Determination of the absolute structure of (+)-akaterpin

Article abstract of DOI:10.1248/cpb.60.137

We describe the total synthesis and structural determination of (+)-akaterpin (1), an inhibitor of phosphatidylinositol- specific phospholipase C (PI-PLC). The key features of the synthetic strategy include the resolution of β,γ-unsaturated ketone (±)-2a with chiral sulfoximine 6. The absolute stereochemistry was determined by comparison of the specific optical rotation data of (+)-1 and (-)-1 with that of natural akaterpin.

Full text of DOI:10.1248/cpb.60.137

—
January 2012
Regular Article
Chem. Pharm. Bull. 60(1) 137 143 (2012)
137
Determination of the Absolute Structure of (+)-Akaterpin
Hayato Hosoi,a Nobuyuki Kawai,a Hideki Hagiwara,a Takahiro Suzuki,a Atsuo Nakazaki,a
,a
Ken-ichi Takao,a Kazuo Umezawa,b and Susumu Kobayashi*
a Faculty of Pharmaceutical Sciences, Tokyo University of Science (RIKADAI); 2641 Yamazaki, Noda, Chiba 278–
8510, Japan: and b Department of Applied Chemistry, Faculty of Science and Technology, Keio University; 3–14–1
Hiyoshi, Kohoku-ku, Yokohama 223–8522, Japan.
Received October 10, 2011; accepted October 22, 2011; published online October 26, 2011
We describe the total synthesis and structural determination of (+)-akaterpin (1), an inhibitor of phos-
phatidylinositol-specific phospholipase C (PI-PLC). The key features of the synthetic strategy include the res-
olution of β,γ-unsaturated ketone (ꢀ)-2a with chiral sulfoximine 6. The absolute stereochemistry was deter-
mined by comparison of the specific optical rotation data of (+)-1 and (ꢁ)-1 with that of natural akaterpin.
Key words total synthesis; absolute stereochemistry; optical resolution
Umezawa and co-workers originally isolated akaterpin (1)
In this regard, we previously reported the successful reso-
from the marine sponge Callyspongia sp. as an inhibitor of lution of methyl-protected 2b by using chiral sulfoximine 6,
phosphatidylinositol-specific phospholipase C (PI-PLC).1) PI- which was developed by Johnson.5,6) The absolute stereo-
PLC triggers phosphatidylinositol turnover by hydrolyzing chemistry of both enantiomers of 2b was then established by
phosphatidylinositol 4,5-bisphosphate (PIP2) into diacylglycer- X-ray crystallographic analysis of 7b and 9b7) (Chart 2). We
ol (DG) and 1,4,5-trisphosphate (IP3). Thus, a specific PI-PLC envisaged the resolution of benzyl-protected 2a, the synthetic
inhibitor is considered a promising anti-tumor candidate and intermediate of racemic akaterpin,8) would also be possible as
a valuable tool for the investigation of signal transduction.2,3) 2b. Thus, both enantiomers of akaterpin could be synthesized
Until recently the precise structure of akaterpin had not been
determined because of difficulties in isolating this compound
from the natural source. We have been investigating a synthet-
ic study of akaterpin and recently reported the relative stereo-
chemistry of the compound by synthesizing possible isomers
in racemic form and comparing the corresponding spectral
data with those of the authentic natural product.4) Herein we
describe the determination of the absolute stereochemistry of
(+)-akaterpin. Our approach was to synthesize optically active
akaterpin by resolution of the key intermediate in the racemic
synthesis. We reasoned that β,γ-unsaturated ketone 2a was
suitable for this purpose. Having resolved the key intermedi-
ate 2a, each enantiomer was then separately transformed to
akaterpin following the same synthetic procedure as used for
Fig. 1. Relative Stereochemistry of Akaterpin 1
the racemate.
Chart 1. Synthetic Route of Akaterpin 1
*To whom correspondence should be addressed. e-mail: kobaysh@rs.noda.tus.ac.jp
© 2012 The Pharmaceutical Society of Japan

138
Vol. 60, No. 1
Chart 2. Addition of Chiral Sulfoximine (S)-(+)-6 to β,γ-Unsaturated Ketone 2
Chart 3. Thermal Elimination of Sulfoximine (S)-(+)-6 Affording (+)-2a and (−)-2a
Chart 4. Conversion of (−)-2a to Previously Established Enantiomer (+)-2b
from 2a after resolution.
