Stereoselective oxidative rearrangement of 2-aryl tryptamine derivatives

Article abstract of DOI:10.1021/ol8015176

(Chemical Equation Presented) The oxidation of 2-aryl tryptamines followed by a stereoselective rearrangement provides a versatile strategy for the synthesis of CS-quaternary oxindoles bearing a C3-aryl group. Treatment of optically active 2-aryl hydroxyindolenines with scandium trifluoromethanesulfonate in toluene at 110 °C leads to complete and stereoselective isomerization to the corresponding C3-aryl oxindoles which represent versatile intermediates for the synthesis of C3a-aryl hexahydropyrroloindoles.

Full text of DOI:10.1021/ol8015176

ORGANIC
LETTERS
2008
Vol. 10, No. 18
4009-4012
Stereoselective Oxidative Rearrangement
of 2-Aryl Tryptamine Derivatives
Mohammad Movassaghi,* Michael A. Schmidt, and James A. Ashenhurst
Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts
AVenue, 18-292, Cambridge, Massachusetts 02139
moVassag@mit.edu
Received July 3, 2008
ABSTRACT
The oxidation of 2-aryl tryptamines followed by a stereoselective rearrangement provides a versatile strategy for the synthesis of C3-quaternary
oxindoles bearing a C3-aryl group. Treatment of optically active 2-aryl hydroxyindolenines with scandium trifluoromethanesulfonate in toluene
at 110 °C leads to complete and stereoselective isomerization to the corresponding C3-aryl oxindoles which represent versatile intermediates
for the synthesis of C3a-aryl hexahydropyrroloindoles.
Hexahydropyrroloindole alkaloids constitute a large family
of natural products.1 They are isolated from a wide range of
organisms and display an extensive array of biological
activities, including anticancer and analgesic properties.
Many of these alkaloids contain at least one diaryl quaternary
stereogenic center at the junction of two tryptamine-derived
fragments (Figure 1). Alkaloids exhibiting this substructure
present fascinating molecular architectures and significant
challenges for stereoselective total synthesis.2 Herein we
describe the stereoselective oxidative rearrangement of
readily available 2-aryl tryptamines for the synthesis of
3-aryl-3-alkyl oxindoles, offering a versatile entry to the
desired C3a-aryl-substituted hexahydropyrroloindole sub-
structure found in many natural alkaloids.
Overman and co-workers have developed and successfully
applied an elegant Pd-catalyzed intramolecular Heck cyclization
reaction in their synthesis of 3-aryl-3-alkyl oxindoles en route
to a number of complex hexahydropyrroloindole alkaloids.2 We
described a strategy for the simultaneous stereocontrolled
introduction of vicinal quaternary (Csp3-Csp3) stereocenters
via a Co-mediated reductive dimerization of C3a-halo hexahy-
(1) (a) Hino, T.; Nakagawa, M. The Alkaloids: Chemistry and Phar-
Figure 1. Representative hexahydropyrroloindole alkaloids.
macology; Brossi, A., Ed.; Academic Press: New York, 1989; Vol. 34, pp
1-75. (b) Anthoni, U.; Christophersen, C.; Nielsen, P. H. Alkaloids
Chemical and Biological PerspectiVes; Pelletier, S. W., Ed.; Pergamon:
London, 1999; Vol. 13, pp 163-236.
dropyrroloindoles.3 As an outgrowth of these studies, we sought
a general strategy for a late-stage stereocontrolled introduction
(2) Steven, A.; Overman, L E. Angew. Chem., Int. Ed. 2007, 46, 5488.
10.1021/ol8015176 CCC: $40.75
Published on Web 08/23/2008
2008 American Chemical Society

of the Csp3-Csp2 quaternary stereocenters found in related
hexahydropyrroloindole alkaloids (Figure 1).4 The oxidative
rearrangement of 2,3-disubstituted indoles to the corresponding
3,3-disubstituted oxindoles enjoys a rich history.5,6 However,
only a few reported examples involve the migration of an
aryl group.5
We envisioned that the oxidation of the 2-aryl tryptamine
1 would result in the desired oxindole 4 via the isomerization
of intermediate 3 (Scheme 1). However, the involvement and
crude sample of 8a in THF-water (9:1) followed by the
addition of p-toluenesulfonic acid (15 equiv)7 afforded the
desired oxindole 4a in 20% yield along with 48% of the
hydroxylindolenine 5a upon complete consumption of 8a.
