Synthetic studies on (-)-FR182877: construction of the ABCD ring system via the intramolecular cycloadditions (1)

Article abstract of DOI:10.1016/j.tetlet.2007.07.051

Construction of the ABCD ring system of (-)-FR182877 via the highly diastereoselective intramolecular Diels-Alder (IMDA) reaction is described. The IMDA reaction of the α,β-unsaturated aldehyde generated in situ from the corresponding acetal successfully provided the desired product 14 possessing the AB ring system as the single diastereomer. The CD ring system was constructed by the subsequent IMHDA reaction and the additional experiment suggested that the diastereoselectivity of the IMHDA reaction could be related to the E/Z geometry of alkene 17, which was generated in situ from 16.

Full text of DOI:10.1016/j.tetlet.2007.07.051

Tetrahedron Letters 48 (2007) 6483–6487
Synthetic studies on (–)-FR182877: construction of the ABCD
ring system via the intramolecular cycloadditions (1)
Takahiro Suzuki, Natsumi Tanaka, Takehiko Matsumura,
Yosuke Hosoya and Masahisa Nakada*
Department of Chemistry and Biochemistry, Faculty of Science and Engineering, Waseda University, 3-4-1 Ohkubo,
Shinjuku-ku, Tokyo 169-8555, Japan
Received 13 June 2007; revised 6 July 2007; accepted 10 July 2007
Available online 13 July 2007
Abstract—Construction of the ABCD ring system of (–)-FR182877 via the highly diastereoselective intramolecular Diels–Alder
(IMDA) reaction is described. The IMDA reaction of the a,b-unsaturated aldehyde generated in situ from the corresponding acetal
successfully provided the desired product 14 possessing the AB ring system as the single diastereomer. The CD ring system was con-
structed by the subsequent IMHDA reaction and the additional experiment suggested that the diastereoselectivity of the IMHDA
reaction could be related to the E/Z geometry of alkene 17, which was generated in situ from 16.
Ó 2007 Elsevier Ltd. All rights reserved.
Sato and co-workers in Fujisawa Pharmaceutical Com-
pany isolated (–)-FR182877 (Fig. 1) from Streptomyces
sp. no. 9885 in 1998.1a (–)-FR182877 exhibited the
taxol-like potent activity of promoting microtubule
assembly to induce cell cycle arrest.1b The structure of
(–)-FR182877 was unprecedented, possessing a hexa-
cyclic skeleton incorporating a bridgehead alkenyl ether
and twelve stereogenic centers. Its absolute configura-
tion was first reported as the enantiomer of the structure
shown in Figure 11c but was corrected later.1d,2,3
reported (–)-FR182876 (Fig. 1),1e which was more stable
and water-soluble than (–)-FR182877 but showed
almost same bioactivity as that of (–)-FR182877, incited
further interest in these polycyclic natural products.
Although two groups succeeded in the total synthesis
of (–)-FR182877,2,3 the complex polycyclic structure
and the taxol-like bioactivity of (–)-FR182877 have
heightened our interest4 and that of other synthetic
chemists in its total synthesis via different synthetic
approaches.5–8 We herein report construction of the
ABCD ring system of (–)-FR182877 via the two intra-
molecular cycloadditions.
The novel and complex structure as well as the promis-
ing bioactivity of (–)-FR182877 have attracted synthetic
chemists to its total synthesis. In addition, recently
Since our report of the synthesis of the AB ring system
of (–)-FR182877 via the diastereoselective intramole-
cular Diels–Alder (IMDA) reaction,4 the construction of
the CDEF ring system has remained undone. The EF
ring system was highly strained; hence, it was rational
to construct this moiety in the late stage of the total syn-
thesis. Consequently, we next sought to construct the
CD ring system of (–)-FR182877 from the compound
incorporating the AB ring system.
