Synthesis of New Bicycloalkane Derivatives from Allylic Alcohols/Lactols by a Tandem Isomerization-Intramolecular Aldolization Process

Abstract

New bicyclo[3.2.1]octanes are easily prepared in a few steps from norbornene. The key reaction in this process is the tandem isomerization-intramolecular aldol reaction from lactol 4 and/or allylic alcohol 5, mediated by transition-metal catalysts. This reaction affords bicyclic derivative 6 as a single stereoisomer and the stereoselectivity of this process could be explained by analysis of the different transition states using high-level computational studies. The key intermediate enone 7 is easily obtained from 6 through the corresponding mesylate. The synthetic potential of bicyclic enone 7 is illustrated with several examples.

allylic alcohols - aldol - catalyst - bicycloalkenones - DFT calculations

References and Notes

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The geometries of allyl alcohol 5, of Z and E-enols and of the aldolization transition states were optimized using the B3LYP^¹7-¹9 density functional method with the 6-31G(d) basis set. Harmonic vibrational frequencies of all structures were calculated in order to fully characterize their energy minima or transition states. All calculations were performed using the Gaussian-03 program.^²0 The most stable conformers of 5, and Z and E-enols were determined through a Montecarlo conformational search^²¹ using the MMFF force field^²² implemented in the Macromodel program.^²³

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Procedure for Aldolization using an Fe(CO) ₅ Catalyst: CAUTION: all reactions involving Fe(CO)₅ must be carried out under a well ventilated hood. At the end of the reaction the residue of Fe(CO)₅ can be destroyed by addition of strong oxidizing agents such as Ce(NH₄)₂ (NO₃)₆ or FeCl₃. To a solution of a 93:7 mixture of lactol 4 and alcohol 5 (1 mmol) in anhydrous THF (10 mL) in a 25 mL pyrex flask, was added Fe(CO)₅ (7 µL, 5 %mol) at r.t. under nitrogen. The mixture was irradiated with a Philips HPK 125W lamp until disappearance of starting material was observed (1 h). The reaction mixture was filtered through silica gel (diameter 1 cm, length 2 cm) and purified by column chromatography (CH₂Cl₂-Et₂O, 9:1) to give aldol product 6 [100 mg, 65%; R _f = 0.1 (CH₂Cl₂-Et₂O, 9:1)] and ketone 10 [20 mg, 12%; R _f = 0.5 (CH₂Cl₂-Et₂O, 9:1)]. Spectral data for aldol 6: ^¹H NMR (500 MHz, C₆D₆): δ = 1.16 (d, J = 6.8 Hz, 2 H), 1.20-1.38 (m, 3 H), 1.44-1.57 (m, 1 H), 1.93 (br, 1 H), 2.10 (quin, J = 6.3 Hz, 1 H), 2.21 (m, 1 H), 2.38 (d, J = 12.1 Hz, 1 H), 2.77 (t, J = 5.4 Hz, 1 H), 3.69 (m, 1 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 10.0, 25.3, 26.9, 33.0, 42.0, 43.1, 50.9, 76.7, 212.7. HRMS (EI): m/z [M⁺] calcd C₉H₁₄O₂: 154.09938; found: 154.0997.

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Procedure for Synthesis of Enone 7: To an ice-cold solution of aldol 6 (540 mg, 3.5 mmol), and Et₃N (0.98 mL, 2 equiv) in CH₂Cl₂, was added MsCl (410 µL, 1.5 equiv) at 0 ˚C. After being stirred at r.t. for 1 h, the reaction was cooled to 0 ˚C and DBU (626 µL, 1.2 equiv) was added and the solution was stirred at r.t. overnight. The mixture was diluted with CH₂Cl₂ and H₂O, the organic phase was separated and the aqueous phase was extracted with CH₂Cl₂. The combined organic phases were dried over MgSO₄, filtered and concentrated under vacuum to afford a residue, which was purified by chromatography on silica gel (pentane-Et₂O, 90:10) to afford enone 7 as a colorless oil (328 mg, 69%). ^¹H NMR (300 MHz, CDCl₃): δ = 1.37-0.48 (m, 4 H), 1.6 (d, J = 1.4 Hz, 3 H), 1.8 (m, 1 H), 1.9 (d, J = 12.0 Hz, 1 H), 1.9-2.1 (m, 2 H), 2.8 (quin, J = 4.1 Hz, 1 H), 2.9 (dd, J = 7.2, 6.9 Hz, 1 H), 6.9 (dt, J = 6.9, 1.5 Hz, 1 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 15.0, 24.4, 29.2, 37.5, 40.4, 50.1, 133.3, 151.4, 203.9. HRMS (EI): m/z [M⁺] calcd for C₉H₁₂O: 136.08882; found: 136.0889.

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