Total synthesis of (±)-symbioimine

Article abstract of DOI:10.1002/anie.200601418

(Chemical Equation Presented) An inside job: A Lewis acid induced intramolecular Diels-Alder (IMDA) reaction is used as the key step in the formation of symbioimine, an iminium alkaloid. The intermediate octahydronaphthalene is obtained from the IMDA reaction, after which extension of the aldehyde to a nitrile, alkylation of the nitrile, and imine formation allows for an efficient route to the target compound (see scheme; TBS = tert-butyldimethylsilyl).

Full text of DOI:10.1002/anie.200601418

Angewandte
Chemie
Cycloaddition
DOI: 10.1002/anie.200601418
Total Synthesis of (ꢀ )-Symbioimine**
Georgy N. Varseev and Martin E. Maier*
Symbioimine (1) is a novel tricyclic iminium alkaloid that was
recently isolated from the symbiotic marine dinoflagellate
Symbiodinium sp.[1] This rather unusual compound occurs in
nature as an inner salt of an imine and an aryl sulphuric acid
(Scheme 1). Such zwitterionic compounds are very rare,[2,3]
and the total synthesis of 1 certainly poses a challenging task.
Scheme 1. Structures of the iminium alkaloids symbioimine (1) and
neosymbioimine (2).
[*] G. N. Varseev, Prof. Dr. M. E. Maier
Institut für Organische Chemie
Universität Tübingen
Auf der Morgenstelle 18, 72076 Tübingen (Germany)
Fax: (+49)7071-295-137
E-mail: martin.e.maier@uni-tuebingen.de
[**] Financial support from the Deutsche Forschungsgemeinschaft and
the Fonds der Chemischen Industrie is gratefully acknowledged. We
thank Dr. Cäcilia Maichle-Mössmer for the X-ray structures and
Graeme Nicholson for measuring the high-resolution mass spectra.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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A related compound is the amphoteric neosymbioimine (2).[4]
Besides its unique structural features,the biological activity of
1 is noteworthy as well: it inhibits the differentiation of
progenitor cells (RAW264) into mature osteoclasts with
EC50 = 44 mgmLꢁ1 (116 mm). Therefore, 1 might show the
way to a new lead structure in the search for drugs directed at
the treatment of osteoporosis. In addition, 1 significantly
reduces cyclooxygenase-2 (COX-2) activity at 10 mm.[3]
Most likely 1 is constructed through the polyketide
pathway,as illustrated with structure A,which consists of
eight acetate and one propionate groups. The key step in the
biosynthesis of 1 might involve an intramolecular Diels–
Alder (IMDA) reaction,[5] either of a trienone via an exo
transition state of type B followed by cyclization to an imine
(Scheme 2). Alternatively,an endo IMDA reaction of a
Scheme 3. Retrosynthetic plan for the synthesis of 1.
As an initial milestone,we targeted an efficient and large
scale synthesis of (E,E,E)-undeca-2,8,10-trienals 12 (structure
H). A key step of this synthesis is the preparation of the 1-
aryl-1,3-E,E-diene moiety,which might be accessible through
a palladium-catalyzed Stille or Suzuki coupling. E-Vinyl
halide building blocks are required for both methods. How-
ever,all attempts to prepare suitable Stille or Suzuki
precursors were more or less unsuccessful. Therefore,we
turned to the palladium-catalyzed oxygen-promoted Heck-
type coupling of alkenes with vinyl boronates.[10,11] Accord-
[12–14]
ingly,the styrene
4 and the vinyl boronate[15] 6 were
prepared by standard procedures (Scheme 4). Under the
reported reaction conditions (5 mol% Pd(OAc)2,dimethyl-
amine (DMA),23 8C,slow addition of 6),we got only 30% of
the coupling product. We significantly improved the yield for
Scheme 2. Model reactions for biosynthetic key steps towards 1.
