Enantioselective Conjugate Allylation of Cyclic Enones

Abstract

Enantioselective organocatalytic 1,2-allylation of a cyclic enone followed by anionic oxy-Cope rearrangement delivered the ketone as a mixture of diastereomers. This appears to be a general method for the net enantioselective conjugate allylation of cyclic enones.

Several procedures have been put forward in recent years¹ for enantioselective conjugate addition to prochiral cyclic enones. To date, however, there has been only one report^1b of enantioselective conjugate addition to an α-substituted cyclic enone such as 1a. It occurred to us that catalytic enantioselective 1,2-allylation² followed by oxy-Cope rearrangement³ could offer a solution^4,5 to this long-standing problem (Eq 1).

(1)

α-Iodo and α-alkyl⁶ cyclic enones (Table 1) are easily prepared.⁷ Of the several methods² that have been put forward for the catalytic enantioselective allylation of ketones, we were attracted to that of Schaus,^{2g, 8} that employed the easily-prepared allylboronate 2 as the allyl donor and the commercially-available 3, 3′-dibromobinol as the enantioselective catalyst.

Table 1.

Enantioselective Allylation of Cyclic Enones.

Enonea	Yieldb	Product	ee
1 1a	84%	3a	98% ee
2 1bc,d	46%	3b	97% ee
3 1c	92%	3c	93% ee
4 1d	95%	3d	92% ee
5 1e	89%	3e	85% ee

^aAdditions were carried out using 5 mol % (S)-3,3′-dibromobinol.

^bYields are for pure isolated substances.

^cAddition was effected using 5 mol % (R)-3,3′-dibromobinol.

^dBoth the starting material and the product were volatile.

We initiated our studies with the enone 1a^{6a, f} (Table 1). Following the updated Schaus protocol,⁸ stirring the enone with 2 in concentrated t-BuOH solution with a catalytic amount of (S)-3,3′-dibromo-1,1′-bi-2-naphthol at room temperature for 24 h, we found that the 1,2-addition proceeded smoothly. It was gratifying that 5 mol % of the organocatalyst was sufficient, and that > 90% of the catalyst could be recovered by extraction.

We found that this protocol worked equally well for 5, 6, and 7-membered rings, and with 2-alkyl and 2-iodo substitution. The enantiomeric excess for each of the 1, 2-allylations was established by chiral HPLC, except for 3b, the ee of which was secured by comparison of the optical rotation of the chromatographed and distilled product with that of the same substance prepared by methyl coupling of 3d.

For the oxy-Cope rearrangements (Table 2), we found it convenient to use KH in paraffin.⁹ With the alkyl enones, it was also necessary to include an equivalent of 18-crown-6.¹⁰ The oxy-Cope rearrangement of the aryl-substituted allylated alcohols (3dAr, 3cAr) proceeded efficiently without 18-crown-6, but the yields were slightly higher when it was included.

Table 2.

KH-Mediated oxy-Cope Rearrangement.

Alcohola	Productb	Yieldc
1 3a	4a	70%
2 3bd	4b	64%
3 3dAre	4c	89%
4 3cAlke	4d	80%
5 3cAre	4e	67%
6 3eMef	4f	52%

^aOxy-Cope rearrangement was carried out with dicyclohexyl-18-crown-6 and KH in THF.

^bProducts were a mixture of α-epimers.

^cYields are for pure isolated substances.

^dt-BuOK was used for the rearrangement.

^ePrepared by Stille coupling of the corresponding iodoalkene.

^fPrepared by Kumada coupling of the corresponding alkene.

Of the substances reported here, only 4b had previously been reported, in racemic form and without characterization.¹¹ We expect that the net catalytic enantioselective conjugate allylation of cyclic enones introduced here will have many applications in target-directed synthesis. The practicality of the Schaus organocatalytic allylation (room temperature in t-BuOH, 5 mol % catalyst, commercial and easily recoverable) is particularly noteworthy.

