Enantioselective cyclopropanation of indoles: Construction of all-carbon quaternary stereocenters

Article abstract of DOI:10.1021/ol302388t

The first enantioselective copper-catalyzed cyclopropanation of N-acyl indoles is described. Using carbohydrate-based bis(oxazoline) ligands (glucoBox), the products were obtained in up to 72% ee. Cyclopropanation of N-Boc 3-methyl indole yielded a product with an all-carbon quaternary stereocenter, which is a valuable building block for the synthesis of indole alkaloids: Deprotection and rearrangement gave a tricyclic hemiaminal ester in 96% ee, which was subsequently employed as a key intermediate for the synthesis of (-)-desoxyeseroline.

Full text of DOI:10.1021/ol302388t

ORGANIC
LETTERS
2012
Vol. 14, No. 19
4990–4993
Enantioselective Cyclopropanation
of Indoles: Construction of All-Carbon
Quaternary Stereocenters
€
Gulsum Ozuduru, Thea Schubach, and Mike M. K. Boysen*
€ €
€
Institute of Organic Chemistry, Gottfried-Wilhelm-Leibniz University of Hannover,
D-30167 Hannover, Germany
mike.boysen@oci.uni-hannover.de
Received July 9, 2012
ABSTRACT
The first enantioselective copper-catalyzed cyclopropanation of N-acyl indoles is described. Using carbohydrate-based bis(oxazoline) ligands
(glucoBox), the products were obtained in up to 72% ee. Cyclopropanation of N-Boc 3-methyl indole yielded a product with an all-carbon
quaternary stereocenter, which is a valuable building block for the synthesis of indole alkaloids: Deprotection and rearrangement gave a tricyclic
hemiaminal ester in 96% ee, which was subsequently employed as a key intermediate for the synthesis of (ꢀ)-desoxyeseroline.
Chiral cyclopropanes are important motifs in natural
products and pharmaceuticals, and cyclopropyl units with
donor and acceptor substituents1 can be transformed into
valuable synthetic intermediates via ring opening or ring
expansion. Unsurprisingly considerable effort has gone
into the development of stereoselective routes toward these
compounds;2 one convenient approach is the copper-
catalyzed cyclopropanation of alkenes using diazo com-
pounds. Chiral bis(oxazoline) ligands (Box),3 such as (S)-1
(Figure 1), are powerful tools for this process.4 Carbohy-
drates, which are available in large amounts and diverse
architectures, are interesting but comparatively rarely used
starting materials for the design of chiral ligands.5 In the
course of our work we have introduced Ac glucoBox (2)
based on D-glucosamine (Figure 1), which gave 82% ee in
the cyclopropanation of styrene with ethyl diazoacetate.6
To optimize the pyranosidic scaffold for this reaction,
ligand family 3-O-R1 glucoBox (3aꢀg) was designed.7
The asymmetric induction of ligands 3aꢀg was strongly
dependent on the steric demand and type of the 3-O
residues with small acyl-based groups giving the best
results (up to 95% ee with 3g).
€
(5) Reviews: (a) Lehnert, T.; Ozuduru, G.; Grugel, H.; Albrecht, F.;
€
Telligmann, S. M.; Boysen, M. M. K. Synthesis 2011, 2685. (b) Wood-
ꢀ
ꢁ
ward, S.; Dieguez, M.; Pamies, O. Coord. Chem. Rev. 2010, 254, 2007. (c)
Benessere, V.; Del Litto, R.; De Roma, A.; Ruffo, F. Coord. Chem. Rev.
2010, 254, 390. (d) Boysen, M. M. K. Chem.;Eur. J. 2007, 13, 8648. (e)
(1) (a) Yu, M.; Pagenkopf, B. L. Tetrahedron 2005, 61, 321. (b)
Reissig, H.; Zimmer, R. Chem. Rev. 2003, 103, 1151. (b) Wong,
H. N. C.; Hon, M.-Y.; Tse, C.-W.; Yip, Y.-C.; Tanko, J.; Hudlicky, T.
Chem. Rev. 1989, 89, 165.
(2) Reviews: (a) Pellissier, H. Tetrahedron 2008, 64, 7041. (b) Lebel,
H.; Marcoux, J.-F.; Molinaro, C.; Charette, A. B. Chem. Rev. 2003, 103,
977. (c) Doyle, M. P.; Forbes, D. C. Chem. Rev. 1998, 98, 911.
(3) Reviews: (a) Desimoni, G.; Faita, G.; Jørgensen, K. A. Chem.
Rev. 2006, 106, 3561. (b) McManus, H. A.; Guiry, P. J. Chem. Rev. 2004,
104, 4151.
