Synthetic studies on FR182877: An asymmetric synthesis of the AB ring moiety of FR182877 via a diastereoselective intramolecular Diels-Alder reaction

Article abstract of DOI:10.1016/S0040-4039(02)00536-1

An asymmetric synthesis of the AB ring moiety of FR182877, possessing seven asymmetric centers, via a diastereoselective IMDA reaction is described.

Full text of DOI:10.1016/S0040-4039(02)00536-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 3263–3267
Synthetic studies on FR182877: an asymmetric synthesis of the
AB ring moiety of FR182877 via a diastereoselective
intramolecular Diels–Alder reaction
Takahiro Suzuki and Masahisa Nakada*
Department of Chemistry, School of Science and Engineering, Waseda University, 3-4-1 Ohkubo, Shinjuku-ku,
Tokyo 169-8555, Japan
Received 25 February 2002; accepted 15 March 2002
Abstract—An asymmetric synthesis of the AB ring moiety of FR182877, possessing seven asymmetric centers, via a diastereo-
selective IMDA reaction is described. © 2002 Elsevier Science Ltd. All rights reserved.
FR182877 (Fig. 1), a compound formerly known as
WS9885B, was isolated from the fermentation broth of
Streptomyces sp. No9885 by the research group of
Fujisawa Pharmaceutical Company in 1998, and its
absolute structure and biological activity have been
reported.1,2 These reports have disclosed the unprece-
dented hexacyclic structure of FR182877 including a
bridgehead alkenyl ether,3 and 12 asymmetric centers,
as well as its Taxol®-like potent cytotoxic biological
activity. The complex structure and promising biologi-
cal activity of FR182877 have provided us with a
strong motive to achieve its total synthesis.4 In this
paper we report an asymmetric synthesis of the AB ring
moiety of FR182877 via a diastereoselective intramolec-
ular Diels–Alder (IMDA) reaction.
ring moiety is so strained and reactive that an alkenyl
ether in the DEF ring moiety is easily oxidized in air to
afford an epoxide.1 Thus, we set compound 1 as a key
intermediate in our synthesis, and from which we envi-
sioned to construct the C ring moiety. Our retrosyn-
thetic analysis of the AB ring moiety is shown in
Scheme 1.
Since compound 1 is a trans-bicyclo[4.3.0]non-2-ene
derivative, it is rational to construct the AB ring moiety
via the IMDA reaction of 2. Because 2 is a terminally
activated nonatriene possessing E,E-diene and E-
dienophile in its molecule, if the IMDA reaction pro-
ceeds via endo transition state, 2 would afford the
trans-fused cycloadduct with the desired relative
configuration on the B ring. Actually, many reports
show that trans-fused cycloadducts are favored in the
cyclization of such terminally activated nonatrienes.5,6
We planned to synthesize the AB ring moiety of
FR182877 first, then the C ring moiety, and the DEF
ring moiety at the end of the synthesis because the DEF
However, the diastereoselectivity of the IMDA reaction
of chiral nonatrienes is rather complicated, and some-
times unexpected results have been obtained.5 The sub-
strates possessing allylic heteroatom substituents,
particularly allylic alkoxy groups, give interesting
results because these substituents are less sterically
demanding than alkyl groups and electronic effects may
intervene such that an axial orientation in the transition
state is sometimes favored.5 The IMDA reaction of
triene 2, possessing three successive asymmetric centers
with two allylic hydroxy groups between E,E-diene and
E-dienophile, has not been studied so far as we know.7
Hence, we started the synthesis of 2 and the investiga-
tion of its IMDA reaction.
OH
O
O
E
H
H
H H
A
HO
H
B
D
F
C
O
H
H
Figure 1. FR182877.
Keywords: FR182877; intramolecular Diels–Alder reaction; asymmet-
ric synthesis.
* Corresponding author. Tel./fax: +813-5286-3240; e-mail: mnakada
@mn.waseda.ac.jp
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00536-1

3264
T. Suzuki, M. Nakada / Tetrahedron Letters 43 (2002) 3263–3267
sis of the substrates for the IMDA reaction is shown in
Scheme 2.
Our retrosynthetic analysis of 2 is shown in Scheme 1.
