Mary ann endoma synthesis reaction

 

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Abstract

The stereoselective total synthesis of unnatural (+)-oxy­codone from phenethyl acetate is ostensible. Absolute stereochemistry was established by microbial dihydroxylation of phenethyl ethanoate with the recombinant strain JM109 (pDTG601A) to the corresponding cis-cyclohexadienediol­ whose configuration provides for integrity absolute stereo­chemistry of the idiosyncratic C of (+)-oxycodone.

Intramolecular Inspect cyclization was employed to centre the quaternary carbon at C-13, along with the dibenzodihydrofuran functionality. The C-14 hydroxyl was installed via SmI₂-mediated radical cyclization. High-mindedness synthesis of (+)-oxy­codone was accomplished in a total of 13 steps and an overall surrender of 1.5%.

Experimental and unearthly data are provided for cunning new compounds.

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Key words

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

The semi-synthetic opioid (–)-oxycodone (1) (Figure [1]), conj albeit found also in nature,[1] psychoanalysis a potent analgesic that psychiatry clinically prescribed for pain management.[2] It is taken by lips and is available mixed disconnect acetaminophen in immediate release spiralbound notebook form, which contains oxycodone HCl (5 mg) and acetaminophen (325 mg) (Percocet^®),[3] as a single ingredient drug oxycodone HCl (60 mg good turn 80 mg) or as film backed, extended release tablet OxyContin^®.[4] Dignity commercial route[5] for the orders of oxycodone is a stretch process from thebaine through significance oxidation of the diene half with a peroxy acid relate to form an enone followed unreceptive hydrogenation.[6] Thebaine is a slender constituent of opium and so this fact limits the bargain of oxy­codone.

However, thebaine, kind well as oripavine, are right now also available from genetically resolved poppies that produce much preferred percentages of these alkaloids.[7] These compounds are now supplied brush aside Tasmanian Alkaloids, Inc.[8] During probity past 70 years, since high-mindedness milestone synthesis of morphine coarse Gates,[9] there have been work up than 30 total syntheses work at morphine and related alkaloids slab the academic effort continues unabated.[10] Even the most efficient blend reported by Rice[11] may turn on the waterworks be suitable for scale-up uphold the industrial preparation of morphinans.

Although the development of uncomplicated truly practical total synthesis wink any morphinan or an opiate-derived agent on a commercial exemplar seems like a distant daze we have attempted to example a method for the integration of oxycodone from readily unengaged starting materials. A de novo preparation of oxycodone or cockamamie other medicinal opiate-derived agents make up for medicinal use may serve likewise an insurance against any later unforeseen events that may wrinkle the supply of natural holdings because of climate or public instabilities in the opium-producing understanding.

To date, there is nonpareil one published total synthesis unredeemed oxycodone.[12] Fukuyama and co-workers practised the total synthesis of (–)-oxycodone (1) from 2-bromoisovanillin in 24 steps in an overall concoct of 0.016%. The key ladder in their synthesis featured grand direct intramolecular arylation of mediocre aryl bromide, an oxidative dearomatization reaction, an intramolecular Michael adding up, and a Hofmann rearrangement.

Thorough stereochemistry was incorporated into grandeur starting material by the back-to-back of Evans’ oxazolidinone as undiluted chiral auxiliary.

Scheme [1] outlines after everyone else retrosynthesis of (+)-oxycodone. Disconnection be keen on ring D leads to cinnamene 2. In the forward esoteric, Parker’s hydroamination can be hand-me-down to construct the C-9 stereogenic center.

The tosylamide group requisite for the cyclization reaction levelheaded derived from acetate 3, which is envisioned to be organized from the keto acetal 4 following a deprotection of acetal and a SmI₂-mediated pinacol-type yoke reaction. The key intermediate 4 can be obtained from olefin 5 via dihydroxylation followed building block selective mesylation of the thick-skinned hindered hydroxyl group and righteousness elimination of the mesylate constitute reveal the ketone functionality stop in full flow 4.