Experimental Section

General Procedures

¹H NMR and ¹³C NMR spectra were recorded, as solutions in deuteriochloroform (CDCl₃) unless otherwise indicated, at 400 MHz and 100 MHz, respectively. ¹³C multiplicities were determined with the aid of a JVERT pulse sequence, differentiating the signals for methyl and methine carbons as “d” from methylene and quaternary carbons as “u”. The infrared (IR) spectra were determined as neat oils. R_f values indicated refer to thin layer chromatography (TLC) on 2.5 × 10 cm, 250 μm analytical plates coated with silica gel GF and developed in the solvent system indicated. All glassware was oven dried and rinsed with dry solvent before use. THF was distilled from sodium metal/benzophenone ketyl under dry nitrogen. Toluene, dichloromethane and acetonitrile were distilled from calcium hydride under dry nitrogen. CH₂Cl₂ is dichloromethane, MTBE is methyl-tertbutyl ether and PE is petroleum ether. All reactions were conducted under N₂ and stirred magnetically. We prepared KH in paraffin, but it is now commercially available.

(R)-1-(2-Propenyl)-2-(3-phenoxymethoxypropyl)-2-cyclohexenol (3a)

To a dry 10 mL round bottom flask was charged (S)-(−)-3,3′-dibromo-1,1′-bi-2-naphthol (73 mg, 0.165 mmol), followed by t-butyl alcohol (362 mg, 8.23 mmol) and allyl borane 2 (778 mg, 6.17 mmol). This suspension was stirred until all of the BINOL was dissolved. To this clear solution was charged enone 1a (1.00 g, 4.12 mmol), and the reaction was stirred at room temperature overnight. The reaction was concentrated directly to silica and chromatographed to give 3a (938 mg, 84% yield, 98% ee) as a yellow oil; enantioselective HPLC (3% i-PrOH/Hexanes, Chiralpak IA 4.6 mm × 250 mm, UV detection at 254 nm, 0.08 mL/min) t_r= 6.74 (major) t_r= 4.68 (minor) TLC R_f = 0.24 (MTBE:PE, 20:80) [α]_D +23.3 (DCM, 20°C); IR (neat, cm⁻¹) 3439 (s), 2928 (s), 2850 (m), 1668 (m), 1633.8 (s), 1442.1 (s), 1363.5 (s) ¹H NMR (400 MHz, CDCl₃) δ ppm 1.5–2.5 (m, 13H), 3.5 (m, 2H), 4.5 (s, 2H), 5.1 (m, 1H), 5.2 (m, 1H), 5.8 (m, 1H), 7.3–7.4 (m, 5H) ¹³C NMR (400 MHz, CDCl₃) δ ppm u: 139.9, 138.0, 117.6, 77.0, 76.7, 76.3, 72.5, 71.4, 69.9, 43.5, 35.7, 28.4, 27.0, 25.3, 18.5; d: 133.9, 127.9, 127.3, 127.1, 124.9; HRMS calcd for C₁₉H₂₅O (M⁺ -OH) 269.1905, Found 269.1909.

(S)-1-(2-Propenyl)-2-methyl-2-cyclohexenol (3b)

Light yellow oil. [α]²⁰_D = −34.9° (c = 1.00, CH₂Cl₂); TLC: R_f (MTBE/PE, 1:4) = 0.46; ¹H-NMR δ 5.78 (m, 1H), 5.64 (m, 1H), 5.2 (m, 2H), 2.40 (dt, J = 7.2, 1.2 Hz, 2H), 1.98 (m, 2H), 1.77 (m, 1H), 1.76 (s, 3H), 1.64 (m, 4H); ¹³C-NMR δ u: 137.0, 118.2, 71.6, 43.6, 35.7, 25.6, 19.1; d: 134.1, 126.6, 17.8; IR: 1639, 1440, 1174, 973, 912 cm⁻¹; HRMS calcd for C₁₀H₁₅ (M – OH): 135.1174, obsd: 135.1173.

