Reactions of indole derivatives with oxiranes and aziridines on silica. Synthesis of β-carbolin-1-one mimic of pancratistatin

Article abstract of DOI:10.1021/jo040292c

(Chemical Equation Presented) Indole and several indoles functionalized at C-2 were condensed with oxiranes, vinyloxiranes, aziridines, and vinylaziridines in the solid state on the surface of silica. The yields of these reactions were compared to those o

Full text of DOI:10.1021/jo040292c

Reactions of Indole Derivatives with Oxiranes and Aziridines on
Silica. Synthesis of â-Carbolin-1-one Mimic of Pancratistatin
Tomas Hudlicky,*,† Uwe Rinner,†,‡ Kevin J. Finn,† and Ion Ghiviriga§,|
Department of Chemistry, Brock University, St. Catharines, Ontario, Canada L2S 3A1, and
Department of Chemistry, University of Florida, Gainesville, Florida 35702
thudlicky@brocku.ca
Received December 22, 2004
Indole and several indoles functionalized at C-2 were condensed with oxiranes, vinyloxiranes,
aziridines, and vinylaziridines in the solid state on the surface of silica. The yields of these reactions
were compared to those obtained from Lewis acid-catalyzed ring-opening reactions performed in
solution and found to be superior in each case. The solid-phase aziridine opening constituted a key
step in the synthesis of the â-carbolin-1-one mimic of pancratistatin. Methyl 2-indolecarboxylate
was found to react on the silica gel surface with N-tosylvinylaziridine in 68% yield. A nine-step
synthesis of the pancratistatin mimic has been attained. The additional key transformation in this
synthesis involved silica gel-catalyzed opening of an epoxide and hydrolysis of an acetonide. Detailed
experimental procedures and full characterization are reported for all new compounds.
Introduction
of effort has been expended in the preparation and
biological evaluation of unnatural and truncated deriva-
tives of Amaryllidaceae constituents, including those
related to the congeners lacking the 7-hydroxy group,
namely 7-deoxypancratistatin (3) and lycoricidine (4),6
Figure 1.
For the most part, the activities of unnatural deriva-
tives were 10- to 100-fold lower than those of the natural
products.6a,b,d The strategy toward developing a better
analogue through rational study of structure-activity
Amaryllidaceae constituents pancratistatin (1) and
narciclasine (2) are the most potent anticancer agents
isolated from Pancratium litorale and Narcissus poeticus,
respectively.1 Both compounds have been tested against
human cancer cell lines2 and P388 lymphocytic leukemia
with GI50 values on the order of 0.02 µg/mL.3 Their
structures continue to elicit the interest of the synthetic
community, and many strategically diverse syntheses
have been reported.4,5 Although little is known about the
precise mode of action of these compounds, a great deal
(3) GI50 may be defined as the in µg/mL cell solution necessary to
stop the growth of 50% of the cancer cells. For studies detailing the
biological activity of Amaryllidaceae constituents, see: (a) Fitzgerald,
D. B.; Hartwell, J. L.; Leiter, J. J. Nat. Cancer Inst. 1958, 20, 763. (b)
Ceriotti, G. Nature 1967, 11, 595. (c) Carrasco, L.; Fresno, M.; Vazquez,
D. FEBS Lett. 1975, 52, 236. (d) Jimenez, A.; Sanchez, L.; Vazquez,
D. FEBS Lett. 1975, 55, 53. (e) Jimenez, A.; Santos, A.; Alsonso, G.;
Vazquez, D. Biochim. Biophys. Acta 1976, 425, 342. (f) Pettit, G. R.;
Gaddamidi, D. L.; Herald, D. L.; Singh, S. B.; Cragg, G. M.; Schmidt,
J. M.; Boettner, F. E.; Williams, M.; Sagawa, Y. J. Nat. Prod. 1986,
49, 995. (g) Gabrielsen, B.; Monath, T. P.; Huggins, J. W.; Kefauver,
D. F.; Pettit, G. R.; Groszek, G.; Hollingshead, M.; Kirsi, J. J.; Shannon,
W. M.; Schubert, E. M.; DaRe, J.; Urgarkar, B.; Ussery, M. A.; Phelan,
M. J. J. Nat. Prod. 1992, 55, 1569.
(4) For reviews of synthetic approaches, see: (a) Martin, S. F. In
The Alkaloids; Brossi, A. R., Ed.; Academic: New York, 1987; Vol. 40,
p 251. (b) Polt, R. In Organic Synthesis: Theory and Applications;
Hudlicky, T., Ed.; JAI Press: Greenwich, CT, 1996; Vol. 3, p 109. (c)
Hoshino, O. In The Alkaloids; Cordell, G. A., Ed.; Academic: New York,
1998; Vol. 51, p 323. (d) Jin, Z. Nat. Prod. Rep. 2003, 20, 606. (e) Rinner,
U.; Hudlicky, T. Synlett 2005, 365.
* Corresponding author.
† Brock University.
‡ Current Address: Institut fu¨r Organische Chemie, Universita¨t
Wien, Wa¨hringer Strasse 38, 1090 Wien, Austria. E-mail: uwe.rinner@
univie.ac.at.
§ University of Florida.
| To whom correspondence regarding 2-D NMR should be addressed.
(1) Narciclasine is isolated from the daffodil (Narcissus poeticus):
(a) Ceriotti, G. Nature 1967, 11, 595. Pancratistatin was first isolated
by Pettit from Hymenocallis littoralis, the Hawaiian plant formerly
known as Pancratium littorale. (b) Pettit, G. R.; Gaddamidi, V.; Cragg,
G. M.; Herald, D. L.; Sagawa, Y. J. Chem. Soc., Chem. Commun. 1984,
1693. (c) Pettit, G. R.; Gaddamidi, V.; Herald, D. L.; Singh, S. B.; Cragg,
G. M.; Schmidt, J. M.; Boettner, F. E.; Williams, M.; Sagawa, Y. J.
Nat. Prod. 1986, 49, 995.
(2) Cancer types: P388 (lymphocytic leukemia); human lines BX-
PC-3 (pancreas adenocarcinoma); MCF-7 (breast adenocarcinoma);
KM20L2 (colon adenocarcinoma); SF268 (CNS gliobaltoma); NCI-H460
(lung large cell), and DU-145 (prostate carcinoma).
10.1021/jo040292c CCC: $30.25 © 2005 American Chemical Society
Published on Web 04/02/2005
3490
J. Org. Chem. 2005, 70, 3490-3499

Reactions of Indole Derivatives with Oxiranes and Aziridines
FIGURE 1. Amaryllidaceae constituents and some unnatural mimics.
relationship is hampered by the almost complete lack of
understanding of the mode of action of 1 and 2. A limited
study conducted with narciclasine indicated that the
mode of action may be connected to the inhibition of
protein synthesis by interference with RNA transcription
at the ribosomal level.7 Narciclasine appears to inhibit
transfer of the 60S subunit at the 3′ end of the peptidyl
transfer center. Pettit devoted considerable effort to the
synthesis of pancratistatin-based prodrugs8 and more
bioavailable analogues9 as well as the chemical conver-
sion of the more abundant member, 2, into pancratista-
tin.10 Thus, at this point we are only able to speculate
about the exact mode of interaction of these compounds
at the cellular level.
Their structural motifs, however, do permit some
degree of speculation. The aminoinositol moiety of 1 and
the conduramine unit in 2 are no doubt the structural
elements responsible for the antiviral activities reported
for these compounds.3g On the other hand, the oxygenated
phenanthridone unit may be involved in DNA intercala-
tion; this statement would be supported by the observa-
tion that the cis-fused derivatives of 1 are inactive11
perhaps because their three-dimensional structures are
more concave. Another structural element affecting the
levels of activity is the donor-acceptor hydrogen bond
pairing found in the 7-hydroxyl derivatives: the enolized
â-acylamide moiety of 1 and 2 is responsible for a 10-
fold increase in activity over 3 and 4.12 Successful binding
to DNA domains could be invoked to explain this differ-
ence. Until a complete study of the mode of action
emerges the efforts toward a more bioavailable or more
potent analogue will be guided solely by intuition.
Recently, a lactone-containing mimic of 3, compound 9,
was synthesized,6c but no biological data have been
reported for this compound. However, a recent disclosure
of Chapleur13 provided further insight into the impor-
tance of the amide functionality. Lactone analogues of
lycoricidine (Figure 1, 5 and 7) and narciclasine (Figure
(5) Total syntheses of pancratistatin: (a) Danishefsky, S.; Lee, J.
