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
a
Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
b
The 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
Pederin (1), a potent insect toxin isolated from Paederus antiviral activity, and immunosuppressive action via
fuscipes, is the ®rst member of the pederin family (Fig. 1). inhibition of T-cell activation, which is 10-fold more potent
In 1968, the absolute and relative structure of 1 was deter- than FK-506.6
mined by X-ray crystallographic analysis.1 The unique
structure bearing two tetrahydropyran rings bridged by an Their unique structure and potent biological activity have
N-acyl aminal remained as only one example in the realm of attracted the attention of numerous synthetic organic
natural products until 1988 when mycalamide A (2)2a and chemists. The total syntheses have been reported for
onnamide A3a were isolated from New Zealand and pederin,7±9 mycalamides A10,11 and B,9,12 onnamide A,13
Japanese marine sponges, respectively. At the present, this and theopederin D.14 However, a more ef®cient method
family grew to a large family that included pederin, for the synthesis of the left and right halves is still required.
mycalamides A and B,2 onnamides A±F,3 and theopederins Recently, we reported a substantially improved, short and
A±L.4 All of these natural compounds contain an identical highly ef®cient synthesis of (1)-methyl benzoylpederate (3)
left half, but slightly different right halves. Many members (Fig. 2), the identical left half of the pederin family, in nine
of this family exhibit remarkable biological acitivity as anti- steps with a 23% overall yield from the Evans chiral
tumour and antiviral agents. Pederin (1) inhibits mitosis in 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: [email protected] Figure 2.

0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S 0040- 402 0( 02) 00635-X
6360 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-
2.1. Synthetic plan pot Swern oxidation±Wittig reaction to give the a,b-
unsaturated ester 6 in 89% yield. Deprotection of the
Our synthetic strategy for (1)-benzoylpedamide (4) is acetonide in 6 under acidic conditions followed by mono-
outlined in Scheme 1. The C15 side chain of 4 would be silylation with TBSCl afforded the TBS ether 7 in 99%
constructed from d-lactone ii via i by stereoselective allyl- yield.
ation and dihydroxylation. The key intermediate ii should be
synthesized by the C13±C14 bond formation. We antici- The alcohol 7 was then converted into the aldehyde 9, which
pated that this cyclization could be stereoselectively is the substrate for the SmI2-mediated Reformatsky reaction,
performed by the SmI2-mediated intramolecular a key reaction in this synthesis. The acylation of 7 with
Reformatsky reaction16 of 2-bromoisobutyrate and aldehyde 2-bromoisobutyryl bromide in CH2Cl2 in the presence of
in iii. The 2-bromoisobutyrate iii will be prepared from the Et3N quantitatively afforded 2-bromoisobutyrate 8. Oxida-
commercially available (S)-malic acid. 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
(from 8). The 1H 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
Scheme 1.
intramolecular Reformatsky reaction ef®ciently took place
with complete stereoselection even in the sterically hindered
bromoester.
