A formal total synthesis of the telomerase inhibitor dictyodendrin B

Article abstract of DOI:10.1016/j.tetlet.2009.11.083

A formal synthesis of the telomerase inhibitory marine pyrrolocarbazole alkaloid dictyodendrin B is described. The key features are consecutive palladium-catalyzed cross-coupling reactions and intramolecular reductive coupling reaction to construct the pyrrolo[2,3-c]carbazole framework.

Full text of DOI:10.1016/j.tetlet.2009.11.083

Tetrahedron Letters 51 (2010) 533–536
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A formal total synthesis of the telomerase inhibitor dictyodendrin B
Shotaro Hirao a, Yuki Yoshinaga a, Masatomo Iwao b, Fumito Ishibashi a,
*
a Graduate School of Science and Technology, Nagasaki University, 1-14 Bunkyo-Machi, Nagasaki 852-8521, Japan
b Faculty of Engineering, Nagasaki University, 1-14 Bunkyo-Machi, Nagasaki 852-8521, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A formal synthesis of the telomerase inhibitory marine pyrrolocarbazole alkaloid dictyodendrin B is
described. The key features are consecutive palladium-catalyzed cross-coupling reactions and intramo-
lecular reductive coupling reaction to construct the pyrrolo[2,3-c]carbazole framework.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 12 October 2009
Revised 10 November 2009
Accepted 19 November 2009
Available online 26 November 2009
Dictyodendrins A–E (1–5) are tyramine-based pyrrolocarbazole
alkaloids isolated from the marine sponge Dictyodendrilla verongi-
formis collected in southern Japan by Fusetani et al. in 2003
(Fig. 1).1 These alkaloids completely inhibit telomerase at a con-
intramolecular pinacol coupling and subsequent dehydration of
the keto-aldehyde 7. In our preliminary approach, we found that
installation of the aldehyde function at the later stage of the syn-
thesis was quite challenging due to low reactivity of the indole
2-position of 8 in electrophilic substitution reactions.6 Thus, in
the present synthesis, we planned to synthesize the pinacol cou-
pling precursor 7 via a palladium-catalyzed cross-coupling reac-
tion of triflate 10 with indole-3-boronate 11 having an aldehyde
equivalent substituent at the 2-position. The intermediate triflate
10 has been prepared as an intermediate in our previous synthesis
centration of 50 lg/ml and are reported to be the first telome-
rase-inhibitory marine natural products. They also demonstrated
that the sulfate functions of the molecules are essential for the bio-
activity as the desulfated compound was completely inactive. Re-
cently, Fürstner et al. reported that dictyodendrins B (2), E (5)
and its desulfated derivative have the ability to cleave double
strand DNA under oxidative conditions.2 The first total synthesis
of dictyodendrin B (2) was achieved by Fürstner’s group in
2005.3 They utilized a low-valent titanium-mediated reductive
cyclization and subsequent photochemical dehydrogenative cycli-
zation for the formation of the core pyrrolo[2,3-c]carbazole ring.
Thereafter, they extended this strategy to the total syntheses of
dictyodendrins C (3) and E (5).4 Two groups including us recently
reported the synthesis of core structures of dictyodendrin. Álvarez
and co-workers reported a synthesis of the pyrrolo[2,3-c]carbazole
core of dictyodendrin based on a Suzuki–Miyaura cross-coupling
reaction of
a
3-arylpyrrole-4-boronate with
a 3-bromoindole
derivative and tandem photochemical 6
p
–electrocyclization/aro-
matization.5 We also synthesized the putative precursor to dictyo-
dendrins having the core pyrrolo[2,3-c]carbazole system by using
Hinsberg-type pyrrole synthesis and consecutive palladium-cata-
lyzed cross-coupling reactions.6 Here, we describe a formal total
synthesis of 2 based on the strategy with modification in the B-ring
construction.
Our retrosynthetic analysis of 2 is depicted in Scheme 1. The
target compound has been previously synthesized by Fürstner’s
group from the intermediate 6 through three steps involving sulfa-
tion of the 20-hydroxyl group and demethylation.3 We envisioned
that the pyrrolo[2,3-c]carbazole system would be constructed by
* Corresponding author. Tel.: +81 95 819 2833; fax: +81 95 819 2799.
E-mail address: fumito@nagasaki-u.ac.jp (F. Ishibashi).
Figure 1. Structure of dictyodendrins A–E.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.11.083

