Synthetic studies towards optically active 13-oxyingenol via asymmetric cyclopropanation

Article abstract of DOI:10.1055/s-0030-1259430

The enantioselective synthesis of a seven-membered enone compound, the key intermediate of our previous synthesis of the inside-outside framework of 13-oxyingenol in racemic form, was achieved by using asymmetric cyclopropanation and reductive deoxygenation as key steps. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1259430

PAPER
769
Synthetic Studies towards Optically Active 13-Oxyingenol via Asymmetric
Cyclopropanation
S
ynthetic Studies to
h
wards
O
ptic
a
i
lly Ac
r
tive 13-O
o
xyingenol Hayakawa, Yamato Miyazawa, Takayuki Ohyoshi,1 Yuki Asuma, Kenta Aoki, Hideo Kigoshi*
Department of Chemistry, Graduate School of Pure and Applied Sciences, University of Tsukuba, Ibaraki 305-8571, Japan
Fax +81(29)8534313; E-mail: kigoshi@chem.tsukuba.ac.jp
Received 16 November 2010; revised 4 January 2011
dimethylsilyl enol ether 4. Pfaltz and co-workers had re-
ported the asymmetric cyclopropanation of cyclic silyl
enol ethers.7 Therefore, it was planned to construct the op-
tically active intermediate 5 of our previous synthesis of
the inside–outside framework of 13-oxyingenol 11 in ra-
cemic form by using asymmetric cyclopropanation. In this
paper, we report our synthetic approach to optically active
13-oxyingenol (1).
Abstract: The enantioselective synthesis of a seven-membered
enone compound, the key intermediate of our previous synthesis of
the inside–outside framework of 13-oxyingenol in racemic form,
was achieved by using asymmetric cyclopropanation and reductive
deoxygenation as key steps.
Key words: 13-oxyingenol, asymmetric cyclopropanation, chiral
aza-semicorrin ligand, reductive deoxygenation, intramolecular
aldol reaction
TBSO
TBSO
TBSO
13-Oxyingenol (1) is a diterpenoid isolated from Euphor-
bia kansui,2 whose derivatives have strong protein kinase
C activation and anti-HIV activities (Figure 1).3 Particu-
larly, 13-oxyingenol derivatives such as 2 have strong
anti-HIV activity. The structural features of ingenol (3)
and 13-oxyingenol (1) are a high degree of oxygenation
and a highly strained inside–outside bicyclic ring system.
Because of their unique structures and strong bioactivi-
ties, ingenols have attracted the interest of synthetic or-
ganic chemists, and several groups have achieved the total
synthesis of ingenol (3).4 In 2004, we reported the formal
total synthesis of optically active ingenol (3) by using
ring-closing olefin metathesis as a key step.5
regioselective
cyclopropanation
HO
HO
OTHP
OTHP
CO2Me
6
4
5
Me
Me
Br
Si
TBSO
O
oxidative cleavage and
intramolecular aldol reaction
MeO2C
MeO2C
O
O
8
7
Me
Me
C11H23COO
O
Me Si
13
O
Me Si
O
O
B
D
D
C
C
intramolecular
radical cyclization
1
H
1
H
10
8
8
10
H
A
A
B
MeO2C
R1O
O
O
HO
O
H
O
HO
OR2
H
H
HO
OH
9
10
ingenol (3)
13-oxyingenol (1)
1 = H, R2 = COC5H11
13-oxyingenol derivative RD4-2138 (2)
1 = CO-t-Bu, R2 = H
Me
R
O
Me Si
ring-closing
olefin metathesis reaction
R
O
Figure 1 Structures of ingenol, 13-oxyingenol, and its derivative
H
RD4-2138
H
In 2007, we reported the construction of an inside–outside
framework of 13-oxyingenol 11 in racemic form by using
intramolecular radical cyclization and ring-closing olefin
metathesis as key steps (Scheme 1).6 In that synthesis, the
cyclopropane ring in intermediate ( )-5 was constructed
by using regioselective cyclopropanation of tert-butyl-
inside–
outside framework of
13-oxyingenol (11)
Scheme 1 Synthetic study of 13-oxyingenol (1): construction of the
full carbon framework by our group.
The tert-butyldimethylsilyl enol ether 4, a precursor of
asymmetric cyclopropanation was synthesized from 2-(4-
hydroxyphenyl)ethanol (12) (Scheme 2).6 The selective
protection of the primary hydroxy group of 2-(4-hydroxy-
SYNTHESIS 2011, No. 5, pp 0769–0777
Advanced online publication: 31.01.2011
DOI: 10.1055/s-0030-1259430; Art ID: F20810SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
1
1

770
I. Hayakawa et al.
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phenyl)ethanol (12) gave the THP ether 13, which was ee) and 15b (29%, 52% ee) (entry 2). Next, an asymmetric
converted into the TBS ether 14. The Birch reduction of cyclopropanation was attempted by using tert-butyl di-
14 afforded the tert-butyldimethylsilyl enol ether 4.
azoacetate with aza-semicorrin ligand 18. However, the
diastereoselectivity was not improved (trans/cis = 1.1:1)
(entry 3). Other asymmetric cyclopropanations of 4 by us-
ing asymmetric Rh-catalyst8 [Rh2(S-DOSP)4 and Rh2(S-
PTTL)4] were not effective in this case. The determination
of the stereostructures of 15a and 15b with the absolute
configuration is discussed later (Scheme 7).
OH
OH
DHP
p-TsOH⋅H2O
CH2Cl2, r.t.
TBSCl
imidazole
DMF, r.t.
quant
70%
OH
OTHP
Thus, the optimization of a precursor for this asymmetric
cyclopropanation was investigated next (Table 2). First,
the asymmetric cyclopropanation of the sterically bulky
silyl enol ethers, such as TIPS enol ether 19 or TES enol
ether 20 was attempted. However, the diastereoselectivity
was not affected (entries 1 and 2). The less-hindered
methyl enol ether 21 undergoes cyclopropanation with
high diastereoselectivity (trans/cis = 7.2:1), but the enan-
tioselectivity was low (26a = 31% ee, entry 3). Also, the
cyclopropanation of MEM enol ether 22 and SEM enol
ether 23 gave results similar to that of 21 (entries 4 and 5).
12
13
OTBS
TBSO
Li, liq. NH3
t-BuOH–THF
–33 °C
99%
OTHP
OTHP
14
4
Scheme 2 Synthesis of tert-butyldimethylsilyl enol ether 4
From these results, the asymmetric cyclopropanation was
most efficiently effected by using tert-butyldimethylsilyl
enol ether 4 and ethyl diazoacetate with aza-semicorrin
ligand 18 (Table 1, entry 2). Next, the transformation of
compound 15a into the optically active intermediate 5 re-
ported in our previous synthetic study was tried
(Scheme 3). Thus, the methylation of ester 15a and the re-
duction of the ethyl ester group in compound 29 afforded
the alcohol 30. The stereochemistry of the methyl group
at C-15 in 30 was determined by the NOESY correlation
between C-14 proton and C-16 methyl protons.
Our attempts at asymmetric cyclopropanation of tert-bu-
tyldimethylsilyl enol ether 4 are summarized in Table 1.
Pfaltz and co-workers reported that the use of CuOTf with
chiral heterocyclic nitrogen ligands such as bisoxazoline
17 or aza-semicorrin 18 was the most efficient method.7
We followed their procedure and found that an asymmet-
ric cyclopropanation between tert-butyldimethylsilyl enol
ether 4 and ethyl diazoacetate with bisoxazoline ligand 17
gave the desired cyclopropanes 15a and 15b, but the yield
was low (entry 1). The reaction with aza-semicorrin
ligand 18 gave the desired cyclopropanes 15a (46%, 91%
Table 1 Optimization of Reaction Conditions for Asymmetric Cyclopropanation
asymmetric ligand
CO2R
H
CO2R
H
OTBS
TBSO 15
TBSO15
(CuOTf)2⋅C6H6
2,2,6,6-tetramethylpiperidine
diazo compound
trans
cis
H
14 H
14
solvent, r.t.
+
OTHP
O
OTHP
OTHP
4
Me
N
15b R = Et
16b R = t-Bu
15a R = Et
16a R = t-Bu
O
N
N
N
N
t-Bu
t-Bu
TMSO
OTMS
17
18
Entry
Asymmetric ligand
Diazo compound
ethyl diazoacetate
Solvent
CHCl3
Yield (%) (ee, %)a,b
dra,c trans/cis
1
2
3
17
15a = 9.5 (73)
15b = 9.8 (78)
1.0:1
18
18
ethyl diazoacetate
DCE
DCE
15a = 46 (91)
15b = 29 (52)
1.6:1
1.1:1
tert-butyl diazoacetate
16a = 44 (82)
16b = 40 (76)
a The relative stereochemistry and the enantiomeric excess were determined after the removal of the THP group to the corresponding alcohol.
b The enantiomeric excess was determined by HPLC analysis using a chiral column (DAICEL CHIRALCEL OD).
c The relative stereochemistry was determined by coupling constant analysis of 1H NMR between H-14 and H-15.