2.2. Synthesis of (1)-benzoylpedamide (4)
The introduction of the C15 side chain was then examined
(S)-Malic acid (5) was ®rst converted into the d-hydroxy by allylation to the lactol derivative and stereoselective
a,b-unsaturated ester 7 by a modi®cation of a published dihydroxylation to the ole®n. The reduction of the lactone
procedure (Scheme 2).17 The hydroboration of 5 followed 10 with DIBAH gave the lactol, which was treated with

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
Figure 3. 16. Another coupling partner 17, methyl pedimidate, was
prepared by treatment of 4 with Me3O1BF42. The coupling
PhCOCl to give the dibenzoate 11 in 89% yield as a 2.2:1 of 16 and 17 in the presence of Et3N gave N-acylimidate,
anomeric mixture. The treatment of 11 with 5 equiv. of which was immediately reduced with NaBH4 in EtOH to
allyltrimethylsilane in the presence of BF3´Et2O give a separable 1:3 mixture of (1)-dibenzoylpederin (18)
(0.2 equiv.) and TMSOTf (0.2 equiv.) in MeCN at room and the C10-epimer 19 in 36% overall yield from 4. The
temperature effected the allylation with complete axial spectral data of the dibenzoate 18 were identical with those
stereoselectivity.18 The products were the alcohol 12a of the authentic (1)-dibenzoylpederin.7,8 Completion of the
(91%) and TBS ether 12b (9%). The alcohol 12a was total synthesis of pederin (1) has already been performed by
quantitatively converted to the TBS ether 12b by treatment the hydrolysis of 18 with 1N LiOH in MeOH.7
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 3. Conclusion
as the ligand, which generally gives good results for mono-
substituted terminal ole®ns.20 The treatment of 12b under We have developed a simple and ef®cient method for the
conditions using (DHQ)2PYR, K3Fe(CN)6, K2CO3, OsO4, synthesis of (1)-benzoylpedamide (4), the right half of
and MeSO3NH2 in t-BuOH±H2O provided the desired pederin (1). The total synthesis of pederin (1) was accom-
(17S)-alcohol 14 (68%) and its (17R)-epimer 13 (22%). plished via coupling of the right and left halves. Further
studies on the ef®cient synthesis of the right halves of
The remaining tasks for the synthesis of (1)-benzoylpeda- mycalamides and theopederins based on the present method
mide (4) are the formation of the C17,18-dimethoxy and are now in progress in this laboratory.
C11-amide functions. After dimethylation of the diol 14
with NaH and MeI, treatment with Jones reagent effected 4. Experimental
desilylation and oxidation to give the carboxylic acid 15.
Finally, amidation was performed by the procedure21 using 4.1. General
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 Flash column chromatography was performed using Kanto
of 4 were identical with those of the authentic sample,8 silica gel 60N (spherical, neutral; 40±100 mm). Melting
previously prepared by this group. Thus, the ef®cient points were determined using a Yanaco MP-500 apparatus
synthesis of (1)-benzoylpedamide (4), the right half of and are uncorrected. Optical rotations were measured using
pederin, was performed in 16 steps with a 35% overall a JASCO DIP-370 digital polarimeter. Infrared spectra were
yield from (S)-malic acid (5). recorded using a JASCO VALOR-III FT-IR spectrometer.
Mass spectra were measured using a JEOL AX-505. 1H and
13
2.3. Total synthesis of pederin (1) C NMR spectra were recorded on a JEOL JNM-AL and a
JEOL JNM-ECP.
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.
6362 T. Takemura et al. / Tetrahedron 58 (2002) 6359±6365

(408.4 mg, 1.91 mmol) in THF (7.6 mL) was added 1N HCl CHCl3); IR (neat) 3447, 1733, 1713 cm21; 1H NMR
(5.0 mL) at room temperature. After stirring for 23 h, NaCl (300 MHz, CDCl3) d 4.71 (ddt, Jˆ11.0, 7.2, 3.9 Hz, 1H),
(7.6 g) and EtOAc were added. The organic layer was 3.91 (br d, W1/2ˆ4.5 Hz, 1H), 3.89 (dd, Jˆ11.0, 3.7 Hz, 1H),
washed with brine and the aqueous layer was extracted 3.68 (dd, Jˆ11.0, 2.7 Hz, 1H), 2.38 (ddd, Jˆ14.3, 11.0,
with EtOAc. The combined organic layers were washed 2.7 Hz, 1H), 2.05 (s, 1H), 1.83 (ddd, Jˆ14.3, 4.5, 4.5 Hz,
with brine, dried over MgSO4, and concentrated in vacuo 1H), 1.34 (s, 3H), 1.28 (s, 3H), 0.89 (s, 9H), 0.08 (s, 3H),
(108C) to give diol (332.2 mg, 1.91 mmol) as a yellow oil. 0.07 (s, 3H); 13C NMR (75 MHz, CDCl3) d 177.3, 76.6,
To a stirred solution of the diol in pyridine (6.6 mL) was 72.0, 64.8, 43.2, 28.2, 25.8 (3£C), 22.0 (2£C), 18.2,
added TBSCl (373.6 mg, 2.48 mmol) at 08C under an argon 25.4, 25.6. HRMS (FAB) calcd for C14H28O4SiNa
atmosphere. After stirring at room temperature for 17 h, (M1Na1) 311.1655, found 311.1655.
