Stereoselective construction of the octalin unit of symbioimine using an intramolecular Diels-Alder reaction

Article abstract of DOI:10.1016/j.tetlet.2006.07.012

The octalin unit of symbioimine (1) has been synthesized stereoselectively via an intramolecular Diels-Alder reaction.

Full text of DOI:10.1016/j.tetlet.2006.07.012

Tetrahedron Letters 47 (2006) 6343–6345
Stereoselective construction of the octalin unit of symbioimine
using an intramolecular Diels–Alder reaction
Emi Sakai,a Keisuke Araki,a Hiroyoshi Takamuraa and Daisuke Uemuraa,b,
*
aDepartment of Chemistry, Graduate School of Science, Nagoya University, Furo-cho, Chikusa, Nagoya 464-8602, Japan
bInstitute for Advanced Research, Nagoya University, Furo-cho, Chikusa, Nagoya 464-8602, Japan
Received 21 June 2006; revised 5 July 2006; accepted 6 July 2006
Abstract—The octalin unit of symbioimine (1) has been synthesized stereoselectively via an intramolecular Diels–Alder reaction.
Ó 2006 Elsevier Ltd. All rights reserved.
A number of natural products with unique structures
and biological activities are found in marine organisms.
However, the true origins of these metabolites are not
completely clear.1–3 It is suggested that the possible pro-
ducer of secondary metabolites would be microalgae,
bacteria, and fungi, and they are carried through a sym-
biosis and a food chain. We have been interested in bio-
active metabolites produced by marine symbiotic
microorganisms. In our search for biologically active
compounds, we recently isolated unique amphoteric
iminium compounds, symbioimine (1) and neosymbio-
imine (2) from a cultured marine dinoflagellate Symbio-
dinium sp. (Scheme 1).4–6 Symbioimine (1) inhibits
osteoclastogenesis in the murine monocytic cell line
RAW264 (EC50 = 44 lg/mL). Meanwhile, it does not
affect the cell viability even at 100 lg/mL. Thus, 1 is
thought to be a drug candidate for the prevention and
treatment of osteoporosis in postmenopausal women.
Moreover, 1 also inhibits cyclooxygenase-2 (COX-2)
activity (32%) at 10 lM, indicating that 1 may be useful
for the development of new anti-inflammatory drugs.5,6
We originally suggested the biogenetic pathway of 1 and
2 as shown in Scheme 1.6 An exo transition state intra-
molecular Diels–Alder (IMDA) reaction of (E)-enone 3
would provide cycloadduct 5. The subsequent imine for-
mation of 5 could construct the carbon framework of
symbioimines. Moreover, it can be also considered that
the tricyclic system could be synthesized from (Z)-enone
Scheme 1. Plausible biomimetic pathway to symbioimines.
4. Symbioimines could be synthesized via imine forma-
tion and an endo transition state IMDA reaction of
2,3-dihydropyridinium cation 6, followed by epimeriza-
tion. Very recently, Snider et al. reported the synthesis of
Keywords: Symbioimine; Intramolecular Diels–Alder reaction; Stereo-
selective construction; Octalin unit.
*
Corresponding author. Tel./fax: +81 52 789 3654; e-mail: uemura@
chem3.chem.nagoya-u.ac.jp
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.07.012