Synthesis 2011, No. 5, 769–777 © Thieme Stuttgart · New York

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Synthetic Studies towards Optically Active 13-Oxyingenol
771
Table 2 Optimization of Reaction Precursor for Asymmetric Cy-
clopropanation
OH
Cl
TBSO
TBSO
TBSO
Ph3P
i-Pr2NEt
CCl4
H
H
CO2Et
H
CO2Et
H
RO15
RO 15
asymmetric ligand 18
(CuOTf)2⋅C6H6
2,2,6,6-tetramethylpiperidine
ethyl diazoacetate
DCE, r.t.
RO
trans
+
cis
reflux
14 H
H
14
OTHP
OTHP
OTHP
31
32
87%
30
OTHP
24b–28b
OTHP
24a–28a
OTHP
19–23
OMs
O
TBSO
MsCl, Et3N
THF, –78 °C
Entry
1
R
Yield (%) (ee, %)a,b
dra,c trans/cis
H
TIPS (19)
24a 33 (91)
24b 21 (58)
1.6:1
OTHP
OTHP
2
3
4
5
TES (20)
Me (21)
25a 33 (77)
25b 19 (41)
1.7:1
7.2:1
8.3:1
10:1
33a
34
70%
Scheme 4 Introduction of leaving groups in 30
26a 56 (31)
26b 7.8d
(trace) and undesired ring-opened compounds, such as 32
and 34 (entry 1). In entry 2, compound 30 was trans-
formed into the diphenyl phosphate 33b,9 which was then
treated with LiBHEt3 to give the desired compound (–)-5
(ca. 29%) along with the undesired ring-opened com-
pounds. N,N,N¢,N¢-Tetramethylphosphodiamidate 33c10
generated in situ from compound 30 was reduced by
LiBHEt3 to provide the desired compound (–)-5 in 74%
yield without a ring-opening reaction (entry 3). Com-
pound (–)-5 is the optically active form of our previous in-
termediate for an inside–outside framework of 13-
oxyingenol.6
MEM (22)
SEM (23)
27a 48 (39)
27b 5.8d
28a 65 (36)
28b 6.5d
a The relative stereochemistry and the enantiomeric excess were de-
termined after the removal of the THP group to corresponding alco-
hol.
b The enantiomeric excess was determined by HPLC analysis using a
chiral column (DAICEL CHIRALCEL OD).
c The relative stereochemistry was determined by coupling constant
of 1H NMR between H-14 and H-15.
d The enantiomeric excess was not determined.
To determine the absolute stereochemistry of the cyclo-
propane part in (–)-5 by using a modified Mosher’s meth-
od,11 compound (–)-5 was converted into the MTPA ester
40.6 Selective removal of the THP group in (–)-5 gave al-
cohol 35,12 which was oxidized to carboxylic acid 37 by
Dess–Martin oxidation and subsequent Pinnick oxidation.
Carboxylic acid 37 was transformed into methyl ester 38
CO2Et
TBSO
TBSO
15
CO2Et
H
H
H
LDA, MeI
THF, –78 °C
OTHP
OTHP
29
15a
16
OH
TBSO
13
15
14
TBSO
TBSO
17
LiAlH4, THF
0 °C
13
OTBS
H
H
Dess–Martin
periodinane
CH2Cl2, r.t.
NOESY
14
80% in 2 steps
Me
16
THPO
15
OTHP
OR
HO
17
CHO
30
propylene glycol
140 °C, 70%
(–)-5 R = THP
35 R = H
36
Scheme 3 Synthesis of 30
TBSO
TBSO
The deoxygenation of the primary hydroxy group in 30
was attempted next by reducing the corresponding chlo-
ride 31 or mesylate 33a (Scheme 4). However, the chlori-
nation or mesylation of 30 gave undesired ring-opened
compounds 32 or 34 because of the instability of com-
pound 31 or 33a.
NaClO2
11
NaH2PO4⋅2H2O
2-methylbut-2-ene
t-BuOH, r.t.
9
OsO4, NMO
acetone–H2O, r.t.
HO
10
HO
75%
CO2Me
(–)-6
CO2R
37 R = H
TMSCHN2
MeOH, r.t.
85% in 3 steps
Alternatively, reductive deoxygenation without the isola-
tion of 33a–c was tried (Table 3). Mesylation of the pri-
mary hydroxy group in 30 at –78 °C followed by
treatment with LiAlH4 gave the desired compound (–)-5
38 R = Me
Scheme 5 Synthesis of diol (–)-613
Synthesis 2011, No. 5, 769–777 © Thieme Stuttgart · New York

772
I. Hayakawa et al.
PAPER
Table 3 Study of Reductive Deoxygenation of Primary Hydroxy Group in 30a
OR
OH
TBSO
TBSO
TBSO
H
H
conditions 2
THF
conditions 1
THF
OTHP
OTHP
OTHP
33a–c
30
(–)-5
Entry
Conditions 1
33a–c
Conditions 2
Yield (%)
1
2
3
MsCl, Et3N, –78 °C
33a R = Ms
LiAlH4, –78 °C
LiBHEt3, –78 °C to r.t.
LiBHEt3, reflux
trace
<29b
74
(PhO)2P(O)Cl, LDA, –78 °C
(Me2N)2P(O)Cl, LHMDS, r.t.
33b R = P(O)(OPh)2
33c R = P(O)(NMe2)2
a The reaction was conducted with racemic 30.
b This compound contained by-products such as 32 and 34, which could not be isolated.
–0.04
by TMS diazomethane. Dihydroxylation of 38 gave diol
(–)-6 as the sole product because of steric hindrance of the
methyl group at the cyclopropane ring (Scheme 5). Diol
(–)-6 was converted into acetate 39, the NOESY spectrum
TBSO
–0.05
–0.18
*
–0.01
(R)- or (S)-MTPACl
*
–0.01
py, r.t.
*
*
+0.02
+0.03
15a
MTPAO
(–)-6
of which showed the correlation between H-11 and the
HO
+0.18
methyl group at the cyclopropane ring to indicate the rel-
ative stereochemistry of acetate 39, as depicted in
Scheme 6.
CO2Me
+0.19
40
+0.04
Esterification of the secondary hydroxy group in diol (–)-
6 afforded the MTPA ester 40, and the absolute stere-
ochemistry of 40 was determined as depicted in Scheme 7
by the modified Mosher’s method. The ester 15b was also
converted into MTPA ester 41 in the same manner, and
the absolute stereochemistry of 41 was determined as
shown in Scheme 7. Thus, the absolute structures of cy-
clopropanation products in Table 1 were determined as
the structural formulas 15a and 15b.
TBSO
+0.04
+0.18
*
*
0
*
(R)- or (S)-MTPACl
+0.01
–0.02
–0.03
py, r.t.
*
MTPAO
15b
(+)-6
HO
–0.18
–0.19
CO2Me
41
Scheme 7 Determination of absolute stereochemistries of cyclopro-
pane part in 15a and 15b
Oxidative cleavage of the diol group in (–)-6 and a spon-
taneous intramolecular aldol reaction afforded the seven-
membered aldol 42 and the seven-membered enone (–)-7
(Scheme 8). The former was transformed into the latter by
acetylation. This seven-membered enone (–)-7 is an opti-
cally active form of the key intermediate of our previous
synthesis of the inside–outside framework of 13-oxyin-
genol in racemic form.6
TBSO
TBSO
TBSO
11
10
HO
11
10
Pb(OAc)4
benzene, r.t.
+
11
9
9
9
HO
MeO2C
MeO2C
10
HO
O
O
CO2Me
(–)-6
42
(–)-7
O
O
O
O
Ac2O, py, r.t.
42% in 2 steps
Os
Scheme 8 Synthesis of optically active seven-membered enone
(–)-713
H
OH
9
CO2Me
9
H
OsO4, NMO
CO2Me
OR
TBSO
11
TBSO
acetone–H2O, r.t.
In conclusion, we have achieved the enantioselective syn-
thesis of the key intermediate (–)-7 of the 13-oxyingenol
skeleton by using asymmetric cyclopropanation and re-
ductive deoxygenation as key steps. Efforts toward the to-
tal synthesis are currently under way, and the results will
be reported elsewhere.
11
75%
Me
H
Me
C
H
H
Me
H
NOESY
38
Ac2O, py, r.t.
98%
(–)-6 R = H
39 R = Ac
O
O
O
Os
O
Scheme 6 Diastereoselective dihydroxylation of 38
Synthesis 2011, No. 5, 769–777 © Thieme Stuttgart · New York

PAPER
Synthetic Studies towards Optically Active 13-Oxyingenol
773
HRMS-ESI: m/z [M + Na]+ calcd for C19H32O3Si + Na: 359.2018;
found: 359.2013.
Optical rotations were measured with a Jasco DIP-1000 polarimeter
or a Jasco DIP-370 polarimeter. Melting points were recorded on a
Yanaco MP-J8 micro melting point apparatus and are uncorrected.
