Key words enzymatic dihydroxylation - total synthesis - oxycodone - Parker’s hydroamination - pinacol-type coupling
The semi-synthetic opioid (–)-oxycodone (1 ) (Figure [1 ]), although found also in nature,[1 ] is a potent analgesic that is clinically prescribed for pain management.[2 ] It is taken by mouth and is available mixed with acetaminophen in immediate release tablet form, which contains oxycodone HCl (5 mg) and acetaminophen (325 mg) (Percocet® ),[3 ] as a single ingredient medication oxycodone HCl (60 mg and 80 mg) or as film coated, extended release tablet OxyContin® .[4 ] The commercial route[5 ] for the preparation of oxycodone is a two-step process from thebaine through the oxidation of the diene moiety with a peroxy acid to form an enone followed by hydrogenation.[6 ] Thebaine is a minor constituent of opium and thus this fact limits the production of oxycodone. However, thebaine, as well as oripavine, are now also available from genetically modified poppies that produce much higher percentages of these alkaloids.[7 ] These compounds are now supplied by Tasmanian Alkaloids, Inc.[8 ] During the past 70 years, since the milestone synthesis of morphine by Gates,[9 ] there have been more than 30 total syntheses of morphine and related alkaloids and the academic effort continues unabated.[10 ] Even the most efficient synthesis reported by Rice[11 ] may not be suitable for scale-up in the industrial preparation of morphinans. Although the development of a truly practical total synthesis of any morphinan or an opiate-derived agent on a commercial scale seems like a distant dream we have attempted to design a method for the synthesis of oxycodone from readily available starting materials. A de novo preparation of oxycodone or any other medicinal opiate-derived agents for medicinal use may serve as an insurance against any future unforeseen events that may limit the supply of natural sources because of climate or political instabilities in the opium-producing regions. To date, there is only one published total synthesis of oxycodone.[12 ] Fukuyama and co-workers accomplished the total synthesis of (–)-oxycodone (1 ) from 2-bromoisovanillin in 24 steps in an overall yield of 0.016%. The key steps in their synthesis featured a direct intramolecular arylation of an aryl bromide, an oxidative dearomatization reaction, an intramolecular Michael addition, and a Hofmann rearrangement. Absolute stereochemistry was incorporated into the starting material by the use of Evans’ oxazolidinone as a chiral auxiliary.
Figure 1 Structure of (–)-oxycodone (with numbering system shown)
Scheme [1 ] outlines our retrosynthesis of (+)-oxycodone. Disconnection of ring D leads to styrene 2 . In the forward sense, Parker’s hydroamination can be utilized to construct the C-9 stereogenic center. The tosylamide group necessary for the cyclization reaction is derived from acetate 3 , which is envisioned to be prepared from the keto acetal 4 following a deprotection of acetal and a SmI2 -mediated pinacol-type coupling reaction. The key intermediate 4 can be obtained from alkene 5 via dihydroxylation followed by selective mesylation of the less hindered hydroxyl group and the elimination of the mesylate to reveal the ketone functionality in 4 . Alkene 5 can be obtained in two steps from alcohol 7 via a sequence of steps that involves a Mitsunobu coupling with an iodophenol acetal to furnish aryl ether 6 followed by an intramolecular Heck reaction. The absolute stereochemistry in 7 is incorporated via microbial dihydroxylation with 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 found widespread use in enantioselective synthesis of natural products.[14 ]
Scheme 1 Retrosynthetic analysis of the route to ent -oxycodone
