Total synthesis of (±)-symbioimine

Article abstract of DOI:10.1021/ol062333s

The synthesis of (±)-symbioimine (1) has been completed in only 12 linear steps in 8% overall yield. The key step is the treatment of 13b with BF3·Et2O to generate N-carboalkoxydihydropyridinium cation 14b, which undergoes a novel stereospecific intramole

Full text of DOI:10.1021/ol062333s

ORGANIC
LETTERS
2
006
Vol. 8, No. 24
605-5608
Total Synthesis of (±)-Symbioimine
Yefen Zou, Qinglin Che, and Barry B. Snider*
5
Department of Chemistry MS 015, Brandeis UniVersity,
Waltham, Massachusetts 02454-9110
snider@brandeis.edu
Received September 21, 2006
ABSTRACT
The synthesis of (
BF Et O to generate N-carboalkoxydihydropyridinium cation 14b, which undergoes a novel stereospecific intramolecular Diels
to give adduct 16b in 42% yield. Cleavage of the N-Troc group of 16b afforded imine 24b stereospecifically. Cleavage of the TBDMS ethers and
sulfation provided ( )-symbioimine (1).
±
)-symbioimine (1) has been completed in only 12 linear steps in 8% overall yield. The key step is the treatment of 13b with
3
‚
2
−Alder reaction
±
Uemura and co-workers recently reported the isolation of
the novel tricyclic iminium sulfate symbioimine (1) from a
cultured marine dinoflagellate Symbiodinium sp.1 Symbio-
imine (1) inhibits the differentiation of RAW264 cells into
osteoclasts (EC50 ) 44 µM) and significantly inhibits
cyclooxygenase-2 activity at 10 µM, thus indicating that 1
is a potential antiresorptive and anti-inflammatory drug.
Uemura later isolated the dimethyl homologue neosymbio-
imine (2) from the same source.1
give ketone 5a in 67% yield (see Scheme 1). Reduction of
the ketone afforded alcohol 6a in 91% yield, which was
a,b
3 2 2 2
treated with BF ‚Et O in CH Cl to generate N-alkoxycar-
bonyl dihydropyridinium cation 7a, which underwent the
desired intramolecular Diels-Alder reaction through an endo
transition state from the face opposite the two alkyl groups
to give adduct 8a. Loss of a proton provided ene carbamate
9a in 87% yield from 6a. Deprotection of 9a with activated
Zn in AcOH/MeOH at 60 °C followed by protonation with
TFA afforded symbioimine analogue 10a in 83% yield.
Unfortunately 5b could not be prepared by Fowler
c
3
reduction of pyridine 3 (treatment with TrocCl and a hydride
reducing agent). We therefore developed an alternate route
to 5b from aldehyde 4, which is readily available in six steps
4
and 53% overall yield from ethyl acetoacetate. Wittig
reaction of aldehyde 4 with cinnamylidenetriphenylphos-
phorane afforded diene 5b as a 2:1 E/Z mixture that was
2 2 2
isomerized with I in CH Cl to afford 5b as a 6:1 E/Z
We recently reported an efficient biomimetic synthesis of
()-deoxysymbioimine (10b) (see Scheme 1). Treatment
of pyridine 3 with TrocCl and then EtMgBr gave a
methoxydihydropyridine that was hydrolyzed with HCl to
2
(
(3) (a) Fowler, F. W. J. Org. Chem. 1972, 37, 1321-1323. (b) Raucher,
S.; MacDonald, J. E. Synth. Commun. 1980, 10, 325-331. (c) Sundberg,
R. J.; Bloom, J. D. J. Org. Chem. 1981, 46, 4836-4842. (d) Sundberg, R.
J.; Hamilton, G.; Trindle, C. J. Org. Chem. 1986, 51, 3672-3679. (e) Zhao,
G.; Deo, U. C.; Ganem, B. Org. Lett. 2001, 3, 201-203.
(1) (a) Kita, M.; Kondo, M.; Koyama, T.; Yamada, K.; Matsumoto, T.;
(4) Our original procedure required two steps to hydrolyze a dioxolane
protecting group by first converting it to a dimethyl acetal. The sequence
has been shortened one step by alkylating ethyl acetoacetate with 3-bromo-
1,1-dimethoxypropane rather than 2-(2-bromoethyl)-1,3-dioxolane so that
the acetal exchange is not necessary. Full details are provided in the
Supporting Information.
Lee, K.-H.; Woo, J.-T.; Uemura, D. J. Am. Chem. Soc. 2004, 126, 4794-
4
795. (b) Kita, M.; Uemura, D. Chem. Lett. 2005, 34, 454-459. (c) Kita,
M.; Ohishi, N.; Washida, K.; Kondo, M.; Koyama, T.; Yamada, K.; Uemura,
D. Bioorg. Med. Chem. 2005, 13, 5253-5258.
(2) Snider, B. B.; Che, Q. Angew. Chem., Int. Ed. 2006, 45, 932-935.
1
0.1021/ol062333s CCC: $33.50
© 2006 American Chemical Society
Published on Web 11/04/2006