none 11 and subsequent pyridinium chlorochromate (PCC)
Our synthesis commenced with the addition of the lithio oxidation of alcohol 12 afforded the known methyl-protected
derivative of (S)-(+)-6 to the ketone ( )-2a. The resulting ketone (+)-2b for which absolute stereochemistry had already
—
four diastereomers 7a 10a were separated by flash column been established (Chart 4). HPLC analysis using a chiral col-
chromatography. The stereochemistry of each isomer was not umn (DAICEL Chiralpak AD, Hexane/i-PrOH=9/1, 254nm,
established because these adducts were unsuitable for X-ray 0.5mL/min: tR of (+)-2b, 12.5min, tR of (−)-2b, 19.9min)
crystallographic analysis. Consequently, the stereochemistry gave results that were consistent with the determined absolute
—
of the four diastereomers 7a 10a was tentatively estimated stereochemistry.
by comparing the yield and chromatographic behavior (TLC) After completion of the resolution of key intermediate 2a,
—
of 7b 10b whose absolute stereochemistry were unambigu- both enantiomers of 2a were transformed to akaterpin by the
ously determined.7) Then, thermal elimination of each isomer same synthetic route as described previously.4) First, deproto-
7a and 8a was carried out. As anticipated 7a and 8a afforded nation of ketone (+)-2a with sodium bis(trimethylsilyl) amide
°
the same isomer (+)-2a upon heating at 120 C in toluene, (NaHMDS) generated the corresponding dienolate anion, and
while 9a and 10a gave (−)-2a (Chart 3). The absolute stereo- subsequent attack by iodoacetate from the α-face occurred
chemistry of (−)-2a was established by converting (−)-2a to with complete regio- and stereoselectivity to afford cis-decalin
methyl ether (+)-2b. Thus, after removal of the benzyl group (−)-13 as a single isomer (Chart 5). Hydrogenation of (−)-13
—
11)
9
’
of (−)-2a, methylation of the hydroxyl group of hydroqui- with Crabtree s catalyst
afforded (−)-14 in quantitative

January 2012
139
Chart 5. Synthesis of Dienophile (−)-3 and Intermolecular Diels–Alder
Reaction with Diene 4
(c=0.43, MeOH)).
Comparison of the specific optical rotation data for each
enantiomer with that of the natural akaterpin ([α]D24 +15
°
(c=0.59, MeOH))1) unambiguously demonstrates that the abso-
lute structure of akaterpin is (+)-1.
In conclusion, we were able to establish the absolute stereo-
chemistry of akaterpin.
Fig. 2. HPLC Comparison of ( )-2b and (+)-2b
yield. After conversion of ester (−)-14 to Weinreb amide,12,13)
addition of butenyllithium to amide provided the dienophile
Experimental
All non-aqueous reactions were performed under an atmo-
(−)-3. The intermolecular Diels–Alder reaction of enone (−)- sphere of dry argon in oven-dried glassware unless otherwise
3 and vinylcyclohexene 414,15) proceeded to give exo-adducts indicated. Solvents were distilled under an atmosphere of
(+)-5 and undesired (−)-15 as a separable mixture.
argon before use and transferred via an oven-dried syringe
Next, deoxygenation of the ketone at C11 and exo-meth- or cannula. Dichloromethane, toluene, acetonitrile (MeCN),
ylenation at the C10′ were conducted (Chart 6). After the triethylamine, diisopropylethylamine, N,N-dimethylformamide
reduction of (+)-5 with LiAlH4 to obtain the diol as a single (DMF), and pyridine were distilled from calcium hydride. Dry
isomer, the treatment of the diol with methoxymethyl chloride tetrahydrofuran (41001-85) and diethyl ether (14547-95) were
(MOMCl) selectively afforded mono-MOM ether (+)-16. The purchased from KANTO Chemical Industries Ltd. (Japan) in
hydroxyl group of (+)-16 was then removed by following anhydrous Grade.
the Barton–McCombie deoxygenation protocol16,17) to give
Flash column chromatography was performed with silica
MOM ether (+)-17. Cleavage of MOM ether by treatment with gel (PSQ-100B, Fuji Silysia Co., Ltd., Japan). Solvents for
—
20)
B-bromocatecholborane18
and subsequent tetra-n-propyl- chromatography are listed as volume/volume ratios. Analytical
ammonium perruthenate (TPAP) oxidation21) provided ketone thin layer chromatography was performed using commercial
(+)-18. Introduction of the exomethylene group at the C10′ silica gel plates (E. Merck, Silica Gel 60 F254).
position was accomplished by using Takai and Utimoto condi-
Infrared spectra were recorded on a PerkinElmer Spectrum
tion22,23) to give (+)-19 albeit in a moderate yield. Finally, re- 100 FTIR spectrometer. Absorbance frequencies are recorded
moval of the benzyl group of (+)-19 with Li naphthalenide24,25) in reciprocal centimeters (cm−1). High resolution mass spec-
and subsequent treatment of the resulting hydroquinone with tra (HR-MS) were obtained from Applied Biosystems mass
—
26 28)
°
SO3·Py at 80 C in pyridine
completed the synthesis of spectrometer (API QSTAR pulsar i) for electrospray ionization
°
the target compound (+)-1 ([α]D23 +17.2 (c=0.43, MeOH)). (ESI), or from Hitachi M-80B for electroimpact ionization (EI,
Employment of the same synthetic sequence to the ketone 70eV). HR-MS data are reported as m/z (relative intensity),
(−)-2a provided another target compound (−)-1 ([α]D23 −19.8
with accurate mass reported for the molecular ion [M+Na]+.
