Design, synthesis, and biological evaluation of air-stable nafuredin-γ analogs as complex i inhibitors

Article abstract of DOI:10.1016/j.bmc.2015.01.030

Nafuredin-γ (2), converted from nafuredin (1) under mild basic conditions, demonstrates potent and selective inhibitory activity against helminth complex I. However, 2 is unstable in air because the conjugated dienes are oxygen-labile. To address this, we

Full text of DOI:10.1016/j.bmc.2015.01.030

Bioorganic & Medicinal Chemistry 23 (2015) 932–943
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Design, synthesis, and biological evaluation of air-stable nafuredin-
analogs as complex I inhibitors
c
Masaki Ohtawa a, Mari Matsunaga a, Keiko Fukunaga a, Risa Shimizu a, Eri Shimizu a, Shiho Arima a,
Junko Ohmori c, Kiyoshi Kita c, Kazuro Shiomi b, Satoshi Omura b, Tohru Nagamitsu a,
⇑
a Graduate School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan
b Graduate School of Infection Control Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan
c Department of Biomedical Chemistry, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Nafuredin-
selective inhibitory activity against helminth complex I. However, 2 is unstable in air because the conju-
gated dienes are oxygen-labile. To address this, we designed and synthesized air-stable nafuredin- ana-
analogs were lower than that
c (2), converted from nafuredin (1) under mild basic conditions, demonstrates potent and
Received 10 December 2014
Revised 14 January 2015
Accepted 16 January 2015
Available online 22 January 2015
c
logs. Although the complex I inhibitory activities of all the new nafuredin-
c
of 2, all were in the high nM range (IC50: 300–820 nM).
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Nafuredin-
c
Air-stable analogs
Complex I inhibitor
1. Introduction
analogs 6, 7, and 8 were designed as structurally simpler analogs
lacking one (compound 6) or both (compounds 7 and 8) of the ste-
reogenic centers in the side chain. In particular, analog 8 is amena-
ble to large scale synthesis. Although these new analogs contain a
common saturated lactone moiety, the effect of removing the enol
unit on complex I inhibitory activity had not been investigated.8
Therefore, the synthesis and biological evaluation of 3, in which
Nafuredin (1)1–3 was isolated from the fermentation broth of a
fungal strain, Aspergillus niger FT-0554, during screening for selec-
tive complex I inhibitors and proved to be a potent and selective
inhibitor against helminth complex I (Fig. 1). In addition, 1 demon-
strated anthelmintic activity against Haemonchus contortus in
in vivo trials with sheep.1 Therefore, nafuredin (1) holds promise
as a selective antiparasitic agent. A subsequent total synthetic
the 2-hydroxy-a,b-unsaturated lactone moiety of 2 was replaced
with the saturated lactone, was carried out first, followed by the
study of 1 identified a novel and structurally simpler
c-lactone
synthesis of derivatives 4 to 8. Herein, we report the design, syn-
compound, nafuredin-
c
(2), which was generated from 1 under
thesis, and biological evaluation of air-stable nafuredin-
as complex I inhibitors.
c analogs
mild basic conditions.4,5 Moreover, the helminth complex I inhibi-
tory activity of 2 was identical to that of 1. The total synthesis of 2
has been achieved by our group;6 several nafuredin-
c analogs were
2. Results and discussion
then synthesized using this total synthesis approach and their
complex I inhibitory activities were examined. Consequently, the
importance of the stereochemistries of C4 and C5 for complex I
inhibitory activity was revealed.7
2.1. Synthesis and complex I inhibitory activity of 3
We first synthesized new analog 3 using a convergent approach
based on our synthesis of nafuredin-c 7 Starting chiral epoxide 99
On the other hand, nafuredin (1), nafuredin-c (2), and their ana-
.
logs are all unstable in air because the conjugated dienes are oxy-
gen-labile. Therefore, these compounds must be stored as solutions
in appropriate solvents. We addressed this instability by synthesiz-
was converted to lactone 10 in 94% yield over 2 steps via ozonoly-
sis, followed by Pinnick oxidation and lactonization through epox-
ide opening of the resulting carboxylic acid (Scheme 1). A two-step
sequence of protecting group manipulations provided primary
alcohol 11. Dess–Martin oxidation of 11 gave aldehyde 12 (diaste-
reopurity >99:1)10 in 86% yield, which was subjected to Takai olef-
ination to afford E-vinyl iodide 13 in 76% yield. Coupling partner
boronate 16 was synthesized from known alcohol 14.4 Dess-Martin
ing the air-stable nafuredin-c analogs 4-8 containing aromatic
rings or non-conjugated (E)-olefins in the side chain (Fig. 2). The
⇑
Corresponding author. Tel.: +81 3 5791 6376; fax: +81 3 3444 4742.
E-mail address: nagamitsut@pharm.kitasato-u.ac.jp (T. Nagamitsu).
http://dx.doi.org/10.1016/j.bmc.2015.01.030
0968-0896/Ó 2015 Elsevier Ltd. All rights reserved.

M. Ohtawa et al. / Bioorg. Med. Chem. 23 (2015) 932–943
933
nafuredin-
c analogs could be synthesized by Suzuki coupling of
the common vinyl iodide 13 with the arylboronic ester 18 or bor-
onate intermediates 19–21 derived from the corresponding alkyl
iodides.
2.3. Synthesis of new nafuredin-c analog 4
Figure 1.
The synthesis of 4 is shown in Scheme 3. Known 2-naphthol
2213 was converted to triflate 23 in 92% yield, which was subjected
to Negishi coupling with Zn(CN)214 to afford 24 in 78% yield. DIBAL
reduction of 24 gave aldehyde 25 in 93% yield. The aldehyde 25
was coupled with an aryl lithium species derived from the known
aryl bromide 2615 to afford the alcohol 27 in 99% yield. Removal of
the benzylic hydroxyl group of 27 and deprotection of the MOM
group gave phenol 29, which was converted to arylboronic ester
18 via the triflate according to the Miyaura protocol.16 The Suzuki
coupling of 18 with vinyl iodide 13 afforded 30. Finally, deprotec-
oxidation of 14 followed by Takai olefination using Cl2CHB(pinaco-
late)11 afforded vinylboronic ester 16 with high diastereopurity
(>99:1)10 in 48% yield over 2 steps. With the required fragments
13 and 16 in hand, Suzuki coupling furnished the bis-diene 17;
exposure to acidic conditions provided the desired new nafur-
edin-c
analog 3 in 28% yield over 2 steps.12
The inhibitory activity of 3 against complex I (Ascaris suum) was
evaluated; the IC50 value was 32 nM, indicating that replacement
of 2-hydroxy-a,b-unsaturated lactone with the saturated lactone
tion of the MOM group of 30 provided new nafuredin-c-analog 4 in
was tolerated and potent complex
I
inhibitory activity was
38% yield (2 steps).12
retained.
2.4. Synthesis of new nafuredin-c analogs 5, 6, and 7
2.2. Synthetic plan for new nafuredin-
c
analogs 4–7
Next, compounds 5 and 6, containing non-conjugated (E)-ole-
fins in the side chain, were synthesized. Lithium-iodide exchange
of the known iodides 31 and 32,17 followed by treatment with
We next turned to synthesizing new nafuredin-c analogs 4–7,
which were expected to be stable in air. The retrosynthetic analysis
of analogs 4–7 is shown in Scheme 2. It was envisaged that these
Figure 2.
O
O
O
O
a,b
c,d
e
f
O
O
O
O
CHO
I
OBn
OBn
OH
OMOM
11
O
OH
OMOM
OMOM
9
10
12
13
g
h
HO
O
OHC
B
O
14
15
16
i
O
O
j
O
O
OH
OMOM
3
17
Scheme 1. Reagents and conditions: (a) O3, CH2Cl2 rt, then Me2S, ꢀ78 °C; (b) NaClO2, NaH2PO4ꢁ2H2O, 2-methyl-2-butene, t-BuOH/H2O = 1:1, rt, 2 steps 94% (c) MOMCl, i-
Pr2NEt, CH2Cl2, rt, 95%; (d) H2, Pd(OH)2/C, MeOH, rt, 90%; (e) DMP, CH2Cl2, rt, 86%; (f) CrCl2, CHI3, THF/dioxane, rt, 76% (g) DMP, CH2Cl2, rt; (h) CrCl2, LiI, Cl2CHB(pinacolate),
THF, rt, 2 steps 48% (i) Pd(PPh3)4, PPh3, 2 M Na2CO3 aq, toluene, EtOH, 80 °C; (j) CBr4, i-PrOH, 70 °C, 2 steps 28%.

934
M. Ohtawa et al. / Bioorg. Med. Chem. 23 (2015) 932–943
Scheme 2.
a
c
b
+
HO
TfO
NC
OHC
MOMO
Br
22
23
24
25
26
d
e
f
HO
MOMO
MOMO
OH
29
g, h
28
27
O
O
i
j
O
O
O
B
O
OMOM
OH
18
30
4
Scheme 3. Reagents and conditions: (a) Tf2O, DMAP, 2,6-lutidine, CH2Cl2, rt, 92%; (b) Pd(PPh3)4, Zn(CN)2, DMF, 150 °C, 78%; (c) DIBAL, CH2Cl2, ꢀ78 °C, 93%; (d) t-BuLi, THF,
ꢀ78 °C, 99%; (e) Et3SiH, TFA, CH2Cl2, rt, 75%; (f) CBr4, i-PrOH, 75 °C, quant.; (g) Tf2O, DMAP, 2,6-lutidine, CH2Cl2, rt, 99%; (h) PdCl2(dppf), bis(pinacolato)diboron, dppf, AcOK,
dioxane, 80 °C, 93%; (i) 13, Pd(PPh3)4, 2 M Na2CO3, toluene, EtOH, 80 °C; (j) CBr4, i-PrOH, 75 °C, 2 steps 38%.
OMe
c-e
a
R1
b
R1
TBDPSO
R1
NC
R1
Li+
I
B
31: R1 = Me
32: R1 = H
33: R1 = Me
34: R1 = H
36: R1 = Me
37: R1 = H
38: R1 = Me
39: R1 = H
f, g
OMe
a
h
R1
R1
R1
Li+
B
I
HO
19: R1 = Me
20: R1 = H
42: R1 = Me
43: R1 = H
40: R1 = Me
41: R1 = H
i
O
O
j
R1
I
O
R1
O
TBDPSO
OH
35
OMOM
44: R1 = Me
45: R1 = H
5: R1 = Me
6: R1 = H
Scheme 4. Reagents and conditions: (a) t-BuLi, Et2O, then 9-BBNOMe, THF, ꢀ78 °C to rt; (b) 35, PdCl2(dppf), 3 M K3PO4 aq, dppp, DMF, rt, 36: 93%, 37: 83%; (c) TBAF, THF, rt;
(d) p-TsCl, Et3N, Me3NꢁHCl, CH2Cl2, 0 °C; (e) KCN, DMSO, 100 °C, 38: 3 steps 83%; 39: 3 steps 82%; (f) DIBAL, CH2Cl2, ꢀ78 °C; (g) NaBH4, MeOH, 0 °C, 40: 2 steps 81%; 41: 2 steps
77%; (h) I2, PPh3, imidazole, CH2Cl2, 0 °C, 42: 86%; 43: 90%; (i) 13, PdCl2(dppf), 3 M K3PO4 aq, dppp, DMF, rt, 44: 48%; 45: 73%; (j) CBr4, i-PrOH, 65 °C, 5: 92%, 6: 68%.
9-BBNOMe, gave boronate intermediates 33 and 34 (Scheme 4),
which were subjected to B-alkyl Suzuki coupling18 with known
vinyl iodide 3519 to afford 36 (93%) and 37 (83%). The three-step
conversions of 36 and 37 to nitriles 38 and 39 were successful.
Stepwise reduction of the nitriles using DIBAL and NaBH4 afforded
primary alcohols 40 (81% over 2 steps) and 41 (77% over 2 steps).
Subsequent iodination gave alkyl iodides 42 (86%) and 43 (90%) as
precursors of the second B-alkyl Suzuki coupling. The coupling of
boronate intermediates 19 and 20, derived from iodides 42 and
43 by the same procedure as the preparation of 33 and 34, with

