Divergent and expeditious access to fused skeletons inspired by indole alkaloids and transtaganolides

Article abstract of DOI:10.1021/ol901020a

We report the development of a divergent synthetic process entailing four-step access to the elaborate fused skeletons reminiscent of aspidophytines and transtaganolides. A variety of branched precursors were synthesized on the basis of Ugi condensations and installation of diazoimide and subjected to rhodium-catalyzed tandem reactions. Switching of cyclization modes was demonstrated by the choice of the amine building blocks installed at site C.

Full text of DOI:10.1021/ol901020a

ORGANIC
LETTERS
2009
Vol. 11, No. 14
3016-3019
Divergent and Expeditious Access to
Fused Skeletons Inspired by Indole
Alkaloids and Transtaganolides
Haruki Mizoguchi,† Hiroki Oguri,*,†,‡ Kiyoshi Tsuge,§ and Hideaki Oikawa†
DiVision of Chemistry, Graduate School of Science, and DiVision of InnoVatiVe
Research, CreatiVe Research InitiatiVe “Sousei” (CRIS), Hokkaido UniVersity,
N21, W10, Sapporo 001-0021, Japan
oguri@sci.hokudai.ac.jp
Received May 11, 2009
ABSTRACT
We report the development of a divergent synthetic process entailing four-step access to the elaborate fused skeletons reminiscent of
aspidophytines and transtaganolides. A variety of branched precursors were synthesized on the basis of Ugi condensations and installation
of diazoimide and subjected to rhodium-catalyzed tandem reactions. Switching of cyclization modes was demonstrated by the choice of the
amine building blocks installed at site C.
A family of indole alkaloids is one of the most valuable
resources for discovering biologically intriguing natural
products.1 In addition to the densely functionalized multi-
cyclic molecular architectures, we took notice of the char-
acteristic structural features of these alkaloids: the fused
skeleton composed of indole and piperidine as the common
substructures as shown in Figure 1a. Inspired by the
structural features, we began to develop an expeditious
synthetic process that allows coupling of the substructures
followed by pairing of the functional groups to construct
fused skeletons reminiscent of the indole alkaloids. Previ-
ously, we developed a synthetic process to access indole
alkaloid-like fused skeletons utilizing a piperidine-based
scaffold.2 Although this approach is capable of generating
skeletal diversity based on variations of the cyclization
modes, laborious manipulations required preparation of a
series of cyclization precursors, a major drawback in the
development of pilot libraries.
In this work, we devised a second-generation strategy based
on a unified four-step synthetic process that provides access to
natural product analogues.3-5 As shown in Scheme 1a, Ugi
four-component condensation6 of the piperidine scaffold 1
(3) (a) Boldi, A. M. Curr. Opin. Chem. Biol. 2004, 8, 281–286. (b)
Wender, P. A.; Verma, V. A.; Paxton, T. J.; Pillow, T. H. Acc. Chem. Res.
2008, 41, 40–49. (c) Hu¨bel, K.; Lebmann, T.; Waldmann, H. Chem. Soc.
ReV. 2008, 37, 1361–1374. (d) Sunderhaus, J. D.; Martin, S. F. Chem.sEur.
J. 2009, 15, 1300–1308. (e) Nandy, J. P.; Prakesch, M.; Khadem, S.; Reddy,
P. T.; Sharma, U.; Arya, P. Chem. ReV. 2009, 109, 1999–2060.
(4) Recent reviews for diversity-oriented synthesis (DOS), see: (a) Burke,
M. D.; Schreiber, S. L. Angew. Chem., Int. Ed. 2004, 43, 46–58. (b) Arya,
P.; Joseph, R.; Gan, Z.; Rakic, B. Chem. Biol. 2005, 12, 163–180. (c) Tan,
D. S. Nat. Chem. Biol. 2005, 1, 74–84. (d) Nielsen, T. E.; Schreiber, S. L.
Angew. Chem., Int. Ed. 2008, 47, 48–56. (e) Spandl, R. J.; Bender, A.;
Spring, D. R. Org. Biomol. Chem. 2008, 6, 1149–1158. (f) Cordier, C.;
Morton, D.; Murrison, S.; Nelson, A.; O’Leary-Steele, C. Nat. Prod. Rep.
2008, 25, 719–737.
† Graduate School of Science.
‡ Creative Research Initiative “Sousei” (CRIS).
