Total synthesis of pederin, a potent insect toxin: The efficient synthesis of the right half, (+)-benzoylpedamide

Article abstract of DOI:10.1016/S0040-4020(02)00635-X

A simple and efficient synthesis of (+)-benzoylpedamide, the right half of pederin, was achieved in 16 steps with a 35% overall yield from (S)-malic acid. The key steps include the SmI₂-mediated intramolecular Reformatsky reaction, stereoselective allylation, the Sharpless asymmetric dihydroxylation, and amidation. The total synthesis of pederin was accomplished via coupling of the left and right halves.

Full text of DOI:10.1016/S0040-4020(02)00635-X

TETRAHEDRON
Pergamon
Tetrahedron 58 (2002) 6359±6365
Total synthesis of pederin, a potent insect toxin: the ef®cient
synthesis of the right half, (1)-benzoylpedamide
Takahiro Takemura,a Yoshinori Nishii,b Shunya Takahashi,b Jun'ichi Kobayashia
and Tadashi Nakatab,p
aGraduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
bThe Institute of Physical and Chemical Research (RIKEN), Wako-shi, Saitama 351-0198, Japan
Received 11 April 2002; accepted 23 May 2002
AbstractÐA simple and ef®cient synthesis of (1)-benzoylpedamide, the right half of pederin, was achieved in 16 steps with a 35% overall
yield from (S)-malic acid. The key steps include the SmI2-mediated intramolecular Reformatsky reaction, stereoselective allylation, the
Sharpless asymmetric dihydroxylation, and amidation. The total synthesis of pederin was accomplished via coupling of the left and right
halves. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
HeLa cells and blocks protein and DNA biosynthesis.5
Mycalamide A (2) exhibits in vivo potent antitumor and
antiviral activity, and immunosuppressive action via
inhibition of T-cell activation, which is 10-fold more potent
than FK-506.6
Pederin (1), a potent insect toxin isolated from Paederus
fuscipes, is the ®rst member of the pederin family (Fig. 1).
In 1968, the absolute and relative structure of 1 was deter-
mined by X-ray crystallographic analysis.1 The unique
structure bearing two tetrahydropyran rings bridged by an
N-acyl aminal remained as only one example in the realm of
natural products until 1988 when mycalamide A (2)2a and
onnamide A3a were isolated from New Zealand and
Japanese marine sponges, respectively. At the present, this
family grew to a large family that included pederin,
mycalamides A and B,2 onnamides A±F,3 and theopederins
A±L.4 All of these natural compounds contain an identical
left half, but slightly different right halves. Many members
of this family exhibit remarkable biological acitivity as anti-
tumour and antiviral agents. Pederin (1) inhibits mitosis in
Their unique structure and potent biological activity have
attracted the attention of numerous synthetic organic
chemists. The total syntheses have been reported for
pederin,7±9 mycalamides A10,11 and B,9,12 onnamide A,13
and theopederin D.14 However, a more ef®cient method
for the synthesis of the left and right halves is still required.
Recently, we reported a substantially improved, short and
highly ef®cient synthesis of (1)-methyl benzoylpederate (3)
(Fig. 2), the identical left half of the pederin family, in nine
steps with a 23% overall yield from the Evans chiral
amide.15 Our attention then turned to the ef®cient synthesis
of the right halves of this family. We herein describe a
simple and highly ef®cient synthesis of (1)-benzoyl-
pedamide (4), the right half of pederin (1), and the total
synthesis of 1.
Figure 1.
Keywords: samarium diiodide; Reformatsky reaction; Sharpless asym-
metric dihydroxylation; allylation.
p
Corresponding author. Tel.: 181-48-467-9373; fax: 181-48-462-4666;
e-mail: nakata@postman.riken.go.jp
Figure 2.
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00 635-X

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T. Takemura et al. / Tetrahedron 58 (2002) 6359±6365
2. Results and discussion
by acetonization gave 1,2-O-isopropylidene-(S)-butane-
1,2,4-triol in 91% yield, which was subjected to the one-
pot Swern oxidation±Wittig reaction to give the a,b-
unsaturated ester 6 in 89% yield. Deprotection of the
acetonide in 6 under acidic conditions followed by mono-
silylation with TBSCl afforded the TBS ether 7 in 99%
yield.
2.1. Synthetic plan
Our synthetic strategy for (1)-benzoylpedamide (4) is
outlined in Scheme 1. The C15 side chain of 4 would be
constructed from d-lactone ii via i by stereoselective allyl-
ation and dihydroxylation. The key intermediate ii should be
synthesized by the C13±C14 bond formation. We antici-
pated that this cyclization could be stereoselectively
performed by the SmI2-mediated intramolecular
Reformatsky reaction16 of 2-bromoisobutyrate and aldehyde
in iii. The 2-bromoisobutyrate iii will be prepared from the
commercially available (S)-malic acid.
