Oxycyclization of Enallenols
FULL PAPER
114.3 (2C), 85.5, 77.2, 59.7, 57.6, 55.5, 29.6, 23.0, 10.8 ppm; IR (CHCl3):
shown that a combination of metal-mediated hydroalkoxyla-
tion and allenic aminocyclization reactions can lead to a
n˜ =1741 cmÀ1; MS (ES): m/z (%): 340 (100) [M+H]+, 339 (19) [M]+.
General procedure for FeIII-catalyzed cyclizations of enallenols 1: FeCl3
(0.10 mmol) was added to a stirred solution of the appropriate enallenol
1 (1.0 mmol) in 1,2-dichloroethane (1.0 mL). The resulting mixture was
heated at 808C in a sealed tube until complete disappearance (TLC) of
the starting material. The reaction mixture was allowed to cool to room
temperature and was then quenched with aqueous saturated NH4Cl
(1.0 mL). The mixture was extracted with ethyl acetate (3ꢄ5 mL), and
the combined extracts were washed twice with brine. The organic layer
was dried (MgSO4) and concentrated under reduced pressure. Chroma-
tography of the residue with elution with ethyl acetate/hexanes mixtures
gave analytically pure tetrahydrofuran adducts 6, 8, 11, and 13.
useful preparation of the tetrahydrofuroACTHNUTRGNE[NUG 3,2-b]piperidine
core of the antimalarial alkaloid isofebrifugine. These diver-
gent heterocyclization reactions have been developed exper-
imentally and their mechanisms have additionally been in-
vestigated by a computational study that showed that the
À
protonolysis of the Au C bond constitutes the step on
which the chemoselectivity is based.
Tetrahydrofuran (Æ)-6a: This compound was obtained from enallenol 1a
(122 mg, 0.5 mmol). Chromatography of the residue with hexanes/ethyl
acetate 3:1 as eluent gave compound 6a (101 mg, 83%) as a colorless
solid. M.p.: 107–1088C (hexanes/ethyl acetate); 1H NMR (300 MHz,
CDCl3, 258C): d=7.26 and 6.87 (d, J=9.3 Hz, each 2H), 4.88 (m, 3H),
4.62 (t, J=4.5 Hz, 1H), 3.79 (s, 3H), 3.55 (d, J=4.4 Hz, 1H), 1.83 (td, J=
3.2, 0.7 Hz, 3H), 1.55 and 1.31 ppm (s, each 3H); 13C NMR (75 MHz,
CDCl3, 258C): d=204.3, 163.1, 156.2, 130.9, 117.8, 114.6, 100.3, 80.5, 76.7,
76.5, 63.2, 60.8, 55.5, 28.3, 25.4, 16.5 ppm; IR (CHCl3): n˜ =2995, 1945,
1750 cmÀ1; MS (ES): m/z (%): 300 (100) [M+H]+, 299 (18) [M]+; ele-
mental analysis calcd (%) for C18H21NO3 (299.4): C 72.22, H 7.07, N 4.68;
found: C 72.34, H 7.04, N 4.71.
Experimental Section
General methods: 1H NMR and 13C NMR spectra were recorded with
Bruker AMX 500, Bruker Avance 300, Varian VRX 300S, or Bruker
AC 200 instruments. NMR spectra were recorded in CDCl3 solutions
unless otherwise stated. Chemical shifts are given in ppm relative to
TMS (1H, 0.0 ppm) or CDCl3 (13C, 76.9 ppm). Low- and high-resolution
mass spectra were taken with a HP5989A spectrometer and use of the
electronic impact (EI) or electrospray modes (ES) unless otherwise
stated. Specific rotation [a]D is given in 10À1 degcm2 gÀ1 at 208C, and the
concentration (c) is expressed in g per 100 mL (see the Supporting Infor-
mation). All commercially available compounds were used without fur-
ther purification.
Procedure for the silver-induced reaction of bicyclic NH-b-lactam 14—
preparation of tetrahydrofuroACHTNUTRGNE[NUG 3,2-b]piperidine 15: Silver nitrate
(0.30 mmol) was added to a stirred solution of the bicyclic NH-b-lactam
14 (60 mg, 0.30 mmol) in acetone/water (1:1, 1.0 mL). The reaction mix-
ture was heated in a sealed tube at 1408C until disappearance of the
starting material (TLC). The mixture was allowed to reach room temper-
ature, after which brine (3 mL) was added and it was then extracted with
ethyl acetate (4ꢄ5 mL). The organic extract was washed with brine and
dried (MgSO4). Removal of solvent under reduced pressure yielded the
adduct 15 (38 mg, 60%) in analytically pure form.