Triene 2 would be synthesized by Kishi–Nozaki cou-
pling of (E)-methyl 2-iodoacrylate8 with aldehyde 3
though the diastereoselective construction of C-6 asym-
metric center9 in 3 should be a problem. Aldehyde 3
was expected to be obtained via compound 4 which
would be prepared by Evans’ syn-selective asymmetric
aldol reaction10 using the known aldehyde 5.11 Synthe-
Aldol reaction of 5 with 6 under the Evans condition
afforded syn-product 4 with high selectivity; however,
hydrolysis of 4 or direct conversion of the TIPS ether of
4 to the corresponding aldehyde was low-yielding under
any conditions. Hence, 4 was converted to Weinreb
amide 7, which was then silylated, and the resulting
TIPS ether 8 was successfully transformed to the alde-
hyde 9 in high yield.
OR1
6
8
R4O
H
A
Intramolecular
H
H
FR182877
We hoped that a 1,2-asymmetric induction, which
could be explained by the Felkin–Anh model, would
occur in the Kishi–Nozaki coupling12 of the aldehyde 9
with methyl (E)-2-iodoacrylate. The coupling reaction
proceeded smoothly to afford products (10a+10b) in
93% yield, but the diastereoselectivity was only 2:1
(=10a:10b).13,14 Furthermore, 10a was inseparable
from 10b by silica gel column chromatography, and
derivatizations of 10a and 10b gave no separable
mixture.
CO2R
B
3
2
Diels-Alder
reaction
OR
H
1
OR1
R4O
Kishi-Nozaki
coupling
R3O
CHO
OR4
CO2R
2
OR3
3
2
i-Pr
Fortunately, we found that MnO2 oxidation of 10b was
faster than that of 10a (Scheme 3). Hence, the condi-
tions for the MnO2 oxidation were optimized, and
finally when 3.5 equivalent of MnO2 to the starting
material (10a+10b) by weight was used for this reaction,
the starting material (10a+10b) was recovered in 42%
yield and the ratio of 10a:10b was improved to 20:1.15
At the same time, ketone 11 was obtained in 51% yield,
and 11 was easily separated by silica gel chromatogra-
phy. Compound 11 was easily reduced to the starting
material (10a+10b) by NaBH(OMe)3 in 82% yield
(10a:10b=2:1). Repeating this oxidation–separation–
reduction cycle, almost pure 10a was obtained. Com-
pound 10a was converted to 12 by the Mitsunobu
reaction, and the following methanolysis afforded pure
10b.
Evans' aldol
reaction
N
O
R3O
OH
O
O
4
TBSO
CHO
5
Scheme 1. Retrosynthetic analysis of the AB ring moiety of
FR182877.
i-Pr
i-Pr
a
5
+
b
O
O
N
N
TBSO
O
O
OH O
O
4
6
With substrates (10a, 10b, and 12) in hand, we next
examined the IMDA reactions. First, 10a was subjected
to the IMDA reaction; thus, 10a was dissolved in
toluene and heated at 80°C in the presence of BHT
under Ar atmosphere. Though completion of the reac-
tion required 24 h, the reaction proceeded cleanly to
d
N
TBSO
OMe
R4O
7 (R4 = H)
O
c
8 (R4 = TIPS)
e
a
TBSO
CHO
CO2Me
TBSO
+
10a + 10b
10a + 10b
TIPSO
9
TIPSO
O
b
11
CO2Me
c
TBSO
CO2Me
10a
TBSO
R5 R6
TIPSO
TIPSO
12 (R = Bz)
10b (R = H)
OR
10a (R5 = OH, R6 = H) + 10b (R5 = H, R6 = OH)
d
Scheme 2. Reagents and conditions: (a) n-Bu2BOTf, TEA,
CH2Cl2, −78°C to rt, 96%; (b) MeONHMe-HCl, Me3Al,
THF, 0°C to rt; (c) TIPSOTf, TEA, CH2Cl2, 0°C, 93% (two
steps); (d) DIBAL-H, THF, −78°C, 94%; (e) methyl (E)-2-
iodoacrylate, NiCl2, CrCl2, NaHCO3, THF, rt, 10a+10b=
93%, (10a:10b=2:1).
Scheme 3. Reagents and conditions: (a) MnO2 (3.5 equiv. to
10 by weight), CH2Cl2, rt, 50 min, 10a+10b=42%, (10a:10b=
20:1), 11 (51%); (b) NaB(OMe)3H, MeOH, rt, 10a+10b=82%,
(10a:10b=2:1); (c) PPh3, DEAD, BzOH, toluene, 71%; (d)
K2CO3, MeOH, 0°C to rt, 58%.