The alcohol 7 was then converted into the aldehyde 9, which
is the substrate for the SmI2-mediated Reformatsky reaction,
a key reaction in this synthesis. The acylation of 7 with
2-bromoisobutyryl bromide in CH2Cl2 in the presence of
Et3N quantitatively afforded 2-bromoisobutyrate 8. Oxida-
tive cleavage of the double bond in 8 by ozonolysis gave the
required aldehyde 9. The treatment of 9 with 3 equiv. of
SmI2 in THF at 08C effected the reductive cyclization to
give the d-lactone 10 as a single product in 85% yield
1
(from 8). The H NMR analysis suggested that the product
10 has the desired axial hydroxyl group. The present reac-
tion would stereoselectively proceed through a tight cyclic
transition state by chelation of the Sm(III) ester enolate and
aldehyde as shown in Fig. 3.16 Thus, the SmI2-mediated
intramolecular Reformatsky reaction ef®ciently took place
with complete stereoselection even in the sterically hindered
bromoester.
Scheme 1.
2.2. Synthesis of (1)-benzoylpedamide (4)
The introduction of the C15 side chain was then examined
by allylation to the lactol derivative and stereoselective
dihydroxylation to the ole®n. The reduction of the lactone
10 with DIBAH gave the lactol, which was treated with
(S)-Malic acid (5) was ®rst converted into the d-hydroxy
a,b-unsaturated ester 7 by a modi®cation of a published
procedure (Scheme 2).17 The hydroboration of 5 followed
Scheme 2.

T. Takemura et al. / Tetrahedron 58 (2002) 6359±6365
6361
ef®cient procedure,15 to give pederin (1) (Scheme 3).
Coupling of both segments 3 and 4 was performed in a
manner similar to that reported by Matsumoto et al.7
Hydrolysis of the methyl ester 3 with n-PrSLi in HMPA
followed by treatment with SOCl2 afforded the acid chloride
16. Another coupling partner 17, methyl pedimidate, was
prepared by treatment of 4 with Me3O1BF42. The coupling
of 16 and 17 in the presence of Et3N gave N-acylimidate,
which was immediately reduced with NaBH4 in EtOH to
give a separable 1:3 mixture of (1)-dibenzoylpederin (18)
and the C10-epimer 19 in 36% overall yield from 4. The
spectral data of the dibenzoate 18 were identical with those
of the authentic (1)-dibenzoylpederin.7,8 Completion of the
total synthesis of pederin (1) has already been performed by
the hydrolysis of 18 with 1N LiOH in MeOH.7
Figure 3.
PhCOCl to give the dibenzoate 11 in 89% yield as a 2.2:1
anomeric mixture. The treatment of 11 with 5 equiv. of
allyltrimethylsilane in the presence of BF3´Et2O
(0.2 equiv.) and TMSOTf (0.2 equiv.) in MeCN at room
temperature effected the allylation with complete axial
stereoselectivity.18 The products were the alcohol 12a
(91%) and TBS ether 12b (9%). The alcohol 12a was
quantitatively converted to the TBS ether 12b by treatment
with TBSCl. Dihydroxylation of the double bond in 12b was
then carried out by the Sharpless asymmetric dihydroxyla-
tion (AD).19 After several attempts, we chose (DHQ)2PYR
as the ligand, which generally gives good results for mono-
substituted terminal ole®ns.20 The treatment of 12b under
conditions using (DHQ)2PYR, K3Fe(CN)6, K2CO3, OsO4,
and MeSO3NH2 in t-BuOH±H2O provided the desired
(17S)-alcohol 14 (68%) and its (17R)-epimer 13 (22%).
3. Conclusion
We have developed a simple and ef®cient method for the
synthesis of (1)-benzoylpedamide (4), the right half of
pederin (1). The total synthesis of pederin (1) was accom-
plished via coupling of the right and left halves. Further
studies on the ef®cient synthesis of the right halves of
mycalamides and theopederins based on the present method
are now in progress in this laboratory.
The remaining tasks for the synthesis of (1)-benzoylpeda-
mide (4) are the formation of the C17,18-dimethoxy and
C11-amide functions. After dimethylation of the diol 14
with NaH and MeI, treatment with Jones reagent effected
desilylation and oxidation to give the carboxylic acid 15.
Finally, amidation was performed by the procedure21 using
PyBOP, HOBT, and NH4Cl to give the amide 4 in 86% yield
from 14. The spectral data (1H, 13C NMR, and [a]D) and mp
of 4 were identical with those of the authentic sample,8
previously prepared by this group. Thus, the ef®cient
synthesis of (1)-benzoylpedamide (4), the right half of
pederin, was performed in 16 steps with a 35% overall
yield from (S)-malic acid (5).