M. Ohtawa et al. / Bioorg. Med. Chem. 23 (2015) 932–943
935
c,d
a,b
47
O
I
TBSO
I
46
48
49
I
TBSO
a,e
O
f
O
O
OH
OMOM
7
50
Scheme 5. Reagents and conditions: (a) t-BuLi, Et2O, then 9-BBNOMe, THF, ꢀ78 °C to rt; (b) 47, PdCl2(dppf), 3 M K3PO4 aq, dppp, DMF, rt, 83%; (c) TBAF, THF, rt, 93%; (d) I2,
PPh3, imidazole, CH2Cl2, 0 °C to rt, 91%; (e) 13, PdCl2(dppf), 3 M K3PO4 aq, dppp, DMF, rt; (f) CBr4, i-PrOH, 65 °C, 2 steps, 44%.
a
c
b
HO
TESO
TESO
TESO
OAc
OAc
OH
R
O
51
52
53
54: R = OH
d
55: R = I
e,f
PhO2S
56
g
TESO
OHC
O
O
57
i,j
h
58
O
O
O
OH
OH
8
59
Scheme 6. Reagents and conditions: (a) TESCl, imidazole, CH2Cl2, rt, 91%; (b) K2CO3 aq, MeOH, rt, 76%; (c) (ꢀ)-DET, Ti(Oi-Pr)4, MS4Å, t-BuOOH, CH2Cl2, ꢀ20 °C, 78%, 90% ee;
(d) I2, PPh3, imidazole, CH2Cl2, 0 °C, 78%; (e) 56, n-BuLi, HMPA, THF, ꢀ78 °C; (f) Pd(OAc)2, dppp, NaBH4, DMSO, rt, 2 steps 64%; (g) CrO3, pyridine, CH2Cl2, rt, 58: 54%; 59: 5%; (h)
NaClO2, NaH2PO4ꢁ2H2O, 2-methyl-2-butene, t-BuOH/H2O = 1:1, rt, 86%; (i) TBAF, THF, rt; (j) PPTS, CH2Cl2, rt, 2 steps 89%.
vinyl iodide 13 in the presence of Pd catalyst afforded 44 (48%) and
45 (73%). Finally, deprotection of the MOM group under acidic con-
oxidation after desilylation of the TES ether. Finally, Pinnick oxida-
tion of 58 gave the desired new nafuredin- derivative 8 in 86%
yield. Although this completed the synthesis of all desired nafur-
edin- derivatives, tetrahydrofuran 59, obtained as a by-product,
c
ditions gave new nafuredin-
The structurally simpler analog
c
analogs 5 (92%) and 6 (68%).12
7
was also synthesized
c
(Scheme 5). TBS ether 48 was derived from commercially available
alkyl iodide 46 and known vinyl iodide 4720 via B-alkyl Suzuki cou-
pling in 83% yield. TBS-deprotection and iodination of compound
48 afforded alkyl iodide 49 in 85% yield over 2 steps. The coupling
reaction between 49 and 13 followed by MOM-deprotection gave 7
in 44% yield over 2 steps.12
was also an attractive compound for structure-activity relationship
study. Therefore, conversion of 57 into 59 was achieved in high
yield via deprotection of the TES ether, followed by cyclization
under acidic conditions (2 steps, 89%).
2.6. Complex I inhibitory activities of the synthetic analogs
Complex I inhibitory activities of the new nafuredin-c analogs
2.5. Synthesis of nafuredin-
c
derivative 8
derivative 8 is shown in
4–8 and 59 were evaluated (Table 1).1,27 The IC50 values of
The synthesis of new nafuredin-
c
Scheme 6. TES protection of known allyl acetate 5121 (91%) fol-
lowed by solvolysis gave allyl alcohol 53 in 76% yield. Sharpless
asymmetric epoxidation of 53 afforded chiral epoxy alcohol 5422
in 78% yield; the enantiomeric excess of 54 (90% ee) was
determined using the improved Moscher procedure.23 Iodination
of 54 gave epoxy iodide 55 in 78% yield. Coupling reaction of 55
with a lithiated sulfone derived from sulfone 5624 followed by
Pd-catalyzed reductive desulfoxylation25 afforded 57 (2 steps,
64%). Oxidation of TES ether 57 under Collins conditions26 gave
desired aldehyde 58 in moderate yield (54%); a small amount of
tetrahydrofuran 59 (5%) was also formed via cyclization prior to
Table 1
Inhibitory activities of the synthesized nafuredin-
suum)
c
analogs against complex I (Ascaris
Compound
IC50 (nM)
Nafuredin-
4
5
6
7
8
59
c
(2)
6
550
550
300
340
820
500

936
M. Ohtawa et al. / Bioorg. Med. Chem. 23 (2015) 932–943
derivatives 4 and 5, bearing aryl substituents and non-conjugated
(E)-olefins, respectively, were both 550 nM. In addition, the struc-
turally simpler analogs 6 and 7, lacking one or both of the stereo-
genic centers in the side chain, respectively, showed complex I
inhibitory activities similar to those of 4 and 5. These results dem-
onstrated that the methyl groups at C10 and C16, and their stere-
1H), 3.50 (dd, J = 9.7, 7.3 Hz, 1H), 2.76–2.40 (m, 3H), 1.95–1.82
(m, 1H), 1.35 (s, 3H); 13C NMR (75 MHz, CDCl3) d 176.8, 137.4,
128.5, 127.9, 127.8, 86.8, 74.4, 73.6, 70.1, 29.7, 29.0, 22.4; HRMS
(FAB, m-NBA + NaI) [M+Na]+ calcd for C14H18O4Na 273.1103, found
273.1109.
ogenic centers in the side chain of the nafuredin-
c
analogs, are not
4.1.2. (S)-5-[(R)-2-(Benzyloxy)-1-(methoxymethoxy)ethyl]
dihydro-5-methylfuran-2(3H)-one
important for complex I inhibitory activity. Two structurally sim-
pler analogues, 8 and 59, were synthesized; the IC50 value of analog
8 was slightly larger than that of 59. The complex I inhibitory activ-
A solution of 10 (1.94 g, 7.77 mmol) in CH2Cl2 (78.0 mL) was
treated with i-Pr2NEt (2.71 mL, 15.5 mmol) and MOMCl (1.17 mL,
15.5 mmol) at 0 °C. After stirring for 40 h at room temperature,
the reaction mixture was quenched with H2O. The aqueous layer
was extracted with CH2Cl2. The organic layers were combined,
dried over Na2SO4, filtered, and concentrated in vacuo. The residue
was purified by flash silica gel column chromatography (3:1 hex-
anes/EtOAc) to afford (S)-5-[(R)-2-(benzyloxy)-1-(methoxyme-
thoxy)ethyl]dihydro-5-methylfuran-2(3H)-one (2.18 g, 95%) as a
ities of all the new nafuredin-
c analogs were lower than that of
nafuredin- (2), but all were in the high nM range. As expected,
c
these analogs were resistant to air oxidation.
3. Conclusion
In conclusion, we designed and synthesized new air-stable
nafuredin-c analogs. All the new analogs exhibited high inhibitory
activity (nM) against complex I and were resistant to air oxidation.
The efficient synthetic route of the structurally simplest nafuredin-
colorless oil.
24
[
a]
D
ꢀ32.7 (c 0.10, CHCl3); IR (KBr) 2941, 2895, 1772, 1454,
1371, 1246, 1207, 1157, 1109, 1028 cmꢀ1 1H NMR (300 MHz,
;
CDCl3) d 7.38–7.27 (m, 5H), 4.79 (d, J = 6.8 Hz, 1H), 4.67 (d,
J = 6.8 Hz, 1H), 4.55 (d, J = 12.0 Hz, 1H) , 4.44 (d, J = 12.0 Hz, 1H) ,
3.78 (dd, J = 4.9, 3.4 Hz, 1H), 3.69 (dd, J = 10.7, 3.4 Hz, 1H), 3.60
(dd, J = 10.7, 4.9 Hz, 1H), 3.37 (s, 3H), 2.71–2.45 (m, 3H), 1.93–
1.79 (m, 1H), 1.37 (s, 3H); 13C NMR (75 MHz, CDCl3) d 177.1,
137.7, 128.4, 127.8, 127.6, 96.9, 87.4, 80.1, 73.6, 69.9, 56.0, 29.6,
29.5, 23.9; HRMS (FAB, m-NBA) [M+H]+ calcd for C16H23O5
295.1545, found 295.1552.
c
analog, 59, will be particularly helpful for scale-up synthesis for
upcoming in vivo tests. Further SAR studies of nafuredin- analogs
aimed at developing novel antiparasitic drugs are currently under-
way in our laboratory.
c
4. Experimental
4.1. General
4.1.3. (S)-Dihydro-5-[(R)-2-hydroxy-1-(methoxymethoxy)ethyl]-
5-methylfuran-2(3H)-one (11)
IR spectra were obtained using a Horiba FT-710 spectrophotom-
eter and JASCO FT/IR 460-plus. 1H and 13C NMR spectra were
obtained using Agilent Technologies Mercury-300 and UNITY-400
spectrometers, and chemical shifts were reported on the d scale
based on internal TMS. MS spectra were measured with JEOL
JMS-AX505HA, JMS-700 MStation, and JEOL JMS-T100LP spectrom-
eters. Optical rotations were recorded on a JASCO DIP-1000 polar-
imeter. Commercial reagents and solvents were used without
further purification unless otherwise indicated. Flash chromatog-
raphy was carried out on silica gel 60N (spherical, neutral, particle
A
suspension of (S)-5-[(R)-2-(benzyloxy)-1-(methoxyme-
thoxy)ethyl]dihydro-5-methylfuran-2(3H)-one (367 mg,
1.25 mmol) and 20% Pd(OH)2/C (73 mg) in MeOH (13.0 mL) was
vigorously stirred under a H2 atmosphere at room temperature
for 12 h. The catalyst was filtered through a pad of celite, and the
celite was washed with Et2O. The filtrate was concentrated in
vacuo. The residue was purified by flash silica gel column chroma-
tography (1:1 hexanes/EtOAc) to afford 11 (229 mg, 90%) as a col-
orless oil.
25
[
a
]
D
+45.2 (c 0.10, CHCl3); IR (KBr) 3473, 2949, 2895, 2829,
size 40–50 lm). TLC was performed on 0.25 mm Merck silica gel
60 F254 plates and visualized by UV (254 nm) and cerium ammo-
nium molybdenate or p-anisaldehyde.
1768, 1456, 1415, 1385, 1292, 1209, 1157, 1099, 1034 cmꢀ1
;
1H
NMR (300 MHz, CDCl3) 4.75 (d, J = 6.5 Hz, 1H), 4.66 (d,
d
J = 6.5 Hz, 1H), 3.75 (t, J = 9.1 Hz, 1H), 3.73–3.56 (m, 2H), 3.41 (s,
3H) , 3.02–3.00 (m, 1H), 2.62 (ddd, J = 17.8, 10.4, 7.1 Hz, 1H), 2.53
(ddd, J = 17.8, 10.4, 7.1 Hz, 1H), 2.44–2.39 (m, 1H), 1.89–1.84 (m,
1H), 1.38 (s, 3H); 13C NMR (75 MHz, CDCl3) d 176.7, 98.0, 86.9,
86.4, 61.9, 56.0, 29.6, 29.3, 23.6; HRMS (FAB, m-NBA) [M+H]+ calcd
for C9H17O5 205.1076, found 205.1072.
4.1.1. (S)-5-[(R)-2-(Benzyloxy)-1-hydroxyethyl]dihydro-5-
methylfuran-2(3H)-one (10)
Ozone was bubbled through a solution of 99 (1.14 g, 4.40 mmol)
in CH2Cl2 (44.0 mL) for 30 min at ꢀ78 °C. To remove residual
ozone, oxygen was subsequently bubbled through the solution
for 15 min at ꢀ78 °C and Me2S (323
lL, 8.80 mmol) was added.
4.1.4. (S)-2-[(S)-Tetrahydro-2-methyl-5-oxofuran-2-yl]-2-
(methoxymethoxy)acetaldehyde (12)
After stirring for 1 h at room temperature, the reaction mixture
was concentrated in vacuo. A solution of the crude aldehyde in t-
BuOH (22.0 mL) and H2O (22.0 mL) was treated with 2-methyl-2-
A solution of 11 (333 mg, 1.63 mmol) in CH2Cl2 (16.3 mL) was
treated with DMP (2.07 g, 4.90 mmol) at 0 °C. After stirring for
3 h at room temperature, the reaction mixture was quenched with
satd Na2S2O3 aq and the aqueous layer was extracted with CH2Cl2.
The organic layers were combined, dried over Na2SO4, filtered, and
concentrated in vacuo. The residue was purified by flash silica gel
column chromatography (1:1 hexanes/EtOAc) to afford 12
butene (1.86
l
L, 17.6 mmol), NaH2PO4ꢁ2H2O (1.19 g, 13.2 mmol)
and NaClO2 (2.06 g, 13.2 mmol) at 0 °C. After stirring for 5 h at
room temperature, the reaction mixture was quenched with satd
NaHCO3 aq, then extracted with EtOAc. The organic layers were
combined, dried over Na2SO4, filtered, and concentrated in vacuo.
The residue was purified by flash silica gel column chromatogra-
phy (3:2 hexanes/EtOAc) to afford 10 (969 mg, 2 steps, 94%) as a
(282 mg, 86%) as a colorless oil.
28
[
a]
D
ꢀ49.4 (c 1.00, CHCl3); IR (KBr) 3437, 2981, 2949, 2900,
colorless oil.
2831, 2359, 1772, 1630, 1456, 1385, 1246, 1213, 1157,
28
1093 cmꢀ1 1H NMR (300 MHz, CDCl3) d 9.70 (d, J = 1.5 Hz, 1H),
;
[
a]
+4.55 (c 1.00, CHCl3); IR (KBr) 3456, 3060, 3030, 2978,
D
2935, 2875, 1768, 1599, 1454, 1377, 1265, 1244, 1209, 1159,
1113, 1074, 1016 cmꢀ1 1H NMR (300 MHz, CDCl3) d 7.40–7.28
(m, 5H), 4.56 (s, 2H), 3.90–3.84 (m, 1H), 3.64 (dd, J = 9.7, 3.2 Hz,
4.70 (s, 2H), 4.05 (d, J = 1.5 Hz, 1H), 3.39 (s, 3H), 2.71 (ddd,
J = 18.1, 10.3, 7.7 Hz, 1H), 2.56 (ddd, J = 18.1, 10.3, 5.6 Hz, 1H),
2.38 (ddd, J = 18.1, 10.3, 5.6 Hz, 1H), 1.93 (ddd, J = 18.1, 10.3,
;