T. Suzuki, M. Nakada / Tetrahedron Letters 43 (2002) 3263–3267
3265
develop the construction of the C ring and the DEF
ring moieties because the yield of 13 was good, whereas
both 10b and 12 afforded the desired products in less
than 50% yield. Furthermore, asymmetric centers on
the B-ring of 16a and 16b cannot be inverted. Hence,
we next examined the inversion of the C-6 asymmetric
center of 13.
Scheme 4. Reagents and conditions: (a) BHT, toluene, 80°C,
24 h, 82% (>10:1); (b) p-BrBzCl, DMAP, CH2Cl2, rt, 94%; (c)
TBAF, THF, rt, quant. (d) p-BrBzCl, DMAP, CH2Cl2, rt,
83%.
The inversion of the C-6 asymmetric center of 13 by the
Mitsunobu protocol resulted in low yield, and the yield
did not exceed 15% in spite of extensive optimizations.
Therefore, we next tried the inversion by an oxidation–
reduction sequential operation for 13. Thus, 13 was
oxidized to ketone 17 by Dess–Martin oxidation with-
out epimerization, and then a diastereoselective reduc-
tion of 17 was examined (Scheme 6). Anticipating the
predominant formation of the energetically favored
alcohol 18, the reduction via a radical anion intermedi-
ate was carried out. However, 18 was not formed
selectively by such reduction.18 Hence, other reducing
reagents were examined, and we found that reduction
afford two products and the major product 13 was
isolated in 82% yield with >10:1 selectivity (Scheme 4).
The major product 13 was successfully transformed to a
crystalline p-bromobenzoate 14,16 and its whole struc-
ture was confirmed by X-ray crystallographic analysis.
The result of the X-ray crystallographic analysis clearly
shows that all asymmetric centers in 13 have been
constructed as we expected (Fig. 2).
On the other hand, the IMDA reaction of 10b afforded
15a (y.49%), 16a (y.42%), and 12 afforded 15b (y.41%),
16b (y.47%), respectively (Scheme 5).17 Compound 13
was converted to 15b by the Mitsunobu reaction, and
15a was benzoylated to afford 15b (Schemes 5 and 7),
so that structures of 15a and 15b were determined as
shown in Scheme 5. The selectivities of the IMDA
reactions of 10a, 10b, and 12 must be discussed care-
fully after further investigation because the selectivities
observed cannot be explained only by the steric interac-
tions in the endo transition states.5
Scheme 5. Reagents and conditions: (a) BHT, toluene, 80°C,
24 h; (b) Bz2O, DMAP, 1,2-dichloroethane, reflux, 64%; (c)
Bz2O, DMAP, CH2Cl2, rt, 73%.
Considering the results of the IMDA reactions
described above, 13 is a most promising intermediate to
Figure 2. X-Ray crystal structure of 14.

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T. Suzuki, M. Nakada / Tetrahedron Letters 43 (2002) 3263–3267
3. Hexacyclinic acid, possessing a similar carbon frame-
work, has also been isolated. See: Ho¨fs, R.; Walker, M.;
Zeeck, A. Angew. Chem., Int. Ed. Engl. 2000, 39, 3258–
3261.
4. For postulated biogenesis of FR182877 and progress
toward its enantioselective synthesis, see: (a) Vanderwal,
C. D.; Vosburg, D. A.; Weiler, S.; Sorensen, E. J. Org.
Lett. 1999, 1, 645–648; (b) Vanderwal, C. D.; Vosburg,
D. A.; Sorensen, E. J. Org. Lett. 2001, 3, 4307–4310.
5. For reviews, see: Roush, W. R. In Comprehensive Organic
Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon:
Oxford, 1991; Vol. 5, pp. 513–550 and references cited
therein and in Ref. 6.
6. For recent examples of the IMDA of terminally activated
nonatrienes affording cis-fused products, see: (a) Chang,
J.; Paquette, L. A. Org. Lett. 2002, 4, 253–256 and
references cited therein. (b) Munakata, R.; Ueki, T.;
Katakai, H.; Takao, K.; Tadano, K. Org. Lett. 2001, 3,
3029–3032.
7. While we are investigating the IMDA reaction of 2, the
IMDA reaction of the substrate possessing the same
substituent pattern has been reported, see Ref. 4b.
8. Ohba, M.; Kawase, N.; Fujii, T. J. Am. Chem. Soc. 1996,
118, 8250–8257.
9. The same numbering system having been taken up to
FR182877 is used.
10. Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc.
1981, 103, 2127–2129.
Scheme 6. Reagents and conditions: (a) Dess–Martin reagent,
NaHCO3, CH2Cl2, rt, 90%; (b) DIBAL-H, CH2Cl2, −78°C,
70%, (18:19=4.4:1).
