Communication
tography (3.5 × 8.5 cm silica gel; hexanes/ethyl acetate, 7:3 to 65:35
as eluent) to yield enyne 21 as a yellow solid: 197.0 mg, 76 %. TLC
Rf (hexanes/EtOAc, 3:2): 0.36; m.p. 84–85 °C. 1H NMR (300 MHz,
CDCl3): δ = 4.56 (s, 2 H), 2.74 (s, 1 H), 2.58 (t, J = 6.0 Hz, 2 H), 2.42
(t, J = 7.3, 6.2 Hz, 2 H), 1.97 (quint, J = 6.1 Hz, 2 H), 0.20 (s, 9 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 195.8, 169.1, 119.9, 104.3, 96.7,
64.4, 37.4, 27.0, 21.5, –0.2 ppm.
modest yield, which possesses all the functionality as found in
escobarine A.
6-(Hydroxymethyl)-1-[(trimethylsilyl)ethynyl]-7-oxabicyclo-
[4.1.0]heptan-2-one (22): A solution of the corresponding cyclo-
hexenone 21 (42.0 mg, 0.19 mmol), and tetrabutylammonium bro-
mide (20.0 mg, 0.06 mmol) in DCM was cooled down to 0 °C before
H2O2 (48 mg, 0.70 mmol, 50 % in water) and NaOH (20.0 μL, 1.6 mg,
Scheme 4. Pathway to installing acetylene and oxidations. Reagents and con-
ditions: (a) ethynyl trimethylsilane, PdCl2(PPh3)2, CuI, DIPA, THF, 0 °C to room
temp., 13 h; (b) H2O2, NaOH cat., TBAB cat., CH2Cl2, 2 h; (c) TBAF, THF 0 °C,
15 min; (d) PCC, CH2Cl2.
0.04 mmol, aq. 2
for 5 h at 0 °C. The solution was treated with CH2Cl2 and washed
with saturated Na2S2O3 solution, HCl (aqueous 0.5 ) and brine.
N) were added. The resulting solution was stirred
N
Conclusions
Combined organic layer was dried with MgSO4, filtered and concen-
trated under vacuum. The crude product was purified by flash col-
umn chromatography (2.0 × 10.0 cm silica gel; hexanes/ethyl ace-
tate, 7:3 as eluent) to yield epoxide 22 as a colorless oil: 34 mg,
In summary, the functionalized ring C of escobarines A and B
were prepared starting from cyclohexenone. Installation of the
β-hydroxymethyl group on cyclohexenone was accomplished
by the umpolung effect. β-(Hydroxymethyl)cyclohexenone was
iodinated with trfluoroacetyl hypoiodite and further functional-
ized into ring C of escobarine B in four more steps and finally,
oxidation of the hydroxymethyl group gave ring C of escobar-
ine A. Synthesis of these natural products from sclareolide will
be reported in due course.
1
76 %. TLC Rf (hexanes/EtOAc, 3:2): 0.48. H NMR (300 MHz, CDCl3):
δ = 3.91 (d, J = 6.0 Hz, 2 H), 2.59 (dt, J = 17.3, 4.9 Hz, 1 H), 2.35 (dt,
J = 15.0, 4.9 Hz, 1 H), 2.21–2.02 (m, 3 H), 1.87 (dtd, J = 13.8, 10.2,
5.1 Hz, 1 H), 1.70 (dtd, J = 13.5, 10.9, 5.2 Hz, 1 H), 0.19 (s, 9 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 200.1, 95.9, 95.6, 70.7, 65.4, 58.5, 36.0,
23.8, 17.3, –0.4 ppm.
1-Ethynyl-6-(hydroxymethyl)-7-oxabicyclo[4.1.0]heptan-2-one
(23): A solution of silane 22 (32.0 mg, 0.13 mmol) in THF (1 mL)
was cooled down to 0 °C and stirred for 10 min before tetrabutyl-
ammonium fluoride (1.0 M, 0.15 mL, 39.2 mg, 0.15 mmol) was added
Experimental Section
dropwise over 5 min. Reaction was allowed to be stirred from
10 min at 0 °C. Then, reaction was quenched with brine and ex-
tracted three times with CH2Cl2. Combined organic layer was dried
with MgSO4, filtered and concentrated under vacuum. The crude
product was purified by flash column chromatography (2.0 × 7.0 cm
silica gel; hexanes/ethyl acetate, 3:2 as eluent) to yield alkyne 23 as
a colorless liquid: 21.6 mg, 98 %. TLC Rf (hexanes/EtOAc, 3:2): 0.28.