534
S. Hirao et al. / Tetrahedron Letters 51 (2010) 533–536
Scheme 1. Retrosynthetic analysis of dictyodendrin B.
concomitant removal of the TBS protecting group to give hydro-
xy-diacid 20 in quantitative yield. In order to activate the carbox-
ylic acid functions for the next aryl anion addition reaction, the
diacid 20 was esterified with 2-chloro-4,6-dimethoxy-1,3,5-tri-
azine10 in the presence of N-methylmorpholine, whereupon one
of the carboxyl group located near the 2-hydroxymethylindole
moiety was lactonized to give 21 in 83% yield. Treatment of 21
with 3.86 equiv of 4-methoxyphenylmagnesium bromide in ether
gave 22 in 71% yield, which on Dess–Martin oxidation afforded
the keto-aldehyde 7 in 99% yield. The B-ring of the tetracyclic sys-
tem was constructed by SmI2-promoted intramolecular pinacol
coupling11 of 7, in which diol 23 was obtained in 78% yield. Anal-
ysis of the 1H NMR spectrum of the cyclized product confirmed
that the reaction afforded only a single diastereomer, whose rela-
tive stereochemistry was identified as 4S*,5R* on the basis of
strong NOE correlation between 5-H and 20-H. A similar ring con-
struction by a low-valent titanium-mediated oxo-ester coupling
reaction has been reported for the synthesis of benzo[c]carbazole
analogs of dictyodendrin.2 However, the low-valent titanium
(TiCl4/Zn)12 and the magnesium (Mg, TMSCl)13 reagents were not
effective for the pinacol coupling of 7. An acid-catalyzed dehydra-
tion of 23 using CSA in CH2Cl2, which was accompanied by depro-
tection of the SEM ether, methylation of the resulting hydroxyl
group, and debenzylation afforded a single product, however, its
1H NMR spectrum data did not match with those of 6 reported
by Fürstner et al.3 The compound thus obtained was identified to
be the rearranged compound 27 on the basis of 1H NMR spectrum
(Fig. 2), in which both methylenes of the phenethyl moiety of 27
(dH 3.09 and 4.67 ppm), which are out of the shielding cone of
the adjacent aromatic ring, resonate 0.57–0.71 ppm downfield to
those of 6 (dH 2.52 and 3.96 ppm). The assignment was further sup-
ported by NOE correlations observed between 20-H/6-NH and 10-H/
4-OCH3 in its NOESY spectrum.14 The unexpected product might be
formed through a pinacol rearrangement during the dehydration
process as illustrated in Figure 2. The aryl migration appears to
be driven by the release of strain energy caused by the steric inter-
action between the migrating aryl group and the phenethyl substi-
tuent at the pyrrole nitrogen atom. The undesirable rearrangement
Scheme 2. Reagents and conditions: (a) (CO2Et)2, t-BuOK, ether, reflux, 22 h, then
Fe, AcOH, 80 °C, 17 h, 76%; (b) SEM-Cl, NaH, DMF, rt, 1 h, 93%; (c) LiAlH4, THF, rt,
50 min, 90%; (d) TBS-Cl, imidazole, DMF, rt, 12 h, 98%; (e) NBS, THF, ꢀ78 °C to rt,
then rt, 1 h, 100%; (f) bis(pinacolato)diboron, KOAc, 7 mol %, PdCl2(dppf), DMSO,
80 °C, 19 h, 76%.
of 3,4-diarylpyrrole marine alkaloids7 by a Suzuki–Miyaura cross-
coupling reaction of 3,4-dihydroxy-pyrrole bistriflate 12 obtained
via a Hinsberg-type reaction of iminodiacetate 13.
The indole boronate 11, a requisite for the cross-coupling reac-
tion with 10, was prepared via a Reissert indole synthesis as shown
in Scheme 2. Condensation of 3-benzyloxy-2-nitrotoluene (14)
with diethyl oxalate followed by a reduction with iron in AcOH
gave 7-benzyloxyindole-2-carboxylate 158 in 76% yield. After pro-
tection of the indole nitrogen atom with SEM ether, the ester was
reduced with LAH and the primary hydroxyl group was protected
as TBS ether to give 18 in high yield. Bromination of 18 with NBS
in THF at a low temperature (ꢀ78 °C) exclusively occurred at 3-po-
sition, affording 19 as the sole product in quantitative yield. Final-
ly, the boronate 11 was obtained by a palladium-catalyzed cross-
coupling reaction9 of 19 with bis(pinacolato)diboron in 76% yield.
A palladium-catalyzed cross-coupling reaction of the triflate 10
with the indole-3-boronate 11 using 10 mol % of Pd(PPh3)4 and
K2CO3 as the base in refluxing DME furnished 9 in 72% yield
(Scheme 3). Alkaline hydrolysis of the diester 9 proceeded with