saturated aqueous NH4Cl was added and the mixture was
extracted with EtOAc. The combined organic layers were 4.1.4. Dibenzoate 11. To a stirred solution of 10 (347.3 mg,
washed with brine, dried over MgSO4, and concentrated in 1.20 mmol) in CH2Cl2 (10 mL) was added DIBAH (1.0 M
vacuo. The residue was puri®ed by ¯ash column chromato- in hexane, 2.40 mL, 2.40 mmol) at 2788C under an argon
graphy (SiO2; n-hexane/EtOAc, 10:1, 5:1) to give 7 atmosphere. After stirring at 2788C for 5 min, i-PrOH,
(544.6 mg, 99%) as a colorless oil. [a ]D27ˆ21.2 (c 1.11, EtOAc and saturated aqueous NH4Cl were added. After
CHCl3); IR (neat) 3468, 1720, 1655 cm21; 1H NMR stirring at room temperature for 40 min, the aqueous layer
(300 MHz, CDCl3) d 6.98 (dt, Jˆ15.6, 7.2 Hz, 1H), 5.90 was extracted with EtOAc. The combined organic layers
(dt, Jˆ15.6, 1.5 Hz, 1H), 4.18 (q, Jˆ7.2 Hz, 2H), 3.79 (m, were washed with 1N HCl, dried over MgSO4, and concen-
1H), 3.64 (dd, Jˆ10.1, 3.9 Hz, 1H), 3.45 (dd, Jˆ9.9, 6.6 Hz, trated in vacuo to give lactol (322.4 mg, 1.11 mmol) as an
1H), 2.37 (ddd, Jˆ8.3, 6.8, 1.5 Hz, 2H), 1.28 (t, Jˆ14.3, oil. To a stirred solution of the lactol in pyridine (9.1 mL)
7.2 Hz, 3H), 0.90 (s, 9H), 0.08 (s, 6H); 13C NMR (75 MHz, was added PhCOCl (562 mL, 4.80 mmol) at 08C under an
CDCl3) d 166.2, 144.7, 123.6, 70.5, 66.4, 60.2, 35.9, 25.8 argon atmosphere. After stirring at room temperature for
(3£C), 18.2, 14.2, 25.47, 25.50. HRMS (FAB) calcd for 11 h, MeOH was added and the mixture was stirred for
C14H28O4SiNa (M1Na1) 311.1655, found 311.1655. 40 min. The mixture was diluted with Et2O, washed with
H2O and brine, dried over MgSO4, and concentrated in
4.1.2. 2-Bromoisobutyrate 8. To a solution of 7 (463.0 mg, vacuo. The residue was puri®ed by ¯ash column chromato-
1.61 mmol) in CH2Cl2 (8.3 mL) were added Et3N (477 mL, graphy (SiO2; n-hexane/EtOAc, 15:1) to give 11 (532.6 mg,
3.21 mmol) and 2-bromoisobutyryl bromide (407 mL, 89%, 2.2:1 anomeric mixture) as a colorless oil. IR (neat)
3.21 mmol) at 08C under an argon atmosphere. After stirring 1739, 1733, 1717, 1602, 1586 cm21; 1H NMR (300 MHz,
at room temperature for 18 h, saturated aqueous NH4Cl was CDCl3) d 7.35±8.10 (m, 10H), 6.20 (s, 0.69H), 6.14 (m,
added and the mixture was extracted with Et2O. The 0.31H), 5.27 (m, 0.69H), 5.24 (m,.0.31H), 4.30 (m,
