Simple and efficient synthesis of highly functionalized cyclohexanes; Formal total synthesis of ovalicin and fumagillin

Article abstract of DOI:10.1016/j.tetasy.2011.03.015

Two chiral cyclohexanes 4 and 6, which are key intermediates for the total synthesis of ovalicin 1 and fumagillin 2, respectively, were synthesized from (2R,3S) 1,2-epoxy-4-penten-3-ol. The key steps involve an efficient construction of divinylalcohol 7 u

Full text of DOI:10.1016/j.tetasy.2011.03.015

Tetrahedron: Asymmetry 22 (2011) 703–707
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Simple and efficient synthesis of highly functionalized cyclohexanes;
formal total synthesis of ovalicin and fumagillin
⇑
Shunya Takahashi , Yayoi Hongo, Yue Qi Ye, Hiroyuki Koshino
RIKEN, Wako, Saitama 351-0198, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Two chiral cyclohexanes 4 and 6, which are key intermediates for the total synthesis of ovalicin 1 and
fumagillin 2, respectively, were synthesized from (2R,3S) 1,2-epoxy-4-penten-3-ol. The key steps involve
an efficient construction of divinylalcohol 7 using methallyl Grignard reagent 9c, and an intramolecular
olefin metathesis of 7.
Received 9 March 2011
Accepted 23 March 2011
Available online 7 May 2011
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
O
O
O
O
H
O
O
OH
O
Ovalicin 1 is a highly oxygenated sesquiterpenoid that was first
isolated from cultures of Pseudorotium ovalis Stolk (Fig. 1), and
exhibits antibiotic, antitumor and immunosuppressive activi-
ties.1–3 Recent studies revealed 1 to be a nontoxic, noninflamma-
OMe
OMe
CO2H
a
more potent angiogenesis inhibitor4 than the
2
tory and
1
2
structurally related fumagillin 2,5–8 a well known anti-angiogene-
Li
sis agent.9 Angiogenesis, the growth and development of new cap-
3
illary blood vessels, is an essential process of
a variety of
O
CHO
O
CH2OH
pathological states, such as diabetic retinopathy, psoriasis, rheu-
matoid arthritis, and tumor growth.10 Thus, angiogenesis inhibitors
are promising candidates for new types of drugs. The unique struc-
tural complexity of 1 and its biological activity have attracted
much attention as an interesting synthetic target, and, since the
first total synthesis of ( )-1 reported by Corey et al.,11 many ap-
proaches to this natural product have been devised.4,12–18 Amongst
them, the synthesis developed by Quiclet-Sire and Samadi et al.
was based on a highly convergent strategy, which involved a cou-
pling reaction of vinyllithium reagent 3 and a highly functionalized
O
OMe
O
OR
TESO
R'O
4
5
6
R'O
OMPM
OR
7
cyclohexanone 4 synthesized from L-quebrachitol, and required
only three steps for preparation of 1 from the coupling prod-
uct.12,13 The alternative synthesis of 4 from (ꢀ)-quinic acid was
also reported by Pollini et al.14 In a previous paper,15 we described
O
Metal
OP
+
OR
a novel synthesis of 4 from D-mannose and an improved route from
8
9
there to 1. These synthetic examples, however, have mainly relied
on the chemical manipulations of natural polyols, which required
rather long synthetic routes, and were inconvenient for prepara-
tion of the antipode. More efficient syntheses of the key intermedi-
ate 4 are still required for further studies on the total synthesis of 1
Figure 1. Structures of angiogenesis inhibitors and their synthetic plan.
and detailed examination of its biological activity with significant
therapeutic potential.
Herein we report a short and efficient synthesis of 4 starting
from 8. In addition, the method developed here enabled us to
achieve a high-yield synthesis of Sorensen’s key intermediate
619,20 for the total synthesis of 2. This result is also discussed.
⇑
Corresponding author. Fax: +81 48 462 4627.
E-mail address: shunyat@riken.jp (S. Takahashi).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.03.015

704
S. Takahashi et al. / Tetrahedron: Asymmetry 22 (2011) 703–707
O
2. Results and discussion
2.1. Synthetic plan
b, c
a
OTBS
8b
OH
MPMO
MgCl
9c
OMPM
10
As shown in Figure 1, we envisioned cyclohexenol derivative 5
as a pivotal key intermediate for formal total synthesis of 1 and 2
because stereo- or chemoselective oxidation of 5 would be ex-
pected to produce the key intermediates 4 or 6, respectively. Our
synthetic strategy toward 5 included an efficient construction of
divinylalcohol 7 using a coupling of chiral epoxide 8 with methal-
lyllic reagent 9, and an intramolecular olefin metathesis21 as key
steps.