IR spectra were recorded on a Jasco FT/IR-230 instrument and only
selected peaks are reported. 1H and 13C NMR spectra were recorded
on a Jeol JNM-EX270 spectrometer, a Bruker Avance 500 spec-
tert-Butyldimethyl{4-[2-(tetrahydro-2H-pyran-2-yloxy)eth-
yl]cyclohexa-1,4-dienyloxy}silane (4)
To stirred liquid NH3 (240 mL) were added a solution of TBS ether
14 (8.04 g, 23.9 mmol) in THF (20 mL), the rinse (THF, 2 × 20 mL)
of the flask of TBS ether 14, THF (36 mL), t-BuOH (240 mL), and
Li wire (1.10 g, 248 mmol) at –78 °C. The mixture was stirred at re-
flux for 2 h, and NH4Cl (120 g) was added. The resultant mixture
was stirred at r.t. for 2 h to evaporate NH3, diluted with H2O (270
mL), and extracted with hexane (2 × 100 mL). The combined ex-
tracts were washed with brine (100 mL), dried (Na2SO4), and con-
centrated. The residual oil was purified by column chromatography
on silica gel (80 g, hexane–EtOAc, 40:1) to give 4 (7.90 g, 99%) as
a colorless oil.
1
trometer, or a Bruker Avance 600 spectrometer. The H and 13C
chemical shifts were referenced to the solvent peaks (dH = 7.26 ppm
and dC = 77.0 ppm in CDCl3). J values are given in Hz. The follow-
ing abbreviations are used for spin multiplicity: s = singlet,
d = doublet, t = triplet, q = quartet, m = multiplet, br = broad. ESI
mass spectra were recorded on an Applied Biosystems QStar/Pulsar
i spectrometer or a Jeol AccuTOFCS JMS-T100CS spectrometer.
TLC analyses were conducted on E. Merck precoated silica gel 60
F254 (0.25 mm layer thickness). Fuji Silysia silica gel BW-820 MH
(75–200 mm) and FL-60D (45–75 mm) were used for column chro-
matography, unless otherwise noted. Chiral HPLC was performed
on Jasco 880 PU and 875 UV instruments using a DAICEL
CHIRALCEL OD, 4.6 mm × 25 cm column. Anhyd benzene,
CH2Cl2, DCE, DMF, MeOH, THF, and toluene were used as ob-
tained from commercial supplies. Other organic solvents for
moisture-sensitive reactions were distilled by standard procedure.
IR (film): 3000, 2950, 2935, 2861, 1700, 1660, 2410, 1470, 1380,
1260 cm–1.
1H NMR (270 MHz, CDCl3): d = 5.41 (br s, 1 H), 4.81 (br s, 1 H),
4.58 (dd, J = 4.1, 2.7 Hz, 1 H), 3.89–3.78 (m, 2 H), 3.52–3.43 (m, 2
H), 2.76–2.62 (m, 4 H), 2.27 (t, J = 7.0 Hz, 2 H), 1.86–1.40 (m, 6
H), 0.91 (s, 9 H), 0.13 (s, 6 H).
13C NMR (67.8 MHz, CDCl3): d = 147.9, 132.2, 119.2, 100.9, 98.7,
66.2, 62.2, 36.8, 31.2, 30.8, 30.3, 25.7 (3 C), 25.5, 19.7, 18.1, –4.3
(2 C).
HRMS-ESI: m/z [M + Na]+ calcd for C19H34O3Si + Na: 361.2175;
found: 361.2174.
4-[2-(Tetrahydro-2H-pyran-2-yloxy)ethyl]phenol (13)
To a suspension of 2-(4-hydroxyphenyl)ethanol (12; 10.1 g, 73.7
mmol) in CH2Cl2 (260 mL) were added 3,4-dihydropyran (10.0 mL,
111 mmol) and p-TsOH·H2O (139 mg, 733 mmol) at r.t. The mixture
was stirred at the same temperature for 2 h, diluted with sat. aq
NaHCO3 (50 mL), and extracted with EtOAc (7 × 40 mL). The
combined extracts were washed with brine (100 mL), dried
(Na2SO4), and concentrated. The residual oil was purified twice by
column chromatography on silica gel (200 g, hexane–EtOAc, 24:1;
FL-60D 100 g, hexane–EtOAc, 7:1 → 5:1) to give 13 (11.4 g, 70%)
as a colorless oil.
Asymmetric Cyclopropanation; General Procedure
To copper(I) triflate benzene complex (2.0 mol%) was added a so-
lution of chiral aza-semicorrin ligand 18 (2.2 mol%) in DCE (1.3
mL) under an argon atmosphere. The resulting suspension was
stirred at r.t. for 1 h. To a stirred solution of enol ether 4 (0.91 mmol)
in DCE (7.0 mL) were added the supernatant solution of the green-
ish suspension prepared as above and 2,2,6,6-tetramethylpiperidine
(1.9 mol%). A solution of ethyl diazoacetate (1.0 M in DCE, 4.5
mL, 4.5 mmol) was added slowly to the reaction mixture through a
syringe pump over 2.5 h at r.t. After stirring at r.t. for 21 h, the mix-
ture was concentrated, filtered through Florisil (100–200 mesh, 0.5
g, hexane–Et2O, 1:1), and concentrated. The residual oil was puri-
fied by column chromatography on silica gel to give the cyclopro-
pane compounds. The enantiomeric excess was determined by
HPLC (DAICEL CHIRALCEL OD) after removal of the THP
group to the corresponding alcohol.
IR (film): 3600, 3340 (br), 3010, 2950, 2870, 1624, 2495, 2424,
1440, 1355, 1260 cm–1.
1H NMR (270 MHz, CDCl3): d = 7.07 (d, J = 8.6 Hz, 2 H), 6.73 (d,
J = 8.6 Hz, 2 H), 5.19–5.13 (m, 1 H), 4.63 (dd, J = 3.5, 2.7 Hz, 1 H),
3.91 (dt, J = 9.7, 7.3 Hz, 1 H), 3.84–3.76 (m, 1 H), 3.58 (dt, J = 9.7,
7.3 Hz, 1 H), 3.53–3.46 (m, 1 H), 2.83 (t, J = 7.3 Hz, 2 H), 1.88–
1.49 (m, 6 H).
13C NMR (125 MHz, CDCl3): d = 154.2, 130.8, 130.0 (2 C), 115.1
(2 C), 98.8, 68.7, 62.3, 35.3, 30.6, 25.4, 19.4.
HRMS-ESI: m/z [M + Na]+ calcd for C13H18O3 + Na: 245.1154;
found: 245.1136.
Ethyl (1R,6S,7S)-1-(tert-Butyldimethylsilyloxy)-4-[2-(tetrahy-
dro-2H-pyran-2-yloxy)ethyl]bicyclo[4.1.0]hept-3-ene-7-car-
boxylate (15a)
tert-Butyldimethyl{4-[2-(tetrahydro-2H-pyran-2-yloxy)eth-
yl]phenoxy}silane (14)
Yield: 46%; 91% ee; [a]D27 +17.6 (c 1.1, CHCl3).
To a stirred solution of THP ether 13 (17.6 g, 79.2 mmol) in DMF
(270 mL) were added imidazole (13.1 g, 192 mmol) and TBSCl
(14.9 g, 98.7 mmol) at 0 °C. The mixture was stirred at r.t. for 2 h,
diluted with H2O (100 mL), and extracted with Et2O (4 × 60 mL).
The combined extracts were washed with brine (100 mL), dried
(Na2SO4), and concentrated. The residual oil was purified by col-
umn chromatography on silica gel (200 g, hexane–EtOAc, 25:1) to
give 14 (27.0 g, quant) as a colorless oil.
IR (film): 3008, 2950, 2930, 2899, 2858, 1721, 1258, 1211, 1182,
1160 cm–1.
1H NMR (500 MHz, CDCl3): d = 5.26 (br d, J = 3.2 Hz, 1 H), 4.56
(br s, 1 H), 4.12 (dq, J = 9.9, 7.1 Hz, 1 H), 4.10 (dq, J = 9.9, 7.1 Hz,
1 H), 3.83 (t, J = 9.4 Hz, 1 H), 3.78–3.72 (m, 1 H), 3.52–3.46 (m, 1
H), 3.39 (dt, J = 9.4, 7.1 Hz, 1 H), 2.77–2.72 (m, 1 H), 2.56–2.44
(m, 2 H), 2.26–2.16 (m, 3 H), 2.11–2.07 (m, 1 H), 1.83–1.78 (m, 1
H), 1.77–1.73 (m, 1 H), 1.73–1.67 (m, 1 H), 1.60–1.47 (m, 4 H),
1.25 (t, J = 7.1 Hz, 3 H), 0.87 (s, 9 H), 0.12 (s, 3 H), 0.10 (s, 3 H).
13C NMR (67.8 MHz, CDCl3): d = 170.2, 131.6 (0.5 C), 131.5 (0.5
C), 119.2 (0.5 C), 119.1 (0.5 C), 98.7 (0.5 C), 98.7 (0.5 C), 66.2 (0.5
C), 66.1 (0.5 C), 62.6, 62.3, 60.3, 37.5 (0.5 C), 37.4 (0.5 C), 33.3,
30.8, 28.5, 28.4, 27.0, 25.7 (3 C), 25.5, 19.7, 18.0, 14.5, –3.5, –3.5.
IR (film): 3000, 2950, 2935, 2860, 1610, 2410, 1470, 1260 cm–1.
1H NMR (270 MHz, CDCl3): d = 7.09 (br d, J = 8.4 Hz, 2 H), 6.76
(br d, J = 8.4 Hz, 2 H), 4.59 (dd, J = 3.8, 3.0 Hz, 1 H), 3.90 (dt,
J = 9.6, 7.3 Hz, 1 H), 3.78–3.69 (m, 1 H), 3.58 (dt, J = 9.6, 7.3 Hz,
1 H), 3.48–3.40 (m, 1 H), 2.84 (t, J = 7.3 Hz, 2 H), 1.87–1.49 (m, 6
H), 0.98 (s, 9 H), 0.18 (s, 6 H).
