A Convenient Transformation of 2-Alkylidenecycloalkanones into Alkyl-Substituted Bicyclo[n.1.0]alkan-1-ols: Application to the Synthesis of Capsaicin

Abstract

Treatment of 2-alkylidenecycloalkanones with hydrogen iodide in benzene and subsequent reaction of the obtained β-iodo ketones with zinc dust in THF in the presence of chlorotrimethyl­silane or titanium(IV) chlorotriisopropoxide led to exo- and endo-(n+3)-alkylbicyclo[n.1.0]alkan-1-ols in high yields. Cyclization of the intermediate β-iodo ketones under these conditions proceeded in a moderate to good diastereoselectivity, and the resulted bicyclic cyclopropanols were easily separated by column chromatography over silica gel. exo-7-Isopropylbicyclo[4.1.0]heptan-1-ol obtained in this manner was efficiently employed as a key intermediate in the synthesis of capsaicin.

cyclopropanols - stereoselectivity - ring closure - ring opening - capsaicin

References and Notes

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11

Compounds 3 could be stored in solution at r.t. for a few hours without noticeable decomposition.

12

General Procedure for the Preparation of (n+3)-Alkylbicyclo[ n .1.0]alkan-1-ols 1 in the Presence of TMSCl as Activating Reagent (Procedure A)
Chlorotrimethylsilane (6.3 mL, 50 mmol) was added to the suspension of zinc dust (3.25 g, 50 mmol) in THF (25 mL), the resulted mixture was sealed with a rubber septum and stirred for 5-10 min. An equivalent amount of solution of HI in dry benzene (ca. 0.5-1.5 M) [²²] was added in 1-2 min to the solution of an unsaturated ketone 2 (25 mmol) in dry benzene (15 mL). Freshly prepared red-brown solutions of β-iodo ketones 3 were added in one portion within 1-2 min via syringe to the suspension of zinc dust. After a few minutes an exothermic reaction started, and the reaction mixture became colorless. When the reaction was completed (1-2 h, TLC monitoring) the mixture was poured into sat. solution of NH₄Cl (50 mL), the organic layer was separated, and the aqueous phase was extracted with Et₂O (3 × 15 mL). The combined organic phases were washed with sat. solutions of NaHCO₃, NaCl, and dried with Na₂SO₄. Solvent was removed under reduced pressure, and compounds 1 were isolated as colorless oils or white crystalline solids by column chromatography over silica gel, treated with Et₃N (ca. 0.1 mL per 2 g of SiO₂; eluent: PE-EtOAc; see Table  [¹] ).

13

^¹H NMR spectra of the solutions of β-iodo ketones 3 demonstrated the absence of the olefinic proton signals of starting compounds 2. The multiplet signals from protons of CHI groups in diastereomeric β-iodo ketones were observed at δ = 4.0-4.5 ppm.

14

Stereochemical configurations for compounds 1a were confirmed by 1D NOESY experiments, which were carried out with their trimethylsilyl ethers 4a. Irradiation of signal of TMS group led to enhancement of signals from both cyclopropane protons at δ = 1.06 and 1.37 ppm in the case of endo-isomer, whereas in the same experiment for exo-isomer the signal of cyclopropane proton at δ = 0.87 ppm and the signals of ethyl CH₂ group (δ = 1.22 and 1.53 ppm) were enhanced. Values of ^³ J coupling constants between the cyclopropyl protons (J = 4.0 Hz and 7.3 Hz for exo- and endo-isomers of 1a, respectively) are also agreed with the stereochemical assignment.

