Chemoenzymatic Total Synthesis of (+)-Oxycodone from Phenethyl Acetate

Mary Ann A. Endoma-Arias; Mariia Makarova; Helen E. Dela Paz; Tomas Hudlicky

doi:10.1055/s-0037-1611335

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CC BY-ND-NC 4.0 · Synthesis 2019; 51(01): 225-232
DOI: 10.1055/s-0037-1611335

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Chemoenzymatic Total Synthesis of (+)-Oxycodone from Phenethyl Acetate

Mary Ann A. Endoma-Arias

,

Mariia Makarova

,

Helen E. Dela Paz

,

Tomas Hudlicky *

Chemistry Department and Centre for Biotechnology, Brock University, 1812 Sir Isaac Brock Way St. Catharines, Ontario, L2S 3A1, Canada Email: thudlicky@brocku.ca

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Abstract

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Abstract

The stereoselective total synthesis of unnatural (+)-oxycodone from phenethyl acetate is described. Absolute stereochemistry was established via microbial dihydroxylation of phenethyl acetate with the recombinant strain JM109 (pDTG601A) to the corresponding cis-cyclohexadienediol whose configuration provides for the absolute stereochemistry of the ring C of (+)-oxycodone. Intramolecular Heck cyclization was employed to establish the quaternary carbon at C-13, along with the dibenzodihydrofuran functionality. The C-14 hydroxyl was installed via SmI₂-mediated radical cyclization. The synthesis of (+)-oxycodone was completed in a total of 13 steps and an overall yield of 1.5%. Experimental and spectral data are provided for all new compounds.

Key words

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

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References

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20 The outcome of the hydroamination was dependent on the condition of the reaction. Initial experiments resulted in the formation of an undesirable side product 15 (isolated as 16) from the reduction of the cinnamyl alcohol moiety (Scheme 3). The formation of this product was eliminated by reversing the order of addition of reagents. Thus, Li was added last in the reaction and in several portions (see experimental section). The same phenomenon has been observed originally by Birch²¹ and later by Hall²² in their studies with dissolving 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]_D ²⁰ +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.
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