(R)-1-(2-Propenyl)-2-iodo-2-cyclopentenol (3c)

Yellow solid (mp 32–35 °C, 92% yield, 93% ee); TLC R_f = 0.29 (DCM:MTBE:PE 10:20:70); chiral HPLC (3% i-PrOH/Hexanes, Chirapak IA 4.6 mm × 250 mm, UV detection at 254 nm, 0.08 mL/min) t_r= 8.420 (major), t_r= 9.205 (minor): [α]_D +52.4 (DCM, 20 °C); IR (neat, cm⁻¹) 3400 (s), 3066 (m), 2918 (s), 2840 (m), 1638 (m), 1599 (m), 1427 (m), 1373 (m), 1309 (m) ¹H NMR (400 MHz, CDCl₃) δ ppm 1.9 (m, 2H), 2.2–2.6 (m, 5H), 5.1–5.2 (dd, 2H), 5.6–5.9 (m, 1H), 6.3 (s, 1H) ¹³C NMR (400 MHz, CDCl₃) δ ppm u: 119, 134.0, 106.5, 86.0, 123.5, 44.5, 33.0, 32.8 d: 142.1, 132.7; HRMS calcd for C₈H₁₀I (M⁺-OH) 232.9827, Found 232.9826.

(R)-1-(2-Propenyl)-2-iodo-2-cyclohexenol (3d)

Clear oil (95% yield, 92% ee); TLC R_f = 0.29 (MTBE:PE 20:80) [α]_D -34.9 (DCM, 20°C); chiral HPLC (2% i-PrOH/Hexanes, Chirapak IA 4.6 mm × 250 mm, UV detection at 254 nm, 0.08 mL/min) t_r= 17.34 (major), t_r= 16.80 (minor); IR (neat, cm⁻¹) 3436 (s), 3074 (m), 2937 (m), 1638 (m), 1435 (s); ¹H NMR (400 MHz, CDCl₃) d ppm 1.6–1.8 (m, 2H), 1.8–2.2 (m, 5H), 2.4–2.5 (d, 2H), 5.1–5.2 (m, 2H), 5.7–5.9 (m, 1H), 6.6 (m, 1H); ¹³C NMR (400 MHz, CDCl₃) d ppm u: 118.9, 111.7, 73.0, 47.1, 34.1, 29.6, 18.9; d: 141.9, 132.9; HRMS calcd for C₉H₁₂I (M⁺ -OH) 246.9992, Found 246.9984

(R)-1-(2-Propenyl)-2-iodo-2-cycloheptenol (3e)

Yellow oil (89% yield, 85% ee); TLC R_f = 0.50 (MTBE:PE, 20:80); [α]_D -46 (DCM, 20°C); chiral HPLC (0.1% i-PrOH/Hexanes, Chiracel OJH 4.6 mm × 250 mm, UV detection at 254 nm, 0.08 mL/min) t_r= 10.721 (major), t_r= 12.399 (minor); IR (neat, cm⁻¹) 3459 (b), 3076 (m), 2918 (s), 2859 (m), 1682 (m), 1643 (m), 1609 (m), 1442 (m), 1343 (m) ¹H NMR (400 MHz, CDCl₃) δ ppm 1.6–1.9,(m, 5H), 2.0–2.2 (m, 4H), 2.5 (m, 2H), 5.2(ds, 2H), 5.8–5.9 (m, 1H), 6.7 (t, 1H); ¹³C NMR (400 MHz, CDCl₃) δ ppm 141.5, 132.5, 118.6, 118.0, 77.7, 44.3, 33.0, 28.5, 24.7, 20.7; HRMS calcd for C₁₀H₁₄I (M⁺-OH) 261.0141, Found 261.0198.

(1S, 2S)- 2-(3-Phenoxymethoxypropyl)- 3-(2-propenyl)-cyclohexanone (4a)