4. Experimental
4.1. General
Flash column chromatography was performed using Kanto
silica gel 60N (spherical, neutral; 40±100 mm). Melting
points were determined using a Yanaco MP-500 apparatus
and are uncorrected. Optical rotations were measured using
a JASCO DIP-370digital polarimeter. Infrared spectra were
recorded using a JASCO VALOR-III FT-IR spectrometer.
Mass spectra were measured using a JEOL AX-505. 1H and
13C NMR spectra were recorded on a JEOL JNM-AL and a
JEOL JNM-ECP.
2.3. Total synthesis of pederin (1)
Having completed the synthesis of the right half 4, we
carried out its union with the left half 3, prepared by our
4.1.1. a,b-Unsaturated ester 7. To a stirred solution of 6
Scheme 3.

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T. Takemura et al. / Tetrahedron 58 (2002) 6359±6365
(408.4 mg, 1.91 mmol) in THF (7.6 mL) was added 1N HCl
(5.0mL) at room temperature. After stirring for 23 h, NaCl
(7.6 g) and EtOAc were added. The organic layer was
washed with brine and the aqueous layer was extracted
with EtOAc. The combined organic layers were washed
with brine, dried over MgSO4, and concentrated in vacuo
(108C) to give diol (332.2 mg, 1.91 mmol) as a yellow oil.
To a stirred solution of the diol in pyridine (6.6 mL) was
added TBSCl (373.6 mg, 2.48 mmol) at 08C under an argon
atmosphere. After stirring at room temperature for 17 h,
saturated aqueous NH4Cl was added and the mixture was
extracted with EtOAc. The combined organic layers were
washed with brine, dried over MgSO4, and concentrated in
vacuo. The residue was puri®ed by ¯ash column chromato-
graphy (SiO2; n-hexane/EtOAc, 10:1, 5:1) to give 7
CHCl3); IR (neat) 3447, 1733, 1713 cm21 1H NMR
;
(300 MHz, CDCl3) d 4.71 (ddt, Jˆ11.0, 7.2, 3.9 Hz, 1H),
3.91 (br d, W1/2ˆ4.5 Hz, 1H), 3.89 (dd, Jˆ11.0, 3.7 Hz, 1H),
3.68 (dd, Jˆ11.0, 2.7 Hz, 1H), 2.38 (ddd, Jˆ14.3, 11.0,
2.7 Hz, 1H), 2.05 (s, 1H), 1.83 (ddd, Jˆ14.3, 4.5, 4.5 Hz,
1H), 1.34 (s, 3H), 1.28 (s, 3H), 0.89 (s, 9H), 0.08 (s, 3H),
0.07 (s, 3H); 13C NMR (75 MHz, CDCl3) d 177.3, 76.6,
72.0, 64.8, 43.2, 28.2, 25.8 (3£C), 22.0(2 £C), 18.2,
25.4, 25.6. HRMS (FAB) calcd for C14H28O4SiNa
(M1Na1) 311.1655, found 311.1655.
4.1.4. Dibenzoate 11. To a stirred solution of 10 (347.3 mg,
1.20mmol) in CH 2Cl2 (10mL) was added DIBAH (1.0M
in hexane, 2.40mL, 2.40mmol) at 2788C under an argon
atmosphere. After stirring at 2788C for 5 min, i-PrOH,
EtOAc and saturated aqueous NH4Cl were added. After
stirring at room temperature for 40min, the aqueous layer
was extracted with EtOAc. The combined organic layers
were washed with 1N HCl, dried over MgSO4, and concen-
trated in vacuo to give lactol (322.4 mg, 1.11 mmol) as an
oil. To a stirred solution of the lactol in pyridine (9.1 mL)
was added PhCOCl (562 mL, 4.80mmol) at 0 8C under an
argon atmosphere. After stirring at room temperature for
11 h, MeOH was added and the mixture was stirred for
40min. The mixture was diluted with Et 2O, washed with
H2O and brine, dried over MgSO4, and concentrated in
vacuo. The residue was puri®ed by ¯ash column chromato-
graphy (SiO2; n-hexane/EtOAc, 15:1) to give 11 (532.6 mg,
89%, 2.2:1 anomeric mixture) as a colorless oil. IR (neat)
27
(544.6 mg, 99%) as a colorless oil. [a]D ˆ21.2 (c 1.11,
CHCl3); IR (neat) 3468, 1720, 1655 cm21 1H NMR
;
(300 MHz, CDCl3) d 6.98 (dt, Jˆ15.6, 7.2 Hz, 1H), 5.90
(dt, Jˆ15.6, 1.5 Hz, 1H), 4.18 (q, Jˆ7.2 Hz, 2H), 3.79 (m,
1H), 3.64 (dd, Jˆ10.1, 3.9 Hz, 1H), 3.45 (dd, Jˆ9.9, 6.6 Hz,
1H), 2.37 (ddd, Jˆ8.3, 6.8, 1.5 Hz, 2H), 1.28 (t, Jˆ14.3,
7.2 Hz, 3H), 0.90 (s, 9H), 0.08 (s, 6H); 13C NMR (75 MHz,
CDCl3) d 166.2, 144.7, 123.6, 70.5, 66.4, 60.2, 35.9, 25.8
(3£C), 18.2, 14.2, 25.47, 25.50. HRMS (FAB) calcd for
C14H28O4SiNa (M1Na1) 311.1655, found 311.1655.
