First Total Synthesis of Antimitotic Compound, (+)-Phomopsidin

Article abstract of DOI:10.1021/ol036338q

(Equation presented) The first total synthesis of (+)-phomopsidin has been achieved via a diastereoselective transannular Diels-Alder (TADA) reaction. Key steps in the synthesis include diastereoselective ynone reduction with (-)-α-pinene and 9-BBN, macrocyclization by E-selective intramolecular Horner-Wadsworth-Emmons (HWE) reaction, as well as carbometalation under Wipf's conditions, followed by HWE reaction at low temperature to selectively construct the (E)-1-methylpropenyl and (1E,2E)-4-carboxy-1,3-butadienyl substituents.

Full text of DOI:10.1021/ol036338q

ORGANIC
LETTERS
2004
Vol. 6, No. 4
553-556
First Total Synthesis of Antimitotic
Compound, (+)-Phomopsidin
Takahiro Suzuki,† Kenji Usui,† Yoshiharu Miyake,† Michio Namikoshi,‡ and
,†
Masahisa Nakada*
Department of Chemistry, School of Science and Engineering, Waseda UniVersity,
3-4-1 Ohkubo, Shinjuku-ku, Tokyo 169-8555, Japan, and Department of Ocean
Sciences, Tokyo UniVersity of Marine Science and Technology,
Minato-ku, Tokyo 108-8477, Japan
mnakada@waseda.jp
Received December 1, 2003
ABSTRACT
The first total synthesis of (+)-phomopsidin has been achieved via a diastereoselective transannular Diels−Alder (TADA) reaction. Key steps
in the synthesis include diastereoselective ynone reduction with (−)-r-pinene and 9-BBN, macrocyclization by E-selective intramolecular Horner−
Wadsworth−Emmons (HWE) reaction, as well as carbometalation under Wipf’s conditions, followed by HWE reaction at low temperature to
selectively construct the (E)-1-methylpropenyl and (1E,2E)-4-carboxy-1,3-butadienyl substituents.
Phomopsidin (Figure 1) was isolated from marine-derived
fungus, Phomopsis sp. strain TUF 95F47, collected in
Pohnpei as a new inhibitor of microtubule assembly by
Namikoshi et al. in 1997.1 Phomopsidin shows strong
inhibitory activity against assembly of the microtubule
proteins purified from porcine brain at an IC50 of 5.7 µM.1
The relative stereochemistry of phomopsidin was determined
on the basis of NMR data,1,2 and recently, its absolute
configuration has been elucidated by the exciton chirality
method.3
Phomopsidin possesses six stereogenic centers on a cis-
fused dehydrodecaline ring, which is substituted with hy-
Figure 1. (+)-Phomopsidin and the proposed biogenesis.3
droxyl, methyl, (1E,2E)-4-carboxy-1,3-butadienyl, and (E)-
1-methylpropenyl groups. The biosynthesis of phomopsidin
was proposed to involve an intramolecular Diels-Alder
(IMDA) reaction4 of a linear precursor 1. The 16Z-isomer
† Waseda University.
‡ Tokyo University of Marine Science and Technology.
of phomopsidin (MK8383) has also been isolated and found
(1) Namikoshi, M.; Kobayashi, H.; Yoshimoto, T.; Hosoya, T. J. Antibiot.
to have activity similar to that of phomopsidin.5 The potent
1997, 50, 890-892.
(2) Namikoshi, M.; Kobayashi, H.; Yoshimoto, T.; Meguro, S.; Akano,
K. Chem. Pharm. Bull. 2000, 48, 1452-1457.
(3) Kobayashi, H.; Meguro, S.; Yoshimoto, T.; Namikoshi, M. Tetra-
hedron 2003, 59, 455-459.
(4) For reviews, see: Roush, W. R. ComprehensiVe Organic Synthesis;
Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 5, pp 513-
550 and references therein and in ref 6.
10.1021/ol036338q CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/16/2004