combined organic layers were washed with H2O and 0.31H), 4.14 (m, 0.69H), 3.72 (m, 1.38H), 3.69 (m,
brine, dried over MgSO4, and concentrated in vacuo. The 0.62H), 2.19 (m, 0.31H), 2.10 (m, 0.69H), 1.85 (m, 1H),
residue was puri®ed by ¯ash column chromatography (SiO2; 1.56 (s, 3H), 1.31 (s, 0.94H), 1.30 (s, 2.06H), 0.85 (s, 9H),
n-hexane/EtOAc, 10:1) to give 8 (699.3 mg, 100%) as a 0.03 (s, 3H), 0.01 (s, 3H); 13C NMR (75 MHz, CDCl3) major
yellow oil. [a ]D27ˆ23.4 (c 1.11, CHCl3); IR (neat) 1736, d 165.3, 164.9, 133.2, 133.1, 129.8, 129.7, 129.6 (2£C),
1716, 1659 cm21; 1H NMR (300 MHz, CDCl3) d 6.91 (dt, 129.4 (2£C), 128.4 (2£C), 128.3 (2£C), 96.3, 76.6, 73.1,
Jˆ15.2, 7.3 Hz, 1H), 5.90 (d, Jˆ15.2 Hz, 1H), 4.98 (m, 1H), 65.4, 37.9, 28.9, 25.9 (3£C), 20.9, 18.8, 15.3, 25.2, 25.3.
4.18 (q, Jˆ7.3 Hz, 2H), 3.70 (m, 2H), 2.60 (m, 2H), 2.00 (s, Minor 166.0, 165.4, 132.9, 132.8, 130.3, 130.2, 129.9
3H), 1.91 (s, 3H), 1.28 (t, Jˆ7.2 Hz, 3H), 0.89 (s, 9H), 0.06 (2£C), 129.5 (2£C), 128.2 (2£C), 128.1 (2£C), 97.5,
(s, 6H); 13C NMR (75 MHz, CDCl3) d 171.1, 165.7, 143.0, 76.6, 73.9, 66.9, 36.6, 28.3, 25.9 (3£C), 21.2, 18.3, 15.3,
124.5, 74.2, 63.1, 60.3, 55.6, 33.1, 30.7 (2£C), 25.7 (3£C), 25.2, 25.3. HRMS (FAB) calcd for C28H38O6SiNa
18.1, 14.2, 25.5 (2£C). HRMS (FAB) calcd for (M1Na1) 521.2335, found 521.2359.
C18H33O5BrSiNa (M1Na1) 461.1160, found 461.1182.
4.1.5. Allylation of 11. To a stirred solution of 11 (61.4 mg,
4.1.3. d-Lactone 10. Ozone was bubbled to a stirred solu- 123.1 mmol) in MeCN (3 mL) were added BF3´Et2O
tion of 8 (791.1 mg, 1.81 mmol) in CH2Cl2 (15 mL) at (3.2 mL, 24.6 mmol), TMSOTf (4.6 mL, 24.6 mmol) and
2788C for 20 min. After N2 gas was bubbled to remove allyltrimethylsilane (98 mL, 615.6 mmol) at 08C under an
excess ozone, dimethyl sul®de (3.98 mL, 54.3 mmol) was argon atmosphere. After stirring at room temperature for
added. After stirring at 2788C for 30 min, at 08C for 1 h and 24 h, saturated aqueous NaHCO3 was added and the mixture
at room temperature for 1 h, the yellow solution was was extracted with EtOAc. The combined organic layers
concentrated in vacuo to give 9 as a yellow oil. To a stirred were washed with brine, dried over MgSO4, and concen-
solution of 9 in THF (5.3 mL) was added SmI2 (0.1 M in trated in vacuo. The residue was puri®ed by ¯ash column
THF, 54.3 mL, 5.43 mmol) at 08C under an argon chromatography (SiO2; n-hexane/EtOAc, 10:1) to give 12a