Y. J. Am. Chem. Soc. 1989, 111, 4829. (b) Tian, X.; Hudlicky, T.;
Ko¨nigsberger, K. J. Am. Chem. Soc. 1995, 117, 3643. (c) Trost, B. M.;
Pulley, S. R. J. Am. Chem. Soc. 1995, 117, 10143. (d) Hudlicky, T.;
Tian, X.; Ko¨nigsberger, K.; Maurya, R.; Rouden, J.; Fan, B. J. Am.
Chem. Soc. 1996, 118, 10752. (e) Doyle, T. J.; Hendrix, M.; Van
Derveer, D.; Javanmard, S.; Haseltine, J. Tetrahedron 1997, 53, 11153.
(f) Magnus, P.; Sebhat, I. K. J. Am. Chem. Soc. 1998, 120, 5341. (g)
Rigby, J. H.; Maharoof, U. S. M.; Mateo, M. E. J. Am. Chem. Soc. 2000,
122, 6624. (h) Pettit, G. R.; Melody, N.; Herald, D. L. J. Org. Chem.
2001, 66, 2583. (i) Kim, S.; Ko, H.; Kim, E.; Kim, D. Org. Lett. 2002,
4, 1343. Total syntheses of 7-deoxypancratistatin: (j) Paulsen, H.;
Stubbe, M. Liebigs Ann. Chem. 1983, 535. (k) Tian, X.; Maurya, R.;
Ko¨nigsberger, K.; Hudlicky, T. Synlett 1995, 1125. (l) Keck, G. E.;
McHardy, S. F.; Murry, J. A. J. Am. Chem. Soc. 1995, 117, 7289. (m)
Chida, N.; Jitsuoka, M.; Yamamoto, Y.; Ohtsuka, M.; Ogawa, S.
Heterocycles 1996, 43, 1385. (n) Hudlicky, T.; Tian, X.; Ko¨nigsberger,
K.; Maurya, R.; Rouden, J.; Fan, B. J. Am. Chem. Soc. 1996, 118,
10752. (o) Keck, G. E.; Wager, T. T.; McHardy, S. F. J. Org. Chem.
1998, 63, 9164. (p) Keck, G. E.; McHardy, S. F.; Murry, J. A. J. Org.
Chem. 1999, 64, 4465. (q) Acena, J. L.; Arjona, O.; Leon, M. L.; Plumet,
J. Org. Lett. 2000, 2, 3683. For syntheses of narciclasine, see: (r)
Rigby, J. H.; Mateo, M. E. J. Am. Chem. Soc. 1997, 119, 12655. (s)
Gonzalez, D.; Martinot, T.; Hudlicky, T. Tetrahedron Lett. 1999, 40,
3077. (t) Keck, G. E.; Wager, T. T.; Rodriquez, J. F. D. J. Am. Chem.
Soc. 1999, 121, 5176. (u) Elango, S.; Yan, T.-H. J. Org. Chem. 2002,
67, 6954. (v) Hudlicky, T.; Rinner, U.; Gonzalez, D.; Akgun, H.;
Schilling, S.; Siengalewicz, P.; Martinot, T. A.; Pettit, G. R. J. Org.
Chem. 2002, 67, 8726. For syntheses of lycoricidine, see: (w) Ohta,
S.; Kimoto, S. Tetrahedron Lett. 1975, 2279. (x) Paulsen, H.; Stubbe,
M. Liebigs Ann. Chem. 1983, 535; Paulsen, H.; Stubbe, M. Tetrahedron
Lett. 1982, 23, 3171. (y) Ugarkar, B. G.; DaRe, J.; Schubert, E. M.
Synthesis 1987, 715. (z) Chida, N.; Ohtsuka, M.; Ogawa, S. Tetrahedron
Lett. 1991, 32, 4525. (aa) Hudlicky, T.; Olivo, H. F.; McKibben, B. J.
Am. Chem. Soc. 1994, 116, 5108. (bb) Keck, G. E.; Wager, T. T. J. Org.
Chem. 1996, 61, 8366. (cc) Keck, G. E.; Wager, T. T.; Rodriquez, J. F.
D. J. Am. Chem. Soc. 1999, 121, 5176. (dd) Elango, S.; Yan, T.-H.
Tetrahedron 2002, 58, 7335.
(8) (a) Pettit, G. R.; Freeman, S.; Simpson, M. J.; Thompson, M. A.;
Boyd, M. R.; Williams, M. D.; Pettit, G. R., III; Doubek, D. L. Anti-
Cancer Drug Des. 1995, 10, 243. (b) Pettit, G. R.; Melody, N.; Herald,
D. L. J. Nat. Prod. 2004, 67, 322.
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Pettit; G. R.; Melody, N.; Herald, D. L.; Schmidt, J. M.; Pettit, R. K.;
Chapuis, J.-C. Heterocycles 2002, 56, 139. (c) Phung, A. N.; Zannetti,
M. T.; Whited, G.; Fessner, W. D. Angew. Chem., Int. Ed. 2003, 42,
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(12) For comparison of biological activity of lycoricidine and narci-
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see: (a) Pettit, G. R.; Pettit, G. R., III; Backhaus, R. A.; Boyd, M. R.;
Meerow, A. W. J. Nat. Prod. 1993, 56, 1682. (b) Pettit; G. R.; Melody,
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J. Org. Chem, Vol. 70, No. 9, 2005 3491

Hudlicky et al.
acidic conditions, i.e., 10% HOAc aq, indole reacts with
cyclic imines in high yield as demonstrated in the
synthesis of aspidosperma alkaloids by Wenkert.18 Lewis
acid catalysis by lanthanides (In or Sc) permits the
synthesis of tryptamines and tryptophols through the
opening of aziridines (or Mannich products) and epoxides,
respectively.19 Silica gel20 and alumina21 have been widely
used as both acid or surface catalysts, and in general,
the use of such catalysts leads to either milder conditions
or rate acceleration or both. In addition, zeolite catalysts
used in conjunction with transition metals have recently
been shown22 to promote electrophilic substitution reac-
tions between indole and aldehydes. A silica gel-sup-
ported ionic liquid catalyst system has also been shown
to facilitate oxime-carbonyl transformations under rela-
tively mild conditions.23 A recent report from Baskaran
decribes the opening of N-tosylaziridines by various
nucleophiles catalyzed by phosphomolybdic acid on a
silica gel surface,24 although no example of this reaction
employing aromatic nucleophiles is offered in this paper.
We chose to investigate a series of epoxides and
aziridines in their reactivity toward indole, indole-2-
methylcarboxylate, and indole-3-methylcarboxylate as
such reactions would lead to the above-mentioned
tryptamine or tryptophol derivatives. The reactions were
performed by adsorbing a solution of both reactants in
methylene chloride on previously activated silica gel,
evaporating to dryness, and heating the solid mixture
under argon atmosphere at 70 °C for 15-48 h. In all
cases, a 3-fold excess of the indole nucleophile was added
to the epoxide or aziridine. Considering the success of
the recently reported InCl3/CH2Cl2 solution catalysis25
and silica surface catalysis, we developed a hybrid InCl3/
silica catalyst system in which 5% (by weight) InCl3 was
added to silica gel before the standard activation protocol.
We hoped initially that the reactions could be performed
at room temperature; however, heating was required in
order to effect opening of azirdines and epoxides in the
presence InCl3 on silica. The products derived from the
InCl3-treated silica gel contained a significant amount
of impurities in both the aziridine and epoxide series. The
reactivity of an alternative InCl3/silica surface (entry d
in Table 1) was examined by pretreating silica gel with
10% aq InCl3 prior to the standard activation protocol
and the yield found to be equal to that for 5% InCl3-doped
silica surface reactions in the case of epoxide 14. Our
results demonstrate that the mildest and the most
FIGURE 2. Cyclopropylindolenine generation from â-carbo-
lin-1-one mimics and structural comparison to DNA-binding
cyclopropylquinoids.
1, 6 and 8) have been synthesized and shown to be
completely inactive in screening against cancer cell lines,
suggesting that the amide moiety is essential for activity.
We became interested in the synthesis of indole-
containing analogues of 1 on the basis of several ideas.
First, indoles found in agents such as CC-106514 or
yatakemycin15 generate reactive cyclopropylquinoid spe-
cies that covalently attach to AT-rich regions of DNA.
Second, the design of indole mimics of 1, such as 10,
permits the preparation of cyclopropylindolenines 11,
which could trigger interactions similar to those observed
for CC-1065 type compounds, as shown in Figure 2.
