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Synlett 2009(12): 1969-1973  
DOI: 10.1055/s-0029-1217527
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

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

Dinh Hung Maca, Thierry Roisnelb, Vicenc Branchadell*c, René Grée*a
a Laboratoire de Chimie et Photonique Moléculaires, CNRS UMR 6510, Université de Rennes 1, Avenue du Général Leclerc, 35042 Rennes Cedex, France
Fax: +33(2)23236978; e-Mail: rene.gree@univ-rennes1.fr;
b Sciences Chimiques de Rennes, CNRS UMR 6226, Université de Rennes 1, Avenue du Général Leclerc, 35042 Rennes Cedex, France
c Departament de Química, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain
e-Mail: vicenc@klingon.uab.cat;
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Publikationsverlauf

Received 14 April 2009
Publikationsdatum:
01. Juli 2009 (online)

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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.

Key words

allylic alcohols - aldol - catalyst - bicycloalkenones - DFT calculations

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12

The geometries of allyl alcohol 5, of Z and E-enols and of the aldolization transition states were optimized using the B3LYP¹7-¹9 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 search²¹ using the MMFF force field²² implemented in the Macromodel program.²³

13

The crystal structure corresponding to adduct 12 has been deposited at the Cambridge Crystallographica Data Centre and allocated the deposition number CCDC 715243. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

15

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.

16

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.