1H NMR (300 MHz, CDCl3): δ = 3.95 (s, 2 H), 2.68 (s, 1 H), 2.67–2.57
(m, 1 H), 2.39 (dt, J = 15.1, 5.0 Hz, 1 H), 2.30–2.08 (m, 3 H), 1.91
(ddq, J = 20.5, 10.2, 5.1 Hz, 1 H), 1.76 (ddq, J = 13.7, 11.0, 5.6 Hz, 1
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 200.3 (CO), 77.7 (CH), 74.9
(C), 70.6 (C), 65.2 (CH2), 58.3 (C), 35.8 (CH2), 23.7 (CH2), 17.2 (CH2)
3-(Hydroxymethyl)-2-iodocyclohex-2-en-1-one (19): To a solu-
tion of iodine (2.01 g, 7.93 mmol) and pyridine (1.4 mL, 1.375 g,
17.38 mmol) in dry CH2Cl2 (9.0 mL), was added PhI(OCOCF3)2
(3.41 g, 7.93 mmol) and BHT (35 mg) at room temperature and
stirred for 20 min under Ar atmosphere. To the reaction mixture
was added cyclohexenone 12 (1.0 g, 7.93 mmol) and stirred in the
dark for 24 h. The reaction mixture was quenched with saturated
aqueous NaHCO3 and extracted with EtOAc. The organic phase was
then washed with saturated aqueous Na2S2O3 and brine. Each
aqueous phase was extracted two more times with EtOAc. Com-
bined organic layers were dried then over Na2SO4, filtered and con-
centrated under vacuum, protecting from light to avoid decomposi-
tion. The crude product was purified by flash column chromatogra-
phy (3.0 × 8.0 cm silica gel; hexanes/ethyl acetate, 85:15 as eluent)
to yield 2-iodo-enone 19 as a yellowish solid: 1.075 g, 54 %. TLC Rf
ppm. HRMS (ESI+): calcd. for C9H11O3 [M + H]+ 167.0708, found
+
167.0711.
6-Ethynyl-5-oxo-7-oxabicyclo[4.1.0]heptane-1-carbaldehyde
(24):
A suspension of pyridinium chlorochromate (42 mg,
1
(hexanes/EtOAc, 6:4): 0.43; m.p. 79–81 °C (decomposition). H NMR
0.19 mmol), ammonium chloride (21 mg, 0.27 mmol), and molecular
sieves 4 Å (53 mg) in CH2Cl2 (2.9 mL) was cooled to 0 °C. To this
orange reaction mixture was added a solution of the allylic alcohol
23 (18 mg, 0.11 mmol) in CH2Cl2 over a period of 10 min. The
cooling bath was removed after ten minutes and the reaction mix-
ture warmed up to room temperature. An equivalent of PCC (24 mg,
0.11 mg) was added after 5 h. Reaction was stirred overnight. The
reaction mixture was diluted with CH2Cl2 and filtered through a
small plug of celite and solvent evaporated under vacuum. The
(300 MHz, CDCl3): δ = 4.49 (s, 2 H), 2.78–2.58 (m, 4 H), 2.11 (s, 1 H),
2.09–1.99 (m, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 192.0, 167.4,
104.0, 71.5, 37.0, 29.9, 22.1 ppm.
3-(Hydroxymethyl)-2-[(trimethylsilyl)ethynyl]cyclohex-2-en-1-
one (21): A mixture of 2-iodocyclohexenone 19 (300.0 mg,
1.19 mmol), PdCI2(PPh3)2 (42.0 mg, 0.06 mmol), and Cul (23.0 mg,
0.12 mmol) were suspended in THF (3.1 mL), and cooled down to
0 °C under Ar atmosphere and in the dark. Ethynyltrimethylsilane
(0.34 mL, 236.0 mg, 2.40 mmol) and diisopropylamine (0.4 mL, crude product was purified by flash column chromatography
288.0 mg, 2.85 mmol) were added after ten minutes, and the result- (2.0 × 12.0 cm silica gel; hexanes/ethyl acetate, 65:35 as eluent) to
ing yellow to dark brown solution was stirred for 13 h from 0 °C to yield aldehyde 24 as a yellowish oil: 9 mg, 53 %. TLC Rf (hexanes/
room temperature. The reaction mixture was partitioned between EtOAc, 3:2): 0.45. 1H NMR (300 MHz, CDCl3): δ = 9.36 (s, 1 H), 2.75
CH2Cl2 and a solution 0.5
M
of HCI. The aqueous layer was extracted
(s, 1 H), 2.68 (dt, J = 17.7, 5.6 Hz, 1 H), 2.43 (ddd, J = 15.4, 9.4, 5.8 Hz,
with CH2Cl2 (three times). Combined organic layer was washed with 1 H), 2.31–2.15 (m, 2 H), 1.99–1.75 (m, 2 H) ppm. 13C NMR (75 MHz,
brine and dried with MgSO4. Filtration and concentration gave the CDCl3): δ = 197.3 (CO), 195.8 (CO), 79.5 (CH), 72.9 (C), 69.6 (C), 56.4
crude reaction mixture. The crude was filtered through a short pad
of silica. The crude product was purified by flash column chroma-
(C), 35.7 (CH2), 20.0 (CH2), 17.3 (CH2) ppm. HRMS (ESI+): calcd. for
+
C9H8O3 [M + H]+ 165.0552, found 165.0547.
Eur. J. Org. Chem. 2016, 51–54
53
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