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Synlett 2005(5): 0819-0823  
DOI: 10.1055/s-2005-863748
LETTER
© Georg Thieme Verlag Stuttgart · New York

An Unusual Intramolecular Acetal Alkylation

Xiuchun Gao, Punit P. Seth, John K. Bitok, Nancy I. Totah*
Department of Chemistry, Syracuse University, Syracuse, NY 13244, USA
Fax: +1(315)4434070; e-Mail: ntotah@syr.edu;
Further Information

Publication History

Received 2 December 2004
Publication Date:
09 March 2005 (online)

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Abstract

Upon treatment with Grignard reagents, suitably functionalized cis-fused bicyclic ketone acetals undergo intramolecular acetal alkylation to provide oxabicyclo[3.3.1]nonane derivatives. This transformation results in the formation of up to three stereogenic centers with high levels of stereoselectivity. Product distribution and stereochemistry vary with substrate substitution and the Grignard reagent utilized.

Key words

acetals - alkylation - annulation - Grignard reagents - stereoselectivity

    References

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1

Taken in part from the MS thesis of X. Gao, University of Iowa, 2001.

7

This structure was confirmed by X-ray crystallography. Crystallographic data have been deposited at the Cambridge Crystallographic Data Centre (CCDC-254147). These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

10

The regiochemistry of intermolecular addition (e.g. 9) was determined by evaluation of chemical shifts in the corresponding acetate.

12

Stereochemical assignments are supported by NOE studies.

