Chiral holmium complex-catalyzed Diels-Alder reaction of silyloxyvinylindoles: Stereoselective synthesis of hydrocarbazoles

Article abstract of DOI:10.1021/ol402559z

The catalytic and asymmetric cycloaddition between 3-[1-(silyloxy)vinyl] indoles and electron-deficient olefins gave substituted hydrocarbazoles in up to 99% yield and 94% ee. This reaction was catalyzed by a novel chiral holmium(III) complex. Alkylation of the cycloadduct gave a tricyclic compound with four continuous chiral centers, one of which was a quaternary carbon.

Full text of DOI:10.1021/ol402559z

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Chiral Holmium Complex-Catalyzed
DielsꢀAlder Reaction of
Silyloxyvinylindoles: Stereoselective
Synthesis of Hydrocarbazoles
Shinji Harada, Takahiro Morikawa, and Atsushi Nishida*
Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana,
Chuo-ku, Chiba 260-8675, Japan
anishida@faculty.chiba-u.jp
Received September 5, 2013
ABSTRACT
The catalytic and asymmetric cycloaddition between 3-[1-(silyloxy)vinyl]indoles and electron-deficient olefins gave substituted hydrocarbazoles
in up to 99% yield and 94% ee. This reaction was catalyzed by a novel chiral holmium(III) complex. Alkylation of the cycloadduct gave a tricyclic
compound with four continuous chiral centers, one of which was a quaternary carbon.
Hydrocarbazoles, which possess a heterotricyclic ring
system, are an important class of organic compounds.
This motif is a common scaffold of many natural and
biologically active alkaloids (Figure 1).1 Although
hydrocarbazoles are quite important structures, methods
for constructing them are limited. The most common
approach is the cycloaddition of indole derivatives. Pre-
vious reports have used 3-vinylindoles2 or 2-vinylindoles3
as a diene.4 However, in these cases, the obtained cycload-
ducts mostly sufferedfrom air-oxidation or a thermal [1,3]-
hydride shift, resulting in the loss of a chiral center (Scheme 1,
X = H).5 Therefore, a reliable and versatile method for
obtaining highly substituted chiral hydrocarbazoles in a
single step is still needed.
(1) For reviews, see: (a) Saxton, J. E. Nat. Prod. Rep. 1997, 14, 559.
€
(b) Knolker, H. -J.; Reddy, K. R. Chem. Rev. 2002, 102, 4303.
(2) (a) Saroja, B.; Srinivasan, P. C. Synthesis 1986, 748. (b) Murase,
M.; Hosaka, T.; Koike, T.; Tobinaga, S. Chem. Pharm. Bull. 1989, 37,
1999. (c) Pindur, U.; Lutz, G.; Fischer, G.; Schollmeyer, D.; Massa, W.;
€
Schroder, L. Tetrahedron 1993, 49, 2863. (d) Bleile, M.; Wagner, T.;
Otto, H. -H. Helv. Chim. Acta 2005, 88, 2879. (e) Gioia, C.; Hauville, A.;
Bernardi, L.; Fini, F.; Ricci, A. Angew. Chem., Int. Ed. 2008, 47, 9236.
ꢀ
(f) Tan, B.; Hernandez-Torres, G.; Barbas, C. F., III. J. Am. Chem. Soc.
2011, 133, 12354.
(3) (a) Eitel, M.; Pindur, U. J. Org. Chem. 1990, 55, 5368. (b) Jones,
S. B.; Simmons, B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2009, 131,
13606. (c) Cao, Y.-J.; Cheng, H.-G.; Lu, L.-Q.; Zhang, J.-J.; Cheng, Y.;
Chen, J.-R.; Xiao, W.-J. Adv. Synth. Catal. 2011, 353, 617. (d) Jones,
S. B.; Simmons, B.; Mastracchio, A.; MacMillan, D. W. C. Nature 2012,
475, 183. See also ref 2c.
(4) For other recent strategies, see: (a) Liu, Y.; Nappi, M.; Arceo, E.;
Vera, S.; Melchiorre, P. J. Am. Chem. Soc. 2011, 133, 15212. (b) Liu, Y.;
ꢀ
Nappi, M.; Escudero-Adan, E. C.; Melchiorre, P. Org. Lett. 2012, 14,
1310. (c) Xiao, Y.-C.; Zhou, Q.-Q.; Dong, L.; Liu, T.-Y.; Chen, Y.-C.
