Total synthesis of (-)-herbindoles A, B, and C via transition-metal- catalyzed intramolecular [2 + 2 + 2] cyclization between ynamide and diynes

Article abstract of DOI:10.1021/ol300571b

The total syntheses of (-)-herbindoles A, B, and C as naturally occurring forms were accomplished for the first time through transition-metal-catalyzed intramolecular [2 + 2 + 2] cyclization between ynamide and diynes. This strategy provided a highly effi

Full text of DOI:10.1021/ol300571b

ORGANIC
LETTERS
2012
Vol. 14, No. 7
1914–1917
Total Synthesis of (ꢀ)-Herbindoles A, B,
and C via Transition-Metal-Catalyzed
Intramolecular [2 þ 2 þ 2] Cyclization
between Ynamide and Diynes
Nozomi Saito,* Taisuke Ichimaru, and Yoshihiro Sato*
Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
nozomi-s@pharm.hokudai.ac.jp; biyo@pharm.hokudai.ac.jp
Received March 6, 2012
ABSTRACT
The total syntheses of (ꢀ)-herbindoles A, B, and C as naturally occurring forms were accomplished for the first time through transition-metal-
catalyzed intramolecular [2 þ 2 þ 2] cyclization between ynamide and diynes. This strategy provided a highly efficient synthetic route to all three
herbindoles from an identical indoline derivative as a common intermediate.
(ꢀ)-Herbindoles A, B, and C (Figure 1), belonging to
polylalkylated cyclopent[g]indole alkaloids, were isolated
in 1990 from a Western Australian sponge, Axinella sp.,
and were shown to exert cytotoxicity against KB cells as well
as general antifeedant activity against fishes.1,2 In 1992,
Natsume reported the first total synthesis of (þ)-herbindoles
A, B, and C through an indole cyclization of pyrrole
derivatives, by which the absolute configurations of the
naturally occurring herbindoles A, B, and C were unambigu-
ously determined to be antipodes of their synthetic ones.3
Figure 1. (ꢀ)-Herbindoles A, B, and C.
Although syntheses of racemic herbindoles A and B were
independently reported by Kerr’s group4a,b and Buszek’s
group,4c there have been no reports on the total synthesis of
Transition-metal-catalyzed inter- and intramolecular
natural (ꢀ)-herbindoles.
[2 þ 2 þ 2] cycloaddition of three unsaturated bonds has
been recognized as a useful and promising methodology
(1) Herb, R.; Carroll, A. R.; Yoshida, W. Y.; Scheuer, P. J.; Paul,
for the synthesis of polycyclic compounds in recent organic
V. J. Tetrahedron 1990, 46, 3089.
synthesis.5,6 In particular, the [2 þ 2 þ 2] cycloaddition of
(2) For recent reviews on synthetic studies of herbindoles and their
structurally related indole alkaloids, trikentrins, see: Silva, L. F., Jr.;
triynes isknowntobe anefficient syntheticprotocol for the
ꢀ ꢀ
Craveiro, M. V.; Tebeka, I. R. M. Tetrahedron 2010, 66, 3875.
synthesis of various aromatic compounds. In this context,
the [2 þ 2 þ 2] cycloaddition of three alkynes including
an ynamide7ꢀ9 (1 and 2) has been recently established as
a new method for the construction of indole skeleta 3
(Scheme 1).10
With this as a background, we planned the total syn-
thesis of (ꢀ)-herbindoles A, B, and C by intramolecular
(3) For total synthesis of unnatural (þ)-herbindoles A, B, and
C and determination of their absolute configurations, see: (a) Muratake,
H.; Mikawa, A.; Natsume, M. Tetrahedron Lett. 1992, 33, 4595.
(b) Muratake, H.; Mikawa, A.; Seino, T.; Natsume, M. Chem. Pharm.
Bull. 1994, 42, 854.