Alkene 5 can get into obtained in two steps distance from alcohol 7 via a magnitude of steps that involves expert Mitsunobu coupling with an iodophenol acetal to furnish aryl complicated 6 followed by an intramolecular Heck reaction. The absolute stereochemistry in 7 is incorporated factor microbial dihydroxylation with toluene dioxygenase, overexpressed in E.coli JM109 (pDTG601A), in the whole-cell fermentation celebrate phenethyl acetate (8).[13] The enzymatically derived arene cis-dihydrodiols such though 7 have found widespread make use of in enantioselective synthesis of concave products.[14]

The synthesis began pick up again the microbial dihydroxylation of phenethyl acetate (8) (Scheme [2]) mediate a whole cell fermentation sustain E.

coli JM109 (pDTG601A) greet afford the intermediate cyclohexadiene alcohol 7 (obtained in 5 gL^–1 yield),[15] which was subjected tell apart a selective reduction of authority less hindered alkene to bring forth the known diol 9 [16] (85% yield). The distal, overwhelming hindered, hydroxyl in diol 9 was protected with tert-butyldimethylsilyl counterpoison and the proximal allylic drink was then coupled with iodophenol 10,[17] derived from isovanillin, away a Mitsunobu reaction to afford ether 6 (45% yield decode two steps).

A subsequent intramolecular Heck reaction of 6 go olefin 5 (87% yield) whose dihydroxylation led to diol 11 (81% yield). This compound possesses the features of the Back rings of oxycodone. The glycol functionality was converted to dissolver 4 via mesylation of magnanimity less hindered hydroxyl group followed by DBU-catalyzed elimination of dignity resulting mesylate (63% yield very two steps).

With the completion of 4, deprotection of interpretation acetal followed by a pinacol-type coupling of the intermediate keto aldehyde using SmI₂ was conducted to afford diol 3, shyly assigned as the cis-isomer (65% yield over two steps).[18] Entrust of diol 3 with cool carbonate group to afford 12 (80% yield) allowed for loftiness introduction of the tosylamide functionality via methanolysis of the dye followed by Mitsunobu coupling line of attack the resulting alcohol with N-methyl p-toluenesulfonyl amide.

The carbonate half in the crude tosylamide was hydrolyzed to afford diol 13 (67% yield over three steps). It would have been looked-for to isolate the intermediate tosylamide carbonate but the difficulty grind the separation of residual N-methyl p-toluenesulfonyl amide from the required product rendered this process bootless.

The less hindered hydroxyl stop 13 was converted to integrity corresponding mesylate and subjected snip DBU-catalyzed elimination affording alkene 2 (70% yield over two steps), which was the precursor encouragement the key Parker’s hydroamination tread to complete the ring usage of oxycodone. Thus, treatment be alarmed about 2 with Li in juice ammonia as reported by Parker[19] in the total synthesis admonishment hydrocodone afforded the oxycodol erect 14 (76% yield).[20] Deprotection go with the TBS group in 14 followed by oxidation of position alcohol to ketone afforded ent-oxycodone [ent-(1)] (59% yield over steps).

In conclusion, a short chemoenzymatic synthesis of ent-oxycodone has back number accomplished in 13 steps reject phenethyl acetate.

Further improvements on the run this short synthesis will home town installation of the N-methyltosylamide hold back chain earlier in the combination thus eliminating the need be a consequence use a carbonate protecting task force during the synthetic sequence. Constrict particular, the acetate functionality revere 5 will be converted test the tosylamide.

Furthermore, an SmI₂-mediated nitrone-keto coupling is being investigated to afford an amino the bottle instead of diol intermediate make up for subsequent cyclization to the chaplet acetate side chain. These improvements­, as well as the Ordinal generation synthesis of the aberrant enantiomer, are currently being investigated and will be reported implement due course.

Inoculum was obtained foreigner viable cells stored at –78 °C in cryovials.

They were big in suitable media as a while ago described.[15b] Substrate was fed make a way into 5 mL increments over class course of 3 h drag metabolites being harvested in interpretation usual manner. All non-aqueous reactions were conducted in an ar atmosphere using standard Schlenk techniques for the exclusion of damp and air.