Interestingly, formation of the oxindole derivative was
favored (5:1, 4b:5b) in the case of an electron-rich migrating
C2-aryl group, while the hydroxyindolenine was favored
(>6:1, 5c:4c) when an electron-deficient C2-aryl group was
involved (Scheme 2). Notably, the mass balance in these
Scheme 1
.
Stereoselective Rearrangement of 2-Aryl
Tryptamines
Scheme 2. Oxidative Rearrangement of 2-Aryl Tryptamines
rearrangement of intermediate 5 would give the isomeric
indoxyl 6. For an effective application of this strategy in
stereoselective hexahydropyrroloindole alkaloid synthesis, the
selective formation of 4 over 6 upon oxidation of 1 would
be required in addition to a high level of stereochemical
control in the rearrangement of oxidized intermediates. The
considerable literature precedent6,7 for the efficient haloge-
native oxidation of 2,3-disubstituted indoles prompted our
initial studies to rely on chlorination of 2-aryltryptamines.
Oxidation of N-phthaloyl-2-phenyl tryptamine (1a, Scheme
2) with t-butyl hypochloride cleanly afforded the chloroin-
dolenine 8a. Removal of the volatiles and dissolution of a
reactions was predominantly the corresponding indoxyl
derivative (i.e., 6, Scheme 1). Early observations led to the
hypothesis that oxindoles 4a-c were formed, at least in part,
upon hydrolysis of 8a-c followed by the rearrangement of
hydroxyindolenines 5a-c. Thus, we explored the direct
conversion of 2-aryl tryptamines to the corresponding
hydroxyindolenines. Under optimal conditions, substrate 1a
was oxidized with in situ generated dimethyldioxirane to
afford 5a in 84% yield (eq 1).
(3) (a) Movassaghi, M.; Schmidt, M. A. Angew. Chem., Int. Ed. 2007,
46, 3725. (b) Movassaghi, M.; Schmidt, M. A.; Ashenhurst, J. A. Angew.
Chem., Int. Ed. 2008, 47, 1485.
(4) Schmidt, M. A.; Movassaghi, M. Synlett 2008, 3, 313.
(5) For examples of aryl migration, see: (a) Witkop, B.; Ek, A. J. Am.
Chem. Soc. 1951, 73, 5664. (b) Evans, F. J.; Lyle, G. G.; Watkins, J.; Lyle,
R. E. J. Org. Chem. 1962, 27, 1553. (c) Hishmat, O. H.; Abd-El Rahman,
A. H.; El-Ebrashi, N. M. A.; Ishmail, M. M. F. Chem. Ind. Med. 1986, 4,
With efficient access to hydroxyindolenine 5a, we focused
on the development of optimal conditions for its isomeriza-
tion to the desired oxindole 4a. Treatment of 5a with protic
acid led to almost exclusive conversion to indoxyl 6a, albeit
with poor efficiency (Table 1, entry 1). Use of Lewis acids
such as titanium tetrabutoxide and lithium perchlorate also
promoted the rearrangement of 5a to the indoxyl 6a (Table
1, entries 2 and 3). Use of ytterbium, copper, zinc, and
scandium trifluoromethanesulfonate all led to isomerization
of 5a to the desired indoxyl 4a but with varying levels of
efficiency. Notably, treatment of 5a with copper or scandium
trifluoromethanesulfonate in toluene at 110 °C led to
exclusive isolation of 4a upon complete consumption of
starting material (Table 1, entries 5 and 9). Under optimal
142
.
(6) For elegant examples, please see: (a) Williams, R. M.; Cox, R. J.
