Gold(III)-Catalyzed Enynamine–Cyclopentadiene

The chirality transfer occurs through a helical-shaped transition state with allenic ...... acetate as eluent (20:1) afforded 213 mg (0.550 mmol, 82%)...
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Gold(III)-Catalyzed Enynamine−Cyclopentadiene Cycloisomerization with Chirality Transfer: An Experimental and Theoretical Study Indicating Involvement of Dual Au(III) Push−Pull Assisted cis−trans Isomerism Tom Wirtanen,‡ Mikko Muuronen,‡ Michele Melchionna, Michael Patzschke,* and Juho Helaja* Department of Chemistry, University of Helsinki, A.I. Virtasen aukio 1, P.O. Box 55, Helsinki, Finland S Supporting Information *

ABSTRACT: A synthetic approach for asymmetric ring-fused cyclopentadienes (Cps) with a chiral carbon at the ring junction has been established from chiral enynamines by achiral Au(III) catalysis. On the basis of experimental and theoretical data, the proposed mechanistic pathway from enynamines to Cps occurs via a Au(III) ene cis−trans isomerization step. Computational studies at DFT and NEVPT2 levels advocate that the cis−trans isomerization step proceeds via a dual Au(III) push−pull assisted intermediate with a low computed rotation barrier. The chirality transfer occurs through a helical-shaped transition state with allenic character. The scope of the catalysis encompasses sterically bulky enynamines including terpene natural products.

1. INTRODUCTION Cyclopentadienes (Cps) are key synthetic intermediates, widely used in organic and organometallic chemistry. Most notably, they are the direct ligand precursors in the assembly of metallocenes, a very important and well-known class of metal complexes, extensively employed as homogeneous catalysts in many single- or multistep chemical processes. In addition to simpler symmetrical metallocenes, access to more sophisticated asymmetric derivatives is often achieved by endowing the cyclopentadiene ligand precursors with a chiral center.1 Significantly, there are several natural products possessing cyclopentadiene moieties, which can be foreseen as a functional Cp ligand in metallocene assembly.2−4 Another prominent area of application of Cps is in the construction of complex natural and related biologically active products, where Cps can offer a phase selective platform for intermolecular Diels−Alder cycloadditions; once again, enantiopurity of the chiral Cp moiety represents an extraordinary advantage in terms of stereocontrol over the resulting chiral product.2,5−8 Despite their relevance and multipurpose roles, there are very few direct accesses to chiral Cps from acyclic substrates,9−12 with most synthetic protocols still relying on multistep postmodification of cyclic derivatives.5,6,13−16 Homogeneous Au(I) and Au(III) catalysis has been shown to be a powerful tool in various asymmetric cycloisomerization reactions, where alkyne or allene groups may be activated for internal nucleophilic addition by, e.g., alkenes or heteroatoms.17−22 For instance, related compounds to Cps, cyclopentenones, have been enantioselectively cycloisomerized from © 2014 American Chemical Society

1-ethynyl-2-propenyl pivalates by cationic Au(I) catalysis, where the asymmetry from the pivalate moiety is transferred to the carbon at the β-ketoposition.23 On the other hand, in the pioneering Au(I)-catalyzed cyclopentadiene synthesis reported by Toste and Lee, chiral enallene led to a racemic mixture of product.24 Remarkably, a fresh report by Sanz and co-workers describes the synthesis of asymmetric β-alkoxy-Cps for many substrates with good yields and with high to excellent e.r. by use of cationic Au(I) catalysts bearing chiral biphosphine ligands.11 In our previous work, we documented a Au(III) saltcatalyzed synthetic route from enynamines to Cps through a Au(III)metallacycle intermediate, whose existence was also confirmed by single-crystal X-ray diffraction.25 In the present work, after optimizing the reaction conditions and improving yields to synthetically significant levels, we have established the center-to-center chirality transfer and studied the scope and mechanism of the reaction. A combination of extensive experimental work and thorough theoretical study allowed us to confidently reveal the features of the key cis−trans isomerization step.

2. RESULTS AND DISCUSSION Synthetic Scope. We began our study by screening different reaction conditions for the cyclopentadiene (2a) synthesis from chiral enynamines (1a), which were prepared from alkenyltriflates (3) and propargylic amines (4) (Scheme Received: August 18, 2014 Published: October 13, 2014 10269

dx.doi.org/10.1021/jo501905q | J. Org. Chem. 2014, 79, 10269−10283

The Journal of Organic Chemistry

Article

Scheme 1. Synthesis of Enynamines and Cyclopentadienes

Table 1. Screening of Reaction Conditions

a

entry

solvent

catalyst (mol %)

R

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19

MeCN MeCN MeCN TCE TCE DCE DCE DCE AcOH PhMe TCE TCE TCE TCE TCE TCE TCE TCE TCE

KAuCl4 (10) KAuCl4 (10) KAuCl4 (10) KAuCl4 (10 KAuCl4 (10 KAuCl4 (10) KAuCl4 (5) KAuCl4 (10) KAuCl4 (10) KAuCl4 (10) KAuCl4 (10) HAuCl4 (5) HAuCl4 (10) HAuCl4 (15) HAuCl4 (10) KAuCl4 (10) KAuCl4 (10) KAuCl4 (10) HAuCl4 (10)