Third, serotonin-regulating activites have been associ-
ated with compounds that display the â-carbolin-1-one
or constrained tryptamine motifs, both of which are found
in 10. The indole mimic has been compared to pancrat-
istatin in modeling of the electrostatic potential energy
surface and was shown to have significant structural and
electrostatic overlap with the natural product except for
the benzene portion of the indole region.16 In this paper,
we report the details of a nine-step synthesis of 10 along
with a study of the silica surface catalysis in the reaction
of indole derivatives with strained three-membered
heterocycles.
Results and Discussion
Reactions of indole with electrophiles at C-3 under
Lewis or protic acid catalysis are well documented,17
although strongly acidic conditions lead to the formation
of indirubin, indigo, and other dimers. Under weakly
(18) Wenkert, E.; Hudlicky, T. J. Org. Chem. 1988, 53, 1953.
(19) For recent examples of tryptamine synthesis, see: (a) Bennani,
Y. L.; Zhu, G. D.; Freeman, J. C. Synlett 1998, 754. (b) Yadaf, J. S.;
Reddy, B. V. S.; Abraham, S.; Sabitha, G. Tetrahedron Lett. 2002, 43,
1565. (c) Nishikawa, T.; Kajii, S.; Wada, K.; Ishikawa, M.; Isobe, M.
Synthesis 2002, 12, 1658. (d) Janczuk, A.; Zhang, W. Xie, W.; Lou, S.;
Cheng, J.; Wang, P. G. Tetrahedron Lett. 2002, 43, 4271. For examples
of tryptophol synthesis, see: (e) Kotsuki, H.; Teraguchi, M.; Shimomoto,
N.; Ochi, M. Tetrahedron Lett. 1996, 37, 3727. (f) Kotsuki, H.;
Nishiuchi, M.; Kobayashi, S.; Nishizawa, H. J. Org. Chem. 1990, 55,
2969. (g) Fagnou, K.; Lautens, M. Org. Lett. 2000, 2, 2319.
(20) (a) Hudlicky, M. J. Org. Chem. 1974, 39, 3460. (b) Kotsuki, H.;
Hayashida, K.; Shimanouchi, T.; Nishizawa, H. J. Org. Chem. 1996,
61, 984. (c) Bobbit, J. M. J. Org. Chem. 1998, 63, 9367.
(14) (a) Chidester, C. G.; Krueger, W. C.; Mizsak, S. A.; Duchamp,
D. J.; Martin, D. G. J. Am. Chem. Soc. 1981, 103, 7629. (b) Boger, D.
L.; Johnson, D. S. Angew. Chem., Int. Ed. Engl. 1996, 35, 1438. (c)
Parrish, J. P.; Hughes, T. V.; Hwang, I.; Boger, D. L. J. Am. Chem.
Soc. 2004, 126, 80.
(15) (a) Igarashi, Y.; Futamata, K.; Fujita, T.; Sekine, A.; Senda,
H.; Naoki, H.; Furumai, T. J. Antibiot. 2003, 56, 107. (b) Tichenor, M.
S.; Kastrinsky, D. B.; Boger, D. L. J. Am. Chem. Soc. 2004, 126, 8396.
(16) Rinner, U.; Hudlicky, T.; Gordon, H.; Pettit, G. R. Angew.
Chem., Int. Ed. 2004, 43, 5342.
(17) (a) Sundberg, R. J. The Chemistry of Indoles; Academic Press:
New York, 1970. (b) Pindur, U.; Akgun, E. Chem.-Ztg. 1984, 108, 371.
(c) Janczuk, A.; Zhang, W.; Xie, W.; Lou, S.; Cheng, J.; Wang, P.
Tetrahedron Lett. 2002, 43, 4271. (d) Bandini, M.; Cozzi, P. G.;
Melchiorre, P.; Umani-Ronchi, A. J. Org. Chem. 2002, 63, 5386.
(21) Hudlicky, T.; Srnak, T. Tetrahedron Lett. 1981, 22, 3351.
(22) Karthik, M.; Tripathi, A. K.; Gupta, N. M.; Palanichamy,
Murugesan, V. Catal. Commun. 2004, 5, 371.
(23) Li, D.; Shi, F.; Deng, Y. Tetrahedron Lett. 2004, 45, 6791.
(24) Kumar, G. D.; Baskaran, S. Synlett 2004, 10, 1719.
(25) Yadaf, J. S.; Reddy, B. V. S.; Abraham, S.; Sabitha, G.
Tetrahedron Lett. 2002, 43, 1565.
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Reactions of Indole Derivatives with Oxiranes and Aziridines
TABLE 1. Reaction of Epoxides and Aziridines with
Indole on Silica and in Solution
TABLE 2. Reaction of 2-substituted Indoles with
Aziridine 17
* Yields are isolated: (a) silica gel surface at 70 °C; (b) 0.1 equiv
of InCl3 in CH2Cl2; (c) InCl3-doped silica at 70 °C.
expected for the acetonide moiety represented in 20; (iii)
the proton at 1.45 ppm displays an NOE with the protons
at 4.76, but not with that at 3.89 ppm.
Synthesis of â-Carbolin-1-one Mimic. The intitial
strategy for the synthesis of 10 was pursued with the
well-documented premise in mind that indoles substi-
tuted at C-3 readily participate in the Pictet-Spengler
reaction at C-2.26 Thus, compound 24, prepared by the
silica gel-promoted condensation of N-carbomethoxyaziri-
dine 18 and indole, was subjected to the modified
conditions of Banwell27 in an attempt to generate the
â-carbolin-1-one nucleus as shown in Scheme 1. However,
in our hands, treatment of 24 with 5 equiv of triflic
anhydride and 3 equiv of DMAP in methylene chloride
failed to effect the desired closure to 30, possibly because
of the reactive nature of the indole nitrogen toward triflic
anhydride, the product of which would contribute toward
deactivating the nucleophilicity at the indole C-2 position.
An additional competitive reaction pathway that was
observed under forcing conditions was the aromatization
of the aminocyclitol portion in compound 24.
Our preliminary silica-surface reactions established
that N-tosylaziridines are superior electrophiles to N-
carbomethoxy- or N-Boc-protected aziridines toward in-
dole nucleophiles. The initial ring-opening experiments
simply involved pouring a solution in methylene chloride
of both indole nucleophile and aziridine electrophile onto
an analytical TLC plate and allowing the plate to stand
at rt for 12 h. The silica gel containing the adsorbed
* Electrophiles 13-18 were prepared according to literature
procedures. References may be found in the Supporting Informa-
tion. ** Yields are isolated: (a) silica gel surface at 70 °C; (b) 0.1
equiv of InCl3 in CH2Cl2; (c) InCl3-doped silica at 70 °C; (d) 10%
aq InCl3-treated silica at 70 °C; (e) rt, TLC plate silica.
efficient method for the ring-opening catalysis in the
presence of several indole nucleophiles is the silica-
surface reaction (entry a in Tables 1 and 2). The results
of these experiments are shown in Tables 1 and 2.
We were initially concerned about the possibility of
vinyl epoxide opening at the distal olefinic center via an
SN2′ mechanism (producing 20-alt in Figure 3), rather
than the expected 1,2-opening resulting from an SN2-like
mechanism. A detailed NMR study demonstrated that
the opening of vinyl epoxide 14 occurred in a 1,2-fashion
to yield compound 20. The sequence 3.54-3.89-4.22-
4.76 ppm, revealed by the coupling constants seen in the
1H NMR spectrum, supports the connectivity assignment
in 20. The proton at 3.54 ppm is adjacent to the indole
ring because it couples with three carbons of the indole
moiety. One can easily make three arguments for as-
signment of structure 20, as opposed to 20-alt: (i) the
proton at 3.89 ppm displays two large couplings, 9.0 and
10.0 Hz; therefore, it is axial and its vicinal protons at
3.54 and 4.22 ppm are also axial, which would imply a
trans relationship of the protons in the acetonide moiety
in 20-alt; (ii) the chemical shifts of the protons at 4.22
and 4.76 ppm and their coupling constant of 6.6 Hz are
(26) For comprehensive reviews of the Pictet-Spengler reaction,
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D.; Hardcastle, K. I.; McClure, M. S. J. Org. Chem. 2003, 68, 929. (i)
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(27) Banwell, M. G.; Bissett, B. D.; Busato, S.; Cowden, C. J.;
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Hudlicky et al.
FIGURE 3. 1H and 13C chemical shift assignments in 20.
SCHEME 1
SCHEME 2
reaction mixture was transferred to a flash silica gel
column and eluted to provide the condensation product
in 70% yield. Changing to flash chromatography grade
silica and heating the adsorbed mixture of reactants to
70 °C provided 48% isolated yield of 23.