Acc. Chem. Res. 2003, 36, 127, and references cited therein. (b) Lindel, T.;
Bra¨uchle, L.; Golz, G.; Bo¨hrer, P. Org. Lett. 2007, 9, 283. (c) Poriel, C.;
Lachia, M.; Wilson, C.; Davies, J. R.; Moody, C. J. J. Org. Chem. 2007,
72, 2978. (d) Lachia, M.; Poriel, C.; Slawin, A. M. Z.; Moody, C. J. Chem.
Commun. 2007, 286. (e) Pettersson, M.; Knueppel, D.; Martin, S. F. Org.
Lett. 2007, 9, 4623. (f) Baran, P. S.; Richter, J. M. J. Am. Chem. Soc. 2005,
127, 15394. (g) Ito, M.; Clark, C. W.; Mortimore, M.; Goh, J. B.; Martin,
S. F. J. Am. Chem. Soc. 2001, 123, 8003. (h) Zhang, X.; Foote, C. S. J. Am.
Chem. Soc. 1993, 115, 8867. (i) Awang, D. V. C.; Vincent, A.; Kindack,
D. Can. J. Chem. 1984, 62, 2667. (j) Walser, A.; Blount, J. F.; Fryer, R. I.
J. Org. Chem. 1973, 38, 3077. (k) Acheson, R. M.; Snaith, R. W.; Vernon,
J. M. J. Chem. Soc. 1964, 3229. (l) Finch, N.; Taylor, W. I. J. Am. Chem.
Soc. 1962, 84, 3871
.
(7) Cushing, T. D.; Sanz-Cervera, J. F.; Williams, R. M. J. Am. Chem.
Soc. 1996, 118, 557
.
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Org. Lett., Vol. 10, No. 18, 2008

afforded a 2:1 mixture of diastereomeric hydroxyindolenines
(-)-(3R)-5d and (-)-(3S)-5d, respectively, in 93% combined
yield (Scheme 3). The diastereomers were separated, and
the stereochemistry of the minor diastereomer (-)-(3S)-5d
was established by X-ray crystallography (Scheme 3).
Table 1. Rearrangement of Hydroxyindolenine 5a
Scheme 3. Oxidation of 2-Phenyl L-Tryptophan Derivative 1d
mol %
(5a:6a:4a)a
entry
conditions
1
2
3
4
5
6
7
8
9
HCl (1 equiv), THF-H2O (9:1), 70 °C, 22 h ∼90:10:0
Ti(OtBu)4 (1 equiv), PhMe, 110 °C, 12 h
LiClO4 (3 equiv), THF, 70 °C, 24 h
Yb(OTf)3 (1 equiv), PhMe, 110 °C, 24 h
Cu(OTf)2 (1 equiv), PhMe, 110 °C, 3 h
Zn(OTf)2 (1 equiv), PhMe, 110 °C, 24 h
Sc(OTf)3 (1 equiv), PhMe, 23 °C, 4.3 h
85:15:0
89:11:0
0:17:83
0:0:100 (35%)b
0:31:69
(18:56:18)c
Sc(OTf)3 (0.25 equiv), PhMe, 110 °C, 19 h 0:15:85
Sc(OTf)3 (1 equiv), PhMe, 110 °C, 5 h
0:0:100 (90%)b
10 Sc(OTf)3 (1 equiv), MeCN, 82 °C, 5 h
11 Sc(OTf)3 (1 equiv), DMF, 120 °C, 5 h
0:60:40
36:64:0
a
Ratios determined by H NMR. b Isolated yield of (()-4a. c Ratio of
1
isolated compounds (instead of mol %).
Treatment of diastereomerically pure samples of hydroxy-
indolenines (-)-(3R)-5d and (-)-(3S)-5d with one equivalent
of scandium trifluoromethanesulfonate in refluxing toluene
for 1.5 h afforded the corresponding oxindoles (-)-(3S)-4d
and (+)-(3R)-4d, respectively (Scheme 4). Importantly, this
conditions, the use of stoichiometric quantities of scandium
trifluoromethanesulfonate afforded the desired product in
90% isolated yield (Table 1, entry 9).8 Using a substoichio-
metric amount of scandium trifluoromethanesulfonate or
lower reaction temperatures led to slower conversion to 4a.
