Studies towards the synthesis of the marine alkaloid chartelline C

Article abstract of DOI:10.1016/j.tetlet.2007.07.040

2,6-Dibromoindole 5 underwent regioselective Sonogashira coupling at the 2 position with simple acetylenic partners. While, imidazole-acetylene 16 failed to couple to 5, cyclic carbonate 19 succeeded to give 20, which was further elaborated into indole-imidazole 23.

Full text of DOI:10.1016/j.tetlet.2007.07.040

Tetrahedron Letters 48 (2007) 6364–6367
Studies towards the synthesis of the marine alkaloid chartelline C
Phillip J. Black, Evan A. Hecker and Philip Magnus*
Department of Chemistry and Biochemistry, University of Texas at Austin, 1 University Station A5300, Austin, TX 78712-1167, USA
Received 5 June 2007; revised 25 June 2007; accepted 2 July 2007
Available online 30 July 2007
Abstract—2,6-Dibromoindole 5 underwent regioselective Sonogashira coupling at the 2 position with simple acetylenic partners.
While, imidazole-acetylene 16 failed to couple to 5, cyclic carbonate 19 succeeded to give 20, which was further elaborated into
indole-imidazole 23.
Ó 2007 Elsevier Ltd. All rights reserved.
The chartelline marine alkaloids were isolated from the
bryozoan Chartella papyracea and characterized in the
1980s.1–3 A related bryozoan Securiflustra securifrons
also produces the securines and securamines,4,5 and they
are plausible biogenetic precursors to the chartellines. It
was reported that solutions of securine B 1 in DMSO-d6
converted into securamine B 2, presumably via 1a,
Scheme 1.4 Redissolving 2 in CDCl3 converted 2 back
into 1. One could imagine that if this isomerization were
carried out in the presence of an electropositive source
of chlorine, 1 could be converted into chartelline C 3
through the intermediacy of 1b and 1c. The transforma-
tion of 1c into 3 can be written as a [1,5]-shift and is a
key step in the recently reported biogenetically inspired
strategy for the synthesis of 3 by Baran and Shenvi.6,7
Several other groups have reported on synthetic
approaches to chartelline C6,8–11 as well as related
alkaloids.12,13
H
O
H
O
H
N
O
N
Br
H
N
H
N
N
N
H
Br
Br
Br
Br
N
N
Cl
Me
N
H
N
H
H
Me
H
Me
N
Me
Me
Cl
Me HN
Cl
Cl
1, Securine B
2, Securamine B
1a
Br
2Cl
O
O
H
H
O
N
N
Br
Br
-2HCl
Cl
N
[1,5]
N
N
Cl
see ref 6
Br
Cl
N
N
Br
Br
Me
Me
N
N
Me
N
N
H
H
Me
Me HN
Me
1b
1c
3, Chartelline C
Cl
Br
Scheme 1.
Keywords: Chartelline C; Securines; Securamines; Biogenetic; Sonogashira coupling.
*
Corresponding author. Tel.: +1 512 471 3966; fax: +1 512 471 7839; e-mail: p.magnus@mail.utexas.edu
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.07.040