H NO2 NMe2 NO2 NMe2 H H H H H H H H H H H H H H

conditions (equiv)

AcOH (10)

dg dg 0.01 M, dg 0.1 M, dg dg, r.t.

time (h)

yield (%)

16 16 16 18 18 16 20 20 18 20 18 18 18 18 16 18 18 18 18

15 11a 99%) of the desired product. 1H NMR (300 MHz, CDCl3) δ 6.95 (d, J = 8.4 Hz, 1H), 6.60 (dd, J = 8.4, 2.7 Hz, 1H), 6.38 (d, J = 2.7 Hz, 1H), 3.96 (s, 2H), 3.10 (t, J = 6.0 Hz, 2H), 2.88 (s, 6H), 2.68 (t, J = 6.0 Hz, 2H), 2.22 (s, 1H). 13 C NMR (75 MHz, CDCl3) δ 149.2, 136.3, 129.9, 123.1, 111.8, 110.3, 48.7, 44.3, 41.0, 28.2. IR (cm−1, neat): 2924, 2798, 1676, 1513, 1345, 801. HRMS (EI+) calcd for [C11H16N2]+ m/z 176.1313, found: 176.1310. Computational Methods. All computations at the DFT level were performed using the Turbomole 6.4 program package.57 Solvation effects were taken into account using the COSMO solvation model in all DFT computations with a dielectric constant of 1,1,2,2tetrachloroethane (ε = 8.42) unless otherwise noted.58 The TPSSD337,38 functional was chosen with the triple ζ quality basis set, def2TZVP.39 Grid m4 was used in all computations. The MARI-J approximation was used in all computations with a suitable auxiliary basis set.59−62 The scalar relativistic effects for gold were taken into account using the def2-ecp from the Stuttgart group.63 Vibrational frequencies were calculated numerically for all complexes to obtain the chemical potential at 298.15 K (chem. pot.) and to confirm the nature of the stationary point (minima or TS). The Gibbs free energies were then calculated: G = E(0) + chem. pot. All multireference calculations (CASSCF and NEVPT2) were performed using the ORCA 2.9.1 program package.64 The enantioselectivity determining cyclization step was also computed using various different DFT methods, namely, PBE-D3,65 PBE0-D3,65,66 TPSSh-D3,37,67 B3LYP-D3,68−70 and a double-hybrid functional B2PLYP-D3.71 The D3 empirical dispersion corrections were used with zero damping. Pictures were generated with CYLview,72 Gabedit,73 and VMD.74 Density differences were calculated using DGrid.75