(4) For total synthesis of racemic herbindoles, see: (a) Jackson, S. K.;
Banfield, S. C.; Kerr, M. A. Org. Lett. 2005, 7, 1215. (b) Jackson, S. K.;
Kerr, M. A. J. Org. Chem. 2007, 72, 1405. (c) Buszek, K. R.; Brown, N.;
Luo, D. Org. Lett. 2009, 11, 201.
r
10.1021/ol300571b
Published on Web 03/27/2012
2012 American Chemical Society

ring would be constructed by transition metal-catalyzed
[2 þ 2 þ 2] cyclization of the dialkynylynamide 5. Con-
struction of the ynamide part of 5 could be performed by
CꢀN coupling between bromoalkyne 6and the correspond-
ing nitrogen nucleophile. Furthermore, the bromoalkyne 6
could be easily synthesized from the known optically active
alcohol 711 via CoreyꢀFuchs alkyne synthesis.
Scheme 1. Construction of an Indole Skeleton via [2 þ 2 þ 2]
Cycloaddition of AlkyneꢀAlkyneꢀYnamide
Scheme 2. Retrosynthesis of (ꢀ)-Herbindoles A, B, and C
[2 þ 2 þ 2] cyclization of ynamide-diynes using a transi-
tion metal catalyst. Our retrosynthetic analysis of them is
shown in Scheme 2. All three herbindoles could potentially
be synthesized from the identical cyclopentane-fused indo-
line derivative 4 as a key intermediate, whose aromatic
(5) For reviews on transition-metal-catalyzed [2 þ 2 þ 2] cycloaddi-
tion of three unsaturated bonds, see: (a) Lautens, M.; Klute, W.; Tam,
W. Chem. Rev. 1996, 96, 49. (b) Saito, S.; Yamamoto, Y. Chem. Rev.
ꢀ
2000, 100, 2901. (c) Varela, J. A.; Saa, C. Chem. Rev. 2003, 103, 3787.
(d) Kotha, S.; Brahmachary, E.; Lahiri, K. Eur. J. Org. Chem. 2005,
4741. (e) Chopade, P. R.; Louie, J. Adv. Synth. Catal. 2006, 348, 2307.
(f) Gandon, V.; Aubert, C.; Malacria, M. Chem. Commun. 2006, 2209.
(g) Tanaka, K. Synlett 2007, 1977. (h) Shibata, T.; Tsuchikama, K. Org.
Biomol. Chem. 2008, 6, 1317. (i) Pla-Quintana, A.; Roglans, A. Mole-
cules 2010, 15, 9230. (j) Inglesby, P. A.; Evans, P. A. Chem. Soc. Rev.
Preparation of the bromoalkyne unit is shown in Scheme 3.
First, the known alcohol 7 (97% ee) was transformed into
dibromoalkene 8, from which alkyne formation followed
by deprotection of the TBS group was conducted to give
an alcohol 9. Then dibromoalkene prepared from 9 via
ꢀ
´
nguez, G.; Perez-Castells, J. Chem. Soc. Rev.
2010, 39, 2791. (k) Domı
2011, 40, 3430.
(6) For our reports on transition-metal-catalyzed [2 þ 2 þ 2]
cycloaddition leading to polycyclic compounds including some natural
products, see: (a) Sato, Y.; Nishimata, T.; Mori, M. J. Org. Chem. 1994,
59, 6133. (b) Sato, Y.; Nishimata, T.; Mori, M. Heterocycles 1997, 44,
443. (c) Sato, Y.; Ohashi, K.; Mori, M. Tetrahedron Lett. 1999, 40, 5231.
(d) Sato, Y.; Tamura, T.; Mori, M. Angew. Chem., Int. Ed. 2004, 43,
2436. (e) Sato, Y.; Tamura, T.; Kinbara, A.; Mori, M. Adv. Synth. Catal.
2007, 349, 647. (f) Tanaka, D.; Sato, Y.; Mori, M. J. Am. Chem. Soc.
2007, 129, 7730. (g) Saito, N.; Shiotani, K.; Kinbara, A.; Sato, Y. Chem.
Commun. 2009, 4284. (h) Iwayama, T.; Sato, Y. Chem. Commun. 2009,
5245. (i) Iwayama, T.; Sato, Y. Heterocycles 2010, 80, 917.
Scheme 3. Preparation of Bromoalkyne Part
(7) For reviews on the chemistry of ynamides, see: (a) Zificsak, C. A.;
Mulder, J. A.; Hsung, R. P.; Rameshkumar, C.; Wei, L.-L. Tetrahedron
2001, 57, 7575. (b) Mulder, J. A.; Kurtz, K. C. M.; Hsung, R. P. Synlett
2003, 1379. (c) Hsung, R. P., Ed. In Tetrahedron Symposia-in-Print No.