M. Ohtawa et al. / Bioorg. Med. Chem. 23 (2015) 932–943
937
7.7 Hz, 1H), 1.49 (s, 3H); 13C NMR (75 MHz, CDCl3) d 199.6, 176.2,
ether in i-PrOH (1.0 mL) was treated with CBr4 (47.1 lg,
97.3, 85.5, 84.9, 56.3, 29.6, 29.1, 23.8; HRMS (FAB, m-NBA + NaI)
0.0142 mmol) at room temperature, then the temperature was
immediately changed to 70 °C. After stirring for 4 h at 70 °C, the
reaction mixture was quenched with satd NaHCO3 aq and
extracted with CH2Cl2. The organic layers were combined, dried
over Na2SO4, filtered, and concentrated in vacuo. The residue was
purified by flash silica gel column chromatography (2:1 hexanes/
[M+Na]+ calcd for C9H14O5Na 225.0739, found 225.0735.
4.1.5. (S)-Dihydro-5-[(R,E)-3-iodo-1-(methoxymethoxy)allyl]-5-
methylfuran-2(3H)-one (13)
A solution of 12 (412 mg, 2.04 mmol) in THF/dioxane (10:1,
22.0 mL) was treated with CrCl2 (1.50 g, 12.2 mmol) and CHl3
(1.04 g, 2.65 mmol) at room temperature. After stirring for 13 h
in the dark, the reaction mixture was quenched with satd Na2S2O3
aq, then stirred for 1 h. The reaction mixture was extracted with
EtOAc. The organic layers were combined, dried over Na2SO4, fil-
tered, and concentrated in vacuo. The residue was purified by flash
silica gel column chromatography (8:1 hexanes/EtOAc) to afford 13
EtOAc) to afford 3 (8.8 mg, 2 steps, 28%) as a colorless oil.
25
[
a]
+29.7 (c 0.10, CHCl3); IR (KBr) 3431, 2960, 2924, 2860,
D
1767, 1658, 1455, 1379, 1260, 1204, 1085, 1022, 1379, 1260,
1204, 1085 cmꢀ1 1H NMR (400 MHz, CDCl3) d 6.33 (dd, J = 15.4,
;
10.4 Hz, 1H), 6.17 (ddd, J = 15.2, 10.8, 0.9 Hz, 1H), 6.00 (dd,
J = 15.4, 10.4 Hz, 1H), 5.76 (d, J = 10.8 Hz, 1H), 5.69 (dd, J = 15.4,
7.2, Hz, 1H), 5.50 (dd, J = 15.4, 6.8 Hz, 1H), 5.45 (dd, J = 15.2,
7.9 Hz, 1H), 4.23 (d, J = 6.8 Hz, 1H), 2.67 (ddd, J = 18.0, 10.6,
6.5 Hz, 1H), 2.57 (ddd, J = 12.9, 10.2, 6.5 Hz, 1H), 2.44–2.37 (m,
2H), 2.11–2.02 (m, 2H), 1.95 (dd, J = 13.4, 7.9 Hz, 1H), 1.77 (ddd,
J = 12.9, 10.2, 6.5 Hz, 1H), 1.70 (s, 3H), 1.36 (s, 3H), 1.33–1.27 (m,
2H), 0.99 (d, J = 6.6 Hz, 3H), 0.96 (d, J = 6.7 Hz, 3H), 0.86 (t,
J = 7.4 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 177.4, 142.6, 138.8,
134.9, 134.2, 127.2, 127.1, 126.5, 124.9, 88.4, 77.2, 47.7, 38.8,
35.0, 30.1, 29.7, 27.9, 24.0, 20.4, 19.8, 16.8, 12.0; HRMS (ESI)
[M+Na]+ calcd for C22H34NaO3 369.2405, found 369.2397.
(507 mg, 76%) as a colorless oil.
19
[a]
ꢀ38.3 (c 0.1, CHCl3); IR (KBr) 3514, 3446, 3055, 2983,
D
2952, 2889, 2825, 2359, 1774, 1606, 1450, 1290, 1248, 1209,
1157, 1095 cmꢀ1 1H NMR (300 MHz, CDCl3)
;
d
6.57 (d,
J = 14.6 Hz, 1H), 6.41 (dd, J = 14.6, 7.7 Hz, 1H), 4.65 (d, J = 6.8 Hz,
1H), 4.54 (d, J = 6.8 Hz, 1H), 4.09 (d, J = 7.7 Hz, 1H), 3.34 (s, 3H),
2.46–2.78 (m, 2H), 2.44–2.32 (m, 1H), 1.92–1.79 (m, 1H), 1.37 (s,
3H); 13C NMR (75 MHz, CDCl3) d 176.8, 140.4, 94.1, 85.9, 82.6,
82.3, 56.0, 29.6, 28.6, 24.3; HRMS (FAB, m-NBA) [M+H]+ calcd for
C10H16IO4 327.0093, found 327.0094.
4.1.8. 2-Ethylnaphthalen-7-yl trifluoromethanesulfonate (23)
A solution of 2213 (2.05 g, 11.9 mmol) in CH2Cl2 (60.0 mL) was
treated with Tf2O (3.00 mL, 17.8 mmol), 2,6-lutidine (2.78 mL,
23.8 mmol) and DMAP (727 mg, 5.95 mmol) at 0 °C. After stirring
for 3 h at room temperature, the reaction mixture was quenched
with satd NaHCO3 aq, then extracted with CH2Cl2. The organic lay-
ers were combined, dried over Na2SO4, filtered, and concentrated
in vacuo. The residue was purified by flash silica gel column chro-
matography (hexanes) to afford 23 (3.34 g, 92%) as a colorless oil.
IR (KBr) 3056, 2970, 2936, 2876, 2361, 1793, 1705, 1635, 1606,
4.1.6. 4,4,5,5-Tetramethyl-2-[(1E,3R,5E,7E,9S)-3,5,9-
trimethylundeca-1,5,7-trienyl]-1,3,2-dioxaborolane (16)
A solution of 144 (109 mg, 0.560 mmol) in CH2Cl2 (6.0 mL) was
treated with DMP (471 mg, 1.11 mmol) at 0 °C. After stirring for
1.5 h at room temperature, the reaction mixture was quenched
with satd Na2S2O3 aq, then the aqueous layer was extracted with
CH2Cl2. The organic layers were combined, dried over Na2SO4, fil-
tered, and concentrated in vacuo. A solution of the crude aldehyde
15 in THF (2.0 mL) was treated with Cl2CHB(pinacolate)9 (141
lg,
0.67 mmol) in THF (1.0 mL) solution and LiI (179 mg, 1.33 mmol)
in THF (3.0 mL) at room temperature. After stirring for 15 h at
room temperature, the reaction mixture was quenched with satd
Na2S2O3 aq, then extracted with EtOAc. The organic layer was com-
bined, dried over Na2SO4, filtered, and concentrated in vacuo. The
residue was purified by flash silica gel column chromatography
(40:1 hexanes/EtOAc) to afford 16 (82.5 mg, 2 steps, 48%) as a col-
1509, 1459, 1424, 1213, 1143, 1109 cmꢀ1 1H NMR (300 MHz,
;
CDCl3) d 7.88 (d, J = 8.6 Hz, 1H), 7.81 (d, J = 8.6 Hz, 1H), 7.68 (d,
J = 2.5 Hz, 1H), 7.65 (d, J = 1.7 Hz, 1H), 7.43 (dd, J = 8.6, 1.7 Hz,
1H), 7.30 (dd, J = 8.6, 2.5 Hz, 1H), 2.84 (q, J = 7.6 Hz, 2H), 1.33 (t,
J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 147.2, 143.8, 133.7,
130.8, 130.2, 130.2, 128.5, 125.6, 125.6, 120.4, 118.7, 118.6,
117.2; HRMS (FAB, m-NBA) [M+H]+ calcd for C13H12F3O3S
305.0459, found 305.0457.
orless oil.
23
[a]
+38.4 (c 0.10, CHCl3); IR (KBr) 2964, 2925, 2867, 1738,
D
1636, 1457, 1363, 1323, 1266, 1217, 1147, 1107 cmꢀ1
;
1H NMR
4.1.9. 2-Cyano-7-ethylnaphthalene (24)
(400 MHz, CDCl3) d 6.56 (dd, J = 18.2, 6.7 Hz, 1H), 6.19 (ddd,
J = 15.4, 10.8, 1.0 Hz, 1H), 5.77 (d, J = 10.8 Hz, 1H), 5.45 (dd,
J = 15.4, 7.6 Hz, 1H), 5.39 (dd, J = 18.2, 1.4 Hz, 1H), 2.45–2.38 (m,
1H), 2.17 (dd, J = 13.3, 6.0 Hz, 1H), 2.10–2.03 (m, 1H), 1.90 (dd,
J = 13.3, 8.7 Hz, 1H), 1.71 (s, 3H), 1.35–1.28 (m, 2H), 1.26 (s, 12H),
0.98 (d, J = 6.7 Hz, 3H), 0.94 (d, J = 6.5 Hz, 3H), 0.86 (t, J = 7.5 Hz,
3H); 13C NMR (100 MHz, CDCl3) d 159.7, 138.4, 134.1, 126.8,
124.8, 83,0, 46.7, 38.5, 37.4, 28.8, 29.8, 24.7, 24.6, 20.9, 20.2,
A solution of 23 (103 mg, 0.340 mmol) in DMF (1.7 mL) was
treated with Zn(CN)2 (79.7 mg, 0.680 mmol) and Pd(PPh3)4
(39.2 mg, 0.0300 mmol) at room temperature. After stirring for
15 h at 150 °C, the reaction mixture was brought to room temper-
ature and quenched with satd NaHCO3 aq The reaction mixture
was extracted with EtOAc. The organic layers were combined,
dried over Na2SO4, filtered, and concentrated in vacuo. The residue
was purified by flash silica gel column chromatography (50:1 hex-
anes/EtOAc) to afford 24 (46.5 mg, 78%) as a white solid.
IR (KBr) 3055, 2974, 2935, 2874, 2226, 1631, 1603, 1508, 1458,
18.9, 16.5, 11.8; HRMS (FAB, m-NBA) [M]+ calcd for C 20H35O121
B
318.2734, found 318.2728.
1369, 1341, 1317, 1268, 1197, 1175, 1139 cmꢀ1
;
1H NMR
4.1.7. (S)-Dihydro-5-[(1R,2E,4E,6R,8E,10E,12S)-1-hydroxy-6,8,
12-trimethyltetradeca-2,4,8,10-tetraenyl]-5-methylfuran-
2(3H)-one (3)
A solution of 13 (29.4 mg, 0.0900 mmol) and 16 (35.6 mg,
0.110 mmol) in toluene (1.8 mL) and EtOH (0.45 mL) was treated
(300 MHz, CDCl3) d 8.17 (d, J = 1.6 Hz, 1H), 7.87 (d, J = 8.6 Hz, 1H),
7.81 (d, J = 8.6 Hz, 1H), 7.67 (d, J = 1.6 Hz, 1H), 7.54 (dd, J = 8.6,
1.6 Hz, 1H), 7.51 (dd, J = 8.6, 1.6 Hz, 1H), 2.85 (q, J =7.6 Hz, 2H),
1.33 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 143.8, 133.6,
133.1, 132.5, 130.3, 128.8, 127.9, 126.0, 125.5, 119.4, 109.2, 28.9,
15.2; HRMS (EI) [M]+ calcd for C13H11ON 181.0891, found
181.0897.
with Pd(PPh3)4 (5.4 mg, 4.70 lmol), PPh3 (1.2 mg, 4.70 lmol) and
2 M Na2CO3 aq (1.1 mL) at room temperature. After stirring for
2 h at 80 °C, the reaction mixture was brought to room tempera-
ture and quenched with H2O. The aqueous layer was extracted
with EtOAc. The organic layers were combined, dried over Na2SO4,
filtered, and concentrated in vacuo. A solution of the crude MOM
4.1.10. 7-Ethylnaphthalene-2-carbaldehyde (25)
A solution of 24 (583 mg, 3.22 mmol) in CH2Cl2 (16.0 mL) was
treated with DIBAL (1.03 M sol. in hexane, 6.43 mL, 6.43 mmol)

