Cyclopropylazetoindolines as precursors to C(3)-quaternary-substituted indolines

Article abstract of DOI:10.1021/ja103428y

This manuscript describes the generation and use of a cyclopropylazetoindoline, a novel fused heterocycle, in coupling reactions with hetero- and carbon nucleophiles to give C(3)-quaternary-substituted pyrroloindolines.

Full text of DOI:10.1021/ja103428y

Published on Web 06/02/2010
Cyclopropylazetoindolines as Precursors to C(3)-Quaternary-Substituted
Indolines
Vinson R. Espejo, Xi-Bo Li, and Jon D. Rainier*
Department of Chemistry, UniVersity of Utah, 315 South 1400 East, Salt Lake City, Utah 84112
Received April 22, 2010; E-mail: rainier@chem.utah.edu
Scheme 2. Hall’s Synthesis of Bicyclo[2.1.0] Analogue 4
Table 1. Cyclopropylazetoindoline Formation
In light of their presence in a wide variety of structurally complex
and biologically active substrates, including those shown in Figure
1,1-3 it is not surprising that C(3)-quaternary-substituted pyrro-
loindolines have received a significant amount of attention from
the synthetic and medicinal chemistry communities.4,5 While a
number of very elegant approaches to these structures have been
described,6 new and especially more general routes are still needed.
Outlined here are our efforts to help to address this problem through
the use of a new class of fused heterocycles, cyclopropylazetoin-
dolines, as useful electrophiles in the synthesis of C(3)-quaternary-
substituted pyrroloindolines.
entry
equiv of KOt-Bu
solvent
yield of 5a
5:6:1b
1
2
3
4
5
1.0
1.2
1.5
2.0
1.2
CH3CN
CH3CN
CH3CN
CH3CN
THF
45%
55%
20%
1:0:1
11:3:5
1:2:1
0%
89-95%
0:1:0c
1:0:0
a Isolated yield. b Determined by 1H NMR analysis of the crude
reaction mixture. c 6 was isolated in 42% yield.
Scheme 3. Decomposition of 5
Figure 1. C(3)-quaternary-substituted pyrroloindoline natural products.
Scheme 1. Mechanistic Hypothesis for the Coupling Chemistry of 1
of this reaction was contingent upon the generation of enolate A
and proposed that A is involved in assisting the bromide in leaving
via cyclopropylazetoindoline transient B (Scheme 1).
In spite of the extensive use of pyrroloindolines in synthetic
chemistry,9 to the best of our knowledge, cyclopropylazetoindolines
such as B are unique. Thus, we became intrigued with the question
of whether cyclopropylazetoindolines are isolable, and if they are,
whether their subsequent reactivity would match the reactivity of
bromopyrroloindoline 1. We were at least partly driven to answer
these questions by an earlier report from Hall describing the
synthesis, isolation, and use of bicyclo[2.1.0]pentane 4 in anionic
polymerization reactions (Scheme 2).10,11
As part of our synthesis of C(3)-N(1′) indoline dimers, including
members of the kapakahine family, we recently reported that
bromopyrroloindoline 1, which is readily available in a single step
in high diastereoselectivity from the corresponding tryptophan
derivative,7 undergoes a novel anionic coupling reaction with
indoles that leads to the stereoselective generation of C(3)-
quaternary-substituted pyrroloindolines such as 2 (Scheme 1).8
During preliminary mechanistic studies, we found that the success
With the isolation of the cyclopropylazetoindoline as our target,
we studied the behavior of bromopyrroloindoline 1 when it was
subjected to KOt-Bu in the absence of nucleophile. Our initial
9
8282 J. AM. CHEM. SOC. 2010, 132, 8282–8284
10.1021/ja103428y  2010 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Reactions of Cyclopropylazetoindoline 5 with Nucleophiles
entry
nucleophile (equiv)
conditions
R
product
yield
1
2
3
4
5
6
7
8
indole (1.5)
NaBH4 (10)
NaN3 (10)
C6H5OH (5)
p-MeOC6H4OH (5)
p-NO2C6H4OH (5)
C6H5SH (5)
p-NO2C6H4SH (5)
AlMe3 (2)
KCN (10)
CH3NO2
CNCH2CN (10)
methyl acetoacetate (5)
p-MeC6H4MgBr, CuCN (5)
KOt-Bu, CH3CN, 0 °C, 5 min
THF, rt, 2 h
PPTS, DMF, rt, 2 h
DBU, THF, rt, 6 h
DBU, THF, rt, 10 h
DBU, THF, rt, 48 h
DBU, THF, rt, 5 h
DBU, THF, rt, 1 h
CH2Cl2, -40 to 0 °C, 0.5 h
PPTS, 18-crown-6, THF, rt, 4 h
DBU, THF:CH3NO2 (4:1), rt, 2 h
DBU, THF, rt, 2 h
DBU, THF, rt, 2 h
THF, -78 °C, 15 min
N-indolyl
H
N3
2-endo
8
9
70%
75%
72%
70%
76%
70%
84%
80%
76%
70%
50%
60%
75%
70%
C6H5O
10
11
12
13
14
15
16
17
18
19
20
p-MeOC6H4O
p-NO2C6H4O
C6H5S
p-NO2C6H4S
Me
CN
CH2NO2
CNCHCN
CH3C(O)CHCO2CH3
p-MeC6H4
9
10
11
12
13
14
Scheme 4. Enantioselective Formal Synthesis of
(-)-Physostigmine
conditions with a wide range of hetero- and carbon nucleophiles.
For example, 5 reacts with excess indole (1.5 equiv) in the presence