13C NMR (67.8 MHz, CDCl3): d = 153.8, 131.7, 129.7 (2 C), 119.7
(2 C), 98.5, 68.5, 62.1, 35.6, 30.7, 25.8 (3 C), 25.5, 19.5, 18.3, –4.3
(2 C).
HRMS-ESI: m/z [M + Na]+ calcd for C23H40O5Si + Na: 447.2543;
found: 447.2519.
Synthesis 2011, No. 5, 769–777 © Thieme Stuttgart · New York

774
I. Hayakawa et al.
PAPER
Ethyl (1S,6R,7S)-1-(tert-Butyldimethylsilyloxy)-4-[2-(tetrahy-
dro-2H-pyran-2-yloxy)ethyl]bicyclo[4.1.0]hept-3-ene-7-car-
boxylate (15b)
1H NMR (500 MHz, CDCl3): d = 5.27 (br d, J = 4.8 Hz, 1 H), 4.57–
4.53 (m, 1 H), 4.17–4.05 (m, 2 H), 3.86–3.79 (m, 1 H), 3.77–3.71
(m, 1 H), 3.53–3.46 (m, 1 H), 3.38 (dt, J = 9.6, 7.0 Hz, 1 H), 2.80
(dd, J = 17.7, 4.8 Hz, 1 H), 2.57–2.48 (m, 2 H), 2.25–2.16 (m, 3 H),
2.14 (dd, J = 5.5, 4.8 Hz, 1 H), 1.85–1.78 (m, 1 H), 1.78–1.74 (m,
1 H), 1.72–1.65 (m, 1 H), 1.59–1.47 (m, 4 H), 1.25 (t, J = 7.1 Hz, 3
H), 1.06–1.04 (m, 21 H).
13C NMR (67.8 MHz, CDCl3): d = 170.2, 131.5, 119.2, 98.7 (0.5 C),
98.7 (0.5 C), 66.2 (0.5 C), 66.1 (0.5 C), 62.5 (0.5 C), 62.4 (0.5 C),
62.3, 60.3, 37.5, 33.3, 30.7, 29.2, 28.7, 27.4, 25.5, 19.6, 18.2 (3 C),
18.1 (3 C), 14.5, 13.1 (3 C).
Yield: 29%; 52% ee; [a]D27 +10.5 (c 0.67, CHCl3).
IR (film): 2952, 2930, 2359, 2341, 1716, 1168, 1030 cm–1.
1H NMR (500 MHz, CDCl3): d = 5.18 (br d, J = 4.7 Hz, 1 H), 4.58–
4.53 (m, 1 H), 4.05 (dq, J = 10.8, 7.1 Hz, 1 H), 3.99–3.92 (m, 1 H),
3.87–3.81 (m, 1 H), 3.78–3.72 (m, 1 H), 3.52–3.46 (m, 1 H), 3.43–
3.37 (m, 1 H), 2.86–2.78 (m, 1 H), 2.57–2.47 (m, 2 H), 2.33–2.26
(m, 1 H), 2.24–2.16 (m, 1 H), 2.16–2.08 (m, 1 H), 1.83–1.76 (m, 1
H), 1.81 (d, J = 10.5 Hz, 1 H), 1.73–1.65 (m, 1 H), 1.60–1.47 (m, 5
H), 1.21 (t, J = 7.1 Hz, 3 H), 0.85 (s, 9 H), 0.14 (s, 3 H), 0.13 (s, 3
H).
HRMS-ESI: m/z [M + Na]+ calcd for C26H46O5Si + Na: 489.3012;
found: 489.3031.
13C NMR (67.8 MHz, CDCl3): d = 168.9, 132.2 (0.5 C), 132.1 (0.5
C), 119.0 (0.5 C), 119.0 (0.5 C), 98.9 (0.5 C), 98.6 (0.5 C), 66.2 (0.5
C), 66.0 (0.5 C), 62.4 (0.5 C), 62.3 (0.5 C), 60.1, 58.1 (0.5 C), 58.0
(0.5 C), 37.5, 30.9, 30.8, 29.4, 26.3 (0.5 C), 26.2 (0.5 C), 25.7 (3 C),
25.5, 24.4, 19.8 (0.5 C), 19.7 (0.5 C), 17.7, 14.3, –3.3, –3.7.
Ethyl (1S,6R,7S)-4-[2-(Tetrahydro-2H-pyran-2-yloxy)ethyl]-1-
(triisopropylsilyloxy)bicyclo[4.1.0]hept-3-ene-7-carboxylate
(24b)
Yield: 21%; 58% ee; [a]D25 +16.4 (c 0.28, CHCl3).
IR (film): 2946, 2868, 1716 cm–1.
HRMS-ESI: m/z [M + Na]+ calcd for C23H40O5Si + Na: 447.2543;
found: 447.2532.
1H NMR (500 MHz, CDCl3): d = 5.20 (br s, 1 H), 4.57–4.54 (m, 1
H), 4.05 (dq, J = 10.8, 7.1 Hz, 1 H), 3.99–3.93 (m, 1 H), 3.87–3.82
(m, 1 H), 3.78–3.72 (m, 1 H), 3.52–3.46 (m, 1 H), 3.44–3.37 (m, 1
H), 2.93–2.86 (m, 1 H), 2.59–2.49 (m, 2 H), 2.33–2.26 (m, 1 H),
2.26–2.17 (m, 1 H), 2.17–2.09 (m, 1 H), 1.86 (d, J = 10.6 Hz, 1 H),
1.83–1.77 (m, 1 H), 1.72–1.67 (m, 1 H), 1.63 (dd, J = 10.6, 6.0 Hz,
1 H), 1.58–1.47 (m, 4 H), 1.20 (t, J = 7.1 Hz, 3 H), 1.06–1.03 (m,
21 H).
13C NMR (67.8 MHz, CDCl3): d = 169.0, 131.9, 119.3 (0.5 C),
119.3 (0.5 C), 98.9 (0.5 C), 98.6 (0.5 C), 66.2 (0.5 C), 66.0 (0.5 C),
62.4 (0.5 C), 62.3 (0.5 C), 60.1, 58.0 (0.5 C), 58.0 (0.5 C), 37.5 (0.5
C), 37.5 (0.5 C), 31.1, 30.8, 29.7, 26.5 (0.5 C), 26.4 (0.5 C), 25.5,
25.1, 19.8 (0.5 C), 19.7 (0.5 C), 18.2 (3 C), 18.2 (3 C), 14.3, 12.8 (3
C).
tert-Butyl (1R,6S,7S)-1-(tert-Butyldimethylsilyloxy)-4-[2-(tet-
rahydro-2H-pyran-2-yloxy)ethyl]bicyclo[4.1.0]hept-3-ene-7-
carboxylate (16a)
Yield: 44%; 82% ee; [a]D23 +23.1 (c 0.72, CHCl3).
IR (film): 3008, 2930, 2858, 1714, 1367, 1221, 1148 cm–1.
1H NMR (270 MHz, CDCl3): d = 5.28–5.23 (m, 1 H), 4.60–4.53 (m,
1 H), 3.87–3.68 (m, 2 H), 3.53–3.35 (m, 2 H), 2.81–2.68 (m, 1 H),
2.58–2.37 (m, 2 H), 2.27–2.15 (m, 3 H), 2.04–1.96 (m, 1 H), 1.86–
1.49 (m, 7 H), 1.44 (s, 9 H), 0.87 (s, 9 H), 0.12 (s, 3 H), 0.10 (s, 3 H).
13C NMR (125 MHz, CDCl3): d = 169.3, 131.7, 119.4 (0.5 C), 119.3
(0.5 C), 98.7 (0.5 C), 98.7 (0.5 C), 79.7, 66.1 (0.5 C), 66.1 (0.5 C),
62.2, 62.0 (0.5 C), 62.0 (0.5 C), 37.4 (0.5 C), 37.3 (0.5 C), 33.2,
30.6, 29.2, 28.3, 28.3 (3 C), 26.0, 25.6 (3 C), 25.4, 19.5 (0.5 C), 19.5
(0.5 C), 17.8, –3.6, –3.7.
HRMS-ESI: m/z [M + Na]+ calcd for C26H46O5Si + Na: 489.3012;
found: 489.3016.
HRMS-ESI: m/z [M + Na]+ calcd for C25H44O5Si + Na: 475.2856;
found: 475.2873.
Ethyl (1R,6S,7S)-4-[2-(Tetrahydro-2H-pyran-2-yloxy)ethyl]-1-
(triethylsilyloxy)bicyclo[4.1.0]hept-3-ene-7-carboxylate (25a)
Yield: 33%; 77% ee; [a]D24 +20.7 (c 0.69, CHCl3).