Org. Lett. 2012, 14, 5940. (d) Kawano, M.; Kiuchi, T.; Negishi, S.;
Tanaka, H.; Hoshikawa, T.; Matsuo, J.-I.; Ishibashi, H. Angew. Chem.,
Int. Ed. 2013, 52, 906.
Figure 1. Selected examples of natural and biologically active
compounds that contain hydrocarbazole.
r
10.1021/ol402559z
XXXX American Chemical Society

Based on our previous studies6 using a Danishefsky
diene,7 we envisioned that 3-[1-(silyloxy)vinyl]indole
(siloxyvinylindole) (1, X = OSi) could be used as a diene,
which would exhibit high reactivity and allow direct
access to hydrocarbazole 2 by [4 þ 2] cycloaddition, as
outlined in Scheme 1. Ordinary transformation of the
cycloadduct provides hydrocarbazolone 3 with a qua-
ternary carbon. To our surprise, there is no synthetically
useful example of the use of siloxyvinyl-substituted
heteroaromatics as a diene for catalytic and enantiose-
lective [4 þ 2] cycloaddition.8 We report here a method
for the catalytic synthesis of optically active hydrocarba-
zoles using siloxyvinylindole as a diene, in which new
holmium (Ho) salt and chiral bis-thiourea complexes
were used as a catalyst.
the reaction conditions as well as under silica gel column
chromatography. The perfect regioselectivity suggested
that the Lewis acidic activation of dienophile 7a occurred
site-specifically at N-acyloxazolidinone. With the use of
bis-thiourea ligand 5 (entry 2), the chemical yield was
dramatically increased to be quantitative and the diaste-
reoselectivity was perfect, yet the ee was still unsatisfac-
tory. By changing the side chain of the ligand, we found
that smaller substituents gave better enantioselectivity,
and a methylgroup gave thebestresults:75%ee (entry 3).11
For the development of a catalytic system with broader
substrate generality, 7b with a simple alkyl chain was used.
However, 2b was obtained in only 9% yield and 16% ee.
Screening of other lanthanide triflates12 revealed that
holmium triflate (entry 5) was the most effective in terms
of enantioselectivity: 32% ee. Further investigation of
metal sources showed that trifluoromethanesulfonimide
salt13 dramatically improved the results: 90% yield,
Scheme 1. DielsꢀAlder Reaction of 3-Siloxyvinylindole
Followed by Alkylation To Construct Hydrocarbazoles with
Four Continuous Chiral Centers
Table 1. Optimization of the Catalyst
We initiated screening using our chiral Yb complex,6
fumaric acid derivative 7a, and 1 (X = OSi) with various
N-protective groups and silyl groups. After concise screening,
N-(p-methoxybenzenesulfonyl)-3-[1-(triisopropylsiloxy)-
vinyl]indole (1a) was found to be both sufficiently stable
and reactive as a diene.9 With our Yb catalyst, 1a and 7a
gave encouraging results (Table 1, entry 1).10 Notably, the
silyl enol ether moiety of the adduct 2a was intact under
time
yield
(%)
ee
(%) (exo/endo)
drb
entry
R
metal salt ligand (h)
1a
2
7a Yb(OTf)3
7a Yb(OTf)3
7a Yb(OTf)3
7b Yb(OTf)3
7b Ho(OTf)3
7b Ho(NTf2)3
7b Ho(NTf2)3
4
5
6
6
6
6
6
5
3
3
2
2
2
3
18
52
59
75
16
32
87
93
9/1
quant
quant
9
exo only
exo only
exo only
exo only
exo only
exo only
(5) Prof. MacMillan’s group avoided these problems by using the
strategy of a cascade sequence: ref 3b,3d. See also ref 2c,2e.
3
4c
5c
6
(6) Catalytic and asymmetric DielsꢀAlder reaction of Danishefsky
diene and electron-deficient olefins reported by our group, see: (a) Sudo,
Y.; Shirasaki, D.; Harada, S.; Nishida, A. J. Am. Chem. Soc. 2008, 130,
12588. (b) Harada, S.; Toudou, N.; Hiraoka, S.; Nishida, A. Tetrahedron
Lett. 2009, 50, 5652. (c) Hiraoka, S.; Harada, S.; Nishida, A. J. Org.
Chem. 2010, 75, 3871. (d) Harada, S.; Morikawa, T.; Hiraoka, S.;
Nishida, A. J. Synth. Org. Chem. Jpn. 2013, 71, 818. The reaction above
reported by other group, see: (e) Orimoto, K.; Oyama, H.; Namera, Y.;
Niwa, T.; Nakada, M. Org. Lett. 2013, 15, 768.