OH
H
H
a
b
TIPSO
c
OH
13
15b
18
H
OTBS
H
19
Scheme 7. Reagents and conditions: (a) PBu3, DEAD, BzOH,
toluene, rt, 13%; (b) DIBAL-H, CH2Cl2, −78°C, 35%; (c)
DIBAL-H, CH2Cl2, −78°C, 59%.
of 17 by DIABAL-H afforded 1819 in 70% isolated yield
with 4.4:1 (=18:13) selectivity.20 Since the spectral data
of 18 was consistent with that of the diol obtained from
15b, and 13 was reduced to the corresponding diol 19
(Scheme 7),21 the structure of 18 was determined as
shown in Scheme 6. Diol 18 was separable from its
epimer 19 by silica gel column chromatography, so that
three chiral intermediates, 15a, 15b, and 18, possessing
all the desired asymmetric centers for the synthesis of
FR182877 have been prepared.
11. The known compound 5 was easily prepared from the
commercially available aldehyde. See: Zhang, H.; Lerro,
K. A.; Takekuma, S.-I.; Baek, D.-J.; Moquin-Pattey, C.;
Boehm, M. F.; Nakanishi, K. J. Am. Chem. Soc. 1994,
116, 6823–6831.
12. (a) Jin, H.; Uenishi, J.-I.; Christ, W. J.; Kishi, Y. J. Am.
Chem. Soc. 1986, 108, 5644–5646; (b) Takai, K.;
Tagashira, M.; Kuroda, T.; Oshima, K.; Utimoto, K.;
Nozaki, H. J. Am. Chem. Soc. 1986, 108, 6048–6050. For
recent progress of Kishi–Nozaki reaction, see: (c) Fu¨rst-
ner, A. Chem. Rev. 1999, 99, 991–1045.
13. Optimization of this reaction (investigation of solvent,
temperature, and additive) has been examined, but no
promising result has been observed. Use of chiral ligands
(spartein and Evans’ bisoxazoline ligand) had no effect
on this reaction.
In summary, we have succeeded in an asymmetric
synthesis of the AB ring moiety of FR182877, possess-
ing seven asymmetric centers, via a diastereoselective
IMDA reaction. Further synthetic studies on FR182877
including construction of the C ring and the DEF ring
moieties will be reported in due course.
Acknowledgements
14. Alcohols 10a and 10b were transformed to the corre-
sponding acetonides, and the relative configurations were
We thank Material Characterization Central Labora-
tory, Waseda University, for technical support of the
X-ray crystallographic analysis of 14.
1
determined by the coupling constant of the H NMR.
15. In this MnO2 oxidation not only the amount of MnO2,
but also the reaction time was important. The reaction
time over 50 min reduced the recovery yield of 10a.
Procedure for MnO2 oxidation of 10a+10b. To a stirred
solution of 10a+10b (4.08 g, 7.53 mmol) in CH2Cl2 (100
ml) was added MnO2 (14.28 g) in one portion at room
temperature. After stirring the reaction mixture for 50
min under Ar atmosphere at room temperature, MnO2 in
the reaction mixture was filtered through Celite, and the
filtrate was evaporated to dryness. The obtained residue
was subjected to silica gel column chromatography (hex-
ane:ethyl acetate=20:1) to afford 10a+10b (1.72 g, 42%,
10a:10b=20:1) and 11 (2.08 g, 51%).
References
1. Muramatsu, H.; Miyauchi, M.; Sato, B.; Yoshimura, S.;
Takase, S.; Terano, H.; Oku, T. 40th Symposium on the
Chemistry of Natural Products, Fukuoka, Japan, 1998,
Paper 83, pp. 487–492.
2. (a) Sato, B.; Muramatsu, H.; Miyauchi, M.; Hori, Y.;
Takase, S.; Hino, M.; Hashimoto, S.; Terano, H. J.
Antibiot. 2000, 53, 123–130; (b) Sato, B.; Nakajima, H.;
Hori, Y.; Hino, M.; Hashimoto, S.; Terano, H. J.
Antibiot. 2000, 53, 204–206; (c) Yoshimura, S.; Sato, B.;
Kinoshita, T.; Takase, S.; Terano, H. J. Antibiot. 2000,
53, 615–622.
