reports that describe the asymmetric syntheses of trans-1,2-
disubstituted 3-indolylcyclopropanes are remarkably rare.5
In 1995, Nichols and co-workers reported a diastereoselective
palladium-catalyzed cyclopropanation of chiral N-enoyl
sultams 1 using diazomethane (Scheme 1).5a The reaction
particular, the pybox-Ru(II) catalysts developed by Nish-
iyama and Itoh have been well documented to provide useful
levels of enantio- and diastereocontrol in the formation of
trans-cyclopropylesters from conjugated olefins.7 Implemen-
tation of this strategy required the use of 3-vinylindoles as
substrates. To the best of our knowledge, 3-vinylindoles have
never been examined in asymmetric diazoacetate cyclopro-
panations.8
Scheme 1
Our effort began with the synthesis of the requisite
3-vinylindoles. For this purpose, 1-tosylindole-3-carboxal-
dehydes were readily prepared in two steps from the parent
indoles by Vilsmeir formylation and N-sulfonylation.9 Wittig
methylenation of the protected indole carboxaldehydes 8
provided the corresponding 1-tosyl-3-vinylindoles 9 in good
yields (Table 1).10 With the exception of 9e, the vinylindoles
Table 1. Preparation of 3-Vinylindoles
afforded the corresponding cyclopropane 2 with 72% overall
yield and 65% diastereomeric excess (de). The major
diastereomer was separated and transformed into the rigid
tryptamine analogue 4.
Additionally, Charette and co-workers have described an
enantioselective Simmons-Smith cyclopropanation of in-
dolyl alcohol 5 using bis(iodomethyl)zinc and 0.25 equiv of
the chiral titanium-TADDOLate ligand 6 (Scheme 2).5b The
entry
R1
R2
R3
yield of 9, %
a
b
c
d
e
f
H
F
CN
OCH3
H
H
H
H
H
CH3
H
H
H
H
H
H
CH3
86a
87
71
82a
92
H
79
a Literature preparation; see ref 10.
Scheme 2
were stable crystalline solids that could be stored at room
temperature for several months without noticeable decom-
position. The 4-methyl derivative 9e slowly dimerized when
stored in solution, as evidenced by LC mass spectra analysis.
Asymmetric cyclopropanation of 1-tosyl-3-vinyl-1H-indole
(9a) with ethyl diazoacetate using 5.0 mol % (R,R)-trans-
Cl2Ru(pybox-ip)(CH2dCH2) ((R)-10) provided a 9.2:1.0
mixture of trans- and cis-cyclopropylesters (Table 2, entry
1).11 The pure trans product, 11a, was isolated in 78% yield
after a single purification using silica gel column chroma-
tography.12 Gratifyingly, compound 11a was determined to
cyclopropylmethyl alcohol 7 was obtained in good yield and
86% enantiomeric excess (ee).
While the methods of Nichols and Charette are clearly
effective, we desired a scalable synthesis that precluded the
use of diazomethane and proceeded with greater catalytic
efficiency than the Simmons-Smith method. Consequently,
we choose to explore an alternative strategy involving
catalytic asymmetric diazoacetate cyclopropanation.6 In
(7) (a) Nishiyama, H.; Itoh, Y.; Sugawara, Y.; Matsumoto, H.; Aoki,
K.; Itoh, K. Bull. Chem. Soc. Jpn. 1995, 68, 1247. (b) Nishiyama, H.; Itoh,
Y.; Matsumoto, H.; Park, S.-B.; Itoh, K. J. Am. Chem. Soc. 1994, 116,
2223.
(8) Cyclopropanation of 1-benzenesulfonyl-3-vinylindole using ethyl
diazoacetate and a chiral bisoxozoline Cu(II) complex has been reported;
however, no details regarding the enantioselectivity of the reaction were
provided. Raj, T. T.; Eftink, M. R. Synth. Commun. 1998, 28, 3787.
(9) Representative yields for the preparation of 8c and 8e were 49 and
70%, respectively. See Supporting Information for more details.
(10) Yang, C.-G.; Wang, J.; Tang, X.-X.; Jiang, B. Tetrahedron:
Asymmetry 2002, 13, 383.
(3) Mattson, R.; Denhart, D.; Deskus, J.; Ditta, J.; Marcin, L.; Epperson,
J.; Catt, J.; King, D.; Higgins, M. Preparation of cyclopropylindoles as
selective serotonin reuptake inhibitors. PCT Int. Appl. WO 0279152, 2002.
(4) Rich, D. H. Stereochemical Aspects of Drug Action I: Conforma-
tional Restriction, Steric Hindrence, and Hydrophobic Collapse. In Practice
of Medicinal Chemistry, 2nd ed.; Wermuth, C. G., Ed.; Elsevier: London,
UK, 2003; pp 373-386.
(5) (a) Vangveravong, S.; Nichols, D. E. J. Org. Chem. 1995, 60, 3409.
(b) Charette, A. B.; Molinaro, C.; Brochu, C. J. Am. Chem. Soc. 2001,
123, 12168.
(11) Studies were limited to using Cl2Ru(pybox-ip)(CH2dCH2), because
of its widespread utility and ease of preparation. See ref 7a.
1
(12) In the H NMR spectra, the trans product shows a downfield shift
(∼0.5 ppm) of the -OCH2CH3 protons relative to the same protons of the
(6) Doyle, M. P.; Protopopova, M. N. Tetrahedron 1998, 54, 7919.
cis product.
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Org. Lett., Vol. 7, No. 13, 2005