118, Tetrahedron 2006, 62, 3783. (d) Evano, G.; Coste, A.; Jouvin, K.
Angew. Chem., Int. Ed. 2010, 49, 2840. (e) DeKorver, K. A.; Li, H.;
Lohse, A. G.; Hayashi, R.; Lu, Z.; Zhang, Y.; Hsung, R. P. Chem. Rev.
2010, 110, 5064.
(8) For most recent examples of the preparation and reactions of
ynamides, see: (a) Schotes, C.; Mezzetti, A. Angew. Chem., Int. Ed. 2011,
€
50, 3072. (b) Kramer, S.; Odabachian, Y.; Overgaard, J.; Rottlander,
M.; Gagosz, F.; Skrydstrup, T. Angew. Chem., Int. Ed. 2011, 50, 5090.
(c) Davies, P. W.; Cremonesi, A.; Dumitrescu, L. Angew. Chem., Int. Ed.
2011, 50, 8931. (d) Fadel, A.; Legrand, F.; Evano, G.; Rabasso, N. Adv.
Synth. Catal. 2011, 353, 263. (e) Davies, P. W.; Cremonesi, A.; Martin,
N. Chem. Commun. 2011, 47, 379. (f) Pizzetti, M.; Russo, A.; Petricci, E.
Chem.;Eur. J. 2011, 17, 4523. (g) Greenaway, R. L.; Campbell, C. D.;
Holton, O. T.; Russell, C. A.; Anderson, E. A. Chem.;Eur. J. 2011, 17,
14366. (h) Shindoh, N.; Takemoto, Y.; Takasu, K. Heterocycles 2011,
82, 1133. (i) Shindoh, N.; Kitaura, K.; Takemoto, Y.; Takasu, K. J. Am.
Chem. Soc. 2011, 133, 8470. (j) Mak, X. Y.; Crombie, A. L.; Danheiser,
R. J. Org. Chem. 2011, 76, 1852. (k) DeKorver, K. A.; Johnson, W. L.;
Zhang, Y.; Hsung, R. P.; Dai, H.; Deng, J.; Lohse, A. G.; Zhang, Y.-S.
J. Org. Chem. 2011, 76, 5092. (l) Lu, Z.; Kong, W.; Yuan, Z.; Zhao, X.;
Zhu, G. J. Org. Chem. 2011, 76, 8524. (m) Xu, C.-F.; Xu, M.; Jia, Y.-X.;
Li, C.-Y. Org. Lett. 2011, 13, 1556. (n) Kramer, S.; Friis, S. D.; Xin, Z.;
Odabachian, Y.; Skrydstrup, T. Org. Lett. 2011, 13, 1750. (o) DeKorver,
K. A.; Walton, M. C.; North, T. D.; Hsung, R. P. Org. Lett. 2011, 13,
4862. (p) Wang, Y.-P.; Danheiser, R. L. Tetrahedron Lett. 2011, 52, 2111.
(9) For our reports on transition metal catalysis utilizing ynamide as
a platform, see: (a) Saito, N.; Sato, Y.; Mori, M. Org. Lett. 2002, 4, 803.
(b) Mori, M.; Wakamatsu, H.; Saito, N.; Sato, Y.; Narita, R.; Sato, Y.;
Fujita, R. Tetrahedron 2006, 62, 3872. (c) Saito, N.; Katayama, T.; Sato,
Y. Org. Lett. 2008, 10, 3829. (d) Saito, N.; Katayama, T.; Sato, Y.
Heterocycles 2011, 82, 1181. (e) Saito, N.; Saito, K.; Shiro, M.; Sato, Y.
Org. Lett. 2011, 13, 2718.
(10) For examples of transition-metal-catalyzed [2 þ 2 þ 2] cycload-
dition of alkyneꢀalkyneꢀynamide leading to an indole skeleton, see:
(a) Witulski, B.; Stengel, T. Angew. Chem., Int. Ed. 1999, 38, 2426.