°

140
Vol. 60, No. 1
by column chromatography on silica gel (hexane/AcOEt=10/1
to 8/1 to 6/1 to 3/1) and PTLC (hexane/AcOEt=3/1) to afford
7a (119mg, 44% yield) as a white amorphous, 8a (11.6mg,
4% yield) as a white amorphous, 9a (64.7mg, 24% yield) as
a white amorphous, and 10a (61.0mg, 23% yield) as a white
amorphous.
7a: Rf 0.32 (hexane/AcOEt=3/1); [α]D23 +51.6 (c=1.39,
°
CHCl3); IR (neat) cm−1: 3274, 3028, 2940, 2805, 1736, 1606,
1585, 1494; 1H-NMR (400MHz, CDCl3) δ: 0.69 (s, 3H),
—
—
0.92 1.05 (m, 1H), 1.15 (d, J=6.8Hz, 3H), 1.58 1.92 (m,
5H), 1.98 (d, J=12.2Hz, 1H), 2.08 (t, J=12.5Hz, 1H), 2.39 (d,
J=13.8Hz, 1H), 2.60 (s, 3H), 2.78 (d, J=13.2Hz, 1H), 2.89 (d,
J=13.8Hz, 1H), 3.20 (d, J=13.7Hz, 1H), 3.75 (d, J=13.7Hz,
1H), 5.00 (s, 2H), 5.01 (s, 2H), 5.36 (d, J=10.2Hz, 1H),
—
5.67 5.78 (m, 1H), 6.31 (s, 1H), 6.76 (dd, J=2.9, 8.8Hz, 1H),
—
6.83 (d, J=8.8Hz, 1H), 6.96 (d, J=2.9Hz, 1H), 7.28 7.47 (m,
10H), 7.54 7.66 (m, 3H), 7.88 (d, J=6.8Hz, 2H); 13C-NMR
—
(100MHz, CDCl3) δ: 17.5, 17.8, 21.9, 25.4, 28.8, 32.0, 35.6,
36.8, 37.7, 38.8, 49.3, 64.2, 70.5, 70.8, 74.3, 112.1, 112.9, 118.1,
121.6, 127.0, 127.4, 127.6, 127.7, 128.3, 128.4, 128.9, 129.5,
130.2, 133.0, 135.7, 137.3, 137.6, 139.1, 152.0, 152.4; HR-ESI-
MS m/z: 672.3124 (Calcd for C41H47NO4NaS: 672.3118).
8a: Rf 0.44 (hexane/AcOEt=3/1); [α]D23 +50.4 (c=1.80,
°
CHCl3); IR (neat) cm−1: 3028, 2932, 2873, 1585, 1496, 1453,
1379, 1217, 1144, 1080, 1026; 1H-NMR (400MHz, CDCl3)
—
δ: 0.70 (s, 3H), 0.85 0.95 (m, 1H), 1.00 (d, J=6.8Hz, 3H),
—
1.19 1.37 (m, 2H), 1.47 (d, J=14.2Hz, 1H), 1.59 (s, 1H), 1.73
(d, J=12.2Hz, 1H), 1.81 (t, J=6.6Hz, 1H), 1.94 (d, J=11.2Hz,
1H), 2.19 (d, J=13.2Hz, 1H), 2.25 (d, J=13.8Hz, 1H), 2.76 (s,
3H), 3.07 (d, J=13.8Hz, 1H), 3.29 (d, J=14.7Hz, 1H), 3.51
—
(d, J=14.7Hz, 1H), 4.97 (s, 2H), 5.00 (s, 2H), 5.66 5.72 (m,
1H), 5.75 (d, J=11.2Hz, 1H), 6.25 (brs, 1H), 6.76 (dd, J=2.9,
8.8Hz, 1H), 6.81 (d, J=8.8Hz, 1H), 6.90 (d, J=2.9Hz, 1H),
—
—
7.27 7.45 (m, 10H), 7.54 7.66 (m, 3H), 7.89 (d, J=6.8Hz,
2H); 13C-NMR (100MHz, CDCl3) δ: 17.3, 18.0, 22.9, 24.9,
29.3, 32.1, 37.48, 37.53, 37.7, 38.9, 50.9, 58.8, 70.6, 70.8,
72.8, 112.3, 112.9, 118.1, 122.1, 127.1, 127.4, 127.6, 127.8,
128.4, 128.5, 129.0, 129.5, 129.8, 133.0, 135.0, 137.3, 137.6,
Chart 6. Synthesis of (+)-1
Melting points were recorded on Yanaco MP-3S.