antimitotic activity, structure, and proposed biosynthesis of
phomopsidin all make it an attractive synthetic target. We
report herein the first total synthesis of phomopsidin.
Linear precursor 1 was considered for a synthesis of
phomopsidin featuring a biomimetic Diels-Alder reaction
(Figure 1); however, this route was not pursued because 1
possesses a sensitive triene, as well as (E,Z)-dienes that are
known to react poorly in Diels-Alder reactions due to the
energetically unfavored s-cis conformation in the transition
state. We decided thus to employ a transannular Diels-Alder
(TADA) reaction4,6 to generate the cis-dehydrodecaline
skeleton of phomopsidin. An intramolecular Horner-Wads-
worth-Emmons (HWE) reaction of 5 was expected to
provide (E)-R,â-unsaturated macrocyclic lactone 4, which
was expected to entropically activate and diastereoselectively
control the TADA reaction to form cis-dehydrodecaline 3
(Scheme 1).
Scheme 2 a
Scheme 1. Retrosynthetic Analysis of (+)-Phomopsidin
a Reagents and conditions: (a) Ethylvinyl ether, PPTS, CH2Cl2,
rt. (b) LiAlH4, Et2O, 0 °C. (c) I2, PPh3, imidazole, benzene/
CH3CN(10/1), rt, 85% (three steps). (d) CH2(CO2Et)2, NaH, THF,
reflux. (e) NaCl, H2O, DMSO, reflux, 81% (two steps). (f) Me2AlCl,
MeONHMe-HCl, CH2Cl2, rt, 78%. (g) Ethylvinyl ether, PPTS,
CH2Cl2, rt, 95%. (h) TMSCCH, n-BuLi, THF, 0 °C. (i) (-)-R-
pinene, 9-BBN, THF, rt. (j) TBAF, THF, rt, 88% (three steps). (k)
TIPSOTf, TEA, CH2Cl2, rt, 76%. (l) (i) 9-BBN, THF, reflux; (ii)
PhCHO, rt; (iii) ethyl (Z)-3-iodo-2-butenoate, [Pd2(dba)3]-CHCl3,
AsPh3, K2CO3, DMF, THF, H2O, rt. (m) DIBAL, CH2Cl2, -78
°C, 76% (two steps). (n) (EtO)2P(O)CH2CO2H, CBr4, PPh3, Py,
CH2Cl2, rt, 92%. (o) PPTS, EtOH, rt, 98%. (p) Dess-Martin
periodinane, CH2Cl2, rt. (q) K2CO3, 18-crown-6, toluene, 0.005 M,
rt, 78% (two steps).
by TBAF (88%, three steps), and the hydroxyl group was
protected as TIPS ether 10 (76%).
With alkyne 10 in hand, Suzuki-Miyaura coupling10 of
10 and ethyl (Z)-3-iodo-2-butenoate was carried out. Thus,
alkyne 10 was reacted with 9-BBN first, followed by
treatment with benzaldehyde to convert the byproduct, 1,1-
bisboryl adduct, to the desired trans-alkenylborane,10b and
finally reacted with ethyl (Z)-3-iodo-2-butenoate under
condition l in Scheme 2. The coupling reaction proceeded
successfully; however, concomitant impurities were also
produced. Therefore, the crude product was used for the next
step without purification. The crude product was reduced
by DIBAL-H, and to our delight, pure 11 was obtained by
silica gel chromatography (76%, two steps). Alcohol 11 was
condensed with diethylphosphonoacetic acid (92%), followed
by treatment with PPTS in ethanol to deprotect the ethoxy-
ethyl group (98%). Oxidation of the resultant alcohol with
Dess-Martin periodinane furnished 5, the substrate for the
intramolecular HWE reaction.
Suzuki-Miyaura coupling between propargyl ether 10 and
ethyl (Z)-3-iodo-2-butenoate7 was envisioned to construct the
(E,Z)-diene in 11 (Scheme 2). The synthesis of alkyne 10
began with protection of methyl (S)-3-hydroxy-2-methyl-
propionate as an ethoxyethyl ether, which was reduced with
LiAlH4 and transformed to the corresponding iodide (85%,
three steps). Coupling of the obtained iodide with diethyl
malonate, followed by decarboxylation, which was ac-
companied with removal of the ethoxyethyl group, afforded
δ-lactone 6 (81%, two steps), which was converted into the
corresponding Weinreb amide (78%) and then protected as
ethoxyethyl ether 7 (95%). Lithium trimethylsilylacetylide
reacted with amide 7 to give ynone 8, which was reduced
stereoselectively with (-)-R-pinene and 9-BBN to afford
secondary alcohol 9.8,9 The TMS group in 9 was removed
(5) Wakui, F.; Harimaya, K.; Iwata, M.; Sashita, R.; Chiba, N.; Mikawa,
T. Jpn. Kokai Tokkyo Koho JP 07,126,211, May 16, 1995, Appl. Oct. 29,
1993; Chem. Abstr. 1995, 123, 105272b.
(6) Marsault, E.; Toro´, A.; Nowak, P.; Deslongchamps, P. Tetrahedron
2001, 57, 4243-4260.
(7) Piers, E.; Wong, T.; Coish, P. D.; Rogers, C. Can. J. Chem. 1994,
72, 1816-1819.
(8) Midland, M. M.; McDowell, D. C.; Hatch, R. L.; Tramontano, A. J.
Am. Chem. Soc. 1980, 102, 867-869.
(9) Another diastereomer could not be observed by 400 MHz NMR.
(10) (a) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457-2483 and
references therein. (b) Colberg, J. C.; Rane, A.; Vaquer, J.; Soderquist, J.
A. J. Am. Chem. Soc. 1993, 115, 6065-6071.
554
Org. Lett., Vol. 6, No. 4, 2004

