Synthesis of (±)-Bistellettadine A

Article abstract of DOI:10.1021/ol902895e

(Figure Presented) Esterification of the trienoic acid with o-xylylene dibromide gave the bis ester that underwent a templated Diels-Alder reaction to afford the macrodiolide stereospecifically In a single step. The synthesis of bistellettadine A was completed In four steps by hydrolysis and side chain elaboration.

Full text of DOI:10.1021/ol902895e

ORGANIC
LETTERS
2010
Vol. 12, No. 4
828-831
Synthesis of (()-Bistellettadine A
Min Yu, Susan S. Pochapsky, and Barry B. Snider*
Department of Chemistry MS 015, Brandeis UniVersity,
Waltham, Massachusetts 02454-9110
snider@brandeis.edu
Received December 16, 2009
ABSTRACT
Esterification of the trienoic acid with o-xylylene dibromide gave the bis ester that underwent a templated Diels-Alder reaction to afford the
macrodiolide stereospecifically in a single step. The synthesis of bistellettadine A was completed in four steps by hydrolysis and side chain
elaboration.
As part of our continuing interest in the synthesis of
guanidine-containing alkaloids, we were intrigued by the
biologically active, dimeric, tetra guanidines bistellettadines
A (1a) and B (2), which were recently isolated by Fusetani
and co-workers from a Stelletta sponge collected from
Shikine-jima island, 200 km south of Tokyo (see Figure 1).1,2
They inhibit Ca2+/calmodulin-dependent phosphodiesterase
(40% inhibition at 100 µM) and the growth of yeast and E.
coli at 10 µg/disk. The structures of the bistellettadines were
determined by spectroscopic analysis and the cis relationship
of the two unsaturated side chains on the cyclohexene was
established by NOE experiments. Bistellettazine A (3), a
structurally related dimeric marine natural product with trans
unsaturated side chains, was isolated by Capon in 2008.2f
Dimers 1a and 2 are probably biosynthesized by a
Diels-Alder reaction of two monomers analogous to stel-
lettadine A (7)2b (see Scheme 1). The stereochemistry of the
Diels-Alder reaction may be controlled in the biosynthesis.
However, closely related bis sesquiterpene dimers have been
isolated as mixtures of cis and trans isomers.3 This raises
the possibility that the Diels-Alder reactions are not
stereoselective and that the trans isomer 1b and the cis isomer
of 3 were present in the sponges but were not isolated and
characterized.
(1) Tsukamoto, S.; Yamashita, T.; Matsunaga, S.; Fusetani, N. J. Org.
Chem. 1999, 64, 3794–3795
.
Mori and co-workers synthesized stellettadine A (7)2b by
coupling Boc-protected agmatine 4 and acyl chloride 5 to
provide the diacylated product 6 in 62% yield (see Scheme
1).4 Removal of the Boc group of 6 under acidic conditions
(2) For related compounds isolated from other Stelletta sponges, see:
(a) Hirota, H.; Matsunaga, S.; Fusetani, N. Tetrahedron Lett. 1990, 31, 4163–
4164. (b) Tsukamoto, S.; Kato, H.; Hirota, H.; Fusetani, N. Tetrahedron
Lett. 1996, 37, 5555–5556. (c) Shin, J.; Seo, Y.; Cho, K. W.; Rho, J. R.;
Sim, C. J. J. Nat. Prod. 1997, 60, 611–613. (d) Matsunaga, S.; Yamashita,
T.; Tsukamoto, S.; Fusetani, N. J. Nat. Prod. 1999, 62, 1202–1204. (e)
Tsukamoto, S.; Yamashita, T.; Matsunaga, S.; Fusetani, N. Tetrahedron
Lett. 1999, 40, 737–738. (f) El-Naggar, M.; Piggott, A. M.; Capon, R. J.
(3) Mao, S.-C.; Manzo, E.; Guo, Y.-W.; Gavagnin, M.; Mollo, E.;
Ciavatta, M. L.; van Soest, R.; Cimino, G. Tetrahedron 2007, 63, 11108–
11113.
Org. Lett. 2008, 10, 4247–4250
.
10.1021/ol902895e  2010 American Chemical Society
Published on Web 01/15/2010