IR (film): 3019, 2954, 2877, 1720, 1221, 1185, 1160, 1031 cm–1.
tert-Butyl (1S,6R,7S)-1-(tert-Butyldimethylsilyloxy)-4-[2-(tet-
rahydro-2H-pyran-2-yloxy)ethyl]bicyclo[4.1.0]hept-3-ene-7-
carboxylate (16b)
1H NMR (500 MHz, CDCl3): d = 5.26 (br d, J = 5.5 Hz, 1 H), 4.55
(br s, 1 H), 4.11 (q, J = 7.1 Hz, 2 H), 3.85–3.80 (m, 1 H), 3.77–3.71
(m, 1 H), 3.52–3.47 (m, 1 H), 3.42–3.36 (m, 1 H), 2.79–2.73 (m, 1
H), 2.55–2.44 (m, 2 H), 2.26–2.16 (m, 3 H), 2.13–2.07 (m, 1 H),
1.83–1.76 (m, 1 H), 1.76–1.73 (m, 1 H), 1.73–1.66 (m, 1 H), 1.60–
1.47 (m, 4 H), 1.25 (t, J = 7.1 Hz, 3 H), 0.95 (t, J = 7.9 Hz, 9 H),
0.64 (dq, J = 15.7, 7.9 Hz, 3 H), 0.61 (dq, J = 15.7, 7.9 Hz, 3 H).
13C NMR (67.8 MHz, CDCl3): d = 170.3, 131.5 (0.5 C), 131.5 (0.5
C), 119.1 (0.5 C), 119.1 (0.5 C), 98.7 (0.5 C), 98.7 (0.5 C), 66.2 (0.5
C), 66.1 (0.5 C), 62.6, 62.3, 60.2, 37.4 (0.5 C), 37.4 (0.5 C), 33.3,
30.7, 28.7, 28.5 (0.5 C), 28.5 (0.5 C), 27.5, 25.5, 19.6, 14.5, 6.9 (3
C), 5.7 (3 C).
Yield: 40%; 76% ee; [a]D23 +20.6 (c 0.88, CHCl3).
IR (film): 3006, 2930, 2857, 1711, 1257, 1221, 1155 cm–1.
1H NMR (270 MHz, CDCl3): d = 5.20–5.13 (m, 1 H), 4.60–4.52 (m,
1 H), 3.65–3.39 (m, 2 H), 3.53–3.33 (m, 2 H), 2.89–2.84 (m, 1 H),
2.60–2.39 (m, 2 H), 2.36–2.03 (m, 3 H), 1.92–1.43 (m, 8 H), 1.38
(s, 9 H), 0.85 (s, 9 H), 0.14 (s, 6 H).
13C NMR (125 MHz, CDCl3): d = 168.1, 132.3 (0.5 C), 132.3 (0.5
C), 119.1 (0.5 C), 119.1 (0.5 C), 98.9 (0.5 C), 98.6 (0.5 C), 80.0,
66.1 (0.5 C), 65.9 (0.5 C), 62.4 (0.5 C), 62.2 (0.5 C), 57.6 (0.5 C),
57.6 (0.5 C), 37.7 (0.5 C), 37.6 (0.5 C), 30.9, 30.7, 30.4, 28.0 (3 C),
26.0 (0.5 C), 26.0 (0.5 C), 25.6 (3 C), 25.5, 23.7 (0.5 C), 23.7 (0.5
C), 19.6 (0.5 C), 19.6 (0.5 C), 17.6, –3.4, –3.9.
HRMS-ESI: m/z [M + Na]+ calcd for C23H40O5Si + Na: 447.2543;
found: 447.2520.
HRMS-ESI: m/z [M + Na]+ calcd for C25H44O5Si + Na: 475.2856;
found: 475.2867.
Ethyl (1S,6R,7S)-4-[2-(Tetrahydro-2H-pyran-2-yloxy)ethyl]-1-
(triethylsilyloxy)bicyclo[4.1.0]hept-3-ene-7-carboxylate (25b)
Yield: 19%; 41% ee; [a]D24 +8.0 (c 0.53, CHCl3).
IR (film): 2955, 2877, 1716, 1168, 1030 cm–1.
1H NMR (500 MHz, CDCl3): d = 5.18 (br d, J = 2.9 Hz, 1 H), 4.58–
4.53 (m, 1 H), 4.05 (dq, J = 10.8, 7.1 Hz, 1 H), 3.99–3.92 (m, 1 H),
3.87–3.82 (m, 1 H), 3.77–3.72 (m, 1 H), 3.52–3.46 (m, 1 H), 3.43–
3.36 (m, 1 H), 2.87–2.81 (m, 1 H), 2.58–2.48 (m, 2 H), 2.33–2.26
Ethyl (1R,6S,7S)-4-[2-(Tetrahydro-2H-pyran-2-yloxy)ethyl]-1-
(triisopropylsilyloxy)bicyclo[4.1.0]hept-3-ene-7-carboxylate
(24a)
Yield: 33%; 91% ee; [a] D25 +20.2 (c 0.33, CHCl3).
IR (film): 3019, 2945, 2868, 1719, 1209 cm–1.
Synthesis 2011, No. 5, 769–777 © Thieme Stuttgart · New York

PAPER
Synthetic Studies towards Optically Active 13-Oxyingenol
775
(m, 1 H), 2.24–2.17 (m, 1 H), 2.16–2.08 (m, 1 H), 1.83 (d, J = 10.7
Hz, 1 H), 1.84–1.77 (m, 1 H), 1.72–1.65 (m, 1 H), 1.62–1.47 (m, 5
H), 1.21 (t, J = 7.1 Hz, 3 H), 0.94 (t, J = 8.0 Hz, 9 H), 0.63 (q,
J = 8.0 Hz, 6 H).
13C NMR (67.8 MHz, CDCl3): d = 168.9, 132.1 (0.5 C), 132.1 (0.5
C), 119.0 (0.5 C), 119.0 (0.5 C), 98.9 (0.5 C), 98.6 (0.5 C), 66.2 (0.5
C), 66.0 (0.5 C), 62.4 (0.5 C), 62.3 (0.5 C), 60.2, 57.9, 37.5, 31.0,
30.8, 29.4, 26.3 (0.5 C), 26.2 (0.5 C), 25.6 (0.5 C), 25.5 (0.5 C),
24.5, 19.8 (0.5 C), 19.7 (0.5 C), 14.3, 6.9 (3 C), 5.5 (3 C).
13C NMR (67.8 MHz, CDCl3): d = 170.4, 131.3 (0.5 C), 131.3 (0.5
C), 119.0 (0.5 C), 119.0 (0.5 C), 98.8 (0.5 C), 98.8 (0.5 C), 94.3,
67.2, 66.1 (0.5 C), 66.1 (0.5 C), 65.9, 62.4 (0.5 C), 62.4 (0.5 C),
60.5, 37.4 (0.5 C), 37.4 (0.5 C), 31.0, 30.8, 28.3, 28.2 (0.5 C), 28.2
(0.5 C), 26.4, 25.5, 19.7, 18.2, 14.4, –1.3 (3 C).
HRMS (ESI): m/z [M + Na]+ calcd for C23H40O6Si + Na: 463.2492;
found: 463.2492.
(1R,6S,7S)-1-(tert-Butyldimethylsilyloxy)-7-methyl-4-[2-(tet-
rahydro-2H-pyran-2-yloxy)ethyl]bicyclo[4.1.0]hept-3-en-7-
yl)methanol (30)
HRMS-ESI: m/z [M + Na]+ calcd for C23H40O5Si + Na: 447.2543;
found: 447.2521.
To a stirred solution of LDA (1.10 mmol), prepared from i-Pr2NH
(0.17 mL, 1.20 mmol) and n-BuLi (1.57 M solution of in hexane,
0.70 mL, 1.10 mmol) in THF (0.75 mL), was added a solution of
15a [153 mg, 87% purity (contaminated with maleic acid diethyl es-
ter), 313 mmol] in THF (1.5 mL) via cannula at –78 °C. After stir-
ring at –78 °C for 1 h, MeI (0.12 mL, 1.93 mmol) was added. The
mixture was stirred at –78 °C for 4 h, diluted with sat. aq NH4Cl
(2 mL), and extracted with Et2O (3 × 10 mL). The combined ex-
tracts were washed with brine (10 mL), dried (MgSO4), filtered, and
concentrated. The residual oil was purified by column chromatog-
raphy on silica gel (5 g, hexane–Et2O, 15:1 → 10:1) to give 29 [137
mg (contaminated with unidentified impurities)] as a colorless oil.
A suspension of LiAlH4 (98.6 mg, 2.60 mmol) in THF (7 mL) was
heated to reflux over 2 h. To this stirred suspension was added a so-
lution of 29 (130 mg) in THF (4 mL) at 0 °C. After stirring the mix-
ture at 0 °C for 3.5 h, LiAlH4 (254 mg, 5.30 mmol) was added in
four portions during 3.5 h to complete the reaction. After stirring the
mixture at 0 °C for 1 h, the mixture was diluted with MeOH (4 mL)
and sat. aq Na/K tartrate (30 mL), and warmed to r.t. The mixture
was stirred at r.t. for 17 h and extracted with EtOAc (3 × 20 mL).
The combined extracts were washed with brine (20 mL), dried
(Na2SO4), and concentrated. The residual oil was purified twice by
column chromatography on silica gel (0.8 g, hexane–EtOAc, 4:1;
1.0 g, hexane–EtOAc, 6:1 → 2:1) to give 30 (98.9 mg, 80% in 2
steps) as a colorless oil; [a]D25 –23.3 (c 0.98, CHCl3).