To a 100 mL round bottom flask was charged 3a (1.07 g, 3.77 mmol), followed by 18-crown-6 (996 mg, 3.77 mmol) and 50 mL of THF. The reaction was sparged with N₂ for 10 minutes and KH(P) (452 mg 5.65 mmol) was added portion wise. The reaction was heated to reflux for 1 hour and then quenched with saturated aqueous ammonium chloride. The organic layer was partitioned between Et₂O and water. The organic layer was dried (anhydrous Na₂SO₄) and concentrated. The residue was chromatographed giving 4a (749 mg, 70% yield) as a yellow oil. TLC R_f = 0.20 (DCM:MTBE:PE, 10:20:70); [α]_D +18 (c = 0.02, CH₂CL₂, 20°C) IR (neat, cm⁻¹) 3029 (m), 2931 (s), 1709 (m), 1639 (m), 1495 (s), 1453 (s), 1360 (s); major diastereomer: ¹H NMR (400 MHz, CDCl₃) δ ppm 1.49 – 2.45 (m, 14H) 3.5 (t, 2 H) 4.5 (s, 2 H) 5.1 (m, 2 H) 5.8 (m, 1 H) 7.21 - 7.4 (m, 5H); ¹³C NMR (400 MHz, CDCl₃) δ ppm u: 213.3, 138.6, 117.0, 72.7, 70.3, 37.8, 28.7, 27.3, 26.2, 24.7, 24.1, 22.0 d: 135.7, 128.3, 127.5, 54.6, 41.9; HRMS calcd for C₁₉H₂₇O₂ (M+H) 287.2011, Found 287.2002.

(1R, 2R)- 2-Methyl-3-(2-propenyl)-cyclohexanone (4b)

To a 500 mL round bottom flask was charged toluene (140 mL), 18-crown-6 (6.48 g, 24.5 mmol) and potassium tert-butoxide (5.49 g, 49 mmol). Ketone 3b (5.33 g, 35 mmol) was charged in 30 mL of toluene. The reaction was heated to 84 °C for 1 hour and was then quenched with saturated aqueous NH₄Cl. The toluene/PE solution was then diluted with more PE and placed directly on a column for purification by silica gel chromatography to afford ketone 4b (2.162 g, 64% yield, mixture of trans/cis diastereomers) as a light yellow oil. [α]²⁰_D = +10.0° (c = 1.00, CH₂Cl_2, 2:1 mixture of trans:cis diastereomers); TLC: R_f (MTBE/PE, 1:4) = 0.67; ¹H-NMR δ 5.85-5.73 (m, 1H, trans diastereomer), 5.75-5.63 (m, 1H, cis diastereomer), 5.11-5.03 (m, 2H, trans diastereomer), 5.03-4.98 (m, 2H, cis diastereomer), 2.66-2.00 (m, 6H), 1.93-1.41 (m, 4H), 1.05 (d, J = 12.8 Hz, 3H, trans diastereomer), 1.02 (d, J = 12.8 Hz, 3H, cis diastereomer); ¹³C-NMR (trans diastereomer) δ u: 213.4, 117.1, 41.5, 38.2, 30.3, 25.7; d: 135.5, 49.4, 45.2, 11.9; (cis diastereomer) δ u: 214.5, 116.3, 39.8, 33.7, 26.7, 23.7; d: 136.5, 48.7, 41.9, 11.5; IR: 1711, 1640, 1447, 1221, 999, 914 cm⁻¹; HRMS calcd for C₁₀H₁₇O (M + H): 153.1279, obsd: 153.1283.

(1R, 2S)- 2-(2,3-Dimethoxyphenyl)- 3-(2-propenyl)-cyclohexanone (4c)

White solid, 89% yield, mp = 70–75 °C); TLC R_f = 0.5 (MTBE:PE 20:80); [α]²⁰_D – 64° (c = 0.2 CH₂Cl₂, 20° C); IR (neat, cm⁻¹) 2934 (s), 2931 (s), 1710 (s), 1584 (m), 1475 (s), 1267 (s), ¹H NMR (400 MHz, CDCl₃) δ ppm 1.5 (m, 2H) 1.8 (m, 2 H) 2.0–2.2 (m, 4 H) 2.4 (m, 1H) 2.6 (m, 1 H), 3.6 (d, 1H, J=9.2 Hz), 3.7 (s, 3H), 3.9 (s, 3H), 4.9 (m, 2H), 5.6–5.8 (m, 1H), 6.6 (d, 1H, J= 8.2 Hz) 6.8 (d, 1H, J= 8.2 Hz) 7.1 (t, 1H, J= 8.2 Hz) ¹³C NMR (400 MHz, CDCl₃) δ ppm u: 210.0, 152.6, 147.4, 131.6, 116.8, 41.8, 39.0, 30.6, 25.1 d: 135.8, 123.7, 121.7, 111.0, 60.4, 56.8, 55.6, 43.5; HRMS calcd for C₁₇H₂₃O₃ (M+H) 275.1647, Found 275.1659.