938
M. Ohtawa et al. / Bioorg. Med. Chem. 23 (2015) 932–943
at ꢀ78 °C. After stirring for 0.5 h at ꢀ78 °C, the reaction mixture
was quenched with 2 M HCl and diluted with EtOAc. The organic
layer was washed with 2 M HCl and H2O, dried over Na2SO4, fil-
tered, and concentrated in vacuo. The residue was purified by flash
silica gel column chromatography (200:1 hexanes/EtOAc) to afford
25 (3.34 g, 93%) as a white solid.
tography (30:1 hexanes/EtOAc) to afford 29 (245 mg, quant.) as a
white solid.
IR (KBr) 3376, 3046, 2964, 2928, 2870, 1595, 1488, 1455, 1349,
1264, 1153, 1073 cmꢀ1 1H NMR (400 MHz, CDCl3) d 7.73 (d,
;
J = 8.4 Hz, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.57–7.56 (m, 2H), 7.31
(dd, J = 8.4, 1.6 Hz, 1H), 7.25 (dd, J = 8.4, 1.6 Hz, 1H), 7.16 (ddd,
J = 7.6, 7.5, 0.9 Hz, 1H), 6.83–6.81 (m, 1H), 6.69–6.66 (m, 2H),
4.80–4.65 (br, 1H), 4.08 (s, 2H), 2.80 (q, J = 7.6 Hz, 2H), 1.32 (t,
J = 7.6 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 155.6, 143.0, 142.0,
138.2, 133.8, 130.6, 129.6, 127.8, 127.5, 126.8, 126.7, 126.6,
125.2, 121.5, 115.9, 113.0, 41.9, 29.0, 15.5; HRMS (FAB, m-NBA)
[M]+ calcd for C19H18O 262.1358, found 262.1363.
IR (KBr) 2971, 2935, 2871, 2821, 2721, 1694, 1603, 1458, 1375,
1338, 1270, 1205, 1169, 1123, 1058 cmꢀ1 1H NMR (300 MHz,
;
CDCl3) d 10.2 (s, 1H), 8.26 (s, 1H), 7.90 (d, J = 8.5 Hz, 1H), 7.87 (d,
J = 8.5 Hz, 1H), 7.82 (d, J = 8.5 Hz, 1H), 7.77 (s, 1H), 7.51 (d,
J = 8.5 Hz, 1H), 2.85 (q, J = 7.6 Hz, 2H), 1.35 (t, J = 7.6 Hz, 3H); 13C
NMR (75 MHz, CDCl3) d 192.3, 143.2, 134.9, 134.1, 134.1, 132.9,
130.4, 128.7, 127.9, 127.1, 121.9, 28.9, 15.3; HRMS (FAB, m-NBA+-
NaI) [M+Na]+ calcd for C13H12ONa 207.0786, found 207.0790.
4.1.14. 3-((2-Ethylnaphthalen-7-yl)methyl)phenyl
trifluoromethanesulfonate
4.1.11. 2-Ethylnaphthalen-7-yl[3-(methoxymethoxy)
phenyl]methanol (27)
A solution of 29 (298 mg, 1.13 mmol) in CH2Cl2 (11.0 mL) was
treated with Tf2O (229 lL, 1.36 mmol), 2,6-lutidine (199 lL,
A solution of 2615 (533 mg, 2.46 mmol) in THF (16.0 mL) was
treated with t-BuLi (1.59 M sol. in pentane, 3.09 mL, 4.91 mmol)
at ꢀ78 °C. After stirring for 10 min at ꢀ78 °C, 25 (302 mg,
1.63 mmol) in THF (8.6 mL) was added. After stirring for 1 h at
ꢀ78 °C, the reaction mixture was quenched with satd NH4Cl aq
The aqueous layer was extracted with EtOAc. The organic layers
were combined, dried over Na2SO4, filtered, and concentrated in
vacuo. The residue was purified by flash silica gel column chroma-
tography (10:1 hexanes/EtOAc) to afford 27 (523 mg, 99%) as a
white solid.
1.70 mmol) and DMAP (69.4 mg, 0.580 mmol) at 0 °C. After stirring
for 0.5 h at room temperature, the reaction mixture was quenched
with satd NaHCO3 aq and extracted with CH2Cl2. The organic layers
were combined, dried over Na2SO4, filtered, and concentrated in
vacuo. The residue was purified by flash silica gel column chroma-
tography (hexanes) to afford 3-((2-ethylnaphthalen-7-yl)methyl)-
phenyl trifluoromethanesulfonate (441 mg, 99%) as a white solid.
IR (KBr) 3454, 2697, 2929, 2365, 1611, 1580, 1483, 1422, 1213,
1141 cmꢀ1 1H NMR (300 MHz, CDCl3) d 7.75 (d, J = 8.4 Hz, 1H),
;
7.74 (d, J = 8.4 Hz, 1H), 7.57–7.55 (m, 2H), 7.37 (dd, J = 7.7, 0.9 Hz,
1H), 7.34–7.31 (m, 1H), 7.26–7.19 (m, 2H), 7.14–7.11 (m, 2H),
4.17 (s, 2H), 2.81 (q, J = 7.6 Hz, 2H), 1.32 (t, J = 7.6 Hz, 3H); 13C
NMR (100 MHz, CDCl3) d 149.7, 144.2, 142.2, 136.9, 133.8, 130.7,
130.1, 129.0, 128.1, 127.6, 127.0, 126.8, 125.2, 121.8, 120.3,
118.9, 117.1, 41.6, 29.0, 15.5; HRMS (FAB, m-NBA) [M]+ calcd for
IR (KBr) 3448, 2964, 2347, 1633, 1605, 1511, 1486, 1451, 1403,
1314, 1246, 1207, 1150 cmꢀ1 1H NMR (300 MHz, CDCl3) d 7.86 (s,
;
1H), 7.79 (d, J = 8.6 Hz, 1H), 7.77 (d, J = 8.6 Hz, 1H), 7.66 (s, 1H),
7.42 (dd, J = 6.6 Hz, 1H), 7.37 (dd, J = 6.6 Hz, 1H), 7.29 (t,
J = 7.6 Hz, 1H), 7.17 (s, 1H), 7.08 (d, J = 7.6 Hz, 1H), 7.01–6.97 (m,
1H), 6.00 (d, J = 3.3 Hz, 1H), 5.20 (s, 2H), 3.50 (s, 3H), 2.86 (q,
J = 7.6 Hz, 2H), 1.36 (t, J = 7.6 Hz, 3H); 13C NMR (75 MHz, CDCl3) d
157.4, 145.4, 142.1, 141.0, 133.5, 131.3, 129.5, 128.0, 127.5,
127.2, 125.7, 124.7, 123.9, 120.2, 115.1, 114.7, 94.4, 76.2, 56.0,
29.0, 15.5 ; HRMS (ESI) [M+Na]+ calcd for C21H22O3Na 345.1467,
found 345.1464.
C20H17F3O3S 394.0851, found 394.0851.
4.1.15. 2-(3-((2-Ethylnaphthalen-7-yl)methyl)phenyl)-4,4,5,5-
tetramethyl-1,3,2-dioxaborolane (18)
A solution of 3-((2-ethylnaphthalen-7-yl)methyl)phenyl trifluo-
romethanesulfonate (201 mg, 0.510 mmol) in dioxane (5.1 mL)
was treated with PdCl2(dppf) (74.8 mg, 0.100 mmol), bis(pinacola-
to)diboron (160 mg, 0.610 mmol), dppf (56.6 mg, 0.100 mmol) and
KOAc (150 mg, 1.53 mmol) at room temperature. After stirring for
12 h at 80 °C, the reaction mixture was quenched with H2O and
extracted with EtOAc. The organic layers were combined, dried
over Na2SO4, filtered, and concentrated in vacuo. The residue was
purified by flash silica gel column chromatography (hexanes) to
afford 18 (176 mg, 93%) as a pale yellow solid.
4.1.12. 2-(3-(Methoxymethoxy)benzyl)-7-ethylnaphthalene (28)
A solution of 27 (281 mg, 0.870 mmol) in CH2Cl2 (9.0 mL) was
treated with Et3SiH (557 lL, 3.49 mmol) and TFA (134 lL,
1.74 mmol) at 0 °C. After stirring for 2 h at room temperature,
the reaction mixture was quenched with satd NaHCO3 aq and
extracted with CH2Cl2. The organic layers were combined, dried
over Na2SO4, filtered, and concentrated in vacuo. The residue was
purified by flash silica gel column chromatography (100:1 hex-
anes/EtOAc) to afford 28 (201 mg, 75%) as a white solid.
IR (KBr) 2972, 2927, 2364, 1734, 1635, 1606, 1428, 1358, 1269,
1204, 1144, 1078 cmꢀ1; 1H NMR (300 MHz, CDCl3) d 7.74–7.65 (m,
4H), 7.57–7.64 (m, 2H), 7.31–7.23 (m, 4H), 4.13 (s, 2H), 2.79 (q,
J = 7.5 Hz, 2H), 1.34 (s, 12H), 1.32 (t, J = 7.5 Hz, 3H); 13C NMR
(75 MHz, CDCl3) d 141.2, 140.3, 138.7, 135.3, 133.8, 132.6, 132.1,
130.5, 128.0, 127.7, 127.5, 126.8, 126.6, 126.5, 125.2, 83.7, 42.1,
IR (KBr) 2961, 2927, 1600, 1487, 1449, 1313, 1248, 1207, 1150,
1079 cmꢀ1 1H NMR (400 MHz, CDCl3) d 7.74 (d, J = 8.4 Hz, 1H),
;
7.73 (d, J = 8.4 Hz, 1H), 7.59 (br s, 1H), 7.57 (br s, 1H), 7.30 (dd,
J = 8.4, 1.7 Hz, 1H), 7.27 (dd, J = 8.4, 1.7 Hz, 1H), 7.22 (ddd, J = 8.0,
7.7, 0.6 Hz, 1H), 6.93–6.87 (m, 3H), 5.16 (s, 2H), 4.11 (s, 2H), 3.48
(s, 3H), 2.81 (q, J = 7.6 Hz, 2H), 1.33 (t, J = 7.6 Hz, 3H); 13C NMR
(75 MHz, CDCl3) d 157.4, 142.7, 141.9, 138.3, 133.8, 130.5, 129.4,
127.8, 127.5, 126.8, 126.7, 126.6, 125.2, 122.6, 117.1, 113.7, 94.4,
56.0, 42.1, 29.0, 15.5; HRMS (FAB, m-NBA) [M]+ calcd for
29.7, 29.0, 24.8, 15.5; HRMS (FAB, m-NBA) [M]+ calcd for
11
C
H BO2 372.2261, found 372.2259.
25 29
4.1.16. (S)-5-((R,E)-3-(3-((7-Ethylnaphthalen-2-yl)methyl)
phenyl)-1-hydroxyallyl)-5-methyldihydrofuran-2(3H)-one (4)
A solution of 13 (40.2 mg, 0.123 mmol) and 18 (45.9 mg,
C21H22O2 306.1620, found 306.1619.
0.123 mmol) in toluene (2.5 mL) and EtOH (615 lL) was treated
4.1.13. 3-((2-Ethylnaphthalen-7-yl)methyl)phenol (29)
with a catalytic amount of Pd(PPh3)4 and 2 M Na2CO3 aq (1.5 mL)
at room temperature. After stirring for 1 h at 80 °C, the reaction
mixture was brought to room temperature and quenched with
H2O. The aqueous layer was extracted with EtOAc. The organic
layers were combined, dried over Na2SO4, filtered, and concen-
trated in vacuo. A solution of the crude MOM ether in i-PrOH
A solution of 28 (286 mg, 0.930 mmol) in i-PrOH (19.0 mL) was
treated with CBr4 (1.23 g, 3.73 mmol) at room temperature. After
stirring for 0.5 h at 75 °C, the reaction mixture was quenched with
satd NaHCO3 aq and extracted with CH2Cl2. The organic layers
were combined, dried over Na2SO4, filtered, and concentrated in
vacuo. The residue was purified by flash silica gel column chroma-
(1.5 mL) was treated with CBr4 (61.5 lg, 0.185 mmol) at room tem-