The synthesis began with the microbial dihydroxylation of phenethyl acetate (8 ) (Scheme [2 ]) in a whole cell fermentation with E. coli JM109 (pDTG601A) to afford the intermediate cyclohexadiene diol 7 (obtained in 5 gL–1 yield),[15 ] which was subjected to a selective reduction of the less hindered alkene to afford the known diol 9
[16 ] (85% yield). The distal, less hindered, hydroxyl in diol 9 was protected with tert -butyldimethylsilyl chloride and the proximal allylic alcohol was then coupled with iodophenol 10 ,[17 ] derived from isovanillin, via a Mitsunobu reaction to furnish ether 6 (45% yield over two steps). A subsequent intramolecular Heck reaction of 6 produced olefin 5 (87% yield) whose dihydroxylation led to diol 11 (81% yield). This compound possesses the features of the ACE rings of oxycodone. The diol functionality was converted to ketone 4 via mesylation of the less hindered hydroxyl group followed by DBU-catalyzed elimination of the resulting mesylate (63% yield over two steps). With the attainment of 4 , deprotection of the acetal followed by a pinacol-type coupling of the intermediate keto aldehyde using SmI2 was conducted to afford diol 3 , tentatively assigned as the cis -isomer (65% yield over two steps).[18 ] Protection of diol 3 with a carbonate group to afford 12 (80% yield) allowed for the introduction of the tosylamide functionality via methanolysis of the acetate followed by Mitsunobu coupling of the resulting alcohol with N -methyl p -toluenesulfonyl amide. The carbonate moiety in the crude tosylamide was hydrolyzed to afford diol 13 (67% yield over three steps). It would have been desirable to isolate the intermediate tosylamide carbonate but the difficulty in the separation of residual N -methyl p -toluenesulfonyl amide from the desired product rendered this process impractical. The less hindered hydroxyl of 13 was converted to the corresponding mesylate and subjected to DBU-catalyzed elimination affording alkene 2 (70% yield over two steps), which was the precursor for the key Parker’s hydroamination step to complete the ring system of oxycodone. Thus, treatment of 2 with Li in liquid ammonia as reported by Parker[19 ] in the total synthesis of hydrocodone afforded the oxycodol ether 14 (76% yield).[20 ] Deprotection of the TBS group in 14 followed by oxidation of the alcohol to ketone afforded ent -oxycodone [ent -(1 )] (59% yield over two steps).
Scheme 2 Synthesis of ent -oxycodone. Reagents and conditions : i) E. coli JM 109 (pDTG601A), 5 gL–1 ; ii) potassium azodicarboxylate, MeOH, AcOH, 85%; iii) TBSCl, imidazole, CH2 Cl2 , 54%; iv) 10 , TMAD, n -Bu3 P, THF, 0 °C to r.t., 83%; v) Ag2 CO3 , dppp, Pd(OAc)2 , DMF, reflux, 87%; vi) cat. OsO4 , NMO, acetone/H2 O, 81%; vii) a. MsCl, NEt3 , CH2 Cl2 , b. DBU, toluene, reflux, 63% over 2 steps; viii) a. aq TFA, toluene, 50 °C, b. SmI2 , THF, –78 °C, 65% over 2 steps; ix) carbonyldiimidazole, toluene, 80 °C, 80%; x) a. K2 CO3 , MeOH, b. TsNHMe, TMAD, n -Bu3 P, THF, c. aq NaOH, MeOH, 67% over 3 steps; xi) a. MsCl, NEt3 , CH2 Cl2 , b. DBU, toluene, reflux, 70% over 2 steps; xii) Li, t -BuOH, THF, liq NH3 , –78 °C, 76%; xiii) a. TBAF, THF, b. Dess–Martin periodinane, CH2 Cl2 , 59% yield over 2 steps.
In conclusion, a short chemoenzymatic synthesis of ent -oxycodone has been accomplished in 13 steps from phenethyl acetate. Further improvements in this short synthesis will address installation of the N -methyltosylamide side chain earlier in the synthesis thus eliminating the need to use a carbonate protecting group during the synthetic sequence. In particular, the acetate functionality in 5 will be converted to the tosylamide. Furthermore, an SmI2 -mediated nitrone-keto coupling is being investigated to afford an amino alcohol instead of diol intermediate for subsequent cyclization to the pendant acetate side chain. These improvements, as well as the 2nd generation synthesis of the natural enantiomer, are currently being investigated and will be reported in due course.