OH
H
OH
H
O
H
O
E
O
O
E
H
H
H
A
A
H
H H
HO
HO
F
O
F
OR
H
H
D
D
B
B
C
C
O
H
H
H
H
(-)-FR182877
(-)-FR182876
AcNH(CH2)2CONH
O
N
N
R=
We set compound 1 (Scheme 1) as a target molecule in
this study because 1 possesses the ABCD ring system
of (–)-FR182877. The configuration of one hydroxyl
group in the A-ring system is reversed, but this has been
found to be inverted.4a This reversed configuration in 1
was originally set in 5 (Scheme 1) to attain the high
Figure 1. Structure of (–)-FR182877 and (–)-FR182876.
*
Corresponding author. Tel./fax: +813 5286 3240; e-mail: mnakada@
waseda.jp
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.07.051

6484
T. Suzuki et al. / Tetrahedron Letters 48 (2007) 6483–6487
OR1
OR1
OR1
OR1
CO2Me
O
H
CO2Me
O
CO2Me
H
H
H
H
H
H
E
E
H
H
A
TIPSO
TIPSO
TIPSO
TIPSO
Z
H
H
B
H
H
D
O
C
OTBS
OTBS
OTBS
OTBS
H
H
H
H
H
4
3
1
2
OR1
E
O
Me
NMe(OMe)
TIPSO
TIPSO
Z
N
TBSO
AcO
OMe
+
TIPSO
O
OTBS
OTBS
7
8
5
6
Scheme 1. Retrosynthetic analysis of 1.
diastereoselectivity in the IMDA reaction.4b The CD
ring system of 1 was envisioned to be constructed via
the intramolecular hetero- Diels–Alder (IMHDA) reac-
tion of 2. The enone system in 2 was anticipated to be
reactive because of its highly electron deficient nature
due to the two attached electron withdrawing groups.
Hence, 2 was planned to generate in situ from b-keto
ester 3 by dehydrogenation, or alternatively, from
aldehyde 4 (Z = CHO) via Knoevenagel condensation.
b-Keto ester 3 would be obtained by the alkylation of
methyl 3-oxo-pentanoate with 4 (Z = CH2I), which
ly, the yield was increased to 99%. Reduction of 6 with
DIBAL-H provided the corresponding aldehyde in
excellent yield (97%), which was subjected to Nozaki–
Hiyama–Kishi reaction with (E)-methyl 2-iodoacrylate4
to afford a mixture of 10a and 10b (98%, 2:1). This mix-
ture was fortunately separated to 10a (40%) and 10b0
(49%) by the kinetic oxidative separation using MnO2,
which was previously reported by us.4
The IMDA reaction of 10a provided a mixture of 11a
(60%) and 11b (20%) (Scheme 2). The structure of 11a
was elucidated by the NOE experiments on its deriva-
tive,11 revealing that 11a had the desired stereochemis-
try. Although 11a was the potential intermediate for
further synthetic studies, the overall yield in Scheme 2
was unsatisfactory; hence, another synthetic approach
was pursued. Since we found that 10a was stereoselec-
tively obtained by the reduction of 10b0, the substrate
for the IMDA reaction, which was actually its precursor
13, was prepared from 12 (Scheme 3).
was thought to be derived from aldehyde
4
(Z = CHO), which in turn could be prepared via the
IMDA reaction of 5. Compound 5 was expected to be
obtained from amide 6, which would be obtained by
Negishi coupling reaction9 of the readily available 7 with
8.