OH
d
OMPM
OH
O
17
16
O
g
OMPM
OH
f
2.2. Formal total synthesis of ovalicin 1
e
O
O
The known epoxide 8a22 was prepared by Sharpless asymmetric
epoxidation of commercially available 10 followed by O-methyla-
tion (Scheme 1). However, the introduction of a requisite C4 unit
into 8a was not easy. The dianion23 obtained by treatment of meth-
allyl alcohol 9a with n-BuLi-TMEDA or Grignard reagent24 pre-
pared via its transmetallation by MgBr2 did not react cleanly
with 8a. The reaction of 8a with Grignard reagent 9c25 derived
from 9b resulted in a low yield (ꢁ50%) of 11 because of the forma-
tion of ring-opened chlorohydrin, while the addition of CuI im-
proved the reaction, giving the desired alcohol in high yield. This
coupling reaction was quite sensitive toward oxygen, meaning that
restricted oxygen-free conditions were required for obtaining 11 in
high yield. This compound, however, was isolated as an insepara-
ble mixture with degradation products of the Grignard reagent.
Hence, the crude coupling product was, after chromatography
O
O
18
19
O
O
CHO
H
O
O
OMe
O
CO2H
O
2
6
2
Scheme 2. (a) Ref. 27; (b) 9c, CuI (0.22 equiv), THF, 0 °C–>rt; (c) TBAF (1.1 equiv),
THF, rt, 89% from 8b over two steps; (d) 2,2-dimethoxypropane (1.5 equiv), CSA
(0.2 equiv), CH2Cl2, rt, 95%; (e) Grubbs cat. 2nd generation (0.06 equiv), CH2Cl2,
45 °C, 91%; (f) DDQ (2.5 equiv), phosphate buffer (pH 7.4), CH2Cl2, 0 °C, 86%; (g)
Dess–Martin periodinane (1.5 equiv), NaHCO3 (1.5 equiv), CH2Cl2, 0 °C, 86%.
O
a
b
through a short column of silica gel, submitted to silylation with
chlorotriethylsilane–imidazole, giving TES derivative 12 in a pure
form (92% yield from 8a). Ring closing metathesis of 12 was
effected by treatment of Grubbs catalyst 2nd generation in dichlo-
romethane at 45 °C to afford a cyclohexene derivative 13 in 93%
yield.26 Upon treatment with DDQ in the presence of a phosphate
buffer (pH 7.4), 13 gave 14 in 95% yield. The stereoselective oxida-
tion of this with OsO4-trimethylamine N-oxide proceeded nicely to
afford 15 as a single isomer (90%). The spectroscopic and physical
data were well matched with those of the known compound.14,15
According to the previous method (1. p-TsCl, DMAP, Et3N, CH2Cl2;
2. K2CO3, MeOH; 3. Dess–Martin periodinane, NaHCO3,
CH2Cl2),14,15 15 was transformed into 4 in 90% overall yield. Since
the synthesis of 1 from 4 has already been established (39% overall
yield15 with four steps),13 the present preparation of 4 constitutes
a formal total synthesis of ovalicin 1.
R1
OR2
OMe
OH
10
8a
9a: R1 = R2 = H
9b: R1 = Cl, R2 = MPM
9c: R1 = MgCl, R2 = MPM
OH
MPMO
OTES
OMPM
c
d
OMe
OMe
11
12
OMPM
OH
OH
HO
OH
e
f
OMe
OMe
OMe
OTES
OTES
TESO
15
13
14
2.3. Formal total synthesis of fumagillin 2
A similar method via an oxirane-ring opening by Grignard re-
agent was applied to easily prepare compound 6 as follows
(Scheme 2). The TBS analog 8b27 was prepared according to a
known procedure. The coupling reaction of 8b with Grignard re-
agent 9c in THF proceeded nicely to give diol 16 in 89% yield after
desilylation with TBAF. Isopropylidenation of 16 afforded 17 in 95%
yield. Intramolecular olefin metathesis of this was performed by
the action of Grubbs 2nd generation catalyst in dichloromethane
at 45 °C to afford cyclohexene 18 in 91% yield.26 After removing
the MPM group, the resulting alcohol 1928 was oxidized with
Dess–Martin periodinane in the presence of NaHCO3, to give the
key intermediate 6 in high yield, thus completing the formal total
synthesis of fumagillin 2.19,20
O
O
O
OH
O
O
g-i
OMe
OMe
TESO
1
4
Scheme 1. (a) Ref. 22; (b) 9c, CuI (0.14 equiv), THF, 0 °C–>rt; (c) chlorotriethylsi-
lane (3.2 equiv), imidazole (6.4 equiv), DMF, rt, 92% from 8a over two steps; (d)
Grubbs cat. 2nd generation (0.05 equiv), CH2Cl2, 45 °C, 93%; (e) DDQ (3.0 equiv),
phosphate buffer (pH 7.4), CH2Cl2, 0 °C, 95%; (f) OsO4 (0.16 equiv), Me3NO
(1.5 equiv), t-BuOH, H2O, rt, 90%; (g) p-TsCl (1.4 equiv), DMAP (0.1 equiv), Et3N
(5.0 equiv), CH2Cl2, 0 °C; (h) K2CO3 (0.88 equiv), methanol, 0 °C, 93% over two steps;
(i) Dess–Martin periodinane (1.8 equiv), NaHCO3 (2.2 equiv), CH2Cl2, 0 °C, 97%.