8
90
7d
86
a 2.0 equiv of 1a was used. b Determined from the 1H NMR spectrum
ofthe crude mixture. c Carried outatrt. d 5 mol % ofHo(NTf2)3, 10 mol%
of 6, and 10 mol % of DBU were used.
(7) Danishefsky, S.; Kitahara, T. J. Am. Chem. Soc. 1974, 96, 7807.
(8) See ref 2d. For furan derivatives, see: Benıtez, A.; Herrera, F. R.;
ꢀ
Romero, M.; Talamas, F. X. J. Org. Chem. 1996, 61, 1487.
(11) For the screening of other ligands, see the Supporting Informa-
tion. For the organocatalytic use of binaphthyldiamine-derived bis-
thiourea, see: (a) Fleming, E. M.; McCabe, T.; Connon, S. J. Tetrahedron
Lett. 2006, 47, 7037. (b) Liu, X.-G.; Jiang, J.-J.; Shi, M. Tetrahedron:
Asymmetry 2007, 18, 2773. (c) Rampalakos, C.; Wulff, W. D. Adv. Synth.
(9) N-Benzyl-protected siloxyvinylindole 1 predominately under-
went Michael addition to 7a. For the silyl group of 1, TMS was rather
unstable and decomposed under the reaction conditions. Compound 1a
is stable against water and can be purified by silica gel column chroma-
tography. Moreover, it can be stored in a freezer for months.
(10) This reaction between 1a and 7 catalyzed by lanthanide metal is
exo selective with or without chiral ligand. For details, see the Support-
ing Information.
~
Catal. 2008, 350, 1785. (d) Crespo-Pena, A.; Monge, D.; Martın-Zamora,
ꢀ
ꢀ
E.; Alvarez, E.; Fernandez, R.; Lassaletta, J. M. J. Am. Chem. Soc. 2012,
134, 12912.
(12) For details, see the Supporting Information.
B
Org. Lett., Vol. XX, No. XX, XXXX

87% ee (entry 6). When a Ho(NTf2)3/(R)-6/DBU = 1/2/2
complex was used, both the reactivity and enantioselectivity
were improved to give the cycloadduct in 86% yield and 93%
ee even with 5 mol % of the catalyst (entry 7).14 The ee of 2
could be enriched by recrystallization. In particular, with an
86% ee sample of 2a, we obtained optically enriched 2a in 99%
ee after a single recrystallization.15 Under these conditions,
we examined the scope and limitations of the dienophile.16
The reaction with thioester 7c proceeded smoothly to
give the desired product in 94% yield, but the enantio-
selectivity decreased to 78% ee (Table 2, entry 2). Acetyl,
cyano, and trifluoromethyl groups gave similarly good
results with respect to reactivity and enantioselectivity
(entries 3ꢀ5). A phenyl substituent (entry 6) was associated
with a slight decrease in enantioselectivity. Alkyl-substituted
dienophiles (7hꢀj, and 7b, entries 7ꢀ10) gave excellent
yields (86ꢀ96%) and good ee’s (90ꢀ94% ee), although
7i had relatively low reactivity. Acrylate derivative 7k
(entry 11) was unstable under these conditions. Therefore,
the substrate was added at ꢀ20 °C, and the reaction mixture
was stirred at the same temperature for 30 min to give the
desired product 2k in 95% yield and 86% ee.
This holmium chemistry could be extended to dienes from
other heterocycles (Figure 2). Pyrrole-type substrate gave
hydroindole 8 in 92% yield, and the enantioselectivity was
still good, i.e., 87% ee. Similar to the results in Table 2, we
did not observe the generation of anendo isomer. Benzofuran
derivative could also be used in this reaction, although 10 mol %
of the catalyst was required to complete the reaction:
96% yield and 81% ee. The formation of chiral 8 and 9 is
noteworthy, since there is no previous report on the synthesis
of these skeletons as well as 2 using a single catalytic system.