ꢀ
ꢁ
Dieguez, M.; Pamies, O.; Claver, C. Chem. Rev. 2004, 104, 3189. (f) Hale,
K. J. In Second Supplement to the Second Edition of Rodd’s Chemistry of
Carbon Compounds, Vol. 1E/F/G; Sainsbury, M., Ed.; Elsevier: Am-
sterdam, 1993; Chapter 23b, p 273.
(6) Irmak, M.; Groschner, A.; Boysen, M. M. K. Chem. Commun.
2007, 177.
(7) (a) Minuth, T.; Boysen, M. M. K. Synlett 2008, 1483. (b) Minuth,
T.; Irmak, M.; Groschner, A.; Lehnert, T.; Boysen, M. M. K. Eur. J.
Org. Chem. 2009, 997. (c) Minuth, T.; Boysen, M. M. K. Beilstein J. Org.
Chem. 2010, 6, DOI: 10.3762/bjoc.6.23
(4) Evans, D. A.; Woerpel, K. A.; Hinman, M. M.; Faul, M. M. J.
Am. Chem. Soc. 1991, 113, 726.
r
10.1021/ol302388t
Published on Web 09/25/2012
2012 American Chemical Society

Table 1. Cyclopropanation of N-Acyl Indoles 4a,ba
ligand
6
temp
yield
[%]
ee (exo)
entry
3-O-R1
[°C]
R2
exo/endod
[%]
1
3g formyl
3a Ac
rt
Ac
Ac
75b
71b
84:16
82:18
nd
34e
34e
45f
55f
45f
38f
rac.f
53e
51e
61e
45e
69f
72f
55f
2
rt
3
3g formyl
3a Ac
rt
Boc (67)c
Boc (70)c
Boc (54)c
Boc (70)c
Boc (68)c
4
rt
nd
5
3b Bz
rt
nd
Figure 1. Conventional Box ligand (S)-1, carboydrate-based
ligands Ac glucoBox (2) and 3-O-R1 glucoBox (3aꢀg).
6
3c Piv
rt
nd
7
2
ꢀ
rt
nd
8
3a Ac
3a Ac
3a Ac
3a Ac
3a Ac
3a Ac
3a Ac
10
0
Ac
Ac
Ac
Ac
75b
76b
56b
9b
87:13
92:8
>99:1
>99:1
nd
Thus optimized ligand 3-O-formyl glucoBox (3g) was
obtained, which was suitable even for challenging aliphatic
olefins:with1-nonene, 90% eewas obtained, andthetrans-
product was used in the stereoselective synthesis of the
natural product grenadamide.8 Recently ligands 2 and 3
were employed by Reddy in copper(II)-catalyzed Henry
reactions9 and FriedelꢀCrafts alkylations.10
9
10
11
12
13
14
ꢀ5
ꢀ10
10
0
Boc (76)c
Boc (57)c
Boc (62)c
nd
ꢀ10
nd
a Ligand (3.3 mol %), CuOTf 0.5C6H6 (3 mol %), 4 (1 equiv), 5
3
(2.5 equiv). b Combined yield of 6 after chromatography. c Yield for of exo-
6b; product contains 0.06ꢀ0.4 equiv of diethyl fumarate; yield calculated
from 1H NMR ratio of exo-6b to fumarate. d Determined after separation
of the diastereomers. e Determined by GC. f Determined by HPLC.
In contrast to other electron-rich heterocycles such as
furans, benzofurans, and pyrrols, indoles have rarely been
employed in cyclopropanation reactions.11 The first ex-
amples with achiral copper catalysts were reported by
Welstead,12 Wenkert,13 and Lehner,14 followed by later
reports by Reiser,15 Yan,16 and Wee.17 Recently, cyclo-
propanation products of 3-substituted indoles were used
as key intermediates in syntheses of complex indole
alkaloids18 containing quaternary stereocenters: Qin used
intramolecular reactions of tryptamine and tryptophol
derivatives for racemic syntheses of communesin19
and minfiensine.20 Diastereoselective examples were re-
ported by Spino and again by Qin, who performed
cyclopropanations on chiral indole derivatives for the
syntheses of aspidofractinine21 and ardeemin.22 To the
best of our knowledge, no enantioselective variant of this
transformation has been described so far. Now we report
the first enantioselective cyclopropanation of N-acyl in-
doles using copper(I) triflate and carbohydrate ligands 2
and 3.