S. Takahashi et al. / Tetrahedron: Asymmetry 22 (2011) 703–707
705
J = 14.9, 11.0, 5.9 Hz), 1.69–1.56 (2H, m), 0.96 (9H, t, J = 8.0 Hz),
0.60 (6H, q, J = 8.0 Hz); 13C NMR (125 MHz, CDCl3): d 159.1,
146.2, 135.6, 130.5, 129.3, 118.9, 113.7, 111.3, 86.3, 74.5, 72.9,
71.5, 56.4, 55.2, 31.2, 29.1, 6.9, 5.1; HRMS (ESI+) calcd for
3. Conclusion
In summary, we have developed a short and efficient method
for the synthesis of the key intermediates 4 and 6 for the total
synthesis of angiogenesis inhibitors 1 and 2. The synthesis of 4 re-
quired only eight steps and proceeded in 64% overall yield from
chiral epoxide 8a whereas 6 was obtained from 8b within six steps
in 57% overall yield. The strategy described herein would be useful
for preparing analogues of 1 and 2 suitable for clinical usage.
C
24H40O4SiNa [M+Na]+ 443.2594, found 443.2601.
4.3. (3S,4R)-3-Methoxy-1-((4-methoxybenzyloxy)methyl)-4-
(triethylsilyloxy)cyclohex-1-ene 13
To a stirred solution of 12 (110 mg, 0.26 mmol) in dichloro-
methane (11.0 mL) was added Grubbs 2nd generation catalyst
(14 mg, 16 lmol) and the resulting mixture was stirred at 45 °C
4. Experimental
for 2.5 h, and then cooled. After the addition of florisil, the resulting
mixture was filtered through a pad of Celite, and then concen-
trated. The residue was chromatographed on silica gel (n-hex-
4.1. General procedures
All reactions were carried out under an argon atmosphere, un-
less otherwise noted. Optical rotations were measured with a JAS-
CO DIP-370 polarimeter. IR spectra were recorded with a JASCO
VALOR-III spectrophotometer by ATR method. 1H NMR spectra
were recorded at 500 MHz with Varian V-500 spectrometers.
Chemical shifts were referenced to a residual signal of CDCl3 (dH
7.26) or the solvent signal (dC 77.0). ESIMS were recorded on a
Waters Micromass Quattro Premier XE mass spectrometer or JEOL
JMS-T100LC mass spectrometer. Column chromatography was per-
ane–ether = 1:0?30:1?10:1) to give 13 (96 mg, 93%) as
a
colorless oil: ½a D25
ꢂ
¼ þ70:0 (c 0.99, CHCl3); IR (ZnSe) 2874, 1612,
1513, 1245, 1081, 819, 724 cmꢀ1
;
1H NMR (500 MHz, CDCl3): d
7.26 (2H, d, J = 8.6 Hz), 6.87 (2H, d, J = 8.6 Hz), 5.80 (1H, m), 4.40
(2H, s), 3.89–3.84 (3H, m), 3.80 (3H, s), 3.63 (1H, m), 3.50 (3H, s),
2.18 (1H, m), 2.04 (1H, m), 1.98 (1H, m), 1.64 (1H, m), 0.98 (9H,
t, J = 8.1 Hz), 0.62 (6H, q, J = 8.1 Hz); 13C NMR (125 MHz, CDCl3):
d 159.1, 138.9, 130.3, 129.2, 122.3, 113.7, 76.5, 73.3, 71.7, 70.3,
58.4, 55.2, 26.4, 25.4, 6.8, 4.8; HRMS (ESI+) calcd for C22H36O4SiNa
[M+Na]+ 415.2281, found 415.2266.
formed on Kanto silica gel 60 N (spherical, neutral; 40–100 lm).
Merck precoated Silica Gel 60 F254 plates, 0.25 mm thickness,
was used for analytical thin-layer chromatography. The solvent ex-
tracts were dried with magnesium sulfate, and the solutions were
evaporated under diminished pressure at 40–42 °C.