1H-NMR spectra were acquired at 400MHz on a JEOL 139.9, 151.9, 152.4; HR-ESI-MS m/z: 672.3126 (Calcd for
JNM-LD400 spectrometer or 500MHz on a JNM-ECP500 C41H47NO4NaS: 672.3118).
°
spectrometer. Chemical shifts are reported in delta (δ) units
9a: Rf 0.53 (hexane/AcOEt=3/1); [α]D23 −41.3 (c=0.98,
in parts per million (ppm) relative to the singlet (7.26ppm) CHCl3); IR (neat) cm−1: 3270, 3029, 2935, 2872, 2365, 1736,
1
for chloroform-d or the quartet (3.30ppm) for methanol-d4. 1497, 1455, 1376, 1217; H-NMR (400MHz, CDCl3) δ: 0.74
Splitting patterns are designated as s, singlet; d, doublet; t, (s, 3H), 0.90 (d, J=7.1Hz, 3H), 1.05 (td, J=3.3, 12.3Hz,
—
triplet; q, quartet; sept, septet; m, multiplet and br, broad. 1H), 1.17 1.95 (m, 7H), 2.02 (d, J=11.0Hz, 1H), 2.27
Coupling constants are recorded in Hertz (Hz). 13C-NMR (d, J=13.9Hz, 1H), 2.60 (s, 3H), 2.92 (d, J=13.0Hz, 1H),
spectra were acquired at 100MHz on a JEOL JNM-LD400 3.16 (d, J=13.9Hz, 1H), 3.21 (d, J=14.2Hz, 1H), 3.24 (d,
—
—
spectrometer or 125MHz on a JNM-ECP500 spectrometer. J=14.2Hz, 1H), 4.94 5.06 (m, 4H), 5.58 5.68 (m, 1H),
Chemical shifts are reported in ppm relative to the central line 5.78 (d, J=10.0Hz, 1H), 6.75 (dd, J=2.9, 8.8Hz, 1H), 6.82
—
of the triplet at 77.0ppm for chloroform-d or the double quar- (d, J=8.8Hz, 1H), 6.89 (d, J=2.9Hz, 1H), 7.27 7.46 (m,
—
tet at 49.0ppm for methanol-d4.
10H), 7.57 7.68 (m, 3H), 7.89 (d, J=7.1Hz, 2H); 13C-NMR
—
Alcohol 7a 10a To a solution of (S)-(+)-N,S-dimethyl- (100MHz, CDCl3) δ: 17.3, 18.1, 23.7, 25.1, 28.9, 32.1, 37.7,
S-phenylsulfoximine 6 (244mg, 1.44mmol) in tetrahydrofu- 37.8, 38.0, 38.9, 50.5, 57.7, 70.6, 70.9, 74.7, 112.1, 112.9, 118.1,
ran (THF) (12.0mL) was added n-BuLi 1.63M in n-hexane 112.3, 127.1, 127.4, 127.6, 127.8, 128.4, 128.5, 129.0, 129.6,
°
(834µL, 1.36mmol) at 0 C. After stirring for 30min, a solu- 129.9, 133.1, 134.6, 137.3, 137.6, 138.9, 152.0, 152.4; HR-ESI-
tion of ketone ( )-2a (198mg, 0.412mmol) in THF (9.0mL) MS m/z: 672.3112 (Calcd for C41H47NO4NaS: 672.3118).
10a: Rf 0.15 (hexane/AcOEt=3/1); [α]D24 +10.8 (c=1.46,
°
°
°
was added at −78 C. After stirring for 1h at −78 C, the
reaction was quenched with a saturated aqueous solution of CHCl3); IR (neat) cm−1: 3450, 3021, 2960, 2934, 2797, 1604,
NH4Cl. The mixture was extracted with Et2O. The combined 1500, 1453, 1385, 1225, 1131; 1H-NMR (400MHz, CDCl3)
—
organic layer was washed with brine, dried over Na2SO4, δ: 0.69 (s, 3H), 0.82 0.97 (m, 1H), 1.11 (d, J=6.8Hz, 3H),
—
filtered, and concentrated in vacuo. The residue was purified 1.29 (td, J=4.6, 13.3Hz, 1H), 1.57 2.04 (m, 6H), 2.31 (d,

January 2012
141
J=13.7Hz, 1H), 2.36 (d, J=13.9Hz, 1H), 2.72 (s, 3H), 3.16 (d, (5.7mg, 40% yield) as a red oil.
