Synthesis of ent-ketorfanol via a C-H alkenylation/torquoselective 6π electrocyclization cascade

doi:10.1002/anie.201505604

. 2015 Oct 5;54(41):12044-8.

doi: 10.1002/anie.201505604. Epub 2015 Aug 17.

Synthesis of ent-ketorfanol via a C-H alkenylation/torquoselective 6π electrocyclization cascade

Eric M Phillips¹, Tehetena Mesganaw¹, Ashay Patel², Simon Duttwyler¹, Brandon Q Mercado¹, Kendall N Houk³, Jonathan A Ellman⁴

Affiliations

¹ Department of Chemistry, Yale University, 225 Prospect St., New Haven, CT 06520 (USA).
² Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA 90095-1569 (USA).
³ Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA 90095-1569 (USA). houk@chem.ucla.edu.
⁴ Department of Chemistry, Yale University, 225 Prospect St., New Haven, CT 06520 (USA). jonathan.ellman@yale.edu.

PMID: 26385263
PMCID: PMC4676713
DOI: 10.1002/anie.201505604

Synthesis of ent-ketorfanol via a C-H alkenylation/torquoselective 6π electrocyclization cascade

Eric M Phillips et al. Angew Chem Int Ed Engl. 2015.

. 2015 Oct 5;54(41):12044-8.

doi: 10.1002/anie.201505604. Epub 2015 Aug 17.

Authors

Eric M Phillips¹, Tehetena Mesganaw¹, Ashay Patel², Simon Duttwyler¹, Brandon Q Mercado¹, Kendall N Houk³, Jonathan A Ellman⁴

Affiliations

¹ Department of Chemistry, Yale University, 225 Prospect St., New Haven, CT 06520 (USA).
² Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA 90095-1569 (USA).
³ Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA 90095-1569 (USA). houk@chem.ucla.edu.
⁴ Department of Chemistry, Yale University, 225 Prospect St., New Haven, CT 06520 (USA). jonathan.ellman@yale.edu.

PMID: 26385263
PMCID: PMC4676713
DOI: 10.1002/anie.201505604

Abstract

The asymmetric synthesis of ent-ketorfanol from simple and commercially available precursors is reported. A Rh(I) -catalyzed intramolecular CH alkenylation/torquoselective 6π electrocyclization cascade provides a fused bicyclic 1,2-dihydropyridine as a key intermediate. Computational studies were performed to understand the high torquoselectivity of the key 6π electrocyclization. The computational results demonstrate that a conformational effect is responsible for the observed selectivity. The ketone functionality and final ring are introduced in a single step by a redox-neutral acid-catalyzed rearrangement of a vicinal diol to give the requisite carbonyl, followed by intramolecular Friedel-Crafts alkylation.

Keywords: CH activation; alkaloids; asymmetric synthesis; heterocycles; torquoselectivity.

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Figures

**Figure 1**
ωB97x-D/6-31+G(d,p)-optimized transition structures and their relative free energies (in kcal mol⁻¹).

**Figure 2**
Free energy diagram of the electrocyclization of 1-aza-3,5-triene E and the computed structures of the reactant conformers of E. Free energies (in kcal mol⁻¹) and structures were determined using ωB97x-D/6-31+G(d,p).

**Scheme 1**
*ent*-Ketorfanol retrosynthesis.

**Scheme 2**
Synthesis of imine 15. *Reagents and conditions*: (a) (COCl)₂, DMSO, Et₃N, CH₂Cl₂, −78 °C; (b) nBuLi, iPr₂NH, *(E)*-ethyl-4-(diethoxyphosphoryl)but-2-enoate, −78 → 0 °C; (c) AD-mix-α, MeSO₂NH₂, tBuOH, H₂O, 0 °C; (d) 2,2-dimethoxypropane, pTsOH (10 mol %), CH₂Cl₂, 0 °C; (e) 3-TBSOPhCH₂Cl, PdCl₂(CH₃CN)₂ (5 mol %), XPhos (15 mol %), Cs₂CO₃, THF, 65 °C; (f) DIBAL, CH₂Cl₂, −78 °C; (g) Dess–Martin periodinane, pyridine, CH₂Cl₂, 0 °C; (h) cyclopropylmethyl amine, toluene, 3Å MS.

**Scheme 3**
Rh(I)-catalyzed C–H insertion reaction. *Reagents and conditions:* (a) [RhCl(coe)₂]₂ (2.5 mol %), 4-(diethylphosphino)-N,N-dimethylaniline (5 mol %), toluene, 65 °C; (b) NaHB(OAc)₃, AcOH, EtOH, 0 → 23 °C.