4.4. (3S,4R)-1-Hydroxymethyl-3-methoxy-4-(triethylsilyloxy)-
cyclohex-1-ene 14
4.2. (3S,4R)-3-Methoxy-7-((4-methoxybenzyloxy)methyl)-4-
To a stirred solution of 13 (26.0 mg, 66.2 lmol) in dichloro-
triethylsilyloxyocta-1,7-diene 1229
methane (5.0 mL) and phosphate buffer (pH 7.4; 0.5 mL) was
added DDQ (45.0 mg, 0.20 mmol) at 0 °C and the resulting mixture
was stirred for 2.5 h, and diluted with ether. The organic layer was
separated and washed successively with saturated aqueous NaH-
CO3: saturated aqueous Na2S2O3 = 1:1, water, and brine. After re-
moval of the solvent, the residue was chromatographed on silica
gel (n-hexane–ethyl acetate = 1:0?10:1?4:1) to give 14
To
13.9 mmol) in tetrahydrofuran (2.0 mL) was added dropwise 1,2-
dibromoethane (20 L) at 0 °C. When the reaction started, the mix-
a stirred suspension of magnesium turnings (340 mg,
l
ture was diluted with tetrahydrofuran (1.0 mL). A solution of 9b
(453 mg, 1.99 mmol) in tetrahydrofuran (7.0 mL) was added drop-
wise during 1.5 h, and the resulting mixture was stirred for an
additional 1 h. To the solution (3.0 mL) was added CuI (5.2 mg,
(17.2 mg, 95%) as a colorless oil: ½a D24
ꢂ
¼ þ112:5 (c 0.23, CHCl3);
IR (ZnSe) 3380, 2859, 1450, 1230, 1098, 1078, 843, 719 cmꢀ1
;
1H
27.3 lmol) at 0 °C with stirring. After 10 min, a solution of 8a
NMR (500 MHz, CDCl3): d 5.75 (1H, m), 3.98 (2H, s), 3.87 (1H, dt,
J = 10.5, 3.4 Hz), 3.62 (1H, t, J = 3.4 Hz), 3.49 (3H, s), 2.19–2.07
(2H, m), 2.02–1.90 (2H, m), 1.63 (1H, m), 0.96 (9H, t, J = 8.3 Hz),
0.61 (6H, q, J = 8.3 Hz); 13C NMR (125 MHz, CDCl3): d 141.7,
119.9, 76.4, 70.5, 66.0, 58.6, 26.3, 25.0, 6.8, 4.8; HRMS (ESI+) calcd
for C14H28O3SiNa [M+Na]+ 295.1705, found 295.1715.
(22 mg, 0.19 mmol) in tetrahydrofuran (0.3 mL) was added drop-
wise to the above solution at 0 °C and the resulting mixture was
stirred for 1.5 h. After being quenched by the addition of saturated
aqueous NH4Cl, the resulting mixture was extracted with ethyl
acetate. The combined organic layers were washed successively
with water, and brine. After removal of the solvent, the residue
was passed through a short column of silica gel (n-hexane–ethyl
acetate = 10:1–>4:1) to give 105 mg of a yellow syrup containing
11, which was dissolved in N,N-dimethylformamide (2.0 mL). To
this solution were added sequentially imidazole (82 mg, 1.2 mmol)
and chlorotriethylsilane (0.1 mL, 0.6 mmol) at 0 °C with stirring,
and the resulting mixture was stirred at the same temperature
for 3 h. After the addition of ice-water, the resulting mixture was
extracted with ether. The combined organic layers were washed
successively with 5% HCl, water, saturated aqueous NaHCO3, water,
and brine. After removal of the solvent, the residue was chromato-
graphed on silica gel (n-hexane–ether = 20:1?10:1?5:1) to give
4.5. (1S,2S,3R,4R)-1-Hydroxymethyl-3-methoxy-4-(triethylsilyl-
