Microwave-assisted intramolecular Diels-Alder reaction towards the total synthesis of symbioimine

Article abstract of DOI:10.1055/s-0028-1083501

Uemura's proposed biosynthetic pathway of symbioimine was demonstrated by microwave-assisted intramolecular Diels-Alder reaction of a trans-enone precursor. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1083501

LETTER
2877
Microwave-Assisted Intramolecular Diels–Alder Reaction towards the Total
Synthesis of Symbioimine
M
icrowave-
A
t
d
e
Intramolecu
p
lar
D
iels–A
h
Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, Mail Code 0343, La Jolla, CA 92093-
0343, USA
E-mail: ykoba@ucsd.edu
Received 10 July 2008
trol the stereoselectivity in the intramolecular exo-Diels–
Abstract: Uemura’s proposed biosynthetic pathway of symbio-
Alder reaction. Several groups have reported a total syn-
thesis of symbioimine featuring an intramolecular Diels–
Alder reaction of 2,3-dihydropyridine derivatives as a pu-
tative intermediate, although the originally proposed ste-
imine was demonstrated by microwave-assisted intramolecular
Diels–Alder reaction of a trans-enone precursor.
Key words: biomimetic reaction, marine natural product, intramo-
lecular Diels–Alder reaction, microwave-assisted reaction, symbio-
imine
reoselective reaction from the trans-enone 1 has never
been executed.5
Uemura’s proposed biosynthetic pathway seems reason-
able except the exo-selectivity in the intramolecular
Diels–Alder reaction. A synthesis of a similar type of oc-
talone has been reported to exclusively afford an endo-ad-
duct by the intramolecular Diels–Alder reaction of a
trans-enone precursor.6 On the other hand, the attempt of
this Diels–Alder reaction with a nonionic model com-
pound A (R1 = Me, R2 = Boc) under conventional condi-
tions was unsuccessful as reported by Maier
(Scheme 2).5a,7 Interestingly, only slow decomposition of
the substrate was observed, and even the endo-adduct was
not formed, probably due to the steric hindrance.5a There-
fore, the validity of the biosynthetic route remains to be
verified. Herein, we describe a microwave-assisted bio-
mimetic Diels–Alder reaction towards the total synthesis
of symbioimine.
In 2004, Uemura reported the isolation of symbioimine,1
an alkaloid produced by the symbiotic marine dinoflagel-
late Symbiodinium sp. which is found in many marine in-
vertebrates (Scheme 1).2 It was discovered that this
molecule inhibited osteoclastogenesis in the murine
monocytic cell line RAW264 (EC50 = 44 mM)3 and was
nontoxic to cells at concentrations of 100 mg/mL. These
properties suggest that symbioimine could be a potential
drug candidate for the prevention and treatment of os-
teoporosis.2 Symbioimine also inhibits cyclooxygenase-2
(COX-2) activity at 10 mM which also suggests it as a po-
tential anti-inflammnatory agent.4 Uemura originally pro-
posed a biosynthetic pathway of symbiomime that
entailed a stereoselective intramolecular exo-Diels–Alder
reaction of zwitterionic trans-enone 1, followed by cyclic
imine formation from octalone 2.1 Interestingly, the pres-
ence of a single stereocenter at the g-position should con-
Based on our own preliminary results (A: R1 = Me,
R2 = Alloc), we decided to investigate on the feasibility of
+
H3N+
OSO3
NH3
OSO3
–
–
exo-Diels–Alder
reaction
O
H
H
O
OH
OH
H
H
2
1
cyclic imine
formation
–
OMe
OSO3
HN+
H
N
endo-Diels–Alder
reaction
H
OMe
OH
followed by
isomerization
H
H
2,3-dihydropyridine
symbioimine
Scheme 1 Uemura’s proposal of the biosynthesis of symbioimine from trans-enone 1 and the reported approach via 2,3-dihydropyridine
SYNLETT 2008, No. 18, pp 2877–2881
1
4
.1
1
.2
0
0
8
Advanced online publication: 15.10.2008
DOI: 10.1055/s-0028-1083501; Art ID: S06508ST
© Georg Thieme Verlag Stuttgart · New York

2878
S. Born et al.
LETTER
col
(Scheme 4).9
Suzuki
coupling
between
H3N+
OSO3
R2HN
OR1
–
pinacolboronate 4 and vinyliodide 58 afforded diene 6 in
70% yield. Then, IBX oxidation10 of 6 furnished aldehyde
7 in 71% yield.