Scheme 1. Synthesis of (()-Deoxysymbioimine
Scheme 2. Synthesis of Diels-Alder Adducts 15a,b
dienyl ketone 12a as a 6:1 E/Z mixture in 67% yield.
Reduction of the ketone with NaBH and CeCl in MeOH
4 3
at -78 °C to 0 °C provided 13a in 94% yield. Unfortunately,
treatment of 13a with BF ‚Et O under a variety of conditions
gave only 5-10% of the 3,5-dimethoxyphenyl Diels-Alder
product 16a. We looked carefully at the structures of the
byproducts to understand this reaction better and hopefully
improve the yield of the Diels-Alder reaction.
mixture in 83% yield from 4. Reduction afforded alcohol
3
2
6b in 95% yield, which was treated with BF
3
‚Et
2
O as
described above for 6a to afford the desired Diels-Alder
adduct 9b in only 31% yield. Deprotection of 9b with
activated Zn in AcOH/MeOH at 60 °C and protonation with
TFA afforded (()-deoxysymbioimine (10b) in 75% yield.
Reaction of 13a with BF ‚Et O (1 equiv) in Et O at -78
3
2
2
To complete the synthesis of (()-symbioimine (1), we
needed to adapt this chemistry to a bis-oxygen-substituted
aromatic ring and optimize the intramolecular Diels-Alder
reaction, which gave the ethyl homologue 9a in 87% yield,
but gave deoxysymbioimine precursor 9b in only 31% yield.
While this work was in progress, Varseev and Maier reported
the synthesis of (()-symbioimine via an intramolecular
Diels-Alder reaction of an unsaturated aldehyde, followed
to 25 °C gave a ∼10:35:1 mixture of 16a, 18a, and 20a in
1
∼46% yield (see Scheme 3). The H NMR spectrum of 18a
Scheme 3. Formation of Byproducts 18 and 20
5
by elaboration of the heterocyclic ring in 22 steps. Uemura
reported the preparation of bicyclic intermediates by a similar
strategy.6
The preparation of diene alcohol 13a was carried out
analogously to the preparation of diene alcohol 6b (see
Scheme 2). Wittig reaction of aldehdye 4 with phosphorane
7
,8
1
2 2 2
1a followed by equilibration with I in CH Cl afforded
(
5) Varseev, G. N.; Maier, M. E. Angew. Chem., Int. Ed. 2006, 45, 4767-
771.
6) Sakai, E.; Araki, K.; Tamkamura, H.; Uemura, D. Tetrahedron Lett.
006, 47, 6343-6345.
7) Wittig reaction of 3,5-dimethoxybenzaldehyde with methyl triphen-
4
(
2
(
ylphosphoranylideneacetate afforded the cinnamate ester that was reduced
to the alcohol with DIBAl-H, converted to the bromide with PBr3, and
was hard to interpret because of slow rotation about the
Troc-N bond. Deprotection of the mixture with activated
Zn in AcOH/MeOH at 60 °C for 30 min afforded the free
amine 19a in 35% overall yield from 13a. Treatment of 13a
8
reacted with Ph3P to give the phosphonium salt. Treatment of the
8
phosphonium salt with n-BuLi afforded 11a.
(
8) Taira, S.; Danjo, H.; Imamoto, T. Tetrahedron Lett. 2002, 43, 8893-
8
896.
5606
Org. Lett., Vol. 8, No. 24, 2006

