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. 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 Phillips  1 , Tehetena Mesganaw  1 , Ashay Patel  2 , Simon Duttwyler  1 , Brandon Q Mercado  1 , Kendall N Houk  3 , Jonathan A Ellman  4
Affiliations

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

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

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
Figure 1
ωB97x-D/6-31+G(d,p)-optimized transition structures and their relative free energies (in kcal mol−1).
Figure 2
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
Scheme 1
ent-Ketorfanol retrosynthesis.
Scheme 2
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
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
Scheme 4
Intramolecular Friedel–Crafts alkylation with concomitant redox neutral diol to ketone interconversion.
Scheme 5
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
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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