Synthesis of the marine sponge alkaloid oroidin and its analogues via Suzuki cross-coupling reactions

Article abstract of DOI:10.1016/S0040-4039(02)00947-4

A new synthesis of the natural product oroidin was described using a Suzuki coupling reaction as key step. This method was extended to the synthesis of various analogues of oroidin and hymenidin.

Full text of DOI:10.1016/S0040-4039(02)00947-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 4935–4938
Synthesis of the marine sponge alkaloid oroidin and its
analogues via Suzuki cross-coupling reactions
Fabienne Berre´e, Pascale Girard-Le Bleis and Bertrand Carboni*
Synthe`se et Electrosynthe`se Organiques, UMR CNRS 6510, Bat 10A, Institut de Chimie, Universite´ de Rennes 1,
Campus de Beaulieu, F-35042 Rennes CEDEX, France
Received 18 April 2002; accepted 16 May 2002
Abstract—A new synthesis of the natural product oroidin was described using a Suzuki coupling reaction as key step. This method
was extended to the synthesis of various analogues of oroidin and hymenidin. © 2002 Elsevier Science Ltd. All rights reserved.
Marine sponges are the source of the greatest diversity
of marine natural products. Among these is the
pyrrole–imidazole alkaloid family, where the common
skeleton is observed in oroidin 1.1 Various modes of
cyclization give rise to a large number of natural prod-
ucts with different geometries and functionalizations.
Many of these compounds display a broad range of
biological properties including antibacterial, antiinflam-
matory, anticancer and antiviral activities. With respect
to the discovery of new biologically active molecules, it
is therefore promising to explore new approaches for
the synthesis of oroidin 1 and its structural analogues.
Four syntheses of this natural product have been hith-
erto reported. These previous preparations were based
on a Wittig–Schweizer reaction,2 a cyclization reaction
of an a-haloketone with N-acetylguanidine,3 and the
preparation and transformation of 2-amino-4,5-
dialkoxy-4,5-dihydroimidazoline.4 While this work was
in progress, another route has been described using a
Sonogashira alkynylation.5 In this paper, we present an
alternative approach for the synthesis of oroidin 1 and
its analogues, which involves the vinylboronate 2 as key
building block. Scheme 1 illustrates a retrosynthetic
analysis, in which the (E)-allylic amide is assembled in
a stereoselective manner via a palladium-catalyzed
cross-coupling reaction.
The boronate 2 was easily prepared from the commer-
cially available propargylamine. Protection as a N-Boc
derivative6 was followed by hydroboration with
diisopinocampheylborane (Ipc2BH), prepared in situ
from (−)-a-pinene and BH3–SMe2. Dealkylation with
acetaldehyde and ester exchange with pinacol was then
effected. The stable isomerically pure (E)-boronic ester
2 was obtained in a 54% yield after purification by silica
gel chromatography.7 N-Trityl-4(5)-iodoimidazole 3
was separately prepared by iodination of imidazole,
followed by sodium sulfite reduction of the triiodo
O
H
O
H
N
O
N
R
NHBoc
B
+
Het
X
+
R
Het
N
H
Cl3C
O
Br
Br
2
N
NH2
oroidin
Het =
1
, R = Br
NHBoc
NH
Scheme 1.
* Corresponding author. Tel.: 33(0)2 23 23 67 47; fax: 33 (0)2 23 23 69 78; e-mail: bertrand.carboni@univ-rennes1.fr
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00947-4

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F. Berre´e et al. / Tetrahedron Letters 43 (2002) 4935–4938
Scheme 2. Reagents and conditions: (a) (i) Ipc2BH, THF, 0°C, 6 h, (ii) CH3CHO (30 equiv.), rt, 16 h, (iii) pinacol (1.2 equiv.),
THF, rt, 16 h, 54%; (b) 3, Pd(OAc)2, (o-Tolyl)3P (5%), K2CO3 (2 M, 2.5 equiv.), DME, reflux, 18 h, 51%; (c) (i) n-BuLi (3 equiv.),
THF, −78°C, 15 min, (ii) TsN3 (1.5 equiv.), −78°C, 15 min, 64%; (d) MeOH (50 equiv.), CH3COCl (50 equiv.), AcOEt, rt, 18 h,
95%; (e) 4,5-dibromo-2-trichloroacetylpyrrole, Na2CO3 (1 equiv.), DMF, rt, 6 h, 25%; (f) H2/Pd-Lindlar, MeOH, 1 atm, rt, 3 h,
89%.