Inoculum was obtained from viable cells stored at –78 °C in cryovials. They were grown in suitable media 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. All non-aqueous reactions were conducted in an argon atmosphere using standard Schlenk techniques for the exclusion of moisture and air. CH2 Cl2 was distilled from CaH2 ; THF and toluene were dried over Na/benzophenone. Analytical TLC was performed 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. IR spectra were obtained on a PerkinElmer One FT-IR spectrophotometer. Optical rotation was measured on a PerkinElmer 341 polarimeter at a wavelength of 589 nm. 1 H and 13 C spectra were recorded on a 300 MHz and 400 MHz Bruker spectrometer. All chemical shifts are referenced to TMS or residual nondeuterated solvent. Data of proton spectra are reported as follows: chemical shift in ppm [multiplicity (standard abbreviations), coupling constants (Hz), integration]. 13 C NMR spectra were recorded with complete proton decoupling and the chemical shifts are reported in ppm (δ) relative to solvent resonance as internal standard. Mass spectra and high-resolution mass spectra were performed by the Analytical Division at Brock University.
2-[(5S ,6R )-5,6-Dihydroxycyclohexa-1,3-dien-1-yl]ethyl Acetate (7)[16 ]
2-[(5S ,6R )-5,6-Dihydroxycyclohexa-1,3-dien-1-yl]ethyl Acetate (7)[16 ]
This compound was prepared according to a literature procedure.[16 ]
[α]D
20 +32.07 (c = 0.4, CHCl3 ) {Lit.[16 ] [α]D
28 +40.7 (c = 2.0, CHCl3 )}; Rf
= 0.18 (hexanes/EtOAc 1:2).
IR (CHCl3 ): 3392, 2955, 2925, 1735, 1383, 1366, 1238, 1037, 803 cm–1 .
1 H 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, J = 6.0 Hz, 1 H), 2.97 (s, 2 H), 2.57–2.48 (m, 2 H), 2.01 (s, 3 H).
13 C 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 C10 H14 O4 : 198.0892; found: 198.0889.
2-[(5S ,6R )-5,6-Dihydroxycyclohex-1-enyl]ethyl Acetate (9)[17 ]
2-[(5S ,6R )-5,6-Dihydroxycyclohex-1-enyl]ethyl Acetate (9)[17 ]
To a stirred mixture of diol 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). The reaction was complete after 30 min, as monitored by TLC (2:1 EtOAc/hexanes). The mixture was concentrated via rotary evaporation to afford a crude product that was resuspended in CH2 Cl2 (10 mL), and the CH2 Cl2 layer was washed with sat. aq NaHCO3 (5 mL). The organic extract was dried (MgSO4 ), filtered, and evaporated to remove solvent to afford a crude oily residue that was chromatographed on silica gel using 2:1 EtOAc/hexanes as eluent to afford 9 as an oil; yield: 128 mg (85%); [α]D
20 –65.9 (c = 1.0, CHCl3 ) {Lit.[17 ] [α]D
20 –53.0 (c = 0.2, CHCl3 )}; Rf
= 0.25 (hexanes/EtOAc 1:2).
1 H 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, 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).
13 C 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.
2-{(5S ,6S )-5-[(tert -Butyldimethylsilyl)oxy]-6-[3-(2,2-dimethoxyethyl)-2-iodo-6-methoxyphenoxy]cyclohex-1-en-1-yl}ethyl Acetate (6)
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 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 n Bu3 P (3.5 mL, 14.0 mmol), followed by TMAD (2.3 g, 13.0 mmol). The reaction mixture was allowed to warm up to r.t. and stirred for 16 h at r.t. The solvent was removed by rotary evaporation and the residue was chromatographed on silica gel using hexanes/EtOAc as eluent (4:1 to 2:1) to afford the product 6 as an oil; yield: 5.2 g (83%); [α]D
20 +48.4 (c = 1.2, CH2 Cl2 ); Rf
= 0.58 (2:1 hexanes/EtOAc).