M. Ohtawa et al. / Bioorg. Med. Chem. 23 (2015) 932–943
939
26
perature. After stirring for 1 h at 75 °C, the reaction mixture was
quenched with satd NaHCO3 aq and extracted with CH2Cl2. The
organic layers were combined, dried over Na2SO4, filtered, and con-
centrated in vacuo. The residue was purified by flash silica gel col-
umn chromatography (5:1 hexanes/EtOAc) to afford 4 (18.7 mg, 2
[
a]
ꢀ13.4 (c 1.00, CHCl3); IR (KBr) 3054, 2961, 2923, 2246,
D
1723, 1457, 1381, 1267 cmꢀ1 1H NMR (300 MHz, CDCl3) d 5.18
;
(t, J = 7.0 Hz, 1H), 2.31 (dd, J = 16.5, 4.8 Hz, 1H), 2.15 (dd, J = 16.5,
6.9 Hz, 1H), 2.07–1.89 (m, 5H), 1.53 (s, 3H), 1.40–1.06 (m, 5H),
1.05 (d, J = 6.3 Hz, 3H), 0.89–0.83 (m, 6H); 13C NMR (75 MHz,
CDCl3) d 131.7, 128.7, 119.2, 46.7, 36.7, 34.3, 29.6, 28.7, 25.7,
23.9, 19.7, 19.3, 15.9, 11.6; HRMS (FAB, m-NBA) [M+H]+ calcd for
steps 38%) as a white solid.
26
[a]
ꢀ29.2 (c 0.10, CHCl3); IR (KBr) 3425, 2925, 1762, 1633,
D
1452, 1077; 1H NMR (300 MHz, CDCl3) d 7.75 (d, J = 8.4 Hz, 2H),
7.56 (s, 2H), 7.31 (dd, J = 8.5, 1.6 Hz, 1H), 7.27–7.13 (m, 5H), 6.72
(dd, J = 16.0, 0.9 Hz, 1H), 6.14 (dd, J = 16.0, 6.6 Hz, 1H), 4.80 (dd,
J = 6.6, 0.9 Hz, 1H), 4.12 (s, 2H), 2.80 (q, J = 7.6 Hz, 2H), 2.73–2.55
(m, 2H), 2.53–2.42 (m, 1H), 2.25–1.95 (br, 1H), 1.86–1.77 (m,
1H), 1.41 (s, 3H), 1.31 (t, J = 7.6 Hz, 3H); 13C NMR (75 MHz, Ace-
tone-d6) d 177.1, 142.8, 142.6, 139.8, 138.0, 134.9, 133.1, 131.6,
129.6, 129.2, 128.6, 128.6, 128.4, 128.2, 127.6, 127.4, 127.3,
126.0, 125.1, 88.2, 77.5, 42.4, 30.0, 29.5, 29.0, 23.8, 15.9; HRMS
(ESI) [M+Na]+ calcd for C27H28O3Na 423.1936, found 423.1936.
C14H26N 208.2065, found 208.2059.
4.1.19. (3R,9S,E)-3,5,9-Trimethylundec-5-en-1-ol (40)
A solution of 38 (174 mg, 0.840 mmol) in CH2Cl2 (8.4 mL) was
treated with DIBAL (1.04 M sol. in hexane, 1.20 mL, 1.26 mmol)
at ꢀ78 °C. After stirring for 1.5 h at ꢀ78 °C the reaction mixture
was quenched with 2 M HCl and diluted with EtOAc. The organic
layer was washed with 2 M HCl and H2O, dried over Na2SO4, fil-
tered, and concentrated in vacuo. A solution of the crude aldehyde
in MeOH (8.4 mL) was treated with NaBH4 (63.6 lg, 1.68 mmol) at
0 °C. After stirring for 20 min at 0 °C, the reaction mixture was
quenched with acetone and diluted with EtOAc. The organic layer
was washed with brine, dried over Na2SO4, filtered, and concen-
trated in vacuo. The residue was purified by flash silica gel column
chromatography (200:1 hexanes/EtOAc) to afford 40 (144 mg, 2
4.1.17. tert-Butyldiphenyl((2R,8S,E)-2,4,8-trimethyldec-4-
enyloxy)silane (36)
A solution of 3117 (108 mg, 0.508 mmol) in Et2O (5.0 mL) was
treated with t-BuLi (1.55 M sol. in pentane, 0.700 mL, 1.09 mmol)
at ꢀ78 °C. After stirring for 10 min at ꢀ78 °C, 9-BBNOMe (1.0 M
sol. in hexane, 1.18 mL, 1.18 mmol) and THF (5.0 mL) were added.
After stirring for 1.5 h at room temperature, the reaction mixture
was treated with 3519 (110 mg, 0.231 mmol) in DMF (5.0 mL),
steps, 81%) as a pale yellow oil.
27
[
a]
+5.74 (c 1.00, CHCl3); IR (KBr) 3331, 2958, 2921, 2231,
D
1662, 1457, 1379, 1057 cmꢀ1 1H NMR (300 MHz, CDCl3) d 5.09
;
(dt, J = 7.0, 1.1 Hz, 1H), 3.74–3.60 (m, 2H), 2.01–1.90 (m, 3H),
1.82–1.67 (m, 3H), 1.64–1.53 (m, 1H), 1.57 (s, 3H), 1.38–1.24 (m,
4H), 1.19–1.06 (m, 2H), 0.85 (t, J = 7.2 Hz, 3H) 0.85 (d, J = 5.7 Hz,
3H), 0.83 (d, J = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 133.1,
126.8, 61.2, 48.0, 39.7, 36.7, 34.0, 29.4, 27.4, 25.5, 19.4, 19.1,
3 M K3PO4 aq (385
lL, 1.16 mmol), PdCl2(dppf) (18.9 mg,
23.1 mol) and dppf (12.8 mg, 23.1
l
lmol) at room temperature.
After stirring for 13 h at room temperature, the reaction mixture
was quenched with H2O and diluted with EtOAc. The organic layer
was washed with H2O and brine, dried over Na2SO4, filtered, and
concentrated in vacuo. The residue was purified by flash silica
gel column chromatography (hexanes) to afford 36 (93.3 mg,
15.7, 11.4.; HRMS (FAB, m-NBA) [M+H]+ calcd for C14H29
O
213.2218, found 213.2228.
93%) as a colorless oil.
4.1.20. (3R,9S,E)-1-Iodo-3,5,9-trimethylundec-5-ene (42)
25
[a]
+10.3 (c 1.00, CHCl3); IR (KBr) 3062, 2957, 2925, 2862,
D
A solution of 40 (70.3 mg, 0.331 mmol) in CH2Cl2 (5.0 mL) was
treated with I2 (126 mg, 0.497 mmol), PPh3 (113 mg, 0.868 mmol)
and imidazole (126 mg, 2.00 mmol) at 0 °C. After stirring for
10 min at 0 °C, the reaction mixture was quenched with satd
Na2S2O3 aq and diluted with EtOAc. The organic layer was
washed with brine, dried over Na2SO4, filtered, and concentrated
in vacuo. The residue was purified by flash silica gel column chro-
matography (hexanes) to afford 42 (144 mg, 86%) as a pale yellow
2361, 1463, 1436, 1383, 1106 cmꢀ1 1H NMR (300 MHz, CDCl3) d
;
7.68–7.65 (m, 4H), 7.42–7.34 (m, 6H), 5.08 (t, J = 7.0 Hz, 1H),
3.51–3.40 (m, 2H), 2.18 (dd, J = 12.8, 5.4 Hz, 1H), 1.97–1.93 (m,
2H), 1.82–1.78 (m, 1H), 1.72 (dd, J = 12.8, 8.4 Hz, 1H), 1.53 (s,
3H), 1.35–1.06 (m, 5H), 1.05 (s, 9H), 0.88–0.82 (m, 9H); 13C NMR
(75 MHz, CDCl3) d 135.9, 134.4, 133.3, 129.7, 127.8, 126.9, 69.0,
44.1, 36.9, 34.3, 34.0, 29.7, 27.1, 25.8, 19.6, 19.3, 16.9, 16.0, 11.6;
HRMS (FAB, m-NBA) [M-t-Bu]+ calcd for C25H35OSi 379.2457, found
379.2453.
oil.
27
[
a]
ꢀ2.23 (c 1.00, CHCl3); IR (KBr) 3437, 2958, 2919, 2154,
D
1637, 1456, 1379, 1256, 1215, 1177 cmꢀ; 1H NMR (300 MHz,
CDCl3) d 5.10 (dt, J = 7.0, 1.0 Hz, 1H), 3.31–3.12 (m, 2H), 2.06–
1.91 (m, 3H), 1.90–1.64 (m, 3H), 1.63–1.51 (m, 1H), 1.58 (s, 3H),
1.42–1.26 (m, 3H), 1.22–1.05 (m, 2H), 0.91–0.81 (m, 9H); 13C
NMR (75 MHz, CDCl3) d 133.0, 127.4, 47.4, 40.8, 36.9, 34.2, 32.0,
29.7, 25.7, 19.4, 18.9, 16.0, 11.6, 5.6.; HRMS (EI) [M]+ calcd for
4.1.18. (3R,9S,E)-3,5,9-Trimethylundec-5-enenitrile (38)
A solution of 36 (442 mg, 1.02 mmol) in THF (10.0 mL) was trea-
ted with TBAF (1.0 M sol. in THF, 3.06 lL, 3.06 mmol) at room tem-
perature. After stirring for 3 h at room temperature, the reaction
mixture was quenched with satd NaHCO3 aq and diluted with
EtOAc. The organic layer was washed with brine, dried over
Na2SO4, filtered, and concentrated in vacuo. A solution of the crude
C14H27I 322.1157, found 322.1155.
alcohol in CH2Cl2 (10.0 mL) was treated with p-TsCl (290
lg,
4.1.21. (S)-5-((1R,2E,6S,8E,12S)-1-(Methoxymethoxy)-6,8,12-
trimethyltetradeca-2,8-dien-1-yl)-5-methyldihydrofuran-
2(3H)-one (44)
A solution of 42 (152 mg, 0.160 mmol) in Et2O (1.6 mL) was
treated with t-BuLi (1.59 M sol. in pentane, 0.209 mL, 0.333 mmol)
at ꢀ78 °C. After stirring for 10 min at ꢀ78 °C, 9-BBNOMe (1.0 M sol.
in hexane, 0.359 mL, 0.832 mmol) and THF (1.6 mL) were added.
After stirring for 1.5 h at room temperature, the reaction mixture
was treated with 13 (43.4 mg, 0.133 mmol) in DMF (1.6 mL), 3 M
1.52 mmol), Et3N (423
l
L, 3.05 mmol) and Me3NꢁHCl (9.7 mg,
0.102 mmol) at 0 °C. After stirring for 1.5 h at 0 °C, the reaction
mixture was quenched with satd NaHCO3 aq and diluted with
EtOAc. The organic layer was washed with brine, dried over
Na2SO4, filtered, and concentrated in vacuo. A solution of the crude
tosylate in DMSO (10.0 mL) was treated with KCN (79.3 mg,
1.22 mmol) at room temperature. After stirring for 3.5 h at
100 °C, the reaction mixture was quenched with satd NaHCO3 aq
and diluted with EtOAc. The organic layer was washed with brine,
dried over Na2SO4, filtered, and concentrated in vacuo. The residue
was purified by flash silica gel column chromatography (200:1
hexanes/EtOAc) to afford 38 (175 mg, 3 steps, 83%) as a pale yellow
oil.
K3PO4 aq (222
l
L, 0.655 mmol), PdCl2(dppf) (10.9 mg, 13.3
lmol)
and dppf (7.4 mg, 13.3
lmol) at room temperature. After stirring
for 17 h at room temperature, the reaction mixture was quenched
with H2O and diluted with EtOAc. The organic layer was washed