S. Hirao et al. / Tetrahedron Letters 51 (2010) 533–536
535
Scheme 3. Reagents and conditions: (a) 10 mol % Pd(PPH3)4, K2CO3, DME 95 °C 26 h, 72%; (b) 3 M, NaOH, EtOH, dioxane, 90 °C, 15 h; (c) 2-chloro-4,6-dimethoxy-1,3,5-
triazine, N-methylmorpholine, THF, rt, 22 h, 83% (2 steps); (d)4-MeOC6H4MgBr, ether, rt, 40 min, 71%; (e) DMP, CH2Cl2, rt, 20 min, 99%; (f) SmI2, THF, 0 °C, 1 h, 78%; (g) Ac2O,
pyridine, cat. DMAP, 65 °C, 1 h; (h) NaOMe, DMF, rt, 1 h, then MeI, rt, 1.5 h, 91%, (2 steps); (i) CSA, THF, rt, 5 h; (j) H2, Pd(OH)2/C, EtOAc, 50 °C, 1 h, 97% (2 steps).
whose 1H and 13C NMR data were identical to those reported in
the literature.3
In conclusion, we have accomplished a formal total synthesis of
dictyodendrin B by using consecutive palladium-catalyzed cross-
coupling reactions of 3,4-dihydroxypyrrole bistriflate and intramo-
lecular pinacol coupling as the key reactions. Further studies direc-
ted toward the total synthesis of other dictyodendrins from the
intermediate 9 are currently underway in our laboratory.
Acknowledgment
This study was supported financially by a grant-in-aid for scien-
tific research No. 19580238 from the Ministry of Education,
Culture, Sports, Science, and Technology of Japan.
Supplementary data
Experimental procedures and 1H NMR spectrum chart of the
new compounds are available. Supplementary data associated with
this article can be found, in the online version, at doi:10.1016/
j.tetlet.2009.11.083.
References and notes
Figure 2. Proposed mechanism of formation of 27.
1. Warabi, K.; Matsunaga, S.; van Soest, R. W. M.; Fusetani, N. J. Org. Chem. 2003,
68, 2765–2770.
2. Buchgraber, P.; Domostoj, M. M.; Scheiper, B.; Wirtz, C.; Mynott, R.; Rust, J.;
Fürstner, A. Tetrahedron 2009, 65, 6519–6534.
3. Fürstner, A.; Domostoj, M. M.; Scheiper, B. J. Am. Chem. Soc. 2005, 127, 11620–
could be reduced by simply conducting the dehydration under
nonacidic condition. Heating of 23 in a mixture of Ac2O and pyri-
dine containing a catalytic amount of DMAP followed by deacety-
lation and methylation predominantly gave 25 in 91% yield with a
small amount of the rearranged product 28 (6%). Finally, deprotec-
tions of the SEM and the benzyl ethers afforded 6 in 97% yield,
11621.
4. Fürstner, A.; Domostoj, M. M.; Scheiper, B. J. Am. Chem. Soc 2006, 128, 8087–
8094.
5. Ayats, C.; Soley, R.; Albericio, F.; Álvarez, M. Org. Biomol. Chem. 2009, 7, 860–
862.

536
S. Hirao et al. / Tetrahedron Letters 51 (2010) 533–536
6. Hirao, S.; Sugiyama, Y.; Iwao, M.; Ishibashi, F. Biosci., Biotechnol., Biochem. 2009,
10. Blotny, G. Tetrahedron 2006, 62, 9507–9522.
73, 1764–1772.
11. Namy, J. L.; Souppe, J.; Kagan, H. B. Tetrahedron Lett. 1983, 24, 765–766.
12. Mukaiyama, T.; Sato, T.; Hanna, J. Chem. Lett. 1973, 1041–1044.
13. Maekawa, H.; Yamamoto, Y.; Shimada, H.; Yonemura, K.; Nishiguchi, I.
Tetrahedron Lett. 2004, 45, 3869–3872.
7. Iwao, M.; Takeuchi, T.; Fujikawa, N.; Fukuda, T.; Ishibashi, F. Tetrahedron Lett.
2003, 44, 4443–4446.
8. Albrecht, R.; Heindl, J.; Loge, O. Eur. J. Med. Chem. 1985, 20, 57–60.
9. Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60, 7508–7510.
14. See Supplementary data.