Stereoselective Synthesis of Tetrahydrofurans
A R T I C L E S
Scheme 7. Synthesis of Intermediates to (-)-Allomuscarine and
(+)-Epimuscarine
Experimental Section
General Procedure for Tetrahydrofuran Cyclization Reaction
Using Allylsilanes. Boron trifluoride etherate (2.0 equiv) was added
over 15 min to a -78 °C solution of protected R-hydroxy aldehydes
(1.0 equiv), allylsilane (1.2-1.5 equiv), and 2,6-di-tert-butyl-4-methyl-
pyridine (1.0 equiv) in CH2Cl2 (0.1 M). The reaction was stirred at
-78 °C for 24 h. The reaction mixture was then poured into a stirred
solution of saturated NaHCO3 and the aqueous layer was extracted with
CH2Cl2 (3 × 20 mL). The combined organic layer was dried (MgSO4)
and concentrated to afford the crude product(s). Flash chromatography
on silica gel (7:1 to 3:1 hexanes/EtOAc) gave product(s) in the yields
shown.
General Procedure for Tetrahydrofuran Cyclization Reaction
Using Crotylsilanes. Boron trifluoride etherate (5.0 equiv) was added
over 30 min to a -78 °C solution of protected R-hydroxy aldehydes
(1.0 equiv), allylsilane (1.2 equiv), and 2,6-di-tert-butyl-4-methylpyr-
idine (1.0 equiv) in CH2Cl2 (0.1 M). The reaction was left to stir at
-78 °C for 24 h. The reaction mixture was then poured into a stirred
solution of saturated NaHCO3 and the aqueous layer was extracted with
CH2Cl2 (3 × 30 mL). The combined organic extracts were dried
(MgSO4) and concentrated to afford crude product(s). Flash chroma-
tography on silica gel (7:1 then 3:1 hexanes/EtOAc) gave product(s)
in the yields shown.
(2S,3R,5R)-5-Hydroxymethyl-2-methyltetrahydrofuran-3-ol (53).
A solution of n-Bu4NF (0.68 mL of a 1 M solution in THF, 0.68 mmol)
was added dropwise to a 0 °C solution of 25 (144 mg, 0.43 mmol) in
THF (5 mL). After 30 min, MeOH (1.2 mL) was added to the reaction
mixture followed by KHCO3 (70 mg, 0.69 mmol) and H2O2 (30%, 0.5
mL, 4.9 mmol). The ice bath was removed and the reaction mixture
was allowed to warm to room temperature. After 12 h the reaction
mixture was refluxed for 1 h, then it was cooled to room temperature
and diluted with MeOH and stirred then filtered through silica plug.
The resulting mixture was concentrated and purified by flash chroma-
tography (1:1 MeOH:ether) to provide 53 (47 mg, 83%) as a colorless
oil: [R]D -41.5 (c 0.065, CHCl3) (lit.24 (+) enantiomer [R]D +45.0 (c
0.5, CHCl3); 1H NMR (300 MHz, CDCl3) δ 4.27 (m, 1H), 4.12 (dq, J
) 6.7, 1.6 Hz, 1H), 3.97 (dt, J ) 5.7, 2.1 Hz, 1H), 3.80 (dq, J ) 9.3,
2.6 Hz, 1H), 3.53 (dd, J ) 11.8, 3.1 Hz, 1H), 3.12 (s, 2H), 2.41 (ddd,
J ) 13.9, 9.2, 6.2 Hz, 1 H), 1.81 (ddd, J ) 13.9, 3.1, 2.1 Hz, 1H), 1.11
(d, J ) 6.7 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 83.1, 77.4, 76.1,
64.2, 35.1, 18.8; IR (CDCl3) 3619, 3386, 2972, 1456, 1375 cm-1; MS
(DEI) m/z 133 (MH+, 19), 101(81); HRMS (DEI) m/z calcd for C6H13O3
(MH+) 133.0865, found 133.0861.