940
M. Ohtawa et al. / Bioorg. Med. Chem. 23 (2015) 932–943
with H2O and brine, dried over Na2SO4, filtered, and concentrated
in vacuo. The residue was purified by flash silica gel column chro-
matography (50:1 hexanes/EtOAc) to afford 44 (25.2 mg, 48%) as a
4.1.25. (R,E)-3,5,9-Trimethyldec-5-en-1-ol (41)
According to the procedure for 40. Yield: 2 steps, 77%.
29
[
a]
D
ꢀ2.79 (c 1.00, CHCl3); IR (KBr) 3393, 3052, 2956, 2925,
pale yellow oil.
2871, 1637, 1459, 1265, 1055 cmꢀ1 1H NMR (400 MHz, CDCl3) d
;
27
[
a]
ꢀ53.49 (c 1.00, CHCl3); IR (KBr) 3527, 2923, 1777, 1456,
5.10 (t, J = 6.9 Hz, 1H), 3.73–3.64 (m, 2H), 2.02–1.94 (m, 3H),
1.83–1.68 (m, 2H), 1.62–1.48 (m, 1H) 1.58 (s, 3H), 1.38–1.26 (m,
1H), 1.24–1.17 (m, 3H), 0.91–0.83 (m, 9H); 13C NMR (100 MHz,
CDCl3) d 133.1, 126.7, 61.2, 48.0, 39.7, 39.0, 27.6, 27.4, 25.8, 22.6,
22.5, 19.4, 15.7; HRMS (EI) [M]+ calcd for C13H26O 198.1984, found
198.1991.
D
1377, 1206, 1156, 1093 cmꢀ1 1H NMR (300 MHz, CDCl3) d 5.80
;
(dt, J = 15.4, 6.7 Hz, 1H), 5.25 (dd, J = 15.4, 8.2 Hz, 1H), 5.09 (t,
J = 6.7 Hz, 1H), 4.67 (d, J = 6.7 Hz, 1H), 4.49 (d, J = 6.7 Hz, 1H),
4.06 (d, J = 8.2 Hz, 1H), 3.35 (s, 3H), 2.80–2.66 (m, 1H), 2.59–2.44
(m, 1H), 2.43–2.32 (m, 1H), 2.14–1.92 (m, 6H), 1.88–1.70 (m,
3H), 1.55 (s, 3H), 1.44–1.08 (m, 6H), 1.25 (s, 3H), 0.86 (d,
J = 7.1 Hz, 3H), 0.86 (d, J = 6.3 Hz, 3H), 0.81 (d, J = 6.6 Hz, 3H); 13C
NMR (100 MHz, CDCl3) d 176.2, 138.3, 134.2, 132.4, 124.0, 95.8,
89.9, 82.1, 55.6, 47.1, 39.0, 38.1, 32.9, 31.6, 28.8, 28.3, 28.2, 27.6,
24.4, 23.3, 21.5, 17.9, 16.6, 11.6; HRMS (ESI) [M+Na]+ calcd for C24-
H42NaO4 417.2981, found 417.2972.
4.1.26. (R,E)-1-Iodo-3,5,9-trimethyldec-5-ene (43)
According to the procedure for 42. Yield: 90%.
29
[
a]
D
ꢀ9.42 (c 1.00, CHCl3); IR (KBr) 3055, 2984, 2960, 1636,
1425, 1382, 1265, 1216, 1179 cmꢀ1 1H NMR (400 MHz, CDCl3) d
;
5.10 (dt, J = 7.2, 1.0 Hz, 1H), 3.30–3.13 (m, 2H), 2.02–1.94 (m,
3H), 1.90–1.68 (m, 3H), 1.62–1.50 (m, 2H) 1.58 (s, 3H), 1.25–1.18
(m, 2H), 0.88 (d, J = 6.7 Hz, 6H), 0.82 (d, J = 6.3 Hz, 3H); 13C NMR
(100 MHz, CDCl3) d 132.7, 127.1, 47.2, 40.5, 39.0, 31.7, 27.6, 25.8,
22.6, 18.6, 15.8, 5.5; HRMS (FAB, Thioglycerol+glycerol) [MꢀH]+
calcd for C13H24I 307.0928, found 307.0932.
4.1.22. 4(S)-5-((1R,2E,6S,8E,12S)-1-Hydroxy-6,8,12-
trimethyltetradeca-2,8-dien-1-yl)-5-methyldihydrofuran-
2(3H)-one (5)
A solution of 44 (12.1 mg, 31.4
lmol) in i-PrOH (1.0 mL) was
treated with CBr4 (31.3 mg, 94.3 mol) at room temperature. After
l
4.1.27. (S)-5-((1R,2E,6S,8E)-1-(Methoxymethoxy)-6,8,12-
trimethyltrideca-2,8-dien-1-yl)-5-methyldihydrofuran-2(3H)-
one (45)
stirring for 6 h at 65 °C, the reaction mixture was quenched with
satd NaHCO3 aq and diluted with EtOAc. The organic layer was
washed with H2O and brine, dried over Na2SO4, filtered, and con-
centrated in vacuo. The residue was purified by flash silica gel col-
umn chromatography (5:1 hexanes/EtOAc) to afford 5 (10.1 mg,
According to the procedure for 44. Yield: 73%.
29
[
a]
D
ꢀ36.76 (c 1.00, CHCl3); IR (KBr) 3021, 2957, 1766, 1667,
1423, 1265, 1217, 1031 cmꢀ1 1H NMR (300 MHz, CDCl3) d 5.79
;
92%) as a pale yellow oil.
28
(dt, J = 15.4, 6.7 Hz, 1H), 5.23 (dd, J = 15.4, 8.4 Hz, 1H), 5.07 (t,
J = 6.0 Hz, 1H), 4.66 (d, J = 6.7 Hz, 1H), 4.48 (d, J = 6.7 Hz, 1H),
4.05 (d, J = 8.4 Hz, 1H), 3.34 (s, 3H), 2.78–2.66 (m, 1H), 2.57–2.49
(m, 1H), 2.47–2.36 (m, 1H), 2.16–1.89 (m, 4H), 1.88–1.35 (m,
5H), 1.53 (s, 3H), 1.33 (s, 3H), 1.28–1.08 (m, 4H), 0.87 (d,
J = 6.7 Hz, 6H), 0.79 (d, J = 6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 176.2, 138.3, 134.2, 132.4, 124.0, 95.8, 89.9, 82.1, 55.6, 47.1,
39.0, 38.1, 32.9, 31.6, 28.8, 28.3, 28.2, 27.6, 24.4, 23.3, 21.5, 17.9,
16.6; HRMS (ESI) [M+Na]+ calcd for C23H40NaO4 403.2824, found
403.2805.
[
a]
ꢀ3.00 (c 1.00, CHCl3); IR (KBr) 3438, 2921, 1768, 1456,
D
1379, 1205, 1086 cmꢀ1 1H NMR (300 MHz, CDCl3) d 5.88–5.80
;
(m, 1H), 5.42 (dd, J = 15.4, 7.0 Hz, 1H), 5.09 (t, J = 6.7 Hz, 1H),
4.18 (d, J = 7.0 Hz, 1H), 2.74–2.52 (m, 2H), 2.49–2.37 (m, 1H),
2.20–1.90 (m, 6H), 1.85–1.70 (m, 3H), 1.55 (s, 3H), 1.45–1.09
(m, 6H), 1.26 (s, 3H), 0.86 (t, J = 7.2 Hz, 3H), 0.86 (d, J = 6.3 Hz,
3H), 0.81 (d, J = 6.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 176.1,
138.3, 134.2, 132.4, 124.0, 92.1, 77.9, 47.1, 39.0, 38.1, 32.9,
31.6, 28.8, 28.3, 28.2, 27.6, 24.4, 23.3, 21.5, 17.6, 16.6, 11.7;
HRMS (ESI) [M+Na]+ calcd for C22H38NaO3 373.2719, found
373.2705.
4.1.28. (S)-5-((1R,2E,6S,8E)-1-Hydroxy-6,8,12-trimethyltrideca-
2,8-dien-1-yl)-5-methyldihydrofuran-2(3H)-one (6)
4.1.23. (R,E)-tert-Butyldiphenyl((2,4,8-trimethylnon-4-en-1-
yl)oxy)silane (37)
According to the procedure for 5. Yield: 68%.
29
[
a]
D
ꢀ10.07 (c 0.100, CHCl3); IR (KBr) 3440, 3054, 1630, 1422,
According to the procedure for 36. Yield: 83%.
1265 cmꢀ1 1H NMR (300 MHz, CDCl3) d 5.84 (dt, J = 15.3, 6.9,
;
27
[
a]
+7.40 (c 1.00, CHCl3); IR (KBr) 3071, 3050, 2956, 2929,
D
1.0 Hz, 1H), 5.41 (dd, J = 15.3, 7.0, 1.4 Hz, 1H), 5.08 (dt, J = 7.4,
1.2 Hz, 1H), 4.17 (d, J = 7.0 Hz, 1H), 2.69–2.54 (m, 2H), 2.46–2.38
(m, 1H), 2.17–1.94 (m, 4H), 1.82–1.72 (m, 1H), 1.64–1.49 (m,
3H), 1.55 (s, 3H), 1.43–1.29 (m, 1H), 1.35 (s, 3H), 1.24–1.09 (m,
4H), 0.88 (d, J = 6.7 Hz, 6H), 0.81 (d, J = 6.7 Hz, 3H); 13C NMR
(100 MHz, CDCl3) d 176.1, 138.3, 134.2, 132.4, 124.0, 92.1, 77.9,
47.1, 39.0, 38.1, 32.9, 31.6, 28.8, 28.3, 28.2, 27.6, 24.4, 23.3, 21.5,
17.6, 16.6; HRMS (ESI) [M+Na]+ calcd for C21H36NaO3 359.2562,
found 359.2573.
2859, 1590, 1469, 1428, 1101 cmꢀ1 1H NMR (400 MHz, CDCl3) d
;
7.71–7.68 (m, 4H), 7.46–7.26 (m, 6H), 5.10 (t, J = 7.0 Hz, 1H, 3.52
(dd, J = 9.7, 5.3 Hz, 1H), 3.46 (dd, J = 9.7, 6.3 Hz, 1H), 2.19 (dd,
J = 12.9, 5.8 Hz, 1H), 1.97 (dd, J = 15.3, 7.0 Hz, 1H), 1.88–1.80 (m,
1H), 1.73 (dd, J = 12.9, 8.3 Hz, 1H), 1.59–1.49 (m, 1H), 1.56 (s,
3H), 1.24–1.17 (m, 2H) 1.08 (s, 9H), 0.87–0.85 (m, 9H); 13C NMR
(100 MHz, CDCl3) d 135.6, 134.1, 133.0, 129.5, 127.6, 126.5, 68.8,
43.8, 39.1, 33.7, 27.6, 26.9, 25.8, 22.6, 19.3, 16.7, 15.8; HRMS
(FAB, m-NBA) [M-tBu]+ calcd for C24H33OSi 365.2301, found
365.2312.
4.1.29. (E)-tert-Butyl((5,9-dimethyldec-5-en-1-yl)oxy)
dimethylsilane (48)
4.1.24. (R,E)-3,5,9-Trimethyldec-5-enenitrile (39)
A solution of 46 (156 lL, 1.19 mmol) in Et2O (12.0 mL) was trea-
According to the procedure for 38. Yield: 3 steps, 82%.
ted with t-BuLi (1.55 M sol. in pentane, 1.58 mL, 2.55 mmol) at
ꢀ78 °C. After stirring for 10 min at ꢀ78 °C, 9-BBNOMe (1.0 M sol.
in hexane, 2.76 mL, 2.76 mmol) and THF (12 mL) were added. After
stirring for 1 h at room temperature, the reaction mixture was
treated with 4717 (192 mg, 0.542 mmol) in DMF (12 mL), 3 M
28
[
a]
ꢀ25.05 (c 1.00, CHCl3); IR (KBr) 3055, 2959, 2927, 2871,
D
1722, 1458, 1422, 1265 cmꢀ1 1H NMR (400 MHz, CDCl3) d 5.18
;
(t, J = 7.0 Hz, 1H), 2.31 (dd, J = 16.6, 4.8 Hz, 1H), 2.14 (dd, J = 16.6,
6.7 Hz, 1H), 2.06–1.95 (m, 5H), 1.57 (s, 3H), 1.56–1.49 (m, 1H),
1.25–1.17 (m, 2H), 1.05 (d, J = 6.5 Hz, 3H), 0.96–0.87 (m, 6H); 13C
NMR (100 MHz, CDCl3) d 131.5, 128.4, 118.9, 46.4, 38.9, 28.4,
27.7, 25.8, 23.6, 22.5, 19.5, 15.6; HRMS (FAB, m-NBA) [M+H]+ calcd
for C13H24N 194.1909, found 194.1905.
K3PO4 aq (903
l
L, 2.71 mmol), PdCl2(dppf) (44.3 mg, 54.2
lmol)
and dppf (30.0 mg, 54.2
for 1.5 h at room temperature, the reaction mixture was quenched
with H2O and diluted with EtOAc. The organic layer was washed
l
mol) at room temperature. After stirring