ꢀ
ꢀ
(b) Witulski, B.; Stengel, T.; Fernandez-Hernandez, J. M. Chem. Commun.
2000, 1965. (c) Witulski, B.; Alayrac, C. Angew. Chem., Int. Ed. 2002, 41,
3281. For related transition-metal-catalyzed [2 þ 2 þ 2] cycloaddition of
alkyneꢀnitrileꢀynamide leading to hetroaromatic comounds, see:
(d) Alayrac, C.; Schollmeyer, D.; Witulski, B. Chem. Commun. 2009, 1464.
(e) Garcia, P.; Moulin, S.; Miclo, Y.; Leboeuf, D.; Gandon, V.; Aubert,
C.; Malacria, M. Chem.;Eur. J. 2009, 15, 2129. (f) Nissen, F.; Detert,
H. Eur. J. Org. Chem. 2011, 2845. (g) Nissen, F.; Richard, V.; Alayrac,
C.; Witulski, B. Chem. Commun. 2011, 47, 6656. (h) Garcia, P.; Evanno,
Y.; George, P.; Sevrin, M.; Ricci, G.; Malacria, M.; Aubert, C.; Gandon,
V. Org. Lett. 2011, 13, 2030.
ꢁ
(q) Balieu, S; Toutah, K.; Carro, L.; Chamoreau, L.-M.; Rousseliere, H.;
Courillon, C. Tetrahedron Lett. 2011, 52, 2876. (r) Dateer, R. B.; Shaibu,
B. S.; Liu, R.-S. Angew. Chem., Int. Ed. 2012, 51, 113. (s) Smith, D. L.;
Goundry, W. R. F.; Lam, H. W. Chem. Commun. 2012, 48, 1505.
(t) Jouvin, K.; Heimburger, J.; Evano, G. Chem. Sci. 2012, 3, 756.
(u) Schotes, C.; Althaus, M.; Aardoom, R.; Mezzetti, A. J. Am. Chem.
Soc. 2012, 134, 1331.
€
(11) Prusov, E.; Rohm, H.; Maier, M. E. Org. Lett. 2006, 8, 1025.
Org. Lett., Vol. 14, No. 7, 2012
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oxidationꢀdibromoalkenylation was treated with LHMDS12
to afford the bromoalkyne unit 10.
(þ)-herbindole A except for the sign of [R]D.3 It it note-
worthy that the overall yield of (ꢀ)-herbindole A from the
known compound 7 was 49% yield in 15 steps (average ca.
95.3% yield in each step).
The hydroxy group of the known compound 1113 was
protected by the MOM group, and deprotection of the Boc
group by heating gave tosylamide 12 (Scheme 4). In the
presence of a copper catalyst,14 bromoalkyne 10 and amide
12 were coupled to give dialkynylynamide 13, which was
converted into the [2 þ 2 þ 2] cyclization precursor 14 in
good yield.
Table 1. Construction of a Cyclopent[g]indole Skeleton
by Transition-Metal-Catalyzed [2 þ 2 þ 2] Cyclization
of 14
Next, we examined the [2 þ 2 þ 2] cyclization of 14 using
various transition metal catalysts, which have been em-
ployed previously in a variety of inter- and intramolecular
[2 þ 2 þ 2] cycloadditions5 (Table 1). The cyclization of 14
in the presence of a Cp*RuCl(cod) catalyst proceeded at
room temperature to give the expected indoline derivative
15 in 91% yield (run 1). Group 9 metal complexes, CpCo-
(CO)2 and RhCl(PPh3)3, also showed good catalytic activ-
ity for the [2 þ 2 þ 2] cyclization of ynamide derivative 14,
and the cyclizedproduct 15 was obtained in excellent yields
(runs 2 and 3). The reaction of 14 by using an Ni(0)-PPh3
catalyst also afforded 15 in good yield (run 4). On the other
hand, a Pd(0)-PPh3 catalyst did not promote the cycliza-
tion, and the starting 14 was recovered in almost quanti-
tative yield (run 5). Thus, we decided to employ the
Wilkinson’s catalyst to synthesize herbindoles.
catalyst
(mol %)
temp
time
(h)
yield
(%)
run
solvent
(°C)
1
2
3
4
Cp*RuCl(cod) (5)
CpCo(CO)2 (10)
RhCl(PPh3)3 (4)
Ni(cod)2 (5)
toluene
p-xylene
toluene
THF
rt
48
24
5
91
95a
97
80
140
50
50
24
PPh3 (10)
5
Pd2dba3 CHCl3 (2.5)
toluene
50
24
(98)b
3
PPh3 (10)
a NMR yield using 1,3,5-trimethoxybenzene as an internal stan-
dard. b The values in parentheses are the yields of starting dialkynyly-
namide 14.