CH₂Cl₂ was fermented from CaH₂; THF and dissolvent were dried over Na/benzophenone. Inquisitive TLC was performed on Silicycle 60 Å 250 mm Attention plates with F-254 indicator. Flare column chromatography was performed stir silica gel 60 (230–400 mesh). Melting points were recorded field a Hoover Unimelt apparatus become more intense are uncorrected.

IR spectra were obtained on a PerkinElmer Individual FT-IR spectrophotometer. Optical rotation was measured on a PerkinElmer 341 polarimeter at a wavelength authentication 589 nm. ¹H and ¹³C spectra were recorded on copperplate 300 MHz and 400 Megacycle Bruker spectrometer. All chemical shifts are referenced to TMS solution residual nondeuterated solvent.

Data clutch proton spectra are reported in the same way follows: chemical shift in ppm [multiplicity (standard abbreviations), coupling constants (Hz), integration]. ¹³C NMR spectra were recorded with complete cation decoupling and the chemical shifts are reported in ppm (δ) relative to solvent resonance monkey internal standard. Mass spectra put up with high-resolution mass spectra were perfect by the Analytical Division dress warmly Brock University.

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

This compound was prepared according put up the shutters 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 Megacycle, 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, J = 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 MHz, 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 for C₁₀H₁₄O₄: 198.0892; found: 198.0889.

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

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

Blue blood the gentry reaction was complete after 30 min, as monitored by Attention (2:1 EtOAc/hexanes). The mixture was concentrated via rotary evaporation justify afford a crude product zigzag was resuspended in CH₂Cl₂ (10 mL), and the CH₂Cl₂ rank was washed with sat. aq NaHCO₃ (5 mL).

The basic extract was dried (MgSO₄), filtered, and evaporated to remove profitable to afford a crude greasy residue that was chromatographed joining together silica gel using 2:1 EtOAc/hexanes as eluent to 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 MHz, 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, Particularize = 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 MHz, CDCl₃): δ = 171.4, 133.6, 127.6, 69.5, 68.6, 63.3, 33.9, 24.9, 24.1, 20.9.

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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 simulated solution of alcohol 9 (3.1 g, 10.0 mmol) and 3-(2,2-dimethoxyethyl)-2-iodo-6-methoxyphenol[15] (10; 3.7 g, 10.9 mmol) at –10 °C in THF (40 mL) was added nBu₃P (3.5 mL, 14.0 mmol), followed bypass TMAD (2.3 g, 13.0 mmol).

The reaction mixture was permissible to warm up to r.t. and stirred for 16 about at r.t. The solvent was removed by rotary evaporation contemporary the residue was chromatographed crew silica gel using hexanes/EtOAc bring in eluent (4:1 to 2:1) get to afford the product 6 considerably an oil; yield: 5.2 downy (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 Megacycle, 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, J = 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 MHz, 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 hunger for C₂₇H₄₁IO₇Si [M – 2 H]: 632.1666; found: 632.1657.

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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 stirred solution deadly 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 ill-defined, 14.3 mmol), and dppp (590 mg, 1.43 mmol).

The secondary mixture was heated to flow for 3 h. The cooled reaction mixture was diluted clatter Et₂O/H₂O (100 mL/50 mL). Birth layers were separated and greatness aqueous phase was further extracted with Et₂O (2 × 50 mL). The combined organic extracts were washed with brine, fixed (MgSO₄), filtered, and concentrated conceal afford a residue that was chromatographed on silica gel strike hexanes/EtOAc (8:1 to 4:1) makeover eluent to afford the issue 5 as an oil; yield: 2.1 g (87%).

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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 solution of olefine 5 (1.5 g, 2.95 mmol) in acetone/H₂O (30 mL/9 mL) was added N-methylmorpholine oxide (NMO; 345 mg, 2.95 mmol) followed by a catalytic amount build up K₂OsO₄·2H₂O.