4.1.2. 2-Bromoisobutyrate 8. To a solution of 7 (463.0mg,
1.61 mmol) in CH2Cl2 (8.3 mL) were added Et3N (477 mL,
3.21 mmol) and 2-bromoisobutyryl bromide (407 mL,
3.21 mmol) at 08C under an argon atmosphere. After stirring
at room temperature for 18 h, saturated aqueous NH4Cl was
added and the mixture was extracted with Et2O. The
combined organic layers were washed with H2O and
brine, dried over MgSO4, and concentrated in vacuo. The
residue was puri®ed by ¯ash column chromatography (SiO2;
n-hexane/EtOAc, 10:1) to give 8 (699.3 mg, 100%) as a
1
1739, 1733, 1717, 1602, 1586 cm21; H NMR (300 MHz,
CDCl3) d 7.35±8.10(m, 10H), 6.20(s, 0.69H), 6.14 (m,
0.31H), 5.27 (m, 0.69H), 5.24 (m,.0.31H), 4.30 (m,
0.31H), 4.14 (m, 0.69H), 3.72 (m, 1.38H), 3.69 (m,
0.62H), 2.19 (m, 0.31H), 2.10 (m, 0.69H), 1.85 (m, 1H),
1.56 (s, 3H), 1.31 (s, 0.94H), 1.30 (s, 2.06H), 0.85 (s, 9H),
0.03 (s, 3H), 0.01 (s, 3H); 13C NMR (75 MHz, CDCl3) major
d 165.3, 164.9, 133.2, 133.1, 129.8, 129.7, 129.6 (2£C),
129.4 (2£C), 128.4 (2£C), 128.3 (2£C), 96.3, 76.6, 73.1,
65.4, 37.9, 28.9, 25.9 (3£C), 20.9, 18.8, 15.3, 25.2, 25.3.
Minor 166.0, 165.4, 132.9, 132.8, 130.3, 130.2, 129.9
(2£C), 129.5 (2£C), 128.2 (2£C), 128.1 (2£C), 97.5,
76.6, 73.9, 66.9, 36.6, 28.3, 25.9 (3£C), 21.2, 18.3, 15.3,
25.2, 25.3. HRMS (FAB) calcd for C28H38O6SiNa
(M1Na1) 521.2335, found 521.2359.
27
yellow oil. [a]D ˆ23.4 (c 1.11, CHCl3); IR (neat) 1736,
1
1716, 1659 cm21; H NMR (300 MHz, CDCl3) d 6.91 (dt,
Jˆ15.2, 7.3 Hz, 1H), 5.90(d, Jˆ15.2 Hz, 1H), 4.98 (m, 1H),
4.18 (q, Jˆ7.3 Hz, 2H), 3.70(m, 2H), 2.60(m, 2H), 2.00(s,
3H), 1.91 (s, 3H), 1.28 (t, Jˆ7.2 Hz, 3H), 0.89 (s, 9H), 0.06
(s, 6H); 13C NMR (75 MHz, CDCl3) d 171.1, 165.7, 143.0,
124.5, 74.2, 63.1, 60.3, 55.6, 33.1, 30.7 (2£C), 25.7 (3£C),
18.1, 14.2, 25.5 (2£C). HRMS (FAB) calcd for
C18H33O5BrSiNa (M1Na1) 461.1160, found 461.1182.
