abilities,10 asthma,12 and anxiety.11 Furthermore, the piperi-
dine ring is found in many natural products,12 and so the
ability to produce these systems asymmetrically is of
particular interest.
When (R)-1,2-epoxypentane13 (2f) is used in our sequence,
one additional step involving δ-lactam to piperidine reduc-
tion14 yields natural (-)-halosaline (8b) and its isomer (-)-
epihalosaline (8a) in five steps and 12% and 23% overall
yields, respectively (Scheme 3).
regiospecifically monosubstituted ꢀ-lactams 10a and 10b20
(Scheme 4).
Scheme 4. 6 + 3 - 2 Cyclohexanone Ring Expansion Leading
to a Pair of Diastereomeric Lactams
Scheme 3. Lactam Reduction
(21) Typical procedure: Formation of lactones 4a and 4b from epoxide
2f: A 25 mL flask was charged with (cyclopentenyloxy)trimethylsilane
(1) (0.300 g, 1.92 mmol) and dissolved in THF (1.5 mL). To this, at 0 °C,
was added MeLi (1.26 mL, 2.02 mmol, 1.6 M in Et2O) dropwise over the
course of about 1 min. After 5 min, the reaction was cooled to -78 °C,
and (R)-1,2-epoxypentane (2f) (0.083 g, 0.96 mmol) in THF (1.5 mL) was
added via canula. The reaction was stirred for 5 min before BF3‚Et2O (0.122
mL,0.96 mmol, neat) was added very slowly (1drop/4 s), using a 100 µL
syringe, while cooling the needle with a piece of dry ice. After 1 h, the
reaction was quenched with phosphate buffer (3.0 mL, pH 7.0) and warmed
to room temperature. The mixture was extracted with Et2O (3 × 25 mL),
and the combined organics were dried over MgSO4 and concentrated in
vacuo. The crude product was purified by silica gel chromatography (90%
hexanes, 10% ethyl acetate, ∼1% TEA) to give hemiketal 3 as a colorless
oil. Hemiketal 3 (0.163 g, 0.96 mmol) was placed in a 50 mL flask with
CH2Cl2 (16 mL) and the solution was cooled to 0 °C. To this was added
PhI(OAc)2 (0.339 g, 1.05 mmol) and then I2 (0.243 g, 0.96 mmol, crystals).
The reaction immediately turned dark purple. The reaction was stirred for
5 h at 0 °C before being quenched with a saturated solution of sodium
thiosulfate. The mixture was extracted with CH2Cl2 (2 × 20 mL), and the
combined organics were dried over MgSO4 and concentrated in vacuo. The
crude product was purified by silica gel chromatography (90% hexanes,
10% ethyl acetate) to give lactones 4a and 4b (0.172 g, 2 stepss61%) as
a 2:1 separable mixture of diastereomers. Major, 40%: 1H NMR (CDCl3)
δ 4.67-4.61 (m, 1H), 4.21-4.15 (m, 1H), 2.72-2.66 (m, 1H), 2.54-2.26
(m, 5H), 1.96-1.86 (m, 2H), 1.67-1.58 (m, 1H), 1.50-1.29 (m, 3H), 0.09
(t, J ) 7.2 Hz, 3H); 13C NMR (CDCl3) δ 175.9, 80.1, 65.8, 51.5, 41.6,
37.1, 31.8, 28.6, 26.0, 18.5, 13.6; IR (neat, cm-1) 2960, 2870, 1711, 1357,
1252, 1056, 1008; HRMS (FAB) m/z (M + H+) calcd for C10H18O2I+
297.03516, found 297.03492; [R]25D 48.83 (c 0.056, CHCl3). Minor, 20%:
1H NMR (CDCl3) δ 4.55-4.49 (m, 1H), 4.34-4.38 (m, 1H), 2.74-2.66
(m, 1H), 2.48-2.42 (m, 1H), 2.37-2.33 (m, 2H), 2.17-2.12 (m, 2H), 2.00-
1.90 (m, 2H), 1.74-1.67 (m, 1H), 1.53-1.20 (m, 3H), 0.92 (t, J ) 8.0 Hz,
3H); 13C NMR (CDCl3) δ 175.1, 78.3, 48.9, 37.1, 36.9, 31.2, 28.2, 27.8,
18.6, 13.7; IR (neat, cm-1) 2958, 2871, 1727, 1459, 1242, 1120, 1023;
HRMS (FAB) m/z (M + H+) calcd for C10H18O2I+ 297.03516, found
297.03480; [R]25D -6.95 (c 0.029, CHCl3). Formation of azido lactone 5b
from iodolactones 4b: A 15 mL flask was charged with lactone 4b (0.030
g, 0.10 mmol), DMSO (1 mL), and 4Å mol sieves. The flask was warmed
to 40 °C before sodium azide (0.066 g, 1.0 mmol) was added and the
solution was allowed to stir at this temperature overnight. After 24 h, the
reaction was quenched with water, extracted with dichloromethane (2 ×
25 mL), dried over MgSO4, and concentrated in vacuo. The crude product
was purified by silica gel chromatography (90% hexanes, 10% ethyl acetate)
Previous syntheses of these two sedum alkaloids have
involved many synthetic steps,15 or two separations of
diastereomeric intermediates,16 or relatively complex and
expensive starting material,17 or 7-10 day reaction times.18
To increase the scope of this ring enlargement methodol-
ogy, we have shown that the reaction is also adaptable to
the construction of 7-membered ring lactams.19 For example,
commercially available (cyclohexenyloxy)trimethylsilane (9)
was reacted with epoxide 2a to produce 1-atom enlarged,
(11) (a) Flammia, D.; Dukat, M.; Damaj, I.; Martin, B.; Glennon, R. J.
