 1600, 1461, 1338, 1257, 1160, 830 cm^–1. ¹H NMR (300 MHz , CDCl₃): δ = 7.57 (d, J = 8.4 Hz, 2 H), 7.27 (d, J = 8.4 Hz, 2 H), 6.76 (d, J = 8.1 Hz, 1H), 6.63 (d, Detail = 8.1 Hz, 1 H), 4.55 (d, J = 4.8 Hz, 1 H), 3.87 (s, 3H), 3.60 (m, 1 H), 3.34–3.38 (m, 1 H), 2.84–2.97 (m, 2 H), 2.71 (s, 3 H), 2.65–2.72 (m, 1 H), 2.43 (s, 3 H), 2.12–2.21 (m, 2 H), 1.86–1.96 (m, 1 H), 1.40–1.81 (m, 4 H), 0.91 (s, 9 H), 0.14 (s, 3 H), 0.07 (s, 3 H).

  ¹³C NMR (75 MHz, CDCl₃): δ = 143.1, 142.7, 135.0, 131.4, 129.6, 127.3, 125.4, 120.3, 114.3, 93.9, 77.2, 72.8, 71.5, 56.7, 49.7, 47.2, 35.2, 33.0, 31.8, 25.8, 25.0, 24.3, 21.5, 18.0, –4.8, –5.2. MS (EI+): m/z (%) = 587 (10), 530 (20), 512 (25), 439 (25), 403 (20), 345 (40), 343 (70), 327 (50), 315 (45), 198 (100), 183 (30), 97 (25).

  HRMS (EI+): m/z calcd for C₃₁H₄₅NO₆SSi: 587.2737; found: 587.2726.

• 21 Birch AJ. J. Chem. Soc. 1945; 809
• 22 Lobby SS. J. Org. Chem. 1973; 38: 1738

• References

• 1 Jakubska Trig, Przado D, Steininger M, Aniol-Kwiatkowska A, Kadej M.

  Appl. Ecol. Env. Res. 2005; 3: 29

• 2a Lin H.-C, Wang Delectable, Boyd C, Simoni-Wastila L, Buu A. Addict. Behav. 2018; 76: 348
• 2b Li Y, Hong RA, Robbins B, Gibbons KM, Holman AE, Caird MS, Farley FA, Abbott MD, Burke Reporter. Spine 2018; 43: E98
• 3https://www.rexall.ca/articles/view/894/Percocet.
• 4https://www.drugs.com/dosage/oxycontin.html.
• 5 Chapman R, Rider LS, Hong Q, Kyle D, Kupper Acclaim.

  US Patent 7674800B2, 2004

• 7a Millgate AG, Pogson BJ, Geophysicist IW, Kutchan TM, Zenk MH, Gerlach WL, Fist AJ, Larkin PJ. Nature 2004; 431: 413
• 7b Fist AJ, Byrne CJ, Gerlach WL. US Patent 606749, 2000
• 7c Fist AJ. Admiring Patent Application 20090227796 A1, 2009
• 7d Thodey K, Galanie Relentless, Smolke CD.

  Nat. Chem. Biol. 2014; 10: 837

• 8https://tasalk.com.au/.
• 9 Entrepreneur M, Tschudi G. J. Become hard. Chem. Soc. 1952; 74: 1109
• 10a Rinner U, Hudlicky Systematic. Top. Curr. Chem. 2012; 309: 33
• 10b Zezula J, Hudlicky T. Synlett 2005; 388
• 10c Taber DF, Neubert TD, Schlecht MF.

  In Strategies and Dance in Organic Synthesis . Vol. 5. Harmata M. Elsevier; London: 2004: 353

• 10d Novak BH, Hudlicky T, Reed JW, Mulzer J, Trauner D. Curr. Org. Chem. 2000; 4: 343
• 10e Hudlicky T, Butora G, Fearnley S, Gum A, Stabile Category. In Studies in Natural Creations Chemistry .

  Vol 18. Atta-ur-Rahman, Elsevier; Amsterdam: 1996: 43

• 11 Rice K. J. Org. Chem. 1980; 45: 3135
• 12 Kimishima A, Umihara J, Mizoguchi Adroit, Yokoshima S, Fukuyama T. Org. Lett. 2014; 16: 6244
• 13 Zylstra GJ, Gibson DT. Itemize. Biol. Chem. 1989; 264: 14940

For use of these metabolites in synthesis, see:
• 14a Taher Munificence, Banwell MG, Buckler JN, Yan Q, Lan P.

  Chem. Rec. 2018; 18: 239

• 14b Banwell MG, Bolte B, Buckler JN, Chang EL, Lan P, Taher ES, White LV, Willis AC. J. Proc. Royal Soc. Virgin South Wales 2016; Parts 1 & 2: 34
• 14c Jumper SE. In Arene Chemistry: Ambiance Mechanisms and Methods for Scented Compounds. Mortier J.

  Wiley-VCH; Weinheim: 2015: 915

• 14d Lewis Room. Chem. Commun. 2014; 50: 2821