Boc=tert-butyloxycarbonyl, Troc=trichloroethoxycarbonyl, TS=transi-
tion state.
dihydropyridinium cation (compare with transition state D)
followed by epimerization of the cycloadduct via an enamine
might be operative.[4] There is support for the latter mode
from a model study by Snider and Che,[6,7] who prepared
desulfodeoxysymbioimine through an IMDA reaction of a
2,3-dihydropyridinium cation (Scheme 2; Z = Troc,Ar = Ph).
While both routes seem attractive and possible,one should
note that the orbital overlap is not ideal as large and small
coefficients at the termini do not really match. In fact,we
found in preliminary studies that trienone A (Scheme 2; R =
Boc,Ar = 3,5-dimethoxyphenyl) did not undergo any Diels–
Alder reaction,even after heating the substrate in a sealed
tube (xylene,180 8C) for 24 h. Under these conditions,slow
decomposition of the substrate was observed.
We reasoned that positioning an electron-withdrawing
group on the other side of the double bond should allow for a
more facile IMDA reaction (Scheme 3).[8] Some literature
precedence indicates that this approach should be feasible.[9]
However,a solution for extension of the aldehyde function in
the cycloadduct G combined with a diastereoselective intro-
duction of the methyl group would have to be found. Herein,
we present the realization of these goals.
Scheme 4. Synthesis of the Diels–Alder substrates 12. a) ( CHO)2SO2
3
(3.5 equiv), K2CO3, acetone, reflux, 4 h (96%); b) NaBH4 (5 equiv),
DME, MeOH, reflux, 1 h (99%); c) CrO3/pyridine (1.2 equiv), CH2Cl2,
RT, 24 h (81%); d) Ph3PCH3+Brꢁ (1.2 equiv), KOtBu (1.4 equiv), THF,
ꢁ658C to RT (96%); e) TBSCl, imidazole, CH2Cl2, RT, 24 h (99%);
f) catechol borane (1.1 equiv), 708C, 12 h, then pinacol (1.2 equiv),
238C, 3 h (85%); g) 4 (2 equiv), Pd(OAc)2 (0.1 equiv), Na2CO3, DMF,
608C, 6 (1 equiv), 24 h; h) HCl, MeOH, 238C, 0.5 h (68% from 6);
i) MsCl (1.3 equiv), NEt3, CH2Cl2, ꢁ308, 1 h (98%), j) NaI, acetone,
238C, 24 h (93%); k) tBuLi (2.5 equiv), then 9 (1.2 equiv), Et2O,
ꢁ808C, 1 h (60%); l) R3SiCl (2 equiv), imidazole, CH2Cl2, RT, 24 h;
m) amberlyst 15, acetone, RT, 40 min (12a: 80%, 2 steps; 12b: 75%;
12c: 83%). TBS=tert-butyldimethylsilyl, TBDPS=tert-butyldiphenyl-
silyl, TIPS=triisopropylsilyl, DMF=dimethylformamide, DME=dime-
thoxyethane, MsCl=methanesulfonyl chloride.
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this reaction by using 2 equivalents of 4 and 10 mol% of
Pd(OAc)2 in DMF at 608C. The starting styrene was readily
recovered by flash chromatography after acidic cleavage of
the TBS group to provide the dienol 7 in 68% yield based on
recovered 4 and 59% based on 6. This reaction is highly regio-
and stereoselective,and only the E,E diene was found to be
produced in more than 99% diastereomeric purity.
Continuing with the synthesis, 7 was converted into the
iodide 8 in two steps by mesylation (98%) and SN2
substitution by using NaI in acetone (93%). Transmetalation
of 8 with tBuLi at ꢁ808C followed by trapping of the
organolithium intermediate with the known (2E)-4,4-dime-
thoxybut-2-enal[16] 9,successfully afforded aldehydes 12 after
protection of the hydroxy group with a silicon protecting
group followed by hydrolysis of the acetal. Thus,syntheses of
all-E-undeca-2,8,10-trienals 12 with TBDPS,TIPS,and TBS
protecting groups were possible. The synthesis of 12c was
performed on a gram-scale.