P. J. Black et al. / Tetrahedron Letters 48 (2007) 6364–6367
6365
Our plan was also based on the supposition that the
spiro-b-lactam in 3 could arise from a late stage oxida-
tive cyclization of a suitable macrolactam.14 The macro-
lactam precursor to 1c, namely, 1, was envisioned as
arising from macrolactamization, and to eventually
achieve this a regioselective Sonogashira coupling at
the 2-position of a 2-halo-6-bromoindole was required
as a starting point. The only selective coupling of an
acetylene at the 2-position of an indole that has a 6-bro-
mo substituent was a 2-iodo-6-bromoindole,7 and since
this compound required a six-step synthesis from
6-bromoindole, we were interested to see if a 2,6-di-
bromoindole exhibited any selectivity in a Sonogashira
coupling reaction.
verted into a,b-unsaturated ester 1219 (90%) and sub-
jected to deconjugative dimethylation to give 13 (96%).
Reduction of 13 followed by oxidation and treatment
of the resulting aldehyde with Ohira’s reagent [Me-
COCN2PO(OEt)2],20,21 gave the terminal acetylene 14
in 90% yield over three steps.
Dihydroxylation of the internal alkene in 14 followed by
oxidation of the resulting diol with SO3Æpyridine, NEt3,
DMSO in CH2Cl2 gave a-diketone 15 (83%). Treatment
of 15 with NH4OAc, (CH2O)n in acetic acid at 100 °C,
followed by protection of imidazole NH gave 16 in
reproducible yields of 74% from 15.22
Unfortunately, attempts to couple 5 and 16 to give 17,
under a variety of Sonogashira and Castro–Stephens
reaction conditions failed, Scheme 4. In light of Baran’s
reported work6,7 we revisited this reaction applying their
reaction conditions, but no coupling product 17 was ob-
served. Presumably, the more reactive 2-iodo analogue
of 5 would have been successful. It was therefore
decided to construct the imidazole portion after the acet-
ylenic coupling process.
Indole-3-acetonitrile 415,16 was regioselectively bromi-
nated using a known protocol17 to give 5 (after t-butyl
carbamate protection), Scheme 2. Exposure of 5 to
standard Sonogashira coupling reaction conditions
proceeded with complete regioselectivity to give the 2-
coupled indoles 6, 7 and 8, respectively. It was found
that the choice of protecting group on the indole nitro-
gen atom was essential to achieving regioselectivity in
the Sonogashira coupling reaction. For example, when
an N-benzyl-2,6-dibromo indole 9 was subjected to the
coupling reaction conditions with triisopropylsilylacetyl-
ene, a mixture of 10a, 10b and 10c was obtained in a
ratio of 1:2:1.5 and in an overall yield of 72%.
The cyclic carbonate 18 (made from 14 by vic-dihydr-
oxylation followed by triphosgene/pyridine) was treated
with BCl3/CH2Cl2 and the resulting alcohol protected as
its TIPS ether 19 (89% over two steps), Scheme 5. It was
necessary to conduct the exchange of the benzyl ether
since the benzyl analogue of 20 was not compatible with
the cis-hydrogenation of acetylene. Indole 5 could now
With the indole portion in hand, synthesis of imidazole
16 was undertaken, Scheme 3. Aldehyde 1118 was con-
CN
CN
CN
a,b
c
Br
R
R
N
N
N
Br
Br
H
Boc
Boc
4
5
6 (R = TIPS, 92%)
7 (R = i-Pr, 67%)
8 (R = -C6H4OMe-p, 45%)
CO2Et
Br
CO2Et
R1
TIPS)
TIPS)
10a (R1 = Br, R2 =
10b (R2 = Br, R1 =
10c (R1 = R2 =
d
N
N
TIPS)
Br
R2
Bn
Bn
9
Scheme 2. (a) NBS, SiO2, CH2Cl2. (b) Boc2O, NEt3, DMAP, CH2Cl2 54% over two steps. (c) Acetylene, PdCl2(PPh3)2, CuI, NEt3, 45 °C. (d)
Triisopropylsilylacetylene, PdCl2(PPh3)2, CuI, NEt3, MeCN, 25 °C, 72%, 10a, 10b and 10c in a 1:2:1.5 ratio, respectively.
Me Me
a
b
BnO
BnO
CO2Et
BnO
BnO
CO2Et
BnO
BnO
CHO
11
12
13
14
c, d, e
Me Me
MOM
N
O
Me Me
f, g
h, i
N
15
O
Me 16
Me
Scheme 3. Reagents and conditions: (a) triethylphosphonoacetate, NaH, THF, 0 °C, 90%. (b) LiHMDS, HMPA, THF at À78 °C, then MeI and
LiHMDS, HMPA, THF at À78 °C, then MeI, 96% for one-pot procedure. (c) LiAlH4, THF, À78 °C to rt. (d) Dess–Martin periodinane, CH2Cl2,
0 °C, 94% over two steps. (e) Ohira’s reagent, MeOH, K2CO3, 96%. (f) K2OsO4. 2 H2O, NMO, Acetone/H2O, 100%. (g) SO3Æpyr, DMSO, NEt3,
CH2Cl2, 83%. (h) NH4OAc, (CH2O)n, AcOH, 100 °C. (i) MOMCl, NEt3, PhH, 74% over two steps.