§ Present Address: Department of Chemistry, Graduate School of Science,
Osaka University.
(1) Saxton, J. E. In The Alkaloids: Chemistry and Biology; Cordell, G. A.,
Ed.; Academic Press: San Diego, 1998; Vol. 51, pp 1-197.
(2) Oguri, H.; Schreiber, S. L. Org. Lett. 2005, 7, 47–50.
10.1021/ol901020a CCC: $40.75
Published on Web 06/17/2009
 2009 American Chemical Society

Scheme 1. (a) Synthesis of Branched Precursors with Three
Sites A-C for the Pairing of Functional Groups; (b)
Rh(II)-Catalyzed Tandem Cyclization-Cycloadditions; (c)
Divergent Synthesis of Fused Skeletons Reminiscent of
Naturally Occurring Aspidophytines and Transtaganolides
Figure 1. Structures of natural products: (a) fused alkaloids
composed of indole (blue) and piperidine (red) groups; (b) alkaloids
with a piperidine-based core linked with an indole; (c) Ca2+-ATPase
inhibitors, artemisinin, and transtaganolides (basiliolides).
followed by stepwise installation of R-diazocarbonyl group7
affords cyclization precursors in three steps. To perform
annulations between piperidine and indole substructures, we
adopted Padwa’s protocol, a rhodium-catalyzed tandem
cyclization-cycloaddition (Scheme 1b).8,9 As shown in
Scheme 1c, the cycloaddition between the ylide generated
at site A with the indole group at site B would construct a
hexacyclic skeleton analogous to the framework of the indole
alkaloid, aspidophytine.10 Conversely, given the dynamic
conformational equilibrium of the tertiary amide bond, the
(5) For recent DOS approaches generating skeletal diversity, see: (a)
Burke, M. D.; Berger, E. M.; Schreiber, S. L. J. Am. Chem. Soc. 2004,
126, 14095–14104. (b) Spiegel, D. A.; Schroeder, F. C.; Duvall, J. R.;
Schreiber, S. L. J. Am. Chem. Soc. 2006, 128, 14766–14767. (c) Mitchell,
J. M.; Shaw, J. T. Angew. Chem., Int. Ed. 2006, 45, 1722–1726. (d)
Kumagai, N.; Muncipinto, G.; Schreiber, S. L. Angew. Chem., Int. Ed. 2006,
45, 3635–3638. (e) Wyatt, E. E.; Fergus, S.; Galloway, W. R. J. D.; Bender,
A. D.; Fox, J.; Plowright, A. T.; Jessiman, A. S.; Welch, M.; Spring, D. R.
Chem. Commun. 2006, 3296–3298. (f) Thomas, G. L.; Spandl, R. J.;
Glansdorp, F. G.; Welch, M.; Bender, A.; Cockfield, J.; Lindsay, J. A.;
Bryant, C.; Brown, D. F. J.; Loiseleur, O.; Rudyk, H.; Ladlow, M.; Spring,
D. R. Angew. Chem., Int. Ed. 2008, 47, 2808–2812. (g) Morton, D.; Leach,
S.; Cordier, C.; Warriner, S.; Nelson, A. Angew. Chem., Int. Ed. 2009, 48,
104–105.
cycloaddition exploiting the olefin group at site C is also
capable of yielding a distinct tetracyclic product. The
cycloadduct with an intact indole moiety also has a certain
degree of structural resemblance to a series of naturally
occurring alkaloids as shown in Figure 1b. Meanwhile, an
alternative synthetic strategy was pursued for the cyclic
frameworks of the Ca2+-ATPase inhibitors, artemisinins, and
transtaganolides (Figure 1c).11 It was envisaged that the
tetracyclic core formed by the A f C mode cycloaddition
would imitate the fused skeleton of transtaganolides12,13 as
shown in Scheme 1c.
In an effort to access a large group of natural product
analogues, we first synthesized a precursor 6 with an indole
ring and a p-methoxybenzyl group installed at sites B and C,
respectively (Scheme 2). Ugi condensation of racemic scaffold
1, indole-3-carboxaldehyde derivative 2, tert-butylisonitrile 3,
(6) For reviews, see: (a) Do¨mling, A.; Ugi, I. Angew. Chem., Int. Ed.
2000, 39, 3168–3210. (b) Zhu, J. Eur. J. Org. Chem. 2003, 1133–1144. (c)
Do¨mling, A. Chem. ReV. 2006, 106, 17–89.