derivative and finally tritylation, as reported previ-
ously.8 Palladium-catalyzed coupling of 3 with vinyl
boronate 2 gives the alkenylimidazole 4 in only 26%
yield using the usual catalyst Pd(PPh3)4 and potassium
carbonate in DME.9 No significant improvement was
observed by modifying solvent and base, probably due
to a partial deprotection of the trityl group, which was
then responsible for the unsatisfactory purification of
the final product. The use of Pd(Oac)2 and (o-Tolyl)3P
as catalytic system increased the yield up to 51% with
no detectable (Z)-isomer. After azidation of the imida-
zole 2-position employing n-BuLi/tosyl azide according
to reported procedures,2b,5 simultaneous removal of the
Boc and trityl protecting groups by dry HCl, generated
from MeOH and acetyl chloride, afforded the dihy-
drochloride 5. The pyrrole moiety was then introduced
by coupling with 4,5-dibromo-2-trichloroacetyl-
pyrrole.10 Clean reduction of the azido function by
hydrogenation on Lindlar catalyst led to oroidin 1
(Scheme 2).11
(Het–Hal 6a–g) were realized in the presence of
Pd(PPh3)4 as catalyst and potassium carbonate in
DME. Different haloheterocycles were used: commer-
cially available 2- and 3-bromopyridin, 4-iodopyridin
(entries a, b and c), 2-amino-5-bromopyrimidin (entry
d), 5-iodo-1,3-dimethyluracil (entry e) while N-benzyl-
6-chloro-3-aminopyridazin has been first prepared from
benzylamine and 3,6-dichloropyridazin (entry f)12 and
9-benzyl-6-chloropurine by benzylation of 6-chlorop-
urine with benzyl bromide13 (entry g) (Table 1). The
N-Boc allylamines 7a–g were obtained in good to mod-
erate yields (43–82%) after purification by column chro-
matography with no detectable traces of the (Z)
isomers.14 Deprotection of the amino group was
effected for some of them, using the same procedure as
previously described for oroidin. Acylation of the
resulting hydrochloride with 4-bromo- or 4,5-dibromo-
2 trichloroacetylpyrrole proceeded in the presence of
sodium carbonate in DMF in low unoptimized yields.15
In summary, oroidin and several of its analogues were
synthesized stereoselectively via Suzuki reaction as key
step, followed by an amide coupling with pyrrol-2-
yltrichloromethyl ketone. In view of the recent prepara-
tion of diversely substituted alkenyl boronates 216 and
the large availability of heterocycles bearing an halide
or a carboxylic acid group, this approach should allow
the preparation of other structurally diversified ana-
logues of some marine sponge alkaloids.
Having in hand a convenient method to prepare the
oroidin skeleton, we then extended this approach to the
synthesis of analogues of oroidin (R=Br) and
hymenidin (R=H) (Scheme 3). We first replaced the
aminoimidazole moiety with various heterocycles rang-
ing in size and basicity. All these modifications were
effected from the boronate 2. Suzuki cross-coupling
reactions with appropriate functionalized heterocycles
O
b, c
a
H
N
O
+
X
Het
B
Het
NHBoc
Het
N
H
NHBoc
H
N
R
O
Cl3CCO
R
6
7
8 R=H
9 R=Br
2
Br
Br
Scheme 3. Reagents and conditions: (a) Pd(PPh3)4, 5%, K2CO3 (2 M, 2.5 equiv.), DME reflux, 18 h (see Table 1 for yields); (b)
MeOH (50 equiv.), CH3COCl (50 equiv.), AcOEt, rt, 6 h, quantitative; (c) 4-bromo- or 4,5-dibromo-2 trichloroacetylacetylpyrrole,
Na2CO3, DMF, rt, 6 h, R=H: 8a 23%; 8d 43%; 8e 27%; 8f 29%. R=Br: 9a 26%; 9e 30%.

F. Berre´e et al. / Tetrahedron Letters 43 (2002) 4935–4938
4937
Table 1. Synthesis of N-Boc allylamines 7a–g by Suzuki cross-coupling reactions
crude product was purified by silica gel column chro-
matography. Compound 2: yield 54%, mp=72°C, Rf=
0.30 (heptane/ethyl acetate: 80/20). H NMR (200 MHz,
CDCl3) l 1.27 (s, 12H), 1.45 (s, 9H), 3.84 (t, J=4.3 Hz,
2H), 4.66 (br s, 1H), 5.58 (dt, J=1.8 and 17.9 Hz, 1H),
6.59 (dt, J=4.5 and 17.9 Hz, 1H). 13C NMR (50 MHz,
CDCl3) l 25.6 (CH3), 29.3 (CH3), 44.8 (CH2), 80.2 (C),
84.1 (C), 119.0 (br. CH), 150.3 (CH), 156.6 (C).
References
1
1. For reviews on pyrrole–imidazole alkaloids, see: (a) Ass-
mann, M.; Lichte, E.; Pawlik, J. R.; Ko¨ch, M. Mar. Ecol.
Prog. Ser. 2000, 207, 255–262; (b) Lindel, T.; Hoffman,
H.; Hochgu¨rtel, M.; Pawlik, J. R. J. Chem. Ecol. 2000,
26, 1477–1496 and references cited therein.
2. (a) De Nanteuil, G.; Ahond, A.; Poupat, C.; Thoison, O.;
Potier, P. Bull. Soc. Chim. Fr. 1986, 813–816; (b)
Daninos-Zeghal, S.; Al Mourabit, A.; Ahond, A.;
Poupat, C.; Potier, P. Tetrahedron 1997, 53, 7605–7614.
3. Little, T. L.; Webber, S. E. J. Org. Chem. 1994, 59,
7299–7305.
4. Olofson, A.; Yakushijin, K.; Horne, D. A. J. Org. Chem.
1998, 63, 1248–1253.
5. Lindel, T.; Hochgu¨rtel, M. J. Org. Chem. 2000, 65,
2806–2809.
6. Casara, P.; Danzin, C.; Metcalf, B.; Jung, M. J. Chem.
Soc., Perkin Trans. 1 1985, 2201–2207.
7. Experimental procedure: Borane–methyl sulfide complex
(1.7 mL, 16.8 mmol) was added dropwise to a solution of
(−)-a-pinene (5.4 mL, 33.6 mmol) in 10 mL of freshly
distilled THF at 0°C under a nitrogen atmosphere. The
mixture was kept at 0°C for 1 h and then allowed to
reach rt by removing the cold bath. After 2 h, the
resulting suspension of diisopinocampheylborane was
cooled to 0°C when N-Boc-propargylamine (2.0 g, 12.9
mmol) in 5 mL of THF was slowly added. The reaction
mixture was kept at rt for 16 h. The mixture was cooled
to 0°C and freshly distilled acetaldehyde (0.25 mmol, 14.3
mL) was added dropwise. After 5 h at rt, the excess of
acetaldehyde and the solvent were removed under
reduced pressure. 2,3-Dimethylbutane-2,3-diol (2.4 g,
20.1 mmol) and 30 mL of heptane were added and the
mixture was kept at rt for 3 h. After washing the solution
with water (2×10 mL) and drying the organic layer over
magnesium sulfate, the solvent was evaporated and the
8. (a) Iddon, B.; Lim, B. L. J. Chem. Soc., Perkin Trans. 1
1983, 735–739; (b) Kirk, K. L. J. Heterocyclic Chem.
1985, 22, 57–59; (c) Bensusan, H. B.; Naidu, M. S. R.
Biochemistry 1967, 6, 12–15.
9. For a recent review of Suzuki coupling reactions with
heterocyclic compounds, see: Li, J. J.; Gribble, G. W. In
Palladium in Heterocyclic Chemistry; Baldwin, J. E.;
Williams, R. M., Eds.; Pergamon, Elsevier: Oxford, 2000.
10. Behrens, C.; Christoffersen, M. W.; Gram, L.; Nielsen, P.
H. Bioorg. Med. Chem. Lett. 1997, 7, 321–326.
11. Spectroscopic data were identical to those reported previ-
ously in Ref. 5.
12. Parrot, I.; Rival, Y.; Wermuth, C. G. Synthesis 1999, 7,
1163–1168.
13. Gundersen, L. L.; Bakkestuen, A. K.; Aasen, A. J.;
Øvera˚s, H.; Rise, F. Tetrahedron 1994, 50, 9743–9756.
14. Typical procedure: To a solution of boronate 2 (1.0
mmol) in DME (10 mL), under an argon atmosphere,
were successively added heteroaryl halide (1.2 mmol),
Pd(PPh3)4 (0.050 mmol) and 1.25 mL of a degassed 2 M
K2CO3 aqueous solution. The reaction mixture was
stirred at reflux temperature for 18 h, then cooled to rt
and partitioned between water (20 mL) and ethylacetate
(3×20 mL). The combined extracts were washed with
brine (10 mL) and dried over magnesium sulfate. The
solvent was removed in vacuo and the crude product was
purified by silica gel column chromatography. Com-
pound 7a: yield 65%, Rf=0.30 (EtOAc/heptane 20/80).
1H NMR (200 MHz, CDCl3) l 1.46 (s, 9H), 3.96 (t,

4938
F. Berre´e et al. / Tetrahedron Letters 43 (2002) 4935–4938
J=5.2 Hz, 2H), 4.95 (br s, 1H), 6.59 (d, J=15.8 Hz, 1H),
1H), 5.39 (s large, 1H), 6.34 (dt, J=5.5 and 16.0 Hz, 1H),
6.60 (d, J=9.3 Hz, 1H), 6.68 (d, J=16.0 Hz, 1H),
7.18–7.48 (m, 6H). 13C NMR (50 MHz, CDCl3) l 28.8
(CH3), 42.8 (CH2), 43.4 (CH2), 79.9 (C), 113.9 (CH),
125.4 (CH), 127.8 (CH), 128.0 (CH), 129.1 (CH), 138.9
(C), 150.7 (C), 158.4 (C), 156.2 (C). Compound yield 7g:
65%, Rf=0.3 (EtOAc/heptane 80/20). 1H NMR (200
MHz, CDCl3) l 1.38 (s, 9H), 4.06 (t, J=4.1 Hz, 2H), 5.35
(s, 2H, CH2-Ph), 7.01 (d, J=15.9 Hz, 1H), 7.16–7.32 (m,
5H), 7.51 (dt, J=5.1 and 15.9 Hz, 1H), 7.94 (s, 1H), 8.82
(s, 1H). 13C NMR (50 MHz, CDCl3) l 28.8 (CH3), 42.8
(CH2), 47.6 (CH2), 80.0 (C), 125.6 (CH), 128.2 (CH),
128.9 (CH), 129.5 (CH), 131.0 (C), 135.5 (C), 140.5 (CH),
144.5 (CH), 152.3 (C), 152.9 (CH), 153.7 (C), 156.1 (C).
15. A representative procedure is as follows: To a mixture of
50 mmol of methanol and 10 mL of ethyl acetate cooled
at 0°C was added dropwise 50 mmol of acetylchloride.
After 1 h at 0°C, a solution of the N-Boc amine 7 (1
mmol) was slowly added to the reaction mixture. Stirring
was continued at rt for 6 h. The solvent was then
evaporated and the residue was dissolved in 5 mL of
dried DMF. Neutralization with sodium carbonate was
followed by addition of pyrrol-2-yltrichloromethyl
ketone. After being stirred at rt for 6 h, the reaction
mixture was concentrated in vacuo and the residue sus-
pended in water. The precipitate was filtered and purified
by silica gel column chromatography. Selected data for
6.69 (dd, J=5.1 and 15.8 Hz, 1H), 7.12 (ddd, J=1.1, 2.6
and 7.4 Hz, 1H), 7.26 (d, J=7.7 Hz, 1H), 7.61 (dt, J=1.8
and 7.7 Hz, 1H), 8.53 (d, J=4.8 Hz, 1H). 13C NMR (50
MHz, CDCl3) l 29.3 (CH3), 43.1 (CH2), 80.3 (C), 122.3
(CH), 123.0 (CH), 131.4 (CH), 132.2 (CH), 137.4 (CH),
150.2 (CH), 155.9 (C), 156.6 (C). Compound 7b: yield
82%, Rf=0.20 (EtOAc/heptane 20/80). 1H NMR (200
MHz, CDCl3) l 1.47 (s, 9H), 3.90 (t, J=5.3 Hz, 2H), 5.11
(br s, 1H), 6.26 (dt, J=5.5 and 15.9 Hz, 1H), 6.49 (d,
J=15.9 Hz, 1H), 7.22 (dd, J=4.8 and 7.8 Hz, 1H), 7.68
(dt, J=1.5 and 7.8 Hz, 1H), 8.41–8.50 (m, 1H), 8.52–8.64
(m, J=1H). 13C NMR (50 MHz, CDCl3) l 28.7 (CH3),
42.9 (CH2), 79.9 (C), 123.8 (CH), 127.7 (CH), 129.5
(CH), 132.7 (C), 133.2 (CH), 148.5 (CH), 148.8 (CH),
156.2 (C). Compound 7c: yield 70%, Rf=0.20 (EtOAc/
heptane 20/80). 1H NMR (200 MHz, CDCl3) l 1.48 (s,
9H), 3.80–3.95 (m, 2H), 4.96 (s large, 1H), 6.42–6.44 (m,
2H), 7.22 (dd, J=1.5 and 4.4 Hz, 2H), 8.52 (d, J=1.5
and 4.4 Hz, 2H, H). 13C NMR (50 MHz, CDCl3) l 28.3
(CH3), 42.3 (CH2), 79.7 (C), 120.8 (CH), 128.5 (CH),
131.7 (CH), 144.1 (CH), 144.9 (C), 149.9 (CH), 155.7 (C).
Compound yield 7d: 43%, Rf=0.35 (EtOAc/heptane 70/
30). 1H NMR (200 MHz, CDCl3) l 1.46 (s, 9H), 1.80–
1.95 (br s, 1H), 3.88 (t, J=5.6 Hz, 2H), 6.07 (dt, J=5.8
and 15.9 Hz, 1H), 6.30 (d, J=15.9 Hz, 1H), 8.30 (s, 2H);
13C NMR (50 MHz, CDCl3) l 28.4 (CH3), 39.4 (CH2),
79.7 (C), 121.0 (C), 124.7 (CH), 125.6 (CH), 155.7 (C),
156.0 (CH), 162.0 (C). Compound yield 7e: 56%, Rf=
0.35 (EtOAc/heptane 80/20). 1H NMR (200 MHz,
CDCl3) l 1.47 (s, 9H), 3.38 (s, 3H), 3.44 (s, 3H), 3.86 (t,
1
8e: yield 27%. Rf=0.10 (CHCl3/MeOH=95/5). H NMR
(200 MHz, DMSO-d6) l 3.19 (s, 3H), 3.32 (s, 3H), 3.95 (t,
J=5.4 Hz, 2H), 6.19 (d, 1H, J=15.8 Hz), 6.48 (dt, J=5.5
and 15.8 Hz, 1H), 6.94 (s, 1H), 6.99 (s, 1H), 7.92 (s, 1H),
8.37 (t, J=5.4 Hz, 1H), 11.84 (br s, 1H). 13C NMR (50
MHz, DMSO-d6) l 27.4 (CH3), 36.4 (CH3), 40.5 (CH2),
94.8 (C), 108.3 (CH), 111.3 (C), 121.1 (CH), 122.0 (CH),
126.1 (CH), 126.7 (C), 141.7 (CH), 150.5 (C), 159.2 (C),
161.6 (C).
J=5.5 Hz, 2H, CH6 2), 4.77 (br s, 1H), 6.25 (d, J=15.8
Hz, 1H), 6.43 (dt, J=5.8 and 15.8 Hz, 1H), 7.23 (s, 1H).
13C NMR (50 MHz, CDCl3) l 28.0 (CH3), 28.3 (CH3),
37.0 (CH3), 42.8 (CH2), 79.4 (C), 110.6 (C), 122.2 (CH),
127.6 (CH), 139.4 (C), 151.1 (C), 155.7 (C), 162.2 (C).
Compound yield 7f: 69%, Rf=0.40 (EtOAc/heptane 80/
1
16. Nziengui, R. Ph.D. Thesis, University of Rennes 1, Sep-
tember 2001.
20). H NMR (200 MHz, CDCl3) l 1.45 (s, 9H), 4.01 (t,
J=5.4 Hz, 2H), 4.62 (d, J=5.5 Hz, 2H), 4.80–4.95 (br s,