with BF
3
‚Et
2
O generates dihydropyridinium cation 14a,
reaction. Use of nonpolar solvents such as toluene favors
the Diels-Alder product 15 at the expense of 18. Byproduct
23 is formed by Friedel-Crafts cyclization of the Diels-
Alder adduct 15 prior to loss of a proton to form 16. We
thought that this cyclization should be slower with larger
protecting groups on oxygens. TBDMS was chosen for initial
examination because it is large and easily removed after the
Diels-Alder reaction.
which undergoes both the desired Diels-Alder reaction to
give 15a and a stepwise cyclization from the less hindered
top face to give allylic cation 17a, which loses a proton to
give the conjugated diene 18a. The stereochemistry of 18a
and 19a was assigned by analogy to 18b (see below). Minor
byproduct 20a is formed by loss of a proton from dihydro-
pyridinium cation 14a. Diels-Alder reaction in CH
2 2
Cl gave
low yields of a ∼1:2 mixture of 16a and 18a.
Phosphorane 11b was prepared analogously to 11a from
9
,10
Having established the structure of 18, we can rationalize
the formation of the ethyl-substituted Diels-Alder adduct
3,5-bis(TBDMSO)-benzaldehyde.
Reaction of aldehyde
4 with ylide 11b gave dienyl ketone 12b in 83% yield as a
9
a in 87% yield, while the parent adduct 9b is formed in
6:1 mixture of E/Z isomers after equilibration with I
CH Cl . Reduction of the ketone with NaBH and CeCl
3
MeOH at -78 to 0 °C afforded 96% of alcohol 13b. We
were delighted to find that treatment of alcohol 13b with
2
in
in
only 31% yield. Presumably, the ethyl group sterically retards
the stepwise addition of the diene to the iminium cation, so
that byproducts analogous to 18 are formed from iminium
salt 7b, but not from the ethyl homologue 7a. The substit-
uents on the aryl group do not play a crucial role in this
side reaction.
2
2
4
BF
3
‚Et O in 1:1 benzene/toluene at -42 °C for 20 min
2
followed by slow warming to 25 °C over 20 min provided
the desired ene carbamate 16b in 42% yield (49% based on
E-isomer), only 11% of byproduct 18b, and <5% of 20b.
Friedel-Crafts reaction to give 23b did not take place. The
spectral data for 16b corresponded closely to those for
deoxysymbioimine precursor 9b. The stereochemistry of the
diene and the heterocyclic ring of 18b was assigned based
Reaction of 13a with BF
3
2
‚Et O (1 equiv) in toluene at
-
78 to 25 °C gave a ∼1:10 mixture of 16a and 23a, from
which pure 23a was isolated in 31% yield (see Scheme 4).
on the NOE from H
in 90% yield.
8
to H11. Deprotection of 18b gave 19b
Scheme 4. Formation of Byproduct 23a
Deprotection of the Troc group of 16b with Zn in AcOH/
MeOH at 60 °C provided imine 24b in 86% yield (see
Scheme 5). Deprotection of the TBDMS groups proved
Scheme 5. Completion of the Symbioimine (1) Synthesis
In the less polar solvent toluene, the stepwise addition to
give 18a does not occur. The desired Diels-Alder adduct
15a is formed, but reacts further to give byproduct 23a. The
electron-rich dimethoxyphenyl ring of the Diels-Alder
adduct iminium salt 15a is close to the iminium cation.
Friedel-Crafts addition followed by loss of a proton affords
21a, which is protonated on nitrogen and undergoes C-N
bond cleavage to give stabilized benzylic cation 22a, which
loses a proton to give 23a. The structure of 23a was assigned
1
13
by careful analysis of the H, C, COSY and 1D NOESY
NMR spectra.
We considered modification of oxygen protecting groups
and reaction conditions that would improve the selectivity
for the ene carbamate Diels-Alder adduct 16 at the expense
of byproducts 18 and 23. Dihydropyridinium cation 14
cyclizes to give 17 in a polar reaction and undergoes an
intramolecular cycloaddition to give 15 in a concerted
challenging but was achieved by treatment with TBAF/AcOH
(1:1, 2 equiv) in THF at 25 °C for 15 min. The product was
separated from tetrabutylammonium salts by extraction from
water at neutral pH into ether to give desulfato symbioimine
25 in 86% yield with spectral data identical with those
Org. Lett., Vol. 8, No. 24, 2006
5607

5
reported by Varseev and Maier. Reaction of 25 with 10
equiv of SO ‚DMF (2 M in DMF) and anhydrous sodium
sulfate in pyridine afforded a mixture of (()-symbioimine
1) and the bis-sulfate 26 in quantitative yield. Reverse-phase
HPLC separation gave pure (()-symbioimine (1) in 58%
In conclusion, we have completed the synthesis of (()-
symbioimine in only 12 linear steps in 8% overall yield. The
key step is the novel stereospecific intramolecular Diels-
Alder reaction of 14b, with an N-carboalkoxydihydropyri-
dinium cation as the dienophile, which gave adduct 16b in
3
(
1
,5
42% yield. This convergent sequence starting from aldehyde
yield with spectral data identical with those reported. We
also obtained ∼25% of bis-sulfate 26, which hydrolyzed on
concentration to give a mixture of 1, 25, and 26.
4
and ylide 11b is readily amenable to preparation of
analogues for further biological evaluation.
Acknowledgment. We thank the NIH (GM50151) for
generous financial support.
(
9) Guiso, M.; Marra, C.; Farina, A. Tetrahedron Lett. 2002, 43, 597-
98.
10) Wittig reaction of 3,5-bis(TBDMSO)-benzaldehyde with methyl
5
(
Supporting Information Available: Full experimental
triphenylphosphoranylideneacetate afforded the cinnamate ester (91%) that
was reduced to the alcohol (95%) with DIBAl-H, converted to the bromide
80%) with PBr3, and reacted with Ph3P to give the phosphonium salt
1
13
details and copies of H and C NMR spectra. This material
is available free of charge via the Internet at http://pubs.acs.org.
(
(
8
80%). Treatment of the phosphonium salt with n-BuLi afforded 11b. Full
details are provided in the Supporting Information.
OL062333S
5608
Org. Lett., Vol. 8, No. 24, 2006