elaborated to 1a. We hoped that the carboxylate salt of 10
might orient in water to give selectively the desired
Diels-Alder adduct 9a with cis unsaturated side chains.6
Scheme 2. Retrosynthesis of (()-Bistellettadine A (1a)
Figure 1. Structures of bistellettadines A (1a) and B (2), epi-
bistellettadine A (1b), and bistellettazine A (3).
followed by treatment of the resulting amine with aminoimi-
nomethanesulfonic acid constructed the second guanidine
group. The extra acyl group was removed using KOH to
afford stellettadine A (7) in 56% overall yield from 6. The
yield of this four-step sequence is 35% from 4, but only 17%
based on acyl chloride 5.
Mori’s procedure for the introduction of the guanidine side
chain of stellettadine A (7) that proceeds through a bis acyl
guanidine could be used for the conversion of acid 10 to
monomer 8b, but it cannot be used for the conversion of
diacid 9a to 1a. We therefore needed to develop a more
efficient procedure for introduction of the guanidine side
chain that does not proceed through a diacylated intermediate
analogous to 6.
Scheme 1. Mori’s Synthesis of Stellettadine A (7)
Wittig reaction of readily available dienal 125 and ylide
13 was most effectively carried out in THF at 70 °C for 15
min under microwave irradiation to give 11 in 85% yield
(see Scheme 3). The unstable trienoate 11 decomposed
partially and gave some Diels-Alder dimer at longer reaction
times, higher temperatures, or with traditional heating.
Hydrolysis of ester 11 with LiOH in 4:2:1 THF/MeOH/H2O
for 16 h followed by neutralization with 6 M HCl gave crude
acid 10. Coupling7 of acid 10 and 147 in CH2Cl2 using
DIPEA, EDC, and HOBT gave 15 in 59% overall yield from
ester 11, which was treated with bis Boc-protected agmatine
16,8 Et3N, and AgNO3 in DMF at 0 °C for 3 h and at 25 °C
for 4 h to give 8a in 77% yield as a 2:3 mixture of tautomers.
Deprotection of the Boc groups of 8a using TFA gave the
(4) (a) Takikawa, H.; Nozawa, D.; Mori, K. J. Chem. Soc., Perkin. Trans.
1 2001, 657–661. (b) Nozawa, D.; Takikawa, H.; Mori, K. Bioorg. Med.
Chem. Lett. 2001, 11, 1481–1483.
Our retrosynthesis analysis of 1a is shown in Scheme 2.
A Diels-Alder dimerization of two molecules of 8a or 8b
could give 1a (after deprotection if 8a is used). Bis guanidine
8a will be prepared from trienoic acid 10 resulting from the
hydrolysis of ester 11 formed by the Wittig reaction of trienal
125 and ylide 13. Alternatively, the Diels-Alder reaction
of 10 or 11 could be carried out before introduction of the
guanidine side chains to give diacid 9a, which will then be
(5) Spangler, C. W.; McCoy, R. K.; Karavakis, A. A. J. Chem. Soc.,
Perkin. Trans. 1 1986, 1203–1207.
(6) We have previously observed that photochemical [2 + 2] cycload-
ditions of anchinopeptolide D occurs selectively in water, but not MeOH:
Snider, B. B.; Song, F.; Foxman, B. J. Org. Chem. 2000, 65, 793–800.
(7) Weiss, S.; Keller, M.; Bernhardt, G.; Buschauer, A.; Ko¨nig, B.
Bioorg. Med. Chem. 2008, 16, 9858–9866.
(8) Sarabia, F.; Sa´nchez-Ruiz, A.; Chammaa, S. Bioorg. Med. Chem.
2005, 13, 1691–1705.
Org. Lett., Vol. 12, No. 4, 2010
829

with TFA gave 18 as a single compound in which the alkene
proton absorbed at δ 6.86.
Scheme 3. Unsuccessful Approach to Bistellettadine A (1a)
We then investigated the Diels-Alder dimerization of
trienoate ester 11 in organic solvents and the lithium salt of
trienoic acid 10 in water. Hydrolysis of 11 with LiOH
followed by concentration gave the lithium salt, which
underwent a clean Diels-Alder dimerization in water under
microwave irradiation at 110 °C for 50 min to give an
inseparable 5:4 mixture of crude 9a and 9b in 94% yield
(see Scheme 5). Heating trienoate ester 11 in toluene at 125
Scheme 5. Diels-Alder Dimerization of 11 to Give 9a and 9b
bis trifluoroacetate salt 8b. Unfortunately, initial attempts to
carry out Diels-Alder dimerizations of either 8a or 8b
resulted in polymerization of the sensitive trienoyl guanidine.
To establish the structures of the two tautomers of 8a, we
prepared an inseparable 36:64 mixture of the simpler
tautomers 17a and 17b from tiglic acid using the two-step
procedure described above for the conversion of 10 to 8a
(see Scheme 4). The alkene proton at δ 7.08 in the minor
°C for 2 days followed by hydrolysis gave a similar mixture
of 9a and 9b in comparable yield. An NOE between H-11
and the C-6 methyl group in 9a suggested that the unsaturated
side chains of the major isomer 9a have the desired cis
relationship. NOEs between H-11 and H-5 and between H-12
and the C-6 methyl group established that the unsaturated
side chains are trans in the minor isomer 9b.
Scheme 4. Model Tautomers 17a and 17b
Analytical, but not preparative, separation of 9a and 9b
was achieved on reverse phase silica gel. We therefore
coupled the mixture of 9a and 9b with 14, DIPEA, EDC,
and HOBT to afford an inseparable 5:4 mixture of 19a and
19b in 67% overall yield from trienoate ester 11 (see Scheme
6). Treatment of this mixture with 16, Et3N, and AgNO3 in
DMF afforded a 5:4 mixture of 20a and 20b in 69% yield.
Stirring this mixture in 9:1 CDCl3/TFA at 25 °C for 4 days
cleaved all six Boc groups to give a 5:4 mixture of 1a and
1b in 68% yield as the tetra trifluoroacetate salts, which were
1
readily separated by reverse phase HPLC. The H and 13C
NMR spectra of synthetic 1a in DMSO-d6 correspond very
closely to those of natural 1a.1,10 The spectra of 1b are very
similar except that H-11 is shifted downfield by 0.07 ppm
to δ 3.14, the C-6 methyl group is shifted upfield by 0.10
isomer 17a shows a strong NOE only to the geminal methyl
group at δ 1.80. However, the alkene proton at δ 6.74 in the
major isomer 17b shows strong NOEs not only to the
geminal methyl group at δ 1.87, but also to the N-H proton
at δ 12.86. The presence of both tautomers indicates that
the N-H exchange is slow on the NMR time scale.9
Protonation of both 17a and 17b should give the same
diacylguanidinium cation. Treatment of the mixture in CDCl3
(9) Slow N-H exchange has been observed previously in symmetrical
N,N′-bisacyl guanidines. The acetyl methyl groups of 3-(N,N′-
diacetylguanidino)-3,7-dimethyloctane absorb at δ 2.10 and δ 2.15:
Nishikawa, T.; Ohyabu, N.; Yamamoto, N.; Isobe, M. Tetrahedron 1999,
55, 4325–4340. The ortho benzoyl protons of N,N′-dibenzoyl-N′′-
methylguanidine absorb at δ 8.04 and δ 8.30: Newton, C. G.; Ollis, W. D.
J. Chem. Soc., Perkin. Trans. 1 1984, 75–84
.
(10) The assignments in ref 1 for protons and carbons 2′ to 9′ and 2′′ to
9′′ appear to be in the wrong order as discussed in more detail in the
Supporting Information.
830
Org. Lett., Vol. 12, No. 4, 2010

Scheme 6
.
Completion of Bistellettadine A (1a) Synthesis
Scheme 7
.
Use of Templated Diels-Alder Reaction to
Synthesize Bistellettadine (1a)
bis ester 22 and ∼10% of Diels-Alder product 23 had
already formed. Heating for 2 days gave exclusively mac-
rodiolide 23 with the cis configuration of the unsaturated
side chains in 42% overall yield from 11 (80% yield from
21). Remarkably, the intramolecular Diels-Alder reaction
proceeded stereospecifically under milder conditions than the
intermolecular Diels-Alder dimerization of 10 or 11 to form
23 with a 16-membered ring macrodiolide. The stereochem-
istry of 23 was established by NOEs between H-11 and the
C-6 methyl group. Hydrolysis of 23 using LiOH in 5:2 THF/
H2O at 25 °C for 16 h gave 9a. Coupling of 9a with 14
gave 19a in 57% overall yield from 23. Reaction of 19a
with 16 gave 20a in 57% yield, which was deprotected using
TFA for 4 days to give 1a as a single isomer in 68% yield.
In conclusion, trienal 12 has been converted to bistellet-
tadine A (1a) in seven steps in 8% overall yield. Remarkably,
the templated Diels-Alder reaction of 22 afforded macrodi-
olide 23 in excellent yield with complete stereocontrol.
ppm to δ 1.00, C-5 is shifted downfield by 2.7 ppm to δ
153.0 and the C-6 methyl group is shifted upfield by 2.4
ppm to δ 21.7. These shifts are consistent with the upfield
shift expected for gauche butane interactions between C-12
and C-5 in 9a and between C-12 and the C-6 methyl group
in 9b.
Unfortunately, the Diels-Alder dimerization of ester 11
or the salt of acid 10 proceeded cleanly but with poor
stereocontrol. Coupling two molecules of acid 10 to a linker
by a temporarily tether will form a substrate that can undergo
an intramolecular Diels-Alder reaction.11 The tether needs
to be easily attached and removed, long enough to accom-
modate the different lengths of the unsaturated side chains
in the Diels-Alder adduct, and yet short enough to facilitate
an intramolecular Diels-Alder reaction and favor the forma-
tion of the isomer with cis unsaturated side chains. Molecular
mechanics calculations suggested that the intramolecular
Diels-Alder reaction of 22 should give 23 stereospecifi-
cally.12 We therefore treated acid 10 (2.5-4 equiv) with
o-xylylene dibromide (21) and Cs2CO3 in CH3CN at 85 °C
(see Scheme 7). After 3 h, 21 was completely converted to
Acknowledgment. We are grateful to the National Insti-
tutes of Health (GM-50151) for support of this work. The
800 MHz spectrometer in the Landsman Research Facility,
Brandeis University was purchased under NIH RR High-
End Instrumentation program, 1S10RR017269-01.
(11) (a) Cox, L. R.; Ley, S. V. In Templated Organic Synthesis;
Diederich, F., Stang, P. J., Eds.; Wiley-VCH: Weinheim, Germany, 2000;
pp 275-390. (b) Craig, D.; Ford, M. J.; Gordon, R. S.; Stones, J. A.; White,
A. J. P.; Williams, D. J. Tetrahedron 1999, 55, 15045–15066. (c) Craig,
D.; Gordon, R. S. Tetrahedron 1998, 39, 8337–8340. (d) Craig, D.; Ford,
M. J.; Stones, J. A. Tetrahedron Lett. 1996, 37, 535–538.
Supporting Information Available: Complete experi-
mental procedures, tables comparing the spectral data of
1
synthetic and natural products, and copies of H and 13C
(12) MMX calculations using PCMODEL 8.0 (Serena Software: Bloom-
ington, IN) indicated that 23 is >3 kcal/mol more stable than the
stereoisomer. Transition state calculations also indicated that the transition
state leading to 23 was more stable than that leading to the stereoisomer
by >3 kcal/mol.
NMR spectral data. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL902895E
Org. Lett., Vol. 12, No. 4, 2010
831