4.1.5. Allylation of 11. To a stirred solution of 11 (61.4 mg,
123.1 mmol) in MeCN (3 mL) were added BF3´Et2O
(3.2 mL, 24.6 mmol), TMSOTf (4.6 mL, 24.6 mmol) and
allyltrimethylsilane (98 mL, 615.6 mmol) at 08C under an
argon atmosphere. After stirring at room temperature for
24 h, saturated aqueous NaHCO3 was added and the mixture
was extracted with EtOAc. The combined organic layers
were washed with brine, dried over MgSO4, and concen-
trated in vacuo. The residue was puri®ed by ¯ash column
chromatography (SiO2; n-hexane/EtOAc, 10:1) to give 12a
(34.4 mg, 91%) and 12b (4.9 mg, 9%) as colorless oils. 12a:
4.1.3. d-Lactone 10. Ozone was bubbled to a stirred solu-
tion of 8 (791.1 mg, 1.81 mmol) in CH2Cl2 (15 mL) at
2788C for 20min. After N 2 gas was bubbled to remove
excess ozone, dimethyl sul®de (3.98 mL, 54.3 mmol) was
added. After stirring at 2788C for 30min, at 0 8C for 1 h and
at room temperature for 1 h, the yellow solution was
concentrated in vacuo to give 9 as a yellow oil. To a stirred
solution of 9 in THF (5.3 mL) was added SmI2 (0.1 M in
THF, 54.3 mL, 5.43 mmol) at 08C under an argon
atmosphere. After stirring at 08C for 10min, saturated
aqueous NH4Cl was added and the mixture was extracted
with EtOAc. The combined organic layers were washed
with saturated aqueous Na2S2O3±saturated aqueous
NaHCO3 and brine, dried over MgSO4, and concentrated
in vacuo. The residue was puri®ed by ¯ash column chroma-
tography (SiO2; n-hexane/EtOAc, 3:1, 1:1) to give 10
29
[a]D ˆ20.55 (c 1.09, CHCl3); IR (neat) 3456, 1718, 1641,
1
1602, 1585 cm21; H NMR (300 MHz, CDCl3) d 8.04 (m,
2H), 7.59 (m, 1H), 7.47 (m, 2H), 5.91 (m, 1H), 5.14 (m, 2H),
5.05 (t, Jˆ5.6 Hz, 1H), 4.11 (m, 1H), 3.82 (t, Jˆ10.2 Hz,
1H), 3.51 (m, 2H), 2.61 (m, 1H), 2.34 (m, 1H), 2.04 (br, 1H),
1.90 (m, 2H), 1.09 (s, 3H), 1.07 (s, 3H); 13C NMR (75 MHz,
CDCl3) d 166.0, 136.1, 133.1, 130.2, 129.5 (2£C), 128.5
29
(521.7 mg, 85%) as a colorless oil. [a]D ˆ23.1 (c 1.13,

T. Takemura et al. / Tetrahedron 58 (2002) 6359±6365
6363
(2£C), 117.0, 78.3, 75.2, 69.1, 63.0, 37.4, 33.0, 27.7, 24.7
(2£C). HRMS (FAB) calcd for C18H24O4Na (M1Na1)
CHCl3); IR (neat) 1720, 1643, 1602, 1580 cm21; H NMR
calcd for C24H40O6SiNa (M1Na1) 475.2492, found
475.2512.
26
327.1572, found 327.1578. 12b: [a]D ˆ115.1 (c 1.15,
1
4.1.8. Benzoylpedamide (4). To a stirred suspension of
NaH (11.7 mg, 292.8 mmol) in DMF (0.5 mL) was added
a solution of 14 (22.1 mg, 48.8 mmol) and MeI (15.2 mL,
243.8 mmol) in DMF (0.2 mL) at 08C under an argon
atmosphere. After stirring at room temperature for 4 h, 1N
HCl±ice was added and the mixture was extracted with
EtOAc. The combined organic layers were washed with
brine, dried over MgSO4, and concentrated in vacuo to
give dimethoxy compound as an oil. Jones reagent was
added dropwise to a stirred solution of the product in
acetone (0.51 mL) at 08C until faint red color persisted.
After stirring at room temperature for 30min, the excess
Jones reagent was destroyed by the addition of i-PrOH.
The mixture was concentrated in vacuo, and then H2O
was added. The mixture was extracted with EtOAc. The
combined organic layers were dried over MgSO4, and
concentrated in vacuo to give 15 as an oil. The carboxylic
acid 15, PyBOP (60.2 mg, 115.2 mmol), and HOBt
(15.5 mg, 115.2 mmol) were dissolved in DMF (0.3 mL)
at 08C under an argon atmosphere. To the mixture were
added i-Pr2NEt (44.7 mL, 307.2 mmol) and NH4Cl
(0.77 mg, 154.3 mmol) at room temperature. After stirring
at room temperature for 1.5 h, H2O and EtOAc were added
and the mixture was extracted with EtOAc. The combined
organic layers were washed with 1N HCl and saturated
aqueous NaHCO3, dried over MgSO4, and concentrated in
vacuo. The residue was puri®ed by ¯ash column chromato-
graphy (SiO2; EtOAc) to give 4 (15.9 mg, 86%) as colorless
crystals. mp 144±1468C (recrystallized from Et2O±n-
(300 MHz, CDCl3) d 8.06 (m, 2H), 7.58 (m, 1H), 7.46 (m,
2H), 5.95 (m, 1H), 5.15 (m, 2H), 5.05 (m, 1H), 4.00 (dt,
Jˆ10.5, 5.5 Hz, 1H), 3.79 (dd, Jˆ10.5, 5.5 Hz, 1H), 3.71
(dd, Jˆ10.5, 5.5 Hz, 1H), 3.58 (dd, Jˆ10.5, 2.8 Hz, 1H),
2.53 (m, 1H), 2.29 (m, 1H), 1.93 (m, 2H), 1.05 (s, 3H), 1.04
(s, 3H), 0.91 (s, 9H), 0.08 (s, 6H); 13C NMR (75 MHz,
CDCl3) d 165.9, 136.7, 132.9, 130.5, 129.5 (2£C), 128.4
(2£C), 115.8, 79.0, 75.4, 70.1, 64.9, 37.5, 33.3, 28.1, 25.9
(3£C), 24.4 (2£C), 18.2, 25.4, 25.5. HRMS (FAB) calcd
for C24H38O4SiNa (M1Na1) 441.2437, found 441.2427.
