A Practical Asymmetric Synthesis of the ACNO Fragment of Morphine Alkaloids

Abstract

Asymmetric total synthesis of the ACNO skeleton of morphine alkaloids has been achieved in excellent overall yields and optical purities using the Ru-catalyzed asymmetric transfer hydrogenation, Pd-catalyzed cyclization, and Pt-catalyzed hydrogenation as key steps.

asymmetric catalysis - total synthesis - transition metals - hydrogenation - Heck reaction

References and Notes

<A NAME="RW06008ST-1A">1a</A> Willette RE. Analgesic Agents, In Wilson and Gisvold’s Textbook of Organic Medicinal and Pharmaceutical Chemistry   10th ed.:  Delgado JN. Remers WA. Lippincott-Raven; Philadelphia: 1998.  p.687-708  

<A NAME="RW06008ST-1B">1b</A> Fries DS. Opioid Analgesics, In Foye’s Principles of Medicinal Chemistry   5th ed.:  Lemke TL. Williams DA. Lippincott Williams & Wilkins; Baltimore, MD: 2002.  p.453-479  

<A NAME="RW06008ST-1C">1c</A> Michne WF. Chemistry of Opiate Analgesics and Antagonists, In Analgesics: Neurochemical, Behavioral, and Clinical Perspectives   Kuhar M. Pasternak G. Raven Press; New York: 1984.  p.125-148  

<A NAME="RW06008ST-2">2</A> Ciganek E. inventors; U.S. Patent  4243668.  ; Chem. Abstr. 1981, 95, 809241

<A NAME="RW06008ST-3A">3a</A> Ciganek E. J. Am. Chem. Soc.  1981,  103:  6261 

<A NAME="RW06008ST-3B">3b</A> Moos WH. Gless RD. Rapoport H. J. Org. Chem.  1981,  46:  5064 

<A NAME="RW06008ST-3C">3c</A> Shenvi AB. inventors; U.S. Patent  4421916. 

<A NAME="RW06008ST-3D">3d</A> Shenvi AB. Ciganek E. J. Org. Chem.  1984,  49:  2942 

<A NAME="RW06008ST-3E">3e</A> Weller DD. Weller DL. Tetrahedron Lett.  1982,  23:  5239 

<A NAME="RW06008ST-3F">3f</A> Weller DD. Stirchak EP. Weller DL. J. Org. Chem.  1983,  48:  4597 

<A NAME="RW06008ST-3G">3g</A> Cheng CY. Hsin L.-W. Tsai MC. Schmidt WK. Smith C. Tam SW. J. Med. Chem.  1994,  37:  3121 

<A NAME="RW06008ST-3H">3h</A> Laronze J.-Y. Laronze J. Patigny D. Lévy J. Tetrahedron Lett.  1986,  27:  489 

<A NAME="RW06008ST-3I">3i</A> Sapi J. Dridi S. Laronze J. Sigaut F. Patigny D. Laronze J.-Y. Lévy J. Toupet L. Tetrahedron  1996,  52:  8209 

<A NAME="RW06008ST-4">4</A> Cheng C.-Y. Hsin L.-W. Liou J.-P. Tetrahedron  1996,  52:  10935 

<A NAME="RW06008ST-5">5</A> Hsin L.-W. Chang L.-T. Chen C.-W. Hsu C.-H. Chen H.-W. Tetrahedron  2005,  61:  513 

<A NAME="RW06008ST-6">6</A> Hsin L.-W. Chen C.-W. Chang L.-T. J. Chin. Chem. Soc. (Taipei)  2005,  52:  339 

<A NAME="RW06008ST-7">7</A> Lardenois P. Frost J. Dargazanli G. George P. Synth. Commun.  1996,  26:  2305 

<A NAME="RW06008ST-8A">8a</A> Haack K.-J. Hashiguchi S. Fujii A. Ikariya T. Noyori R. Angew. Chem., Int. Ed. Engl.  1997,  36:  285 

<A NAME="RW06008ST-8B">8b</A> Bennett MA. Huang T.-N. Matheson TW. Smith AK. Inorg. Synth.  1982,  21:  74 

<A NAME="RW06008ST-8C">8c</A> Okano K. Murata K. Ikariya T. Tetrahedron Lett.  2000,  41:  9277 

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Chiral HPLC Analysis: The free base of the sample was dissolved in 1% isopropanol (IPA) in n-hexane. Then the sample solution (10 µL) was eluted using 1.5% [for compound (+)-4], 2.5% [for compounds (-)-3 and (-)-6], or 8% [for compound (-)-10] IPA in n-hexane in the presence of 0.2% diethylamine as mobile phase on the CHIRALCEL OD column (250 × 4 mm, DAICEL). The ee values were calculated based on the UV absorption (λ = 254 nm) areas of the two enantiomers.