We prepared 8 from the reported 94b (Scheme 2). Thus,
alcohol 9 was protected as a TIPS ether (100%), fol-
lowed by the selective removal of the TBS ether with
1 M HCl in EtOH (93%) and subsequent acetylation
to provide 8 (98%). Negishi coupling reaction of 7 with
8 under the conventional conditions9 resulted in a cer-
tain leftover amount of 8, but we found that the use
of LiCl and Ph3As greatly improved the yield of 6. We
also found that the carbometalation of 7 under Wipf’s
conditions10 dramatically accelerated the reaction; final-
That is, the reaction of amide 6 with an excess amount
of lithiated dimethyl methylphosphonate provided
b-keto phosphonate 12 in 91% yield. Horner–Wads-
worth–Emmons reaction of 12 with dimethoxyacetalde-
hyde using barium hydroxide as the base12 provided 13
with excellent yield (95%) and E-selectivity. Reduction
of 13 by lithium triethylborohydride at ꢀ100 °C success-
1) 7 (2.0 equiv), Cp2ZrCl2 (0.4 equiv), AlMe3 (2.0 equiv)
CH2Cl2, H2O, rt, 24 h
1) TIPSOTf, TEA, CH2Cl2, rt, 10 min, 100%
2) 1M HCl / EtOH (1/100), rt, 3 h, 93%
Me
N
8
6
TBSO
OMe
3) Ac2O, Py, DMAP, CH2Cl2, rt, 1.5 h, 98%
2) Pd2(dba)3 (2.5 mol %), AsPh3 (0.1 equiv)
LiCl (1.0 equiv), THF, 0 oC, 1.5 h, 99%
HO
O
9
R1
R2
OH
E
E
1) DIBAL-H,THF, -78 oC, 1.5 h, 97%
2) ( )-ICHCHCO2Me (2.5 equiv), NiCl2 (5 mol %)
CrCl2 (5.0 equiv), NaHCO3 (0.5 equiv), THF, rt
1.5 h, 98%
CO2Me
TIPSO
CO2Me
TIPSO
MnO2
E
CH2Cl2, rt
OTBS
OTBS
10a (R1=H, R2=OH); 10b' (R1=R2=O)
10a:10b=2:1
40%
49%
(single diastereomer)
BHT
OH
OH
(0.05 equiv)
H
H
CO2Me
CO2Me
10a
TIPSO
+
TIPSO
toluene, 80 oC
24 h, 80%
H
OTBS
OTBS
H
11a 60%
11b 20%
Scheme 2. Preparation of 10a and its IMDA reaction.

T. Suzuki et al. / Tetrahedron Letters 48 (2007) 6483–6487
6485
1) LiEt3BH, THF, -100 o
30 min, 98% (>10:1)
C
(MeO)2P(O)Me
(3.0 equiv)
O
O
(MeO)2CHCHO (2.0 equiv)
Ba(OH)2-8H2O (1.0 equiv)
OMe
E
TIPSO
TIPSO
6
P(O)(OMe)2
OMe
THF, rt, 30 min, 95%
n
-BuLi (2.5 equiv)
2) HCO2H (0.4 %)
hexane, rt, 2 d, 67%
THF, -78 oC, 2 h, 91%
OTBS
OTBS
12
13
1) Ac2O, Py, DMAP
CH2Cl2, rt, 2 h, 83%
2) NaBH4, MeOH
OAc
OH
H
H
OAc
CO2Me
MeO2CCH2COC2H5
(5.0 equiv)
Cs2CO3 (4.8 equiv)
H
H
H
H
TIPSO
TIPSO
TIPSO
CHO
oC, 30 min, 82%
I
0
H
H
H
O
OTBS
OTBS
OTBS
CH3CN/THF (2/1)
reflux, 64%
3) PPh3, I2, imidazole
CH3CN / Et2O (2 / 1)
rt, 11 h, 90%
H
H
H
14
15
16
OAc
OAc
OAc
CO2Me
O
CO2Me
CO2Me
H
H
H
(PhSeO)2O (2.0 equiv)
SO3-py (2.1 equiv)
H
H
H
H
H
TIPSO
TIPSO
TIPSO
H
H
H
+
O
O
TEA (5.3 equiv)
THF, rt, 2 d
OTBS
OTBS
OTBS
H
H
H
H
H
17
18a 50%
18b 9%
Scheme 3. Synthesis of 18b.
fully provided the desired alcohol (98%) with high dia-
stereoselectivity (>10:1), which was well explained by
the Felkin model.
The plausible transition state models are proposed in
Figure 2, which could explain the diastereoselectivity
of the IMHDA reaction of 17. Considering the A1,3
-
strain existing in 17, we believe that the three transition
state models, TS-1, TS-2, and TS-3, are important. TS-1
could be more stable than TS-2 because the steric strain
shown in Figure 2. Transition states derived from 17E
would be limited to TS-3 because two A1,3-strains arose
from the trisubstituted alkenes. The transition state
models proposed in Figure 2 suggested that the product
18a would be derived from 17Z via TS-1, and 18b from
both 17Z and 17E via TS-2 and TS-3, respectively. Con-
sequently, the desired product 18b could be produced
from 17E.