Med. Chem. 1999, 42, 3726-3731. (b) Jensen, A. A.; Frølund, B.; Liljefors,
T.; Krogsgaard-Larsen, P. J. Med. Chem. 2005, 48, 4705-4745.
(12) Felpin, F. X.; Lebreton, J. Tetrahedron, 2004, 60, 10127-10153.
(13) Enantiomerically pure epoxide made according to the procedure in
the following: Schaus, S. E.; Brandes, B. D.; Larrow, J. F.; Tokunaga, M.;
Hansen, K. B.; Gould, A. E.; Furrow, M. E.; Jacobsen, E. J. Am. Chem.
Soc. 2002, 124, 1307-1315.
(14) Jesudason, C. D.; Beavers, L. S.; Cramer, J. W.; Dill, J.; Finley, D.
R.; Lindsley, C. W.; Stevens, F. C.; Gadski, R. A.; Oldham, S. W.; Pickard,
R. T.; Siedem, C. S.; Sindelar, D. K.; Singh, A.; Watson, B. M.; Hipskind,
P. A. Bioorg. Med. Chem. Lett. 2006, 16, 3415-3418.
(15) (a) Takahata, H.; Kubota, M.; Takahashi, S.; Momose, T. Tetra-
hedron: Asymmetry 1996, 7, 3047-3054. (b) Takahata, H.; Kubota, M.;
Takahashi, S.; Momose, T. Tetrahedron. Lett. 1997, 38, 3451-3454. (c)
Bisai, A.; Singh, V. K. Tetrahedron Lett. 2007, 48, 1907-1910.
(16) Kochi, T.; Tang, T.; Ellman, J. J. Am. Chem. Soc. 2003, 125,
11276-11282.
(17) (a) Stragies, R.; Blechert, S. Tetrahedron, 1999, 55, 8179-8188.
(b) Lesma, G.; Crippa, S.; Danieli, B.; Passarella, D.; Sacchetti, A.; Silvani,
A.; Virdis, A. Tetrahedron 2004, 60, 6437-6442.
(18) Louis, C.; Hootele, C. Tetrahedron: Asymmetry 1995, 6, 2149-
2152.
(19) (a) Galvez, N.; Moreno-Manas, M.; Sebastian, R. M.; Vallribera,
A. Tetrahedron 1996, 52, 1609-1616. (b) Eshghi, H.; Hassankhani, A.;
Mosaddegh, E. J. Chem. Res. 2006, 4, 218-219. (c) Hu, T.; Shen, M.;
Chen, Q.; Li, C. Org. Lett. 2006, 8, 2647-2650.
(20) Compounds 10a and 10b exist as a nonseparable mixture of
diastereomers. To separate them, it was necessary to functionalize the free
alcohol in the lactam side chain as a tert-butyldimethylsilyl ether.
1
to give lactone 5b as a colorless oil (0.015 g, 71 %). H NMR (CDCl3) δ
4.81-4.75 (m, 1H), 3.50-3.43 (m, 1H), 2.49-2.38 (m, 2H), 2.16-2.11
(m, 1H), 1.99-1.87 (m, 5H), 1.71-1.67 (m, 1H), 1.56-1.37 (m, 3H), 0.93
(t, J ) 7.2 Hz, 3H); 13C NMR (CDCl3) δ 176.1, 76.9, 60.9, 43.1, 37.4,
33.8, 32.8, 26.4, 18.6, 15.3, 13.7; IR (neat, cm-1) 2959, 2874, 2094, 1738,
+
1456, 1249, 1153; HRMS (FAB) m/z (M + H+) calcd for C10H18N3O2
212.13990, found 121.13905; [R]25D 29.49 (c 0.008, CHCl3). Formation of
lactam 6b: A 10 mL flask was charged with azido lactone 5b (0.022 g,
1.04 mmol), methanol (1 mL), and Lindlar’s catalyst (0.19 g, 1.04 mmol).
A rubber septum was then placed over the flask and the atmosphere inside
was removed under vacuum before being placed under an atmosphere of
hydrogen via a balloon. After 24 h the reaction mixture was diluted with
ethyl acetate (5 mL) and passed over a short column of celite 545 with a
thin layer of silica gel on top. The column was washed with EtOAc (100
mL) and concentrated in vacuo to give lactam 6b as a colorless oil (0.017
g, 90 %). 1H NMR (CDCl3) δ 7.44 (s, 1H), 3.96 (s, 1H), 3.88-3.82 (s,
1H), 3.73-3.68 (m, 1H), 2.39-2.22 (m, 2H), 1.89-1.80 (m, 2H), 1.76-
1.61 (m, 2H), 1.55-1.32 (m, 6H), 0.92 (t, J ) 3.6, 3H); 13C NMR (CDCl3)
δ 172.9, 67.8, 49.3, 42.6, 39.4, 31.0, 29.0, 19.4, 19.0, 14.0; IR (neat, cm-1
)
3302, 2953, 2871, 1655, 1467, 1411, 1351, 1308; HRMS (FAB) m/z (M +
+
H+) calcd for C10H20NO2 186.14940, found 186.14959.
Org. Lett., Vol. 9, No. 14, 2007
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