J=13.9Hz, 1H), 3.29 (d, J=14.3Hz, 1H), 3.70 (d, J=14.3Hz,
To a suspension of PCC (9.0mg, 0.042mmol) and dried MS-
1H) 4.85 (brs, 1H), 4.98 (s, 2H), 5.01 (s, 2H), 5.50 (d, 3A powder (15.2mg) in CH2Cl2 (0.3mL) was added 12 (5.7mg,
—
J=10.2Hz, 1H), 5.71 5.78 (m, 1H), 6.75 (dd, J=2.9, 8.8Hz, 0.017mmol) in CH2Cl2 (0.3mL). This reaction mixture was
—
1H), 6.82 (d, J=8.8Hz, 1H), 6.94 (d, J=2.9Hz, 1H), 7.27
stirred for 1h at room temperature, diluted with the addition
—
7.45 (m, 10H), 7.53 7.64 (m, 3H), 7.86 (d, J=6.8Hz, 2H); of ether, and filtered through a short column of florisil. The
13C-NMR (100MHz, CDCl3) δ: 17.5, 17.8, 21.8, 25.2, 29.4, residue was concentrated in vacuo. The residue was purified
32.1, 35.9, 37.5, 37.7, 38.8, 48.6, 65.4, 70.5, 70.8, 73.4, 112.2, by column chromatography on silica gel (hexane/Et2O=3/1) to
112.9, 118.1, 121.5, 127.0, 127.4, 127.6, 127.8, 128.3, 128.5, afford ketone (+)-2b (3.2mg, 57% yield) as a white solid.
°
128.8, 129.4, 130.1, 132.8, 136.1, 137.3, 137.7, 140.5, 152.0,
(+)-2b: [α]D23 −3.8 (c=0.10, CHCl3); the other structural
152.4; HR-ESI-MS m/z: 672.3112 (Calcd for C41H47NO4NaS: data of (+)-2b was described in ref. 7.
672.3118). Ketoester (−)-13 To solution of (+)-2a (538mg,
Ketone (+)-2a A solution of 7a (20.9mg, 0.032mmol) 1.12mmol) in THF (28mL) was added NaN[Si(CH3)3]2 1.0M
a
°
°
in deoxygenated toluene (2.1mL) was heated 120 C in a solution in THF (1.23mL 1.23mmol) at 0 C. After stirring for
°
sealed tube for 5h, cooled, and concentrated. The residue was 20min at 0 C, ICH2CO2Et (0.37mL, 3.14mmol) was added at
°
°
purified by column chromatography on silica gel (hexane/ −78 C. After stirring overnight at −78 C, the reaction was
AcOEt=15/1) to afford ketone (+)-2a (15.5mg, 100% yield) as quenched with H2O. The mixture was extracted with AcOEt.
a white solid.
The combined organic layer was washed with brine, dried
A solution of 8a (13.8mg, 0.021mmol) in deoxygenated over Na2SO4, filtered, and concentrated in vacuo. The residue
°
toluene (1.4mL) was heated 120 C in a sealed tube for 5.5h, was purified by column chromatography on silica gel (hexane/
cooled, and concentrated. The residue was purified by column AcOEt=15/1) to afford ketoester (−)-13 (498mg, 80% yield) as
chromatography on silica gel (hexane/AcOEt=15/1) to afford a white solid.
(−)-13: [α]D23 −62.3 (c=1.55, CHCl3); the other structural
°
ketone (+)-2a (8.9mg, 87% yield) as a white solid.
(+)-2a: [α]D23 +0.7 (c=1.63, CHCl3); HPLC condition: data of (−)-13 were described in ref. 4.
°
(DAICEL Chiralpak AD-H, hexane/i-PrOH=9/1, 254nm,
Reduced Product (−)-14 To a solution of (−)-13 (85.2mg,
0.5mL/min, 99% ee (tR=32.0min)); the other structural data 0.153mmol) in CH2Cl2 (6.0mL) was added [Ir(cod)(PCy3)Py]
of (+)-2a were described in ref. 4.
PF6 (2.2mg, 2.75µmol). After stirring for 2d under H2 at room
Ketone (−)-2a A solution of 9a (15.0mg, 0.023mmol) in temperature, the solution was passed through a celite plug,
°
deoxygenated toluene (1.5mL) was heated 120 C in a sealed eluting with AcOEt, and concentrated in vacuo. The residue
tube for 7.5h, cooled, and concentrated. The residue was was purified by column chromatography on silica gel (hexane/
purified by column chromatography on silica gel (hexane/ AcOEt=5/1) to afford reduced product (−)-14 (86.8mg, quanti-
AcOEt=15/1) to afford ketone (−)-2a (10.0mg, 90% yield) as tative yield) as a white solid.
°
a white solid.