Encouraged by the results of silica catalysis in the
condensation of indole with tosylaziridines and the high
yield of tosyl amide 23 (entry e in Table 1), we attempted
its reductive deprotection to 31, Scheme 2. Only partial
reduction of the indole nucleus was observed, and the
free amine 31 was not obtained.
We next examined the reactions of a 2-substituted
indole, acetate 26, with aziridine 17 in the presence of
silica gel at room temperature, providing tosylamide 28
in a modest, unoptimized, yield of 29% (Scheme 3). The
free alcohol 32, obtained by treatment of acetate 28 with
sodium methoxide in methanol, was then subjected to
pyridinium chlorochromate (PCC). Aldehyde 34 was
isolated and subjected to a variety of oxidizing conditions.
PCC was employed in an attempt to oxidize any hemi-
aminals formed from the closure of the tosyl amide onto
the aldehyde, thus driving the equilibrium toward the
desired amide. Unfortunately, treatment of 34 with PCC
returned the starting material unchanged. When treated
with sodium hypochlorite, aldehyde 34 was converted to
the corresponding carboxylic acid, however without sub-
sequent ring closure to the lactam. Under more vigorous
oxidizing conditions, i.e., Jones reagent, decomposition
of the starting material was observed. Since it has been
shown that tosylamides of type 33 are easily oxidized to
imides, which are readily detosylated under mild condi-
tions such as sodium naphthalide,5w such an approach
would allow the installation of the C-6 carbonyl. We also
attempted the closure of 32 to 33 under a variety of
conditions but without success. The failure of these
compounds to form the phenanthridone indicates that
atropisomers exist in this series and are sterically
indisposed to the ring closure, in analogy with the
established precedent for such isomerism.5b,d
To circumvent problems with the formation of the
phenanthridone amide bond, indole-2-methylcarboxylate
25 was used as shown in Scheme 4. We were delighted
that indole-2-methyl ester condensed with tosylaziridine
17 and provided tosylamide 27 in good yields when
adsorbed on silica and heated at 70 °C for 48 h. This
result was especially surprising in view of the fact that
Lewis acid catalysis in solution did not produce signifi-
cant amounts of 27. We attributed the low reactivity to
the decreased electron density at C-3 because of the fully
conjugated vinylogous urethane moiety in indole-2-car-
boxylate. To avoid indole oxidation during functionaliza-
tion of the cyclohexene, ester 27 was hydrolyzed to its
acid with LiOH and immediately subjected to the modi-
fied Danishefsky iodolactonization conditions reported by
Jung28 to produce iodolactone 37, Scheme 4. This mate-
rial was converted to methyl ester 38, and both nitrogen
atoms were protected as Boc-carbamates 39, rendering
the tosylamide moiety more reactive toward its reductive
removal. We were not able to effect selective acylation of
the tosylamide nitrogen under neutral or basic conditions
because of similar acidity and nucleophilicity of the indole
and tosylamide nitrogen atoms. We originally attempted
to selectively protect the N-tosyl as its carbamate in ester
27 early in the synthesis. When 27 was subjected to
(28) Jung, M.; Ham, J.; Song, J. Org. Lett. 2002, 4, 2763.
3494 J. Org. Chem., Vol. 70, No. 9, 2005

Reactions of Indole Derivatives with Oxiranes and Aziridines
SCHEME 3
SCHEME 4
standard carbamate protection conditions (NEt3/Boc2O,
2 equiv), the indolyl nitrogen was selectively protected
in favor of the more deactivated N-tosyl species; higher
temperatures (>50 °C) led to the aromatization of the
aminocyclitol moiety. A solution to these selectivity and
thermal stability issues was realized by treatment of
methyl ester 38 with 2.5 equiv of sodium hydride followed
by neat Boc-anhydride at 40 °C for 48 h. The correspond-
ing bis-protected material 39 was cleanly detosylated
upon treatment with Na/naphthalide to provide bis-Boc
derivative 40.
The Boc-amide 40 was adsorbed on silica suspended
in distilled water and heated at 140 °C for 1 h in a capped
thick-walled tube. These conditions resulted in smooth
deprotection of both Boc-groups via a thermal retro-ene
reaction and the intramolecular closure to â-carbolin-1-
one 41. Further heating at 170 °C for 16 h resulted in
the opening of the epoxide as well as the hydrolysis of
the acetonide to provide 10 in 31% overall yield. The last
sequence of reactions is noteworthy for several reasons.
First, the conditions of the reaction are essentially
neutral. Second, under such conditions, epoxides or
J. Org. Chem, Vol. 70, No. 9, 2005 3495

Hudlicky et al.
as 38, which was found to be inactive. This is a promising
result that merits further investigation and analogue
development.
Conclusion
The enhanced reactivity of indoles with aziridines and
epoxides on silica surface bodes well for further applica-
tions to synthesis of indole derivatives. The investigations
of the â-carbolin-1-one mimic of pancratistatin provided
further insight into the biological activity of Amarylli-
daceae constituents. It is noteworthy that its synthesis
represents to date the shortest approach to compounds
containing an aminoinositol motif attached to an aro-
matic nucleus. Further modifications of the pancratista-
tin pharmacophore should address changes in the aro-
matic portion only, as it now appears that both the
aminoinositol and the enolized acylamide moieties are
essential for high levels of activity. Progress in the
development of analogues and the results of their screen-
ing will be reported in due course.
FIGURE 4. 1H and 13C chemical shift assignment in tetra-
acetate 42.
acetonides would not be expected to hydrolyze. Third,
these conditions are similar, at least as far as pH is
concerned, to those consisting of 5% aqueous sodium
benzoate reported for hydrolysis of acetonide in D-chiro-
inositol synthesis.29 The dilute aqueous solution of so-
dium benzoate is nearly neutral, but the isolation of
products is complicated by the presence of benzoic acid
and its salts. Under such conditions epoxides are difficult
to hydrolyze as well. We attribute the success of this
sequence entirely to the previously reported rate ac-
celerations observed for reactions conducted on silica or
alumina surfaces.20-24
Tetrol 10 was isolated by filtering the silica slurry,
washing the residual silica copiously with methanol, and
evaporating the filtrate to dryness. The material, in-
soluble in most solvents except for methanol and acetone,
was converted to its tetraacetate 42 (pyr, Ac2O, DMAP),
which was then characterized by HMBC, HMQC, and
NOE NMR techniques. The assignment of the 1H and the
13C chemical shifts in 42 is given in Figure 4.
All of the intermediates in the synthesis of 10 have
been screened in a panel of human cancer lines and were
found to be moderately active. The results of the screen-
ing were reported in the preliminary communication.16
We were surprised to find that the most active compound
was the iodolactone 37sits activity against pancreatic
adenocarcinoma BXPC-3 was at 1.9 µg/mL about 100-
fold less than that of pancratistatin. It is active also
against breast adenocarcinoma MCF-7 (4.3 µg/mL) and
P388 lymphocytic leukemia (11.7 µg/mL). It is interesting
to note that certain iodolactones have been identified as
antineoplastic agents in breast tumors where they are
synthesized enzymatically.30 Iodine-rich diet was linked
to lower coincidence of breast cancers. The iodolactone
37 was essentially inactive against colon adenocarcinoma
(KM20L2), whereas epoxides 38 and 41 show reasonable
activity against this particular cell line. This difference
seems to indicate that a different mechanism may be
expected to operate at the cellular level for these com-
pounds as it might be envisioned that the iodolactone
would be converted in vivo to the epoxy carboxylate such
Experimental Section
2-(1H-Indol-3-yl)cyclohex-3-enol (19). Indole (367 mg,
3.12 mmol, 3 equiv) and vinyl epoxide 13 (100 mg, 1.04 mmol,
1.0 equiv) were heated on a previously activated silica gel
surface (1.0 g) at 70 °C for 27 h as described in the general
procedure (Supporting Information). The silica gel supporting
the reaction mixture was cooled to rt and chromatographed
directly on flash silica (hexanes/ethyl acetate; gradient elution,
4:1 to 1:1), providing the title compound as an off-white
crystalline solid (68 mg, 32%). The crystalline material was
recrystallized from methylene chloride/pentane to obtain
product of higher purity: Rf 0.5 (hexanes-ethyl acetate, 1:1);
mp (sealed tube) 121-122 °C; IR (film) ν 3543, 3410, 3056,
3022, 2922, 1618, 1456, 1433, 1339, 1054 cm-1; 1H NMR (400
MHz, CDCl3) δ 8.03 (s, 1H), 7.61 (d, J ) 7.8 Hz, 1H), 7.29 (d,
J ) 8.0 Hz, 1H), 7.15 (m, 1H), 7.00 (m, 2H), 5.77 (m, 1H), 5.66
(dd, J ) 9.7, 1.2 Hz, 1H), 3.91 (ddd, J ) 10.3, 7.3, 2.9 Hz, 1H),
3.48, (m, 1H), 2.2 (m, 2H), 1.98 (m, 1H), 1.84 (bs, 1H), 1.65
(m, 1H); 13C NMR (100 MHz, CDCl3) δ 137.3, 129.0, 127.4,
127.0, 122.9, 122.6, 120.0, 119.8, 117.2, 111.7, 72.3, 43.4, 29.4,
24.8; HRMS (EI) calcd for C14H15NO 213.1153, found 213.1148.