O
OH
O
OR1
A
OMe
catecholborane
1
OMe
(2.2 equiv)
OR1
THF, reflux, 12 h
pinacol (2 equiv)
MeOH, r.t., 3 h
79%
OMe
O
O
OMe
4
B
O
OR1
B
3
OH
Scheme 2 Design of a precursor for intramolecular Diels–Alder re-
5
action
I
(1 equiv)
THF, reflux
2 h
PdCl2dppf (5 mol%)
2 M NaOH (3 equiv)
70%
the intramolecular Diels–Alder reaction without the ter-
minal amino group in A, the reason of which is to avoid a
decomposition pathway initiated by elimination of an
amino group from the g-amino-trans-enone moiety, and
also simplify the analysis of the Diels–Alder products be-
cause the possible products are two diastereomers (endo/
exo) instead of four. Although this model compound B
would not provide a cyclic imine moiety of symbiomine,
we expected that useful information regarding a stereose-
lectivity in the Diels–Alder reaction could be obtained.
OMe
OMe
OH
IBX (1.2 equiv)
CHO
DMSO
r.t., 2 h
71%
OMe
OMe
7
6
Scheme 4 Synthesis of dienal 7
For the synthesis of trans-enone B, the molecule was dis-
connected to three fragments as shown in Scheme 3. The
enone moiety of B can be constructed by a Horner–
Wadsworth–Emmons reaction between isobutyraldehyde
and b-ketophosphonate C, which could be prepared from
dimethyl methylphosphonate and aldehyde D. Phospho-
nate C could also provide A for the total synthesis of sym-
bioimine. The diene moiety can be connected by Suzuki
coupling between known (E)-6-iodohex-5-en-1-ol8 and
styrylbornate E, and the resulting dienol can be oxidized
to give D.
Phosphonate 9 was obtained by a two-step procedure:11
addition of methylphosphonate anion to aldehyde 7 fol-
lowed by IBX oxidation of the resulting alcohol 8
(Scheme 5). The Horner–Wadsworth–Emmons reaction
of 9 with isobutyraldehyde (10) gave trans-enone 11 in
good yield.
With trans-enone 11 in hand, we embarked on the in-
tramolecular Diels–Alder reaction (Scheme 6). As report-
ed by Maier previously,5a we found the Diels–Alder
reaction of 11 does not proceed by conventional heating
or treatment with Lewis acid.12 To our delight, micro-
wave-assisted heating13 of 11 in methanol did provide the
Diels–Alder adducts 12a and 12b quantitatively with a 1:3
exo/endo ratio.14 The exo-adduct 12a has the correspond-
ing stereochemistry to that of symbiomime.
The synthesis of trans-enone 11 (B: R = Me) was success-
fully accomplished as described below. Starting from
commercially available 3,5-dimethoxyphenylacetylene
(3), vinylpinacolboronate 4 was prepared by hydrobora-
tion with catecolborane followed by treatment with pina-
OR
O
P
OR
HWE
reaction
MeO
MeO
CHO
O
OR
O
OR
Suzuki
coupling
B
C
O
OR
OR
OH
MeO
MeO
P
Me
CHO
OR
OR
I
(RO)2B
E
D
Scheme 3 Strategy for synthesis of trans-enone B
Synlett 2008, No. 18, 2877–2881 © Thieme Stuttgart · New York

LETTER
Microwave-Assisted Intramolecular Diels–Alder Reaction
2879
O
OMe
MeO
MeO
P
Li
O
P
OMe
MeO
MeO
(2 equiv)
CHO
THF
–78 °C to r.t.