**Scheme 4**
Intramolecular Friedel–Crafts alkylation with concomitant redox neutral diol to ketone interconversion.

**Scheme 5**
Synthesis of imine 24. *Reagents and conditions:* (a) PdCl₂(CH₃CN)₂ (5 mol %), XPhos (15 mol %), Cs₂CO₃, THF, 65 °C; (b) DIBAL, THF, −78 °C; (c) Dess–Martin periodinane, pyridine, CH₂Cl₂, 0 °C; (d) cyclopropylmethyl amine, toluene, 3Å MS.

**Scheme 6**
Synthesis of *ent*-ketorfanol (1). *Reagents and conditions:* (a) [RhCl(coe)₂]₂ (5 mol %), 4-(diethylphosphino)-N,N-dimethylaniline (10 mol %), toluene, 55 °C; (b) NaHB(OAc)₃, AcOH, EtOH, 0 → 23 °C; (c) 85% phosphoric acid, 125 °C; (d) H₂, Pd/C, NaHCO₃, EtOH.

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References

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8. Mesganaw T, Ellman JA. Org Process Res Dev. 2014;18:1105–1109. - PMC - PubMed

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[1] Typing the name of these drug and drug candidates into the NCGC Pharmaceutical Collection database provides compound structure, bioactivity, full list of literature, and access to ongoing clinical trials, applications, and usage.

[2] Typing the name of these drug and drug candidates into the NCGC Pharmaceutical Collection database provides compound structure, bioactivity, full list of literature, and access to ongoing clinical trials, applications, and usage.

[3] Filizola M, Devi LA. Nature. 2012;485:314–317. - PMC - PubMed

Manglik A, Kruse AC, Kobilka TS, Thian FS, Mathiesen JM, Sunahara RK, Pardo L, Weis WI, Kobilka BK, Granier S. Nature. 2012;485:321–326. - PMC - PubMed

Wu HX, Wacker D, Mileni M, Katritch V, Han GW, Vardy E, Liu W, Thompson AA, Huang XP, Carroll FI, Mascarella SW, Westkaemper RB, Mosier PD, Roth BL, Cherezov V, Stevens RC. Nature. 2012;485:327–332. - PMC - PubMed

Granier S, Manglik A, Kruse AC, Kobilka TS, Thian FS, Weis WI, Kobilka BK. Nature. 2012;485:400–404. - PMC - PubMed

[4] Filizola M, Devi LA. Nature. 2012;485:314–317. - PMC - PubMed

[5] Manglik A, Kruse AC, Kobilka TS, Thian FS, Mathiesen JM, Sunahara RK, Pardo L, Weis WI, Kobilka BK, Granier S. Nature. 2012;485:321–326. - PMC - PubMed

[6] Wu HX, Wacker D, Mileni M, Katritch V, Han GW, Vardy E, Liu W, Thompson AA, Huang XP, Carroll FI, Mascarella SW, Westkaemper RB, Mosier PD, Roth BL, Cherezov V, Stevens RC. Nature. 2012;485:327–332. - PMC - PubMed

[7] Granier S, Manglik A, Kruse AC, Kobilka TS, Thian FS, Weis WI, Kobilka BK. Nature. 2012;485:400–404. - PMC - PubMed

[8] For the synthesis of ketorfanol from the degradation of heavily functionalized natural product starting materials, see: Manmade A, Dalzell HC, Howes JF, Razdan RK. J Med Chem. 1981;24:1437–1440.Ida Y, Nemoto T, Hirayama S, Fujii H, Osa Y, Imai M, Nakamura T, Kanemasa T, Kato A, Nagase H. Bioorg Med Chem. 2012;20:949–961.

[9] For the synthesis of ketorfanol from the degradation of heavily functionalized natural product starting materials, see: Manmade A, Dalzell HC, Howes JF, Razdan RK. J Med Chem. 1981;24:1437–1440.Ida Y, Nemoto T, Hirayama S, Fujii H, Osa Y, Imai M, Nakamura T, Kanemasa T, Kato A, Nagase H. Bioorg Med Chem. 2012;20:949–961.