(−)-14: [α]D23 −18.8 (c=1.05, CHCl3); the other structural
A solution of 10a (14.7mg, 0.023mmol) in deoxygenated data of (−)-14 were described in ref. 4.
toluene (1.5mL) was heated 120 C in a sealed tube for 4.5h,
°
Diketone (−)-3 To
a
solution of N,O-dimethyl-
cooled, and concentrated. The residue was purified by column hydroxylamine (96.8mg, 0.993mmol) in CH2Cl2 (1.3mL) was
chromatography on silica gel (hexane/AcOEt=15/1) to afford slowly added trimethylaluminum 1.08M solution in hexane
° °
(1.02mL, 1.10mmol) at 0 C. After stirring for 30min at 0 C,
ketone (−)-2a (8.9mg, 99% yield) as a white solid.
(−)-2a: [α]D23 −0.8 (c=1.35, CHCl3); HPLC (DAISEL a solution of (−)-14 (86.8mg, 0.153mmol) in CH2Cl2 (1.3mL)
°
°
°
Chiralpak AD-H, hexane/i-PrOH=9/1, 254nm, 0.5mL/min) was added dropwise at 0 C. After stirring for 1h at 0 C, the
99% ee (tR=23.8min); the other structural data of (−)-2a were reaction was quenched with H2O. The mixture was extracted
described in ref. 4.
with AcOEt. The combined organic layer was washed with
Ketone (+)-2b To liquid NH3 (28mL) was added sodium brine, dried over Na2SO4, filtered, and concentrated in vacuo.
°
(72mg, 3.12mmol) at −78 C. After stirring for 10min, a solu- The residue was purified by column chromatography on silica
tion of a solution of ketone (−)-2a (83.9mg, 0.175mmol) in gel (hexane/AcOEt=2/1) to afford Weinreb amide (84.3mg,
°
THF (4.4mL) was added at −78 C. After stirring for 1.5h at 94% yield) as a white solid.
°
−78 C, the reaction was quenched with a saturated aqueous
To a solution of (E)-2-bromobutene (297mg, 2.20mmol) in
solution of NH4Cl. The mixture was extracted with AcOEt. Et2O (1.0mL) was slowly dropped t-BuLi 1.55M in n-pentane
°
The combined organic layer was washed with brine, dried (2.72mL, 4.22mmol) at −78 C, then THF (2.0mL) was added.
over Na2SO4, filtered, and concentrated in vacuo. The residue After stirring for 40min, a solution of Weinreb amide (214mg,
was purified by column chromatography on silica gel (hexane/ 0.367mmol) in THF (1.0mL) was slowly added dropwise.
AcOEt=3/2) to afford debenzyl compound 11 (21.3mg, 40% After 1.5h, the reaction was quenched with MeOH, then 1:1
yield) as a red oil.
mixture of THF and a saturated aqueous solution of NH4Cl.
To solution of debenzyl compound 11 (21.3mg, The mixture was extracted with AcOEt. The combined or-
a
0.070mmol) in DMF was added methyl iodide (13µL, ganic layer was washed with brine, dried over Na2SO4, fil-
0.211mmol) and potassium carbonate (59.9mg, 0.433mmol). tered, and concentrated in vacuo. The residue was purified by
°
After stirring for 4h at room temperature and for 22h at 40 C, column chromatography on silica gel (hexane/AcOEt=8/1 to
the reaction was extracted with AcOEt. The combined organic 6/1 to 3/1) to afford diketone (−)-3 (107mg, 51% yield (82%
layer was dried over Na2SO4, filtered, and concentrated in brsm)) as a white solid, along with the recovered Weinreb
vacuo. The residue was purified by column chromatography amide (81mg, 38%).
°
on silica gel (hexane/AcOEt=10/1) to afford methyl ether 12
(−)-3: [α]D23 −41.0 (c=1.09, CHCl3); the other structural

142
Vol. 60, No. 1
data of (−)-3 were described in ref. 4.
Cycloadduct (+)-5 and (−)-15 To a suspension of dried
amorphous.
(+)-17: White amorphous; [α]D23 +31.0 (c=0.92, CHCl3);
°
ZnCl2 (109mg, 0.80mmol) in CH2Cl2 (4.6mL) was added the other structural data of (+)-17 were described in ref. 4.
vinylcyclohexene 4 (101mg, 0.743mmol) and a solution of Ketone (+)-18 To solution of (+)-17 (25.9mg,
(−)-3 (107mg, 0.186mmol) in CH2Cl2 (7.8mL) was slowly 0.035mmol) in CH2Cl2 (8.7mL) was added bromocathe-
a
°
added at 0 C. After stirring overnight at room temperature, colborane 0.2M solution in CH2Cl2 (226µL, 0.045mmol)
°
the reaction was quenched with a saturated aqueous solu- dropwise at −78 C. After stirring for 1h, the reaction was
tion of NH4Cl. The mixture was extracted with CH2Cl2. The quenched with a saturated aqueous solution of NaHCO3 and
combined organic layer was washed with brine, dried over 0.2M aqueous solution of NaOH. The mixture was extracted
Na2SO4, filtered, and concentrated in vacuo. The residue was with CH2Cl2. The combined organic layer was washed with a
purified by column chromatography on silica gel (hexane/ 0.2M aqueous solution of NaOH and H2O, dried over Na2SO4,
diisopropyl ether=20/1 to 15/1 to 10/1) to afford major product filtered, and concentrated in vacuo. The residue was purified
(+)-5 (103mg, 78% yield) as a white solid and minor product by column chromatography on silica gel (hexane/AcOEt=40/1
(−)-15 (15.9mg, 12% yield) as a white solid.