86%
OMe
OH
OMe
8
7
IBX (3 equiv)
EtOAc, reflux, 3 h
61%
OMe
O
OMe
NaH (1.1 equiv)
THF, r.t., 1 h
MeO
MeO
P
10
(1 equiv)
CHO
O
OMe
O
OMe
r.t., 1 h
80%
11
9
Scheme 5 Synthesis of trans-enone 11
MeOH
160 °C
MW
OMe
O
O
H
H
H
H
H
4 h
Ar
H
Ar
H
+
quant
O
OMe
H
11
12a exo
1:3
12b endo
Scheme 6 Intramolecular Diels–Alder reaction of trans-enone 11
The relative stereochemistry of the Diels–Alder products fortunately found the separation of the corresponding al-
12a and 12b was established by analysis of coupling con- cohols is possible. The reduction of 12 with LAH gave a
stants of a proton (H4) at an angular position and by a separable mixture of secondary alcohols. After separa-
NOE experiment after isolation of each adduct as shown tion, these are oxidized to 12a and 12b by IBX, individu-
in Figure 1. Importantly, we confirmed that octalones 12a ally. The assignments of 1H and 13C NMR chemical shifts
and 12b are kinetic products, which are directly formed by were established by COSY experiments.
Diels–Alder reaction of 11. Isomerization of the epimer-
izable stereocenter was not observed. Although these
compounds are inseparable by SiO2 chromatography, we
Importantly, the intramolecular Diels–Alder reaction of
trans-enone 11 was efficiently accelerated by microwave-
assisted heating, although any other conventional meth-
ods were not as effective. We speculated a steric interac-
exo-product 12a
endo-product 12b
tion between phenyl and isopropyl groups in the transition
state of the Diels–Alder reaction would be the origin of
the difficulty.
OMe
OMe
O
O
H4
H9
H3
H4
H9
H3
To analyze this steric inhibition, as a control experiment,
we investigated the intramolecular Diels–Alder reaction
of vinyl ketone derivative of 11. Allyl alcohol 13 was ob-
tained by addition of vinylmagnesium bromide
(Scheme 7). The IBX oxidation of 13 by heating at 80 °C
for 3 hours gave a mixture of the corresponding enone
(not shown) and endo-Diels–Alder adduct 14 (endo/
exo = 4:1).15 The enone intermediate was readily convert-
ed into 14 by further heating at 80 °C. Indeed, the Diels–
Alder reaction was significantly facilitated compared with
that of trans-enone 11, suggesting steric hindrance as the
determining factor of the reaction rate.16 The relative ste-
reochemistry of major adduct 14 was established by anal-
ysis of coupling constants as shown below.17
OMe
OMe
H
H12
2.62 ppm
(app. t, J = 10.8 Hz)
H4
Ar
H3
C
C
2.43 ppm
C
C
i-Pr
Ar
H
H9
i-Pr
H9
H3
H12
H4
3.15 ppm
(d, J = 10.0 Hz)
NOESY
2.62 ppm (dd, J = 11.2, 4.8 Hz)
Figure 1 Assignment of stereochemistry of Diels–Alder adducts
12a and 12b
Synlett 2008, No. 18, 2877–2881 © Thieme Stuttgart · New York

2880
S. Born et al.
LETTER
OMe
Elliott, R.; Colombero, A.; Elliott, G.; Scully, S.; Hsu, H.;
Sullivan, J.; Hawkins, N.; Davy, E.; Capparelli, C.; Eli, A.;
Qian, Y. X.; Kaufman, S.; Sarosi, I.; Shalhoub, V.; Senaldi,
G.; Guo, J.; Delaney, J.; Boyle, W. J. Cell 1998, 93, 165.
(c) Hsu, H.; Lacey, D. L.; Dunstan, C. R.; Solovyev, I.;
Colombero, A.; Timms, E.; Tan, H.-L.; Elliott, G.; Kelley,
M. J.; Sarosi, I.; Wang, L.; Xia, X.-Z.; Elliott, R.; Chiu, L.;
Black, T.; Scully, S.; Capparelli, C.; Morony, S.;
Shimamoto, G.; Bass, M. B.; Boyle, W. J. Proc. Natl. Acad.
