Total synthesis of (+)-piericidin A1 and (-)-piericidin B1

Article abstract of DOI:10.1016/j.tetasy.2009.07.044

The convergent syntheses of (+)-piericidin A₁ 1 and (-)-piericidin B₁ 2 have been achieved based on classical Julia-Lythgoe olefination between 4-hydroxy-5,6-dimethoxy-3-methyl-2-[5-oxo-3-methyl-pent-(2E)-enyl]-pyridine 3 correspondi

Full text of DOI:10.1016/j.tetasy.2009.07.044

Tetrahedron: Asymmetry 20 (2009) 1975–1983
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Total synthesis of (+)-piericidin A1 and (ꢀ)-piericidin B1
*
Ryosuke Kikuchi, Mikio Fujii, Hiroyuki Akita
Faculty of Pharmaceutical Sciences, Toho University, 2-2-1, Miyama, Funabashi, Chiba 274-8510, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The convergent syntheses of (+)-piericidin A1 1 and (ꢀ)-piericidin B1 2 have been achieved based on clas-
sical Julia-Lythgoe olefination between 4-hydroxy-5,6-dimethoxy-3-methyl-2-[5-oxo-3-methyl-pent-
(2E)-enyl]-pyridine 3 corresponding to the left half of the final molecule, and chiral phenyl sulfones,
(4R,5R)-2,4,6-trimethyl-5-methoxy-1-phenylsulfonyl-octa-(2E,6E)-diene 20 and (4R,5R)-5-tert-butyl-
dimethylsiloxy-2,4,6-trimethyl-1-phenylsulfonyl-octa-(2E,6E)-diene 33, corresponding to the right
halves. The construction of the two stereogenic centers in the right half of piericidins was achieved based
on lipase-catalyzed hydrolysis of methyl (2,3)-anti-3-acetoxy-2,4-dimethyl-hex-(4E)-enoate ( )-22.
Ó 2009 Published by Elsevier Ltd.
Received 24 June 2009
Accepted 16 July 2009
Available online 14 September 2009
1. Introduction
line b) as shown in Figures 1 and 2. The construction of the two
stereogenic centers in the right half 4 could be achieved by li-
Piericidins A1 1 and B1 2 are members of an important class of
biologically active natural products isolated from Streptomyces
mobaraensis and Streptomyces pactam, respectively, which display
a broad range of biological effects, including cytotoxicity, anti-
microbial, and insecticidal activities due to inhibition of the elec-
tron-transport system in the respiratory chain.1 The respiratory
chain includes the so-called complex I, responsible for the oxida-
tion of NADH to NAD+, and this complex is inhibited by rotenone
and barbiturates in addition to piericidins, all of which bind at
the same site in mitochondria in a competitive manner.2 Pierici-
dins contain a 2,3,5,6-tetrasubstituted 4-pyridinol ring, whose sub-
stitution pattern is similar to that of ubiquinone (coenzyme Q),
which functions as a hydrogen acceptor in the oxidation of NADH
to NAD+ in mitochondria. The piericidin side chain contains two
stereogenic centers at the C(9)- and C(10)-positions and four (E)-
olefinic linkage, two of which are isolated double bonds [C(2)-
and C(11)-positions] and two of which are conjugated with each
other [(C(5)- and C(7)-positions] as shown in Figure 1.
We reported previously the synthesis of a ( )-piericidin B1 ana-
logue possessing a benzene ring instead of pyridine ring.3 The first
syntheses of piericidins A1 1 and B1 2 were achieved based on car-
bon–carbon bond formation (at the dotted line a) by Stille cross-
coupling and the construction of the two stereogenic centers in
the side chain by use of an asymmetric anti-aldol reaction.4a,b
Herein, we report a new total synthesis of piericidins A1 1 and B1
2 based on a convergent synthesis via the Julia coupling method.
Our synthetic plan for piericidins A1 1 and B1 2 is based on double
bond formation between the left 3 and right 4 halves (at dotted
pase-catalyzed enantioselective hydrolysis of
ester.
a-methyl-b-acetoxy
2. Results and discussion
2.1. Synthesis of left half 3
The non-conjugated aldehyde 3 corresponding to the C(1)–C(5)
unit of the piericidin side chain was prepared starting from the
known allyl alcohol congener (E)-53a in three steps as shown in
Scheme 1.
The reaction of (E)-5 and methyl chloroformate gave the corre-
sponding carbonate (E)-6 in 60% yield. Pyridyl stannane derivative
7 was prepared from the commercially available 2,3-dimethoxy-
pyridine by the reported procedure.5 The Stille coupling of (E)-6
and 7 in the presence of tri(dibenzylideneacetone)dipalladium(0)
and LiCl afforded a 2.2:1 mixture (E:Z = 2.2:1) of coupled product
in 68% yield. Treatment of this mixture with 2 M aqueous HCl fol-
lowed by separation gave the desired left half 3 in 65% yield. The
geometry of (E)-3 was confirmed by NOE as shown in Scheme 1.
2.2. Attempt synthesis of ( )-piericidin B1
2
At first, racemic synthesis of ( )-piericidin B1 2 was performed
as shown in Scheme 2.
The synthesis of allyl alcohol congener ( )-9 from ( )-anti-8 was
carried out by the reported procedure.3a The reaction of ( )-9 and
1-phenyl-1H-tetrazole-5-thiol (PTSH) in the presence of Ph3P and
diethyl azodicarboxylate (DEAD) to give the corresponding sulfide
( )-10 in 89% yield. Oxidation of ( )-10 with 30% H2O2 in the pres-
ence of Mo7O24(NH4)6ꢁ4H2O provided the corresponding sulfone
* Corresponding author.
E-mail address: akita@phar.toho-u-ac.jp (H. Akita).
0957-4166/$ - see front matter Ó 2009 Published by Elsevier Ltd.
doi:10.1016/j.tetasy.2009.07.044

1976
R. Kikuchi et al. / Tetrahedron: Asymmetry 20 (2009) 1975–1983
OH
N
O
MeO
MeO
Me
a
MeO
Me
OR1
b
2
6
Me
MeO
H
n
1
5
O
Me
Me Me Me
Me
R1 = H (+)-Piericidin A1 1
n = 6~10
Ubiquinone (Co Q)
R1 = Me (-)-Piericidin B1 2
Figure 1.
OH
OR1
MeO
Me
(+)-Piericidin A1 1
(-)-Piericidin B1 2
+
ArO2S
Me
MeO
N
CHO
Me Me Me
right half 4
Me
left half 3
Figure 2.
OSEM
Me
MeO
OH
N
7
b
n.O.e 6.8%
CHO
MeO
MeO
Me
H
H
R2O
MeO
N
SnBu3
CH(OMe)2
Me
Me
n.O.e 6.2%
left half 3
R2 = H (E)-5
a
R2 = COOMe (E)-6
Scheme 1. Reagents: (a) ClCOOMe/pyridine/toluene; (b) (1) 7/Pd2(dba)3/LiCl/DMF; (2) 2 M-HCl aq/i-PrOH.
OMe
OH
ref. 3
MeOOC
R3
Me
Me
Me Me Me
Me Me
( )-anti-8
R3 = OH ( )-9
N
a
b
N
N
R3 = SPT ( )-10
R3 = SO2PT ( )-11
SH
Me
PTSH :
N
Ph
OH
Me
Me
MeO
MeO
Me
c
OH
OMe
N
CHO
MeO
MeO
Me
Me
left-half (3)
Me
+
6
N
H
5
right half ( )-11
H
Me
J5,6 = 11 Hz
( )-(5,6)-cis-piericidin B1 2
Scheme 2. Reagents: (a) PTSH/DEAD/Ph3P/THF; (b) H2O2/Mo7O24(NH4)6ꢁ4H2O/EtOH; (c) KHMDS/THF.
( )-11 in 60% yield. Modified Julia olefination of the left half 3 and
( )-11 in the presence of potassium bis(trimethylsilyl)amide
(KHMDS) gave ( )-(5,6)-cis-piericidin B1 2 in 43% yield as shown
in Scheme 2. The C(5), C(6)-cis geometry was supported by the cou-
pling constant J5,6 = 11 Hz between C(5)–H and C(6)–H. Julia one-
pot olefination between aldehyde 3 and PT-sulfone ( )-11 gave
( )-(5,6)-cis-piericidin B1 (2) with high cis-selectivity. This high
selectivity could be explained as shown in Figure 3.