At the outset, we tested the reaction of N-acetyl indole
(4a) with ethyl diazoacetate (5) at rt in the presence of
CuOTf and ligand 3g or 3a (Table 1, entries 1 and 2), which
gave exo-6a and endo-6a (80:20) in 70ꢀ75% yield and 34%
ee for exo-6a. Products 6b from N-Boc indole (4b) were
isolated together with fumarate and maleate esters, which
are formed by decomposition of ethyl diazoacetate (5).
While exo-6b and endo-6b were separable by chromato-
graphy, the byproduct could not be removed, which pre-
vented the exact determination of yield and the exo/endo
ratio for reactions with substrate 4b. The yields given in
(8) Minuth, T.; Boysen, M. M. K. Synthesis 2010, 2799.
(9) Reddy, B. V. S.; George, J. Tetrahedron: Asymmetry 2011, 22,
1169.
(10) George, J.; Reddy, B. V. S. Org. Biomol. Chem. 2012, 10, 4731.
(11) Davis, H. M. L.; Hedley, S. J. Chem. Soc. Rev. 2007, 36, 1109.
(12) Welstead, W. J., Jr.; Stauffer, H. F., Jr.; Sancilio, L. F. J. Med.
Chem. 1974, 17, 544.
(13) Wenkert, E.; Alonso, M. E.; Gottlieb, H. E.; Sanchez, E. L. J.
Org. Chem. 1977, 42, 3945.
(14) Keller, H.; Langer, E.; Lehner, H. Monatsh. Chem. 1977, 108,
123.
1
(15) Gnad, F.; Poleschak, M.; Reiser, O. Tetrahedron Lett. 2004, 45,
4277.
Table 1 refer to exo-6b and were caclulated from the H
NMR ratio of exo-6b and diethyl fumarate. HPLC analy-
sis permitted the determination of the ee for exo-6b: ligand
3g yielded 45% ee, while 3a with a sterically more
(16) Zhang, X.-J.; Liu, S.-P.; Yan, M. Chin. J. Chem. 2008, 26, 716.
(17) Zhang, B.; Wee, A. G. H. Chem. Commun. 2008, 4837.
(18) Zhang, D.; Song, H.; Qin, Y. Acc. Chem. Res. 2011, 44, 447.
(19) (a) Yang, J.; Song, H.; Wang, J.; Qin, Y. Org. Lett. 2006, 8, 2187.
(b) Yang, J.; Wu, H.; Shen, L.; Qin, Y. J. Am. Chem. Soc. 2007, 129,
13794.
(21) Gagnon, D.; Spino, C. J. Org. Chem. 2009, 74, 6035.
(22) (a) Song, H.; Yang, J.; Qin, Y. Org. Lett. 2006, 8, 6011. (b) He,
B.; Song, H.; Du, Y.; Qin, Y. J. Org. Chem. 2009, 74, 298.
(20) Shen, L.; Zhang, M.; Wu, Y.; Qin, Y. Angew. Chem., Int. Ed.
2008, 47, 3618.
Org. Lett., Vol. 14, No. 19, 2012
4991

demanding 3-O-Ac group produced exo-6b in 55% ee.
Ligands 3b,c with largerBzand Piv groupsled todecreased
ee (entries 5 and 6). Thus the steric demand of the 3-O
substituents in ligands 3 has once again direct influence on
stereoselectivity.7c,8 Ligand 2, lacking the 4,6-O-benzyli-
dene acetal units of 3a, led to a complete loss of stereo-
selectivity (entry 7). This striking difference in the asym-
metric induction of ligands 3a and 2 may be explained
by the distinctly different pyranoside conformations these
ligands adopt due to the presence or absence of the
benzylidene acetal units.7b,c
To improve the ee for substrates 4a and 4b, reactions
with ligand 3a were performed at lower temperature. For
N-acetyl indole (4a), a decrease from rt to ꢀ5 °C led to an
improved exo/endo ratio and ee (entries 8ꢀ10): at ꢀ5 °C
exo-6a was obtained in 61% ee and almost diastereomeri-
cally pure form. Lower temperatures resulted in a severely
reduced yield and stereoselectivity (entry 11). Cyclopropa-
nation of N-Boc indole (4b) at lower temperatures also
improved the ee: while due to fumarate and maleate
byproduct only a calculated yield was determined, HPLC
analysis of exo-6b showed an increase of the enantioselec-
tivity to 72% ee, when the temperature was lowered from
to 0 °C (entries 12ꢀ14). However at ꢀ10 °C the stereo-
selectivity dropped to 55% ee.
after removal of the N-acetates and the ethyl esters, as was
demonstrated by Wenkert for a related racemic example.13
At rt and 10 °C the reaction of 7a produced exo-8a and
endo-8a in modest diastereoselectivity, moderate yield, and
48% ee and 56% ee respectively (entries 1 and 2). A further
decrease in temperature led to strikingly improved exo/
endo ratios, albeit at the expense of the yield, while up to
70% ee was observed.