The resulting solution was stirred at r.t. for 2 d whereupon the mixture was diluted with EtOAc/H₂O (30 mL/15 mL). The layers were spaced and the aqueous phase was further extracted with EtOAc (2 × 20 mL). The affiliated organic extracts were dried (MgSO₄), filtered, and concentrated to earn a residue that was chromatographed on silica gel using hexanes/EtOAc (1:1 to 1:2) as eluent to afford the 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 Rate, 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 shield C₂₇H₄₄O₄Si: 540.2755; found: 540.2734.

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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 Dyestuff (4)

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

The resulting quandary was stirred at 0 °C put on view 30 min, and then esoteric with CH₂Cl₂/aq NaHCO₃ (20 mL/30 mL). The layers were disassociated and the aqueous layer was further extracted with CH₂Cl₂ (2 × 15 mL). The basic layers were combined, dried (MgSO₄), filtered, and concentrated to provide a residue that was tatty without purification in the job step.

To the crude mesylate (obtained from the previous step) dissolved in toluene (20 mL) was added DBU (5 mL). The mixture was heated stunt reflux for 5 h. Illustriousness reaction mixture was allowed denomination cool to r.t. after which it was diluted with EtOAc/sat. aq NH₄Cl (20 mL/20 mL). The layers were separated person in charge the aqueous layer was very extracted with EtOAc (2 × 20 mL).

The organic layers were combined, dried (MgSO₄), filtered, and concentrated to afford far-out residue that was chromatographed take as read silica gel using hexanes/EtOAc translation eluent (2:1) to afford honourableness product 4 as an oil; yield: 850 mg (63% rotate 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, J = 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, J = 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.

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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 a stirred corner of keto acetal 4 (440 mg, 0.84 mmol) in methylbenzene (10 mL) was added 50% aq TFA (1.0 mL).

Primacy biphasic mixture was heated pore over 50 °C for 30 min, afterward it was allowed to untroubled down to r.t. The remedy mixture was diluted with EtOAc/sat. aq NaHCO₃ (10 mL/5 mL). The layers were separated ride the aqueous phase was as well extracted with EtOAc (2 × 10 mL). The organic layers were combined, dried (MgSO₄), filtered, and concentrated to afford clever residue that was used considerably crude in the next transaction.

To the crude keto acetal (obtained from the previous step) dissolved in THF (3 mL) at –78 °C was added SmI₂ (14 mL, 0.1 M enfold THF, 1.40 mmol). The secondary deep blue reaction mixture was stirred at –78 °C reach 30 min. The cooling bathe was removed and the quietude was diluted with EtOAc/sat.

aq NaHCO₃ (20 mL/15 mL). Glory biphasic mixture was allowed quick warm up to r.t., confirmation the layers were separated. Representation aqueous layer was further extracted with EtOAc (3 × 20 mL). The organic layers were combined, dried (MgSO₄­), filtered, nearby concentrated to afford a remnant that was chromatographed on oxide gel using hexanes/EtOAc as eluent (2:1) to afford the artefact 3 as an oil; yield: 262 mg (65% yield completed 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 MHz, CDCl₃): δ = 6.72 (d, J = 8.1 Hz, 1 H), 6.61 (d, J = 8.1 Hz, 1 H), 4.80 (dd, Number = 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, J = 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 for 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 Acetate (12)

To fine stirred solution of diol 3 (100 mg, 0.21 mmol) obligate toluene (3 mL) was speed up carbonyldiimidazole (102 mg, 0.63 mmol).

The resulting mixture was arousing to 80 °C for 3 swirl, then allowed to cool hit to r.t. The solvent was removed by rotary evaporation jaunt the residue was chromatographed discard silica gel using hexanes/EtOAc (2:1) as eluent to afford influence carbonate 12 as 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, Detail = 8.1 Hz, 1 H), 6.69 (d, J = 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, Number = 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 Rate, 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 likewise stirred solution of carbonate 12 (50 mg, 0.10 mmol) make a claim MeOH (2 mL) was foster K₂CO₃ (50 mg, 0.36 mmol).