Ethyl (1R,6S,7S)-1-Methoxy-4-[2-(tetrahydro-2H-pyran-2-
yloxy)ethyl]bicyclo[4.1.0]hept-3-ene-7-carboxylate (26a)
Yield: 56%; 31% ee; [a]D25 +12.4 (c 1.1, CHCl3).
IR (film): 3019, 2944, 1717, 1209, 1176, 1031 cm–1.
1H NMR (500 MHz, CDCl3): d = 5.30 (br d, J = 5.3 Hz, 1 H), 4.55
(br s, 1 H), 4.16 (dq, J = 11.7, 7.1 Hz, 1 H), 4.13 (dq, J = 11.7, 7.1
Hz, 1 H), 3.85–3.79 (m, 1 H), 3.77–3.72 (m, 1 H), 3.51–3.46 (m, 1
H), 3.42–3.36 (m, 1 H), 3.27 (s, 3 H), 2.79 (dd, J = 17.2, 5.3 Hz, 1
H), 2.57–2.47 (m, 2 H), 2.26–2.17 (m, 4 H), 1.83–1.76 (m, 2 H),
1.72–1.66 (m, 1 H), 1.58–1.47 (m, 4 H), 1.26 (t, J = 7.1 Hz, 3 H).
13C NMR (67.8 MHz, CDCl3): d = 170.6, 131.7 (0.5 C), 131.7 (0.5
C), 118.4 (0.5 C), 118.3 (0.5 C), 98.7, 67.6, 66.1 (0.5 C), 66.0 (0.5
C), 62.3, 60.4, 54.7, 37.4 (0.5 C), 37.4 (0.5 C), 30.7, 28.3, 28.2 (0.5
C), 28.2 (0.5 C), 28.1, 26.7, 25.5, 19.6, 14.4.
HRMS-ESI: m/z [M + Na]+ calcd for C18H28O5 + Na: 347.1834;
found: 347.1826.
Ethyl (1R,6S,7S)-1-[(2-Methoxyethoxy)methoxy]-4-[2-(tetrahy-
dro-2H-pyran-2-yloxy)ethyl]bicyclo[4.1.0]hept-3-ene-7-car-
boxylate (27a)
Yield: 48%; 39% ee; [a]D26 +19.6 (c 0.85, CHCl3).
IR (film): 3011, 2944, 1718, 1031 cm–1.
IR (film): 3462 (br), 2952, 2930, 2858, 1258, 1216, 1134, 1029 cm–1.
1H NMR (500 MHz, CDCl3): d = 5.27 (m, 1 H), 4.77 (d, J = 7.1 Hz,
1 H), 4.74 (d, J = 7.1 Hz, 1 H), 4.56–4.53 (m, 1 H), 4.13 (dq,
J = 10.9, 7.1 Hz, 1 H), 4.10 (dq, J = 10.9, 7.1 Hz, 1 H), 3.85–3.80
(m, 2 H), 3.77–3.71 (m, 1 H), 3.67 (ddd, J = 9.7, 6.0, 3.7 Hz, 1 H),
3.57–3.53 (m, 2 H), 3.53–3.46 (m, 1 H), 3.41–3.35 (m, 1 H), 3.38
(s, 3 H), 2.83 (dd, J = 17.5, 5.5 Hz, 1 H), 2.70–2.65 (m, 1 H), 2.57–
2.50 (m, 1 H), 2.28–2.21 (m, 2H ), 2.18 (t, J = 6.8 Hz, 2 H), 1.86–
1.83 (m, 1 H), 1.83–1.76 (m, 1 H), 1.72–1.65 (m, 1 H), 1.60–1.47
(m, 4 H), 1.24 (t, J = 7.1 Hz, 3 H).
13C NMR (67.8 MHz, CDCl3): d = 170.4, 131.4 (0.5 C), 131.3 (0.5
C), 118.9, 98.7, 94.9, 71.7, 67.6, 67.1, 66.1 (0.5 C), 66.0 (0.5 C),
62.3, 60.5, 59.0, 37.4 (0.5 C), 37.4 (0.5 C), 30.7, 30.7, 28.2 (0.5 C),
28.2 (0.5 C), 28.2, 26.3, 25.5, 19.7, 14.4.
1H NMR (500 MHz, CDCl3): d = 5.33 (br s, 1 H), 4.54 (dd, J = 5.0,
2.6 Hz, 0.5 H), 4.47 (dd, J = 5.9, 3.1 Hz, 0.5 H), 3.94–3.38 (m, 6 H),
2.66–2.57 (m, 1 H), 2.50–2.27 (m, 4 H), 2.26–2.11 (m, 2 H), 1.84–
1.77 (m, 1 H), 1.74–1.66 (m, 1 H), 1.60–1.47 (m, 4 H), 1.29 (s, 1.5
H), 1.28 (s, 1.5 H), 0.96–0.90 (m, 1 H), 0.89 (s, 4.5 H), 0.88 (s, 4.5
H), 0.10 (s, 3 H), 0.070 (s, 1.5 H), 0.066 (s, 1.5 H).
13C NMR (67.8 MHz, CDCl3): d = 133.4 (0.5 C), 132.9 (0.5 C),
120.8 (0.5 C), 120.5 (0.5 C), 99.7 (0.5 C), 99.1 (0.5 C), 66.5 (0.5 C),
65.5 (0.5 C), 63.9 (0.5 C), 63.5 (0.5 C), 63.0 (0.5 C), 62.9 (0.5 C),
59.7 (0.5 C), 59.5 (0.5 C), 37.4 (0.5 C), 37.4 (0.5 C), 31.4 (0.5 C),
31.3 (0.5 C), 31.0 (0.5 C), 30.8 (0.5 C), 28.8 (0.5 C), 28.7 (0.5 C),
28.4 (0.5 C), 28.2 (0.5 C), 25.9 (3 C), 25.5 (0.5 C), 25.4 (0.5 C), 25.4
(0.5 C), 24.6 (0.5 C), 20.6 (0.5 C), 20.0 (0.5 C), 18.1 (0.5 C), 18.1
(0.5 C), 18.1 (0.5 C), 18.0 (0.5 C), –3.4 (0.5 C), –3.4 (0.5 C), –3.5
(0.5 C), –3.6 (0.5 C).
HRMS-ESI: m/z [M + Na]+ calcd for C21H34O7 + Na: 421.2202;
found: 421.2213.
HRMS-ESI: m/z [M + Na]+ calcd for C22H40O4Si + Na: 419.2594;
found: 419.2584.
Ethyl (1R,6S,7S)-4-[2-(Tetrahydro-2H-pyran-2-yloxy)ethyl]-1-
{[2-(trimethylsilyl)ethoxy]methoxy}bicyclo[4.1.0]hept-3-ene-7-
carboxylate (28a)
Yield: 65%; 36% ee; [a]D27 +18.1 (c 0.20, CHCl3).
(1R,6S)-tert-Butyl-7,7-dimethyl-4-[2-(tetrahydro-2H-pyran-2-
yloxy)ethyl]bicyclo[4.1.0]hept-3-en-1-yloxy)dimethylsilane [(–)-
5]
To a stirred solution of alcohol 30 (15.3 mg, 38.6 mmol) in THF (0.3
mL) was added LHMDS (1.0 M solution of in THF, 420 mL, 420
mmol) at 0 °C. After stirring the mixture at 0 °C for 30 min, bis(di-
methylamino)phosphoryl chloride (30.0 mL, 208 mmol) was added.
The resulting mixture was stirred at r.t. for 1 h, LiBHEt3 (1.09 M so-
lution of in THF, 700 mL, 763 mmol) was added at r.t., and the mix-
ture was stirred at reflux for 5.5 h. After cooling to r.t., the mixture
IR (film): 3009, 2952, 1717, 1222, 1063, 1029 cm–1.
1H NMR (500 MHz, CDCl3): d = 5.29 (m, 1 H), 4.74 (d, J = 7.1 Hz,
1 H), 4.66 (d, J = 7.1 Hz, 1 H), 4.57–4.54 (m, 1 H), 4.18–4.08 (m,
2 H), 3.86–3.81 (m, 1 H), 3.79–3.70 (m, 2 H), 3.62–3.56 (m, 1 H),
3.52–3.47 (m, 1 H), 3.43–3.36 (m, 1 H), 2.87–2.82 (m, 1 H), 2.72–
2.65 (m, 1 H), 2.58–2.51 (m, 1 H), 2.28–2.23 (m, 2 H), 2.19 (t,
J = 6.9 Hz, 2 H), 1.87–1.84 (m, 1 H), 1.84–1.76 (m, 1 H), 1.72–1.66
(m, 1 H), 1.60–1.48 (m, 4 H), 1.25 (t, J = 7.1 Hz, 3 H), 0.93 (t,
J = 8.6 Hz, 2 H), 0.01 (s, 9 H).
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776
I. Hayakawa et al.
PAPER
was diluted with MeOH (5 mL) and H2O (5 mL), and extracted with
EtOAc (3 × 5 mL). The combined extracts were washed with brine
(5 mL), dried (Na2SO4), and concentrated. The residual oil was pu-
rified by column chromatography on silica gel (0.8 g, hexane–Et2O,
40:1 → 20:1) to give (–)-5 (10.8 mg, 74% in 2 steps) as a colorless
oil; [a]D25 –18.3 (c 0.87, CHCl3).