In the study from Table 1, N-Boc protected indole 4b
had led to a higher ee than its acetylated counterpart 4a, so
we next examined the reaction of N-Boc 3-methyl indole
(7b). Unfortunately, the corresponding cyclopropanes 8b
were again obtained together with fumarate and malonate
impurities that were impossible to remove. Therefore the
raw cyclopropanation product exo-8b was directly trans-
formed into hemiaminal ester 13 (Scheme 1): Acidic re-
moval of the Boc group yielded imine 11 via ring opening
of donorꢀacceptor cyclopropane intermediate 9, and cleav-
age of the ethyl ester24 in 11 gave acid 12, which sponta-
neously cyclized to yield hemiaminal ester 13.
Scheme 1. Transformation of exo-8b into Hemiaminal Ester 13
After these promising initial results we decided to try the
enantioselective cyclopropanation of N-acetyl 3-methyl
indole (7a) with ligand 3a (Table 2). This reaction is
attractive as the diastereomeric products exo-8a and
endo-8a contain an all-carbon quaternary stereocenter,
which are challenging to construct in an asymmetric
manner.23 These cyclopropanes can be further elaborated
into tricyclic hemiaminal ester 13 by cyclopropane opening
Table 2. Cyclopropanation of N-Acetyl 3-Methyl Indole (7a)a
Following this strategy, we studied the enantioselective
synthesis of 13 (Table 3). Cyclopropanation of 7b at rt
using 3-O-Ac glucoBox (3a) followed by N-deprotection
gave imine 11 in modest yield. To our delight, saponifica-
tion of 11 gave (ꢀ)-13 in 87% ee and 63% yield (entry 1).
For comparison, 3-O-formyl ligand 3g and conventional
Box ligand (S)-1 were also tested. With these 13 was
obtained in 82% ee. While 3g and 3a gave the (ꢀ)-
enantiomer of 13, ligand (S)-1 led to (þ)-13 (entries 2
and 3). The formation of (ꢀ)- and (þ)-13 with ligands 3a,g
8a
temp
yield
[%]b
ee (exo)
entry
[°C]
exo/endod
[%]e
1
2
3
4
5
rt
66
65:35
67:33
71:29
>99:1
>99:1
48
56
52
70
71
10
52
0
40c
29c
17c
(23) Reviews: (a) Das, J. P.; Marek, I. Chem. Commun. 2011, 4593.
(b) Steven, A.; Overman, L. E. Angew. Chem., Int. Ed. 2007, 46, 5488. (c)
Cozzi, P. G.; Hilgraf, R.; Zimmermann, N. Eur. J. Org. Chem. 2007,
5969. (d) Trost, B. M.; Jiang, C. Synthesis 2006, 369. (e) Christoffers, J.;
Baro, A. Adv. Synth. Catal. 2005, 347, 1473. (f) Denissova, I.; Barriault,
L. Tetrahedron 2003, 59, 10105. (g) Corey, E. J.; Guzman-Perez, A.
Angew. Chem., Int. Ed. 1998, 37, 388.
ꢀ10
ꢀ20
a Ligand (3.3 mol %), CuOTf 0.5C6H6 (3 mol %), 7a (1 equiv),
3
5 (2.5 equiv). b Combined yield of 8a after chromatography. c Incomplete
conversion, reisolation 7a. d Determined after separation of diastereo-
mers. e Determined by GC.
(24) Ishibashi, H.; Mita, N.; Matsuba, N.; Kubo, T.; Nakanishi, M.;
Ikeda, M. J. Chem. Soc., Perkin Trans. 1 1992, 2821.
4992
Org. Lett., Vol. 14, No. 19, 2012

Table 3. Asymmetric Synthesis of Hemiaminal Ester 13 via
Enantioselective Cyclopropanation of N-Boc Indole 7ba
Scheme 2. Synthesis of (ꢀ)-Desoxyeseroline (14) from 13
The high stereoselectivity obtained for 13 makes the
reaction sequence described above a highly useful ap-
proach toward indole alkaloids comprising a pyrrolo-
indoline core, i.e. desoxyeseroline,25 esermethole,26 and
physostigmine:26 following a route previously described
by Ikeda27 for a racemic synthesis of esermethole,
(ꢀ)-desoxyeseroline (14) was obtained in good overall
yield from hemiaminal ester 13 via N-methylation28 and
aminolysisfollowed by hydride reduction29 (Scheme2). All
spectroscopical data of 14 were in good agreement with the
reported ones,25 the optical purity of 14 (92% ee) was
determined by 1H NMR using the dirhodium method.30
In summary we have reported the first enantioselective
copper-catalyzed cyclopropanation of indoles. N-Boc in-
dole 4b gave exo-6b in up to 72% ee, while 3-substituted
N-Boc indole 7b provided 13 via exo-8b in excellent 96% ee.