Hydrolysis of the acetal in the product with 0.4%
HCO2H in hexane generated the corresponding alde-
hyde, which underwent the IMDA reaction spontane-
ously to provide the desired product 14 as the single
diastereomer (67%). The stereochemistry of 14 was con-
firmed as that shown in Scheme 3 by the chemical corre-
lation with the compound derived from 11a.11
To construct the enone system incorporated in com-
pound 2, Knoevanagel condensation of 14 with methyl
3-oxopentanoate was first attempted, but no desired
product was obtained under any conditions. Hence, 14
was converted to iodide 15 via acetylation (83%),
NaBH4 reduction (82%), and iodination (90%) to exam-
ine the reaction with methyl 3-oxopentanoate. The
alkylation reaction of methyl 3-oxopentanoate with
the iodide 15 in DMF/THF (2/1) using K2CO3 formed
16 (24%) along with the O-alkylated product (35%),
but finally, use of Cs2CO3 in CH3CN/THF provided
16 (64%) and reduced the O-alkylated product (22%).
The E/Z ratio of the enone intermediate 17 in situ gen-
erated from 16 was unable to be determined because 17
was too reactive to isolate. Consequently, to collect the
information about the E/Z ratio of 17, compound 19,
lacking the alkene to be reacted, was prepared and sub-
jected to the same dehydrogenation conditions (Scheme
4). As a result, the E/Z ratio of enone 20 was found to
be 1/2.4.15 This ratio does not exactly correspond to
the ratio of 18a and 18b but suggests the diastereoselec-
tivity of the IMHDA reaction of 17 could be related to
its E/Z ratio. In addition, if the equilibrium between 17E
and 17Z exists under the conditions in Scheme 3 and the
IMHDA from 17Z is faster, preferential formation of
18a could be explained rationally.
b-Keto ester 16 in hand, introduction of the double
bond into 16 for the IMHDA reaction was examined.
Among the conditions surveyed, we found that use of
benzeneselenenic acid anhydride3 gave the best result,
causing dehydrogenation, followed by the IMHDA
reaction to provide 18a (50%) and 18b (9%).
In summary, construction of the ABCD ring system of
FR182877 via two intramolecular cycloadditions was
developed. The IMDA reaction of the a,b-unsaturated
aldehyde generated in situ from 13 provided the desired
product 14 as the single isomer and the subsequent IM-
HDA reaction was found to provide the CD ring sys-
tem. The diastereoselectivity of the IMHDA reaction
should be improved for further synthetic studies, but
the analysis of the transition states of 16 suggested that
the use of E-alkene for the IMHDA could improve the
diastereoselectivity. Consequently, next we examined
the IMHDA reaction of the substrate possessing the
The major product 18a was converted to the crystalline
derivative, and its structure was successfully determined
by the X-ray crystallographic analysis,11,13 indicating
that the structure of 18a was the undesired isomer, as
shown in Scheme 3. The minor product 18b gave no
crystalline derivative and the NOE experiments on 18b
did not determine the structure; however, the NOESY
spectrum of the derivative prepared from 18b success-
fully determined the structure of 18b as the desired
isomer.11

6486
T. Suzuki et al. / Tetrahedron Letters 48 (2007) 6483–6487
OAc
H
CO2Me
O
O
H
TIPSO
H
H
OTBS
TIPSO
H
OTBS
H
H
H
H
CO2Me
H
18a
(Z)
TS-1
17Z
OTBS
H
O
TIPSO
H
OAc
CO2Me
H
CO2Me
O
H
H
TS-2
H
H
(Z)
TIPSO
H
17Z
OTBS
H
H
18b
H
(E)
CO2Me
TIPSO
H
H
H
O
OTBS
TS-3
17E
Figure 2. Plausible transition states of the IMHDA of 17.14
OAc
data associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2007.07.051.