atmosphere. After stirring at 08C for 10 min, saturated (34.4 mg, 91%) and 12b (4.9 mg, 9%) as colorless oils. 12a:
aqueous NH4Cl was added and the mixture was extracted [a ]D29ˆ20.55 (c 1.09, CHCl3); IR (neat) 3456, 1718, 1641,
with EtOAc. The combined organic layers were washed 1602, 1585 cm21; 1H NMR (300 MHz, CDCl3) d 8.04 (m,
with saturated aqueous Na2S2O3 ±saturated aqueous 2H), 7.59 (m, 1H), 7.47 (m, 2H), 5.91 (m, 1H), 5.14 (m, 2H),
NaHCO3 and brine, dried over MgSO4, and concentrated 5.05 (t, Jˆ5.6 Hz, 1H), 4.11 (m, 1H), 3.82 (t, Jˆ10.2 Hz,
in vacuo. The residue was puri®ed by ¯ash column chroma- 1H), 3.51 (m, 2H), 2.61 (m, 1H), 2.34 (m, 1H), 2.04 (br, 1H),
tography (SiO2; n-hexane/EtOAc, 3:1, 1:1) to give 10 1.90 (m, 2H), 1.09 (s, 3H), 1.07 (s, 3H); 13C NMR (75 MHz,
(521.7 mg, 85%) as a colorless oil. [a ]D29ˆ23.1 (c 1.13, CDCl3) d 166.0, 136.1, 133.1, 130.2, 129.5 (2£C), 128.5
 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 calcd for C24H40O6SiNa (M1Na1) 475.2492, found
(2£C). HRMS (FAB) calcd for C18H24O4Na (M1Na1) 475.2512.
327.1572, found 327.1578. 12b: [a ]D26ˆ115.1 (c 1.15,
CHCl3); IR (neat) 1720, 1643, 1602, 1580 cm21; 1H NMR 4.1.8. Benzoylpedamide (4). To a stirred suspension of
(300 MHz, CDCl3) d 8.06 (m, 2H), 7.58 (m, 1H), 7.46 (m, NaH (11.7 mg, 292.8 mmol) in DMF (0.5 mL) was added
2H), 5.95 (m, 1H), 5.15 (m, 2H), 5.05 (m, 1H), 4.00 (dt, a solution of 14 (22.1 mg, 48.8 mmol) and MeI (15.2 mL,
Jˆ10.5, 5.5 Hz, 1H), 3.79 (dd, Jˆ10.5, 5.5 Hz, 1H), 3.71 243.8 mmol) in DMF (0.2 mL) at 08C under an argon
(dd, Jˆ10.5, 5.5 Hz, 1H), 3.58 (dd, Jˆ10.5, 2.8 Hz, 1H), atmosphere. After stirring at room temperature for 4 h, 1N
2.53 (m, 1H), 2.29 (m, 1H), 1.93 (m, 2H), 1.05 (s, 3H), 1.04 HCl±ice was added and the mixture was extracted with
(s, 3H), 0.91 (s, 9H), 0.08 (s, 6H); 13C NMR (75 MHz, EtOAc. The combined organic layers were washed with
CDCl3) d 165.9, 136.7, 132.9, 130.5, 129.5 (2£C), 128.4 brine, dried over MgSO4, and concentrated in vacuo to
(2£C), 115.8, 79.0, 75.4, 70.1, 64.9, 37.5, 33.3, 28.1, 25.9 give dimethoxy compound as an oil. Jones reagent was
(3£C), 24.4 (2£C), 18.2, 25.4, 25.5. HRMS (FAB) calcd added dropwise to a stirred solution of the product in
for C24H38O4SiNa (M1Na1) 441.2437, found 441.2427. acetone (0.51 mL) at 08C until faint red color persisted.