(7) Zhang, Z.; Wang, J. Tetrahedron 2008, 64, 6577–6605.
(8) (a) Padwa, A.; Hornbuckle, S. F. Chem. ReV. 1991, 91, 263. (b)
Padwa, A.; Weingarten, M. D. Chem. ReV. 1996, 96, 223. (c) Padwa, A.
Top. Curr. Chem. 1997, 189, 121. (d) Padwa, A. Pure Appl. Chem. 2004,
76, 1933. (e) Padwa, A.; Brodney, M. A.; Lynch, S. M.; Rashatasakhon,
P.; Wang, Q.; Zhang, H. J. Org. Chem. 2004, 69, 3735
.
(9) For recent examples for the total synthesis of natural products using
a Rh(II)-catalyzed cyclization/cycloaddition cascade, see: (a) Graening, T.;
Bette, V.; Neudo¨rfl, J.; Lex, J.; Schmalz, H.-G. Org. Lett. 2005, 7, 4317–
4320. (b) Hirata, Y.; Nakamura, S.; Watanabe, N.; Kataoka, O.; Kurosaki,
T.; Anada, M.; Kitagaki, S.; Shiro, M.; Hashimoto, S. Chem.sEur. J. 2006,
12, 8898–8925. (c) Nakamura, S.; Sugano, Y.; Kikuchi, F.; Hashimoto, S.
Angew. Chem., Int. Ed. 2006, 45, 6532–6535. (d) Lam, S. K.; Chiu, P.
Chem.sEur. J. 2007, 13, 9589–9599. (e) England, D. B.; Padwa, A. J.
Org. Chem. 2008, 73, 2792–2802. (f) Kim, C. H.; Jang, K. P.; Choi, S. Y.;
(10) For the total synthesis of aspidophytine, see: (a) He, F.; Bo, Y.;
Altom, J. D.; Corey, E. J. J. Am. Chem. Soc. 1999, 121, 6771–6772. (b)
Sumi, S.; Matsumoto, K.; Tokuyama, H.; Fukuyama, T. Tetrahedron 2003,
59, 8571–8587. (c) Mejia-Oneto, J. M.; Padwa, A. Org. Lett. 2006, 8, 3275–
3278. (d) Marino, J. P.; Cao, G. Tetrahedron Lett. 2006, 47, 7711–7713.
(e) Nicolaou, K. C.; Dalby, S. M.; Majumder, U. J. Am. Chem. Soc. 2008,
130, 14942–14943.
(11) Oguri, H.; Yamagishi, Y.; Hiruma, T.; Oikawa, H. Org. Lett. 2009,
11, 601–604.
Chung, Y. K.; Lee, E. Angew. Chem., Int. Ed. 2008, 47, 4009–4011
.
Org. Lett., Vol. 11, No. 14, 2009
3017

Scheme 2
.
Four-Step Synthesis of Hexacyclic 7 and Tetracyclic (16-19 and 26-28) Based on Ugi Reaction and Rhodium-Catalyzed
Divergent Cyclizations of Branched Precursors 6, 12-15, and 23-25a
a Reagents and conditions: S1: amine (4, 8-11, 20-21), MeOH, reflux; S2: 5, toluene, reflux; S3: MsN3, Et3N, CH3CN; S4: Rh2(OAc)4 (5 mol %);
benzene, reflux. Yields for each step are shown in Table 1.
and p-methoxybenzylamine 4 afforded a dipeptidyl product as
a 1:1 diastereomeric mixture in 78% yield (Table 1, entry 1).
mixture of indole alkaloid analogues 7a and 7b was easily
separated by conventional silica gel chromatography. Rhodium-
catalyzed reaction of 12 effected an 1,3-dipolar cycloaddition
of the ylide intermediate with the terminal olefin at site C to
form 16 as a separable 1:1 diastereomeric mixture in 94% yield.
The nosyl groups in 7b and 16a were efficiently removed with
PhSH and Cs2CO3 to liberate aniline and indole groups,
respectively.14 X-ray analyses of the crystalline 7b and 16b
clearly showed the multicyclic core structures with consecutive
quaternary centers.15 The stereochemistry of each diastereomer
is also determined as depicted in Scheme 2. X-ray analysis also
showed that both cycloadditions via distinct cyclization modes
exhibit identical and exquisite stereoselectivities. By this means,
complete switching of the cyclization modes was accomplished
by installation of a dipolarophile at site C. The divergence of
the synthetic process with high levels of stereoselectivity is
promising for the development of small molecule libraries with
structural diversity.