oxy)cyclohexane-1,2-diol 15
To a stirred solution of 14 (17.0 mg, 62
lmol) and trimethyla-
mine N-oxideꢃ2H2O (10.0 mg, 94 mol) in 2-methyl-2-propanol
l
(0.60 mL) and water (0.4 mL) was added dropwise a 2.5 wt % solu-
tion of OsO4 in 2-methyl-2-propoanol (0.1 mL) at rt and the result-
ing mixture was stirred at the same temperature for 8 h. After the
addition of Na2SO3, the resulting mixture was stirred at rt for
30 min and then the organic layer was separated. The aqueous
layer was extracted with ethyl acetate. The combined organic lay-
ers were washed successively with water, and brine. After removal
of the solvent, the residue was chromatographed on silica gel (n-
hexane–ethyl acetate = 10:1?4:1?1:1) to give 15 (17.1 mg, 90%)
12 (75 mg, 92% from 8a) as a light-yellow liquid: ½a D24
¼ þ14:8 (c
ꢂ
0.80, CHCl3); IR (ZnSe) 3074, 2875, 1612, 1513, 1247, 1086, 889,
; d 7.26 (2H, d,
818, 737 cmꢀ1 1H NMR (500 MHz, CDCl3):
J = 8.6 Hz), 6.87 (2H, d, J = 8.6 Hz), 5.74 (1H, ddd, J = 17.3, 10.5,
7.9 Hz), 5.28 (1H, br d, J = 10.5 Hz), 5.22 (1H, br d, J = 17.3 Hz),
5.04 (1H, br s), 4.93 (1H, br s), 4.42 (2H, s), 3.93 (2H, s), 3.80 (3H,
s), 3.72 (1H, dt, J = 7.8, 4.1 Hz), 3.45 (1H, dd, J = 7.9, 4.1 Hz), 3.27
(3H, s), 2.23 (1H, ddd, J = 14.9, 11.0, 4.1 Hz), 2.05 (1H, ddd,
as a colorless oil: ½a D24
ꢂ
¼ ꢀ66:2 (c 0.31, CHCl3) {lit. ½a D25
¼ ꢀ63 (c
ꢂ
2.39, CHCl3),14
½
a 2D8
ꢂ
¼ ꢀ66:7 (c 1.18, CHCl3)15}; IR (ZnSe) 3384,
2875, 1119, 1072, 723 cmꢀ1 1H NMR (500 MHz, CDCl3): d 4.24
;
(1H, m), 3.90 (1H, d, J = 11.2 Hz), 3.75 (1H, d, J = 11.2 Hz), 3.42

706
S. Takahashi et al. / Tetrahedron: Asymmetry 22 (2011) 703–707
(1H, br d, J = 3.4 Hz), 3.39 (3H, s), 3.21 (1H, dd, J = 9.3, 2.5 Hz), 2.99
ethyl acetate = 10:1?6:1?4:1?1:1) to give 16 (126 mg, 89%
(1H, br s), 2.92–2.80 (2H, br s), 1.73 (1H, m), 1.67 (1H, m), 1.64 (1H,
from 8b) as a light-yellow liquid: ½a D24
¼ þ2:5 (c 0.33, CHCl3); IR
ꢂ
m), 1.45 (1H, m), 0.95 (9H, t, J = 8.0 Hz), 0.58 (6H, q, J = 8.0 Hz); 13
C
(ZnSe) 3305, 3220, 2840, 1655, 1612, 1517, 1250, 1030, 923,
NMR (125 MHz, CDCl3): d 82.8, 73.4, 72.8, 70.7, 65.4, 57.1, 27.1,
26.0, 6.8, 4.9; HRMS (ESI+) calcd C14H30O5SiNa [M+Na]+ 329.1760,
found 329.1753.
818 cmꢀ1 1H NMR (500 MHz, CDCl3): d 7.26 (2H, d, J = 8.8 Hz),
;
6.87 (2H, d, J = 8.8 Hz), 5.88 (1H, ddd, J = 17.2, 10.5, 6.6 Hz), 5.31
(1H, dt, J = 17.2, 1.5 Hz), 5.24 (1H, dt, J = 10.5, 1.5 Hz), 5.06 (1H,
br s), 4.96 (1H, br s), 4.42 (2H, s), 4.08 (1H, br s), 3.94 (2H, s),
3.80 (3H, s), 3.68 (1H, m), 2.40 (1H, d, J = 4.7 Hz), 2.33 (1H, s),
2.30 (1H, ddd, J = 14.4, 9.3, 5.9 Hz), 2.15 (1H, dt, J = 14.4, 8.0 Hz),
1.65–1.52 (2H, m); 13C NMR (125 MHz, CDCl3): d 159.2, 145.5,
136.1, 130.2, 129.4, 117.5, 113.7, 112.5, 75.9, 73.5, 72.9, 71.7,
55.2, 29.9, 29.3; HRMS (ESI+) calcd for C17H24O4Na [M+Na]+
315.1572, found 315.1568.