Scheme 4. Synthesis of Dialkynylynamide 14 as a [2 þ 2 þ 2]
Cyclization Precursor
The synthesis of (ꢀ)-herbindole B was also achieved as
shown in Scheme 6. Thus, after removal of the MOM
group of 15, oxidation of the corresponding alcohol 18 by
Dess-Martin periodinane (DMP) followed by methylena-
tion using Tebbe reagent and hydrogenation afforded
indoline derivative 19. Finally, (ꢀ)-herbindole B was
synthesized through deprotection of 19 followed by aro-
matization in excellent yield (average ca. 94.2% yield in
each step).
Scheme 5. Synthesis of (ꢀ)-Herbindole A from 15
With the supposed common intermediate 15 in hand, we
set out to conduct the transformation of 15 into three
herbindoles. The cyclized product 15 was treated with
BBr3, giving benzylic bromide derivative 16 which, after
radical reduction, gave 17 in high yield (Scheme 5). Finally,
deprotection of the tosyl group followed by aromatiza-
tion in the presence of a cobalt(II) catalyst15 produced
(ꢀ)-herbindole A, whose spectral data were identical to
those reported for naturally occurring herbindole A.
The value of [R]D was also identical with the synthetic
(12) Huang, Z.; Negishi, E. J. Am. Chem. Soc. 2007, 129, 14788.
(13) Miclo, Y.; Garcia, P.; Evanno, Y.; George, P.; Sevrin, M.;
Malacria, M.; Gandon, V.; Aubert, C. Synlett 2010, 2314.
(14) Zhang, X.; Zhang, Y.; Huang, J.; Hsung, R. P.; Kurtz, K. C. M.;
Oppenheimer, J.; Petersen, M. E.; Sagamanova, I. K.; Shen, L.; Tracey,
M. R. J. Org. Chem. 2006, 71, 4170.
As shown in Scheme 7, the above alcohol 18 was easily
converted into 20 in 91% yield through oxidation,
(15) Inada, A.; Nakamura, Y.; Morita, Y. Chem. Lett. 1980, 1287.
1916
Org. Lett., Vol. 14, No. 7, 2012

Scheme 6. Synthesis of (ꢀ)-Herbindole B from 15
Scheme 7. Synthesis of (ꢀ)-Herbindole C from 18
Grignard reaction and subsequent dehydration. The syn-
thesis of (-)-herbindole C was also achieved by similar
transformation from 20 as the above-described procedure
(average ca. 95.3% yield in each step).
Acknowledgment. This work was partly supported by a
Grant-in-Aid for Scientific Research (B) (No. 23390001)
from JSPS and by a Grant-in-Aid for Scientific Research
on Innovative Areas “Molecular Activation Directed to-
ward Straightforward Synthesis” (No. 23105501) from
MEXT, Japan and by the research fund from the Fugaku
Trust for Medicinal Research. N.S. acknowledges the NO-
VARTIS Foundation (Japan) for the Promotion of Science
and Takeda Science Foundation for financial support.
In summary we have achieved, for the first time, an
efficient synthesis of (ꢀ)-herbindoles A, B, and C in
naturally occurring forms. The key reaction of the total
syntheses was transition metal-catalyzed [2 þ 2 þ 2]
cycloaddition of an ynamide-diyne, with ruthenium,
cobalt, and rhodium as well as nickel complexes cata-
lyzing the cyclization to give the cyclopent[g]indole
skeleton in high yield. This strategy provides a highly
efficient synthetic route to all three herbindoles
from an identical indoline derivative as a common
intermediate.
Supporting Information Available. Experimental pro-
cedure and spectral data. This material is available free of
charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 7, 2012
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