Total Syntheses of (±)-(Z)- and (±)-(E)-9

718 J.-L. Zhu et al. PAPER
18
a, b
82% over 2 steps
O
(±)-3
Scheme 5 Reagents and conditions: (a) TBAF (5.0 equiv), THF,
r.t., 3 h; (b) PDC (2.0 equiv, based on 24), CH2Cl2, r.t., 2 h.
In summary, we have accomplished the total synthesis of
1 and 2 in 13 steps through a novel synthetic approach. Although
the ultimate synthesis did not strictly follow the
initially designed scheme, our original goals of using the
Diels–Alder reaction to construct the A-ring and the reductive
alkylation of the Diels–Alder adduct to create the
spiro quaternary center with the suitable functionalities
for accessing the B-ring have been well realized. In the
synthetic sequence, some intermediates were produced as
the isomeric mixtures, but the separations of them were
shown to be unnecessary since all of the isomers could be
eventually converted into either of the targets. In comparison
with the previously reported syntheses (overall
yields: 0.31% 6 and 4.51% 7 for 1, 2.12% 6 and 0.45% 7 for
2, respectively), the current study did not result in a significant
improvement on the overall yields of 1 (0.85%) and
2 (1.74%), but the synthetic route developed by us appears
to be more general and the generality has been demonstrated
by the ready achievement of (±)-majusculone (3)
from the intermediate leading to 1 and 2. The application
of the same strategy for the syntheses of other members of
chamigrene family is the focus of our ongoing studies.
Unless otherwise noted, all starting materials and reagents were
purchased from commercial suppliers and used without further purification.
THF was distilled from sodium-benzophenone; toluene,
benzene, CH 2Cl 2, and DMF were distilled from CaH 2 before use.
TLC analysis and preparative TLC were performed on Macherey-
Nagel DC-Fertigplatten. Durasil-25 UV 254 glass-backed plates, and
visualized by UV, or KMnO 4 or I 2 treatment. All of the products
were purified by flash chromatography on Merck Kieselgel 60 (Art.
9385) (230–400 mesh) or neutral aluminum oxide. IR spectra were
recorded on a Jasco FT/IR 410 spectrometer. NMR spectra ( 1 H, 13 C,
DEPT, NOESY) were recorded on a Bruker Avance DPE-400 or a
Bruker Avance DPE-600 spectrometer using CDCl 3 or C 6D 6 as solvent.
High-resolution mass spectra (HRMS) and low-resolution
mass spectra (LRMS) were recorded on a Finnigan/Thermo Quest
MAT 95XL spectrometer in a fast atom bombardment (FAB) model.
Ethyl 2-Cyano-3-methylbut-2-enoate (4)
This known compound was prepared by a modified procedure as
follows. LiBr (7.82 g, 0.09 mol) and molecular sieves 3Å (300 mg)
were added to a mixture of ethyl cyanoacetate (2.0 g, 0.018 mol)
and acetone (60 mL). The suspension was refluxed for 18 h, cooled
to r.t., filtered, and concentrated in vacuo. The residue was diluted
with EtOAc (300 mL), washed with H 2O (2 × 50 mL) and brine (50
mL), and concentrated. The crude mixture was subjected to chromatographic
purification on silica gel (hexane–EtOAc, 20:1) to
yield 4 (1.82 g, 66%).
Synthesis 2011, No. 5, 715–722 © Thieme Stuttgart · New York
O
4-(tert-Butyldimethylsilyloxy)-1-cyano-2,6,6-trimethylcyclohex-3-enecarboxylic
Acid Ethyl Ester (6) and 1-[(1R*,2S*,6S*)-
4-(tert-Butyldimethylsilyloxy)-2,6-dimethylcyclohex-3enyl]ethanone
(11)
To a flame-dried 100 mL round-bottom flask were added anhyd
ZnCl 2 (804 mg, 5.9 mmol) and anhyd toluene (20 mL). The resulting
suspension was stirred under a N 2 atmosphere for 20 min before
treating with a solution of 4 (904 mg, 5.9 mmol) in anhyd toluene
(4 mL). After stirring for an additional 30 min, a solution of diene
5 10 (5.85 g, 29.5 mmol) in anhyd toluene (8 mL) was added to the
mixture. The mixture was then stirred at 80 °C for 20 h, cooled to
r.t., and diluted with EtOAc (120 mL). The solution was successively
washed with H 2O (2 × 30 mL) and brine (20 mL), dried
(Na 2SO 4), filtered, and concentrated under reduced pressure. Chromatographic
purification of the crude residue on silica gel (hexane–
EtOAc, 100:1, 60:1, and 40:1) afforded 11 11 (500 mg, generated
from 0.6 out of 5 equiv of 5) as a colorless sticky oil, followed by 6
(1.7 g, 82%) as a mixture of two isomers (50:50).