M. Ohtawa et al. / Bioorg. Med. Chem. 23 (2015) 932–943
941
with H2O and brine, dried over Na2SO4, filtered, and concentrated
in vacuo. The residue was purified by flash silica gel column chro-
matography (hexanes) to afford 48 (135 mg, 83%) as a colorless oil.
IR (KBr) 3464, 2956, 2932, 2860, 1712, 1265, 1217, 1095 cmꢀ1;
1H NMR (400 MHz, CDCl3) d 5.10 (dt, J = 7.2, 1.3 Hz, 1H), 3.60 (t,
J = 6.4 Hz, 2H), 2.00–1.94 (m, 4H), 1.58 (s, 3H), 1.56–1.39 (m, 5H),
1.25–1.17 (m, 2H), 0.89 (s, 9H), 0.88 (d, J = 6.6 Hz, 6H), 0.05 (s,
6H); 13C NMR (100 MHz, CDCl3) d 139.9, 130.2, 68.4, 44.7, 44.4,
37.7, 32.9, 31.2, 31.0, 29.3, 27.8, 23.6, 20.0, 0.0; HRMS (FAB, m-
NBA) [M+H]+ calcd for C18H39Osi 299.2770, found 299.2768.
and brine, dried over Na2SO4, filtered, and concentrated in vacuo.
The residue was purified by flash silica gel column chromatogra-
phy (10:1 hexanes/EtOAc) to afford 7 (19.1 mg, 2 steps 44%) as a
pale yellow oil.
27
[
a]
ꢀ15.25 (c 0.10, CHCl3); IR (KBr) 3429, 2956, 2924, 2854,
D
1773, 1083 cmꢀ1 1H NMR (400 MHz, CDCl3) d 5.88–5.80 (m, 1H),
;
5.42 (dd, J = 15.4, 7.0 Hz, 1H), 5.09 (t, J = 6.7 Hz, 1H), 4.18 (d,
J = 7.0 Hz, 1H), 2.74–2.52 (m, 2H), 2.49–2.37 (m, 1H), 2.20–1.90
(m, 6H), 1.85–1.70 (m, 1H) 1.65–1.50 (m, 1H), 1.55 (s, 3H), 1.45–
1.09 (m, 6H), 1.26 (s, 3H), 0.82 (d, J = 6.6 Hz, 6H); 13C NMR
(100 MHz, CDCl3) d 177.1, 136.4, 134.5, 126.0, 125.0, 88.1, 77.1,
39.4, 39.1, 32.3, 29.5, 27.6, 27.5, 27.4, 27.3, 25.6, 23.8, 22.6, 15.8;
HRMS (ESI) [M+Na]+ calcd for C20H34NaO3 345.2406, found
345.2416.
4.1.30. (E)-5,9-Dimethyldec-5-en-1-ol
A solution of 48 (135 mg, 0.453 mmol) in THF (4.5 mL) was
treated with TBAF (1.0 M sol. in THF, 0.904 lL, 0.904 mmol) at
room temperature. After stirring for 2.5 h at room temperature,
the reaction mixture was quenched with satd NaHCO3 aq and
diluted with EtOAc. The organic layer was washed with brine, dried
over Na2SO4, filtered, and concentrated in vacuo. The residue was
purified by flash silica gel column chromatography (30:1 hex-
anes/EtOAc) to afford (E)-5,9-dimethyldec-5-en-1-ol (77.1 mg,
93%) as a colorless oil.
4.1.33. (E)-3-Methyl-6-((triethylsilyl)oxy)hex-2-en-1-yl acetate
(52)
A solution of 5121 (345 mg, 2.03 mmol) in CH2Cl2 (20.0 mL)
was treated with TESCl (0.408 mL, 2.43 mmol) and imidazole
(276 mg, 4.05 mmol) at 0 °C. After stirring for 1 h at room tem-
perature, the reaction mixture was quenched with satd NH4Cl
aq and diluted with EtOAc. The organic layer was washed with
brine, dried over Na2SO4, filtered, and concentrated in vacuo.
The residue was purified by flash silica gel column chromatogra-
phy (100:1 hexanes/EtOAc) to afford 52 (113 mg, 91%) as a
colorless oil.
IR (KBr) 3437, 2955, 2869, 1634, 1265, 1217 cmꢀ1 1H NMR
;
(400 MHz, CDCl3) d 5.11 (dt, J = 6.6, 1.1 Hz, 1H), 3.63 (t, J = 6.6 Hz,
2H), 2.00–1.93 (m, 4H), 1.88 (br s, 1H), 1.58 (s, 3H), 1.56–1.40
(m, 5H), 1.24–1.16 (m, 2H), 0.87 (d, J = 6.5 Hz, 6H); 13C NMR
(100 MHz, CDCl3) d 134.4, 125.1, 62.9, 39.3, 39.1, 32.3, 27.6, 25.7,
24.0, 22.5, 15.7; HRMS (FAB, m-NBA) [M+H]+ calcd for C12H25
O
IR (neat) 3021, 2954, 2913, 2879, 1729, 1671, 1217, 1096 cmꢀ1
;
185.1905, found 185.1901.
1H NMR (400 MHz, CDCl3) d 5.35–5.31 (m, 1H), 4.56 (d, J = 7.0 Hz,
2H), 3.57 (t, J = 6.1 Hz, 2H), 2.07 (t, J = 7.8 Hz, 2H), 2.03 (s, 3H),
1.68 (s, 3H), 1.65–1.60 (m, 2H), 0.92 (t, J = 8.0 Hz, 9H), 0.57 (q,
J = 8.0 Hz, 6H); 13C NMR (100 MHz, CDCl3) d 171.1, 142.1, 118.2,
62.3, 61.4, 35.7, 30.7, 21.0, 16.4, 6.8, 4.4; HRMS (FAB, m-NBA)
[M+H]+ calcd for C15H31O3Si 287.2038 found 287.2042.
4.1.31. (E)-1-Iodo-5,9-dimethyldec-5-ene (49)
A
solution of (E)-5,9-dimethyldec-5-en-1-ol (77.1 mg,
0.419 mmol) in CH2Cl2 (2.0 mL) was treated with I2 (160 mg,
0.629 mmol), PPh3 (165 mg, 0.629 mmol) and imidazole (85.8 mg,
1.26 mmol) at 0 °C. After stirring for 2.5 h at room temperature,
the reaction mixture was quenched with satd Na2S2O3 aq and
diluted with EtOAc. The organic layer was washed with brine, dried
over Na2SO4, filtered, and concentrated in vacuo. The residue was
purified by flash silica gel column chromatography (hexanes) to
afford 49 (113 mg, 91%) as a pale yellow oil.
4.1.34. (E)-3-Methyl-6-((triethylsilyl)oxy)hex-2-en-1-ol (53)
A solution of 52 (1.05 g, 3.67 mmol) in MeOH (18.0 mL) was
treated with satd K2CO3 aq (18.0 mL, 0.2 M) at 0 °C. After stirring
for 0.5 h at room temperature, the reaction mixture was extracted
with CH2Cl2. The organic layers were combined, dried over Na2SO4,
filtered, and concentrated in vacuo. The residue was purified by
flash silica gel column chromatography (5:1 hexanes/EtOAc) to
afford 53 (312 mg, 76%) as a colorless oil.
IR (KBr) 3019, 2958, 1711, 1265, 1217 cmꢀ1; 1H NMR (400 MHz,
CDCl3) d 5.11 (dt, J = 7.2, 1.3 Hz, 1H), 3.19 (t, J = 7.2 Hz, 2H), 2.00–
1.94 (m, 4H), 1.82–1.75 (m, 2H), 1.58 (s, 3H), 1.56–1.45 (m, 3H),
1.25–1.18 (m, 2H), 0.88 (d, J = 6.5 Hz, 6H); 13C NMR (100 MHz,
CDCl3) d 133.9, 125.5, 39.0, 38.5, 33.0, 28.6, 27.6, 25.8, 22.6, 15.7,
7.2; HRMS (FAB, Thio G+G) [M]+ calcd for C12H23I 294.0844, found
294.0854.
IR (neat) 3021, 1477, 1424, 1216, 1018 cmꢀ1
;
1H NMR
(400 MHz, CDCl3) d 5.44–5.40 (m, 1H), 4.15 (dd, J = 6.8, 0.6 Hz,
2H), 3.60 (t, J = 6.7 Hz, 2H), 2.07 (t, J = 7.9 Hz, 2H), 1.68 (d,
J = 0.6 Hz, 3H), 1.67–1.62 (m, 2H), 0.96 (t, J = 8.0 Hz, 9H), 0.59 (q,
J = 8.0 Hz, 6H); 13C NMR (100 MHz, CDCl3) d 139.3, 123.4, 62.5,
59.2, 35.7, 30.9, 16.2, 6.7, 4.4; HRMS (FAB, m-NBA) [M+H]+ calcd
for C13H29O2Si 245.1937 found 245.1935.
4.1.32. (S)-5-((R, 2E, 8E)-1-Hydroxy-8,12-dimethyltrideca-2,8-
dien-1-yl)-5-methyldihydro-furan-2(3H)-one (7)
A solution of 49 (47.6 lL, 0.162 mmol) in Et2O (1.6 mL) was
treated with t-BuLi (1.61 M sol. in pentane, 0.252 mL, 0.405 mmol)
at ꢀ78 °C. After stirring for 10 min at ꢀ78 °C, 9-BBNOMe (1.0 M sol.
in hexane, 0.432 mL, 0.432 mmol) and THF (1.6 mL) were added.
After stirring for 1 h at room temperature, the reaction mixture
was treated with 13 (43.9 mg, 0.135 mmol) in DMF (1.6 mL), 3 M
4.1.35. ((200R,300R)-30-Methyl-300-(30-((triethylsilyl)oxy)propyl)
oxiran-200-yl)methanol (54)
A mixture of activated MS4Å (868 mg) and Ti(Oi-Pr)4 (1.05 mL,
3.55 mmol) in CH2Cl2 (45.0 mL) was treated with (ꢀ)-DET
(0.760 mL, 4.44 mmol) at –5 °C. After stirring for 45 min at –5 °C,
TBHP (5.0–6.0 M sol. in decane, 3.90 mL, 19.5 mmol) were added
at ꢀ20 °C. After stirring for 1 h, 53 (2.17 g, 8.88 mmol) in CH2Cl2
(45.0 mL) was added and the mixture was stirred at ꢀ20 °C for
1 h. After Me2S (0.975 mL, 13.3 mmol) was added, the mixture
was further stirred at ꢀ20 °C for 1 h. The reaction mixture was
diluted with Et2O, treated with celite (6.51 g) and Na2SO410H2O
(6.51 g) and stirred for 2 h at room temperature. The resulting sus-
pension was filtered through a pad of celite, and the filtrate was
concentrated in vacuo. The residue was purified by flash silica
gel column chromatography (2:1 hexanes/EtOAc) to afford 54
(1.83 mg, 78%) as a colorless oil.
K3PO4 aq (225
lL, 0.405 mmol), PdCl2(dppf) (11.0 mg, 13.5
lmol)
and dppf (7.5 mg, 13.5
l
mol) at room temperature. After stirring
for 18 h at room temperature, the reaction mixture was quenched
with H2O and diluted with EtOAc. The organic layer was washed
with H2O and brine, dried over Na2SO4, filtered, and concentrated
in vacuo. The residue was semi-purified by flash silica gel column
chromatography (30:1 hexanes/EtOAc) to afford crude 50. A solu-
tion of crude 50 in i-PrOH (2.0 mL) was treated with CBr4
(89.5 mg, 270 lmol) at room temperature. After stirring for 8 h at
65 °C, the reaction mixture was quenched with satd NaHCO3 aq
and diluted with EtOAc. The organic layer was washed with H2O