Interestingly, treatment of 5a with stoichiometric quantities
of scandium trifluoromethanesulfonate at 23 °C predomi-
nantly afforded the indoxyl 6a after 4.3 h (Table 1, entry 7).
Similarly, replacement of toluene with acetonitrile or dim-
ethylformamide as the solvent principally gave indoxyl 6a
after 5 h. Significantly, heating the indoxyl 6a with scandium
trifluoromethanesulfonate in toluene over 15 h cleanly
provided the oxindole 4a in 76% yield (eq 2).9
Scheme 4. Completely Stereoselective Rearrangement of
2-Phenyl Hydroxyindolenines (-)-(3R)-5d and (-)-(3S)-5d
completely stereoselective isomerization occurs efficiently
with both diastereomeric hydroxyindolenines and suggests
a process without ionization or dehydration of intermediates
(e.g., 3 or 5).
The relative stereochemistry of oxindole (-)-(3S)-4d was
confirmed by its chemical derivatization to the lactam (+)-9
(Scheme 5). The treatment of (-)-(3S)-4d with hydrazine
provided the corresponding free amine. Warming of the
With optimized conditions for the desired rearrangement
of hydroxyindolenines to the corresponding oxindoles at
hand, we probed the stereochemical course of this interesting
transformation. The 2-phenyl L-tryptophan derivative 1d
served as a versatile system to explore this chemistry. The
oxidation of 2-phenyl indole 1d with Davis’ oxaziridine10,11
(8) While control experiments revealed no product inhibition by either
the indoxyl or the oxindole products, we prefer the use of stoichiometric
quantities of scandium trifluoromethanesulfonate to accelerate the overall
rate of conversion to the desired product (compare entries 8 and 9, Table
1).
(10) For 3-n-butyl-1,2-benzisothiazole-1,1-dioxide oxide, see: Davis,
F. A.; Towson, J. C.; Vashi, D. B.; ThimmaReddy, R.; McCauley, J. P.,
Jr.; Harakal, M. E.; Gosciniak, D. J. J. Org. Chem. 1990, 55, 1254. Use of
this reagent generally resulted in cleaner reaction mixtures than those
observed with in situ generated DMDO.
(9) For an important observation with a dialkyl indoxyl, see: (a) Gu¨ller,
R.; Borscheberg, H. Tetrahedron: Asymmetry 1992, 3, 1197. (b) Gu¨ller,
R.; Borscheberg, H. Tetrahedron Lett. 1994, 35, 865; notably, heating 5a
under these conditions (BF3·OEt2) led to decomposition. (c) Sheehan, J. C.;
Frankenfeld, J. W. J. Am. Chem. Soc. 1961, 83, 4792.
(11) (a) Grubbs, A. W.; Artman, G. D.; Tsukamoto, S.; Williams, R. M.
Angew. Chem., Int. Ed. 2007, 46, 2257. (b) He, F.; Foxman, B. M.; Snider,
B. B. J. Am. Chem. Soc. 1998, 120, 6417.
Org. Lett., Vol. 10, No. 18, 2008
4011

resulting amine in chloroform led to slow intramolecular
transamidation to lactam (+)-9. The stereochemistry of (+)-9
was secured using NOESY experiments and was found to be
consistent with that originating from the oxindole (-)-(3S)-4d.
Scheme 7. Synthesis of the C3a-(7-Indolyl)-oxindole (()-4e
Scheme 5. Derivatization and Stereochemical Assignment of 4d
The oxindoles prepared above serve as versatile precursors
to the corresponding hexahydropyrroloindole derivatives
bearing a C3a-aryl substituent. This is illustrated by the
conversion of oxindole 4a to the corresponding hexahydro-
stage for the planned isomerization. Treatment of 2-(7-
indolyl)-3-hydroxyindolenine 5e with scandium trifluo-
romethanesulfonate in toluene at 110 °C for 2 h afforded
the desired 3-(7-indolyl)oxindole 4e in 65% isolated yield.15
The complete conversion of hydroxyindolenine 5e, as well
as the corresponding indoxyl derivative,15,16 to the desired
oxindole 4e is noteworthy.