IR (film): 2930, 2855, 1738, 1642, 1472, 1249, 1078, 776 cm–1 .
1 H 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, 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).
13 C 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 for C27 H41 IO7 Si [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 ]
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 of ether 6 (3.02 g, 4.76 mmol) in DMF (55 mL) was added Pd(OAc)2 (168 mg, 0.71 mmol), Ag2 CO3 (3.9 g, 14.3 mmol), and dppp (590 mg, 1.43 mmol). The resulting mixture was heated to reflux for 3 h. The cooled reaction mixture was diluted with Et2 O/H2 O (100 mL/50 mL). The layers were separated and the aqueous phase was further extracted with Et2 O (2 × 50 mL). The combined organic extracts were washed with brine, dried (MgSO4 ), filtered, and concentrated to afford a residue that was chromatographed on silica gel using hexanes/EtOAc (8:1 to 4:1) as eluent to afford the product 5 as an 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)
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 alkene 5 (1.5 g, 2.95 mmol) in acetone/H2 O (30 mL/9 mL) was added N -methylmorpholine oxide (NMO; 345 mg, 2.95 mmol) followed by a catalytic amount of K2 OsO4 ·2H2 O. The resulting solution was stirred at r.t. for 2 d whereupon the mixture was diluted with EtOAc/H2 O (30 mL/15 mL). The layers were separated and the aqueous phase was further extracted with EtOAc (2 × 20 mL). The combined organic extracts were dried (MgSO4 ), filtered, and concentrated to afford 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]D
20 +16.6 (c = 16.7, CH2 Cl2 ); Rf
= 0.36 (1:1 hexanes/EtOAc).
IR (film): 3429, 2951, 2856, 1738, 1629, 1433, 1042 cm–1 .
1 H 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).
13 C 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 C27 H44 O4 Si: 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)
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 stirred solution of diol 11 (1.41 g, 2.61 mmol) in CH2 Cl2 (37 mL) at 0 °C was added NEt3 (724 μL, 5.22 mmol) followed by MsCl (303 μL, 3.91 mmol). The resulting solution was stirred at 0 °C for 30 min, and then diluted with CH2 Cl2 /aq NaHCO3 (20 mL/30 mL). The layers were separated and the aqueous layer was further extracted with CH2 Cl2 (2 × 15 mL). The organic layers were combined, dried (MgSO4 ), filtered, and concentrated to afford a residue that was used without purification in the next step. To the crude mesylate (obtained from the previous step) dissolved in toluene (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 diluted with EtOAc/sat. aq NH4 Cl (20 mL/20 mL). The layers were separated and the aqueous layer was further extracted with EtOAc (2 × 20 mL). The organic layers were combined, dried (MgSO4 ), filtered, and concentrated to afford a residue that was chromatographed on silica gel using hexanes/EtOAc as eluent (2:1) to afford the product 4 as an oil; yield: 850 mg (63% over 2 steps); [α]D
20 –60.2 (c = 17.9, CH2 Cl2 ); Rf
= 0.44 (2:1 hexanes/EtOAc).
IR (film): 2952, 2857, 1739, 1713, 1625, 1506, 1233, 1075, 836 cm–1 .
1 H 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).
13 C 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 C27 H42 O8 Si: 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)
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 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 allowed to cool down to r.t. The reaction mixture was diluted with EtOAc/sat. aq NaHCO3 (10 mL/5 mL). The layers were separated and the aqueous phase was further extracted with EtOAc (2 × 10 mL). The organic layers were combined, dried (MgSO4 ), filtered, and concentrated to afford a residue that was used as crude in the next step. 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 in THF, 1.40 mmol). The resulting deep blue reaction mixture was stirred at –78 °C for 30 min. The cooling bath was removed and the mixture was diluted with EtOAc/sat. aq NaHCO3 (20 mL/15 mL). The biphasic mixture was allowed to warm up to r.t., then the layers were separated. The aqueous layer was further extracted with EtOAc (3 × 20 mL). The organic layers were combined, dried (MgSO4 ), filtered, and concentrated to afford a residue that was chromatographed on silica gel using hexanes/EtOAc as eluent (2:1) to afford the product 3 as an oil; yield: 262 mg (65% yield over 2 steps); [α]D
20 +41.5 (c = 0.9, CH2 Cl2 ); Rf
= 0.33 (1:1 hexanes/EtOAc).