to 30/1) to afford alcohol (11.9mg, 49% yield (brsm 92%)) as
a white amorphous, along with the recovered (+)-17 (12.2mg,
23
(+)-5: [α]D23 +2.5 (c=0.65, CHCl3); (−)-15: [α]D −25.9
°
°
(c=1.19, CHCl3); the other structural data of (+)-5 and (−)-15 47%).
were described in ref. 4.
To a solution of alcohol (17.7mg, 0.025mmol) in CH3CN
MOM Ether (+)-16 To a suspension of lithium aluminum (1.6mL), dry MS 3A (63.6mg) was added N-methylmorpholine
hydride (85.2mg, 2.25mmol) in Et2O (16mL) was added a oxide (4.4mg, 0.038mmol), and tetra-n-propylammonium
°
solution of (+)-5 (292mg, 0.408mmol) in Et2O (17mL) at 0 C. perruthenate (2.7mg, 0.008mmol). After stirring for 6h at
After stirring for 15min, the reaction was quenched with H2O room temperature, the reaction was quenched with a saturated
and a saturated aqueous solution of NaHCO3. The mixture aqueous solution of NaHCO3. The mixture was filtered on
was extracted with AcOEt. The combined organic layer was florisil and silica gel, and concentrated in vacuo. The residue
washed with brine, dried over Na2SO4, filtered, and concen- was purified by column chromatography on silica gel (hexane/
trated in vacuo. The residue was purified by column chro- AcOEt=30/1) to afford ketone (+)-18 (17.6mg, quantitative
matography on silica gel (hexane/AcOEt=8/1 to 6/1) to afford yield) as a white amorphous.
(+)-18: [α]D23 +29.8 (c=1.48, CHCl3); the other structural
°
alcohol (248mg, 85% yield) as a white amorphous.
To a solution of alcohol (248mg, 0.345mmol) in CH2Cl2 data of (+)-18 were described in ref. 4.
(34.5mL) were added i-Pr2NEt (2.1mL, 12.1mmol), NaH
(30.1mg, 0.690mmol, 55%), and MOMCl (210µL, 2.76mmol) 13.6mmol) and lead chloride (33.6mg, 0.120mmol) in THF
Exo-methylene (+)-19 To a suspension of zinc (889mg,
°
in order at 0 C. After stirring overnight at room temperature, (6.9mL) was added CH2I2 (610µL, 7.57mmol). After stir-
the reaction was quenched with a saturated aqueous solution ring for 30min, lead chloride (33.6mg, 0.120mmol) was add
of NaHCO3. The mixture was extracted with CH2Cl2. The again. After stirring for 30min, TiCl4 1.0M solution in CH2Cl2
°
combined organic layer was dried over Na2SO4, filtered, and (1.66mL, 1.66mmol) was slowly added to the mixture at 0 C.
concentrated in vacuo. The residue was purified by column After warming up to room temperature, the resulting mixture
chromatography on silica gel (hexane/AcOEt=8/1) to afford was stirred for 1h to afford a solution of CH2l2–Zn–TiCl4
(+)-16 (233mg, 88% yield) as a white amorphous.
reagent.
To a solution of (+)-18 (29.2mg, 0.042mmol) in THF
°
(270µL) was added the CH2l2–Zn–TiCl4 reagent at 0 C. After
(+)-16: [α]D23 +18.9 (c=0.62, CHCl3); the other structural
°
data of (+)-16 were described in ref. 4.
MOM Ether (+)-17 To a solution of (+)-16 (64.3mg, stirring for 4d at room temperature, Et3N (2.6mL) was added
°
0.0841mmol) in THF (6.2mL) was slowly added n-butyl in one portion to the reaction mixture at 0 C and the solution
lithium 1.42M solution in hexane (83µL, 0.126mmol) at was stirred for 20min at room temperature. The solution was
°
0 C. After stirring for 20min, Carbon disulfide (152µL, passed through a celite plug, eluting with AcOEt, and concen-
°
2.52mmol) was added at 0 C. After stirring for 5min, methyl trated in vacuo. The residue was purified by column chroma-
°
iodide (79µL, 1.26mmol) was added at 0 C. After stirring for tography on silica gel (hexane/AcOEt=35/1 to 25/1) and PTLC
30min, the reaction was quenched with a saturated aqueous (hexane/AcOEt=10/1) to afford (+)-19 (9.7mg, 33% yield (54%
solution of NaHCO3. The mixture was extracted with Et2O. brsm)) as a white amorphous, along with the recovered (+)-18
The combined organic layer was washed with brine, dried (11.2mg, 38%).