13

General Methods.
All air sensitive reactions were performed in base washed, flame dried glassware under an atmosphere of argon. THF was dried over Na/benzophenone ketyl and was distilled just prior to use. Pyridine was distilled from CaH2. Analytical thin layer chromatography was performed on EM silica gel 60F glass plates (0.25 mm). Flash column chromatography was performed using EM silica gel 60 (230-400 mesh). 1H NMR spectra were recorded on Bruker AC-300 or WM-360 spectrometers. Chemical shifts are reported in ppm, downfield from tetramethylsilane using residual CHCl3 as the internal standard (δ = 7.27 ppm). 13C NMR spectra were recorded on a Bruker WM-360 (90 MHz) spectrometer with complete proton decoupling. Chemical shifts are reported in ppm, downfield from tetramethylsilane using residual CHCl3 as the internal standard (δ = 77.0 ppm). IR spectra were obtained with a Mattson Cygnus 25 instrument. Elemental Analyses were performed by Atlantic Microlab, Inc.; Norcross, GA.
General Procedure for Intramolecular Alkylation.
To a solution of ketone 1 (0.1 mmol) in 2 mL THF was added the Grignard reagent (3.4 mL of a 3.0 M solution in Et2O, 10.2 mmol), and the mixture warmed to reflux. After 16 h, the reaction mixture was cooled to r.t., quenched with sat. NH4Cl and extracted with CH2Cl2 (3×). The combined organic layers were dried over Na2SO4 and concentrated in vacuo.
Ketone 3: the crude residue was purified by flash chromatography (SiO2; hexane-EtOAc, 3:1) to afford ketone 3 (65%) as a white solid. 1H NMR (300 MHz, CDCl3): δ = 4.40 (1 H, d, J = 11.7 Hz), 4.03 (1 H, m), 3.67 (1 H, d, J = 11.7 Hz), 3.28 (1 H, dt, J = 12.0, 5.2 Hz), 2.95 (1 H, d, J = 11.9 Hz), 2.85 (1 H, m), 2.61 (1 H, m), 2.06 (1 H, t, J = 12.3 Hz), 1.95 (1 H, s), 1.81 (1 H, dd, J = 12.9, 5.3 Hz), 1.56 (1 H, dd, J = 14.7, 1.2 Hz), 1.34 (3 H, s), 1.22 (3 H, s), 1.17 (3 H, s), 1.15 (3 H, s), 1.12 (3 H, d, J = 7.3 Hz). 13C NMR (90 MHz, CDCl3): δ = 217.5, 80.0, 79.9, 73.1, 68.6, 68.5, 64.8, 55.6, 42.2, 34.4, 32.5, 31.7, 27.0, 24.2, 22.2, 22.0. Anal. Calcd for C16H26O4·0.5H2O (%): C, 65.95; H, 9.34. Found: C, 65.59; H, 8.97.
Ketone 7: the crude residue was purified by flash chromatography (SiO2; hexane-EtOAc, 9:1) providing ketone 7 (72%) as a white solid. 1H NMR (300 MHz, CDCl3): δ = 4.40 (1 H, d, J = 11.8 Hz), 3.95 (1 H, m), 3.67 (1 H, d, J = 11.8 Hz), 3.34 (1 H, dt, J = 12.0, 5.3 Hz), 2.88 (1 H, d, J = 11.9 Hz), 2.73 (1 H, dt, J = 13.8, 4.2 Hz), 2.52 (1 H, m), 2.04 (1 H, m), 1.81 (1 H, dd, J = 12.7, 5.5 Hz), 1.63 (1 H, m), 1.45 (3 H, s), 1.24 (3 H, d, J = 7.2 Hz), 1.21 (3 H, s), 1.18 (3 H, s), 1.15 (3 H, s). 13C NMR (90 MHz, CDCl3): δ = 216.3, 81.1, 77.5, 73.0, 68.5, 67.9, 63.3, 55.1, 42.0, 34.9, 34.4, 31.5, 29.2, 26.0, 22.5, 20.9. IR (film): 3433, 1644 cm-1. HRMS (FAB): m/z calcd for C16H27O4 [M + H]+: 283.1909; found: 283.1909.
Diol 8a: The crude residue was purified by flash chromatography (SiO2; hexane-EtOAc, 9:1) providing diol 8a as a white solid (isolated from a 1:1:1 mixture of 7:8a:9a; combined yield 82%). 1H NMR (300 MHz, CDCl3): δ = 4.56 (1 H, d, J = 11.6 Hz), 3.76 (1 H, m), 3.71 (2 H, m, OH), 3.66 (1 H, m), 3.24 (1 H, d, J = 11.6 Hz), 2.40 (2 H, m), 1.97 (1 H, t, J = 12.4 Hz), 1.81 (3 H, s), 1.76 (1 H, dd, J = 13.0, 6.1 Hz), 1.54 (3 H, s), 1.48 (1 H, m), 1.35 (3 H, s), 1.26 (3 H, s), 1.21 (3 H, s), 1.21 (1 H, m), 1.14 (3 H, d, J = 6.7 Hz). 13C NMR (90 MHz, CDCl3): δ = 78.4, 77.5, 73.8, 73.5, 72.0, 67.4, 56.4, 43.0, 42.6, 34.4, 32.6, 31.5, 31.4, 30.6, 29.3, 23.0, 22.2. IR (film): 3336 cm-1. HRMS (FAB): m/z calcd for C17H30O4 [M + Na]+: 321.2042; found: 321.2042.
Ketone 9a: the crude residue was purified by flash chromatography (SiO2; hexane-EtOAc, 9:1) providing ketone 9a as a white solid (isolated from a 1:1:1 mixture of 7:8a:9a; combined yield 82%). 1H NMR (300 MHz, CDCl3): δ = 4.03 (1 H, m), 4.02 (1 H, d, J = 11.0 Hz), 3.85 (1 H, dt, J = 12.1, 5.0 Hz), 3.74 (1 H, d, J = 8.6 Hz), 3.63 (1 H, d, J = 8.6 Hz), 2.33 (2 H, m), 2.07 (1 H, dd, J = 15.1, 12.6 Hz), 1.79 (4 H, m), 1.20 (9 H, s), 1.18 (6 H, s), 1.00 (3 H, d, J = 6.3 Hz). 13C NMR (90 MHz, CDCl3): δ = 218.0, 73.5, 72.9, 72.8, 68.4, 61.7, 55.9, 49.3, 42.4, 35.0, 31.5, 27.3 (3C), 27.1, 22.5, 22.0. IR (film): 3413, 1692 cm-1. HRMS (FAB): m/z calcd for C17H30O4 [M + Na]+: 321.2042; found: 321.2012.