5-(1H-Indol-3-yl)-2,2-dimethyl-3a,4,5,7a-tetrahydroben-
zo[1,3]dioxol-4-ol (20). Indole (211 mg, 1.8 mmol, 3 equiv)
and vinyl epoxide 14 (100 mg, 0.60 mmol, 1.0 equiv) were
heated at 70 °C on a previously activated silica gel surface
(600 mg) for 20 h as described in the general procedure
(Supporting Information). The reaction mixture on silica gel
was purified by chromatography on flash silica gel (hexanes/
ethyl acetate; gradient elution, 4:1 to 1:1), providing a foamy
solid (86 mg, 51%): Rf 0.28 (pentane/ethyl acetate, 1:1); [R]28
D
+35.45 (c 0.35, MeOH); IR (film) ν 3407, 2927, 1456,1379 cm-1
;
1H NMR (400 MHz, CDCl3) δ 8.21 (s, 1H), 7.55 (d, J ) 8.0 Hz,
1H), 7.25 (d, J ) 8.0 Hz, 1H), 7.12 (m, 1H), 7.05-6.95 (m, 2H),
5.93 (s, 2H), 4.66 (d, J ) 6.2 Hz, 1H), 4.12 (m, 1H), 3.80 (t,
J ) 9.3 Hz, 1H), 3.45 (d, J ) 9.8 Hz, 1H), 2.21 (bs, 1H), 1.45
(s, 3H), 1.37 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 137.0, 135.6,
126.8, 123.9, 123.2, 122.7, 119.9, 119.8, 114.5, 111.0, 79.4, 74.0,
73.2, 40.9, 28.7, 26.2; HRMS (EI) calcd for C17H19NO3 285.1364,
found 285.1364.
N-[2-(1H-Indol-3-yl)cyclohexyl]-4-methylbenzenesul-
fonamide (21). Indole (95 mg, 0.81 mmol, 3 equiv) and
N-tosylaziridine 15 (68 mg, 0.27 mmol, 1.0 equiv) were heated
on a previously activated silica gel surface (800 mg) at 70 °C
for 22 h according to the general procedure. The silica gel
containing the adsorbed reaction mixture was loaded onto a
chromatography column, and the condensation product was
purified by flash chromatography (hexanes/ethyl acetate 4:1),
(29) Mandel, M.; Hudlicky, T.; Kwart, L. D.; Whited, G. M. J. Org.
Chem. 1993, 58, 2331.
(30) Torremante, P. Dtsch. Med. Wochenschr. 2004, 641. We thank
Dr. Med. Pompilio Torremante for communicating these facts to us
and providing his paper on the subject.
3496 J. Org. Chem., Vol. 70, No. 9, 2005

Reactions of Indole Derivatives with Oxiranes and Aziridines
affording 21 as a white foam (38 mg, 38%): Rf 0.22 (hexanes/
ethyl acetate, 2:1); IR (film) ν 3404, 2930, 1598, 1457, 1316,
2-Methyl{1H-3-(2,2-Dimethyl-3a,4,5,7a-tetrahydrobenzo-
[1,3]dioxolyl)-4-tosylamine}-3-indolylcarboxylate (27). To
a solution of indole-2-carboxylic acid methyl ester 25 (6.0 g,
34 mmol) and vinyl aziridine 17 (3.1 g, 9.5 mmol) in methylene
chloride (100 mL) was added dry silica gel (approximately 50
g; 250-400 mesh). The solvent was removed under reduced
pressure and the adsorbed material was heated to 70 °C for
48 h under argon atmosphere. After the material was cooled
to room temperature, the silica was loaded on a chromatog-
raphy column, and the reaction mixture was purified by flash
column chromatography (hexanes/ethyl acetate 3:1), affording
coupled product 27 as yellow oil (3.2 g; 6.4 mmol; 68%): Rf
1
1157, 1093 cm-1; H NMR (300 MHz, CDCl3) δ 8.05 (s, 1H),
7.27 (m, 2H), 7.16 (m, 3H), 6.90 (m, 3H), 6.75 (d, J ) 2.5 Hz,
1H), 4.51 (d, J ) 3.3 Hz, 1H), 3.17 (m, 1H), 2.65 (dt, J ) 11.2,
3.5 Hz, 1 H), 2.50 (m, 1H), 2.33 (s, 3H), 1.95 (m, 1H), 1.75 (m,
3H), 1.25 (m, 3H); 13C NMR (75 MHz, CDCl3) δ: 143.0, 136.9,
136.5, 129.4, 126.9, 126.4, 122.2, 122.1, 119.4, 116.7, 111.7,
57.5, 42.0, 35.1, 33.7, 26.4, 25.3, 21.8; HRMS (EI) calcd for
C21H24N2O2S 368.1558, found 368.1553.
N-[2-(1H-Indol-3-yl)cyclohex-3-enyl]-4-methylbenzene-
sulfonamide (22). Indole (141 mg, 1.2 mmol, 3 equiv) and
vinyl aziridine 16 (100 mg, 0.40 mmol, 1.0 equiv) were heated
on a previously activated silica gel surface (1.0 g) at 70 °C for
20 h as described in the general procedure. The silica gel
supporting the starting materials was directly loaded onto a
flash silica gel column and the condensation product purified
by flash chromatography (hexanes/ethyl acetate; gradient
elution, 4:1 to 2:1), providing the tosyl derivative 22 as an off-
white solid (112 mg, 76%): Rf 0.2 (pentane/ethyl acetate, 3:1);
mp 158-160 °C; IR (film) ν 3406, 3285, 3027, 2924,2860, 1598,
0.20 (hexanes/ethyl acetate, 1:1); [R]28 -15.5 (c 1.05 CHCl3);
D
IR ν 3327, 2986, 1692 cm-1; 1H NMR (300 MHz, CDCl3) δ 8.44
(bs, 1 H), 7.62 (d, J ) 8.2 Hz, 2 H), 7.18-7.34 (m, 3 H), 7.06
(t, J ) 7.0 Hz, 1 H), 6.79 (d, J ) 8.5 Hz, 2 H), 6.02-6.14 (m,
2 H), 5.22 (d, J ) 8.2 Hz, 1 H), 4.72 (m, 1 H), 4.41 (d, J ) 9.9
Hz, 1 H), 4.14 (dd, J ) 9.6, 5.8 Hz, 1 H), 3.94 (s, 3 H), 3.80 (q,
J ) 9.9 Hz, 1 H), 2.25 (s, 3 H), 1.55 (s, 3 H), 1.43 (s, 3 H); 13C
NMR (75 MHz, CDCl3) δ 163.0, 141.8, 139.0, 136.2, 135.7,
128.8, 126.3, 126.1, 123.8, 123.6, 122.4, 122.2, 120.8, 112.2,
110.1, 79.3, 72.8, 58.5, 52.4, 38.5, 28.4, 26.4, 21.7; HRMS (EI)
calcd for C26H28SN2O6 496.1668, found 496.1668.
1493, 1457, 1420, 1158 cm-1 1H NMR (400 MHz, CDCl3) δ
;
8.02 (s, 1H), 7.48 (d, J ) 8.0 Hz, 1H), 7.35-7.20 (m, 2 H), 7.17-
7.10 (m, 2H), 7.0 (d, J ) 8.0 Hz, 2H), 6.97 (m, 1H), 6.82 (s,
2H), 5.88 (m, 1H), 5.65 (d, J ) 9.5 Hz, 1H), 4.85 (d, J ) 5.3
Hz, 1H), 3.50 (s, 2H), 2.33 (s, 3H), 2.20 (s, 2H), 2.05-1.95 (m,
1H); 13C NMR (100 MHz, CDCl3) δ 143.3, 137.1, 137.0, 129.7,
128.1, 127.6, 127.2, 123.3, 122.4, 119.7, 119.4, 166.5, 111.5,
53.4, 39.9, 26.3, 22.8, 21.9; HRMS (EI) calcd for C21H22N2O2S
366.1401, found 366.1398.