Figure 1. X-ray structure of cycloadduct 14a.
be realized by using 1.6 equivalents of Me2AlCl,thus yielding,
for example, 12c in 85% yield on a gram-scale. The cyclo-
adducts already contain four of the five required stereocen-
ters with the correct relative configuration.
With substrates 12 in hand,the Lewis acid catalyzed
IMDA reaction was investigated (Scheme 5).[17] A fast
For conversion of the aldehyde function into the amino-
[18]
propyl appendage,several options were considered.
In a
first attempt, 14c was subjected to a Henry condensation[19]
with nitromethane followed by a Michael addition of the
resulting nitroalkene with MeMgBr at ꢁ808C. These trans-
formations proceeded smoothly in good yields and were
highly stereoselective and produced the nitro compound 15
(Scheme 6). Attempts to cleave the silyl ether of 15 with
TBAF surprisingly gave the corresponding lactol,which was
oxidized to lactone 16 with PDC in 65% yield of the isolated
product.
Scheme 5. Lewis acid induced IMDA reaction of trienals 12.
reaction of 12a was observed with MeAlCl2 (1 equiv) as the
Lewis acid in CH2Cl2 at ꢁ808C. However,the reaction did not
stop at the stage of the Diels–Alder product. Rather,a
subsequent intramolecular Friedel–Crafts reaction of the
aldehyde function with the electron-rich aryl ring took place,
thus leading to the tetracyclic compound 13 (50% yield). The
reaction of 12a with one equivalent of the weaker Lewis acid
Me2AlCl at ꢁ808C led to a conversion of approximately 60%
of 12a within 24 h to give a 50% yield of the isolated product
14a as a single diastereomer,and no Friedel–Crafts adducts
were observed.
The configuration of 14a was determined by X-ray
analysis (Figure 1). It is interesting to note that both bulky
substituents (Ar and OSiR3) are axially oriented relative to
the decalin ring. The silicon protecting groups do not
significantly affect the outcome of the IMDA reaction.
Also,the TIPS- and TBS-protected aldehydes 12b and 12c
gave a conversion of approximately 50% to the correspond-
ing cycloadducts under these conditions. A higher yield could
Scheme 6. Extension of cycloadduct 14c through a tandem Henry
Michael addition. a) CH3NO2, NH4OAc, 708C, 24 h (88%),
b) MeMgBr, Et2O, ꢁ808C, 3 h (70%); c) 1. TBAF, THF, RT, 12 h;
2. PDC, CH2Cl2, RT, 24 h (65%); d) LiAlH4, THF, ꢁ208C!RT, 24 h,
then reflux, 1 h; e) Boc2O, NEt3, MeOH, RT, 0.5 h; f) TBAF, THF, 608C,
24 h (55%, 3 steps); g) PDC, CH2Cl2, RT, 24 h; h) AcCl, MeOH, 508C,
30 min (80%, 2 steps). TBAF=tetrabutylammonium fluoride,
PDC=pyridinium dichromate.
The X-ray structure of lactone 16 showed that two
stereocenters were not correct with respect to the natural
product (see the Supporting Information). Most likely,the
conditions of the Henry reaction caused a base-catalyzed
epimerization at the g-atom of the nitroalkene to give the
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thermodynamically favored trans-1,2-substituted cyclohexane
tetrahydropyridine. This approach was initially investigated
by using hydroxy nitrile 20 (Scheme 8). Dess–Martin oxida-
tion of 20 afforded ketone 25 quantitatively. Ketone 25 was
protected with ethylene glycol in toluene to give 68% yield of
compound. The stereochemistry of 16 was also evident from
NOESY data. To probe the formation of the tetrahydropyr-
idine ring,the nitro group of 15 was reduced with LiAlH4,the
amino group protected with Boc anhydride,and the TBS-
group cleaved with TBAF to give alcohol 17. Oxidation of 17
followed by acid-induced Boc cleavage indeed gave imine 18,
an epimeric analogue of 1.