Sci. U. S. A. 1999, 96, 3540.
OMe
BrMg
THF
OH
CHO
66%
OMe
OMe
13
7
EtOAc
IBX
reflux, 81%
H
(4) (a) Kita, M.; Uemura, D. Chem. Lett. 2005, 34, 454.
(b) Kita, M.; Ohishi, N.; Washida, K.; Kondo, M.; Koyama,
T.; Yamada, K.; Uemura, D. Bioorg. Med. Chem. 2005, 13,
5253.
OMe
C
H
H
Ar
H9
O
H4
H9
C
(5) Reported total syntheses of symbioimine, see: (a) Varseev,
G. N.; Maier, M. E. Angew. Chem. Int. Ed. 2006, 45, 4767.
(b) Zou, Y.; Che, Q.; Snider, B. B. Org. Lett. 2006, 24,
5605. (c) Kim, J.; Thomson, R. J. Angew. Chem. Int. Ed.
2007, 46, 3104. For other synthetic studies, see: (d) Snider,
B. B.; Che, Q. Angew. Chem. Int. Ed. 2006, 45, 932.
(e) Sakai, E.; Araki, K.; Takamura, H.; Uemura, D.
Tetrahedron Lett. 2006, 47, 6343. For our own efforts along
with 2,3-dihydropyridine strategy, see: (f) Born, S.;
Kobayashi, Y. Synlett 2008, 2479.
(6) (a) Gras, J.-L.; Bertrand, M. Tetrahedron Lett. 1979, 4549.
(b) Gras, J.-L. J. Org. Chem. 1981, 46, 3738. (c) Taber,
D. F.; Kong, S.; Malcolm, S. C. J. Org. Chem. 1998, 63,
7953. (d) Coe, J. W.; Roush, W. R. J. Org. Chem. 1989, 54,
915. (e) Frankowski, K. J.; Golden, J. E.; Zeng, Y.; Lei, Y.;
Aubé, J. J. Am. Chem. Soc. 2008, 130, 6018.
(7) Sammakia showed an interesting method to prepare an
octalone core structure of dihydrocompactin, see:
Sammakia, T.; Johns, D. M.; Kim, G.; Berliner, M. A. J. Am.
Chem. Soc. 2005, 127, 6504.
(8) Preparation of (E)-6-iodohex-5-en-1-ol: (a) Lipshutz, B. H.;
Kell, R.; Ellsworth, E. L. Tetrahedron Lett. 1990, 31, 7257.
(b) Nishida, A.; Shirato, F.; Nakagawa, M. Tetrahedron:
Asymmetry 2000, 11, 3789.
(9) Synthesis of pinacolboronate: Shirakawa, K.; Arase, A.;
Hoshi, M. Synthesis 2004, 1814.
(10) (a) More, J. D.; Finney, N. S. Org. Lett. 2002, 4, 3001.
(b) Frigerio, M.; Santagostino, M.; Sputore, S. J. Org. Chem.
1999, 64, 4537.
(11) Preparation of b-ketophosphonate: Hosokawa, S.; Seki, M.;
Fukuda, H.; Tatsuta, K. Tetrahedron Lett. 2006, 47, 2439.
(12) Attempted Diels–Alder reaction of 11 under conventional
conditions: (a) xylene, reflux, 2 d, and (b) MeAlCl2,
CH2Cl2, –78 °C.