4.6. (3S,5R,6R)-5-Methoxy-6-triethylsilyloxy-1-oxaspiro[2.5]oct-
an-4-one 4
To a stirred mixture of 15 (583 mg, 1.90 mmol), 4-dimethylami-
nopyridine (23.3 mg, 0.19 mmol), and triethylamine (1.32 ml,
9.51 mol) in dichloromethane (4.0 ml) was added p-toluenesulfo-
nyl chloride (508 mg, 2.67 mol) at 0 °C, and the mixture was stirred
at 0 °C for 21 h. After the addition of ice-water, the resulting mix-
ture was stirred vigorously for 1.5 h, and then extracted with
EtOAc. The combined organic layers were washed successively
with 5% HCl, water, saturated aqueous NaHCO3, water, and brine.
After removal of the solvent, the residue was passed through a
short column of silica gel (n-hexane–ethyl acetate = 7:2) to give a
syrup, which was dissolved in methanol (4.0 ml). Potassium car-
bonate (231 mg, 1.61 mmol) was added to the solution at 0 °C;
the mixture was stirred at 0 °C for 1.9 h, and then concentrated.
Flash chromatography (n-hexane–ethyl acetate = 8:1) gave the cor-
responding epoxide (508 mg, 93%) as a colorless oil. To a stirred
suspension of the epoxide (300 mg, 1.04 mmol) and NaHCO3
(192 mg, 2.29 mmol) in dichloromethane (13.6 ml) was added
Dess–Martin periodinane (794 mg, 1.87 mmol) at 0 °C. The mixture
was stirred at 0 °C?rt for 3 h, and then poured into saturated
aqueous NaHCO3: saturated aqueous Na2S2O3 = 1:1 with stirring.
The resulting mixture was extracted with ether. The combined or-
ganic layers were washed successively with water, and brine. After
removal of the solvent, the residue was chromatographed on silica
gel (benzene–ether = 9:1) to give 4 (289 mg, 97%) as a light-yellow
4.8. (3S,4R)-3,4-Isopropylidendioxy-7-((4-methoxybenzyloxy)-
methyl)octa-1,7-diene 17
To a stirred solution of 16 (0.1 g, 0.34 mmol) and 2,2-dime-
thoxypropane (39
was added CSA (16 mg, 69
l
L, 0.51 mmol) in dichloromethane (1.0 mL)
mol) at rt. The mixture was stirred
l
at rt for 5 h, and diluted with ether. The organic layer was washed
successively with saturated aqueous NaHCO3, water, and brine.
After removal of the solvent, the residue was chromatographed
on silica gel (n-hexane–ethyl acetate = 10:1?4:1) to give 17
(108 mg, 95%) as a colorless oil: ½a D25
¼ þ2:2 (c 0.74, CHCl3); IR
ꢂ
(ZnSe) 2910, 2845, 1610, 1510, 1243, 1065, 1035, 862, 818 cmꢀ1
;
1H NMR (500 MHz, CDCl3): d 7.26 (2H, d, J = 8.5 Hz), 6.88 (2H, d,
J = 8.5 Hz), 5.81 (1H, ddd, J = 17.1, 10.2, 7.8 Hz), 5.30 (1H, d,
J = 17.1 Hz), 5.23 (1H, d, J = 10.2 Hz), 5.07 (1H, br s), 4.95 (1H, br
s), 4.49 (1H, t, J = 7.8 Hz), 4.42 (2H, s), 4.15 (1H, dt, J = 7.8,
4.9 Hz), 3.94 (2H, s), 3.80 (3H, s), 2.26 (1H, ddd, J = 14.9, 10.5,
5.2 Hz), 2.12 (1H, ddd, J = 14.9, 10.3, 5.9 Hz), 1.66 (1H, m), 1.58
(1H, m), 1.49 (3H, s), 1.37 (3H, s); 13C NMR (125 MHz, CDCl3): d
159.2, 145.4, 134.3, 130.3, 129.2, 118.2, 113.6, 111.9, 108.0, 79.6,
77.6, 72.7, 71.5, 55.1, 29.5, 28.4, 28.2, 25.6; HRMS (ESI+) calcd for
oil: ½a 2D9
ꢂ
¼ ꢀ7:7 (c 1.87, CHCl3) {lit. ½a D26
ꢂ
¼ ꢀ9:4 (c 0.55, CHCl3)15
,
½
a 2D0
ꢂ
¼ ꢀ87 (c 1.15, CHCl3)13}; IR (ZnSe) 2955, 1745, 1111, 1098,
C
20H28O4Na [M+Na]+ 355.1885, found 355.1882.
1067, 1021, 749 cmꢀ1 1H NMR (270 MHz, CDCl3): d 4.38 (1H, m),
;
3.92 (1H, br d, J = 2.3 Hz), 3.40 (3H, s), 3.22 (1H, d, J = 4.9 Hz),
2.74 (1H, d, J = 4.9 Hz), 2.45 (1H, m), 2.06–1.98 (2H, m), 1.55 (1H,
dt, J = 14.2, 4.6 Hz), 0.91 (9H, t, J = 7.7 Hz), 0.57 (6H, q, J = 7.7 Hz);
13C NMR (67.5 MHz, CDCl3): d 202.1, 87.2, 71.8, 60.4, 58.2, 51.3,
28.7, 26.8, 6.8, 4.8; Anal. Calcd for C14H26O4Si: C, 58.70; H, 9.15.