Finally,a practical solution was found starting with a
three-step sequence involving the reduction of aldehyde 14c
with NaBH4,conversion of the alcohol into the corresponding
mesylate,and nucleophilic substitution of the mesylate with
cyanide in dimethyl sulfoxide (DMSO),thus leading to nitrile
19 in more than 90% yield from 14c (Scheme 7). Removal of
Scheme 8. Synthesis of nor-methyl-de-sulfo-symbioimine (29). a) Dess–
Martin periodinane, CH2Cl2, RT, 8 h (99%); b) (CH2OH)2, CSA, tolu-
ene, reflux, 12 h, (68% of 26, 20% of 27); c) LiAlH4, Et2O, 08C to RT,
12 h (87%); d) BBr3, CH2Cl2, ꢁ808C to RT, 24 h (55%). Ar=3,5-
dimethoxyphenyl, CSA=camphorsulfonic acid.
the expected dioxolane 26 and 20% yield of the polycycle 27,
which resulted from attack of the aromatic ring to the keto
function. The nitrile group of 26 was then reduced with
LiAlH4 to the amine 28. Cleavage of the aryl methyl ethers,
the 1,3-dioxolane, and cyclization to the imine could be
achieved in one step using BBr3 in CH2Cl2. Imine 29 is a close
analogue of 1.
Hydroxy nitrile 24 served as starting material for the
synthesis of 1. As before,oxidation to the ketone 30 and
protection of the keto function as 1,3-dioxolane led to nitrile
31 (Scheme 9). After reduction of the nitrile to the primary
amine,treatment of 32 with BBr3 generated imine 33.
The sulfatation of the resorcinol posed a real challenge,as
it was not known whether the imine or iminium function
would be compatible with the reaction conditions. In addition,
Scheme 7. Diastereoselective alkylation of lactone 21 and nitrile 19.
a) NaBH4, EtOH, RT, 24 h (99%); b) MsCl, NEt3, CH2Cl2, ꢁ508C to RT,
1 h (96%); c) NaCN, DMSO, 508C, 48 h (95%); d) TBAF, THF, RT,
2 h (98%); e) KOH, EtOH, 808C, 24 h; f) p-TsOH, toluene, 1108C, 1 h
(90% for 2 steps); g) LDA (2 equiv), ꢁ808C, 3 h, then MeI (4 equiv),
0.5 h (65%); h) LDA (2 equiv), ꢁ808C, 2 h, then MeI (2 equiv), 0.5 h
(92%); i) TBAF, THF, RT, 24 h (92%); j) TMSCl, HCl, toluene, reflux,
48 h (75%). DMSO=dimethyl sulfoxide, LDA=lithium diisopropyl-
amide
the TBS group with TBAF in THF followed by nitrile
saponification allowed for the formation of lactone 21.
Although monomethylation of 21 was possible,careful
NMR spectroscopic analysis of the major diastereomer
showed that methylation had taken place from the wrong
side of the enolate. Next,methylation of the nitrile group was
investigated. Deprotonation of 19 with LDA (2 equiv)
followed by addition of MeI gave a single isomer,tentatively
assigned as structure 23,in 92% yield of the isolated product.
Indeed,conversion of 23 into the corresponding lactone
allowed for determination of the stereochemistry from the
NOESY data (see the NOESY correlations indicated in
Scheme 7).
Scheme 9. Completion of the total synthesis of symbioimine (1).
a) Dess–Martin periodinane, CH2Cl2, RT, 8 h (99%); b) (CH2OH)2,
CSA, benzene, reflux, 6 h, (99%); c) LiAlH4, Et2O, 08C to RT, 12 h;
d) BBr3, CH2Cl2, ꢁ808C to RT, 24 h (55% from 31); e) SO3/Py,
pyridine, 708C, 6 h; f) p-TsOH, dioxane, H2O, RT, 3 h (74% from 33).
Py=pyridine.