IR (film): 3435, 2952, 2930, 2855, 1736, 1713, 1632, 1504, 1257, 1030 cm–1 .
1 H 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, 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, 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).
13 C 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 C25 H38 O7 Si: 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)
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 a stirred solution of diol 3 (100 mg, 0.21 mmol) in toluene (3 mL) was added carbonyldiimidazole (102 mg, 0.63 mmol). The resulting mixture was heated to 80 °C for 3 h, then allowed to cool down to r.t. The solvent was removed by rotary evaporation and the residue was chromatographed on silica gel using hexanes/EtOAc (2:1) as eluent to afford the carbonate 12 as an oil; yield: 75 mg (71%); [α]D
20 +51.6 (c = 1.0, CH2 Cl2 ); Rf
= 0.65 (1:1 hexanes/EtOAc).
IR (film): 3436, 2953, 2931, 2856, 1806, 1738, 1637, 1235, 1067 cm–1 .
1 H NMR (300 MHz, CDCl3 ): δ = 6.79 (d, J = 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, 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).
13 C 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 C26 H36 O8 Si: 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)
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 of carbonate 12 (50 mg, 0.10 mmol) in MeOH (2 mL) was added K2 CO3 (50 mg, 0.36 mmol). The resulting suspension was stirred at r.t. for 2 h. The solvent was removed by rotary evaporation and the residue was diluted with EtOAc/sat. aq NaHCO3 (10 mL/5 mL). The layers were separated and the aqueous phase was further extracted with EtOAc (2 × 10 mL). The organic layers were combined, dried (MgSO4 ), filtered, and concentrated to afford a residue that was used as crude in the next step. To the crude alcohol (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 n Bu3 P (35 μL, 0.14 mmol), followed by TMAD (23 mg, 0.13 mmol). The reaction mixture was allowed to warm up to r.t. and stirred for 16 h at r.t. The solvent was removed by rotary evaporation to afford a residue that was used without purification in the next step. To the crude tosylamide carbonate (obtained from the previous step) dissolved in MeOH (2 mL) was added aq 3 N NaOH (0.5 mL). The resulting cloudy solution was stirred at r.t. for 30 min. The solvent was removed by rotary evaporation and the residue was diluted with EtOAc/H2 O (10 mL/5 mL). The aqueous layer was further extracted with EtOAc (2 × 10 mL). The organic layers were combined, dried (MgSO4 ), filtered, and concentrated to afford a residue that was chromatographed on silica gel using hexanes/EtOAc (2:1) as eluent to afford the product 13 as an oil; yield: 40 mg (67% yield over 3 steps); [α]D
20 +18.4 (c = 1.1, CH2 Cl2 ); Rf
= 0.50 (1:1 hexanes/EtOAc).
IR (film): 3466, 2928, 2855, 1633, 1505, 1159 cm–1 .
1 H 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, J = 4.8 Hz, 1 H), 3.50 (t, J = 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, 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).