anhydrous methanol under an argon atmosphere, and the mixture was stirred for 1 h at 60 °C. The temperature was lowered to 0−5 °C (ice bath), and a solution of 7-nitro-1,2,3,4-tetrahydroisoquinoline (61 mg, 0.34 mmol), DIPEA (88 mg, 0.68 mmol), and 1-phenylprop-2-yn-1-yl acetate (30 mg, 0.17 mmol) in 3 mL of anhydrous methanol was added to the mixture. The mixture was stirred overnight, after which the solution was filtered and washed with MeOH. The filtrate was removed under reduced pressure. Purification of the crude by column chromatography (SiO2) using n-hexane and ethyl acetate as eluent (10:1) afforded 37 mg (0.126 mmol, 74%) of the desired product. 1H NMR (300 MHz, CDCl3) δ 7.95 (dd, J = 8.4, 2.4 Hz, 1H), 7.87 (d, J = 2.2 Hz, 1H), 7.66−7.60 (m, 2H), 7.42−7.30 (m, 3H), 7.22 (d, J = 8.4 Hz, 1H), 4.88 (d, J = 2.2 Hz, 1H), 3.82 3.78 (ABq, J = 15.4 Hz, 2H), 3.06−2.77 (m, 4H), 2.61 (d, J = 2.3 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 146.2, 142.6, 137.2, 136.9, 129.7, 128.5, 128.4, 128.2, 122.0, 121.1, 78.7, 77.2, 76.6, 60.8, 51.7, 46.5, 30.0. IR (cm−1, neat): 3290, 1592, 1346, 1101, 752, 697. HRMS (EI+) calcd for [C18H16N2O2]+ m/ z 292.1212, found: 292.1211. (R)-2-(3-(6,6-Dimethylcyclohex-1-en-1-yl)-1-phenylprop-2-yn-1yl)-7-nitro-1,2,3,4-tetrahydroisoquinoline (1l). (PPh3)PdCl2 (5.3 mg, 0.0075 mmol) and CuI (3,2 mg, 0.017 mmol) were dissolved in 6 mL of degassed THF:DEA (1:1). After 5 min, 6,6-dimethylcyclohex-1-en1-yl trifluoromethanesulfonate (78 mg, 0.275 mmol) in 3 mL of THF was added to the mixture, followed by (after 5 min stirring) 4e (61 mg, 0.25 mmol) dissolved in 3 mL of THF. After stirring overnight at 40 °C, the solvent was evaporated. Purification of the crude by column chromatography (SiO2) using n-hexane and ethyl acetate as eluent (20:1) afforded 64 mg (0.16 mmol, 64%) of the desired product. 1H NMR (300 MHz, CDCl3) δ 7.95 (dd, J = 8.4, 2.4 Hz, 1H), 7.88 (d, J = 2.2 Hz, 1H), 7.74−7.55 (m, 2H), 7.42−7.27 (m, 3H), 7.23 (d, J = 8.4 Hz, 1H), 6.12 (t, J = 4.1 Hz, 1H), 5.02 (s, 1H), 3.85 3.80 (ABq, J = 15.4 Hz, 2H), 3.06−2.75 (m, 4H), 2.18−2.00 (m, 2H), 1.73−1.42 (m, 4H), 1.17 (s, 6H). 13C NMR (126 MHz, CDCl3) δ 146.1, 142.7, 138.4, 137.2, 134.9, 130.0, 129.7, 128.5, 128.4, 127.9, 122.1, 121.1, 89.0, 82.9, 61.5, 52.0, 46.8, 37.7, 33.8, 30.1, 29.06, 29.05, 26.3, 19.0. IR (cm−1, neat): 2959, 2928, 2851, 1523, 1346, 1100, 750, 712, 696. HRMS (EI+) calcd for [C26H28N2O2]+ m/z 400.2151, found: 400.2154. (S)-N,N-Dimethyl-2-(1-phenylprop-2-yn-1-yl)-1,2,3,4-tetrahydroisoquinolin-7-amine (4f). Cu(OTf)·(benzene)0.5 (6.9 mg, 0.0275 mmol) and R-(+)-Cl-MeO-BIPHEP (35.8 mg, 0.055 mmol) were dissolved in 5 mL of anhydrous methanol under an argon atmosphere and stirred for 1 h at 60 °C. The temperature was lowered to 0−5 °C (ice bath), and a solution of 7-dimethylamino-1,2,3,4-tetrahydroisoquinoline (98 mg, 0.55 mmol), DIPEA (284 mg, 2.22 mmol), and 1-phenylprop-2-yn-1-yl acetate (96 mg, 0.55 mmol) in 5 mL of anhydrous methanol was added to the mixture. The mixture was stirred overnight, after which the solution was filtered and washed with MeOH. The filtrate was removed under reduced pressure. Purification of the crude by column chromatography (SiO2) using n-hexane and ethyl acetate as eluent (20:1) afforded 84.7 mg (0.292 mmol, 53%) of the desired product. 1H NMR (300 MHz, CDCl3) δ 7.74−7.66 (m, 2H), 7.44−7.29 (m, 3H), 7.00 (d, J = 8.4 Hz, 1H), 6.63 (dd, J = 8.4, 2.7 Hz, 1H), 6.41 (d, J = 2.5 Hz, 1H), 4.87 (d, J = 2.0 Hz, 1H), 3.76 3.73 (ABq, J = 14.7 Hz, 2H), 2.89 (s, 6H), 2.83 (d, J = 5.8 Hz, 4H), 2.61−2.58 (m, 1H). 13C NMR (75 MHz, CDCl3) δ 149.2, 138.1, 135.7, 129.3, 128.4, 128.3, 127.8, 123.0, 112.0, 111.0, 79.5, 76.1, 61.1, 52.4, 47.8, 41.1, 28.8. IR (cm−1, neat): 3285, 2912, 2798, 1616, 1514, 1339, 1088, 721, 698, 649. HRMS (EI+) calcd for [C20H22N2]+ m/z 290.1783, found: 290.1780. (R)-2-(3-(6,6-Dimethylcyclohex-1-en-1-yl)-1-phenylprop-2-yn-1yl)-N,N-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-amine (1m). (PPh3)PdCl2 (10 mg, 0.00145 mmol) and CuI (3.2 mg, 0.017 mmol) were dissolved in 10 mL of degassed THF:DEA (1:1). After 5 min, 6,6-dimethylcyclohex-1-en-1-yl trifluoromethanesulfonate (83 mg, 0.29 mmol) in 5 mL of THF was added to the mixture, followed by (after 5 min stirring) 4f (75 mg, 0.25 mmol) dissolved in 5 mL of THF. After stirring overnight at 40 °C, the solvent was evaporated. Purification of the crude by column chromatography (SiO2) using nhexane and ethyl acetate as eluent (10:1) afforded 86 mg (0.215 10281

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ASSOCIATED CONTENT

S Supporting Information *

NMR spectra, HPLC chromatograms, computational data, and xyz parameters. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: juho.helaja@helsinki.fi (J.H.). *E-mail: [email protected].fi (M.P.). Author Contributions ‡

These authors contributed equally.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the Academy of Finland [J.H. No. 258348]. T.W. is grateful to Finnish Cultural and Magnus Ehrnrooth Foundations for funding. M.M. expresses gratitude to the Emil Aaltonen foundation for funding. M.P. wishes to acknowledge support by the Academy of Finland through its Computational Science Research Programme (LASTU/ 258258).

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