Found: C, 58.59; H, 9.03
4.9. (3S,4R)-3,4-Isopropylidendioxy-1-((4-methoxybenzyl-
oxy)methyl)cyclohex-1-ene 18
Following the same procedure as described for 13, 17 (81.6 mg,
0.25 mmol) gave 18 (67.7 mg, 91%) as a colorless oil: ½a D24
¼ ꢀ21:1
ꢂ
(c 0.23, CHCl3); IR (ZnSe) 2982, 2913, 1611, 1512, 1237, 1214,
4.7. (3S,4R)-7-((4-Methoxybenzyloxy)methyl)octa-1,7-diene-
1085, 1057, 1030, 880, 855, 817 cmꢀ1 1H NMR (500 MHz, CDCl3):
;
3,4-diol 1629
d 7.24 (2H, d, J = 8.6 Hz), 6.86 (2H, d, J = 8.6 Hz), 5.73 (1H, m), 4.50
(1H, t, J = 3.5 Hz), 4.40 (2H, s), 4.28 (1H, dt, J = 6.2, 3.5 Hz), 3.90 (2H,
br s), 3.78 (3H, br s), 2.14 (1H, m), 1.94 (1H, m), 1.90 (1H, m), 1.79
(1H, m), 1.41 (3H, s), 1.37 (3H, s); 13C NMR (125 MHz, CDCl3): d
159.1, 139.6, 130.2, 129.2, 121.7, 113.6, 108.2, 73.1, 72.8, 71.7,
71.6, 55.1, 28.0, 26.2, 25.5, 21.5; HRMS (ESI+) calcd for C18H24O4Na
[M+Na]+ 327.1572, found 327.1561.
To a stirred solution (8.0 mL) of Grignard reagent prepared from
magnesium turnings (340 mg, 13.9 mmol), 9b (453 mg,
2.00 mmol) and a trace amount of 1,2-dibromoethane in tetrahy-
drofuran (10.0 mL) as described for the preparation of 12 was
added CuI (20.0 mg, 0.11 mmol) at 0 °C. After 15 min, a solution
of 8b (104 mg, 0.49 mmol) in tetrahydrofuran (0.7 mL) was added
dropwise to the above solution at 0 °C and the resulting mixture
was stirred for 1.5 h. After being quenched by the addition of sat-
urated aqueous NH4Cl, the resulting mixture was extracted with
ethyl acetate. The combined organic layers were washed succes-
sively with water, and brine. After removal of the solvent, the res-
idue was passed through a short column of silica gel (n-hexane–
ethyl acetate = 10:1–>4:1) to give a yellow syrup (271 mg), which
was dissolved in tetrahydrofuran (2.0 mL). To this solution was
4.10. (3S,4R)-1-Hydroxymethyl-3,4-isopropylidendioxycyclohex-
1-ene 19
Following the same procedure as described for 14, 18 (48.2 mg,
0.16 mmol) gave 19 (25.1 mg, 86%) as a colorless oil: ½a D25
¼ ꢀ18:4
ꢂ
(c 0.54, CHCl3); IR (ZnSe) 3391, 2983, 2919, 1648, 1369, 1213,
1053, 1020, 851 cmꢀ1 1H NMR (500 MHz, CDCl3): d 5.66 (1H, m),
;
4.46 (1H, br s), 4.24 (1H, br dt, J = 3.9, 5.9 Hz), 3.98 (2H, s), 2.55
(1H, br s), 2.08 (1H, m), 1.88–1.80 (2H, m), 1.76 (1H, m), 1.35
(3H, s), 1.32 (3H, s); 13C NMR (125 MHz, CDCl3): d 142.5, 119.0,
108.2, 72.9, 71.6, 65.8, 28.0, 26.1, 25.6, 21.3; HRMS (EI+) calcd for
C9H13O3 [M-Me]+ 169.0865, found 169.0871.
added
a 1.0 M solution of TBAF in tetrahydrofuran (0.5 mL,
0.5 mmol) at 0 °C with stirring. The resulting mixture was stirred
at the same temperature for 2 h, and diluted with ethyl acetate.