4.1.6. TBS ether 12b from 12a. To a stirred solution of 12a
(117.4 mg, 0.39 mmol) in CH2Cl2 (4.8 mL) were added
imidazole (92.1 mg, 1.35 mmol) and TBSCl (175.0mg,
1.16 mmol) at 08C under an argon atmosphere. After stirring
at room temperature for 1.5 h, aqueous NH4Cl was added
and the mixture was extracted with Et2O. The combined
organic layers were washed with H2O and brine, dried
over MgSO4, and concentrated in vacuo. The residue was
puri®ed by ¯ash column chromatography (SiO2; n-hexane/
EtOAc, 10:1) to give 12b (161.3 mg, 100%) as a colorless
oil.
4.1.7. Sharpless AD of 12b. To a stirred suspension of
(DHQ)2PYR (133.0mg, 0.154 mmol) in t-BuOH±H2O
(1:1, 40mL) were added K 2CO3 (830.9 mg, 6.01 mmol),
K3Fe(CN)6 (1.52 g, 4.62 mmol), OsO4 (96.0 mL,
0.924 mmol) and MeSO3NH2 (184.7 mg, 1.69 mmol) at
room temperature. After stirring at room temperature for
30min, a solution of 12b (644.7 mg, 1.54 mmol) in
t-BuOH±H2O (1:1, 8 mL) was added at 08C. After stirring
at room temperature for 13 h, Na2SO3 (2.2 g) was added at
08C. After stirring at room temperature for 2 h, the mixture
was extracted with EtOAc. The combined organic layers
were washed with brine, dried over MgSO4, and concen-
trated in vacuo. The residue was puri®ed by ¯ash column
chromatography (SiO2; toluene/acetone, 7:1, 3:1) to give 13
(158.3 mg, 22%) and 14 (466.6 mg, 68%) as colorless oils.
26
hexane); [a]D ˆ115.7 (c 3.26, CHCl3); IR (KBr) 3432,
1
3330, 1719, 1684 cm21; H NMR (300 MHz, CDCl3) d
8.03 (m, 2H), 7.54 (m, 1H), 7.45 (m, 2H), 5.49 (br. s, 2H),
4.98 (dd, Jˆ10.7, 4.6 Hz, 1H), 4.48 (dd, Jˆ6.6, 2.6 Hz, 1H),
3.61 (m, 2H), 3.55 (dd, Jˆ8.7, 2.7 Hz, 1H), 3.45 (m, 1H),
3.42 (s, 3H), 3.39 (s, 3H), 2.59 (dd, Jˆ13.1, 4.6, 2.7 Hz,
1H), 2.03 (ddd, Jˆ13.1, 10.7, 6.6 Hz, 1H), 1.86 (m, 2H),
1.08 (s, 3H), 0.94 (s, 3H); 13C NMR (75 MHz, CDCl3) d
174.0, 165.5, 133.0, 130.3, 129.6 (2£C), 128.4 (2£C), 78.9,
78.1, 74.9, 74.3, 72.4, 59.1, 56.6, 37.7, 30.1, 23.1, 14.4
(2£C). HRMS (FAB) calcd for C20H29NO6Na (M1Na1)
402.1901, found 402.1891.
29
13: [a]D ˆ114.9 (c 1.20, CHCl3); IR (neat) 3424, 1720,
1
1602, 1586 cm21; H NMR (300 MHz, CDCl3) d 8.01 (m,
2H), 7.56 (m, 1H), 7.42 (m, 2H), 5.01 (dd, Jˆ10.1, 5.1 Hz,
1H), 4.07 (m, 2H), 3.97 (m, 1H), 3.78 (dd, Jˆ11.2, 2.8 Hz,
1H), 3.62 (m, 1H), 3.55 (m, 2H), 3.17 (br, 2H), 1.53±1.93
(m, 4H), 1.07 (s, 3H), 0.93 (s, 3H), 0.90 (s, 9H), 0.09 (s, 6H),
13C NMR (75 MHz, CDCl3) d 165.9, 132.9, 130.2, 129.4
(2£C), 128.4 (2£C), 75.2, 73.2, 71.5, 68.9, 66.5, 65.7, 37.7,
30.8, 27.5, 25.8 (3£C), 18.2, 15.1, 14.9, 25.4, 25.5. HRMS
(FAB) calcd for C24H40O6SiNa (M1Na1) 475.2492, found
4.1.9. Dibenzoylpederin (18) and 10-epi-dibenzoyl-
pederin (19). To a stirred solution of 4 (51.0mg,
2
134.4 mmol) in CH2Cl2 (2.6 mL) was added Me3O1BF4
(199.2 mg, 1.34 mmol) at 08C under an argon atmosphere.