General procedure for Au-catalyzed cyclizations of enallenols 1: AuCl3
(0.05 mmol) was added under argon to a stirred solution of the appropri-
ate enallenol 1 (1.0 mmol) in dichloromethane (1.0 mL). The resulting
mixture was stirred at room temperature until disappearance of the start-
ing material (TLC). The reaction was then quenched with brine (1.0 mL),
the mixture was extracted with ethyl acetate (3ꢄ5 mL), and the com-
bined extracts were washed twice with brine. The organic layer was dried
(MgSO4) and concentrated under reduced pressure. Chromatography of
the residue with elution with ethyl acetate/hexanes mixtures gave analyti-
cally pure dihydrofuran adducts 4, 7, 9, and 12.[23]
TetrahydrofuroACTHNUTRGNEUNG
[3,2-b]piperidine 15: Pale orange oil; 1H NMR (CDCl3,
300 MHz, CDCl3, 258C): d=12.17 (brs, 1H), 5.34 (s, 1H), 5.09 (d, J=
10.6 Hz, 1H), 4.33 (d, J=19.0 Hz, 1H), 3.97 (m, 2H), 3.59 (d, J=6.8 Hz,
1H), 1.90 (s, 3H), 1.54 and 1.26 ppm (s, each 3H); 13C NMR (75 MHz,
CDCl3, 258C): d=172.3, 138.7, 113.7, 84.8, 77.1, 63.3, 53.4, 45.2, 31.7,
25.2, 17.3 ppm; IR (CHCl3): n˜ =3370, 1718 cmÀ1; MS (EI): m/z (%): 211
(20) [M]+, 110 (100) [MÀ101]+; elemental analysis calcd (%) for
C11H17NO3 (211.3): C 62.54, H 8.11, N 6.63; found C 62.41, H 8.15,
N 6.60.
Dihydrofuran (Æ)-4a: This compound was obtained from enallenol 1a
(55 mg, 0.18 mmol). Chromatography of the residue with hexanes/ethyl
acetate 3:1 as eluent gave compound 4a (35 mg, 65%) as a colorless oil.
1H NMR (300 MHz, CDCl3, 258C): d=7.38 and 6.87 (d, J=9.0 Hz, each
2H), 5.48 (m, 1H), 5.22 (d, J=1.0 Hz, 1H), 5.15 (t, J=1.3 Hz, 1H), 5.06
(m, 1H), 4.52 (m, 2H), 4.41 (dd, J=6.1, 3.3 Hz, 1H), 4.01 (d, J=6.1 Hz,
1H), 3.79 (s, 3H), 1.83 (brs, 1H), 1.68 ppm (t, J=1.3 Hz, 3H); 13C NMR
(75 MHz, CDCl3, 258C): d=165.7, 156.3, 136.4, 134.8, 131.1, 123.9, 119.3,
116.3, 114.3, 84.0, 75.0, 59.3, 57.7, 55.5, 23.1, 13.4 ppm; IR (CHCl3): n˜ =
1746 cmÀ1; HRMS (EI): m/z calcd (%) for C18H21NO3 [M]+: 299.1521;
found: 299.1515.
Computational details
General procedure for PdII-catalyzed cyclizations of enallenols 1 in the
presence of allyl bromide: Palladium(II) chloride (0.005 mmol) was
added to a stirred solution of the appropriate enallenol 1 (0.10 mmol)
and allyl bromide (0.50 mmol) in N,N-dimethylformamide (0.6 mL). The
reaction mixture was stirred under argon until disappearance of the start-
ing material (TLC). Water (0.5 mL) was added before extraction with
ethyl acetate (3ꢄ4 mL). The organic phase was washed with water (2ꢄ
2 mL), dried (MgSO4) and concentrated under reduced pressure. Chro-
matography of the residue with elution with hexanes/ethyl acetate mix-
tures gave analytically pure adducts 5 and 10.
All the calculations reported in this paper were performed with the
GAUSSIAN 09 suite of programs.[24] All species were optimized with
Truhlarꢅs dispersion-corrected meta hybrid exchange-correlation func-
tional M06L, which has been recommend for species involving transition
metals,[25] in combination with double-x-quality def2-SVP basis sets.[26]
All minima were characterized by frequency calculations and have posi-
tive definite Hessian matrices. Transition structures (TSs) each show only
one negative eigenvalue in their diagonalized force constant matrices,
and their associated eigenvectors were confirmed to correspond to the
motion along the reaction coordinate under consideration. Solvents ef-
fects were taken into account by use of the Polarizable Continuum
Model (PCM).[27] Single-point calculations (PCM-M06L/def2-SVP) on
the gas-phase optimized geometries were performed to estimate the
changes in the Gibbs energies in the presence of dichloromethane as sol-
vent.
Dihydrofuran (Æ)-5a: This compound was obtained from enallenol 1a
(55 mg, 0.18 mmol). Chromatography of the residue with hexanes/ethyl
acetate 3:1 as eluent gave compound 5a (44 mg, 72%) as a colorless oil.
1H NMR (300 MHz, CDCl3, 258C): d=7.36 (d, J=9.0 Hz, 2H), 6.86 (d,
J=9.3 Hz, 2H), 5.58 (m, 1H), 5.20 (brs, 1H), 5.13 (m, 2H), 5.02 (m,
1H), 4.95 (dd, J=2.2, 1.5H, 1H), 4.46 (m, 2H), 4.42 (dd, J=5.9, 3.2 Hz,
1H), 3.98 (d, J=5.9 Hz, 1H), 3.78 (s, 3H), 2.72 (d, J=6.6 Hz, 2H), 1.80
(s, 3H), 1.58 ppm (d, J=1.0 Hz, 3H); 13C NMR (75 MHz, CDCl3, 258C):
d=165.7, 156.3, 136.4, 134.0, 132.6, 131.1, 127.1, 119.2 (2C), 116.2, 116.1,
Chem. Eur. J. 2011, 17, 15005 – 15013
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
15011