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Microwave Experiments: The reactions under microwave irradiation were conducted in sealed heavy-walled Pyrex tubes. Microwave heating was carried out with a single mode cavity Discover Microwave Synthesizer (CEM Corporation, P.O. Box 200, Matthews, NC 28106, USA), producing continuous irradiation at 2.45 GHz. The reaction temperature was measured and feedback controlled with an infrared device under the reaction vessel.

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Spectral Data: Compound (-)-10: pale yellow solid; [α]_D ^{² 4} -31.1 (c = 1.00, MeOH); ee = 96.3%. ^¹H NMR (300 MHz, CDCl₃): δ = 1.61-1.74 (m, 2 H), 1.85-2.03 (m, 2 H), 2.57-2.61 (m, 2 H), 4.59 (t, J = 5.9 Hz, 1 H), 5.30 (s, 1 H), 7.32 (d, J = 5.0 Hz, 1 H), 8.07 (s, 1 H), 8.11 (d, J = 5.0 Hz, 1 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 19.2, 25.8, 31.8, 66.6, 122.3, 132.4, 146.2, 148.8, 149.2. HRMS (EI): m/z [M]⁺ calcd for C₉H₁₁NO: 149.0841; found: 149.0839.
Compound (+)-9: yellow oil; [α]_D ^{² 0} +60.0 (c = 0.10, MeOH). ^¹H NMR (400 MHz, CDCl₃): δ = 1.37-1.41 (m, 1 H), 1.43-1.49 (m, 1 H), 1.54-1.66 (m, 4 H), 1.82-1.88 (m, 1 H), 2.12 (s, 3 H), 2.27-2.37 (m, 3 H), 2.56 (s, 2 H), 3.69 (s, 1 H), 4.12 (s, 1 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 18.3, 26.8, 27.5, 32.3, 45.2, 52.2, 57.9, 67.0, 128.9, 129.2. HRMS (EI): m/z [M]⁺ calcd for C₁₀H₁₇NO: 167.1310; found: 167.1317.
Compound (-)-6: pale yellow oil; [α]_D ^{² 0} -51.1 (c = 1.90, MeOH); ee = 92%. ^¹H NMR (200 MHz, CDCl₃): δ = 1.39-1.62 (m, 2 H), 1.89-1.91 (m, 2 H), 1.96-2.20 (m, 2 H), 2.29 (m, 1 H), 2.31 (s, 3 H), 2.35-2.39 (m, 1 H), 2.60-2.73 (m, 3 H), 2.91 (d, J = 15.7 Hz, 1 H), 3.76 (s, 3 H), 4.66 (s, 1 H), 6.69 (t, J = 8.0 Hz, 1 H), 6.82 (dd, J = 1.5, 8.2 Hz, 1 H), 7.31 (dd, J = 1.6, 7.8 Hz, 1 H). ^¹³C NMR (50 MHz, CDCl₃): δ = 18.4, 27.80, 27.84, 28.3, 45.6, 52.5, 55.3, 58.4, 77.5, 93.5, 112.4, 124.9, 126.4, 130.9, 132.6, 147.4, 152.5. HRMS (FAB): m/z [M + H]⁺ calcd for C₁₇H₂₃INO₂: 400.0774; found: 400.0783.
Compound (+)-4: pale yellow oil; [α]_D ^{² 0} +105.0 (c = 0.92, MeOH); ee = 92.5%. ^¹H NMR (200 MHz, CDCl₃): δ = 1.10-1.26 (m, 1 H), 1.35-1.47 (m, 1 H), 1.50-1.68 (m, 1 H), 1.84-1.93 (m, 4 H), 2.00-2.17 (m, 1 H), 2.62 (s, 3 H), 2.71-2.82 (m, 2 H), 3.88 (s, 3 H), 4.46 (dd, J = 6.1, 9.4 Hz, 1 H), 5.91 (s, 1 H), 6.74-6.90 (m, 3 H). ^¹³C NMR (50 MHz, CDCl₃):
δ = 22.7, 29.3, 29.7, 37.1, 43.0, 45.9, 46.7, 55.9, 90.8, 106.8, 111.4, 116.8, 120.6, 134.2, 138.2, 145.2, 146.2. HRMS (EI): m/z [M]⁺ calcd for C₁₇H₂₁NO₂: 271.1572; found: 271.1569.