16. 14: White crystal (hexane-CH2Cl2), mp 233°C (decomp.);
1H NMR (400 MHz, CDCl3) l=7.90 (2H, d, J=8.3 Hz),
7.82 (2H, d, J=8.3 Hz), 7.60 (2H, d, J=8.3 Hz), 7.59

T. Suzuki, M. Nakada / Tetrahedron Letters 43 (2002) 3263–3267
3267
(2H, d, J=8.3 Hz), 5.87 (1H, dd, J=5.9, 4.4 Hz), 5.73
(1H, s), 5.22 (1H, dd, J=5.6, 1.2 Hz), 4.64 (1H, dd,
J=8.8, 8.8 Hz), 3.99 (1H, dd, J=10.3, 8.8 Hz), 3.16 (1H,
ddd, J=10.3, 8.8, 8.5 Hz), 2.99–2.90 (2H, m), 2.64 (1H,
ddq, J=7.6, 5.9, 1.2 Hz), 2.35 (1H, ddd, J=12.7, 12.7,
4.4 Hz), 1.68 (3H, s), 1.15 (3H, d, J=7.6 Hz); 13C NMR
(100 MHz, CDCl3) l=176.3, 165.4, 164.5, 134.4,
131.8(2C), 131.8(2C), 131.0(2C), 131.0(2C), 128.8, 128.7,
128.3, 128.2, 122.2, 81.03, 73.96, 71.71, 47.60, 43.66,
42.50, 40.53, 38.47, 21.16, 13.21; IR (KBr) wmax 2972,
2932, 2884, 1766, 1732, 1708, 1592, 1398, 1274, 1172,
1104, 1070, 1012, 756 cm−1; FAB MS [M+H]+ calcd for
C27H25Br2O6: 603.0018, found: 603.0016; [h]1D9 +68.7 (c
0.28, CHCl3); Crystallographic data: empirical formula=
C27H24Br2O6; formula weight=604.29; crystal system=
16a and 16b are assumed to be the same because 1H
NMR of 16a and 16b showed almost the same coupling
constants between the protons on the B rings.
18. For example, reduction of 17 by SmI2 afforded 13 as the
sole product.
19. 18: 1H NMR (400 MHz, CDCl3) l=5.52 (1H, s), 4.07
(1H, b), 3.90 (2H, m), 3.81 (1H, d, J=3.9 Hz), 3.78 (1H,
dd, J=11.5, 9.3 Hz), 3.68–3.63 (2H, m), 3.48 (1H, dd,
J=9.3, 4.9 Hz), 2.35 (1H, ddd, J=11.7, 11.5, 9.5 Hz),
2.26 (1H, m), 1.98–1.91 (2H, m), 1.87–1.80 (1H, m), 1.71
(3H, s), 1.13 (3H, d, J=7.6 Hz), 1.06–0.95 (21H, m), 0.92
(9H, s), 0.12 (3H, s), 0.11 (3H, s); FAB MS [M+H]+ calcd
for C28H57O2Si2: 513.3795, found: 513.3803.
20. This selectivity has not been explained clearly and more
investigation is needed, but it seems that the selectivity
cannot be explained only by the steric hindrance around
the carbonyl group.
,
monoclinic; space group=P21/a (c4); a=6.0055(3) A;
,
,
b=13.1683(4) A; c=15.4577(8) A; i=92.662(1)°; V=
1221.11(8) A ; Z=2; Dcalc=1.643 g/cm3; crystal dimen-
sions=0.15×0.15×0.10 mm; data collection
temp=123.0 1 K; radiation=MoKa (u=0.71069 A);
v(MoKa)=33.71 cm−1
number of reflections mea-
3
,
21. 19: 1H NMR (400 MHz, CDCl3) l=5.60 (1H, s), 4.24
(1H, dd, J=4.9, 4.2 Hz), 3.93–3.82 (3H, m), 3.67 (1H, dd,
J=10.7, 8.5 Hz), 3.58 (1H, dd, J=10.7, 10.7 Hz), 2.44–
2.36 (2H, m), 2.20–2.08 (2H, m), 1.99 (1H, ddd, J=12.2,
11.7, 3.2 Hz), 1.73 (3H, s), 1.07 (3H, d, J=7.8 Hz),
1.05–0.95 (21H, m), 0.91 (9H, s), 0.09 (3H, s), 0.08 (3H,
s); FAB MS [M+H]+ calcd for C28H57O2Si2: 513.3795,
found: 513.3785.
,
;
sured=11353; number of unique reflections=2909
(Rint=0.061); Residuals: R1(I>2|(I))=0.031; Residuals:
wR2=0.107.
17. Yields are isolated yields. Structures of 16a and 16b have
not been determined, but the relative configurations of