2-Methyl{1H-3-(2,2-Dimethyl-3a,4,5,7a-tetrahydrobenzo-
[1,3]dioxolyl)-4-tosylamine}-3-indolylacetate (28). Acetic
acid 1H-indol-2-ylmethyl ester 26 (315 mg, 1.82 mmol 1.2
equiv) and N-tosylaziridine 17 (490 mg, 1.52 mmol, 1.0 equiv)
were dissolved in 2 mL of freshly distilled methylene chloride
and the silica gel containing the adsorbed starting materials
poured over silica gel (1.0 g) in a 50 mL round-bottomed flask.
The solvent was evaporated under reduced pressure, and the
silica was allowed to stand at rt for a period of 16 h. The silica
gel containing the crude reaction mixture was poured onto a
flash silica gel column and the condensation product purified
by flash chromatography (gradient elution, hexanes/ethyl
acetate 5:1 to 1:1) affording the title compound as a tan solid
3-Indolyl-1H-3-(2,2-dimethyl-3a,4,5,7a-tetrahydrobenzo-
[1,3]dioxolyl)-4-tosylamine (23). Indole (73 mg, 0.621 mmol,
2.0 equiv) and vinyl aziridine 17 (100 mg, 0.311 mmol, 1.0
equiv) were allowed to react on a previously activated silica
gel surface (1.0 g) at 70 °C for 17 h as described in the general
procedure. The silica gel supporting the adsorbed reaction
mixture was loaded onto a flash silica column and eluted with
hexanes/ethyl acetate; 4:1 to 2:1, to give the title compound
as a brown crystalline solid (130 mg, 48%): Rf 0.26 (hexanes/
ethyl acetate, 1:1); [R]19D +59 (c 0.99, CHCl3); IR (film) ν 3389,
3039, 2985, 2931, 1718, 1621, 1599, 1458, 1375, 1246, 1093
cm-1; 1H NMR (400 MHz, CDCl3) δ 8.0 (s, 1H), 7.30-7.15 (m,
4H), 7.10 (m, 1H), 6.97 (m, 2 H), 6.83 (d, J ) 7.5 Hz, 2 H),
5.93 (s, 2H), 5.12 (d, J ) 7.3 Hz, 1H), 4.65 (m, 1H), 4.19 (m,
1H), 3.75 (dd, J ) 17, 8.4 Hz, 1H), 3.49 (d, J ) 9.8 Hz, 1H),
2.26 (s, 3H), 1.51 (s, 3H), 1.35 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 142.3, 138.3, 136.8, 135.9, 129.0, 126.8, 126.6, 123.6,
123.5, 122.2, 119.7, 119.3, 114.1, 110.1, 72.7, 57.5, 39.4, 28.4,
26.4, 21.8; HRMS (EI) calcd for C24H26N2O4S 438.16158, found
438.16114. Anal. Calcd for C24H26N2O4S‚H2O: C, 63.14; H,
6.18. Found: C, 63.32; H, 5.95.
(189 mg, 24%): Rf 0.2 (hexanes/ethyl acetate, 1:1); [R]23
)
D
+58.7 (c 0.985, CHCl3); IR (film) ν 3341, 2984, 2932, 1725,
1598, 1494, 1457, 1372, 1324, 1244, 1218, 1155; 1H NMR (300
MHz, CDCl3) δ 8.25 (bs, 1H), 7.40 (d, J ) 8.0 Hz, 1H), 7.19
(m, 2H), 7.07 (d, J ) 8.5 Hz, 2H), 7.00 (t, J ) 6.7 Hz, 1H),
6.78 (d, J ) 8.0 Hz, 2H), 6.07, (dt, J ) 10.0, 3.6 Hz, 1H), 5.94
(d, J ) 9.7 Hz, 1H), 5.17 (d, J ) 13.3 Hz, 1H), 5.09 (d, J )
13.1 Hz, 1H), 4.71 (m, 2H), 4.17 (dd, J ) 9.5, 5.9 Hz, 1H), 3.76
(m, 1H), 3.53 (m, 1H), 2.25 (s, 3H), 2.14 (s, 3H), 1.53 (s, 3H),
1.41 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 172.5, 141.9, 138.2,
136.2, 136.0, 130.2, 128.7, 126.2, 126.1, 123.7, 122.9, 120.2,
119.8, 113.5, 111.5, 110.1, 78.7, 72.8, 57.5, 57.3, 38.8, 28.3, 26.3,
21.6, 21.2; HRMS (EI) calcd for C27H30N2O6S 510.1846, found
510.1824.
5-(1H-2-Carboxyindol-3-yl)-2,2-dimethyl-3a,4,5,7a-tetra-
hydrobenzo[1,3]dioxol-4-tosylamine (34). To a solution of
acetate 28 (70 mg; 0.14 mmol) in 5 mL of methanol was added
a solution of sodium methoxide in methanol (1.0 M; 68 µL,
0.069 mmol). The solution turned yellow immediately. The
reaction mixture was stirred at rt until complete consumption
of the starting material (15 min). The reaction was quenched
with aq NH4Cl (5 mL), and 15 mL of water was added to the
reaction mixture. The contents of the reaction were transferred
to a separatory funnel and extracted with ethyl acetate (6 ×
20 mL). The combined organic phase was dried over Na2SO4
and the solvent removed in vacuo affording alcohol 32 (62 mg,
97%), which was used in the subsequent reaction without
purification.
3-Indolyl-1H-3-(2,2-dimethyl-3a,4,5,7a-tetrahydrobenzo-
[1,3]dioxole)-4-methylcarbamate (24). To a solution of
indole (0.97 g, 8.29 mmol, 1.6 equiv) and vinyl aziridine 18
(1.0 g, 5.18 mmol, 1.0 equiv) in 20 mL of methylene chloride
was added a catalytic amount of InCl3 (115 mg, 0.52 mmol,
0.1 equiv). The solution was stirred at rt until total consump-
tion of starting material was observed by TLC (24 h). The
solvent was removed under reduced pressure and the residue
purified by flash chromatography (gradient elution, hexanes/
ethyl acetate, 5:1 to 3:1), affording 390 mg of the condensation
product (22%): Rf 0.21 (hexanes/ethyl acetate, 2:1); IR ν 3334,
1
1704, 1532 cm-1; H NMR (300 MHz, CDCl3) δ 8.30 (bs, 1H),
7.79 (d, J ) 7.9 Hz, 1H), 7.57 (d, J ) 8.2 Hz, 1 H), 7.40 (t, J )
7.9 Hz, 1H), 7.32 (m, 2H), 6.28 (d, J ) 9.9 Hz, 1H), 6.18 (dt,
J ) 10.2, 3.5 Hz, 1H), 4.93 (t, J ) 5.0 Hz, 1H), 4.83 (m, 1H),
4.63 (bs, 1H), 4.10 (bs, 1H), 4.01 (t, J ) 9.1 Hz, 1H), 3.68 (bs,
3H), 1.77 (s, 3H), 1.64 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
157.2, 136.9, 136.7, 127.0, 122.8, 122.6, 122.1, 119.1, 115.1,
111.6, 109.8, 76.8, 72.8, 60.5, 55.8, 51.9, 38.3, 28.5, 26.2; HRMS
(EI) calcd for C19H22O4N2 342.1580, found 342.1580.
To a solution of alcohol 32 (50 mg, 0.106 mmol) in 10 mL of
dichloroethane was added PCC (46 mg, 0.212 mmol, 2 equiv).
The solution was stirred at rt until total consumption of the
starting material occurred (1 h). The solvent was removed
under reduced pressure and the residue purified by flash
column chromatography (hexanes/ethyl acetate, 2:1) affording
the title compound 34 (21 mg, 40%): Rf 0.35 (hexanes/ethyl
acetate 1:1); IR (neat) ν 3428, 1644 cm-1; 1H NMR (300 MHz,
J. Org. Chem, Vol. 70, No. 9, 2005 3497

Hudlicky et al.