(1S, 2S)- 2-(3-Phenoxymethoxypropyl)- 3-(2-propenyl)-cyclopentanone (4d)

Yellow oil (52% yield); TLC R_f = 0.35 (MTBE:PE, 20:80). [α]²⁰_D -72° (c = 0.1 CH₂Cl₂, 20° C); IR (neat, cm⁻¹) 2909 (m), 2857 (s), 1735 (s), 1700 (s), 1638 (m), 1450 (m) ¹H NMR (400 MHz, CDCl₃) δ ppm 1.3–2.5 (m, 13H) 3.4–3.5 (m, 2H) 4.5 (m, 2H), 2.1 (m, 1H) 5.0–5.1 (m, 2H), 5.7–5.9 (m, 1H), 7.2–7.4 (m, 5H), ¹³C NMR (400 MHz, CDCl₃) δ ppm u: 220.2, 138.1, 116.2, 72.4, 69.9, 38.1, 37.2, 27.3, 26.5, 21.6 d: 137.5, 127.9, 126.5, 126.0, 52.1, 41.9; HRMS calcd for C₁₈H₂₅O₂ (M+H) 273.1854, Found 273.1850.

(1R, 2S)- 2-(2,3-Dimethoxyphenyl)- 3-(2-propenyl)-cyclopentanone (4e)

Yellow oil (67% yield); TLC R_f = 0.67 (MTBE:PE, 20:80);); [α]²⁰_D +38° (c = 0.1 CH₂Cl₂, 20° C) IR (neat, cm⁻¹) 3073 (m), 2939 (s), 2836 (s), 1740 (s), 1640 (m), 1584 (m), 1478 (s), 1268 (s); ¹H NMR (400 MHz, CDCl₃) δ ppm 1.4–1.6 (m, 1H) 2.0 (m, 1H) 2.2–2.4 (m, 2H) 2.4–2.5 (m, 2H) 3.0 (d, 1H, J=10.8 Hz), 3.7 (s, 3H), 3.9 (s, 3H), 5.0 (m, 2H), 5.7 (m, 1H), 6.6 (d, 1H, J= 8.2 Hz), 6.8–6.9 (d, 1H, J= 8.2 Hz), 7.0 (t, 1H, J= 8.2 Hz); ¹³C NMR (400 MHz, CDCl₃) δ ppm u: 218.4, 152.7, 146.9, 132.7, 116.6, 38.2, 38.0, 27.3 d: 135.7, 123.7, 122.8, 111.8, 59.8, 58.4, 55.7, 44.0; HRMS calcd for C₁₆H₂₀O₃ (M+) 260.1412, Found 260.1401.

(1S, 2S)- 2-Methyl-3-(2-propenyl)-cycloheptanone (4f)

Yellow oil (52% yield) as a mixture of diastereomers. TLC R_f = 0.30 (MTBE/PE, 5:95); [α]²⁰_D -45.0° (c = 0.03; CH₂Cl₂, 20° C); IR (neat, cm⁻¹) 3074 (m), 2927 (s), 2862 (s), 1700 (s), 1640 (m), 1451 (m), 1374 (m), ¹H NMR (400 MHz, CDCl₃) δ ppm 1.0–1.1 (d, 2H, J=8.2 Hz) 1.1–1.2 (d, 1H, J=8.2 Hz) 1.5–2.0 (m, 8H) 2.1 (m, 1H) 2.3–2.4 (m, 2H), 2.6 (m, 1H), 2.8–2.9 (m, 1H), 5.0 (m, 2H), 5.0–5.1 (m, 2H), 5.6–5.8 (m, 1H); major ¹³C NMR (400 MHz, CDCl₃) δ ppm u: 215.7, 116.2, 43.3, 34.5, 32.3, 25.9, 24.2 d: 137.2, 49.3, 40.1, 12.9; HRMS calcd for C₁₁H₁₉O (M+H) 167.1436, Found 167.1435.