(PhSeO)2O (2.0 equiv)
SO3-py (2.1 equiv)
CO2Me
H
H
TIPSO
TIPSO
H
O
TEA (5.3 equiv)
THF, rt, 2 d, 85%
OTBS
H
19
O
References and notes
OAc
OAc
CO2Me
H
H
H
H
TIPSO
+
1. FR182877 was first named as WS9885B (a) Sato, B.;
Muramatsu, H.; Miyauchi, M.; Hori, Y.; Takese, 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; (d) Yoshimura,
S.; Sato, B.; Kinoshita, T.; Takase, S.; Terano, H. J.
Antibiot. 2002, 55, C1; (e) Yoshimura, S.; Sato, B.; Takase,
S.; Terano, H. J. Antibiot. 2004, 57, 429–435.
2. (a) Vosburg, D. A.; Vanderwal, C. D.; Sorensen, E. J. J.
Am. Chem. Soc. 2002, 124, 4552–4553; (b) Vanderwal, C.
D.; Vosburg, D. A.; Weiler, S.; Sorensen, E. J. J. Am.
Chem. Soc. 2003, 125, 5393–5407.
3. (a) Evans, D. A.; Starr, J. T. Angew. Chem., Int. Ed. 2002,
41, 1787–1790; (b) Evans, D. A.; Starr, J. T. J. Am. Chem.
Soc. 2003, 125, 13531–13540.
CO2Me
OTBS
H
H
O
OTBS
H
H
20Z
20E
20E:20Z=1:2.415
Scheme 4. Dehydrogenation reaction of 19.
E-alkene and the results will be reported in the following
paper.
Acknowledgments
This work was financially supported in part by a Wase-
da University Grant for Special Research Projects and a
Grant-in-Aid for Scientific Research (C) and Scientific
Research on Priority Areas (Creation of Biologically
Functional Molecules (No. 17035082)) from MEXT,
Japan. We are also indebted to GCOE ‘Practical Chem-
ical Wisdom’.
4. (a) Suzuki, T.; Nakada, M. Tetrahedron Lett. 2002, 43,
3263–3266; (b) Suzuki, T.; Tanaka, N.; Matsumura, T.;
Hosoya, Y.; Nakada, M. Tetrahedron Lett. 2006, 47,
1593–1598.
5. Armstrong, A.; Goldberg, F. W.; Sandham, D. A.
Tetrahedron Lett. 2001, 42, 4585–4587.
6. (a) Clarke, P. A.; Davie, R. L.; Peace, S. Tetrahedron Lett.
2002, 43, 2753–2756; (b) Clarke, P. A.; Grist, M.; Ebden,
M.; Wilson, C. Chem. Commun. 2003, 1560–1561; (c)
Clarke, P. A.; Grist, M.; Ebden, M. Tetrahedron Lett.
2004, 45, 927–929; (d) Clarke, P. A.; Grist, M.; Ebden, M.;
Wilson, C.; Blake, A. J. Tetrahedron 2005, 61, 353–
363.
Supplementary data
The structure determination of 11a, 14, 18a, and 18b
based on the 1H NMR experiments. Supplementary

T. Suzuki et al. / Tetrahedron Letters 48 (2007) 6483–6487
6487
7. Methot, J. L.; Roush, W. R. Org. Lett. 2003, 5, 4223–
13. Crystallographic data (excluding structure factors) for the
structures in this Letter have been deposited with the
Cambridge Crystallographic Data Centre as supplemen-
tary publication numbers CCDC 650070. Copies of the
data can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge CB2 IEZ, UK [fax:
+44 (0)1223 336033 or e-mail: deposit@ccdc.cam.ac.uk].
14. The substituents in the transition state models are omittted
for clarity.
4226.
8. Funel, J.-A.; Prunet, J. J. Org. Chem. 2004, 125, 4555–
4558.
9. Negishi, E. Pure Appl. Chem. 1981, 53, 2333–2356, and
references cited therein.
10. Wipf, P.; Lim, S. Angew. Chem., Int. Ed. Engl. 1993, 32,
1068–1071.
11. See Supplementary Data.
12. Paterson, I.; Yeung, K.-S.; Smaill, J. B. Synlett 1993, 774–
776.
15. The yield was a combined yield and the ratio was
1
determined by 400 MHz H NMR.