Table 2. Scope and Limitation of the Substituent on the
Dienophile 7
Figure 2. Scope of dienes. The reactions were performed in
CH2Cl2 in the presence of the holmium catalyst.
yield of ee of
entry
Ra (substrate)
conditions
0 °C, 30 min
0 °C, 30 min
0 °C, 30 min
0 °C, 30 min
0 °C, 1 h
0 °C, 30 min; rt, 2 h
0 °C, 1 h
0 °C, 2 h
2b (%)
2 (%)
1
CO2CH3
COSPh
COCH3
CN
7a
7c
7d
7e
7f
96
94
95
94
99
99
90
92
96
86
95
87
78
90
92
94
75
94
90
90
93
86
With cycloadducts in hand, we turned to conversion of
the silyl enol ether moiety. When the adduct 2a was treated
with methyl iodide and tetrabutylammonium fluoride,
the corresponding methylated product 3a was obtained
asa single isomer(Scheme2, eq1). Similarly, allylation was
performed, and the product 3b was obtained in 85% yield.
Cyanomethylation gave 3c in 90% yield. Remarkably,
these compounds 3aꢀc have a chiral quaternary carbon
among four continuous chiral stereocenters, which were
synthesized in two steps. Compound 3c could be a poten-
tial synthetic intermediate for strychnos alkaloids.17 Re-
ductive cyclization of 3c with Raney-Ni gave 10 and 11
(Scheme 2, eq 2). Compound 10 could be converted to 11
by hydrogenation with Pd(OH)2. Other transformations
are depicted in Scheme 3. Thioesterification of 2b pro-
ceededsmoothly to give12 in quantitative yield. Fukuyama
reduction18 afforded aldehyde 13. Primary alcohol 14
was obtained by the reduction of thioester 12 with LAH.
Deprotection of indole-nitrogene using Na/anthracene19
gave 15 in 84% yield. Neither epimerization nor racemiza-
tion was observed during these transformations.
2
3
4
5
CF3
6c
7
Ph
7g
7h
7i
CH2Cl
CH2OBn
Me
8c
9
7j
0 °C, 2 h
0 °C, 2 h
ꢀ20 °C. 30 min
10
11
n-Pr
7b
7k
H
a 0.4 mmol of 7 was used in each entry. b In all entries, only the exo
adduct was observed in the crude 1H NMR spectrum. c 0.2 mmol of 7
was used with 10 mol % Ho(NTf2)3, 20 mol % 6, and 20 mol % DBU.
(13) (a) Kobayashi, H.; Nie, J.; Sonoda, T. Chem. Lett. 1995, 307. (b)
Mikami, K.; Kotera, O.; Motoyama, Y.; Sakaguchi, H.; Murata, M.
Synlett 1996, 171. (c) Baudry, D. B.; Dormond, A.; Duris, F.; Bernard,
J. M.; Desmurs, J. R. J. Fluor. Chem. 2003, 121, 233. (d) Takasu, A.;
Makino, T.; Yamada, S. Macromolecules 2010, 43, 144. (e) Oshimura,
M.; Takasu, A. Macromolecules 2010, 43, 2283.
(14) The catalyst might compose oligomers and be in equilibrium.
The composition of Ho, 6, and DBU would affect the amount of the
active catalyst complex. From the experimental results, we hypothesized
that the active catalyst was predominantly generated in the case of Ho/6/
DBU = 1/2/2, which enabled us to reduce the catalyst loading.
(15) The absolute configuration of 2a was unambiguously assigned
by X-ray crystallographic analysis after conversion to p-Br-benzoate.
For details, see the Supporting Information and CCDC 925631. This
result, together with NMR analyses, was used to establish the relative
and absolute configurations of our compounds.
(17) (a) Azzouzi, A.; Perrin, B.; Sinibaldi, M.-E.; Gramain, J.-C.
Tetrahedron Lett. 1993, 34, 5451. (b) Benchekroun-Mounir, N.; Dugat,
D.; Gramain, J.-C.; Husson, H.-P. J. Org. Chem. 1993, 58, 6457. (c)
Beemelmanns, C.; Reißig, H.-U. Angew. Chem., Int. Ed. 2010, 49, 8021.
(18) Fukuyama, T.; Lin, S.-C.; Li, L. J. Am. Chem. Soc. 1990, 112,
7050.
(16) While holmium salts are rarely used in organic synthesis, they
cost the same as or even less than scandium or ytterbium salts. For
selected examples of the use of holmium catalysts in organic synthesis,
see: Trost, B. M.; Schroeder, G. M. J. Am. Chem. Soc. 2000, 122, 3785.
(19) Magnus, P.; Giles, M.; Bonnert, R.; Kim, C. S.; McQuire, L.;
Merritt, A.; Vicker, N. J. Am. Chem. Soc. 1992, 114, 4403.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 2. Alkylation for the Construction of a Quaternary
Carbon and Further Transformation to a Tetracyclic Skeleton
Figure 3. Proposed transition-state model of a holmium cata-
lyst, dienophile 7, and diene 1a complex.