(2S,3S,5S)-5-Hydroxymethyl-2-methyl-tetrahydrofuran-3-ol (54).
The same procedure used for the conversion of 25 to the diol 53 was
carried out with 26 (289 mg, 0.85 mmol). Flash chromatography (3:1
EtOAc/hexanes) provided 54 (99 mg, 88%) as a white solid: mp 66-
67 °C; [R]D +45.3 (c 0.088, CHCl3) (lit.25 [R]D +47.0 (c 0.9, CHCl3);
1H NMR (300 MHz, CD3OD) δ 4.02 (m, 2H), 3.80 (dq, J ) 6.7, 3.6
Hz, 1H), 3.62 (dd, J ) 11.3, 3.6 Hz, 1H), 3.52 (dd, J ) 11.8, 4.6 Hz,
1H), 2.34 (ddd, J ) 14.9, 8.7, 5.6 Hz, 1H), 1.72 (ddd, J ) 13.9, 5.1,
1.5 Hz, 1 H), 1.21 (d, J ) 6.7 Hz, 3H); 13C NMR (75 MHz, CD3OD)
δ 80.7, 79.3, 73.5, 65.4, 38.3, 14.4; IR (CDCl3) 3626, 3410, 2937, 2882,
2678, 2533 cm-1; MS (DEI) m/z 133 (MH+, 17), 115(26), 101(87),
83(12), 69(26), 57(100); HRMS (DEI) m/z calcd for C6H13O3 (MH+)
133.0865, found 133.0868.
their action and have been used in clinical research as an
acetylcholine substitute. This cholinomimetic activity and their
simple but challenging structure has interested chemists over
the years.
Our methodology provided a concise route to an advanced
intermediate in two steps from aldehyde 8 and in very good
yield. Formal cycloaddition of aldehyde 8 with allylsilane 2c
afforded the cycloadducts 25 and 26 in 80% yield and 2.2:1
ratio. Preparative HPLC separation of the mixture provided
quantities of each diastereomer. Fleming-Tamao oxidation of
25 provided the known diol 5324 in 83% yield and g92% ee.
The minor diastereomer 26 was converted to the known25 diol
54 in 88% yield and g96% ee. This constitutes a formal total
synthesis of (-)-allomuscarine and (+)-epimuscarine since both
compounds have been converted to the corresponding natural
products upon treatment with TsCl and Me3N.26
Conclusion
A fundamentally new approach to the cycloaddition reactions
of allylsilanes with aldehydes has been developed. This method
assembles tetrahydrofuran ring systems from allylsilanes and
aldehydes and diverts the normal reaction pathway to another
manifold. The triethylsilyl ether oxygen is a more potent
nucleophile than the Lewis acid complexed alkoxide resulting
in novel cyclization products. It is important to note that no 1,2
silyl shift was observed and only five-membered-ring cyclization
products were isolated.
Acknowledgment. We thank NSF (CHE-9528266) for partial
support of this research. We would like to also thank Dr. Fook
Tham at the UCR X-ray facility for the X-ray structures.
Supporting Information Available: 1H NMR and 13C NMR
spectra of all new compounds, X-ray crystallographic files (CIF)
for compounds where X-ray data were collected. This material
(24) Knight, D. W.; Bew, S. P.; Middleton, R. J. Tetrahedron Lett. 2000, 41,
4453-4456.
(25) Brown, D. M.; Mubarak, A. M. J. Chem. Soc., Perkin Trans. 1 1982, 809-
813.
(26) (a) Brown, D.; Fleet, G. W.; Mantell, S. J. J. Chem. Soc., Chem. Commun.
1991, 1563-1564. (b) Chapleur, Y.; Bandzouzi, A. J. Chem. Soc., Perkin
Trans. 1 1987, 661-664. (c) Ogasawara, K.; Iwabuchi, Y.; Takano, S. J.
Chem. Soc., Chem Commun. 1989, 1371-1372.
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