6
IR (neat): 2960, 2931, 2857, 2242, 1739, 1671, 1463, 1363, 1259,
1207, 838, 781 cm –1 .
1H NMR (400 MHz, CDCl3): d (isomer 1) = 4.57 (br s, 1 H), 4.35–
4.16 (m, 2 H), 3.04–2.95 (m, 1 H), 2.42 (br d, J=17.5 Hz, 1 H),
1.76 (d, J=17.5 Hz, 1 H), 1.33 (t, J=7.2 Hz, 3 H), 1.18–1.05 (m,
9 H), 0.90 (s, 9 H), 0.15 (s, 3 H), 0.14 (s, 3 H); d (isomer 2) = 4.51
(br s, 1 H), 4.35–4.16 (m, 2 H), 2.90–2.82 (m, 1 H), 2.41 (d, J=17.3
Hz, 1 H), 1.74 (d, J=17.3 Hz, 1 H), 1.30 (t, J=7.1 Hz, 3 H), 1.24
(s, 3 H), 1.16–1.05 (m, 6 H), 0.90 (s, 9 H), 0.14 (s, 3 H), 0.13 (s, 3
H).
13C NMR (100 MHz, CDCl3): d (isomer 1) = 167.7, 148.7, 117.6,
105.6, 62.4, 58.9, 43.0, 37.6, 33.4, 27.1, 25.6, 22.0, 18.2, 17.9, 14.2,
–4.3, –4.6; d (isomer 2) = 165.9, 149.3, 119.8, 103.7, 61.9, 57.2,
40.5, 37.0, 35.9, 26.8, 26.0, 25.6, 17.9, 17.3, 14.2, –4.3, –4.5.
HRMS-FAB: m/z calcd for C19H34NO3Si [M + H] + : 352.2308;
found: 352.2298.
11 11
IR (neat): 2958, 2929, 1712, 1673, 1253, 1195, 1180, 838, 779 cm –1 .
1H NMR (400 MHz, CDCl3): d = 4.87 (dd, J=5.2, 1.8 Hz, 1 H),
2.63 (dd, J=12.3, 6.5 Hz, 1 H), 2.51 (dd, J=10.9, 5.3 Hz, 1 H),
2.19–2.10 (m, 1 H), 2.14 (s, 3 H), 2.07 (dd, J=17.0, 5.9 Hz, 1 H),
1.75–1.68 (m, 1 H), 0.92 (d, J=4.7 Hz, 3 H), 0.91 (s, 9 H), 0.80 (d,
J=7.0 Hz, 3 H), 0.13 (s, 3 H), 0.12 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 210.8, 149.2, 109.1, 57.4, 37.9,
30.7, 30.6, 25.6, 24.8, 19.8, 18.0, 17.9, –4.3, –4.4.
HRMS-FAB: m/z calcd for C16H31O2Si [M + H] + : 283.2093; found:
283.2098.
(1S*,2S*)-1-But-3-enyl-4-(tert-butyldimethylsilyloxy)-2,6,6-trimethylcyclohex-3-enecarboxylic
Acid Ethyl Ester (12)
To a solution of 6 (548 mg, 1.56 mmol) in anhyd THF (10 mL) precooled
at –45 °C was added a THF solution of lithium naphthalenide
(0.34 M, 16.1 mL, 5.46 mmol) 13 via syringe under the protection
of a N2 atmosphere. The resulting dark green solution was stirred at
–45 °C for 30 min and successively treated with 4-bromobut-1-ene
(0.63 mL, 6.24 mmol) and HMPA (1.09 mL, 6.24 mmol). The reaction
mixture was stirred at r.t. for 12 h, then poured into sat. aq
NH4Cl (10 mL), and extracted with EtOAc (2 × 60 mL). The combined
organic extracts were washed with H2O (2 × 15 mL) and brine
(15 mL), and concentrated. Chromatographic purification of the
crude mixture on silica gel (hexane–EtOAc, 100:1) afforded 12 as a
colorless oil (416 mg, 70%).
IR (neat): 2958, 2929, 2902, 2857, 1735, 1673, 1641, 1149, 1130,
989, 939 cm –1 .