H4
OMe
H
2.70 ppm
(ddd, J = 13.2, 5.2, 3.2 Hz)
14
Scheme 7 Intramolecular Diels–Alder reaction of vinyl ketone
As Uemura suggested in his proposed biosynthesis of
symbioimine, the intramolecular Diels–Alder reaction of
the trans-enone linear precursor is possible. In our hands,
the reaction proceeded very cleanly under microwave-
heating conditions (MeOH, 160 °C, 4 h), although the
endo/exo selectivity was moderate (3:1). The stereochem-
istry of each adduct was unambiguously determined by
NMR analysis. We anticipated the steric interaction in the
transition state of the Diels–Alder reaction to be signifi-
cant between the substituents at the termini of the diene
and the dienophile and make the reaction rate slow. There-
fore, most likely, the exo-selective Diels–Alder reaction is
catalyzed by an enzyme if it is the biosynthetic route. In-
stallation of a protected amino group in trans-enone 11
might increase the steric hindrance and influence the reac-
tion rate and the endo/exo selectivity. The results will be
reported in due course.
Acknowledgment
We greatly acknowledge the University of California for financial
support, and UCSD undergraduate students, Oren Berger, Janice
Sindac, Karina Chan, Kathy Yue, Wei-Hao Zheng, Brian Nguyen,
and Jin Kim for preliminary studies. We also thank Dr. Yongxuan
Su (UCSD) for Mass Spectroscopy, Dr. Anthony Mrse (UCSD) for
help with NOESY experiments, and Professor Tadeusz Molinski
(UCSD) for a microwave instrument.
(13) Microwave instrument: CEM Discovery Labmate
microwave system.
(14) Microwave-assisted heating of 11 in ethanol provided the
Diels–Alder adducts 12a and 12b in 69% with exo/endo =
1:2.
(15) The minor diastereomer was assumed to be the exo-adduct.
We do not exclude the possibility of epimerization of the
major kinetic endo-adduct 14 to the minor exo-adduct under
the reaction conditions.
References and Notes
(1) Kita, M.; Kondo, M.; Koyama, T.; Yamada, K.; Matsumoto,
T.; Lee, K. H.; Woo, J. T.; Uemura, D. J. Am. Chem. Soc.
2004, 126, 4794.
(2) Rowan, R.; Powers, D. A. Science 1991, 251, 1348.
(3) RANKL induces osteoclast-like multinucleated cell
formation in cultures of bone marrow cells. See:
(16) As expected, the bulky dienophile below did not afford any
Diels–Alder adduct even under the microwave-assisted
heating conditions. The starting material was recovered
quantitatively (Scheme 8).
(17) 1H NMR and 13C NMR Data for Compounds 11, 12a,b,
and 14
(a) Yasuda, H.; Shima, N.; Nakagawa, N.; Yamaguchi, K.;
Kiosaki, M.; Mochizuki, S.-i.; Tomoyasu, A.; Yano, K.;
Goto, M.; Murakami, A.; Tsuda, E.; Morinaga, T.; Higashio,
K.; Udagawa, N.; Takahashi, N.; Suda, T. Proc. Natl. Acad.
Sci. U. S. A. 1998, 95, 3597. (b) Lancey, D. L.; Timms, E.;
Tan, H. L.; Kelley, M. J.; Dunstan, C. R.; Burgess, T.;
Compound 11: 1H NMR (400 MHz, CDCl3): d = 6.78 (q,
J = 11.2, 6.4 Hz, 1 H), 6.70 (dd, J = 11.2, 16.0 Hz, 1 H), 6.51
(d, J = 2.4 Hz, 2 H), 6.35 (d, J = 15.6 Hz, 1 H), 6.32 (t,
J = 2.4 Hz, 1 H), 6.18 (dd, J = 15.6, 10.4 Hz, 1 H), 6.02 (dd,
Synlett 2008, No. 18, 2877–2881 © Thieme Stuttgart · New York

LETTER
Microwave-Assisted Intramolecular Diels–Alder Reaction
2881
129.5, 108.6 (2 C), 97.8, 55.3 (2 C), 51.8, 45.6, 43.9, 43.2,
42.1, 33.0, 28.2, 27.0, 19.5, 19.0.