CDCl3) δ 9.95, (s, 1H), 8.96 (bs, 1H), 7.62 (d, J ) 8.8 Hz, 1H),
7.33 (ddd, J ) 9.3, 6.7, 0.9 Hz, 1H), 7.23 (d, J ) 8.2 Hz, 1H),
7.10 (m, 3H), 6.83 (d, J ) 7.9 Hz, 2H), 6.12 (ddd, J ) 9.6, 6.4,
4.8 Hz, 1H), 6.01 (d, J ) 10.5 Hz, 1H), 5.39 (d, J ) 8.2 Hz,
1H), 4.76 (t, J ) 4.8 Hz, 1H), 4.22 (dd, J ) 9.3, 5.8 Hz, 1H),
4.05 (d, J ) 10.5 Hz, 1 H), 3.92 (m, 1H), 2.26 (s, 3H), 1.54 (s,
3H), 1.42 (s, 3H); HRMS (EI) calcd for C25H26O3N2S 466.1562,
found 466.1575.
3-Indolyl-2-{1H-3-(2,2-dimethyl-3a,4,5,7a-tetrahydro-
benzo[1,3]dioxolyl)-4-tosylamine}carboxylic Acid (36).
To a solution of methyl ester 27 (700 mg; 1.41 mmol) in 15
mL of THF was added a solution of lithium hydroxide (2.50 g;
60 mmol) in water (15 mL). The resulting heterogeneous
reaction mixture was stirred for 14 h at rt. The layers were
separated and the aqueous phase acidified with 1 M HCl to a
pH of approximately 4 before the water layer was extracted
with CH2Cl2 (5 × 10 mL). The combined organic phase was
dried over Na2SO4, and the solvent was removed under
reduced pressure to afford 620 mg (86%) of acid 36 as a pale
yellow oil. The title compound was used in the subsequent
reaction without further purification.
53.4, 36.7, 27.6, 25.6, 21.6; HRMS (EI) calcd for C26H28N2O7S
498.1915, found 498.1437.
N-[(1R,2R,3S,4S,5S,6S)-2-(1,3-Benzodioxol-5-yl)-3,4-ep-
oxy-5,6-(isopropylidenedioxy)cyclohex-1-yl]-5-tert-bu-
toxycarbonyl-3-indolyl-2-(1-tert-butoxycarbonyl)carbox-
ylic Acid Methyl Ester (40). To a suspension of ester 38 (530
mg, 1.03 mmol) in THF (3 mL) was added NaH (60% suspen-
sion in mineral oil; 104 mg, 2.58 mmol). After the hydrogen
formation ceased, (Boc)2O was added (6.0 g, 28 mmol). The
resulting reaction mixture was heated to 40 °C until the
starting material was completely consumed (16 h). The
mixture was poured into a saturated solution of aqueous NH4-
Cl (100 mL) and extracted with ethyl acetate (4 × 50 mL).
The combined organic layer was washed with brine (20 mL)
and dried over anhydrous Na2SO4. The solvent was removed
under reduced pressure and the residue purified by flash
column chromatography (hexanes/ethyl acetate 9:1 to 2:1)
affording the bis-Boc-protected tosylate 39 (642 mg, 0.90 mmol,
88%) as a pale yellow oil as a mixture of atropoisomers: Rf
0.65 (hexanes/ethyl acetate 1:1); [R]20 32.8 (c 1.01, CHCl3);
D
IR ν 3338, 2983, 1734, 1156 cm-1. The epoxide 39 was used
directly in the subsequent reaction.
1-Iodo-2(S),3(S)-hexahydro-2,3-dimethylbenzodioxol-
5(R)-[3-indolyl]-5(R)-toluenesulfonamide (37). To a solu-
tion of acid 36 (1.72 g; 3.57 mmol) in THF (40 mL) was added
NaHCO3 (3.00 g; 35.7 mmol), followed by iodine (3.62 g; 14.3
mmol). The resulting reaction mixture was stirred at rt until
complete consumption of the starting material (16 h). The
reaction mixture was poured into a saturated aqueous solution
of Na2S2O3 (200 mL) and stirred for 30 min to destroy the
excess iodine. The aqueous layer was extracted with ethyl
acetate (4 × 50 mL), the combined organic phase was dried
over Na2SO4, and the solvent was removed under reduced
pressure. The crude material was purified by recrystallization
from hexanes/ethyl acetate affording pure iodolactone 37 (1.54
g; 2.53 mmol; 71%): Rf 0.45 (hexanes/ethyl acetate 1:1); mp
224-225 °C dec (ethyl acetate); [R]22D +6.22 (c 0.201, acetone);
To a solution of tosylate 39 (662 mg; 0.93 mmol) in dry DME
(8 mL) was added a solution of sodium naphthalide (0.54 M)
at -65 °C until the characteristic deep blue-green color
persisted. The reaction mixture was stirred an additional 10
min at this temperature before it was quenched with a
saturated solution of aqueous NH4Cl (20 mL) and warmed to
rt. Water was added (50 mL), and the aqueous layer was
extracted with ethyl acetate (5 × 20 mL). The combined
organic layer was washed with brine (15 mL) and dried over
Na2SO4. The solvent was removed under reduced pressure and
the residue was purified by flash column chromatography
(hexanes/ethyl acetate, 5:1 to 1:1) to afford detosylated mate-
rial (370 mg; 0.66 mmol; 71%) as pale, yellow oil: Rf 0.20
(hexane/ethyl acetate, 1:1); [R]20 -8.8 (c 1.1, CHCl3); IR ν
D
1
cm-1; 3354, 2981, 1727 cm-1; H NMR (300 MHz, CD3OD) δ
1
IR ν 3303, 2962, 2923, 1713 cm-1; H NMR (300 MHz, CD3-
8.14 (bs, 1 H), 7.99 (d, J ) 8.2 Hz, 1 H), 7.34 (t, J ) 7.6 Hz, 1
H), 7.23 (t, J ) 7.7 Hz, 1 H), 4. 60 (m, 2 H), 4.14 (bs, 2 H), 3.87
(s, 3 H) 3. 87 (bs, 1 H), 3.51 (bs, 1 H), 3.42 (d, J ) 3.5 Hz, 1 H),
1.56 (s, 9 H), 1.53 (s, 3 H), 1.33 (s, 3 H), 1.06 (bs, 6 H), 0.86
(bs, 3 H); HRMS (EI) calcd for C29H38N2O6 558.2566, found
558.2591.
OD) δ 7.55 (d, J ) 8. 1 Hz, 1 H), 7.18 (m, 2 H), 6.93 (m, 2 H),
6.72 (d, J ) 8.0 Hz, 2 H), 5.05 (t, J ) 3.8 Hz, 1 H), 4.81 (s,
1H), 4.59 (t, J ) 5.6 Hz, 1 H), 4.53 (t, J ) 5.1 Hz, 1 H), 4.32
(dd, J ) 8.2, 5.3 Hz, 1 H), 3.70 (dd, J ) 12.0, 8.6 Hz, 1 H),
3.54 (dd, J ) 12.1, 3.5 Hz, 1 H), 3.35 (s, 3H), 2.20 (s, 3 H),
1.33 (s, 3 H), 1.21 (s, 3 H); 13C NMR (75 MHz, CD3OD) δ 160.1,
142.2, 138.9, 138.7, 128.6, 126.1, 125.6, 125.4, 123.0, 121.6,
121.3, 120.8, 112.7, 110.2, 85.8, 79.5, 78.7, 55.7, 35.0, 28.5, 27.4,
24.9, 24.1, 20.4; HRMS (EI) calcd for C25H25O6N2SI 608.0110,
found 608.0502.