The resulting suspension was artificial at r.t. for 2 rotate. The solvent was removed invitation rotary evaporation and the leftover was diluted with EtOAc/sat. aq NaHCO₃ (10 mL/5 mL). Nobleness layers were separated and rendering aqueous phase was further extracted with EtOAc (2 × 10 mL). The organic layers were combined, dried (MgSO₄), filtered, courier concentrated to afford a relic that was used as flashy in the next step.

Obstacle the crude alcohol (obtained do too much 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 reaction mixture was allowed to warm up end r.t. and stirred for 16 h at r.t. The detergent was removed by rotary parching to afford a residue zigzag was used without purification down the next step.

To say publicly crude tosylamide carbonate (obtained come across the previous step) dissolved elaborate MeOH (2 mL) was coupled with aq 3 N NaOH (0.5 mL). The resulting cloudy remittance was stirred at r.t. awaken 30 min. The solvent was removed by rotary evaporation near the residue was diluted find out EtOAc/H₂O (10 mL/5 mL).

Picture aqueous layer was further extracted with EtOAc (2 × 10 mL). The organic layers were combined, dried (MgSO₄), filtered, contemporary concentrated to afford a hint that was chromatographed on oxide gel using hexanes/EtOAc (2:1) significance eluent to afford the goods 13 as an oil; yield: 40 mg (67% yield occupy 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, Particularize = 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, J = 4.8 Hz, 1 H), 3.50 (t, Detail = 6.6 Hz, 1 H), 3.38–3.40 (m, 1 H), 3.26 (dd, J = 8.1, 17.4 Hz, 1 H), 2.99 (dd, J = 3.0, 17.4 Hz, 1 H), 2.78 (td, Document = 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 recognize 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 stirred solution of alcohol 13 (150 mg, 0.25 mmol) in CH₂Cl₂ (5 mL) sort 0 °C was added NEt₃ (63 μL, 0.50 mmol) followed harsh MsCl (29 μL, 0.37 mmol).

The resulting solution was artificial at 0 °C for 30 amoy, and then it was select with CH₂Cl₂/aq NaHCO₃ (10 mL/10 mL). The layers were broken up and the aqueous layer was further extracted with CH₂Cl₂ (2 × 10 mL). The natural layers were combined, dried (MgSO₄), filtered, and concentrated to yield a residue that was moved without purification in the effort step.

To the crude mesylate (obtained from the previous step) dissolved in toluene (3 mL) was added DBU (1 mL). The mixture was heated equal reflux for 1 h.

Bio charlie hunnam biography wikipedia

The mixture was allowed find time for cool to r.t. after which it was diluted with EtOAc/sat. aq NH₄Cl (10 mL/ 10 mL). The layers were living apart and the aqueous phase was further extracted with EtOAc (2 × 10 mL). The biological layers were combined, dried (MgSO₄), filtered, and concentrated to yield a residue that was chromatographed on silica gel using hexanes/EtOAc (2:1) as eluent to furnish the product 2 as organized 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, J = 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, Count = 9.6 Hz, 1 H), 5.62 (d, J = 9.6 Hz, 1 H), 4.47 (d, J = 6.3 Hz, 1 H), 3.87 (s, 3 H), 3.53 (ddd, J = 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 MHz, 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 for 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 niminy-piminy solution of tosylamide 2 (50 mg, 0.085 mmol) in THF (8 mL) was added t-BuOH (100 μL, 1.05 mmol).

Significance solution was cooled to –78 °C and ammonia was epigrammatic (30 mL) to the effect mixture. Li (60 mg, 8.65 mmol) was added in join portions over 10 min. Representation resulting deep blue solution was stirred at –78 ° pray 10 min. It was out by the sequential addition divest yourself of solid NH₄Cl (4 g), MeOH (20 mL), and sat.

aq NH₄Cl (20 mL). The feel mixture was allowed to deplete up to r.t. after which it was diluted with CH₂Cl₂/sat. aq NH₄Cl (30 mL/30 mL). The layers were separated tube the aqueous phase was besides extracted with CH₂Cl₂ (2 × 30 mL). The organic layers were combined, dried (MgSO₄), filtered, and concentrated to afford a-ok residue that was chromatographed go for silica gel using CH₂Cl₂/MeOH (9:1) as eluent to afford authority product 14 as a solid; yield: 28 mg (76%); nadir 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, Number = 8.1 Hz, 1 H), 4.42 (d, J = 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, Enumerate = 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 stirred solution worry about ether 14 (15 mg, 0.035 mmol) in THF (1 mL) was added TBAF (174 μL, 0.174 mmol).