Metallated PT-sulfone 11 condenses with aldehyde 3 to give
anti isomer 12 and syn isomer 13, which are converted to interme-
diates 14 and 15, respectively. Direct loss of potassium-tetrazolone
and sulfur dioxide from intermediates 14 and 15 may yield trans
isomer 2 via 18 and cis isomer 2 via 19. The energy barrier to
Smiles rearrangement for the anti isomer 14 is presumably higher
than that for the corresponding syn isomer 15 due to the eclipsed/
gauche arrangement of R4 and R5 in the appropriate transition state

R. Kikuchi et al. / Tetrahedron: Asymmetry 20 (2009) 1975–1983
1977
N
N
N
N
N
N
M
Ph
N
M
H
R5
O
Ph
N
SO2M
R5
M
slow
O
O2S
O
R4
trans-isomer 2
O
S
O
R5
SO2
12
R4
PTO
H
PT
R4
R5
R4
H
H
18
H
14
H
anti-addition
16
OH
OMe
M
MeO
Me
O
S
Me
R5 =
R4 =
M
PT
R5
R4 CHO
+
Me Me Me
Ph
MeO
N
3
O
Me
( )-11
N
N
syn-addition
N
N
N
O
N
R4
N
M
R5
N
O
SO2M
H
Ph
M
R5
fast
O2S
O
cis-isomer 2
R4
O
S
O
R5
R4
15
SO2
13
PTO
PT
H
H
19
H
H
R4
H
R5
17
Figure 3.
for spirocyclization. Therefore, the formation rate of 16 from 14
may be slow, while that of 17 from 15 may be fast. The possibility
of addition/retroaddition in the reaction of metallated PT-sulfone
with aldehyde has been established experimentally.6 Equilibration
between 12 and 13 together with faster Smiles rearrangement/
elimination for the latter provides a reasonable explanation for
the high cis-selectivity. The E/Z selectivity in the modified Julia
olefination depends on the structure of the used aldehyde and het-
erocyclic sulfone.6 In case of using an aliphatic aldehyde possessing
a bulky substituent, cis-selectivity is observed and the present olef-
ination corresponds to the above-mentioned fact.
>99% ee} in 91% yield. Silylation of (ꢀ)-8 afforded the correspond-
ing silyl ether (ꢀ)-24 {½a D21
¼ ꢀ1:6 (c 1.05, CHCl3)} in 86% yield,
ꢂ
which was reduced with Dibal-H to provide alcohol (+)-23
{½a 2D0
¼ þ18:7 (c 1.03, CHCl3)} in 91% yield. Spectroscopic data of
ꢂ
the present (+)-23 were identical with those of the known
(2R,3R)-23 including the sign of the specific rotation. Thus the
absolute structure of enzymatic reaction products, (ꢀ)-22 and
(+)-8, were found to possess the (2S,3R)- and (2R,3S)-configura-
tions, respectively. As the desired (2S,3R)-8 was already obtained
from (2S,3R)-22, (2S,3R)-8 was converted to (ꢀ)-piericidin B1 2 as
shown in Scheme 3. Methylation of (2S,3R)-8 afforded the b-meth-
oxy ester (2S,3R)-25 in 79% yield, which was reduced with Dibal-H
to give the alcohol in 98% yield. Swern oxidation of this alcohol fol-
lowed by Wittig condensation with [1-(ethoxycarbonyl)ethyli-
dene]triphenylphosphorane provided (E)-ester (4R,5R)-26 in 90%
overall yield from (2S,3R)-25. Reduction of (4R,5R)-26 with Dibal-
H gave allyl alcohol (4R,5R)-9 in 98% yield The reaction of
(4R,5R)-9 and iodine in the presence of Ph3P and imidazole gave
the corresponding iodide, which was treated with thiophenoxide
to give the corresponding sulfide (4R,5R)-27 in 85% overall yield.
Oxidation of (4R,5R)-27 with 30% H2O2 in the presence of
Mo7O24(NH4)6ꢁ4H2O provided the corresponding sulfone (4R,5R)-
20 in 93% yield. The reaction of the left half 3 and (4R,5R)-20 in
the presence of n-BuLi gave a diastereomeric mixture of hydro-
xy-sulfone derivatives 28 in 69% yield, which was converted to
the corresponding benzoates 29 in 81% yield. This diastereomeric
mixture of benzoates 29 was treated with 5% sodium amalgam
2.3. Chiral synthesis of (ꢀ)-piericidin B1
2
For the chiral synthesis of piericidin B1 2, classical Julia-Lythgoe
olefination between left half 3 and optically active phenyl sulfone
(4R,5R)-20 was carried out and a resolution of ( )-8 was accom-
plished by enzyme-assisted resolution as shown in Scheme 3.
To determine the enantiomeric excess (ee) of the enzymatic
reaction products, racemate ( )-8 was converted to the corre-
sponding benzoate ( )-21 in 97% yield, which gave two well-sepa-
rated peaks of the enantiomeric isomers in HPLC analysis (see
Section 4), thus allowing the determination of the ee of the enzy-
matic reaction products. Acetylation of ( )-8 gave the correspond-
ing acetate ( )-22 in 88% yield, which was selected as the substrate
for enzyme-assisted hydrolysis by a brief screening experiment.
The screening experiment for finding a suitable enzyme showed
that the most effective lipase was Amano A6 from Aspergillus niger.
When ( )-22 was subjected to enantioselective hydrolysis in phos-
to afford (ꢀ)-piericidin B1 2 {½a D17
¼ ꢀ8:2 (c 0.43, MeOH)} in 42%
ꢂ
yield. The spectral data of the synthetic (ꢀ)-2 were identical with
phate buffer using Amano A6 for 28 h, (ꢀ)-22 {½a D23
ꢂ
¼ ꢀ12:7 (c 1.0,
those of synthetic natural (ꢀ)-piericidin B1 (2)4b {½a D25
¼ ꢀ7:3 (c
ꢂ
CHCl3) corresponding to >99% ee, 44% yield} and (+)-8 {½a D24
ꢂ
¼ þ8:2
0.2, MeOH)} including the sign of specific rotation (Scheme 3).
(c 1.0, CHCl3) corresponding to 79% ee, 51% yield} were obtained.
The ee for each enzymatic product was calculated by HPLC analysis
after conversion of the enzymatic products to the corresponding
benzoates. The E-value7 of this enzymatic reaction was estimated
to be 43.7. To determine the absolute structure of (ꢀ)-22, (ꢀ)-22
2.4. Chiral synthesis of (+)-piericidin A1
1
As the desired (2S,3R)-22 had already been converted to alcohol
(2R,3R)-23, (2R,3R)-23 was converted to (+)-piericidin A1 1 as
shown in Scheme 4.
Swern oxidation of (2R,3R)-23 followed by Wittig condensation
with [1-(ethoxycarbonyl)-ethylidene]triphenylphosphorane provided
was converted to the reported alcohol (2R,3R)-23 {½a D25
¼ þ17:8
ꢂ
(c 0.69, CHCl3)}8 as follows. Deacetylation of acetate (ꢀ)-22 gave
alcohol (ꢀ)-8 {½a D19
¼ ꢀ10:4 (c 1.21, CHCl3) corresponding to
ꢂ

1978
R. Kikuchi et al. / Tetrahedron: Asymmetry 20 (2009) 1975–1983
OAc
OH
MeOOC
c
MeOOC
b
Me
( )-anti-22
+
Me
( )-anti-8
Me Me
(2S,3R)-22
Me Me
a
(2R,3S)-8
OSiMe2But
OCOPh
OSiMe2But
MeOOC
MeOOC
f
Me
Me
Me
HO
Me Me
(2R,3R)-23
Me Me
( )-anti-21
Me Me
(2S,3R)-24
e
OMe
Me
OH
MeOOC
MeOOC
d
g
Me
(2S, 3R)-22
Me Me
(2S,3R)-25
Me Me
(2S,3R)-8
OMe
OMe
EtOOC
h
i
Me
R3
Me
Me Me Me
(4R,5R)-26
Me Me Me
R3 = OH (4R,5R)-9
j
R3 = SPh (4R,5R)-27
k
R3 = SO2Ph (4R,5R)-20
OH
N
MeO
MeO
Me
left half 3
SO2Ph
OMe
l
+
Me
right half (4R,5R)-20
OR4
Me
Me Me Me
R4 = H 28
R4 = COPh 29
m
n
(-)-piericidin B1 2
Scheme 3. Reagents: (a) BzCl/DMAP/pyridine; (b) Ac2O/DMAP/pyridine; (c) lipase ‘Amano A6’/phosphate buffer; (d) K2CO3/NaOMe/MeOH; (e) tBuMe2SiCl/imidazole/DMF; (f)
Dibal-H/toluene;(g) MeI/Ag2O/DMF; (h) (1) Dibal-H/toluene; (2) (COCl)2/DMSO/Et3N/CH2Cl2; (3) Ph3P@C(Me)COOEt/DMSO; (i) Dibal-H/toluene; (j) (1) I2/Ph3P/imidazole/
MeCN–Et2O; (2) PhSH/NaH/DMF; (k) H2O2/Mo7O24(NH4)6ꢁ4H2O/EtOH; (l) n-Buli/THF; (m) BzCl/DMAP/pyridine; (n) Na (Hg)/MeOH.
OSiMe2But
OSiMe2But
Me
EtOOC
a
b
R3
(2R, 3R)-23
Me
Me Me Me
(4R,5R)-30
(2E : 2Z = 5 ; 1)
Me Me Me
R3 = OH (4R,5R)-31
R3 = SPh (4R,5R)-32
c
d
R3 = SO2Ph (4R,5R)-33
OH
N
left half 3
MeO
Me
OSiMe2But
Me
OSiMe2But
SO2Ph
+
e
PhO2S
MeO
Me
Me Me Me
right half (4R,5R)-33
OR4
Me
Me Me Me
R4 = H 34
R4 = COPh 35
f
g
(+)-piericidin A1 1
Scheme 4. Reagents: (a) (1) (COCl)2/DMSO/Et3N/CH2Cl2; (2) Ph3P@C(Me)COOEt/DMSO; (b) Dibal-H/toluene; (c) (1) I2/Ph3P/MeCN–Et2O; (2) PhSH/NaH/DMF; (d) H2O2/
Mo7O24(NH4)6ꢁ4H2O/EtOH; (e) n-Buli/THF; (f) BzCl/DMAP/pyridine; (g) (1) Na (Hg)/MeOH; (2) n-Bu4N+Fꢀ/THF.
a 5:1 mixture (2E:2Z = 5:1) of (4R,5R)-30 in 72% overall yield from
(2R,3R)-23. Reduction of this mixture with Dibal-H gave a 5:1 mix-
ture of allyl alcohols, which were separated to (2E,4R,5R)-31 (62%
yield) and (2Z,4R,5R)-31 (13% yield). The reaction of (2E,4R,5R)-
31 and iodine in the presence of Ph3P and imidazole gave the corre-
sponding iodide, which was treated with thiophenoxide to give the
corresponding sulfide (4R,5R)-32 in 86% overall yield. Oxidation of
(4R,5R)-32 with 30% H2O2 in the presence of Mo7O24(NH4)6ꢁ4H2O
provided the corresponding sulfone (4R,5R)-33 in 57% yield. The
reaction of the left half 3 and (4R,5R)-33 in the presence of n-BuLi
gave a diastereomeric mixture of hydroxysulfone derivatives 34 in
68% yield, which was converted to the corresponding benzoates

R. Kikuchi et al. / Tetrahedron: Asymmetry 20 (2009) 1975–1983
1979
35 in 74% yield. This diastereomeric mixture of benzoates 35 was
treated with 5% sodium amalgam to afford 3:1 mixture
(E:Z = 3:1) of piericidin A1 silyl ethers in 34% yield. This 3:1 mixture
stirred for 5 h. at 100 °C under argon atmosphere. The reaction
mixture was filtered off with the aid of Celite to afford the filtrate.
The filtrate was evaporated to give a crude residue which was
chromatographed on silica gel (130 g, n-hexane/AcOEt = 20:1) to
provide a 2.2:1 mixture (E:Z = 2.2:1) of coupling products (0.344
g, 68% yield).
a
was treated with tetrabutylammonium fluoride to afford a 3:1 mix-
ture (E:Z = 3:1) of piericidins A1 1, from which (+)-piericidins A1
1
{½a 1D4
¼ þ2:1 (c 0.14, MeOH), 69% yield} was isolated. The spectral
ꢂ
data of the synthetic (+)-1 were identical with those of synthetic
(2) To a solution of the above mentioned coupling products
(0.344 g) in iso-PrOH (4 mL) at 0 °C was added 2 M HCl (2 mL)
and the reaction mixture was stood for 12 h at 5 °C. The reaction
mixture was diluted with 7% aqueous NaHCO3 and extracted with
AcOEt. The organic layer was dried over MgSO4. Concentration of
the organic layer gave a crude residue, which was chromato-
graphed on silica gel (20 g, n-hexane/AcOEt = 10:1) to provide
(2E)-3 (0.135 g, 65% yield) as a colorless oil. (2E)-3: IR (neat):
natural (+)-piericidin A1 14b {½a D25
¼ þ1:8 (c 0.1, MeOH)} including
ꢂ
the sign of specific rotation.
3. Conclusion
In conclusion, convergent syntheses of (+)-piericidin A1 1 and
(ꢀ)-piericidin B1 2 have been achieved based on classical Julia-
Lythgoe olefination between the pyridyl aldehyde derivative 3 cor-
responding to the left side of the final molecule, and chiral phenyl
sulfones (4R,5R)-20 and (4R,5R)-33 corresponding to the right
sides. The left half aldehyde 3 was synthesized based on the Stille
cross-coupling between pyridyl stannane derivative (7) and allyl
methyl carbonate congener (E)-6 in 17% overall yield (3 steps).
The construction of the two chiral centers in the right half 4 was
achieved based on lipase-catalyzed hydrolysis of the (2,3)-anti-b-
3227, 1718 cmꢀ1 1H NMR (CDCl3): d 1.80 (3H, s), 2.08 (3H, s),
;
3.06 (2H, dd, J = 1.2, 2.4 Hz), 3.40 (2H, d, J = 6.8 Hz), 3.84 (3H, s),
3.92 (3H, s), 5.55 (1H, dt, J = 1.2, 6.8 Hz), 6.18 (1H, s), 9.61 (1H, t,
J = 2.4 Hz). 13C NMR (CDCl3): d 10.4, 17.3, 34.3, 53.0, 54.2, 60.6,
112.0, 127.1, 127.7, 127.9, 149.8, 153.6, 154.0, 200.5. HRMS (FAB)
(m/z): calcd for C10H18O5 (M++1): 266.1392, found: 266.1406.
4.4. ( ) (4,5)-anti-2,4,6-Trimethyl-5-methoxy-1-(10-phenyl-1H-
tetrazolyl-50-sulfanyl)-octa-(2E,6E)-diene 10
acetoxy-a-methyl ester ( )-22. The right half sulfones (4R,5R)-20
and (4R,5R)-33 were synthesized from the enzymatic reaction
product (2S,3R)-22 (>99% ee) in 37% overall yield (8 steps) and
17% overall yield (7 steps), respectively.
To a solution of ( )-9 (0.500 g, 2.52 mmol), 1-phenyl-1H-tetra-
zole-5-thiol (0.540 g, 3.02 mmol), and triphenylphosphine (0.800
g, 3.0 mmol) in THF (10 mL) at 0 °C under argon atmosphere was
added 2.2 M of DEAD in toluene solution (1.7 mL, 3.78 mmol). After
stirring for 2 h at room temperature, the reaction mixture was di-
luted with H2O and extracted with AcOEt. The organic layer was
washed with brine and dried over MgSO4. Concentration of the or-
ganic layer gave a residue which was chromatographed on silica
gel (30 g, n-hexane/AcOEt = 30:1) to provide ( )-10 (0.807 g, 89%)
4. Experimental
4.1. General
1H and 13C NMR spectra were recorded on JEOL AL-400 or JEOL
ECP-500 NMR spectrometer in CDCl3. Electron impact-mass spec-
trometry (EI-MS) and fast atom bombardment mass spectra
(FAB-MS) were performed with JEOL JMS GC-mate II or JEOL JMS-
600H (matrix; Tokyo Kasei, DDT/TG11). Electron spray ioniza-
tion-mass spectrometry (ESI-MS) was performed with a JEOL
JMS-T100LP mass spectrometer. IR spectra were recorded with a
JASCO FT/IR-4100 spectrometer. Optical rotations were measured
with a JASCO P-2200 digital polarimeter. All evaporations were
performed under reduced pressure. For column chromatography,
Merck Silica Gel 60 was employed.
as a colorless oil. ( )-10: IR (neat): 1597 cmꢀ1 1H NMR (400
;
MHz, CDCl3): d 0.68 (3H, d, J = 6.8 Hz), 1.46 (3H, s), 1.61 (3H, d,
J = 6.4 Hz), 1.69 (3H, s), 2.40–2.50 (1H, m), 3.04 (3H, s), 3.08 (1H,
d, J = 9.0 Hz), 4.00 (2H, s), 5.36 (1H, q, J = 6.4 Hz), 5.43 (1H, d,
J = 9.0 Hz), 7.49–7.57 (5H, m). 13C NMR (CDCl3): d 10.3, 13.0,
15.5, 17.1, 35.5, 43.3, 56.1, 92.2, 124.0 (2C), 124.4, 128.2, 129.7
(2C), 130.0, 133.5, 133.8, 135.9, 154.2. HRMS (EI) (m/z): calcd for
C19H26N4OS (M+): 358.1827, found: 358.1829.
4.5. ( ) (4,5)-anti-2,4,6-Trimethyl-5-methoxy-1-(10-phenyl-1H-
tetrazolyl-50-sulfonyl)-octa-(2E,6E)-diene 11
4.2. 3-Methyl-5,5-dimethoxy-pent-(2E)-enyl methyl
carbonate 6
To a mixture of ( )-10 (0.150 g, 0.42 mmol) and Mo7O24(N-
H4)6ꢁ4H2O (0.105 g, 0.084 mmol) in EtOH (2 mL) at 0 °C was added
30% H2O2 (0.4 mL, 3.36 mmol), and the mixture was stirred for
2.5 h at room temperature. The reaction mixture was diluted with
EtOAc and washed with H2O, 10% aqueous Na2S2O3, and brine. The
organic layer was dried over MgSO4. Concentration of the organic
layer gave a residue which was chromatographed on silica gel
(25 g, n-hexane/AcOEt = 20:1) to provide ( )-11 (0.098 g, 60%) as
To a solution of (2E)-5 (0.50 g, 3.12 mmol) in toluene (5 mL) at
0 °C were added pyridine (1.0 mL, 12.5 mmol) and methyl chloro-
formate (1.0 mL, 12.5 mmol) and the reaction mixture was stirred
for 3 h. The reaction mixture was diluted with 7% aqueous NaHCO3
and extracted with AcOEt. The organic layer was dried over MgSO4.
Concentration of the organic layer gave a crude residue, which was
chromatographed on silica gel (40 g, n-hexane/AcOEt = 20:1) to
provide (2E)-7 (0.403 g, 60% yield) as a colorless oil. (2E)-6: IR
a colorless crystal. ( )-11: IR (neat): 1597, 1347, 1151 cmꢀ1 1H
;
(neat): 1747 cmꢀ1 1H NMR (CDCl3): d 1.72 (3H, s), 2.31 (2H, d,
;
NMR (400 MHz, CDCl3): d 0.66 (3H, d, J = 6.8 Hz), 1.46 (3H, s),
1.61 (3H, d, J = 6.8 Hz), 1.75 (3H, s), 2.43–2.53 (1H, m), 2.99 (3H,
s), 3.03 (1H, d, J = 9.0 Hz), 4.27 (2H, q, J = 14.4 Hz), 5.35–5.41 (2H,
m), 7.52–7.63 (5H, m). 13C NMR (CDCl3): d 10.1, 13.0, 16.7, 16.9,
35.8, 55.9, 65.9, 91.9, 120.0, 125.1, 125.7 (2C), 129.4 (2C), 131.3,
133.0, 133.2, 143.9, 153.1. HRMS (EI) (m/z): calcd for C19H26N4O3S
(M+): 390.1726, found: 390.1726.
J = 5.8 Hz), 3.28 (6H, s), 3.73 (3H, s), 4.46 (1H, t, J = 5.8 Hz), 4.63
(2H, d, J = 7.0 Hz), 5.42 (1H, t, J = 7.0 Hz). 13C NMR (CDCl3): d 17.0,
42.5, 52.8 (2C), 54.6, 64.4, 103.2, 120.7, 138.4, 155.8. HRMS (ESI)
(m/z): calcd for C10H18O5 (M+): 218.1154, found: 218.1114.
4.3. 4-Hydroxy-5,6-dimethoxy-3-methyl-2-[5-oxo-3-methyl-
pent-(2E)-enyl]-pyridine 3
4.6. ( ) (5,6)-cis-Piericidin B1
2
(1) To a solution of (2E)-6 (0.25 g, 1.15 mmol) and 7 (1.20 g,
2.04 mmol) in DMF (10 mL) were added LiCl (0.15 g, 3.45 mmol)
and Pd2(dba)3 (0.16 g, 0.173 mmol) and the reaction mixture was
To a solution of 3 (0.025 g, 0.094 mmol) and ( )-11 (0.037 g) in
THF (2 mL) at ꢀ78 °C under argon atmosphere was added KHMDS

1980
R. Kikuchi et al. / Tetrahedron: Asymmetry 20 (2009) 1975–1983
(0.5 M in toluene, 0.4 mL, 0.198 mmol) and the reaction mixture
was stirred for 12 h at the same temperature. The mixture was di-
luted with 7% aqueous NaHCO3 and extracted with EtOAc. The or-
ganic layer was washed with brine, dried over MgSO4. Evaporation
of the organic layer gave a residue which was chromatographed on
silica gel (5 g, n-hexane/AcOEt = 25:1) to provide ( )-cis-2 (0.017 g,
43%) as a colorless and starting ( )-11 (0.018 g, 48% recovery). ( )-
cis-2 IR (neat): 3364, 1587, 1473 cmꢀ1; 1H NMR (400 MHz, CDCl3):
d 0.73 (3H, d, J = 6.8 Hz), 1.50 (3H, s), 1.62 (3H, d, J = 6.8 Hz), 1.72
(3H, s), 1.74 (3H, s), 2.07 (3H, s), 2.50–2.60 (1H, m), 2.89–2.94
(2H, m), 3.07 (3H, s), 3.14 (1H, d, J = 8.9 Hz), 3.35 (2H, d,
J = 6.8 Hz), 3.84 (3H, s), 3.93 (3H, s), 5.20 (1H, d, J = 8.8 Hz), 5.27–
5.40 (3H, m), 5.89 (1H, d, J = 11.6 Hz), 6.12 (1H, s). 13C NMR
(CDCl3): d 10.37, 10.44, 13.0, 16.8, 17.0, 17.4, 34.6, 35.3, 38.5,
53.0, 56.1, 60.6, 92.8, 111.9, 121.4, 124.2, 127.0, 127.8, 131.7,
133.9, 134.3, 134.4, 135.5, 151.1, 153.4, 153.9. HRMS (EI) (m/z):
calcd for C26H39NO4 (M+): 429.2879, found: 429.2876.
which was chromatographed on silica gel (50 g, n-hexane/
AcOEt = 30:1) to provide (ꢀ)-(2S,3R)-22 (1.32 g, 44% yield) and
(+)-(2R,3S)-8 (1.23 g, 51% yield) as a colorless oil, respectively, in
elution order. NMR data of (ꢀ)-(2S,3R)-22 and (+)-(2R,3S)-8 were
identical with those of ( )-anti-22 and ( )-anti-8, respectively.
Small amount of (ꢀ)-(2S,3R)-22 (ca. 0.02 g) in MeOH was treated
with K2CO3 and NaOMe to give (2S,3R)-8, which was converted
to the corresponding (2S,3R)-benzoate 21. HPLC analysis of
(2S,3R)-benzoate 21 indicated almost single peak (tR = 8.5 min).
Small amount of (+)-(2R,3S)-8 (ca. 0.02 g) was converted to the cor-
responding (2S,3R)-benzoate 21, which was subjected to HPLC
analysis to give two peaks (8.5 min:14.8 min = 10.5:89.5). (ꢀ)-
(2S,3R)-22 {½a 2D3
¼ ꢀ12:7 (c 1.0, CHCl3) corresponding to >99%
ꢂ
ee}, (+)-(2R,3S)-8 {½a D24
ꢂ
¼ þ8:2 (c 1.0, CHCl3) corresponding to
79% ee}, IR (neat): 3454, 1738 cmꢀ1
;
1H NMR (CDCl3): d 0.98 (3H,
d, J = 7.2 Hz), 1.56 (3H, s), 1.59 (3H, d, J = 6.4 Hz), 2.44 (1H, br s),
2.62 (1H, dq, J = 9.2, 7.2 Hz), 3.68 (3H, s), 4.05 (1H, d, J = 9.2 Hz),
5.49 (1H, q, J = 6.4 Hz). 13C NMR (CDCl3): d 10.3, 13.1, 14.3, 43.2,
51.8, 80.0, 123.9, 134.8, 176.5. HRMS (EI) (m/z): calcd for C9H16O3
(M+): 172.1100, found: 172.1099.
4.7. ( ) Methyl (2,3)-anti-3-benzoyloxy-2,4-dimethyl-hex-(4E)-
enoate 21
To a solution of ( )-anti-8 (0.05 g, 0.29 mmol) in pyridine (1 mL) at
0 °C were added benzoyl chloride (0.05 mL, 0.35 mmol) and 4-N,N-
dimethylamino pyridine (0.005 g) and the reaction mixture was
stirred for 1 h at room temperature. The reaction mixture was diluted
with H2O and extracted with AcOEt. The organic layer was washed
with 7% aqueous NaHCO3 and brine, and dried over MgSO4.
Evaporation of the organic layer gave a crude residue, which was
chromatographed on silica gel (5 g, n-hexane/AcOEt = 50:1) to pro-
vide ( )-anti-21 (0.077 g, 97% yield) as a colorless oil ( )-anti-21: IR
4.10. Methyl (2S,3R)-3-tert-butyldimethylsiloxy-2,4-dimethyl-
hex-(4E)-enoate 24
(1) To a solution of (2S,3R)-22 (4.5 g, 21 mmol) in MeOH
(100 mL) were added K2CO3 (1.0 g) and NaOMe (0.005 g, catalytic
amount) and the reaction mixture was stirred for 4 h at room tem-
perature. After 10% aqueous NH4Cl was added to the reaction mix-
ture, whole mixture was condensed under reduced pressure to give
a residue. The residue was diluted with H2O and extracted with
AcOEt. The organic layer was washed with brine and dried over
MgSO4. Evaporation of the organic layer gave a crude residue,
which was chromatographed on silica gel (70 g, n-hexane/
AcOEt = 7:1) to provide (2S,3R)-8 (3.29 g, 91% yield) as a colorless
(neat): 1741, 1723, 1270 cmꢀ1 1H NMR (CDCl3): d 1.09 (3H, d,
;
J = 6.8 Hz), 1.617 (3H, s), 1.623 (3H, d, J = 7.2 Hz), 2.96 (1H, dq,
J = 6.8, 10.2 Hz), 3.60 (3H, s), 5.47 (1H, d, J = 10.2 Hz), 5.74 (1H, q,
J = 7.2 Hz), 7.38–7.42 (2H, m), 7.49–7.54 (1H, m), 7.97–8.00 (2H, m).
13C NMR (CDCl3): d 10.9, 13.2, 14.0, 42.3, 51.8, 81.7, 126.8, 128.3
(2C), 129.6 (2C), 130.4, 130.8, 132.8, 165.1, 174.7. HRMS (EI) (m/z):
calcd for C16H20O4 (M+): 276.1362, found: 276.1363. HPLC (column;
CHIRALPAKAD-H(4.6 ꢃ 250 mm),n-hexane/EtOH = 100:1, flowrate:
1.0 mL/min, UV detection: 254 nm): tR = 8.5, 14.8 min.
oil. (ꢀ)-(2S,3R)-8 {½a D19
¼ ꢀ10:4 (c 1.21, CHCl3) corresponding to
ꢂ
>99% ee}. NMR data of (+)-(2S,3R)-8 were identical with those of
( )-anti-8.
(2) To a solution of (2S,3R)-8 (0.800 g, 4.65 mmol) in DMF
(10 mL) was added imidazole (0.95 g, 14 mmol) and tbutyldimeth-
ylsilyl chloride (TBDMSCl, 2.10 g, 14 mmol) and the reaction mix-
ture was stirred for 3 h at room temperature. The reaction
mixture was diluted with brine and extracted with AcOEt/n-hex-
ane (1:1). The organic layer was dried over MgSO4 and evaporated
to give a residue, which was chromatographed on silica gel (40 g,
n-hexane/AcOEt = 50:1) to afford (2S,3R)-24 (1.14 g, 86% yield) as
4.8. ( ) Methyl (2,3)-anti-3-acetoxy-2,4-dimethyl-hex-(4E)-
enoate 22
To a solution of ( )-anti-8 (10.0 g, 58 mmol) in pyridine (50 mL)
at 0 °C were added Ac2O (8.2 mL, 87 mmol) and 4-N,N-dimethyl-
amino pyridine (0.005 g) and the reaction mixture was stirred for
12 h at room temperature. The reaction mixture was diluted with
H2O and extracted with AcOEt. The organic layer was washed with
7% aqueous NaHCO3 and brine, and dried over MgSO4. Evaporation
of the organic layer gave a crude residue, which was chromato-
graphed on silica gel (150 g, n-hexane/AcOEt = 30:1) to provide
( )-anti-22 (10.9 g, 88% yield) as a colorless oil ( )-anti-22: IR
a colorless oil. (ꢀ)-(2S,3R)-24 {½a D21
¼ ꢀ1:6 (c 1.05, CHCl3)}; IR
ꢂ
(neat): 1741 cmꢀ1
;
1H NMR: d ꢀ0.08 (3H, s), ꢀ0.04 (3H, s), 0.80
(9H, s), 0.87 (3H, d, J = 7.0 Hz), 1.50 (3H, s), 1.58 (3H, d,
J = 6.6 Hz), 2.58 (1H, dq, J = 7.0, 9.8 Hz), 3.64 (3H, s), 4.05 (1H, d,
J = 9.8 Hz), 5.04 (1H, q, J = 6.6 Hz). 13C NMR: d ꢀ5.5, ꢀ4.8, 9.9,
13.0, 14.1, 17.9, 25.6 (3C), 44.8, 51.4, 81.7, 123.6, 135.3, 176.4.
HRMS (FAB) (m/z): calcd for C15H31O3Si (M++1): 287.2042, found:
287.2048.
; d 0.99 (3H, d,
(neat): 1739, 1230 cmꢀ1 1H NMR (CDCl3):
J = 7.2 Hz), 1.53 (3H, d, J = 1.0 Hz), 1.59 (1H, d, J = 6.8 Hz), 1.95
(3H, s), 2.75 (1H, dq, J = 7.2, 10.4 Hz),3.64 (3H, s), 5.23 (1H, d,
J = 10.4 Hz), 5.62 (1H, dq, J = 1.0, 6.8 Hz). 13C NMR (CDCl3): d 10.7,
13.1, 13.9, 21.0, 42.0, 51.7, 81.0, 126.8, 130.7 169.6, 174.7. HRMS
(EI) (m/z): calcd for C11H18O4 (M+): 214.1205, found: 214.1215.
4.11. (2R,3R)-3-tert-Butyldimethylsiloxy-2,4-dimethyl-hex-
(4E)-en-1-ol 23
To a solution of (2S,3R)-22 (1.10 g, 3.84 mmol) in toluene
(15 mL) at 0 °C under argon atmosphere was added 1.5 M solution
of Dibal-H in toluene (5.7 mL, 8.5 mmol) and the reaction mixture
was stirred for 30 min. The reaction mixture was diluted with
MeOH (2 mL), H2O (10 mL) and the whole mixture was stirred
for 12 h at the same temperature. The generated precipitate was
filtered off with the aid of Celite to afford the filtrate. The filtrate
was separated and the organic layer was dried over MgSO4. Evap-
oration of the organic solvent gave (2R,3R)-23 (0.903 g, 91% yield)
4.9. Lipase-catalyzed hydrolysis of ( )-anti-22
A suspension of ( )-anti-22 (3.00 g, 14 mmol) and lipase A6
(1.5 g) in 0.1 M phosphate buffer (pH 7.2; 600 mL) was stirred for
28 at 33 °C. After the reaction mixture was filtered, the precipitate
was washed with AcOEt. The combined organic layer was dried
over MgSO4. Evaporation of the organic layer gave a crude residue,

R. Kikuchi et al. / Tetrahedron: Asymmetry 20 (2009) 1975–1983
1981
as
a
homogeneous oil. (+)-(2R,3R)-23 {½a D20
ꢂ
¼ þ18:7 (c=1.03,
washed with brine and dried over MgSO4. Concentration of the or-
ganic layer gave a residue which was chromatographed on silica
gel (120 g, n-hexane/AcOEt = 50:1) to provide (4R,5R)-26 (3.32 g,
90% overall yield from (2S,3R)-25 as a colorless oil. (4R,5R)-26
CHCl3)}, IR (neat): 3412 cmꢀ1
;
1H NMR: d ꢀ0.04 (3H, s), 0.05 (3H,
s), 0.71 (3H, d, J = 6.8 Hz), 0.86 (9H, s), 1.53 (3H, s), 1.57 (3H, d,
J = 6.4 Hz), 1.76–1.86 (1H, m), 2.99 (1H, br s), 3.58 (2H, d,
J = 5.2 Hz), 3.79 (1H, d, J = 8.4 Hz), 5.37 (1H, q, J = 6.4 Hz). 13C
NMR: d ꢀ5.3, ꢀ4.5, 11.0, 12.9, 14.2, 18.1, 25.8 (3C), 38.3, 67.3,
85.2, 122.1, 136.5. HRMS (EI) (m/z): calcd for C14H30O2Si (M+):
258.2015, found: 258.2020.
{½a 1D9
ꢂ
¼ þ0:8 (c 1.28, CHCl3)}, IR (neat): 1708 cmꢀ1
;
1H NMR
(CDCl3): d 0.78 (3H, d, J = 6.8 Hz), 1.27 (3H, t, J = 7.0 Hz), 1.51 (3H,
s), 1.63 (3H, d, J = 6.8 Hz), 1.83 (3H, d, J = 1.4 Hz), 2.59–2.69 (1H,
m), 3.09 (3H, s), 3.23 (1H, d, J = 9.2 Hz), 4.16 (2H, q, J = 7.0 Hz),
5.43 (1H, q, J = 6.8 Hz), 6.66 (1H, dq, J = 1.4, 9.6 Hz). 13C NMR
(CDCl3): d 10.2, 12.6, 13.0, 14.3, 16.4, 36.0, 56.1, 60.3, 92.1, 125.0,
127.6, 133.3, 146.0, 168.4. HRMS (ESI) (m/z): calcd for C14H24O3
(M+): 240.1725, found: 240.1702.
4.12. Methyl (2S,3R)-3-methoxy 2,4-dimethyl-hex-(4E)-enoate
25
To a solution of (2S,3R)-8 (3.44 g, 20 mmol) and Ag2O (6.95 g,
30 mmol) in DMF (40 mL) at 0 °C was added methyl iodide
(3.74 mL, 60 mL) and the reaction mixture covered with aluminum
foil was stirred for 48 h at room temperature. The reaction mixture
was filtered off with the aid of Celite. The filtrate was diluted with
H2O and extracted with a mixed solvent (n-hexane/AcOEt = 5:1).
The organic layer was dried over MgSO4. Concentration of the or-
ganic layer gave a crude residue, which was chromatographed on
silica gel (120 g, n-hexane/AcOEt = 30:1) to provide (2S,3R)-25
4.14. (4R,5R)-5-Methoxy-2,4,6-trimethyl-octa-(2E,6E)-
dien-1-ol 9
To a solution of (4R,5R)-26 (3.00 g, 13 mmol) in toluene (50 mL)
at 0 °C under argon atmosphere was added 1.5 M solution of Dibal-
H in toluene (19 mL, 29 mmol) and the reaction mixture was stir-
red for 30 min. The reaction mixture was diluted with MeOH
(2 mL), H2O (10 mL) and the whole mixture was stirred for 12 h
at the same temperature. The generated precipitate was filtered
off with the aid of Celite to afford the filtrate. The filtrate was sep-
arated and the organic layer was dried over MgSO4. Concentration
of the organic layer gave a residue which was chromatographed on
silica gel (70 g, n-hexane/AcOEt = 7:1) to provide (4R,5R)-9
(2.939 g, 79% yield) as a colorless oil. (2S,3R)-25: {½a D20
¼ ꢀ21:4 (c
ꢂ
1.1, CHCl3)}, IR (neat): 1738 cmꢀ1 1H NMR (CDCl3): d 0.90 (3H, t,
;
J = 7.1 Hz), 1.47 (3H, s), 1.63 (3H, d, J = 6.7 Hz), 2.58 (1H, dq,
J = 7.1, 10.3 Hz), 3.09 (3H, s), 3.54 (1H, d, J = 10.3 Hz), 3.68 (3H, s),
5.49 (1H, q, J = 6.7 Hz). 13C NMR (CDCl3): d 9.6, 13.1, 14.2, 42.7,
51.7, 55.9, 89.7, 126.3, 131.9, 176.4. HRMS (EI) (m/z): calcd for
C10H18O3 (M+): 186.1256, found: 186.1256.