MeOH (0.3 mL) was added a solution of TMS diazomethane (2.0 M
solution in Et2O, 0.2 mL, 400 mmol) at 0 °C. The mixture was
stirred at r.t. for 50 min and concentrated. The residual oil was pu-
rified by column chromatography on silica gel (0.7 g, hexane–
EtOAc, 100:1) to give 38 (13.0 mg, 85% in 3 steps) as a colorless
oil; [a]D26 –18.7 (c 0.80, CHCl3).
IR (film): 2929, 1222 cm–1.
IR (film): 2953, 2929, 2886, 2858, 1732, 1221 cm–1.
1H NMR (270 MHz, CDCl3): d = 5.28 (br s, 1 H), 4.57 (br s, 1 H),
3.90–3.72 (m, 2 H), 3.53–3.36 (m, 2 H), 2.59–2.33 (m, 3 H), 2.21 (t,
J = 7.0 Hz, 2 H), 1.97–1.89 (m, 1 H), 1.82–1.52 (m, 6 H), 1.14 (s, 3
H), 0.87 (s, 9 H), 0.82 (s, 3 H), 0.72 (d, J = 7.3 Hz, 1 H), 0.10 (s, 3
H), 0.06 (s, 3 H).
13C NMR (67.8 MHz, CDCl3): d = 132.6 (0.5 C), 132.5 (0.5 C),
120.4 (0.5 C), 120.4 (0.5 C), 98.8, 66.5 (0.5 C), 66.4 (0.5 C), 62.3
(0.5 C), 62.3 (0.5 C), 58.8 (0.5 C), 58.8 (0.5 C), 37.5, 30.9 (0.5 C),
30.8 (0.5 C), 26.7, 26.0 (3 C), 25.6, 25.0, 24.9, 22.4 (0.5 C), 22.4
(0.5 C), 22.1, 19.7 (0.5 C), 19.7 (0.5 C), 18.1, 14.4 (0.5 C), 14.4 (0.5
C), –3.3, –3.6.
1H NMR (500 MHz, CDCl3): d = 5.39 (br s, 1 H), 3.65 (s, 3 H), 2.93
(s, 2 H), 2.63–2.55 (m, 1 H), 2.46–2.36 (m, 2 H), 1.98–1.92 (m, 1
H), 1.14 (s, 3 H), 0.87 (s, 9 H), 0.84 (s, 3 H), 0.74 (d, J = 7.4 Hz, 1
H), 0.10 (s, 3 H), 0.064 (s, 3 H).
13C NMR (67.8 MHz, CDCl3): d = 172.0, 128.9, 123.5, 58.5, 51.7,
42.7, 31.0, 26.5, 25.9 (3 C), 24.8, 22.3 (2 C), 18.1, 14.3, –3.4, –3.6.
HRMS-ESI: m/z [M + Na]+ calcd for C18H32O3Si + Na: 347.2018;
found: 347.2013.
2-[(1S,6R)/(1R,6S)-6-(tert-Butyldimethylsilyloxy)-7,7-dimethyl-
bicyclo[4.1.0]hept-3-en-3-yl]ethanol [( )-35]
HRMS-ESI: m/z [M + Na]+ calcd for C22H40O3Si + Na: 403.2644;
found: 403.2648.
The bicyclic compound ( )-5 (2.68 g, 7.04 mmol) was treated with
propylene glycol (25 mL). The mixture was stirred at 100 °C for 15
min. The reaction mixture was cooled at 0 °C, diluted with H2O (40
mL), and extracted with CHCl3 (3 × 45 mL). The combined extracts
were washed with brine (70 mL), dried (Na2SO4), and concentrated.
The residual oil was purified by column chromatography on silica
gel (70 g, hexane–EtOAc, 40:1 → 10:1) to give ( )-35 (1.80 g,
86%) as a colorless oil.
2-[(1S,6R)-6-(tert-Butyldimethylsilyloxy)-7,7-dimethylbicyc-
lo[4.1.0]hept-3-en-3-yl]ethanol (35)
The bicyclic compound (–)-5 (34.8 mg, 91.4 mmol) was treated with
propylene glycol (0.8 mL). After stirring the mixture at 140 °C for
16 h, propylene glycol (1.0 mL) was added in two portions during
18.5 h to complete the reaction. The reaction mixture was cooled at
0 °C, diluted with H2O (2 mL), and extracted with CHCl3 (3 × 5
mL). The combined extracts were washed with brine (5 mL), dried
(Na2SO4), and concentrated. The residual oil was purified by col-
umn chromatography on silica gel (0.6 g, hexane–EtOAc, 40:1 →
Methyl 2-[(1S,6R)/(1R,6S)-6-(tert-Butyldimethylsilyloxy)-7,7-
dimethylbicyclo[4.1.0]hept-3-en-3-yl]acetate [( )-(38)]
To a stirred solution of alcohol ( )-35 (1.58 g, 5.33 mmol) in
CH2Cl2 (35 mL) was added Dess–Martin periodinane (2.95 g, 6.96
mmol) at r.t. The mixture was stirred at the same temperature for 40
min, diluted with sat. aq Na2S2O3 (20 mL) and sat. aq NaHCO3 (20
mL), and extracted with Et2O (3 × 30 mL). The combined extracts
were washed with brine (40 mL) and dried (Na2SO4). Removal of
the solvent afforded aldehyde ( )-36, which was used in the next re-
action without further purification. To a solution of ( )-36 in t-
BuOH (40 mL) were added 2-methylbut-2-ene (12.0 mL, 113
mmol), NaH2PO4 (0.82 M solution in H2O, 20 mL, 16.4 mmol), and
NaClO2 (1.44 g, 15.9 mmol) at r.t. The mixture was stirred at the
same temperature for 1 h and concentrated to afford an aqueous so-
lution of the crude product. The aqueous solution was diluted with
EtOAc (20 mL) and acidified by adding aq 1 M HCl to pH 3. The
mixture was extracted with EtOAc (3 × 30 mL). The combined ex-
tracts were washed with brine (20 mL) and dried (Na2SO4). Remov-
al of the solvent afforded carboxylic acid ( )-37, which was used in
the next reaction without further purification. To a stirred solution
of carboxylic acid ( )-37 in MeOH (30 mL) was added a solution of
TMS diazomethane (2.0 M solution in Et2O, 14.0 mL, 28.0 mmol)
at 0 °C. The mixture was stirred at the r.t. for 10 min and concen-
trated. The residual oil was purified twice by column chromatogra-
phy on silica gel (50 g, hexane–EtOAc, 50:1; 90 g, hexane–EtOAc,
100:1) to give ( )-38 (1.55 g, 90% in 3 steps) as a colorless oil.
25
10:1) to give 35 (19.1 mg, 70%) as a colorless oil; [a]D –27.3 (c
0.74, CHCl3).
IR (film): 3567 (br), 2956, 2930, 2885, 2858, 1647, 1221 cm–1.
1H NMR (500 MHz, CDCl3): d = 5.34 (br s, 1 H), 3.64 (br t, J = 5.8
Hz, 2 H), 2.60–2.53 (m, 1 H), 2.45–2.34 (m, 2 H), 2.23–2.15 (m, 2
H), 1.94–1.88 (m, 1 H), 1.15 (s, 3 H), 0.88 (s, 9 H), 0.82 (s, 3 H),
0.74 (d, J = 7.4 Hz, 1 H), 0.098 (s, 3 H), 0.058 (s, 3 H); a signal due
to one proton (OH) was not observed.
13C NMR (67.8 MHz, CDCl3): d = 131.8, 121.7, 60.5, 58.7, 40.5,
30.9, 26.5, 25.9 (3 C), 24.4, 22.3, 22.2, 18.1, 14.4, –3.4, –3.6.
HRMS-ESI: m/z [M + Na]+ calcd for C17H32O2Si + Na: 319.2069;
found: 319.2085.