[10] For reviews and leading references on syntheses of morphine and related natural products, see: Reed JW, Hudlicky T. Acc Chem Res. 2015;48:674–687.Rinner U, Hudlicky T. Top Curr Chem. 2012;300:33–66.Chida N. Top Curr Chem. 2011;299:1–28.Tissot M, Phipps RJ, Lucas C, Leon RM, Pace RDM, Ngouansavanh T, Gaunt MJ. Angew Chem Int Ed. 2014;53:13498–13501.Angew Chem. 2014;126:13716–13719.Ichiki M, Tanimoto H, Miwa S, Saito R, Sato T, Chida N. Chem Eur J. 2013;19:264–269.Li J, Liu GL, Zhao XH, Du JY, Qu H, Chu WD, Ding M, Jin CY, Wei MX, Fan CA. Chem Asian J. 2013;8:1105–1109.Varghese V, Hudlicky T. Angew Chem Int Ed. 2014;53:4355–4358.Angew Chem. 2014;126:4444–4447.Kimishima A, Umihara H, Mizoguchi A, Yokoshima S, Fukuyama T. Org Lett. 2014;16:6244–6247.

[11] For reviews and leading references on syntheses of morphine and related natural products, see: Reed JW, Hudlicky T. Acc Chem Res. 2015;48:674–687.Rinner U, Hudlicky T. Top Curr Chem. 2012;300:33–66.Chida N. Top Curr Chem. 2011;299:1–28.Tissot M, Phipps RJ, Lucas C, Leon RM, Pace RDM, Ngouansavanh T, Gaunt MJ. Angew Chem Int Ed. 2014;53:13498–13501.Angew Chem. 2014;126:13716–13719.Ichiki M, Tanimoto H, Miwa S, Saito R, Sato T, Chida N. Chem Eur J. 2013;19:264–269.Li J, Liu GL, Zhao XH, Du JY, Qu H, Chu WD, Ding M, Jin CY, Wei MX, Fan CA. Chem Asian J. 2013;8:1105–1109.Varghese V, Hudlicky T. Angew Chem Int Ed. 2014;53:4355–4358.Angew Chem. 2014;126:4444–4447.Kimishima A, Umihara H, Mizoguchi A, Yokoshima S, Fukuyama T. Org Lett. 2014;16:6244–6247.

[12] Colby DA, Bergman RG, Ellman JA. J Am Chem Soc. 2008;130:3645–3651. - PMC - PubMed

Duttwyler S, Lu C, Rheingold AL, Bergman RG, Ellman JA. J Am Chem Soc. 2012;134:4064–4067. - PMC - PubMed

Duttwyler S, Chen S, Takase MK, Wiberg KB, Bergman RG, Ellman JA. Science. 2013;339:678–682. - PMC - PubMed

Ischay MA, Takase MK, Bergman RG, Ellman JA. J Am Chem Soc. 2013;135:2478–2481. - PMC - PubMed

Duttwyler S, Chen S, Lu C, Mercado BQ, Bergman RG, Ellman JA. Angew Chem Int Ed. 2014;53:3877–3880. - PMC - PubMed

Angew Chem. 2014;126:3958–3961.

Mesganaw T, Ellman JA. Org Process Res Dev. 2014;18:1097–1104. - PMC - PubMed

Mesganaw T, Ellman JA. Org Process Res Dev. 2014;18:1105–1109. - PMC - PubMed

[13] Colby DA, Bergman RG, Ellman JA. J Am Chem Soc. 2008;130:3645–3651. - PMC - PubMed

[14] Duttwyler S, Lu C, Rheingold AL, Bergman RG, Ellman JA. J Am Chem Soc. 2012;134:4064–4067. - PMC - PubMed

[15] Duttwyler S, Chen S, Takase MK, Wiberg KB, Bergman RG, Ellman JA. Science. 2013;339:678–682. - PMC - PubMed

[16] Ischay MA, Takase MK, Bergman RG, Ellman JA. J Am Chem Soc. 2013;135:2478–2481. - PMC - PubMed

[17] Duttwyler S, Chen S, Lu C, Mercado BQ, Bergman RG, Ellman JA. Angew Chem Int Ed. 2014;53:3877–3880. - PMC - PubMed

[18] Angew Chem. 2014;126:3958–3961.

[19] Mesganaw T, Ellman JA. Org Process Res Dev. 2014;18:1097–1104. - PMC - PubMed

[20] Mesganaw T, Ellman JA. Org Process Res Dev. 2014;18:1105–1109. - PMC - PubMed

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Synthesis of ent-ketorfanol via a C-H alkenylation/torquoselective 6π electrocyclization cascade

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Synthesis of ent-ketorfanol via a C-H alkenylation/torquoselective 6π electrocyclization cascade

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