After stirring at room temperature for 17 h, saturated
aqueous NaHCO3 and Et2O were added at 08C and the
mixture was extracted with Et2O. The combined organic
layers were washed with saturated aqueous NaHCO3±
brine, dried over MgSO4, and concentrated in vacuo to
give 17. To a stirred solution of 3 (75.0mg, 215.3 mmol)
in HMPA (1.5 mL) was added n-PrSLi (0.55 M in HMPA,
585 mL, 236.8 mmol) at room temperature under an argon
atmosphere. After stirring at room temperature for 6 h, ice
was added and the mixture was extracted with Et2O. To the
aqueous layer were added 0.1N HCl (5 mL) and H2O (5 mL)
at 08C and the mixture was extracted with Et2O. The
combined organic layers were washed with H2O and
brine, dried over MgSO4, and concentrated in vacuo to
29
475.2501. 14: [a]D ˆ11.56 (c 1.11, CHCl3); IR (neat)
3459, 1717, 1602, 1585 cm21
;
1H NMR (300 MHz,
CDCl3) d 8.04 (m, 2H), 7.59 (m, 1H), 7.46 (m, 2H), 5.08
(dd, Jˆ8.0, 5.5 Hz, 1H), 4.15 (m, 1H), 3.92 (m, 2H), 3.79
(dd, Jˆ11.0, 1.4 Hz, 1H), 3.63 (dd, Jˆ11.0, 3.1 Hz, 2H),
3.52 (dd, Jˆ11.0, 6.1 Hz, 1H), 2.36 (br, 1H), 1.98 (m, 1H),
1.89 (m, 2H), 1.62 (m, 1H), 1.07 (s, 3H), 1.01 (s, 3H), 0.93
(s, 9H), 0.12 (s, 3H), 0.11 (s, 3H); 13C NMR (75 MHz,
CDCl3) d 165.9, 133.0, 130.2, 129.5 (2£C), 128.4 (2£C),
79.2, 74.8, 72.5, 70.9, 66.6, 63.9, 37.7, 31.3, 27.5, 25.9
(3£C), 23.9 (2£C), 18.3, 25.50, 25.53. HRMS (FAB)

6364
T. Takemura et al. / Tetrahedron 58 (2002) 6359±6365
give carboxylic acid. To a stirred solution of SOCl2
(21.1 mL, 285.4 mmol) and pyridine (29.5 mL,
References
389.2 mmol) in CH2Cl2 (350 mL) was added dropwise a
solution of carboxylic acid (69.4 mg, 207.6 mmol) in
CH2Cl2 (430 mL) at room temperature under an argon
atmosphere for 3 min. After stirring at room temperature
1. (a) Furusaki, A.; Watanabe, T.; Matsumoto, T.; Yanagiya, M.
Tetrahedron Lett. 1968, 6301. (b) Corradi, A. B.; Mangia, A.;
Nardelli, N.; Pelizzi, G. Gazz. Chim. Ital. 1971, 101, 591.
2. (a) Perry, N. B.; Blunt, J. W.; Munro, M. H. G.; Pannell, L. K.
J. Am. Chem. Soc. 1988, 110, 4850. (b) Perry, N. B.; Blunt,
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1990, 55, 223.
for additional 2 min,
a solution of 17 (55.3 mg,
140.5 mmol) and Et3N (50.0 mL, 331.6 mmol) in CH2Cl2
(555 mL) was added. After stirring at room temperature
for 2.5 h, the solvent was removed in vacuo. To the resulting
residue was added at 2208C a suspension of NaBH4
(128.9 mg, 3.32 mmol) in EtOH (3.25 mL) cooled at
2208C. After stirring at 2208C for 30min, brine was
added and the mixture was extracted with CHCl3. The
combined organic layers were washed with brine, dried
over MgSO4, and concentrated in vacuo. The residue was
puri®ed by ¯ash column chromatography (SiO2; n-hexane/
EtOAc, 4:1, 3:1) to give 18 (8.53 mg, 9% from 4) and 19
3. (a) Sakemi, S.; Ichiba, T.; Kohmoto, S.; Saucy, G.; Higa, T.
J. Am. Chem. Soc. 1988, 110, 4851. (b) Matsunaga, S.;
Fusetani, N.; Nakao, Y. Tetrahedron 1992, 48, 8369.
(c) Kobayashi, J.; Itagaki, F.; Shigemori, H.; Sasaki, T.