13 C 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 C31 H45 NO7 SSi: 603.2686; found: 603.2679.
N -(2-{(3S ,3aS ,3a1
R ,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)
N -(2-{(3S ,3aS ,3a1
R ,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 diol 13 (150 mg, 0.25 mmol) in CH2 Cl2 (5 mL) at 0 °C was added NEt3 (63 μL, 0.50 mmol) followed by MsCl (29 μL, 0.37 mmol). The resulting solution was stirred at 0 °C for 30 min, and then it was diluted with CH2 Cl2 /aq NaHCO3 (10 mL/10 mL). The layers were separated and the aqueous layer was further extracted with CH2 Cl2 (2 × 10 mL). The organic layers were combined, dried (MgSO4 ), filtered, and concentrated to afford a residue that was used without purification in the next step. To the crude mesylate (obtained from the previous step) dissolved in toluene (3 mL) was added DBU (1 mL). The mixture was heated to reflux for 1 h. The mixture was allowed to cool to r.t. after which it was diluted with EtOAc/sat. aq NH4 Cl (10 mL/ 10 mL). The layers were separated and the aqueous phase was further extracted with EtOAc (2 × 10 mL). The organic layers were combined, dried (MgSO4 ), filtered, and concentrated to afford a residue that was chromatographed on silica gel using hexanes/EtOAc (2:1) as eluent to afford the product 2 as a viscous oil; yield: 101 mg (70% over 2 steps); [α]D
20 +59.98 (c = 0.3, CHCl3 ); Rf
= 0.6 (2:1, hexanes/EtOAc).
IR (neat): 3511, 2952, 2927, 2854, 1742, 1631, 1598, 1505, 1333, 1272, 1157, 1115 cm–1 .
1 H 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, J = 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).
13 C 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 C31 H44 NO6 SSi: 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)
(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 ammonia was condensed (30 mL) to the reaction mixture. Li (60 mg, 8.65 mmol) was added in three portions over 10 min. The resulting deep blue solution was stirred at –78 ° for 10 min. It was quenched by the sequential addition of solid NH4 Cl (4 g), MeOH (20 mL), and sat. aq NH4 Cl (20 mL). The reaction mixture was allowed to warm up to r.t. after which it was diluted with CH2 Cl2 /sat. aq NH4 Cl (30 mL/30 mL). The layers were separated and the aqueous phase was further extracted with CH2 Cl2 (2 × 30 mL). The organic layers were combined, dried (MgSO4 ), filtered, and concentrated to afford a residue that was chromatographed on silica gel using CH2 Cl2 /MeOH (9:1) as eluent to afford the product 14 as a solid; yield: 28 mg (76%); mp 120–122 °C (MeOH); [α]D
20 +66.4 (c = 0.3, CH2 Cl2 ); Rf
= 0.43 (9:1 CH2 Cl2 /MeOH).
IR (film): 3411, 2927, 2853, 1634, 1500, 1447, 1257, 1108 cm–1 .
1 H 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, 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, 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).
13 C 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 C24 H37 NO4 Si: 431.2492; found: 431.2482.
(+)-Oxycodone [ent -(1)]
To a stirred solution of ether 14 (15 mg, 0.035 mmol) in THF (1 mL) was added TBAF (174 μL, 0.174 mmol). The reaction mixture was stirred at r.t. for 3 h after which it was diluted with EtOAc/H2 O (10 mL/3 mL). The layers were separated and the aqueous layer was further extracted with CH2 Cl2 (2 × 10 mL). The organic layers were combined, dried (MgSO4 ), filtered, and concentrated to afford a residue that was used as crude in the next step. To the crude alcohol (obtained from the previous step) dissolved in CH2 Cl2 (3 mL) was added Dess–Martin periodinane (60.6 mg, 0.143 mmol). The reaction mixture was stirred at r.t. for 2 h. It was diluted with sat. aq Na2 S2 O3 (1 mL), followed by sat. aq NaHCO3 (1 mL). The layers were separated and the aqueous phase was further extracted with CH2 Cl2 (2 × 10 mL). The organic layers were combined, dried (MgSO4 ), filtered, and concentrated to afford a residue that was chromatographed on silica gel using CH2 Cl2 /MeOH (9:1) as eluent to afford the product ent -(1 ) as a solid; yield: 6.5 mg (59% over 2 steps); mp 206–208 °C (Lit.[12 ] mp 207.4–209.5 °C; [α]D
20 +205 (c = 0.3, CHCl3 ) {Lit.[12 ] [α]D
20 –207 (c = 0.09, CHCl3 ).
1 H 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, J = 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, 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).
13 C 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.
Scheme 3