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E. Sakai et al. / Tetrahedron Letters 47 (2006) 6343–6345
( )-deoxysymbioimine using the IMDA reaction with a
2,3-dihydropyridinium cation as the dienophile.7 In this
letter, we wish to report a highly stereoselective con-
struction of the octalin unit of 1 using the IMDA reac-
tion with an acrylimide as the dienophile.8
Evans and co-workers developed the enantioselective
Diels–Alder reaction catalyzed by bis(oxazoline) copper
complexes with an acrylimide as the dienophile.9 We
planned to use this methodology for the stereoselective
construction of the octalin unit of 1. Before the exami-
nation of the enantioselective Diels–Alder reaction by
using Evans protocol, we decided to utilize the allylic
stereogenic center for the asymmetric induction of the
newly formed chiral centers.10 That is why we chose
an acrylimide as the dienophile. Retrosynthetic analysis
of 1 is shown in Scheme 2. Iminium ring formation and
the introduction of methyl substituent would be carried
out in the later stage. Bicyclic compound 8 would be
synthesized by using the IMDA reaction of acrylimide
9. Compound 9 can be broken down into phosphonate
10 and aldehyde 11. The Horner–Wadsworth–Emmons
reaction of phosphonate 12 and benzaldehyde 13 would
provide the carbon framework of aldehyde 11.
Scheme 3. Synthesis of ( )-17. Reagents and conditions: (a) 12,
tBuOK, THF, À78 °C to rt, 80%; (b) TBAF, THF, rt; (c) IBX, DMSO,
rt, quant. (two steps); (d) acetone cyanohydrin, Ti(OiPr)4, THF, rt,
67%; (e) TBSCl, imidazole, DMAP, DMF, rt, quant.; (f) DIBALH,
CH2Cl2, À78 °C, 94%; (g) 10, Et3N, LiCl, CH3CN, rt, 91%; (h)
toluene, reflux, quant.
Based on the retrosynthetic analysis, diastereoselective
construction of the octalin unit of 1 was investigated
(Scheme 3). The Horner–Wadsworth–Emmons reaction
of the known benzaldehyde 13,11 prepared from 3,5-
dihydroxybenzaldehyde, and phosphonate 12 gave the
desired coupling product 14 possessing the E,E-diene
moiety in 80% yield. Removal of the silyl protecting
group with TBAF followed by IBX oxidation afforded
aldehyde 15. Treatment of 15 with acetone cyanohydrin
in the presence of titanium(IV) isopropoxide provided
cyanohydrin 16.12 After the resulting alcohol was pro-
tected with tert-butyldimethylsilyl chloride, reduction
of the nitrile group with diisobutylaluminium hydride
was carried out to provide aldehyde 11. Compound 11
was converted to trienimide 9, which is the precursor
of Diels–Alder reaction, by the Horner–Wadsworth–
Emmons elongation with the phosphonate reagent 10.9
IMDA reaction of 9 proceeded smoothly under the con-
ditions of reflux in toluene to give the desired product
( )-17 as a single stereoisomer.
Scheme 4. Synthesis of (+)-25. Reagents and conditions: (a)
Ph3P@CHC(O)NMe(OMe), CH2Cl2, rt, 88%; (b) H2, Pd–C, EtOAc,
rt, 96%; (c) DIBALH, THF, À30 °C to rt, 92%; (d) 21, nBuLi, HMDS,
THF, À78 °C to rt, 80%; (e) TBAF, THF, rt; (f) TESCl, imidazole,
DMAP, rt, 86% (two steps); (g) (COCl)2, DMSO, CH2Cl2, À78 to
À40 °C, then Et3N, À78 °C to rt; (h) 10, Et3N, LiCl, CH3CN, rt, 60%
(two steps); (i) toluene, 80 °C, quant.
Scheme 2. Retrosynthetic analysis of symbioimine (1).

E. Sakai et al. / Tetrahedron Letters 47 (2006) 6343–6345
6345
studies toward the total synthesis of symbioimines are
in progress.
Acknowledgments
This work was supported in part by a Grant-in-Aid
for Creative Scientific Research (16GS0206) from the
Ministry of Education, Culture, Sports, Science and
Technology, Japan.
References and notes
Figure 1. Structural determination of (+)-25.
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Next, the examination on the enantioselective construc-
tion of the octalin segment was carried out (Scheme 4).
The known aldehyde 18,13 prepared from L-malic acid,
was subjected to the Wittig reaction with N-methoxy-
N-methyl-2-(triphenylphosphoranylidene)acetamide14
to give the unsaturated Weinreb amide 19 in 88%. After
the hydrogenation of 19 was carried out in the presence
of Pd–C, the amide moiety was reduced with diiso-
butylaluminium hydride to provide aldehyde 20. After
treatment of 20 with phosphonate 21 gave the coupling
product 22 in 80% yield, bis-TBS ether 22 was converted
to bis-TES ether 23. Primary TES ether was selectively
oxidized to the corresponding aldehyde under Swern
condition,15 and then oxadolidinone moiety was intro-
duced to give the trienimide 24. Compound 24 was
subjected to the diastereoselective IMDA reaction to
provide imide (+)-25, which possesses the desired stereo-
chemistries, as a single stereoisomer.
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8. For recent reviews of the IMDA reactions, see: (a) Fallis,
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The absolute stereochemistries of (+)-25 were deter-
1
mined by H–1H coupling constants and NOE experi-
ments (Fig. 1). The small magnitude of the coupling
constant (J4,5 = ꢀ0 Hz) and NOE for H-4/H-5 were ob-
served, suggesting that H-4 was in the syn relationship to
H-5. Three protons, H-3, H-4, and H-9 were considered
to be in all-axial orientations with each other based on
the large coupling constant (J3,4 = 10.8 Hz and
J4,9 = 10.8 Hz) and NOE observation for H-3/H-9.
The aromatic ring moiety would be placed in an axial
conformation because NOE for H-4/H-14 and H-4/H-
18 were observed.
In conclusion, the highly stereoselective construction of
the octalin unit of 1 was executed by using the IMDA
reaction with an acrylimide as the dienophile. Further
´
15. Rodrıguez, A.; Nomen, M.; Spur, B. W.; Godfroid, J. J.
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