The intramolecular HWE reaction of 5 was examined
under various conditions, and it was found that the desired
(E)-R,â-unsaturated macrocyclic lactone 4 was successfully
generated in 78% yield (two steps) under the highly diluted
(0.005 M) condition (q) in Scheme 2. The concentration was
found to be crucial, that is, the macrolactonization afforded
a dimer under the more concentrated reaction condition.
Now the stage was set for the TADA reaction of 4. The
substrates with (E,E)-dienes are particularly reactive in the
TADA reaction, and their reactions are known to proceed
even at room temperature because they can reach the
prerequisite s-cis conformation easily. However, since 4
possesses (E,Z)-diene, the TADA reaction of 4 proceeded
slowly at the reflux temperature of toluene. Actually, the
TADA reaction of 4 took 1 day to complete. The products
3 were found to be an inseparable mixture of two diastere-
verted to p-bromobenzoate 12 (93%), but this p-bromoben-
zoate did not afford a crystal suitable for single-crystal X-ray
analysis. Then, a NOE experiment was carried out on 12.
As shown in Figure 2, compound 12 showed significant NOE
Figure 2. Some representative NOE correlations (r f) for 12.
1
omers (63%, a 2:1 ratio, Scheme 3) by H NMR analysis.
correlations between [H-16-H-6-H-7 and -H-10] and [H-7-
H-11-H-12] (Figure 2). The result of the NOE experiment
with 12 suggested that the major product obtained by the
TADA reaction of 4 has the desired configuration.
Scheme 3 a
A diastereomeric mixture 3 was converted to Weinreb
amide 13 (68%) under Williams conditions,11 and this was
found to be separated from the minor component by silica
gel chromatography. Weinreb amide 13 was prone to
recyclize under acidic or basic conditions to generate 3.
Accordingly, the Weinreb amide 13 was immediately
converted to ethoxyethyl ether 14 (90%), and 14 was reduced
with BH3-NH3 and LDA12 to give alcohol 15 successfully
(89%). Alcohol 15 was converted to BPS ether 16 (98%),
followed by careful removal of the ethoxyethyl group under
acidic conditions to afford 17 (87%). Dess-Martin oxidation
of 17 (78%), followed by the Corey-Fuchs protocol,13 gave
alkyne 2.
Next we attempted to transform 2 to the trisubstituted
iodoalkene 18 (Scheme 5). First, Negishi’s carbometalation-
iodination protocol was applied,14 but the yield was low under
the conditions reported by Negishi et al. After several
attempts, the carbometalation of 2 was found to accelerate
dramatically under Wipf’s conditions,15 affording 18 in 86%
yield. Pd(0)-catalyzed coupling reaction16 of 18 with di-
methylzinc cleanly produced 19 (99%).
a Reagents and conditions: (a) BHT, toluene, reflux, 1 day, 63%
(2:1); (b) MeONHMe-HCl, i-PrMgCl, THF, 0 °C, 68%; (c)
ethylvinyl ether, PPTS, CH2Cl2, rt, 90%; (d) BH3-NH3, LDA, THF,
0 °C to room temperature, 89%; (e) BPSCl, imidazole, CH2Cl2, rt,
98%; (f) 1 N HCl, THF, rt, 87%; (g) Dess-Martin periodinane,
CH2Cl2, rt, 78%; (h) CBr4, PPh3, CH2Cl2, rt, 93%; (i) n-BuLi, THF,
-78 to 0 °C, 73%.
A problem remaining with this synthesis was the construc-
tion of the (1E,2E)-4-carboxy-1,3-butadienyl substituent of
phomopsidin. Hence, conversion of 19 to aldehyde 21 for
the planned HWE reaction was examined. Selective depro-
The relative stereochemistry of the major product was
elucidated as follows. The products 3 were treated with
TBAF to remove the TIPS group, giving the corresponding
alcohols (50%), which were separated easily by silica gel
chromatography (Scheme 4). The major alcohol was con-
(11) Williams, J. M.; Jobson, R. B.; Yasuda, N.; Marchesini, G.; Dolling,
U.-H.; Grabowski, E. J. J. Tetrahedron Lett. 1995, 36, 5461-5464. Other
methods resulted in low yield because Weinreb amide 13 readily recyclized
to afford lactone 3 as mentioned in the text.
(12) Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky, D.
J.; Gleason, J. L. J. Am. Chem. Soc. 1997, 119, 6496-6511.
(13) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 3769-3772.
(14) Negishi, E. Pure Appl. Chem. 1981, 53, 2333-2356 and references
therein.
Scheme 4
(15) Wipf, P.; Lim, S. Angew. Chem., Int. Ed. Engl. 1993, 32, 1068-
1071.
(16) For reviews, see: (a) Roush. W. R. ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol.
3, pp 435-480 and references therein. (b) Knochel, P.; Singer, R. D. Chem.
ReV. 1993, 93 (6), 2117-2188.
Org. Lett., Vol. 6, No. 4, 2004
555