Scheme 6. Synthesis of C3a-Phenyl Hexahydropyrroloindole 12
The chemistry described here offers a general strategy for
the stereocontrolled synthesis of C3a-aryl substituted hexahy-
dropyrroloindoles, a common substructure found in various
natural alkaloids. Importantly, the completely stereoselective
conversion of optically active hydroxylindolenine to the cor-
responding oxindoles (Scheme 4) and the facile and complete
conversion of indoxyls to the desired oxindoles, combined with
advances in catalytic asymmetric oxidation chemistry,17 offer
tremendous potential for application in asymmetric synthesis
of complex alkaloids. Further development and application of
this chemistry will be reported in due course.
Acknowledgment. M.M. is a Beckman Young Investiga-
tor and an Alfred P. Sloan research fellow. M.A.S. acknowl-
edges a Merck Summer Fellowship and a Bristol-Myers
Squibb Graduate Fellowship in Synthetic Organic Chemistry.
J.A.A. acknowledges a postdoctoral fellowship from Fonds
Que´be´cois de la Recherche sur la Nature et les Technologies.
We acknowledge generous support from Amgen, AstraZen-
eca, Boehringer Ingelheim, GlaxoSmithKline, Merck Re-
search Laboratories, and Lilly.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for key compounds in
addition to crystallographic data for compound (-)-(3S)-5d.
This material is available free of charge via the Internet at
http://pubs.acs.org.
pyrroloindole 12 (Scheme 6). The desired imide 10 was
prepared in two steps from oxindole 4a in 80% overall yield.
Reduction12 of the oxindole 10 followed by treatment of the
resulting hemiaminal 11 with camphorsulfonic acid gave the
desired C3a-phenyl hexahydropyrroloindole 12 in 90% yield.
The stereoselective rearrangement of optically active
hydroxyindolenines (3R)-5d and (3S)-5d to the corresponding
C3-aryl-C3-alkyl oxindoles (3S)-4d and (3R)-4d, respec-
tively (Scheme 4), in addition to the synthesis of C3a-aryl
hexahydropyrroloindole 12 from oxindole 4a (Scheme 6)
prompted an investigation into the potential use of this
chemistry in the conversion of bisindoles to the desired C3-
(7-indolyl)oxindoles of interest. The requisite bisindole 1e
was readily prepared via a Pd-catalyzed cross-coupling
reaction as shown in Scheme 7.13 Oxidation of 1e followed
by unraveling of the indolyl fragment upon treatment with
OL8015176
(14) Scheidt, K. A.; Chen, H.; Follows, B. C.; Chemler, S. R.; Coffey,
D. S.; Roush, W. R. J. Org. Chem. 1998, 63, 6436.
(15) Shortening of the reaction time to 1 h led to isolation of the desired
4e along with the corresponding 2-(7-indolyl)-2-(2-phthalimido-ethyl)in-
doxyl (S6e) in 97% yield (4e:S6e, 84:16).
tris(dimethylamino)sulfonium
difluorotrimethylsilicate
(TASF)14 provided the hydroxyindolenine 5e and set the
(16) Please see Supporting Information for details
.
(17) For representative examples, see: (a) Colby Davie, E. A.; Mennen,
S. M.; Xu, Y.; Miller, S. J. Chem. ReV. 2007, 107, 5759, and references
therein. (b) Shi, Y. Acc. Chem. Res. 2004, 37, 488. (c) Jacobsen, E. N.;
Zhang, W.; Muci, A. R.; Ecker, J. R.; Deng, L. J. Am. Chem. Soc. 1991,
113, 7063.
(12) (a) Govek, S. P.; Overman, L. E. J. Am. Chem. Soc. 2001, 123,
9468. (b) Govek, S. P.; Overman, L. E. Tetrahedron 2007, 63, 8499.
(13) Billingsley, K.; Buchwald, S. L. J. Am. Chem. Soc. 2007, 129, 3358.
4012
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