In the solution of Ho(NTf2)3 and ligand 6, a peak of Ho
salt/ligand 6 = 1/2 was observed. This observed ratio is
associated with the best catalytic composition (Table 1).
The subsequent addition of DBU induced a significant
change in the MS spectrum and gave a series of peaks
derived from DBU salts. DBU was strongly suggested to
deprotonate NH of ligand. Based on these experimental
results and the high coordination number of lanthanide as
well as flexible coordination modes, we offer the hypothetical
structure of active catalyst complex shown in Figure 3: the
eight-coordinate dienophile adduct of Ho(NTf2)/(6-H)2.21
In this structure, the diene could approach from only one
side of the dienophile due to the steric barrier of the naphthyl
ring and the thiourea side chain of the ligand, and we can
rationalize the absolute configuration of 2.
Scheme 3. Other Transformations and Deprotection
In summary, we have developed a new catalytic and
enantioselective method for the synthesis of hydrocarbazoles
by the [4 þ 2] cycloaddition of silyloxyvinylindoles and
electron-deficient olefins. This reaction was catalyzed by a
novel chiral holmium complex to give adduct without the
decomposition of silyl enol ether, which should be useful
for the synthesis of various intermediates with a quaternary
carbon. Synthetic applications of the cycloadducts and a
mechanistic study of the holmium catalyst are underway.
To obtain insight into the structure of the catalyst, the
catalyst solution was monitored by ESI-TOF-MS analysis.20
Acknowledgment. We thank Prof. Ishibashi (Chiba
University) for his help with preparative HPLC, Prof.
Hou (RIKEN) for his valuable discussion on the catalyst
structure, and Prof. Masu (Chiba University) for his
support with the X-ray crystallographic analysis. This
work was supported by JSPS KAKENHI (Grant Nos.
22790007, 25460006 (SH), and 21390002, 25293001 (AN))
and the Takeda Science Foundation (SH).
(20) See the Suppporting Information. For selected discussions of the
mechanism of a lanthanide-based catalyst using ESI-MS analysis, see:
(a) Horiuchi, Y.; Gnanadesikan, V.; Ohshima, T.; Masu, H.; Katagiri,
K.; Sei, Y.; Yamaguchi, K.; Shibasaki, M. Chem.;Eur. J. 2005, 11,
5195. (b) Tosaki, S.-Y.; Hara, K.; Gnanadesikan, V.; Morimoto, H.;
Harada, S.; Sugita, M.; Yamagiwa, N.; Matsunaga, S.; Shibasaki, M. J.
ꢁ
Am. Chem. Soc. 2006, 128, 11776. (c) Comelles, J.; Pericas, A.; Moreno-
~
ꢀ
Manas, M.; Vallribera, A.; Drudis-Sole, G.; Lledos, A.; Parella, T.;
Roglans, A.; Garcıa-Granda, S.; Roces-Fernandez, L. J. Org. Chem.
ꢀ
2007, 72, 2077. (d) Mashiko, T.; Kumagai, N.; Shibasaki, M. J. Am.
Chem. Soc. 2009, 131, 14990. (e) Shen, K.; Liu, X.; Zheng, K.; Li, W.;
Hu, X.; Lin, L.; Feng, X. Chem.;Eur. J. 2010, 16, 3736.
(21) Lippard, S. J.; Russ, B. J. Inorg. Chem. 1968, 7, 1686. For
selected examples of the X-ray crystallographic analysis of a holmium
complex, see: (a) Horrocks, W. D., Jr.; Sipe, J. P., III; Luber, J. R. J. Am.
Chem. Soc. 1971, 93, 5258. (b) Kav, J.; Moore, J. W.; Glick, M. D. Inorg.
Chem. 1972, 11, 2818. (c) Arndt, S.; Beckerle, K.; Zeimentz, P. M.;
Spaniol, T. P.; Okuda, J. Angew. Chem., Int. Ed. 2005, 44, 7473. (d)
Supporting Information Available. Experimentaldetails,
substrates supply, spectral data, and supporting figures.
This material is available free of charge via the Internet at
http://pubs.acs.org.
€
Baısch, U.; Pagano, S.; Zeuner, M.; auf der Gunne, J. S.; Oeckler, O.;
Schnick, W. Organometallics 2006, 25, 3027.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX