Catalytic enantioselective intermolecular cycloaddition of diazodiketoester-derived carbonyl ylides with indoles using chiral dirhodium(II) carboxylates

Article abstract of DOI:10.1021/ol2027625

The first example of enantioselective intermolecular cycloaddition of carbonyl ylides with indoles is described. The cycloaddition of five- and six-membered carbonyl ylides derived from diazodiketoesters with N-methylindoles under catalysis by dirhodium(II) tetrakis[N-tetrachlorophthaloyl-(S)-tert- leucinate], Rh₂(S-TCPTTL)₄, gave cycloadducts in high yields and with high levels of enantioselectivity (up to 99% ee) as well as excellent exo diastereoselectivity.

Full text of DOI:10.1021/ol2027625

ORGANIC
LETTERS
2011
Vol. 13, No. 23
6284–6287
Catalytic Enantioselective Intermolecular
Cycloaddition of Diazodiketoester-
Derived Carbonyl Ylides with Indoles
Using Chiral Dirhodium(II) Carboxylates
Naoyuki Shimada, Tadashi Oohara, Janagiraman Krishnamurthi, Hisanori Nambu,
and Shunichi Hashimoto*
Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
hsmt@pharm.hokudai.ac.jp
Received October 14, 2011
ABSTRACT
The first example of enantioselective intermolecular cycloaddition of carbonyl ylides with indoles is described. The cycloaddition of five- and six-
membered carbonyl ylides derived from diazodiketoesters with N-methylindoles under catalysis by dirhodium(II) tetrakis[N-tetrachlorophthaloyl-
(S)-tert-leucinate], Rh2(S-TCPTTL)4, gave cycloadducts in high yields and with high levels of enantioselectivity (up to 99% ee) as well as excellent
exo diastereoselectivity.
Fused indolines are important synthetic targets because
they are found in a large number of biologically active
alkaloids.1 Consequently, the development of efficient
methods for the stereoselective synthesis of these molecules
continues to attract considerable attention in the field of
synthetic organic chemistry.2 Among a variety of methods,
those based on the annulation of indoles offer a distinctive
advantage since a diverse array of indoles are readily
available.3,4 In this context, the dirhodium(II) complex-
catalyzed tandem cyclic carbonyl ylide formationꢀ
1,3-dipolar cycloaddition reaction sequence5,6 has been
regarded as one of the most powerful methods for the
rapid assembly of complex oxapolycyclic indolines. Padwa
et al. demonstrated the efficient participation of the indole
C2ꢀC3 double bond as a 2π component in intramolecular
cycloadditions with pushꢀpull carbonyl ylides.7 The
power of this methodology was verified by the synthesis
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r
10.1021/ol2027625
Published on Web 11/02/2011
2011 American Chemical Society

ofcoreskeleta ofaspidosperma8 and kopsifoline alkaloids9
and by the total synthesis of (()-aspidophytine.10 Boger et
al. developed an elegant approach to (ꢀ)-vindoline and
related alkaloids based on a tandem intramolecular
[4 þ 2]/[3 þ 2] cycloaddition cascade of 1,3,4-oxadiazoles.11
Muthusamy et al. reported the first example of intermole-
cular cycloaddition of five-membered cyclic carbonyl ylides
with a variety of indoles.12
Over the past decade, enantioselective carbonyl ylide
cycloadditions catalyzed by chiral dirhodium(II) com-
plexes have been developed.13ꢀ15 Recently, we reported
catalytic enantioselective cycloadditions of six-membered
carbonyl ylides derived from 2-diazo-3,6-diketoesters with
arylacetylene, alkoxyacetylene, and styrene dipolaro-
philes.16,17 In this process, Rh2(S-TCPTTL)4 (1a)
(Figure 1),18ꢀ20 the chlorinated analogue of Rh2(S-PTTL)4
(1c)21ꢀ23 proved to be the catalyst of choice, providing the
corresponding cycloadducts in good to high yields and
with high levels of enantioselectivity (up to 99% ee) as well
as with perfect exo diastereoselectivity for styrenes. From
frontier molecular orbital (FMO) analysis for the reaction
in the absence of a catalyst, the dominant interaction was
found to be between the LUMO of the carbonyl ylide and
the HOMO of the dipolarophile,24 which predicted the
regiochemistry exactly as observed. As a logical exten-
sion of this catalytic process, we focused on the use of
indoles with high HOMO energy levels as dipolarophiles.
To the best of our knowledge, no examples of an enantio-
selective version of this sequence have been reported
to date.25 Herein, we report the first example of enantio-
selective intermolecular cycloaddition of carbonyl ylides
with indoles, in which Rh2(S-TCPTTL)4 (1a) provides
cycloadducts with high levels of enantioselectivity (up to
99% ee) and excellent exo diastereoselectivity.
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Chem. Soc. 2006, 128, 10596–10612. (d) Kato, D.; Sasaki, Y.; Boger,
D. L. J. Am. Chem. Soc. 2010, 132, 3685–3687. (e) Sasaki, Y.; Kato, D.;
Boger, D. L. J. Am. Chem. Soc. 2010, 132, 13533–13544.
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Lett. 1997, 38, 6471–6472. (b) Hodgson, D. M.; Stupple, P. A.; Johnstone,
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Pierard, F. Y. T. M.; Labande, A. H.; Johnstone, C. Chem.;Eur. J. 2001,
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Natl. Acad. Sci. U.S.A. 2004, 101, 5450–5454. (f) Hodgson, D. M.; Glen,
R.; Redgrave, A. J. Tetrahedron: Asymmetry 2009, 20, 754–757.
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C.; Watanabe, N.; Hashimoto, S. J. Am. Chem. Soc. 1999, 121, 1417–
1418. (b) Kitagaki, S.; Yasugahira, M.; Anada, M.; Nakajima, M.;
Hashimoto, S. Tetrahedron Lett. 2000, 41, 5931–5935. (c) Tsutsui, H.;
Shimada, N.; Abe, T.; Anada, M.; Nakajima, M.; Nakamura, S.;
Nambu, H.; Hashimoto, S. Adv. Synth. Catal. 2007, 349, 521–526.
(15) Suga and co-workers reported enantioselective 1,3-dipolar
cycloadditions of carbonyl ylides using chiral Lewis acid catalysts: (a)
Suga, H.; Inoue, K.; Inoue, S.; Kakehi, A. J. Am. Chem. Soc. 2002, 124,
14836–14837. (b) Suga, H.; Ishimoto, D.; Higuchi, S.; Ohtsuka, M.;
Arikawa, T.; Tsuchida, T.; Kakehi, A.; Baba, T. Org. Lett. 2007, 9,
4359–4362. (c) Suga, H.; Higuchi, S.; Ohtsuka, M.; Ishimoto, D.;
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Baba, T. Tetrahedron 2010, 66, 3070–3089.
Figure 1. Chiral dirhodium(II) complexes.
On the basis of our previous work,16 we initially ex-
plored the cycloaddition ofa six-membered cyclic carbonyl
ylide derived from 2-diazo-3,6-diketoester 2a with 2 equiv
of N-methylindole (3a) in the presence of 1 mol % of
Rh2(S-TCPTTL)4 (1a).18ꢀ20 As expected from FMO ana-
lysis (see Supporting Information (SI)), the reaction in R,
R,R-trifluorotoluene proceeded smoothly at rt to give exo
cycloadduct 4a as the sole product in 81% yield (Table 1,
entry 1). The exo stereochemistry of 4a was established by
a NOESY experiment (SI). The enantioselectivity of this
reaction was determined to be 99% ee by HPLC analysis
(16) Shimada, N.; Anada, M.; Nakamura, S.; Nambu, H.; Tsutsui,
H.; Hashimoto, S. Org. Lett. 2008, 10, 3603–3606.
(17) (a) Shimada, N.; Hanari, T.; Kurosaki, Y.; Takeda, K.; Anada,
M.; Nambu, H.; Shiro, M.; Hashimoto, S. J. Org. Chem. 2010, 75, 6039–
6042. (b) Shimada, N.; Hanari, T.; Kurosaki, Y.; Anada, M.; Nambu,
H.; Hashimoto, S. Tetrahedron Lett. 2010, 51, 6572–6575.
(18) (a) Yamawaki, M.; Tsutsui, H.; Kitagaki, S.; Anada, M.;
Hashimoto, S. Tetrahedron Lett. 2002, 43, 9561–9564. (b) Tanaka, M.;
Kurosaki, Y.; Washio, T.; Anada, M.; Hashimoto, S. Tetrahedron Lett.
2007, 48, 8799–8802. (c) Anada, M.; Tanaka, M.; Shimada, N.; Nambu,
H.; Yamawaki, M.; Hashimoto, S. Tetrahedron 2009, 65, 3069–3077.
(19) Lindsay, V. N. G.; Lin, W.; Charette, A. B. J. Am. Chem. Soc.
2009, 131, 16383–16385.
(22) For a practical synthesis of Rh2(S-PTTL)4 (1c), see: (a) Tsutsui,
H.; Abe, T.; Nakamura, S.; Anada, M.; Hashimoto, S. Chem. Pharm.
Bull. 2005, 53, 1366–1368. For an immobilization of 1c, see:(b) Davies,
H. M. L.; Walji, A. M. Org. Lett. 2005, 7, 2941–2944. (c) Takeda, K.;
Oohara, T.; Anada, M.; Nambu, H.; Hashimoto, S. Angew. Chem., Int.
Ed. 2010, 49, 6979–6983.
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Chem. Soc. 2009, 131, 7230–7231.
(24) Koyama, H.; Ball, R. G.; Berger, G. D. Tetrahedron Lett. 1994,
35, 9185–9188.
(20) Reddy and Davies developed dirhodium(II) tetrakis[N-tetra-
chlorophthaloyl]-(S)-(1-adamantyl)glycinate], Rh2(S-TCPTAD)4. Reddy,
R. P.; Davies, H. M. L. Org. Lett. 2006, 8, 5013–5016.
(21) (a) Watanabe, N.; Ogawa, T.; Ohtake, Y.; Ikegami, S.; Hashimo-
to, S. Synlett 1996, 85–86. (b) Saito, H.; Oishi, H.; Kitagaki, S.; Nakamura,
S.; Anada, M.; Hashimoto, S. Org. Lett. 2002, 4, 3887–3890. (c) Minami,
K.; Saito, H.; Tsutsui, H.; Nambu, H.; Anada, M.; Hashimoto, S. Adv.
Synth. Catal. 2005, 347, 1483–1487.
(25) Recently, we reported asymmetric intramolecular carbonyl ylide
cycloaddition of diazo imides containing a tethered indoles, in which
Rh2(S-TCPTTL)4 (1a) provided cycloadducts in moderate yields and
with enantioselectivities of up to 66% ee. Nambu, H.; Hikime, M.;
Krishnamurthi, J.; Kamiya, M.; Shimada, N.; Hashimoto, S. Tetrahe-
dron Lett. 2009, 50, 3675–3678.
(26) The preferred absolute stereochemistry of cycloadducts was not
determined.
Org. Lett., Vol. 13, No. 23, 2011
6285

poor diastereoselectivity (49% yield, exo/endo = 57:43,
eq 3), though good enantioselectivities were observed
(4b: 82% ee; 5b: 79% ee). Clearly, the indole N-substituent
has a profound effect on diastereoselectivity as well as on
the efficiency of the cycloaddition.
Table 1. Enantioselective Intermolecular Cycloaddition of 2a
with 3a Catalyzed by 1aꢀca
Using Rh2(S-TCPTTL)4 (1a) as a catalyst, we then
explored the use of phenyl-substituted diazodiketoester
2b and a range of indole dipolarophiles (Table 2). The
reaction of 2b with 3a afforded exclusively exo cycloadduct
4c in 83% yield with 97% ee(entry 1). Aside from complete
exo diastereoselectivity, excellent levels of asymmetric
induction (97ꢀ99% ee) were consistently observed with
either electron-donating or -withdrawing groups at the C5
position on the indole ring (entries 2ꢀ4). The use of 4- or
7-methyl-substituted N-methylindoles 3g and 3h resulted
in high yields and enantioselectivities (84ꢀ85% yields,
94ꢀ95% ee, entries 5 and 6).
entry
Rh(II) catalyst
solvent
yield(%)b
ee(%)c
1
2
3
4
5
Rh2(S-TCPTTL)4 (1a)
Rh2(S-TFPTTL)4 (1b)
Rh2(S-PTTL)4 (1c)
Rh2(S-TCPTTL)4 (1a)
Rh2(S-TCPTTL)4 (1a)
CF3C6H5
CF3C6H5
CF3C6H5
toluene
81
77
71
75
33
99
97
89
93
87
CH2Cl2
a All reactions were carried out as follows: a solution of 2a (48.0 mg,
0.2 mmol) and 3a (2 equiv) in CF3C6H5 (1 mL) was added over 1 h to a
solution of Rh(II) catalyst (1 mol %) in CF3C6H5 (1 mL) at rt. b Isolated
yield. c Determined by HPLC.
Table 2. Enantioselective Cycloaddition of 2a and 2b with 3a,
dꢀh Catalyzed by Rh2(S-TCPTTL)4 (1a)a
using a Daicel Chiralcel OD-H column.26 We next evalu-
ated the performance of Rh2(S-TFPTTL)4 (1b)27 and
Rh2(S-PTTL)4 (1c).21ꢀ23 Although complete exo diaster-
eoselectivity was obtained in both cases, product yields
and enantioselectivities were lower than those found with
1a (entries 2 and 3). A survey of solvents with 1a revealed
that R,R,R-trifluorotoluene was the optimal solvent for
this transformation (entries 1 vs 4 and 5). It is notable that
the use of Rh2(OAc)4 as an achiral catalyst gave a 35:65
mixture of exo and endo cycloadducts 4a and 5a in 57%
combined yield (eq 1). While the mechanistic profile for
this reaction is not clear at this time, these results suggest
that the presence of phthalimido groups in the bridging
ligands of dirhodium(II) catalysts 1aꢀc is responsible
for the complete exo selectivity.14a,c,16,19,23 We then exam-
ined the effects of N-substitution of the indole ring. The
use of indole 3b bearing a strongly electron-withdrawing Ts
group failed to give the corresponding cycloadducts (eq 2).
diazodiketoester
R1
dipolarophile
R2
product
entry
yield(%)b ee(%)c
1
2
3
4
5
6
2b
2a
2a
2a
2a
2a
C6H5
Me
Me
Me
Me
3a
3d
3e
3f
3g
3h
H
4c
4d
4e
4f
4g
4h
83
86
80
76
85
84
97
97
97
99
95
94
5-MeO
5-Me
5-Br
4-Me
7-Me
Me
a All reactions were performed on a 0.2 mmol scale with 2 equiv of
dipolarophile. b Isolated yield. c Determined by HPLC.
Armed with these positive results, we next examined the
cycloaddition with a five-membered cyclic carbonyl ylide
for the construction of a hexahydrocarbazole skeleton,
which is a common structural unit found in a diverse array
ofbiologically interesting naturalproducts. While avariety
of intermolecular cycloadditions with five-membered
cyclic carbonyl ylides using achiral dirhodium(II) catalysts
have been reported,5a,b,dꢀf,i,12 its enantioselective variants
using chiral dirhodium(II) catalysts are quite limited.14a,c
The reaction of diazodiketoester 6a29 carrying a gem-
dimethyl group at C4 with 3 equiv of N-methylindole
(27) (a) Tsutsui, H.; Yamaguchi, Y.; Kitagaki, S.; Nakamura, S.;
Anada, M.; Hashimoto, S. Tetrahedron: Asymmetry 2003, 14, 817–821.
(b) Anada, M.; Tanaka, M.; Washio, T.; Yamawaki, M.; Abe, T.;
Hashimoto, S. Org. Lett. 2007, 9, 4559–4562. (c) Shimada, N.; Nakamura,
S.; Anada, M.; Shiro, M.; Hashimoto, S. Chem. Lett. 2009, 38, 488–489.
(28) The reaction at rt gave a complex mixture of products.
(29) It was necessary to block the C4 position of 6 with two sub-
stituents in order for the cycloaddition to occur without the formation of
furanones via proton transfer. (a) Padwa, A.; Chinn, R. L.; Hornbuckle,
S. F.; Zhang, Z. J. J. Org. Chem. 1991, 56, 3271–3278. (b) Padwa, A.;
Curtis, E. A.; Sandanayaka, V. P. J. Org. Chem. 1997, 62, 1317–1325.
The reaction of 2a with an unmasked indole (3c) at
60 °C28 resulted in only modest product yield as well as
6286
Org. Lett., Vol. 13, No. 23, 2011

82% ee for 7b), though a considerable drop in diastereos-
electivity was observed (7b/8b = 87:13, entry 4 vs 1). Not
unexpectedly, the reaction conducted at 60 °C greatly
improved the product yield as well as diastereo- and
enantioselectivity (88% yield, 7b/8b = 92:8, 92% ee for
7b, entry 5). These results suggest that immediate trapping
of the catalyst-bound carbonyl ylide by the indole dipolaro-
phile at a high temperature is crucial for a high yield as well
as high levels of enantio- and diastereocontrol. It is note-
worthy that the reaction of 6b with phenylacetylene (9)
under catalysis by Rh2(S-TCPTTL)4 (1a) at 60°C afforded
the corresponding cycloadduct 10 in 51% yield and with
only poor enantioselectivity (10% ee, eq 4).16 These find-
ings clearly demonstrate that N-methylindoles are parti-
cularly effective dipolarophiles for the LUMO-controlled
carbonyl ylide cycloaddition catalyzed by 1a.
Table 3. Enantioselective Cycloaddition of 6a and 6b with 3a
Catalyzed by Rh2(S-TCPTTL)4 (1a)a
diazodiketoester
R
ee (%)c
entry
temp(°C) yield(%)b
7:8
7
8
1d
2
6a
6a
6a
6b
6b
Me
Me
Me
-CH2CH2-
-CH2CH2-
23
60
80
23
60
40
84
80
69
88
>99:1
>99:1
>99:1
87:13 82
92:8 92
50
61
59
ꢀ
ꢀ
ꢀ
2
3
4e
5
2
a All reactions were performed on a 0.2 mmol scale with 2 equiv (for
6b) or 3 equiv (for 6a) of 3a. b Combined yield of 7 and 8. c Determined by
HPLC. d After the addition of 6a and 3a over 1 h, the reaction mixture
was stirred for an additional 23 h. e After the addition of 6b and 3a over 1
h, the reaction mixture was stirred for an additional 7 h.
In summary, we have developed a highly enantio- and
diastereoselective cycloaddition of carbonyl ylides derived
from diazodiketoesters with N-methylindole dipolaro-
philes under the influence of Rh2(S-TCPTTL)4. This is
the first example of the use of indoles as dipolarophiles in
enantioselective intermolecular carbonyl ylide cycloaddi-
tion reactions. The present catalytic protocol is applicable
not only to six-membered cyclic carbonyl ylides but also to
the five-membered carbonyl ylide containing a cyclopro-
pane ring, providing functionalized indoline derivatives
including a hexahydrocarbazole in optically active forms.
Further application of this methodology to asymmetric
synthesis of biologically active alkaloids as well as mechan-
istic and stereochemical studies are currently in progress.
(3a) in the presence of1 mol % ofRh2(S-TCPTTL)4 (1a) at
rt required a significantly longer time (24 h) to reach
completion, probably due to steric hindrance imposed by
the dimethylgroups, and provided exclusivelyexo cycload-
duct 7a in 40% yield with 50% ee (Table 3, entry 1).
Gratifyingly, increasing the reaction temperature greatly
enhanced product yields and slightly improved enantios-
electivities (80ꢀ84% yields, 59ꢀ61% ee), though 60 °C
was found to be the temperature limit (entries 2 and 3).
These observations indicate that Rh2(S-TCPTTL)4 (1a) is
bound to the carbonyl ylide during the cycloaddition
process even at higher temperatures, because the carbonyl
ylide detached from the catalyst is achiral.13a,14a At this
stage, we envisaged that a carbonyl ylide containing a
sterically less-demanding cyclopropane moiety instead of
the gem-dimethyl group might react smoothly with the
dipolarophile.30 Indeed, the reaction of diazodiketoester
6b with 3a proceeded at rt to completion within 8 h and led
toa higher product yield and enantioselectivity (69% yield,
Acknowledgment. This research was supported, in part,
by a Grant-in-Aid for Scientific Research on Innovative
Areas “Organic Synthesis Based on Reaction Integration”
(No. 2105) from the Ministry of Education, Culture,
Sports, Science and Technology, Japan. We thank Ms. S.
Oka, and M. Kiuchi of the Center for Instrumental
Analysis at Hokkaido University for technical assistance
in the MS and elemental analyses.
(30) The effectiveness of the intermolecular cycloaddition of five-
membered carbonyl ylides derived from R-diazoketones containing a
cyclopropane ring has been demonstrated by the synthesis of biologi-
cally active sesquiterpenoids including illudins, ptaquilosin, pterosins,
and acylfulvenes. (a) Kinder, F. R., Jr.; Bair, K. W. J. Org. Chem. 1994,
59, 6965–6967. (b) Padwa, A.; Curtis, E. A.; Sandanayaka, V. P. J. Org.
Chem. 1996, 61, 73–81. (c) McMorris, T. C.; Hu, Y.; Yu, J.; Kelner, M. J.
Chem. Commun. 1997, 315–316. (d) Padwa, A.; Curtis, E. A.; Sandanayaka,
V. P. J. Org. Chem. 1997, 62, 1317–1325. (e) McMorris, T. C.; Staake,
M. D.; Kelner, M. J. J. Org. Chem. 2004, 69, 619–623.
Supporting Information Available. Experimental de-
tails and spectroscopic data. This material is available
free of charge via Internet at http://pubs.acs.org.
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