(2.553 g, 98% yield) as a colorless oil. (4R,5R)-9 {½a D20
¼ ꢀ1:0 (c
ꢂ
1.28, CHCl3)}, IR (neat): 3404 cmꢀ1 1H NMR (CDCl3): d 0.73 (3H,
;
d, J = 7.2 Hz), 1.50 (3H, s), 1.62 (3H, d, J = 6.8 Hz), 1.65 (3H, s),
1.81 (1H, br s), 2.48–2.59 (1H, m), 3.09 (3H, s), 3.14 (1H, d,
J = 8.8 Hz), 3.97 (2H, s), 5.29 (1H, d, J = 8.8 Hz), 5.39 (1H, q,
J = 6.8 Hz). 13C NMR (CDCl3): d 10.3, 13.0, 13.9, 17.5, 34.8, 56.0,
69.0, 92.7, 124.4, 130.2, 133.7, 134.7. HRMS (EI) (m/z): calcd for
C12H22O2 (M+): 198.1620, found: 198.1592.
4.13. Ethyl (4R,5R)-5-methoxy-2,4,6-trimethyl-octa-(2E,6E)-
dienoate 26
(1) To a solution of (2S,3R)-25 (3.00 g, 16 mmol) in toluene
(25 mL) at 0 °C under argon atmosphere was added 1.5 M solution
of Dibal-H in toluene (24 mL, 36 mmol) and the reaction mixture
was stirred for 30 min. The reaction mixture was diluted with
MeOH (2 mL), H2O (10 mL) and the whole mixture was stirred
for 12 h at the same temperature. The generated precipitate was
filtered off with the aid of Celite to afford the filtrate. The filtrate
was separated and the organic layer was dried over MgSO4.
Evaporation of the organic solvent gave (2,3)-anti-3-methoxy-
2,4-dimethyl-hex-(4E)-en-1-ol (2.50 g, 98% yield). IR (neat):
4.15. (4R,5R)-2,4,6-Trimethyl-5-methoxy-1-phenylsulfanyl-
octa-(2E,6E)-diene 27
(1) To a solution of (4R,5R)-9 (0.500 g, 2.52 mmol), imidazole
(0.43 g, 5.63 mmol), and triphenylphosphine (1.32 g, 4.5 mmol) in
a mixed solvent (Et2O/CH3CN = 1:1, 15 mL) at 0 °C was added I2
(1.60 g, 6.30 mmol). After stirring for 30 min at room temperature,
the reaction mixture was diluted with 10% aqueous Na2S2O3 and
extracted with n-hexane. The organic layer was washed with brine
and dried over MgSO4. Concentration of the organic layer gave
quantitatively a crude iodide which was used for next reaction
without further purification.
3407 cmꢀ1 1H NMR (CDCl3): d 0.62 (3H, d, J = 7.0 Hz), 1.49 (3H,
;
s), 1.62 (3H, d, J = 6.7 Hz), 1.84–1.93 (1H, m), 3.13 (3H, s), 3.26
(1H, d, J = 9.6 Hz), 3.50–3.60 (3H, m), 5.49 (1H, q, J = 6.7 Hz). 13C
NMR (CDCl3): d 9.9, 12.9, 13.7, 37.0, 55.5, 68.8, 94.9, 125.0, 133.2.
MS (EI) (m/z): calcd for C9H18O2 (M+): 158.1307, found: 158.1301.
(2) To a solution of oxalyl chloride (3.4 mL, 40 mmol) in CH2Cl2
(40 mL) at ꢀ78 °C under argon atmosphere was added a solution of
DMSO (5.00 g, 64 mmol) in CH2Cl2 (10 mL) and the whole mixture
was stirred for 15 min at the same temperature. To the above mix-
ture was added a solution of the above alcohol (2.50 g) in CH2Cl2
(10 mL) and the reaction mixture was warmed to ꢀ20 °C. Et3N
(14 mL, 104 mmol) was added to the above reaction mixture and
the whole mixture was warmed to 0 °C. The reaction mixture
was diluted with H2O and extracted with CH2Cl2. The organic layer
was washed with brine and dried over MgSO4. Concentration of the
organic layer gave quantitatively a crude corresponding aldehyde
(2.452 g), which was used for the next reaction without further
(2) To a suspension of 55% NaH in oil (110 mg, 2.5 mmol) in
DMF (5 mL) at 0 °C was added thiophenol (0.3 mL, 2.7 mmol),
and a solution of the above crude iodide in DMF (2 mL) was added
to the above reaction mixture. After stirring for 1 h at 55 °C, the
reaction mixture was diluted with 2 M aqueous NaOH and ex-
tracted with Ether. The organic layer was washed with brine and
dried over MgSO4. Evaporation of the organic layer gave a residue
which was chromatographed on silica gel (40 g, n-hexane/
AcOEt = 100:1) to provide (4R,5R)-27 (0.622 g, 85% yield from
(4R,5R)-9) as a colorless oil. (4R,5R)-27: {½a D18
¼ ꢀ18:4 (c 0.98,
ꢂ
CHCl3)}, IR (neat): 1584, 1480 cmꢀ1 1H NMR (400 MHz, CDCl3): d
;
0.62 (3H, d, J = 7.0 Hz), 1.49 (3H, s), 1.62 (3H, d, J = 6.6 Hz), 1.76
(3H, s), 2.44–2.54 (1H, m), 3.07 (3H, s), 3.51 (2H, q, J = 13.1 Hz),
5.15 (1H, d, J = 8.8 Hz), 5.35 (1H, q, J = 6.6 Hz), 7.13–7.17 (1H, m),
7.22–7.26 (2H, m), 7.33–7.36 (2H, m). 13C NMR (CDCl3): d 10.4,
13.0, 15.6, 17.3, 35.5, 44.5, 56.1, 92.5, 124.2, 126.1, 128.6 (2C),
130.1, 130.6 (2C), 133.4, 133.9, 136.7. HRMS (EI) (m/z): calcd for
C18H26OS (M+): 290.1704, found: 290.1703.
purification. To
a solution of the above aldehyde in DMSO
(40 mL) was added [1-(ethoxycarbonyl)ethylidene]triphenylphos-
phorane (17.4 g, 48 mmol) and the whole mixture was stirred for
48 h at 40 °C under argon atmosphere. The reaction mixture was
diluted with H2O and extracted with Et2O. The organic layer was

1982
R. Kikuchi et al. / Tetrahedron: Asymmetry 20 (2009) 1975–1983
4.16. (4R,5R)-2,4,6-Trimethyl-5-methoxy-1-phenylsulfonyl-
octa-(2E,6E)-diene 20
5.49 (1H, dt, J = 7.1, 15.5 Hz), 6.06 (1H, d, J = 15.5 Hz), 6.12 (1H,
s). 13C NMR (CDCl3): d 10.40, 10.43, 12.9, 13.0, 16.6, 17.7, 34.4,
35.4, 43.1, 53.1, 56.2, 60.6, 92.7, 112.0, 121.9, 124.2, 125.1, 127.8,
133.3, 134.0, 135.0, 135.3, 136.4, 150.9, 153.5, 154.0. HRMS (EI)
(m/z): calcd for C26H39NO4 (M+): 429.2879, found: 429.2885.
To a mixture of (4R,5R)-27 (0.500 g, 1.72 mmol) and Mo7O24(N-
H4)6ꢁ4H2O (0.430 g, 0.34 mmol) in EtOH (8 mL) at 0 °C was added
30% H2O2 (1.6 mL, 13.8 mmol), and the mixture was stirred for
3 h at room temperature. The reaction mixture was diluted with
EtOAc and washed with H2O, 10% aqueous Na2S2O3 and brine.
The organic layer was dried over MgSO4. Evaporation of the organic
layer gave a residue which was chromatographed on silica gel
(30 g, n-hexane/AcOEt = 10:1) to provide (4R,5R)-20 (0.516 g,
4.18. Ethyl (4R,5R)-5-tert-butyldimethylsiloxy-2–2,4,6-
trimethyl-octa-(2E,6E)-dienoate 30
To a solution of oxalyl chloride (0.85 mL, 9.6 mmol) in CH2Cl2
(10 mL) at ꢀ78 °C under argon atmosphere was added a solution
of DMSO (1.20 g, 15 mmol) in CH2Cl2 (2 mL) and the whole mixture
was stirred for 15 min at the same temperature. To the above mix-
ture was added a solution of (2R,3R)-23 (0.903 g, 3.5 mmol) in
CH2Cl2 (2 mL) and the reaction mixture was warmed to ꢀ20 °C.
Et3N (3.2 mL, 23 mmol) was added to the above reaction mixture
and the whole mixture was warmed to 0 °C. The reaction mixture
was diluted with H2O and extracted with CH2Cl2. The organic layer
was washed with brine and dried over MgSO4. Concentration of the
organic layer gave quantitatively a crude corresponding aldehyde,
which was used for the next reaction without further purification.
To a solution of the above aldehyde in DMSO (10 mL) was added
93%) as a colorless crystal. (4R,5R)-20: {½a D16
ꢂ
¼ þ24:0 (c 1.04,
CHCl3)}, IR (neat): 1586, 1498, 1308, 1149, 1138 cmꢀ1
;
1H NMR
(400 MHz, CDCl3): d 0.52 (3H, d, J = 6.8 Hz), 1.44 (3H, s), 1.59 (3H,
d, J = 6.4 Hz), 1.72 (3H, s), 2.38–2.47 (1H, m), 3.02 (3H, s), 3.74
(2H, s), 4.94 (1H, d, J = 9.2 Hz), 5.31 (1H, q, J = 6.4 Hz), 7.48–7.53
(2H, m), 7.58–7.62 (1H, m), 7.83–7.86 (2H, m). 13C NMR (CDCl3):
d 10.2, 13.0, 16.8, 17.0, 35.6, 55.9, 66.3, 92.0, 123.1, 124.7, 128.7,
128.8, 133.35 (2C), 133.39 (2C), 138.5, 140.4. HRMS (EI) (m/z):
calcd for C18H26O3S (M+): 322.1603, found: 322.1404.