MeOH
160 °C
MW
OMe
Compound 12b (endo): 1H NMR (400 MHz, CDCl3):
d = 6.34 (d, J = 2.0 Hz, 2 H), 6.30 (t, J = 1.6 Hz, 1 H), 5.70
(ddd, J = 10.0, 5.2, 2.8 Hz, 1 H), 5.47 (d, J = 9.6 Hz, 1 H),
3.77 (s, 6 H), 3.15 (dd, J = 10.0, 2.4 Hz 1 H), 2.62 (dd,
J = 11.2, 4.8 Hz, 1 H), 2.52 (dt, J = 12.8, 6.0 Hz, 1 H), 2.45–
2.41 (m, 1 H), 2.31–2.26 (m, 2 H), 2.05 (ddd, J = 12.4, 5.2,
3.2 Hz, 1 H), 1.89 (dd, J = 13.2, 3.6 Hz, 1 H), 1.80–1.60 (m,
3 H), 0.79 (d, J = 7.2 Hz, 3 H), 0.75 (d, J = 7.6 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 215.6, 160.7 (2 C), 147.8,
131.5, 128.6, 106.8 (2 C), 97.6, 55.2 (2 C), 52.9, 46.0, 43.1,
40.3, 40.0, 29.4, 29.0, 26.6, 19.9.
5 h
no reaction
O
OMe
Scheme 8
J = 16.0, 1.6 Hz, 1 H), 5.78 (dt, J = 14.4, 7.2 Hz, 1 H), 3.77
(s, 6 H), 2.54 (t, J = 7.2 Hz, 2 H), 2.48–2.38 (m, 1 H), 2.16
(dt, J = 13.6, 6.4 Hz, 2 H), 1.74 (app q, J = 8.0 Hz, 2 H), 1.04
(d, J = 6.8 Hz, 6 H). 13C NMR (100 MHz, CDCl3):
d = 200.8, 160.8 (2 C), 153.4, 139.5, 135.1, 131.1, 130.3,
129.7, 127.5, 104.1 (2 C), 99.6, 55.3 (2 C), 32.2, 31.1, 23.6,
21.3 (2 C).
Compound 14: 1H NMR (400 MHz, CDCl3): d = 6.32 (d,
J = 2.4 Hz, 2 H), 6.30 (t, J = 2.4 Hz, 1 H), 5.87 (ddd,
J = 10.0, 4.8, 2.4 Hz, 1 H), 5.70 (dd, J = 10.4, 1.6 Hz, 1 H),
3.75 (s, 6 H), 3.38 (ddd, J = 11.2, 6.0, 2.4 Hz, 1 H), 2.70
(ddd, J = 13.2, 5.2, 3.2 Hz, 1 H), 2.48–2.40 (m, 1 H), 2.31–
2.27 (m, 2 H), 2.04–1.96 (m, 1 H), 1.92–1.83 (m, 2 H), 1.76
(dd, J = 13.2, 11.2 Hz 1 H), 1.66–1.55 (m, 2 H). 13C NMR
(100 MHz, CDCl3): d = 214.4, 160.8 (2 C), 147.6, 130.9,
129.8, 105.3 (2 C), 98.0, 55.2 (2 C), 50.2, 43.1, 38.5, 37.2,
32.1, 28.3, 24.8.
Compound 12a (exo): 1H NMR (400 MHz, CDCl3): d = 6.44
(d, J = 2.0 Hz, 2 H), 6.35 (t, J = 2.4 Hz 1 H), 5.83 (ddd,
J = 6.8, 4.8, 1.6 Hz, 1 H), 5.64 (dt, J = 9.6, 1.6 Hz, 1 H), 3.77
(s, 6 H), 3.45–3.38 (m, 1 H), 2.62 (app t, J = 10.8 Hz, 1 H),
2.56–2.34 (m, 3 H), 2.25–2.02 (m, 4 H), 1.84–1.58 (m, 2 H),
0.69 (d, J = 7.2 Hz, 3 H), 0.43 (d, J = 7.2 Hz, 3 H). 13C NMR
(100 MHz, CDCl3): d = 212.6, 160.3 (2 C), 144.6, 131.0,
Synlett 2008, No. 18, 2877–2881 © Thieme Stuttgart · New York

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