Table 1. Attempts toward the Four-Step Synthesis Employing a
Variety of Amine Building Blocks As Shown in Scheme 2
overall
entry amine S1a (%) S2a (%) S3a (%) S4a (%) yieldb (%)
1
2
3
4
5
6
7
4
8
9
10
11
20
21
78
76
59
59
56
62
64
80
72
69
87
93
85
74
6, 91
12, 96
13, 88
14, 84
15, 94
23, 84
24, 93
7, 78
16, 94
17, 83
18, 93
19, 80
26, 83
27, 87
44
49
30
40
39
37
38
a Yields for each step were reported for the 1:1 mixtures of diastereomers.
b Overall yields for the four-step manipulations.
To explore the scope of the divergent reactions, we
attempted to control the cyclization modes by altering the
This intermediate was subsequently converted into cyclization
precursor 6 with a diazoimide group in two steps: N-acetoacety-
lation upon heating with 5 and subsequent diazo transfer.2 By
performing three-step manipulations with allyl amine 8 in place
of 4, we then synthesized a branched precursor 12 with an indole
group and a terminal olefin at sites B and C, respectively (entry
2). Upon treatment of 6 with 5 mol % of Rh2(OAc)4 catalyst
in refluxing benzene, the tandem reaction proceeded via a
cyclization mode A f B to yield cycloadduct 7 with a
hexacyclic skeleton in 78% yield. The 1:1 diastereomeric
(12) (a) Saouf, A.; Guerra, F. M.; Rubal, J. J.; Moreno-Dorado, F. J.;
Akssira, M.; Mellouki, F.; Lo´pez; Matias, M.; Pujadas, A. J.; Jorge, Z. D.;
Massanet, G. M. Org. Lett. 2005, 7, 881–884. (b) Appendino, G.; Prosperini,
S.; Valdivia, C.; Ballero, M.; Colombano, G.; Billington, R. A.; Genazzani,
A. A.; Sterner, O. J. Nat. Prod. 2005, 68, 1213–1217.
(13) For synthetic studies, see: (a) Nelson, H. M.; Stoltz, B. M. Org.
Lett. 2008, 10, 25. (b) Kozytska, M. V.; Dudley, G. B. Tetrahedron Lett.
2008, 49, 2899. (c) Zhou, X.; Wu, W.; Liu, Z.; Lee, C.-S. Org. Lett. 2008,
10, 5525. (d) Larsson, R.; Sterner, O.; Johansson, M. Org. Lett. 2009, 11,
657.
(14) Fukuyama, T.; Jow, C.-K.; Chung, M. Tetrahedron Lett. 1995, 36,
6373–6374.
3018
Org. Lett., Vol. 11, No. 14, 2009

group installed at site C. Initially, we intended to shift
cyclization modes from A f C into A f B by increasing
the steric hindrance of the dipolarophiles at site C and
designed a series of cyclization precursors 13-15 bearing
di-, tri-, and tetrasubstituted olefinic groups (Table 1, entries
3-5). Precursors 13-15 were systematically synthesized in
good yields by adapting the three-step transformation with
amine building blocks 9-11. In spite of our intention to shift
cyclization modes, all of the branched precursors 13-15 were
uniformly converted by cyclization mode A f C to afford
cyclized products 17-19 in good to excellent yields. The
indole groups at site B remained intact for all of these
reactions. Notably, the sterically demanding tri- and tetra-
substituted olefins at site C efficiently act as dipolarophiles
to furnish 18 and 19 with multiple (up to five) quaternary
centers on the cyclic core (entries 4 and 5). Similarly,
precursors 23 and 24, bearing acetylene and furan groups at
site C, were then synthesized as above employing 20 and
21 (entries 6 and 7). Both cycloadditions occurred exclusively
at site C to produce cycloadducts 26 and 27 in good to
excellent yields as a 1:1 mixture of separable diastereomers.
In all attempts, both of the diastereomers generated by the
Ugi condensations were equally converted. Thus, this
synthetic process allows simultaneous access to a diastere-
omeric pair of separable cycloadducts and thereby provokes
stereochemical variations in the collections.
With an aim to identify a crucial element for the site
selectivities, we next designed branched precursor 25 and
installed a pair of identically functionalized indole rings in
a branched fashion (Scheme 2). In this attempt, we employed
azide 22 as a precursor to the corresponding amine building
block due to its instability. This azide was then utilized to
conduct a tandem Staudinger/aza-Wittig/Ugi condensation16
to form the tetrapeptidyl product. The rhodium-catalyzed
reaction of 25 again proceeded via the A f C mode to form
28 in 77% yield. Estimating the equivalent reactivities of
each of the indole rings as dipolarophiles, it is likely that
the peptidyl substituent at site B plays a pivotal role in the
control of the cyclization modes.
Scheme 3. Synthesis of Branched Precursors 31 and 32 Using
Amines 29 and 30 with Different Methylene Lengths and
Attempts To Switch the Cyclization Modes
impeded by the entropic barrier for medium-sized ring
formation, and eventually, complete switching of the cy-
clization mode was achieved. Thus, the synthetic process
allows divergent access to hexacyclic and tetracyclic skel-
etons that are analogous to the frameworks of aspidophytines
and transtaganolides, respectively.
In conclusion, a variety of branched precursors were syn-
thesized in three steps employing the Ugi condensation and a
stepwise installation of a diazoimide group. Making use of the
dynamic conformational equibria of the tertiary amides, we
developed an expeditious and flexible synthetic process featuring
divergent cyclizations leading to fused skeletons reminiscent
of indole alkaloids or oxygenated terpenes. Furthermore, site-
controlled cyclizations have been achieved using an appropriate
choice for the amine building block. This four-step procedure
not only generates stereochemical variation in the libraries but
also enables practical access to a collection of highly elaborate
cyclic molecules with sufficient quantities (>100 mg) in
excellent yields (>30% overall yields). Various sorts of the
functional groups incorporated into the core skeletons involving
amino acetal, ꢀ-ketoimide, and indole/olefin groups could be
readily utilized for further manipulations in the development
of small molecule libraries. Further synthetic investigations and
preliminary screenings of biological activities are currently
underway.
The reactions described above demonstrate the preference
of the cycloadditions via the A f C mode; however,
switching the cyclization modes was attempted by increasing
the ring sizes formed via the cycloadditions exploiting an
olefin group at site C (Scheme 3). To this end, precursors
31 and 32 were synthesized in the three steps using amines
29 and 30, respectively. The rhodium-catalyzed cyclization
of 31 afforded a seven-membered ring as a major product,
which resulted in the formation of tetracyclic 33 in 65% yield
and along with hexacyclic 34 in 22% yield via the A f B
mode. In contrast, cycloaddition of 32 proceeded with the
indole group at site B to produce 3615 in 94% yield without
formation of the eight-membered ring to give 35. The
cycloaddition via the A f C mode leading to 35 was
Acknowledgment. We thank Yuko Fujimura (Shionogi
& Co., Ltd.) for performing the X-ray analysis of compound
36. This work was supported by Grants-in-Aid for Young
Scientists (A) (19681022) and for Exploratory Research
(20651054) to H. Oguri and also supported in part by FINDS:
pharma-innovation discovery competition Shionogi and the
Science and Technology Research Partnership for Sustainable
Development (STREP) program of Japan Science and
Technology Agency (JST).
(15) CIF files were deposited with the Cambridge Crystallographic Data
Centre (CCDC): CCDC-247775 (7b), CCDC-727471 (16b), and CCDC-
727472 (36b).
(16) (a) Timmer, M. S. M.; Risseeuw, M. D. P.; Verdoes, M.; Filippov,
D. V.; Plaisier, J. R.; Van der Marel, G. A.; Overkleeft, H. S.; Van Boom,
J. H. Tetrahedron: Asymmetry 2005, 16, 177. (b) Bonger, K. M.; Wennekes,
T.; de Lavoir, S. V. P.; Esposito, D; van den Berg, R. J. B. H. N.; Litjens,
R. E. J. N.; van der Marel, G. A.; Overkleeft, H. S. QSAR Comb. Sci. 2005,
25, 491.
Supporting Information Available: Experimental pro-
1
cedures and H and 13C NMR spectra of compounds 7,
16-19, 26-28, 33, 34, and 36. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL901020A
Org. Lett., Vol. 11, No. 14, 2009
3019