After stirring at room temperature for 30 min, the excess
4.1.6. TBS ether 12b from 12a. To a stirred solution of 12a Jones reagent was destroyed by the addition of i-PrOH.
(117.4 mg, 0.39 mmol) in CH2Cl2 (4.8 mL) were added The mixture was concentrated in vacuo, and then H2O
imidazole (92.1 mg, 1.35 mmol) and TBSCl (175.0 mg, was added. The mixture was extracted with EtOAc. The
1.16 mmol) at 08C under an argon atmosphere. After stirring combined organic layers were dried over MgSO4, and
at room temperature for 1.5 h, aqueous NH4Cl was added concentrated in vacuo to give 15 as an oil. The carboxylic
and the mixture was extracted with Et2O. The combined acid 15, PyBOP (60.2 mg, 115.2 mmol), and HOBt
organic layers were washed with H2O and brine, dried (15.5 mg, 115.2 mmol) were dissolved in DMF (0.3 mL)
over MgSO4, and concentrated in vacuo. The residue was at 08C under an argon atmosphere. To the mixture were
puri®ed by ¯ash column chromatography (SiO2; n-hexane/ added i-Pr2NEt (44.7 mL, 307.2 mmol) and NH4Cl
EtOAc, 10:1) to give 12b (161.3 mg, 100%) as a colorless (0.77 mg, 154.3 mmol) at room temperature. After stirring
oil. at room temperature for 1.5 h, H2O and EtOAc were added
and the mixture was extracted with EtOAc. The combined
4.1.7. Sharpless AD of 12b. To a stirred suspension of organic layers were washed with 1N HCl and saturated
(DHQ)2PYR (133.0 mg, 0.154 mmol) in t-BuOH±H2O aqueous NaHCO3, dried over MgSO4, and concentrated in
(1:1, 40 mL) were added K2CO3 (830.9 mg, 6.01 mmol), vacuo. The residue was puri®ed by ¯ash column chromato-
K3Fe(CN)6 (1.52 g, 4.62 mmol), OsO4 (96.0 mL, graphy (SiO2; EtOAc) to give 4 (15.9 mg, 86%) as colorless
0.924 mmol) and MeSO3NH2 (184.7 mg, 1.69 mmol) at crystals. mp 144±1468C (recrystallized from Et2O±n-
room temperature. After stirring at room temperature for hexane); [a ]D26ˆ115.7 (c 3.26, CHCl3); IR (KBr) 3432,
30 min, a solution of 12b (644.7 mg, 1.54 mmol) in 3330, 1719, 1684 cm21; 1H NMR (300 MHz, CDCl3) d
t-BuOH±H2O (1:1, 8 mL) was added at 08C. After stirring 8.03 (m, 2H), 7.54 (m, 1H), 7.45 (m, 2H), 5.49 (br. s, 2H),
at room temperature for 13 h, Na2SO3 (2.2 g) was added at 4.98 (dd, Jˆ10.7, 4.6 Hz, 1H), 4.48 (dd, Jˆ6.6, 2.6 Hz, 1H),
08C. After stirring at room temperature for 2 h, the mixture 3.61 (m, 2H), 3.55 (dd, Jˆ8.7, 2.7 Hz, 1H), 3.45 (m, 1H),
was extracted with EtOAc. The combined organic layers 3.42 (s, 3H), 3.39 (s, 3H), 2.59 (dd, Jˆ13.1, 4.6, 2.7 Hz,
were washed with brine, dried over MgSO4, and concen- 1H), 2.03 (ddd, Jˆ13.1, 10.7, 6.6 Hz, 1H), 1.86 (m, 2H),
trated in vacuo. The residue was puri®ed by ¯ash column 1.08 (s, 3H), 0.94 (s, 3H); 13C NMR (75 MHz, CDCl3) d
chromatography (SiO2; toluene/acetone, 7:1, 3:1) to give 13 174.0, 165.5, 133.0, 130.3, 129.6 (2£C), 128.4 (2£C), 78.9,
(158.3 mg, 22%) and 14 (466.6 mg, 68%) as colorless oils. 78.1, 74.9, 74.3, 72.4, 59.1, 56.6, 37.7, 30.1, 23.1, 14.4
13: [a ]D29ˆ114.9 (c 1.20, CHCl3); IR (neat) 3424, 1720, (2£C). HRMS (FAB) calcd for C20H29NO6Na (M1Na1)
1602, 1586 cm21; 1H NMR (300 MHz, CDCl3) d 8.01 (m, 402.1901, found 402.1891.