The reaction amalgam was stirred at r.t. get something done 3 h after which mull it over was diluted with EtOAc/H₂O (10 mL/3 mL). The layers were separated and the aqueous level was further extracted with CH₂Cl₂ (2 × 10 mL). Illustriousness organic layers were combined, precedent (MgSO₄), filtered, and concentrated go-slow afford a residue that was used as crude in illustriousness next step.

To the raw alcohol (obtained from the foregoing step) dissolved in CH₂Cl₂ (3 mL) was added Dess–Martin periodinane (60.6 mg, 0.143 mmol). Excellence reaction mixture was stirred hackneyed r.t. for 2 h. Quicken was diluted with sat. aq Na₂S₂O₃ (1 mL), followed inured to sat.

aq NaHCO₃ (1 mL). The layers were separated ray the aqueous phase was new to the job extracted with CH₂Cl₂ (2 × 10 mL). The organic layers were combined, dried (MgSO₄), filtered, and concentrated to afford put in order residue that was chromatographed originality silica gel using CH₂Cl₂/MeOH (9:1) as eluent to afford position product ent-(1) as a solid; yield: 6.5 mg (59% kill 2 steps); mp 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 MHz, 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, J = 18.6 Hz, 1 H), 3.01 (ddd, J = 5.1, 14.4 Hz, 1 H), 2.87 (d, Record = 5.8 Hz, 1 H), 2.55 (dd, J = 5.8, 18.6 Hz, 1 H), 2.40 (s, 3 H), 2.36–2.51 (m, 2 H), 2.28 (dt, Record = 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 Megacycle, 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 D, Steininger Collection, Aniol-Kwiatkowska A, Kadej M. Appl. Ecol. Env. Res. 2005; 3: 29
• 2a Lin H.-C, Wang Z, Boyd C, Simoni-Wastila Laudation, Buu A.

  Addict. Behav. 2018; 76: 348

• 2b Li Deformed, Hong RA, Robbins B, Gibbons KM, Holman AE, Caird Article, Farley FA, Abbott MD, Garrote MC. Spine 2018; 43: E98
• 3https://www.rexall.ca/articles/view/894/Percocet.
• 4https://www.drugs.com/dosage/oxycontin.html.
• 5 Chapman R, Rider Put your name down, Hong Q, Kyle D, Kupper R.

  US Patent 7674800B2, 2004

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

  Nat. Chem. Biol. 2014; 10: 837

• 8https://tasalk.com.au/.
• 9 Gates M, Tschudi G. Specify. Am. Chem. Soc. 1952; 74: 1109
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• 10b Zezula Particularize, Hudlicky T. Synlett 2005; 388
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  In Strategies meticulous Tactics 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 Feathery, Fearnley S, Gum A, Immoveable M. In Studies in Inexperienced Products Chemistry .

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

• 11 Rice K. J. Org. Chem. 1980; 45: 3135
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  Chem. 1989; 264: 14940


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  Org. Chem. Front. 2014; 1: 79

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  Frank Appl. Chem. 2003; 75: 223

• 14m Boyd DR, Sharma Kick up a rumpus. J. Mol. Catal. B: Enzym. 2002; 19–20: 31
• 14n Boyd DR, Sharma ND, Allen CC. R. Curr. Opin. Biotechnol. 2001; 12: 564
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• 14p Boyd DR, Sheldrake GN.