J. Nat. Prod. 1993, 56, 976. (d) Vuong, D.; Capon, R. J.;
Lacey, E.; Gill, J. H.; Heiland, K.; Friedel, T. J. Nat. Prod.
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2002, 65, 59.
25
(25.6 mg, 27% from 4) as colorless oils. 18: [a]D ˆ1102.7
(c 0.110, CHCl3); IR (neat) 3428, 3366, 1723, 1655, 1603,
1
1586 cm21; H NMR (500 MHz, CDCl3) d 8.04±8.11 (m,
4H), 7.59 (m, 2H), 7.46 (m, 4H), 6.77 (d, Jˆ9.6 Hz, 1H),
5.52 (s, 1H), 5.35 (dd, Jˆ9.6, 4.1 Hz, 1H), 5.15 (dd, Jˆ7.8,
4.1 Hz, 1H), 4.87 (s, 1H), 4.80(s, 1H), 3.97 (m, 2H), 3.64
(dd, Jˆ11.0, 1.8 Hz, 1H), 3.44±3.56 (m, 3H), 3.46 (s, 3H),
3.37 (s, 3H), 3.36 (s, 3H), 3.25 (s, 3H), 2.77 (d, Jˆ14.2 Hz,
1H), 2.50(d, Jˆ14.2 Hz, 1H), 2.04±2.23 (m, 3H), 1.78±
1.85 (m, 2H), 1.12 (d, Jˆ6.4 Hz, 3H), 1.01 (s, 3H), 0.99
(s, 3H), 0.94 (d, Jˆ6.9 Hz, 3H); 13C NMR (125 MHz,
CDCl3) d 167.4, 166.0, 165.4, 145.7, 133.5, 133.1, 130.1
(2£C), 129.5 (4£C), 128.5 (4£C), 110.5, 99.3, 81.7, 77.5,
77.3, 75.0, 72.8, 72.6, 70.2, 69.7, 59.2, 56.9, 56.4, 48.6,
41.3, 37.1, 34.1, 29.7, 29.1, 26.6, 24.7, 17.9, 11.9. HRMS
(FAB) calcd for C392H6 53O11NNa (M1Na1) 734.3445, found
734.3525. 19: [a]D ˆ1126.5 (c 0.170, CHCl3); IR (neat)
5. (a) Soldati, M.; Fioretti, A.; Ghione, M. Experientia 1966, 22,
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Tetrahedron Lett. 1976, 4745. (b) Yanagiya, M.; Matsuda, F.;
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1988, 44, 7063.
1
3292, 1724, 1698, 1655, 1602 cm21; H NMR (500 MHz,
CDCl3) d 8.06±8.11 (m, 4H), 7.85 (d, Jˆ9.6 Hz, 1H), 7.57
(m, 2H), 7.44 (m, 4H), 5.41 (s, 1H), 5.35 (dd, Jˆ8.3, 4.6 Hz,
1H), 5.19 (dd, Jˆ9.6, 3.2 Hz, 1H), 4.88 (s, 1H), 4.81 (s, 1H),
4.00 (m, 2H), 3.82 (dd, Jˆ11.5, 2.3 Hz, 1H), 3.75 (dd,
Jˆ10.1, 5.5 Hz, 1H), 3.69 (m, 1H), 3.49 (s, 3H), 3.48 (s,
3H), 3.45 (dd, Jˆ10.1, 4.1 Hz, 1H), 3.37 (s, 3H), 3.26 (s,
3H), 3.09 (d, Jˆ14.2 Hz, 1H), 2.50(d, Jˆ14.2 Hz, 1H), 2.26
(m, 1H), 2.14 (m, 1H), 2.04 (m, 1H), 1.90 (ddd, Jˆ13.8, 8.3,
6.0, Hz, 1H), 1.83 (ddd, Jˆ11.0, 8.7, 2.3, Hz, 1H), 1.19 (d,
Jˆ6.9 Hz, 3H), 1.05 (s, 3H), 1.04 (s, 3H), 1.02 (d,
Jˆ7.3 Hz, 3H); 13C NMR (125 MHz, CDCl3) d 167.2,
166.0, 165.4, 146.3, 133.3, 133.0, 130.0 (2£C), 129.5
(4£C), 128.4 (2£C), 128.3 (2£C), 110.0, 99.7, 83.2, 78.1,
76.8, 75.3, 75.0, 72.2, 69.7, 69.6, 58.9, 56.9, 56.8, 48.2,
41.6, 37.2, 33.7, 29.7, 29.1, 27.7, 24.3, 17.9, 11.9. HRMS
(FAB) calcd for C39H53O11NNa (M1Na1) 734.3445, found
734.3525.
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Acknowledgements
This work was supported in part by Special Project Funding
for Basic Science (Multibioprobe) from RIKEN. The
authors thank Professor F. Matsuda (Hokkaido University)
for useful information about the coupling reaction condi-
tions and Ms K. Harata (RIKEN) for the mass spectral
measurements.
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