4.17. (ꢀ)-Piericidin B1
2
[1-(ethoxycarbonyl)ethylidene]triphenylphosphorane
(4.17 g,
11.5 mmol) and the whole mixture was stirred for 48 h at 40 °C un-
der argon atmosphere. The reaction mixture was diluted with H2O
and extracted with Et2O. The organic layer was washed with brine
and dried over MgSO4. Concentration of the organic layer gave a
residue which was chromatographed on silica gel (40 g, n-
hexane/AcOEt = 70:1) to provide a 5:1 (E:Z = 5:1) mixture of (2E)-
30 and (2Z)-30 (0.859 g, 72% overall yield from (2S,3R)-30) as a
colorless oil. 30 IR (neat): 1712 cmꢀ1; HRMS (FAB) (m/z): calcd
for C19H37O3Si (M++1): 341.2512, found: 341.2524.
(1) To a solution of (4R,5R)-20 (0.100 g, 0.31 mmol) in THF
(5 mL) at ꢀ20 °C under argon atmosphere was added n-BuLi
(2.6 M in n-hexane, 0.26 mL, 0.68 mmol) and the reaction mixture
was stirred for 1 h at the same temperature. A solution of 3
(0.165 g, 0.62 mmol) in THF (1 mL) was added to the above reac-
tion mixture at ꢀ78 °C under argon atmosphere and the reaction
mixture was stirred for 12 h at the same temperature. The mixture
was diluted with 10% aqueous NH4Cl and extracted with EtOAc.
The organic layer was washed with brine, dried over MgSO4. Evap-
oration of the organic layer gave a residue which was chromato-
graphed on silica gel (5 g, n-hexane/AcOEt = 4:1) to provide a
diastereomeric mixture of 28 (0.127 g, 69%) as a colorless oil,
which was used for the next reaction without further purification.
28; IR (neat): 3414, 1586, 1358, 1302, 1125 cmꢀ1; HRMS (EI) (m/z):
calcd for C32H45NO7S (M+): 589.2917, found: 587.2917.
4.19. (4R,5R)-5-tert-Butyldimethylsiloxy-2,4,6-trimethyl-octa-
(2E,6E)-dien-1-ol 31
To a solution of 5:1 mixture of (2E)-30 and (2Z)-30 (0.800 g,
2.35 mmol) in toluene (10 mL) at 0 °C under argon atmosphere
was added 1.5 M solution of Dibal-H in toluene (3.4 mL, 5.2 mmol)
and the reaction mixture was stirred for 30 min. The reaction mix-
ture was diluted with MeOH (2 mL), H2O (10 mL) and the whole
mixture was stirred for 12 h at the same temperature. The gener-
ated precipitate was filtered off with the aid of Celite to afford
the filtrate. The filtrate was separated and the organic layer was
dried over MgSO4. Concentration of the organic layer gave a resi-
due which was chromatographed on silica gel (40 g, n-hexane/
AcOEt = 30:1) to provide (2Z)-31 (0.09 g, 13% yield) and (2E)-31
(0.434 g, 62% yield) as a colorless oil, respectively, in elution order.
(2) To a solution of a diastereomeric mixture of 28 (0.110 g,
0.19 mmol) in pyridine (3 mL) at 0 °C were added 4-dimethylami-
nopyridine (0.115 g, 0.94 mmol) and benzoyl chloride (0.09 mL,
0.75 mmol) and the reaction mixture was stirred for 1 h at room
temperature. The mixture was diluted with 7% aqueous NaHCO3
and extracted with EtOAc. The organic layer was washed with
brine and dried over MgSO4. Evaporation of the organic layer gave
a residue which was chromatographed on silica gel (5 g, n-hexane/
AcOEt = 5:1) to provide a diastereomeric mixture of 29 (0.105 g,
81%) as a colorless oil, which was used for the next reaction
without further purification. 29; IR (neat): 3519, 1743, 1584,
(2Z)-31 (minor product); IR (neat): 3362 cmꢀ1 1H NMR (CDCl3): d
;
;
1266 cmꢀ1 HRMS (EI) (m/z): calcd for C39H49NO8S (M+):
ꢀ0.04 (3Y, s), ꢀ0.03 (3Y, s), 0.71 (3H, d, J = 6.8 Hz), 0.82 (9H, s), 1.55
(3H, s), 1.58 (3H, d, J = 6.8 Hz), 1.76 (3H, s), 2.65–2.75 (1H, m),
2.84–2.86 (1H, m), 3.54 (1H, d, J = 9.2 Hz), 3.79 (1H, dd, J = 7.6,
12.2 Hz), 4.23 (1H, dd, J = 2.0, 12.2 Hz), 5.00 (1H, d, J = 10.4 Hz),
5.31 (1H, q, J = 6.8 Hz). 13C NMR (CDCl3): d ꢀ4.8, ꢀ4.7, 10.4, 12.9,
17.8, 18.3, 22.8, 25.8 (3C), 36.5, 62.8, 83.8, 122.6, 132.5, 135.7,
136.4. HRMS (FAB) (m/z): calcd for C17H35O2Si (M++1): 299.2406,
691.3179, found: 691.3183.
(3) To a solution of a diastereomeric mixture of 29 (0.024 g,
0.035 mmol) in MeOH (2 mL) at 0 °C was added 5% sodium amal-
gam (0.08 g, 0.17 mmol) and the reaction mixture was stirred for
12 h at the same temperature. The mixture was diluted with brine
at 0 °C and extracted with EtOAc. The organic layer was washed
with brine and dried over MgSO4. Evaporation of the organic layer
gave a residue which was chromatographed on silica gel (5 g, n-
hexane/AcOEt = 20:1) to provide (ꢀ)-2 (0.0062 g, 42%) as a color-
found: 299.2385. (2E)-31 (major product); {½a D18
¼ ꢀ2:1 (c 0.94,
ꢂ
CHCl3)}, IR (neat): 3320 cmꢀ1
;
1H NMR (CDCl3): d ꢀ0.10 (3Y, s),
ꢀ0.06 (3Y, s), 0.73 (3H, d, J = 6.9 Hz), 0.81 (9H, s), 1.53 (3H, s),
1.56 (3H, d, J = 6.8 Hz), 1.65 (3H, s), 2.46–2.56 (1H, m), 3.61 (1H,
d, J = 8.1 Hz), 3.96 (2H, d, J = 5.9 Hz), 5.19 (1H, d, J = 9.6 Hz), 5.30
(1H, q, J = 6.8 Hz). 13C NMR (CDCl3): d ꢀ5.1, ꢀ4.7, 10.9, 12.9, 14.1,
17.4, 18.1, 25.7 (3C), 36.8, 69.3, 83.4, 121.3, 130.8, 134.1, 137.1.
HRMS (FAB) (m/z): calcd for C17H35O2Si (M++1): 299.2406, found:
299.2423.
less oil. (ꢀ)-2; {½a D17
¼ ꢀ8:2 (c 0.43, MeOH)}, IR (neat): 3403,
ꢂ
1586, 1469 cmꢀ1
;
1H NMR (400 MHz, CDCl3): d 0.75 (3H, d,
J = 6.9 Hz), 1.50 (3H, s), 1.53 (3H, s), 1.63 (3H, d, J = 6.7 Hz), 1.72
(3H, s), 2.07 (3H, s), 2.57–2.67 (1H, m), 2.75 (2H, d, J = 7.0 Hz),
3.10 (3H, s), 3.14 (1H, d, J = 8.9 Hz), 3.34 (2H, d, J = 6.8 Hz), 3.84
(3H, s), 3.93 (3H, s), 5.27 (1H, d, J = 9.0 Hz), 5.36–5.42 (2H, m),

R. Kikuchi et al. / Tetrahedron: Asymmetry 20 (2009) 1975–1983
1983
4.20. (4R,5R)-5-tert-Butyldimethylsiloxy-2,4,6-trimethyl-1-
phenylsulfanyl-octa-(2E,6E)- diene 32
Evaporation of the organic layer gave a residue which was chro-
matographed on silica gel (5 g, n-hexane/AcOEt = 4:1) to provide
a diastereomeric mixture of 34 (0.121 g, 68%) as a pale yellow
oil, which was used for the next reaction without further purifica-
tion. 34; IR (neat): 3421, 1586, 14727 1125 cmꢀ1; HRMS (EI) (m/z):
calcd for C37H57NO7SSi (M+): 687.3625, found: 687.3631.
(1) To a solution of (2E)-31 (0.200 g, 0.67 mmol), imidazole
(0.115 g, 1.68 mmol), and triphenylphosphine (0.355 g, 1.34 mmol)
in a mixed solvent (Et2O/CH3CN = 1:1, 5 mL) at 0 °C was added I2
(0.425 g, 1.68 mmol). After stirring for 30 min at room tempera-
ture, the reaction mixture was diluted with 10% aqueous Na2S2O3
and extracted with n-hexane. The organic layer was washed with
brine and dried over MgSO4. Concentration of the organic layer
gave quantitatively a crude iodide which was used for next reac-
tion without further purification.