Finally, the high utility of this process for indol alkaloid
synthesis was demonstrated by the stereoselective synthe-
sis of (ꢀ)-desoxyeseroline (14) from hemiaminal ester 13.
Studies on further applications are currently underway in
our laboratories.
ligand
13
11
temp
yield
[%]b
yield
[%]
ee
entry
3-O-R1
[°C]
[%]c
1
2
3
4
5
6
7
3a
Ac
rt
17
14
20
36
61
36
11
63
78
99
75
71
71
90
87 (ꢀ)
82 (ꢀ)
82 (þ)
94 (ꢀ)
96 (ꢀ)
97 (ꢀ)
92 (ꢀ)
3g
formyl
ꢀ
rt
(S)-1
3a
rt
Ac
10
0
3a
Ac
3a
Ac
ꢀ10
3a
Ac
ꢀ20
a Ligand (3.3 mol %), CuOTf 0.5C6H6 (3 mol %), 7b (1 equiv),
3
5 (2.5 equiv). b Isolated yield over two steps from 7b. c Determined by GC.
and (S)-1 respectively was expected, as our carbohydrate
ligands and (S)-1 produced cyclopropanes from styrene in
opposite configurations as well. Again, the ee of 13 was
substantially increased, when the temperature was reduced
from rt to ꢀ10 °C (entries 4ꢀ6) while lower temperatures
were detrimental to yield and ee (entry 7). Cyclopropanation
at 0 °C in the presence of 3a gave 11 in 61% yield from indole
7b, and hemiaminal ester 13 was obtained in 71% yield and
excellent 96% ee after deprotection of 11 (entry 5).
Acknowledgment. This work was generously funded by
the German Research Foundation (DFG) (Grant BO
1938/2-2) and the Volkswagen Foundation. M.M.K.B.
thanks the DFG for a Heisenberg Stipend (Grant BO
1938/4-1). The authors thank Dr. Tanja Gaich and Prof.
Dr. Helmut Duddeck (both from the Institute of Organic
Chemistry, Leibniz University of Hannover, Germany) for
helpful discussions.
(25) Stereoselective syntheses of desoxyeseroline: (a) Kawahara, M.;
Nishida, A.; Nakagawa, M. Org. Lett. 2000, 2, 675. (b) Espejo, V. R.; Li,
X.-B.; Rainier, J. D. J. Am. Chem. Soc. 2010, 132, 8282. (c) Lim, H. J.;
RajanBabu, T. V. Org. Lett. 2011, 13, 6596.
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eomeric examples: (a) Takano, S.; Goto, E.; Hirama, M.; Ogasawara,
K. Chem. Pharm. Bull. 1982, 30, 2641. (b) Tanaka, K.; Taniguchi, T.;
Ogasawara, K. Org. Lett. 2000, 2, 2757. (c) Huang, A.; Kodanko, J. J.;
Overman, L. E. J. Am. Chem. Soc. 2004, 126, 14043. Enantioselective
examples: (d) Lee, T. B. K.; Wong, G. S. K. J. Org. Chem. 1991, 56, 872.
(e) Ashimori, A.; Matsuura, T.; Overman, L. E.; Poon, D. E. J. Org.
Chem. 1993, 58, 6949. (f) Matsuura, T.; Overman, L. E.; Poon, D. E.
J. Am. Chem. Soc. 1998, 120, 6500. (h) Trost, B. M.; Zhang, Y. J. Am.
Chem. Soc. 2006, 128, 4590. (i) Trost, B. M.; Quancard, J. J. Am. Chem.
Soc. 2006, 128, 6314. (j) Nakao, Y.; Ebata, S.; Yada, A.; Hiyama, T.;
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Trans. 1 1977, 1770.
Supporting Information Available. Experimental details,
full characterization of all products, data for the determina-
tion of all enantiomeric excesses. This material is available
free of charge via the Internet at http://pubs.acs.org.
ꢀ
(28) Morales-Rıos, M. S.; Santos-Sanchez, N. F.; Joseph-Nathan, P.
J. Nat. Prod. 2002, 65, 136.
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J. J.; Joseph-Nathan, P. J. Org. Chem. 2001, 66, 1186.
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The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 19, 2012
4993