6366
P. J. Black et al. / Tetrahedron Letters 48 (2007) 6364–6367
BnO
CN
Br
CN
MOM
NMOM
BnO
N
Shonogashira
+
N
N
N
Br
or Castro-Stephens
N
Br
Boc
Boc
Me Me
Me
5
Me
16
17
Scheme 4.
TIPSO
CN
Me Me
Me Me
O
BnO
TIPSO
O
O
O
c
O
a, b
O
O
O
N
5
Br
Boc
Me Me
O
18
19
20
d
TIPSO
NC
TIPSO
NC
TIPSO
NC
H
N
O
O
O
g
e, f
O
N
O
Br
Br
Br
Me
Me
Me
Me
Me
Me
N
N
N
Boc
23
Boc
22
21
Boc
Scheme 5. Reagents and conditions: (a) BCl3, CH2Cl2, 0 °C. (b) TIPSCl, imidazole, ClCH2CH2Cl, 85 °C, 89% over two steps. (c) 5, PdCl2(PPh3)2,
CuI,NEt3, 25 °C, 67%. (d) H2, PtO2 (cat.), EtOH, 60%. (e) NaOH (aq), dioxane. (f) Dess–Martin periodinane, NaHCO3, CH2Cl2, 43% over two
steps. (g) NH4OAc, (CH2O)n, AcOH, 65 °C, 50%.
be successfully coupled with the terminal acetylene 19
under standard Sonogashira reaction conditions to give
20 (67%).
Acknowledgement
The NIH (GM 32718) and the Welch Chair (F-0018) are
thanked for their support of this research. Kevin Wil-
liamson is thanked for his contributions.
Hydrogenation of 20 over Adam’s catalyst (PtO2/H2/
EtOH) reduced the acetylenic bond stereoselectively to
the cis-alkene 21 without competing hydrogenolysis of
the 6-Br substituent in the indole ring. Hydrogenation
of 20 over 10% Pd/C or Raney Ni reduced the acetylenic
bond to the cis-alkene but also removed the 6-Br atom.
Standard hydrogenation catalysts such as Lindlar’s cat-
alyst, Wilkinson’s catalyst and Pt/C proved too unreac-
tive, as were transfer hydrogenation and diimide
(generated in situ).
References and notes
1. Chevolot, L.; Chevolot, A. M.; Gajhede, M.; Larsen, C.;
Anthoni, U.; Christophersen, C. J. Am. Chem. Soc. 1985,
107, 4542–4543.
2. Anthoni, U.; Chevolot, L.; Larsen, C.; Nielsen, P. H.;
Christophersen, C. J. Org. Chem. 1987, 52, 4709–4712.
3. Nielsen, P. H.; Anthoni, U.; Christophersen, C. Acta
Chem. Scand. Ser. B: Org. Chem. Biochem. 1988, B42,
489–491.
4. Rahbaek, L.; Anthoni, U.; Christophersen, C.; Nielsen,
P. H.; Petersen, B. O. J. Org. Chem. 1996, 61, 887–889.
5. Rahbk, L.; Christophersen, C. J. Nat. Prod. 1997, 60, 175–
177.
6. Baran, P. S.; Shenvi, R. A.; Mitsos, C. A. Angew. Chem.,
Int. Ed. 2005, 44, 3714–3717.
7. Baran, P. S.; Shenvi, R. A. J. Am. Chem. Soc. 2006, 128,
14028–14029.
8. Lin, X.; Weinreb, S. M. Tetrahedron Lett. 2001, 42, 2631–
2633.
9. Nishikawa, T.; Kajii, S.; Isobe, M. Synlett 2004, 2025–
2027.
Treatment of 21 with NaOH (aq) in dioxane by
followed oxidation of the resulting diol with the
Dess–Martin periodinane reagent gave a-diketone 22
(43% yield). When 22 was subjected to the earlier
imidazole formation conditions, the starting material
was destroyed without any imidazole formation.
However, by maintaining a lower reaction temperature,
with the same reagents (NH4OAc, paraformaldehyde,
AcOH) imidazole 23 could be obtained in a 50%
yield.
In summary, the regioselective Sonogashira of 2,6-di-
bromoindole 5 can be used to synthesize the 2-iso-
prene-imidazole
constructed after the coupling reaction.
chain
provided
imidazole
is
10. Nishikawa, T.; Kajii, S.; Isobe, M. Chem. Lett. 2004, 33,
440–441.

P. J. Black et al. / Tetrahedron Letters 48 (2007) 6364–6367
6367
11. Sun, C.; Lin, X.; Weinreb, S. M. J. Org. Chem. 2006, 71,
3159–3166.
17. Mistry, A. G.; Smith, K.; Bye, M. R. Tetrahedron Lett.
1986, 27, 1051–1054.
12. Korakas, P.; Chaffee, S.; Shotwell, J. B.; Duque, P.;
Wood, J. L. Proc. Natl. Acad. Sci. U.S.A. 2004, 101,
12054–12057.
13. Sun, C.; Camp, J. E.; Weinreb, S. M. Org. Lett. 2006, 8,
1779–1781.
14. Scott, A. I.; Yoo, S. E.; Chung, S.-K.; Lacadie, J. A.
Tetrahedron Lett. 1976, 17, 1137–1140.
15. Eliel, E. L.; Murphy, N. J. J. Am. Chem. Soc. 1953, 75,
3589–3590.
16. Yamada, F.; Hashizume, T.; Somei, M. Heterocycles 1998,
47, 509–516.
18. Garcia, C.; Martin, T.; Martin, V. S. J. Org. Chem. 2001,
66, 1420–1428.
19. Solladie, G.; Fernandez, I.; Maestro, C. Tetrahedron:
Asymmetry 1991, 2, 801–819.
20. Ohira, S. Syn. Commun. 1989, 19, 561–564.
21. Roth, G. J.; Liepold, B.; Mueller, S. G.; Bestmann, H. J.
Synthesis 2004, 59–62.
22. Comprehensive Heterocyclic Chemistry; Katritzky, A. R.,
Rees, C. W., Eds.; Part 4A: Five-membered Rings with
Two or More Nitrogen Atoms; Pergamon Press, 1984;
Vol. 5.