Methyl 2-[(1S,6R)-6-(tert-Butyldimethylsilyloxy)-7,7-dimethyl-
bicyclo[4.1.0]hept-3-en-3-yl]acetate (38)
To a stirred solution of alcohol 35 (14.0 mg, 47.2 mmol) in CH2Cl2
(0.6 mL) was added Dess–Martin periodinane (87.0 mg, 205 mmol)
at r.t. The mixture was stirred at the same temperature for 2.5 h, di-
luted with half sat. aq Na2S2O3 (5 mL) and sat. aq NaHCO3 (3 mL),
and extracted with Et2O (3 × 5 mL). The combined extracts were
washed with brine (5 mL) and dried (Na2SO4). Removal of the sol-
vent afforded aldehyde 36, which was used for the next reaction
without further purification. To a solution of 36 in t-BuOH (0.9 mL)
were added 2-methylbut-2-ene (0.12 mL, 1.13 mmol), NaH2PO4
(0.71 M solution in H2O, 0.25 mL 178 mmol), and NaClO2 (13.3 mg,
147 mmol) at r.t. The mixture was stirred at the same temperature for
1.5 h and concentrated to afford an aqueous solution of the crude
product. The aqueous solution was diluted with EtOAc (3 mL) and
acidified by adding sat. aq NaH2PO4 (10 mL) to pH 3. The mixture
was extracted with EtOAc (3 × 5 mL). The combined extracts were
washed with brine (5 mL) and dried (Na2SO4). Removal of the sol-
vent afforded carboxylic acid 37, which was used for the next reac-
tion without further purification. To a stirred solution of 37 in
Methyl 2-[(1S,3S,4S,6R)-6-(tert-Butyldimethylsilyloxy)-3,4-di-
hydroxy-7,7-dimethylbicyclo[4.1.0]heptan-3-yl]acetate [(–)-6]
To a stirred solution of methyl ester 38 (12.8 mg, 39.5 mmol) in a
5:1 mixture of acetone and H2O (0.4 mL) were added N-methylmor-
pholine N-oxide (20.8 mg, 178 mmol) and OsO4 (0.2 M solution in
THF, 0.04 mL, 8.0 mmol) at r.t. After stirring at the same tempera-
ture for 24.5 h, the mixture was diluted with a solution of NaHSO3
(108 mg) in H2O (1 mL) and stirred at r.t. for 5.5 h. The mixture was
then extracted with EtOAc (3 × 5 mL). The combined EtOAc layers
were washed with sat. aq Na2S2O3 (2 × 5 mL) and brine (25 × 5
mL), dried (Na2SO4), and concentrated. The residual oil was puri-
fied by column chromatography on silica gel (0.7 g, hexane–
Synthesis 2011, No. 5, 769–777 © Thieme Stuttgart · New York

PAPER
Synthetic Studies towards Optically Active 13-Oxyingenol
777
EtOAc, 40:1 → 5:1) to give diol (–)-6 (10.6 mg, 75%) as colorless
crystals; [a]D25 –3.3 (c 0.48, CHCl3); mp 86.0–86.9 °C (EtOAc).
Methyl (1R,7S)/(1S,7R)-(tert-Butyldimethylsilyloxy)-8,8-di-
methyl-5-oxobicyclo[5.1.0]oct-3-ene-4-carboxylate [( )-7]
To a stirred solution of diol ( )-6 (12.0 g, 33.5 mmol) in benzene
(250 mL) was added Pb(OAc)4 (18.5 g, 11.3 mmol) at 0 °C. The
mixture was stirred at r.t. for 2 h, diluted with sat. aq NaHCO3 (250
mL), and filtered through a pad of Celite. The filtrate was extracted
with EtOAc (3 × 50 mL). The combined extracts were washed with
brine (2 × 80 mL) and dried (Na2SO4). Removal of the solvent af-
forded a mixture of ( )-42 and ( )-7, which was used in the next re-
action without further purification. The mixture was treated with
pyridine (150 mL) and Ac2O (40 mL) at r.t. After stirring at r.t. for
3 h, the mixture was concentrated to afford an oil. The oil was puri-
fied by column chromatography on silica gel (200 g, hexane–
EtOAc, 30:1 → 10:1) to give ( )-7 (8.35 g, 74% in 2 steps) as col-
orless crystals.
IR (film): 3567 (br), 2954, 2929, 2857, 1714, 1439, 1355, 1254,
1222, 1209 cm–1.
1H NMR (500 MHz, CDCl3): d = 3.71 (s, 3 H), 3.55 (br s, 1 H), 3.25
(br s, 1 H), 2.81 (d, J = 15.4 Hz, 1 H), 2.42 (dd, J = 13.8, 6.8 Hz, 1
H), 2.32 (d, J = 15.4 Hz, 1 H), 2.22 (dd, J = 15.4, 10.1 Hz, 1 H),
1.97 (d, J = 10.1 Hz, 1 H), 1.95 (dd, J = 13.8, 10.1 Hz, 1 H), 1.22
(dd, J = 15.4, 3.3 Hz, 1 H), 1.11 (s, 3 H), 0.89 (s, 3 H), 0.86 (s, 9 H),
0.68 (dd, J = 10.1, 3.3 Hz, 1 H), 0.17 (s, 3 H), 0.13 (s, 3 H).
13C NMR (67.8 MHz, CDCl3): d = 173.7, 72.3, 71.0, 62.7, 51.9,
42.0, 36.0, 31.4, 26.1 (3 C), 24.1, 23.9, 22.5, 18.3, 15.7, –3.2 (2 C).
HRMS-ESI: m/z [M + Na]+ calcd for C18H34O5Si + Na: 381.2073;
found: 381.2065.
Methyl 2-[(1S,3S,4S,6R)/(1R,3R,4R,6S)-6-(tert-Butyldimethyl-
silyloxy)-3,4-dihydroxy-7,7-dimethylbicyclo[4.1.0]heptan-3-
yl]acetate [( )-6]
Acknowledgment
This work was supported by a Grant-in-Aid for Scientific Research
from the Ministry of Education, Culture, Sports, Science, and Tech-
nology (MEXT), Japan; by a grant from the Uehara Memorial
Foundation; and by a grant from the Suntory Institute for Bioorga-
nic Research (SUNBOR GRANT).
To a stirred solution of methyl ester ( )-38 (12.9 g, 39.7 mmol) in a
5:1 mixture of acetone and H2O (85 mL) were added N-methylmor-
pholine N-oxide (14.2 g, 120 mmol) and OsO4 (0.4 M solution in
THF, 6.0 mL, 2.4 mmol) at r.t. After stirring at the same temperature
for 9 h, the mixture was diluted with a solution of NaHSO3 (4.9 g)
in H2O (50 mL) and stirred at r.t. for 13 h. The mixture was then ex-
tracted with EtOAc (4 × 70 mL). The combined EtOAc layers were
washed with sat. aq Na2S2O3 (2 × 100 mL) and brine (100 mL),
dried (Na2SO4), and concentrated. The residual oil was purified by
column chromatography on silica gel (210 g, hexane–EtOAc, 40:1
→ 10:1 → 5:1) to give ( )-6 (12.0 g, 86%) as yellow-brown crys-
tals.
References
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Methyl (1R,7S)-1-(tert-Butyldimethylsilyloxy)-8,8-dimethyl-5-
oxobicyclo[5.1.0]oct-3-ene-4-carboxylate [(–)-7]
To a stirred solution of diol (–)-6 (6.5 mg, 18.1 mmol) in benzene
(0.3 mL) was added Pb(OAc)4 (12.6 mg, 28.4 mmol) at 0 °C. The
mixture was stirred at r.t. for 1.5 h, diluted with sat. aq NaHCO3 (1
mL), and filtered through a pad of Celite. The filtrate was extracted
with EtOAc (3 × 10 mL). The combined extracts were washed with
brine (10 mL) and dried (Na2SO4). Removal of the solvent afforded
a mixture of aldol 42 and enone (–)-7, which was used for the next
reaction without further purification. The mixture was treated with
pyridine (0.4 mL) and Ac2O (0.1 mL) at r.t. After stirring at r.t. for
3.5 h, the mixture was concentrated to afford an oil. The oil was pu-
rified by column chromatography on silica gel (0.5 g, hexane–
EtOAc, 20:1 → 10:1) to give (–)-7 (2.6 mg, 42% in 2 steps) as col-
(6) Hayakawa, I.; Asuma, Y.; Ohyoshi, T.; Aoki, K.; Kigoshi,
H. Tetrahedron Lett. 2007, 48, 6221.
(7) Ebinger, A.; Heinz, T.; Umbricht, G.; Pfaltz, A. Tetrahedron
27
orless crystals; [a]D –154 (c 0.21, CHCl3); mp 98.7–100.5 °C
(hexane).
1998, 54, 10469.
IR (film): 3023, 2955, 2921, 2856, 1731, 1254, 1211 cm–1.
(8) Ventura, D. L.; Li, Z.; Coleman, M. G.; Davies, H. M. L.
Tetrahedron 2009, 65, 3052; and references cited therein.
(9) Haley, R. C.; Miller, J. A.; Wood, H. C. S. J. Chem. Soc. C
1969, 264.
(10) Ireland, R. E.; Muchmore, D. C.; Hengartner, U. J. Am.
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(11) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am.
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1H NMR (500 MHz, CDCl3): d = 7.43 (dd, J = 8.7, 3.5 Hz, 1 H),
3.81 (s, 3 H), 2.89 (ddd, J = 17.5, 8.7, 1.2 Hz, 1 H), 2.84 (dd,
J = 13.5, 5.9 Hz, 1 H), 2.58 (dd, J = 17.5, 3.5 Hz, 1 H), 2.17 (dd,
J = 13.5, 11.7 Hz, 1 H), 1.21 (s, 3 H), 1.16 (s, 3 H), 0.83 (s, 9 H),
0.83 (m, 1 H), 0.06 (s, 3 H), 0.02 (s, 3 H).
13C NMR (67.8 MHz, CDCl3): d = 195.9, 166.7, 150.3, 137.5, 70.5,
52.4, 42.4, 34.1, 30.1, 28.7, 25.9 (3 C), 22.7, 18.4, 17.6, –3.5, –3.6.
HRMS-ESI: m/z [M + Na]+ calcd for C18H30O4Si + Na: 361.1811;
(13) This asymmetric synthesis of seven-membered enone (–)-7
had a low yield in comparison with our previous approach in
racemic form, possibly because of the small reaction scale.
The detailed experimental procedures for the seven-
membered enone ( )-76 in multigram scale are given in the
experimental section.
found: 361.1796.
Synthesis 2011, No. 5, 769–777 © Thieme Stuttgart · New York