accomplish the total synthesis of (+)-phomopsidin (93%),
which proved to be identical in all respects to an authentic
sample.
Scheme 5 a
In summary, the first total synthesis of (+)-phomopsidin
via the TADA reaction has been achieved. The key steps
include highly diastereoselective reduction of ynone 8 with
(-)-R-pinene and 9-BBN, Suzuki-Miyaura coupling, and
a highly E-selective intramolecular Horner-Wadsworth-
Emmons (HWE) reaction to synthesize the substrate of the
TADA reaction. Carbometalation under Wipf’s coditions and
HWE reaction at low temperature were crucial to the
stereoselective construction of the (E)-1-methylpropenyl and
(1E,2E)-4-carboxy-1,3-butadienyl substituents. Optimization
of the low-yielding reaction conditions as well as reduction
in the number of steps is now underway, and our efforts are
directed toward studies of the structure-activity relationships
of (+)-phomopsidin.
a Reagents and conditions: (a) Cp2ZrCl2, Me3Al, H2O, CH2Cl2,
-20 to 0 °C; then I2, THF, 0 °C, 86%. (b) Me2Zn, PdCl2(PPh3)2,
THF, rt, 99%. (c) TBAF, THF, reflux, 95%. (d) TBSCl, imidazole,
CH2Cl2, rt, 86%. (e) Bz2O, DMAP, CH2Cl2, 0 °C to room
temperature, 93%. (f) TBAF, THF, rt, 89%. (g) Dess-Martin
periodinane, CH2Cl2, rt, 76%. (h) (EtO)2P(O)CH2CHdCHCO2Et
(22), LHMDS, THF, -78 to -20 °C, quant. (i) LiOH, EtOH, H2O,
93%.
Acknowledgment. We are grateful to Dr. Hisayoshi
Kobayashi, Department of Structural Biology, Institute of
Molecular and Cellular Biosciences, The University of
Tokyo, for the supply of natural (+)-phomopsidin. This work
was financially supported in part by 21COE “Practical Nano-
Chemistry”.
tection of the BPS group in 19 failed under all conditions,
so both silyl groups were removed simultaneously with
TBAF (95%). The resultant primary hydroxyl group was
protected selectively as the TBS ether (86%), followed by
benzoylation of the secondary hydroxyl group (93%), depro-
tection of the TBS group (89%), and Dess-Martin oxidation
to afford aldehyde 21 (76%).
The HWE reaction of 21 with phosphonate 22 at -20 °C
gave (E,E)-R,â,γ,δ-unsaturated ester stereoselectively and
quantitatively. The obtained ester was treated with LiOH to
Supporting Information Available: Spectral data for key
intermediates and synthetic (+)-phomopsidin. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL036338Q
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Org. Lett., Vol. 6, No. 4, 2004