The organic layer was washed with brine. After removal of the sol-
vent, the residue was chromatographed on silica gel (n-hexane–

S. Takahashi et al. / Tetrahedron: Asymmetry 22 (2011) 703–707
707
9. Ingber, D.; Fujita, T.; Kishimoto, S.; Sudo, K.; Kanamaru, T.; Brem, H.; Folkman, J.
Nature 1990, 348, 555–557.
10. Auerbach, W.; Auerbach, R. Pharmacol. Ther. 1994, 63, 265–311.
11. Corey, E. J.; Dittami, J. P. J. Am. Chem. Soc. 1985, 107, 256–257.
12. Bath, S.; Billington, D. C.; Gero, S. D.; Quiclet-Sire, B.; Samadi, M. J. Chem. Soc.,
Chem. Commun. 1994, 1495–1496.
13. Barton, D. H. R.; Bath, S.; Billington, D. C.; Gero, S. D.; Quiclet-Sire, B.; Samadi,
M. J. Chem. Soc., Perkin Trans. 1 1995, 1551–1558.
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Tetrahedron: Asymmetry 1998, 9, 2857–2864.
4.11. (3S,4R)-3,4-Isopropylidendioxycyclohex-1-enecarbalde-
hyde 6
Following the same procedure as described for 4, 19 (21.7 mg,
0.12 mmol) gave 6 (18.4 mg, 86%) as a colorless oil: ½a D24
¼ ꢀ48:3
ꢂ
(c 0.44, CHCl3) {lit.20
½
a 2D3
ꢂ
¼ ꢀ41:0 (c 1.0, CHCl3)}; IR (ZnSe) 2984,
2932, 2845, 1679, 1641, 1371, 1211, 1149, 1055, 1029 cmꢀ1 1H
;
NMR (500 MHz, CDCl3): d 9.47 (1H, s), 6.55 (1H, m), 4.67 (1H, dt,
J = 1.7, 3.4 Hz), 4.40 (1H, dt, J = 3.4, 5.4 Hz), 2.26–2.21 (2H, m),
2.06 (1H, ddd, J = 14.0, 9.3, 4.6 Hz), 1.75 (1H, m), 1.37 (3H, s),
1.32 (3H, s); 13C NMR (125 MHz, CDCl3): d 193.7, 144.9, 142.0,
109.2, 72.8, 71.5, 27.8, 26.1, 24.3, 16.0; HRMS (EI+) calcd for
C9H11O3 [MꢀMe]+ 167.0708, found 167.0714.
15. Takahashi, S.; Hishinuma, N.; Koshino, H.; Nakata, T. J. Org. Chem. 2005, 70,
10162–10165.
16. Yamaguchi, J.; Toyoshima, M.; Shoji, M.; Kakeya, H.; Osada, H.; Hayashi, Y.
Angew. Chem., Int. Ed. 2006, 45, 789–793.
17. For the synthesis of
1 via a similar epoxy ketone with a TBSO group:
Tiefenbacher, K.; Arion, V. B.; Mulzer, J. Angew. Chem., Int. Ed. 2007, 46, 2690–
2693. and also Ref. 18.
18. Yadav, J. S.; Reddy, P. N.; Reddy, B. V. S. Synlett 2010, 457–461.
19. Vosburg, D. A.; Weiler, S.; Sorensen, E. J. Angew. Chem., Int. Ed. 1999, 38, 971–
974.
Acknowledgments
20. Vosburg, D. A.; Weiler, S.; Sorensen, E. J. Chirality 2003, 15, 156–166.
21. Grubbs, R. H., Ed.Handbook of Metathesis; Wiley-VCH, 2003; Vols. 1–3,.
22. Okamoto, S.; Kobayashi, Y.; Kato, H.; Hori, K.; Takahashi, T.; Tsuji, J.; Sato, F. J.
Org. Chem. 1988, 53, 5590–5592.
23. Goodenough, K. M.; Raubo, P.; Harrity, J. P. A. Org. Lett. 2005, 7, 2993–2996.
24. Brioche, J. C. R.; Goodenough, K. M.; Whatrup, D. J.; Harrity, J. P. A. J. Org. Chem.
2007, 72, 1946–1953.
25. Boulet, S. L.; Paquette, L. A. Synthesis 2002, 895–900.
26. Differing from the case in Ref. 25, our substrates 12 and 17 had oxygen
functions around the reactive sites. Hence, 5–6 mol % of Grubbs catalyst 2nd
generation was employed to drive the cyclization efficiently.
27. Nicolaou, K. C.; Webber, S. E.; Pamphal, J.; Abe, Y. Angew. Chem., Int. Ed. Engl.
1987, 26, 1019–1021.
This work was supported in part by the Chemical Genomics
Project (RIKEN) and a Grant-in-Aid for Scientific Research from
the Ministry of Education, Science, Sports, and Culture of Japan.
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