(1R,2R,3S,4S,4aS)-12c-Hexahydro-1,2-epoxy-3,4-benzo-
dioxolylindolyl[2,3-c]-6(5H)-quinolinone (41). To a solu-
tion of bis-Boc derivative 40 (100 mg; 0.18 mmol) in CH2Cl2
(5 mL) was added silica gel (500 mg; 200-400 mesh). The
solvent was removed under reduced pressure, and the ad-
sorbed material was suspended in water (10 mL) and heated
to 140 °C in a sealed tube until total consumption of the
starting material (1.5 h). The reaction mixture was cooled to
rt; the silica gel was removed by filtration and washed with
warm ethyl acetate (5 × 5 mL). The layers were separated,
and the aqueous layer was extracted with ethyl acetate (5 ×
5 mL). The combined organic layer was dried over Na2SO4,
the solvent was removed under reduced pressure, and the
residue was purified by flash column chromatography (chlo-
roform/methanol, 19:1 to 9:1) affording epoxyacetonide 41 as
pale yellow crystals (55 mg, 0.17 mmol, 94%):
N-[(1R,2R,3S,4S,5S,6S)-2-(1,3-Benzodioxol-5-yl)-3,4-di-
hydroxy-5,6-(isopropylidenedioxy)cyclohex-1-yl]-5-tolu-
enesulfonamide-3-indolyl-2-methyl Ester (38). To a solu-
tion of LiOMe in methanol, freshly prepared by dissolving
lithium wire (11 mg; 1.6 mmol) in methanol (2 mL), was added
a solution of iodolactone 37 (200 mg; 0.33 mmol) in methanol
(5 mL). The reaction mixture was allowed to stir at room
temperature until total consumption of the starting material
(16 h). The reaction was quenched with 10 mL of NH4Claq,
water (10 mL) was added, and the solution was extracted with
diethyl ether (3 × 20 mL). The combined organic layer was
washed with brine and dried over Na2SO4, and the solvent was
removed under reduced pressure. The crude residue was
purified by flash column chromatography (hexanes/ethyl ac-
etate 9:1) to provide the desired ester 38 (143 mg; 0.28 mmol;
85%) as a colorless oil: Rf 0.20 (chloroform/ methanol, 4:1);
Rf 0.80 (chloroform/methanol, 9:1); [R]23 +4.12 (c 0.21
D
CHCl3); mp >250 °C; IR ν 3375, 2919, 2522, 1663 cm-1
;
1H
NMR (300 MHz, CDCl3) δ 9.34 (bs, 1 H); 7.75 (d, J ) 8.1 Hz,
1 H), 7.43 (d, J ) 8.3 Hz, 1 H), 7.28 (t, J ) 7.6 Hz, 1 H), 7.12
(t, J ) 7.5 Hz, 1 H), 5.69 (bs, 1 H), 4.63 (dd, J ) 6.9, 3.5 Hz,
1 H), 4.31 (d, J ) 3.7 Hz, 1 H), 4.06 (dd, J ) 9.9, 7.1 Hz, 1 H),
3.91 (t, J ) 11.3 Hz, 1 H), 3.60 (t, J ) 3.6 Hz, 1 H), 3.47 (d,
J ) 12.8 Hz, 1 H), 1.45 (s, 3 H), 1.35 (s, 3 H); 13C NMR (75
MHz, CDCl3) δ 162.8, 137.7, 127.5, 125.7, 124.9, 121.6, 118.1,
113.3, 113.2, 110.5, 76.1, 72.9, 54.9, 53.1, 50.8, 35.6, 27.9, 25.8;
HRMS (EI) calcd for C18H18N2O4 326.1274, found 326.1263.
[R]20D +69 (c 0.82, CH3OH); IR ν 3318, 3267, 2989, 1689 cm-1
;
1H NMR (300 MHz, CD3OD) δ 8.5 (bs, 1H), 7.93 (d, J ) 8.3
Hz, 1 H), 7.21 (m, 2 H), 6.99 (m, 2 H), 6.92 (d, J ) 8.2 Hz, 2
H), 6.69 (d, J ) 8.1 Hz, 2 H), 5.15 (d, J ) 8.3 Hz, 1H), 4.68
(dd, J ) 7.5, 3.0 Hz, 1 H), 4.27 (d, J ) 11.7 Hz, 1 H), 4.08 (t,
J ) 8.1 Hz, 1 H), 3.92 (s, 3H), 3.50 (t, J ) 3.6 Hz, 1 H), 3.33
(m, 1 H), 2.20 (s, 3 H). 1.55 (s, 3 H), 1.36 (s, 3 H); 13C NMR (75
MHz, CD3OD) δ 166.2, 142.9, 139.5, 138.0, 129.6, 127.4, 126.4,
125.8, 123.6, 121.1, 120.8, 113.5, 110.9, 81.1, 74.9, 58.2, 57.1,
(1R,2S,3S,4S,4aS)-12c-Hexahydro-1,2,3,4-tetraolindolyl-
[2,3-c]-6(5H)-quinolinone (10). To a solution of epoxide 40
3498 J. Org. Chem., Vol. 70, No. 9, 2005

Reactions of Indole Derivatives with Oxiranes and Aziridines
(55 mg; 0.17 mmol) in ethyl acetate (8 mL) was added silica
gel (500 mg; 200-400 mesh). The solvent was removed under
reduced pressure, and the adsorbed material was suspended
in water (8 mL) and heated to 170 °C in a sealed tube for 13
h. The reaction mixture was cooled to rt, the water was
removed by azeotropic distillation with benzene under reduced
pressure, and the remaining residue was subjected to purifica-
tion by flash column chromatography (chloroform/methanol 9:1
to 4:1) affording the indole mimic 10 as a yellow crystalline
solid (16 mg; 0.053 mmol; 31%): Rf 0.20 (chloroform/methanol
2.02 (s, 3 H), 1.84 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 171.9,
170.6, 169.8, 168.7, 160.3, 139.6, 129.1, 128.8, 128.4, 124.8,
124.6, 121.0, 116.4, 70.6, 68.1, 67.9, 67.4, 49.2, 39.6, 28.1, 21.2,
21.1, 21.0, 21.0; HRMS (EI) calcd for C25H26N2O10 514.1800,
found 514.1576.
Acknowledgment. We gratefully acknowledge the
following agencies for generous support of this work:
National Science and Engineering Research Council
(NSERC), the Canadian Foundation for Innovation, the
Ontario Innovation Trust, Brock University, the donors
of the Petroleum Research Fund, administered by the
American Chemical Society (PRF-38075-AC), TDC Re-
search Inc., and TDC Research Foundation. We also
thank Professor Pettit (Arizona State University), Dr.
Jean-Charles Chapuis, and Dr. Jean M. Schmidt for
biological screening of some of the compounds (complete
results of the biological screening were reported in the
preliminary communication).16 Brock University is
thanked for providing a graduate fellowship for K.F. We
are grateful to Dr. Gregg Whited (Genencor Interna-
tional, Inc.) and Professor Rebecca Parales (UC-Davis)
for their helpful discussions and assistance regarding
whole-cell fermentations.
4:1); [R]22 +25 (c 0.40, MeOH); IR ν 3270, 2922, 1644 cm-1
;
D
1H NMR (300 MHz, DMSO-d6) δ 11.73 (s, 1 H), 7.72 (d, J )
8.0 Hz, 1 H), 7.46 (d, J ) 8.2 Hz, 1 H), 7.26 (t, J ) 7.5 Hz,
1 H), 7.09 (t, J ) 7.4 Hz, 1 H), 6.58 (s, 1 H), 5.43 (d, J ) 3.4
Hz, 1 H), 5.14 (m, 2 H), 4.08 (m, 2 H); 13C NMR (75 MHz,
DMSO-d6) δ 162.7, 138.2, 128.8, 125.1, 124.6, 122.6, 120.3,
120.2, 113.4, 74.5, 71.8, 70.9, 70.3, 53.7, 39.4; HRMS (EI) calcd
for C15H16N2O5 304.1059, found 304.1055.
(1R,2S,3S,4S,4aS)-12c-Hexahydro-1,2,3,4-tetraacetatein-
dolyl[2,3-c]-6(5H)-quinolinone (42). To a solution of tetrol
10 (20 mg, 0.082 mmol) in pyridine (3 mL) were added acetic
anhydride (3 mL) and a catalytic amount of DMAP. The
solution was stirred at rt for 48 h (until total consumption of
the starting material as determined by TLC) before the solvent
was removed under reduced pressure. The residue was purified
by flash column chromatography (hexanes/ethyl acetate, 2:1)
to afford pure pentaacetate 42 as yellow oil (31 mg, 72%): Rf
0.20 (hexanes/ethyl acetate, 1:1); [R]23D +151 (c 0.65, acetone);
IR ν 2926, 1755, 1669 cm-1; 1H NMR (300 MHz, CDCl3) δ 8.21
(d, J ) 8.6 Hz, 1 H), 7.48 (d, J ) 8.1 Hz, 1 H), 7.41 (t, J ) 7.8
Hz, 1 H), 7.20 (t, J ) 7.6 Hz, 1 H), 6.33 (s, 1 H), 5.85 (m, 1 H),
5.44 (t, J ) 2.8 Hz, 1 H), 5.29 (t, J ) 2.7 Hz, 1 H), 5.21 (dd,
J ) 11.1, 3.4 Hz, 1 H), 4.46 (t, J ) 12.0 Hz, 1 H), 3.62 (dd,
J ) 12.9, 3.1 Hz, 1 H), 2.68 (s, 3 H), 2.14 (s, 3 H), 2.04 (s, 3 H),
Supporting Information Available: 1H and 13C NMR
spectra are available for compounds 10, 19-23, 37, 38, 41,
1
and 42. H NMR spectra are available for compounds 24, 27,
28, and 40. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO040292C
J. Org. Chem, Vol. 70, No. 9, 2005 3499