942
M. Ohtawa et al. / Bioorg. Med. Chem. 23 (2015) 932–943
28
[
a]
+2.47 (c 1.00, CHCl3); IR (neat) 3450, 3021, 2957, 2878,
the reaction mixture was filtered through a pad of celite, and the
D
1476, 1423, 1217 cmꢀ1
;
1H NMR (400 MHz, CDCl3) d 3.85–3.80
filtrate was washed with brine, dried over Na2SO4, filtered, and
concentrated in vacuo. The residue was purified by flash silica
gel column chromatography (10:1 hexanes/EtOAc) to afford 58
(23.9 mg, 54%) and 59 (2.2 mg, 5%) as colorless oils.
(m, 1H), 3.73–3.67 (m, 1H), 3.65–3.59 (m, 2H), 2.98 (dd, J = 6.7,
4.5 Hz, 1H), 1.70–1.53 (m, 4H), 1.31 (s, 3H), 0.95 (t, J = 8.0 Hz,
9H), 0.59 (q, J = 8.0 Hz, 6H); 13C NMR (100 MHz, CDCl3) d 59.1,
58.4, 57.1, 30.8, 24.2, 12.7, 2.7, 0.3, 0.2; HRMS (FAB, m-NBA)
[M+H]+ calcd for C13H29O3Si 261.1886 found 261.1880.
30
4.1.38.2. Data for 58.
[
a]
+8.58 (c 0.83, CHCl3); IR (neat)
D
3020, 2927, 1724, 1431, 1216 cmꢀ1 1H NMR (400 MHz, CDCl3) d
;
4.1.36. Triethyl(30-((20R,30S)-30-(iodomethyl)-20-methyloxiran-20-
yl)propoxy)silane (55)
9.77 (t, J = 1.5 Hz, 1H), 5.16–5.07 (m, 3H), 2.74 (t, J = 6.4 Hz, 1H),
2.54–2.50 (m, 2H), 2.18–1.80 (m, 14H), 1.68 (d, J = 1.2 Hz, 3H), 1.62
(s, 3H), 1.60 (s, 6H), 1.27 (s, 3H); 13C NMR (100 MHz, CDCl3) d
201.4, 136.1, 135.8, 135.1, 124.3, 124.0, 123.1, 63.0, 59.8, 39.7, 39.6,
39.1, 30.4, 28.7, 26.7, 26.6, 25.7, 24.8, 17.7, 16.7, 16.1, 16.0; HRMS
(FAB, m-NAB) [M+H]+ calcd for C22H37O2 333.2794, found 333.2799.
A solution of 54 (132 mg, 0.505 mmol) in CH2Cl2 (5.1 mL) was
treated with I2 (192 mg, 0.758 mmol), PPh3 (199 mg, 0.758 mmol)
and imidazole (103 mg, 1.52 mmol) at 0 °C. After stirring for 1.5 h
at 0 °C, the reaction mixture was quenched with satd Na2S2O3 aq
and diluted with EtOAc. The organic layer was washed with brine,
dried over Na2SO4, filtered, and concentrated in vacuo. The residue
was purified by flash silica gel column chromatography (200:1
20
4.1.38.3. Data for 59.
[a
]
D
+5.16 (c 0.10, CHCl3); IR (neat)
3448, 3058, 2389, 2089, 1636, 1449, 1266 cmꢀ1
;
1H NMR
hexanes/EtOAc) to afford 55 (147 mg, 78%) as a colorless oil.
(400 MHz, CDCl3) d 5.16–5.07 (m, 3H), 3.91–3.80 (m, 2H), 3.53
(dd, J = 10.5, 1.6 Hz, 1H), 2.35 (br s, 1H), 2.29–2.22 (m, 1H), 2.16–
1.87 (m, 12H), 1.67 (s, 3H), 1.63 (s, 3H), 1.59 (s, 6H), 1.51–1.43
(m, 2H), 1.39–1.30 (m, 1H), 1.11 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 135.7, 134.9, 131.2, 124.4, 124.3, 124.2, 85.7, 76.0, 67.9, 39.7,
39.6, 31.9, 30.6, 26.7, 26.6, 26.3, 26.2, 25,7, 25.0, 17.6, 16.0, 15.9;
HRMS (EI) [M]+ calcd for C22H38O2 334.2871, found 334.2872.
ꢀ33.7 (c 1.00, CHCl3); IR (neat) 3432, 1637, 1069 cmꢀ1; 1H
27
[
a]
D
NMR (400 MHz, CDCl3) d 3.63–3.60 (m, 2H), 3.36 (dd, J = 9.8,
5.6 Hz, 1H), 3.09 (dd, J = 8.8, 5.6 Hz, 1H), 2.98 (dd, J = 9.8, 8.8 Hz,
1H), 1.74–1.60 (m, 3H), 1.53–1.46 (m, 1H), 1.28 (s, 3H), 0.98–0.93
(m, 9H), 0.62–0.56 (m, 6H); 13C NMR (100 MHz, CDCl3) d 63.9,
62.4, 62.3, 34.7, 28.5, 15.7, 6.8, 4.4, 2.4; HRMS (FAB, m-NBA)
[M+H]+ calcd for C13H28O2SiI 371.0903, found 371.0910.
4.1.39. (S)-5-((R,40E,80E)-10-Hydroxy-50,90,130-trimethyltetradeca-
40,80,120-trien-10-yl)-5-methyldihydrofuran-2(3H)-one (8)
A solution of 58 (4.4 mg, 0.0132 mmol) in t-BuOH (0.132 mL)
4.1.37. Triethyl(30-((20R,30R)-20-methyl-30-((300E,700E)-400,800,1200-
trimethyltrideca-300,700,1100-trien-100-yl)oxiran-20-yl)propoxy)
silane (57)
and H2O (0.132 mL) was treated with 2-methyl-2-butene (5.6 lL,
A solution of 5624 (93.7
lg, 0.270 mmol) in THF (7.0 mL) was
0.0528 mmol), NaClO2 (3.6 mg, 0.0396 mmol) and NaH2PO4 2H2O
(6.2 mg, 0.0396 mmol) at 0 °C. After stirring for 24 h at room tem-
perature, the reaction mixture was quenched with satd NH4Cl aq
and was diluted with EtOAc. The organic layer was washed with
brine, dried over Na2SO4, filtered, and concentrated in vacuo. The
residue was purified by flash silica gel column chromatography
treated with n-BuLi (1.64 M sol. in hexane, 0.659 mL, 1.08 mmol)
and HMPA (0.470 mL, 2.70 mmol) at ꢀ78 °C. After stirring for 1 h
at ꢀ78 °C, 55 (200 mg, 0.540 mmol) in THF (3.0 mL) was added.
After stirring for 10 min at ꢀ78 °C, the reaction mixture was
quenched with satd NH4Cl aq and diluted with EtOAc. The organic
layer was washed with H2O and brine, dried over Na2SO4, filtered,
and concentrated in vacuo. The residue was semi-purified by flash
silica gel column chromatography (10:1 hexanes/EtOAc) to afford
crude TES ether. A solution of crude TES ether in DMSO (2.7 mL)
(7:1 hexanes/EtOAc) to afford 8 (3.8 mg, 86%) as a colorless oil.
23
[
a]
D
+8.67 (c 0.50, CHCl3); IR (neat) 3448, 3022, 1766, 1639,
1426, 1217 cmꢀ1 1H NMR (400 MHz, CDCl3) d 5.14–5.07 (m, 3H),
;
3.68 (d, J = 10.2 Hz, 1H), 2.67–2.59 (m, 2H), 2.45–2.37 (m, 1H),
2.23–2.18 (m, 1H), 2.17–2.11 (m, 1H), 2.09–1.95 (m, 8H), 1.83–
1.76 (m, 1H), 1.67 (s, 3H), 1.63 (s, 3H), 1.59 (s, 6H), 1.52–1.36 (m,
2H), 1.34 (s, 3H); 13C NMR (100 MHz, CDCl3) d 177.0, 136.4,
135.1, 131.3, 124.4, 124.0, 123.2, 88.8, 75.4, 39.7, 39.8, 30.8, 29.3,
27.6, 26.7, 26.6, 24.5, 22.8, 17.7, 16.1, 16.0, 15.9; HRMS (FAB, m-
NBA) [M+H]+ calcd for C22H37O3 349.2743, found 349.2745.
was treated with Pd(OAc)2 (12.1 mg, 54.0 lmol) and dppp
(27.8 mg, 0.0675 mmol) at room temperature. After stirring for
5 min at room temperature, NaBH4 (12.3 mg, 0.324 mmol) was
added and the mixture was stirred at room temperature for 1 h.
The reaction mixture was quenched with H2O, and diluted with
EtOAc. The organic layer was washed with H2O and brine, dried
over Na2SO4, filtered, and concentrated in vacuo. The residue was
purified by flash silica gel column chromatography (70:1 hex-
4.1.40. Improved synthesis of 59 from 57
anes/EtOAc) to afford 57 (94.6 mg, 2 steps 64%) as a colorless oil.
A solution of 57 (14.3 mg, 0.0427 mmol) in THF (0.4 mL) was
treated with TBAF (1.0 M sol. in THF, 85 lL, 0.0854 mmol) at room
27
[
a]
+4.47 (c 1.00, CHCl3); IR (neat) 3020, 2958, 2877, 1425,
D
1384, 1216, 1098 cmꢀ1
;
1H NMR (400 MHz, CDCl3) d 5.18–5.07
temperature. After stirring for 15 min at room temperature, the
reaction mixture was quenched with satd NaHCO3 aq and diluted
with EtOAc. The organic layer was washed with brine, dried over
Na2SO4, filtered, and concentrated in vacuo. A solution of the crude
alcohol in CH2Cl2 (0.5 mL) was treated with a catalytic amount of
PPTS at room temperature. After stirring for 1 h at room tempera-
ture, the reaction mixture was quenched with satd NaHCO3 aq and
diluted with EtOAc. The organic layer was washed with brine, dried
over Na2SO4, filtered, and concentrated in vacuo. The residue was
purified by flash silica gel column chromatography (8:1 hexanes/
EtOAc) to afford 59 (12.7 mg, 2 steps, 89%) as a colorless oil.
(m, 3H), 3.63–3.58 (m, 2H), 2.72 (t, J = 6.4 Hz, 1H), 2.18–1.95 (m,
10H), 1.68 (d, J = 1.0 Hz, 3H), 1.66–1.57 (m, 4H), 1.62 (s, 3H), 1.60
(s, 6H), 1.56–1.48 (m, 2H), 1.25 (s, 3H), 0.98–0.93 (m, 9H), 0.62–
0.56 (m, 6H); 13C NMR (100 MHz, CDCl3) d 135.9, 135.0, 131.3,
124.3, 124.1, 123.2, 63.2, 62.6, 60.8, 39.7, 35.1, 28.9, 28.6, 26.7,
26.6, 25.7, 24.9, 17.7, 16.6, 16.0, 6.8, 4.4; HRMS (FAB, m-NBA)
[M+H]+ calcd for C28H53O2Si 449.3815, found 449.3807.
4.1.38. 3-((20R,30R)-20-Methyl-30-((300E,700E)-400,800,1200-
trimethyltrideca-300,700,1100-trien-100-yl)oxiran-2-yl)propanal (58)
4.1.38.1. (R,4E,8E)-5,9,13-Trimethyl-1-((S)-2-methyltetrahydro-
furan-2-yl)tetradeca-4,8,12-trien-1-ol (59)
Acknowledgments
A solution of pyridine (0.108 mL, 1.34 mmol) in CH2Cl2 (1.7 mL)
was treated with CrO3 (80.4 mg, 0.804 mmol) at room tempera-
ture. After stirring for 1 h, 57 (60.0 mg, 0.134 mmol) in CH2Cl2
(1.0 mL) was added. After stirring for 21 h at room temperature,
This research was partially supported by JSPS KAKENHI Grant
Number 2350132. We thank Ms. N. Sato and Dr. K. Nagai (Kitasato
University) for kindly measuring NMR and MS spectra.

M. Ohtawa et al. / Bioorg. Med. Chem. 23 (2015) 932–943
16. Ishiyama, T.; Ahiko, T.-A.; Miyaura, N. Tetrahedron Lett. 1996, 37, 6889.
943
References and notes
17. Chemler, S. R.; Trauner, D.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2001, 40,
4544.
18. Igarashi, Y.; Yanase, S.; Sugimoto, K.; Enomoto, M.; Mitanaga, S.; Trujillo, M. E.;
Saiki, I.; Kuwahara, S. J. Nat. Prod. 2011, 74, 862.
19. Lay, S. V.; Armstrong, N. J.; Brasca, M. G.; Clarke, T.; Culshaw, D.; Greck, C.;
Grice, P.; Jones, A. B.; Lygo, B.; Madin, A.; Sheppard, R. N.; Slawin, A. M. Z.;
Williams, D. J. Tetrahedron Lett. 1989, 45, 7161.
20. Kujat, C.; Bock, M.; Kirschning, A. Synlett 2006, 419.
21. Uyanik, M.; Ishihara, K.; Yamamoto, H. Org. Lett. 2006, 8, 5649.
22. The absolute configuration of 54 was determined by conversion to the known
MOM ether 60, followed by comparison of the optical rotation of 60 to the
literature value. Also see, Yadav, J. S.; Haldar, A.; Maity, T. Eur. J. Org. Chem.
2013, 3076
1. Omura, S.; Miyadera, H.; Ui, H.; Shiomi, K.; Yamaguchi, Y.; Masuma, R.;
Nagamitsu, T.; Takano, D.; Sunazuka, T.; Harder, A.; Kolbl, H.; Namikoshi, M.;
Miyoshi, H.; Sakamoto, K.; Kita, K. Proc. Natl. Acad. Sci. U.S.A. 2001, 98, 60.
2. Ui, H.; Shiomi, K.; Yamaguchi, Y.; Masuma, R.; Nagamitsu, T.; Takano, D.;
Sunazuka, T.; Namikoshi, M.; Omura, S. J. Antibiot. 2001, 54, 234.
3. Takano, D.; Nagamitsu, T.; Ui, H.; Shiomi, K.; Yamaguchi, Y.; Masuma, R.;
Kuwajima, I.; Omura, S. Tetrahedron Lett. 2001, 42, 3017.
4. Takano, D.; Nagamitsu, T.; Ui, H.; Shiomi, K.; Yamaguchi, Y.; Masuma, R.;
Kuwajima, I.; Omura, S. Org. Lett. 2001, 3, 2289.
5. Shiomi, K.; Ui, H.; Suzuki, H.; Hatano, H.; Nagamitsu, T.; Takano, D.; Miyadera,
H.; Kita, K.; Harder, A.; Tomoda, H.; Omura, S. J. Antibiot. 2005, 58, 50.
6. Nagamitsu, T.; Takano, D.; Ui, H.; Shiomi, K.; Yamaguchi, Y.; Masuma, R.;
Kuwajima, I.; Omura, S. Tetrahedron Lett. 2003, 44, 6441.
7. Nagamitsu, T.; Takano, D.; Seki, M.; Arima, S.; Ohtawa, M.; Shiomi, K.; Harigaya,
Y.; Omura, S. Tetrahedron 2008, 64, 8117.
8. The synthesis and evaluation of the complex I inhibitory activity of an analog
containing an a,b-unsaturated lactone moiety was previously reported by our
laboratory. See, Ref. 7.
.
9. Asssandri, A.; Moro, L. WO2012052918A1.
23. Ohtani, I.; Kuai, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc. 1991, 113, 4092.
24. Brioche, J. C. R.; Goodenough, K. M.; Whatrup, D. J.; Harrity, J. P. A. Org. Lett.
2007, 9, 3941.
25. Trost, B. M.; Dong, G.; Vance, J. A. Chem. Eur. J. 2010, 16, 6265.
26. Denmark, S. E.; Hammer, R. P.; Weber, E. J.; Habermas, K. L. J. Org. Chem. 1987,
52, 165.
27. Amino, H.; Wang, H.; Hirawake, H.; Saruta, F.; Mizuchi, D.; Mineki, R.; Shindo,
N.; Murayama, K.; Takamiya, S.; Aoki, T.; Kojima, S.; Kita, K. Mol. Biochem.
Parasitol. 2000, 106, 63.
10. The diastereopurity was determined by 1H NMR.
11. Raheem, I. T.; Goodman, S. N.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 706.
12. Although the yields of several reactions in the synthesis of nafuredin-c analogs
were unsatisfactory, our primary interest was in evaluating their complex I
inhibitory activity.
13. Crews, D. A. JR; Ding, A. X.; Tseng, C. WO2011087837A2.
14. Chackal-Catoen, S.; Miao, Y.; Wilson, W. D.; Wenzler, T.; Brun, R.; Boykin, D. W.
Bioorg. Med. Chem. 2006, 14, 7434.
15. Kaiser, F.; Schwink, L.; Velder, J.; Schmalz, H. J. Org. Chem. 2002, 67, 9248.