After the diastereoselective introduction of the methyl
group had been resolved,a method was sought that would
avoid protection of the amino group en route to the
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[5] For a review about Diels–Alder reactions in nature,see: E. M.
sulfonation of the aryl ring might take place with SO3 or
related agents. Although sulfate monoesters are less common
in nature relative to phosphate monoesters,sulfated biomol-
ecules do have a certain role in cellular events. Typical
sulfated biomolecules are carbohydrates,proteins (tyrosines),
and steroids.[20,21] The transfer of sulfate groups to hydroxy
functions is catalyzed by sulfotransferases,which use 3 ’-
phosphoadenosine 5’-phosphosulfate as the sulfate source. In
a laboratory setting,the attachment of the sulfate is prefer-
entially done at the end of the synthesis,as the resulting
products are very polar and the sulfate group is somewhat
acid labile. Common methods for the preparation of aryl
sulfates include the use of SO3/amine complexes[22] (amine =
pyridine,NEt 3) or tetrabutylammonium hydrogen sulfate
Stocking,R. M. Williams, Angew. Chem. 2003, 115,3186 – 3223;
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[6] B. B. Snider,Q. Che, Angew. Chem. 2006, 118,946 – 949; Angew.
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[7] See,also: Y. Kobayashi,E. E. Olson,Abstracts of Papers,229th
ACS National Meeting,San Diego,CA,United States,March
13 – 17, 2005,ORGN-605.
[8] For reviews about IMDA reactions,see: a) E. Ciganek, Org.
React. 1984, 32,1 – 374; b) D. Craig, Chem. Soc. Rev. 1987, 16,
187 – 238; c) W. R. Roush in Comprehensive Organic Synthesis,
Vol. 5 (Ed.: L. A. Paquette),Pergamon,Oxford 1991,pp. 513 –
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(Bu4N+ HSO4 ) in presence of dicyclohexyl carbodiimide
ꢁ
(DCC).[23] In the case at hand,the treatment of imine 33 with
the SO3/pyridine complex (10 equiv) in pyridine for 6 h at
708C afforded about 20% of the inner salt of 1 and 70% of a
compound that was characterized as a bisulfate derivative of
33. The bisulfate is a water soluble analogue of 1,which might
also be biologically active. We found that the bisulfate could
readily be converted into 1 with p-toluenesulfonic acid (p-
TsOH) in a water/dioxane system at room temperature.
Under these conditions,one sulfate group is selectively
hydrolyzed to give additional 1 (54%) and about 10% of
33,which could be recovered. The NMR spectra of 1 were
found to be identical to the spectra from the isolated natural
product.
[9] For some related examples (secondary alcohol next to dien-
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In summary,we developed an efficient synthesis of ( ꢀ )-
symbioimine (1),a novel tricyclic iminium alkaloid. The total
synthesis of 1 was accomplished in 22 steps from 3,5-
dihydroxy benzoic acid (5) in more than 5% total yield,
which corresponds to an average yield of 88% per step. Our
approach features a Lewis acid induced endo-IMDA reaction
of 2,8,10-E,E,E-trienal 12 and a diastereoselective alkylation
of nitrile 19 as key steps. This route opens the way to other
symbioimine-type compounds. This study also emphasizes the
high reactivity of the electron-rich aryl ring if it comes close to
another electrophilic group that yields interesting polycyclic
structures. This strategy might actually be of interest in the
context of diversity oriented synthesis.[24]
Bull. 1983, 31,3024 – 3038.
[13] A. Zanka,H. Ohmori,T. Okamoto, Synlett 1999,1636 – 1638.
[14] L. Gehringer,C. Bourgogne,D. Guillon,B. Donnio,
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[15] Vinyl boronate: a) prepared according to reference [10]; b) for a
review,see: D. E. Kaufmann,N. Ocal, Science of Synthesis,
J. Am.
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[18] For another attempt at extending aldehyde 14c,see the
Supporting Information.
[19] F. A. Luzzio, Tetrahedron 2001, 57,915 – 945.
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[23] D. Barron,R. K. Ibrahim, Tetrahedron 1987, 43,5197 – 5202.
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Received: April 10,2006
Published online: June 27,2006
Keywords: alkaloids · cycloaddition · Diels–Alder reaction ·
.
imines
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