Scope and Limitations of Samarium Diiodide Induced Cyclizations of Alkenyl-Substituted γ-Keto Esters to Benzannulated Cyclooctanol Derivatives

Abstract

A series of γ-keto esters bearing various alkenyl substituents were synthesized and subjected to samarium diiodide mediated 8-endo-trig ketyl-alkene coupling reactions. Highly substituted benzannulated cyclooctanol derivatives were obtained in good yields and with moderate to excellent stereoselectivities. The obtained results demonstrate the influence of steric and electronic factors on the regio- and stereoselectivity of ketyl-alkene cyclizations. Stilbenyl-substituted derivatives can cyclize either to cyclooctanol or to cycloheptanol derivatives depending on the substitution pattern at the carbonyl group.

Key words

samarium diiodide - ketyl - cyclizations - radical reactions - medium-sized rings - cyclooctanols - cycloheptanols

References and Notes

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9

Typical Procedure for SmI ₂ -Induced Cyclizations - Conversion of 5 into 14 and 15
Samarium metal (278 mg, 1.85 mmol) and 1,2-diiodoethane (477 mg, 1.69 mmol) were placed under a flow of argon in a flame-dried, two-necked round-bottomed flask containing a magnetic stirring bar and a septum inlet. THF (20 mL) was added, and the mixture was vigorously stirred at r.t. for 2 h. HMPA (2.40 mL, 13.8 mmol) was added to this solution of SmI₂, and after 10 min of stirring a solution of substrate 5 (200 mg, 0.77 mmol) and t-BuOH (146 µL, 1.54 mmol) in THF (31 mL) was added over 2 h. The mixture was stirred at r.t. for 16 h and quenched with sat. aq NaHCO₃ solution (20 mL). The phases were separated and the aqueous layer was extracted with Et₂O (3 × 25 mL). The combined organic layers were washed with H₂O (10 mL) and brine (10 mL) and dried (Na₂SO₄). The products were purified by column chromatography (silica gel, hexane-EtOAc = 10:1) to furnish 80 mg (40%) 14 as colorless oil and 67 mg (38%) 15 as colorless crystals (mp 130-132 ˚C).
Analytical Data for Methyl (6 RS ,8 RS ,10 RS )-8-Hydroxy-8,10-dimethyl-5,6,7,8,9,10-hexahydrobenzo[8]-annulene-6-carboxylate (14)
Compound 14 shows temperature-dependent NMR spectra. At r.t. some signals appear broad, measurement at 55 ˚C allowed to see the signals more clearly. ^¹H NMR (500 MHz, CDCl₃, 55 ˚C): δ = 1.20 (s, 3 H, 8-Me), 1.33 (dd, J = 11.5, 14.7 Hz, 1 H, 7-H), 1.33 (d, J = 7.1 Hz, 3 H, 10-Me), 1.62 (dd, J = 11.4, 14.3 Hz, 1 H, 9-H), 1.67 (dd, J = 3.8, 14.7 Hz, 1 H, 7-H), 1.79-1.83 (m, 1 H, 9-H), 3.10 (dddd, J = 2.9, 3.8, 7.5, 11.5 Hz, 1 H, 6-H), 3.16 (dd, J = 2.9, 13.9 Hz, 1 H, 5-H), 3.36-3.43 (m, 1 H, 10-H), 3.43 (dd, J = 7.5, 13.9 Hz, 1 H, 5-H), 3.68 (s, 3 H, CO₂Me), 6.97-6.99, 7.06-7.10, 7.17-7.25 (3 m, 1 H, 1 H, 2 H, Ar) ppm. The signal for the OH group could not be assigned unambiguously. ^¹³C NMR (125 MHz, CDCl₃, 55 ˚C): δ = 23.2 (q, 10-Me), 30.2 (d, C-10), 32.3 (t, C-5), 36.0 (q, 8-Me), 36.5 (t, C-7), 42.2 (d, C-6), 55.1 (t, C-9), 71.5 (s, C-8), 125.1, 125.9, 127.1, 129.6, 136.5, 146.3 (4 d, 2 s, Ar), 51.7, 176.1 (q, s, CO₂Me) ppm. IR (neat): ν = 3500 (br, OH), 3100-2840 (=CH, CH), 1715 (C=O) cm^-¹. ESI-TOF: m/z calcd for: 217.1255 [M + H]⁺, 239.1074 [M + Na]⁺, 255.0813 [M + K]⁺; found: 217.1267, 239.1095, 255.0844.
Analytical Data for (2 RS ,5 SR ,7 SR )-5,7-Dimethyl-1,5,6,7-tetrahydro-2,5-methano-4-benzoxonin-3 (2 H )-one (15)
^¹H NMR (500 MHz, CDCl₃): δ = 1.34 (d, J = 6.9 Hz, 3 H, 7-Me), 1.36 (s, 3 H, 5-Me), 1.43 (dd, J = 1.1, 13.9 Hz,1 H, 12-H), 1.55 (dd, J = 11.3, 14.6 Hz, 1 H, 6-H), 1.74-1.79 (m, 1 H, 12-H), 2.05-2.09 (m, 1 H, 6-H), 2.76 (dqd, J = 1.3, 6.9, 11.3 Hz, 1 H, 7-H), 3.15 (dddd, J = 1.1, 2.5, 10.3, 12.8 Hz, 1 H, 2-H), 3.20 (dd, J = 12.8, 14.5 Hz, 1 H, 1-H), 3.31 (dd, J = 2.5, 14.5 Hz, 1 H, 1-H), 7.00-7.02, 7.15-7.18, 7.28-7.36 (3 m, 1 H, 1 H, 2 H, Ar) ppm. ^¹³C NMR (125 MHz, CDCl₃): δ = 22.5 (q, 7-Me), 29.6 (q, 5-Me), 30.0 (d, C-7), 34.2 (t, C-12), 34.5 (t, C-1), 39.3 (d, C-2), 51.4 (t, C-6), 86.3 (s, C-5), 125.4, 126.7, 127.9, 130.4, 136.8, 146.2 (4 d, 2 s, Ar), 181.5 (s, C-3) ppm. IR (KBr): ν = 3065-2825 (=CH, CH), 1755 (C=O) cm^-¹. Anal. Calcd for C₁₅H₁₈O₂ (230.3): C, 78.23; H, 7.88. Found: C, 78.49; H, 7.93.

10

In cis products the lactone bridge is formed under the reaction conditions due to the proximity of the hydroxy and methoxycarbonyl groups.

11

The relative configurations of the 18b and 28 were unambiguously determined by the X-ray crystallography (Brüdgam, I.; Lentz, D. unpublished results, Freie Universität Berlin). For all other cyclization products the suggested relative configuratations are strongly supported by NOESY correlations.