15

Analytical Data of Selected Compounds 2 exo -6-Ethylbicyclo[3.1.0]hexan-1-ol ( exo -1a)
Colorless oil. ^¹H NMR (400 MHz, CDCl₃): δ = 0.69 (dt, J ₁ = 7.2 Hz, J ₂ = 4.0 Hz, 1 H), 0.87 (t, J = 4.0 Hz, 1 H), 0.99 (t, J = 7.3 Hz, 3 H), 1.12 (m, 1 H), 1.35-1.57 (m, 3 H), 1.60 (br s, 1 H, OH), 1.65 (m, 1 H), 1.85 (m, 1 H), 1.92-1.98 (m, 2 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 14.37, 20.44, 21.79, 26.80, 26.90, 29.54, 34.49, 68.02. IR (CCl₄) = 3603, 3400, 3027 cm^-¹. Anal. Calcd for C₈H₁₄O (126.20): C, 76.14; H, 11.18. Found: C, 76.30; H, 11.10.
endo -6-Ethylbicyclo[3.1.0]hexan-1-ol ( endo -1a)
Colorless oil. ^¹H NMR (400 MHz, CDCl₃): δ = 1.00 (t, J = 7.3 Hz, 3 H), 1.13 (m, 1 H), 1.18-1.41 (m, 4 H), 1.46 (ddd, J ₁ = 12.5 Hz, J ₂ = 9.7 Hz, J ₃ = 2.5 Hz, 1 H), 1.86 (m, 1 H), 1.96-2.13 (m, 4 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 14.54, 16.55, 24.22, 24.92, 29.26, 31.97, 32.10, 69.41. IR (CCl₄) = 3596, 3338, 3027. Anal. Calcd for C₈H₁₄O (126.20): C, 76.14; H, 11.18. Found: C, 76.33; H, 11.28. exo -7-Isopropylbicyclo[4.1.0]heptan-1-ol ( exo -1e)
Colorless crystalls, mp 52.4-53.1 ˚C. ^¹H NMR (400 MHz, CDCl₃): δ = 0.22 (dd, J ₁ = 6.0, J ₂ = 9.9 Hz, 1 H), 0.70 (ddd, J ₁ = 1.6 Hz, J ₂ = 6.0 Hz, J ₃ = 7.8 Hz, 1 H), 0.96 (d, J = 6.7 Hz, 3 H), 1.01 (d, J = 6.7 Hz, 3 H), 1.08 (m, 1 H), 1.21 (m, 2 H), 1.35 (m, 1 H), 1.45 (m, 2 H), 1.71 (br s, 1 H, OH), 1.86 (ddd, J ₁ = 5.6 Hz, J ₂ = 9.9 Hz, J ₃ = 13.1 Hz, 1 H), 1.97 (m, 1 H), 2.05 (m, 1 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 21.44, 21.79, 22.50, 23.21, 24.47, 24.51, 28.10, 33.04, 37.50, 58.52. IR (CCl₄) = 3604, 2995. Anal. Calcd for C₁₀H₁₈O (154.25): C, 77.87; H, 11.76. Found: C, 77.69; H, 11.85.

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17

General Procedure for the Preparation of (n+3)-Alkylbicyclo[ n .1.0]alkan-1-ols 1 in the Presence of TiCl(O i -Pr) ₃ as Activating Reagent (Procedure B)
A solution TiCl(Oi-Pr)₃ in THF (1 M, 25 mmol, 25 mL) was added to the suspension of zinc dust [²³] (3.25 g, 50 mmol) in THF (25 mL). Immediately, a solution of β-iodo ketone 3 (25 mmol) in dry benzene (prepared as described above in procedure A) was added. During few minutes, the reaction mixture spontaneously warmed up and turned dark brown. When the reaction was completed (0.5-1 h, TLC moni-toring), sat. solution of NH₄Cl (10 mL) was added to the mixture, precipitate was filtered off and washed thoroughly with Et₂O (5 × 15 mL). The filtrate was washed with sat. solution of NaCl, dried with Na₂SO₄. The solvent was removed under reduced pressure, and compounds 1 (see Table  [¹] , entries 1, 2, 5, and 8) were isolated by column chromatography over silica gel, treated with Et₃N (ca. 0.1 mL per 2 g of SiO₂; eluent: PE-EtOAc).

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19

The fragmentation of trimethylsilyl ether exo-4e was carried out in AcOH in accordance to the procedure, described by Kirihara et al., see ref. 7e. Cyclopropanol exo-1e under these conditions afforded acid 6 in 50-60% yield.

20

Spectral data are consistent with those previously reported for this compound in ref. 18h. On the basis of NMR and GC data, the stereochemical purity of trans-configured carbon-carbon double bond in acid 6 was more than 99%.

21

Spectral data are consistent with those previously reported for this compound in ref. 18h.

22a

Prepared by passing a stream of gaseous HI, generated by dropping 57% HI upon P₂O₅. [²²b] The concentration of HI in the obtained solution was determined after its aqueous workup by titration with sodium hydroxide.

22b Dillon RT. Young WG. J. Am. Chem. Soc.  1929,  51:  2389 

23

Zinc dust was previously activated with few drops of DBE or TMSCl.