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, 4.1.9. Dibenzoylpederin (18) and 10-epi-dibenzoyl-
1H), 3.62 (m, 1H), 3.55 (m, 2H), 3.17 (br, 2H), 1.53±1.93 pederin (19). To a stirred solution of 4 (51.0 mg,
(m, 4H), 1.07 (s, 3H), 0.93 (s, 3H), 0.90 (s, 9H), 0.09 (s, 6H), 134.4 mmol) in CH2Cl2 (2.6 mL) was added Me3O1BF42
13
C NMR (75 MHz, CDCl3) d 165.9, 132.9, 130.2, 129.4 (199.2 mg, 1.34 mmol) at 08C under an argon atmosphere.
(2£C), 128.4 (2£C), 75.2, 73.2, 71.5, 68.9, 66.5, 65.7, 37.7, After stirring at room temperature for 17 h, saturated
30.8, 27.5, 25.8 (3£C), 18.2, 15.1, 14.9, 25.4, 25.5. HRMS aqueous NaHCO3 and Et2O were added at 08C and the
(FAB) calcd for C24H40O6SiNa (M1Na1) 475.2492, found mixture was extracted with Et2O. The combined organic
475.2501. 14: [a ]D29ˆ11.56 (c 1.11, CHCl3); IR (neat) layers were washed with saturated aqueous NaHCO3 ±
3459, 1717, 1602, 1585 cm21; 1H NMR (300 MHz, brine, dried over MgSO4, and concentrated in vacuo to
CDCl3) d 8.04 (m, 2H), 7.59 (m, 1H), 7.46 (m, 2H), 5.08 give 17. To a stirred solution of 3 (75.0 mg, 215.3 mmol)
(dd, Jˆ8.0, 5.5 Hz, 1H), 4.15 (m, 1H), 3.92 (m, 2H), 3.79 in HMPA (1.5 mL) was added n-PrSLi (0.55 M in HMPA,
(dd, Jˆ11.0, 1.4 Hz, 1H), 3.63 (dd, Jˆ11.0, 3.1 Hz, 2H), 585 mL, 236.8 mmol) at room temperature under an argon
3.52 (dd, Jˆ11.0, 6.1 Hz, 1H), 2.36 (br, 1H), 1.98 (m, 1H), atmosphere. After stirring at room temperature for 6 h, ice
1.89 (m, 2H), 1.62 (m, 1H), 1.07 (s, 3H), 1.01 (s, 3H), 0.93 was added and the mixture was extracted with Et2O. To the
(s, 9H), 0.12 (s, 3H), 0.11 (s, 3H); 13C NMR (75 MHz, aqueous layer were added 0.1N HCl (5 mL) and H2O (5 mL)
CDCl3) d 165.9, 133.0, 130.2, 129.5 (2£C), 128.4 (2£C), at 08C and the mixture was extracted with Et2O. The
79.2, 74.8, 72.5, 70.9, 66.6, 63.9, 37.7, 31.3, 27.5, 25.9 combined organic layers were washed with H2O and
(3£C), 23.9 (2£C), 18.3, 25.50, 25.53. HRMS (FAB) brine, dried over MgSO4, and concentrated in vacuo to
6364 T. Takemura et al. / Tetrahedron 58 (2002) 6359±6365

give carboxylic acid. To a stirred solution of SOCl2 References

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Acknowledgements mycalamide B: (b) Kocienski, P.; Raubo, P.; Davis, J. K.;
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This work was supported in part by Special Project Funding Trans. 1 1996, 1797.
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 T. Takemura et al. / Tetrahedron 58 (2002) 6359±6365 6365

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