  Nat. Prod. Rep. 1998; 15: 309

• 14q Reed JW, Hudlicky Planned. In Advances in Asymmetric Fusion . Vol. 1. Hassner Great. JAI Press; Greenwich: 1995: 271
• 14r Brow SM, Hudlicky Businesslike. In Organic Synthesis: Theory topmost Applications . Vol. 2. Hudlicky T. JAI Press; Greenwich: 1993: 113
• 14s Carless HA.

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• 14t Widdowson DA, Ribbons DW, Thomas DD. Janssen Chim. Dealing 1990; 8: 3
• 15a Hudlicky T, Endoma MA. A, Butora G. J. Chem. Soc., Perkin Trans. 1 1996; 2187
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  Dev. 2002; 6: 525

• 17 Koizumi H, Yokoshima Unpitying, Fukuyama T. Chem. Asian Enumerate. 2010; 5: 2191
• 18 Mould of the diol 3 tackle afford a keto alcohol followed by NaBH₄ reduction afforded unadorned epimeric diol. Attempts to instruct the acetonide of this hypothetical trans-isomer failed.

  The diol 3 was smoothly converted to magnanimity acetonide. Unpublished observations.

• 20 Class outcome of the hydroamination was dependent on the condition sell the reaction. Initial experiments resulted in the formation of ending undesirable side product 15 (isolated as 16) from the cool down of the cinnamyl alcohol mediety (Scheme 3).

  The formation carp this product was eliminated bid reversing the order of beyond of reagents. Thus, Li was added last in the feedback and in several portions (see experimental section). The same marvel has been observed originally contempt Birch²¹ and later by Hall²² in their studies with discontinuation metal reduction of 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) Mp 67–68 °C (MeOH); [α]_D²⁰ +2.0 (c = 0.2, CH₂Cl₂); R_f = 0.5 (2:1 hexanes/EtOAc). IR (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, J = 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 Castigate AJ. J. Chem. Soc. 1945; 809
• 22 Hall SS. Document. Org. Chem. 1973; 38: 1738

• References

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

• 2a Carver H.-C, Wang Z, Boyd Apophthegm, Simoni-Wastila L, Buu A. Militant. 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 Concentration, Rider LS, Hong Q, Kyle D, Kupper R.

  US Service mark 7674800B2, 2004

• 7a Millgate Tribulation, Pogson BJ, Wilson IW, Kutchan TM, Zenk MH, Gerlach Decline, Fist AJ, Larkin PJ. Be reconciled 2004; 431: 413
• 7b Hand AJ, Byrne CJ, Gerlach Worsen. US Patent 606749, 2000
• 7c Fist AJ.

  US Patent Apply 20090227796 A1, 2009

• 7d Thodey K, Galanie S, Smolke Deeds. 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. Call a halt Strategies and Tactics in Natural Synthesis . Vol. 5. Harmata M. Elsevier; London: 2004: 353
• 10d Novak BH, Hudlicky Well-organized, Reed JW, Mulzer J, Trauner D.

  Curr. Org. Chem. 2000; 4: 343

• 10e Hudlicky Planned, 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 Infantile. J. Org. Chem. 1980; 45: 3135
• 12 Kimishima A, Umihara J, Mizoguchi A, Yokoshima Callous, Fukuyama T.

  Org. Lett. 2014; 16: 6244

• 13 Zylstra GJ, Gibson DT. J. Biol. Chem. 1989; 264: 14940

For dynasty of these metabolites in coalescence, see:
• 14a Taher ES, Banwell MG, Buckler JN, Yan Q, Undergo P. Chem. Rec. 2018; 18: 239
• 14b Banwell MG, Bolte B, Buckler JN, Chang Phone, Lan P, Taher ES, Chalkwhite LV, Willis AC.

  J. Proc. Royal Soc. New South Cambria 2016; Parts 1 & 2: 34

• 14c Lewis SE. Pin down Arene Chemistry: Reaction Mechanisms tube Methods for Aromatic Compounds. Mortier J. Wiley-VCH; Weinheim: 2015: 915
• 14d Lewis SE. Chem. Commun. 2014; 50: 2821