(2) To a solution of a diastereomeric mixture of 34 (0.110 g,
0.16 mmol) in pyridine (3 mL) at 0 °C were added 4-dimethylami-
nopyridine (0.10 g, 0.8 mmol) and benzoyl chloride (0.06 mL,
0.48 mmol) and the reaction mixture was stirred for 1 h at room
temperature. The mixture was diluted with 7% aqueous NaHCO3
and extracted with EtOAc. The organic layer was washed with
brine and dried over MgSO4. Evaporation of the organic solvent
gave a residue which was chromatographed on silica gel (5 g, n-
hexane/AcOEt = 5:1) to provide a diastereomeric mixture of 35
(0.092 g, 74%) as a pale yellow oil, which was used for the next
reaction without further purification. 35; IR (neat): 3518, 1743,
(2) To a suspension of 55% NaH in oil (0.035 g, 0.74 mmol) in
DMF (2 mL) at 0 °C was added thiophenol (0.08 mL, 0.8 mmol)
and a solution of the above crude iodide in DMF (1 mL) was added
to the above reaction mixture. After stirring for 1 h at 55 °C, the
reaction mixture was diluted with H2O and extracted with AcOEt.
The organic layer was washed with brine and dried over MgSO4.
Evaporation of the organic layer gave a residue which was chro-
matographed on silica gel (30 g, n-hexane/AcOEt = 100:1) to pro-
vide (4R,5R)-32 (0.226 g, 86% overall yield from (2E)-31) as a
1578, 1471, 1265, 1121 cmꢀ1; HRMS (EI) (m/z): calcd for C44H61
-
NO8SSi (M+): 791.3887, found:791.3888.
(3) To a solution of a diastereomeric mixture of 35 (0.090 g,
0.11 mmol) in MeOH (3 mL) at 0 °C was added 5% sodium amalgam
(0.525 g, 1.14 mmol) and the reaction mixture was stirred for 12 h
at the same temperature. The mixture was diluted with brine at
0 °C and extracted with EtOAc. The organic layer was washed with
brine and dried over MgSO4. Evaporation of the organic solvent
gave a residue which was chromatographed on silica gel (5 g,
colorless oil. (4R,5R)-32: {½a D15
¼ ꢀ6:9 (c 0.97, CHCl3)}, IR (neat):
ꢂ
1585, 1471 cmꢀ1
;
1H NMR (400 MHz, CDCl3): d ꢀ0.10 (3H, s),
ꢀ0.06 (3H, s), 0.61 (3H, d, J = 7.2 Hz), 0.82 (9H, s), 1.50 (3H, s),
1.54 (3H, d, J = 6.6 Hz), 1.72 (3H, s), 2.39–2.48 (1H, m), 3.47 (2H,
q, J = 12.8 Hz), 3.57 (1H, d, J = 7.2 Hz), 5.06 (1H, d, J = 9.6 Hz), 5.25
(1H, q, J = 6.6 Hz), 7.12–7.17 (1H, m), 7.21–7.27 (2H, m), 7.31–
7.37 (2H, m). 13C NMR (CDCl3): d -5.0, -4.7, 11.0, 12.9, 15.7, 17.4,
18.1, 25.8 (3C), 37.4, 44.5, 83.1, 121.0, 126.0, 128.6 (2C), 129.4,
130.4 (2C), 133.5, 136.9, 137.1. HRMS (FAB) (m/z): calcd for
C23H39OSSi (M++1): 391.2491, found: 391.2498.
n-hexane/AcOEt = 15:1) to provide
a 3:1 mixture of olefin
compound (E:Z = 3:1, 0.021 g, 34%) as a colorless oil. olefin com-
pound; IR (neat): 3516, 3416, 1587, 1471 cmꢀ1; HRMS (FAB)
(m/z): calcd for C31H52NO4SSi (M++1): 530.3666, found:530.3668.
(4) To a solution of a 3:1 mixture of the above olefin compound
(0.015 g, 0.028 mmol) in THF (1 mL) under argon atmosphere were
added molecular sieves (3A, 0.15 g) and 1.0 M tetrabutylammo-
nium fluoride in THF solution (0.09 mL, 0.05 mmol) and the reac-
tion mixture was heated at 50 °C with stirring for 12 h. The
mixture was diluted with 10% aqueous NH4Cl at 0 °C and extracted
with EtOAc. The organic layer was washed with brine and dried
over MgSO4. Evaporation of the organic solvent gave a residue
which was chromatographed on silica gel (5 g, n-hexane/
AcOEt = 10:1) to provide (+)-piericidin A1 1 (0.0081 g, 69% yield)
4.21. (4R,5R)-5-tert-Butyldimethylsiloxy-2,4,6-trimethyl-1-
phenylsulfonyl-octa-(2E,6E)-diene 33
To a mixture of (4R,5R)-32 (0.200 g, 0.51 mmol) and Mo7O24(N-
H4)6ꢁ4H2O (0.130 g, 0.10 mmol) in EtOH (2 mL) at 0 °C was added
30% H2O2 (0.6 mL, 5.1 mmol), and the mixture was stirred for
12 h at room temperature. The reaction mixture was diluted with
EtOAc and the organic layer was washed with 10% aqueous
Na2S2O3 and brine. The organic layer was dried over MgSO4. Evap-
oration of the organic solvent gave a residue which was chromato-
graphed on silica gel (30 g, n-hexane/AcOEt = 30:1) to provide
as a pale yellow oil. (+)-piericidin A1 (1); {½a D14
¼ þ2:1 (c 0.14,
ꢂ
MeOH)}, IR (neat): 3396, 1587, 1472 cmꢀ1 1H NMR (400 MHz,
;
CDCl3): d 0.79 (3H, d, J = 6.8 Hz), 1.61 (3H, d, J = 5.0 Hz), 1.62 (3H,
s), 1.73 (3H, s), 1.79 (3H, s), 2.07 (3H, s), 2.61–2.70 (1H, m), 2.77
(2H, d, J = 7.3 Hz), 3.35 (2H, d, J = 6.8 Hz), 3.60 (1H, d, J = 9.2 Hz),
3.84 (3H, s), 3.93 (3H, s), 5.19 (1H, d, J = 9.9 Hz), 5.39 (1H, t,
J = 7.0 Hz), 5.44–5.49 (1H, m), 5.59 (1H, dt, J = 6.9, 15.5 Hz), 6.07
(1H, d, J = 15.5 Hz). 13C NMR (CDCl3): d 10.45, 10.52, 13.1, 13.2,
16.6, 17.4, 34.4, 36.9, 43.1, 53.0, 60.6, 82.8, 111.9, 122.2, 123.6,
126.8, 127.8, 133.1, 134.8, 135.5, 135.7, 136.1, 150.8, 153.5,
153.9. HRMS (FAB) (m/z): calcd for C25H38NO4 (M++1): 416.2801,
found:416.2792.
(4R,5R)-33 (0.124 g, 57%) as a colorless oil. (4R,5R)-33: {½a D13
¼
ꢂ
þ49:5 (c 1.03, CHCl3)}, IR (neat): 1586, 1462, 1318, 1150,
1129 cmꢀ1
;
1H NMR (400 MHz, CDCl3): d ꢀ0.15 (3H, s), ꢀ0.13
(3H, s), 0.47 (3H, d, J = 6.8 Hz), 0.76 (9H, s), 1.45 (3H, s), 1.52 (3H,
d, J = 6.8 Hz), 1.73 (3H, s), 2.35–2.44 (1H, m), 3.47 (1H, d,
J = 7.6 Hz), 3.69 (2H, s), 4.82 (1H, d, J = 10.0 Hz), 5.21 (1H, q,
J = 6.8 Hz), 7.48–7.52 (2H, m), 7.57–7.61 (1H, m), 7.81–7.83 (2H,
m). 13C NMR (CDCl3): d ꢀ5.0, ꢀ4.7, 11.0, 12.9, 15.7, 17.4, 18.1,
25.8 (3C), 37.4, 44.5, 83.1, 121.0, 126.0, 128.6 (2C), 129.4, 130.4
(2C), 133.5, 136.9, 137.1.HRMS (FAB) (m/z): calcd for C23H39O3SSi
(M++1): 423.2389, found:423.2366.
References
4.22. (+)-Piericidin A1
1
1. Takahashi, N.; Suzuki, A.; Tamura, S. J. Am. Chem. Soc. 1965, 87, 2066–2068.
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(1) To a solution of (4R,5R)-33 (0.110 g, 0.26 mmol) in THF
(5 mL) at ꢀ20 °C under argon atmosphere was added n-BuLi
(2.6 M in n-hexane, 0.22 mL, 0.57 mmol) and the reaction mixture
was stirred for 1 h at the same temperature. A solution of 3
(0.105 g, 0.39 mmol) in THF (1 mL) was added to the above reac-
tion mixture at ꢀ78 °C under argon atmosphere and the reaction
mixture was stirred for 12 h at the same temperature. The mixture
was diluted with 10% aqueous NH4Cl and extracted with EtOAc.
The organic layer was washed with brine and dried over MgSO4.
3. (a) Ono, M.; Yoshida, N.; Kokubu, Y.; Sato, E.; Akita, H. Chem. Pharm. Bull. 1997,
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1745–1759.
4. (a) Schnermann, M. J.; Boger, D. L. J. Am. Chem. Soc. 2005, 127, 15704–15705; (b)
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7. Chen, C.-S.; Sih, C. J. Angew. Chem., Int. Ed. Engl. 1989, 28, 695–707.
8. Cox, C. M.; Whiting, D. A. J. Chem. Soc., Perkin Trans 1 1991, 1901–1905.