°
over Na2SO4, filtered, and concentrated in vacuo. The residue
(+)-19: [α]D23 +27.2 (c=0.64, CHCl3); the other structural
was purified by column chromatography on silica gel (hexane/ data of (+)-19 were described in ref. 4.
AcOEt=8/1) to afford xanthate (127mg, 91% yield) as a white
amorphous.
Disulfate (+)-1 To a solution of naphthalene (513mg,
4.0mmol) in THF (10mL) was added lithium (28mg,
To a solution of xanthate (58.3mg, 0.068mmol) in toluene 4.03mmol) at room temperature. The mixture was stirred at
(2.4mL) was added tributyltin hydride (74µL, 0.273mmol) that temperature for 2h to afford a solution of lithium naph-
and azobisisobutyronitrile (22.4mg, 0.137mmol). After stir- thalenide.
°
ring for 30min at 90 C, the reaction was quenched with
A portion of the solution of lithium naphthalenide (550µL,
H2O. The mixture was extracted with AcOEt. The combined 0.220mmol, 0.4M in THF) was added dropwise to a solution
°
organic layer was washed with brine, dried over Na2SO4, of (+)-19 (9.7mg, 0.014mmol) in THF (400µL) at −20 C.
filtered, and concentrated in vacuo. The residue was purified After stirring for 1h, the reaction was quenched with a satu-
by column chromatography on silica gel (hexane/AcOEt=15/1) rated aqueous solution of NH4Cl. The mixture was extracted
to afford MOM ether (+)-17 (31.9mg, 63% yield) as a white with Et2O. The combined organic layer was washed with

January 2012
143
7) Kawai N., Fujibayashi Y., Kuwabara S., Takao K., Ijuin Y.,
brine, dried over Na2SO4, filtered, and concentrated in vacuo.
The residue was purified by column chromatography on silica
gel (hexane/AcOEt=10/1 to 6/1 to 5/1) to afford debenzyl com-
pound (6.0mg) as a yellow oil.
To a suspension of debenzyl compound (6.0mg) in pyri-
dine (260µL) was added SO3·Py (18.4mg, 0.116mmol) and
—
Kobayashi S., Tetrahedron, 56, 6467 6478 (2000).
8) The synthesis of akaterpin 1 from the methyl-protected intermediate
failed. So, we used the benzyl-protected intermediate 2a.
—
9) Crabtree R. H., Davis M., J. Org. Chem., 51, 2655 2661 (1986).
10) Suggs J. W., Cox S. D., Crabtree R. H., Quirk J. M., Tetrahedron
—
Lett., 22, 303 306 (1981).
°
the reaction mixture was heated to 80 C for 4h. The reaction
—
11) Crabtree R. H., Morris G. E., J. Organomet. Chem., 135, 395 403
°
mixture was cooled to 0 C, and a saturated aqueous solution
(1977).
—
12) Basha A., Lipton M., Weinreb S. M., Tetrahedron Lett., 18, 4171
of Na2CO3 (1.5mL) was added dropwise. After stirring for
10min, the mixture was concentrated in vacuo. The residue
was purified by column chromatography on silica gel (CHCl3/
CH3OH=5/1 to 2/1) to afford disulfate (+)-1 (6.4mg, 64%
yield for the 2 steps) as a white amorphous.
4174 (1977).
—
13) Nahm S., Weinreb S. M., Tetrahedron Lett., 22, 3815 3818 (1981).
14) Taeyoung Y., Danishefsky S. J., de Gala S., Angew. Chem. Int. Ed.,
—
33, 853 855 (1994).
—
15) Jung M. E., Lui R. M., J. Org. Chem., 75, 7146 7158 (2010).
(+)-1: [α]D23 +17.2 (c=0.43, MeOH); The other structural
°
16) Barton D. H. R., McCombie S. W., J. Chem. Soc., Perkin Trans. 1,
data of (+)-1 were described in ref. 4.
—
1975, 1574 1585 (1975).
—
17) Crich D., Quintero L., Chem. Rev., 89, 1413 1432 (1989).
18) Boeckman R. K. Jr., Potenza J. C., Tetrahedron Lett., 26, 1411
1414 (1985).
Acknowledgments This research was supported in part
by a Grant-in-Aid for Scientific Research (B) (KAKENHI
No. 22390004) from the Japan Society for the Promotion of
Science.
—
19) Paquette L. A., Gao Z., Ni Z., Smith G. F., J. Am. Chem. Soc., 120,
—
2543 2552 (1998).
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—
Soc., 119, 8438 8450 (1997).
References and Notes
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