of a substoichiometric quantity of KOt-Bu (0.5 equiv) to give
heterodimer 2-endo as the exclusive product in 70% yield (Table
2, entry 1). This result represents an improvement over the original
heterodimerization reaction in that the original reaction required
excess bromopyrroloindoline 1 and gave a mixture of 2-endo and
2-exo isomers. Other nucleophiles that react with 5 include inorganic
salts [hydride, azide, and cyanide (Table 2, entries 2, 3, and 10)],
phenols and thiophenols (entries 4-8), CH acids [nitromethane,
malononitrile, and methyl acetoacetate (entries 11-13)], and carbon
nucleophiles [AlMe3 and aryl cuprate (entries 9 and 14)]. It is
noteworthy that all of these reactions gave C(3)-substituted indolines
with high diastereoselectivity (>95:5 endo:exo) and that bromopy-
rroloindoline 1 was inert under all of the reaction conditions except
those used in entry 1.14,15
experiments were run in CH3CN and utilized 1.2 equiv of KOt-
Bu, and they resulted in a mixture of products that included
acetonitrile adduct 6, recovered starting material 1, and, to our
delight, cyclopropylazetoindoline 5 in 55% yield (Table 1, entry
2). The structure of 5 was elucidated both spectroscopically (see
the Supporting Information) and chemically (see below).
As also indicated in Table 1, attempts to optimize the generation
of 5 by modifying the amount of base were generally unsuccessful:
the use of equimolar KOt-Bu led to the recovery of an increased
amount of 1 (entry 1), while the use of larger amounts of KOt-Bu
resulted in increased amounts of acetonitrile adduct 6 (entries 3
and 4). In an attempt to avoid the formation of 6, we also examined
the reaction in THF and were delighted to find that this modification
had a dramatic effect on the reaction in that 5 could be generated
in yields of 89-95% on a gram scale (entry 5). In addition to the
efficiency of its synthesis, we were surprised by the stability of 5,
as it did not undergo noticeable decomposition when subjected to
SiO2 chromatography and was stable when stored for several weeks
at 0 °C.
Having established conditions for the synthesis of 5, we next
carried out a study of its reactivity. We were hopeful that 5 would
react with nucleophiles not only as a result of its inherent strain
and its being a “donor-acceptor” cyclopropane12 but also because
of its proposed intermediacy in our earlier studies. As an indication
of its reactivity, we found that 5 undergoes both a thermal and a
Lewis acid-mediated decomposition to indole 7.13 This transforma-
tion presumably occurs via intermediates C and D, as illustrated
in Scheme 3.
To demonstrate the applicability of this new methodology, we
carried out a formal synthesis of the anticholinergic agent (-)-
physostigmine (Scheme 4).16 To this end, decarboxylation of the
methyl adduct 15 resulted in the generation of pyrroloindoline 21
after removal of the Boc groups and bismethylamine formation
(Scheme 4). The synthesis of 21 intercepts an intermediate used in
the synthesis of (()-physostigmine by Kulkarni and co-workers.17
In summary, this communication has described a unique and
facile entry into quaternary-substituted indolines that takes advan-
tage of the inherent reactivity of cyclopropylazetoindoline 5, which
represents a novel class of fused heterocycle. We intend to continue
studying the reactivity profile of 5 and its application to the synthesis
of biologically active indolines, including natural products.
Acknowledgment. We are grateful to the National Science
Foundation for financial support of this work and to the Center for
High Performance Computing for computer time. We thank the
support staff at the University of Utah and especially Dr. Peter
Flynn (NMR) and Dr. Jim Muller (mass spectrometry) for help in
obtaining data and Dr. Anita Orendt for performing the DFT
calculations on 5.
Supporting Information Available: General experimental procedure
for the cyclization reaction and spectroscopic data for all new cyclic
compounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
In addition to the decomposition studies outlined above, we were
pleased to find that 5 reacts as an electrophile under relatively mild
9
J. AM. CHEM. SOC. VOL. 132, NO. 24, 2010 8283

C O M M U N I C A T I O N S
W. G.; Danishefsky, S. J. J. Am. Chem. Soc. 1999, 121, 11953–11963. (c)
Crich, D.; Huang, X. J. Org. Chem. 1999, 64, 7218–7223. (d) Schiavi,
B. M.; Richard, D. J.; Joullie´, M. M. J. Org. Chem. 2002, 67, 620–624. (e)
Kamenecka, T. M.; Danishefsky, S. J. Chem.sEur. J. 2001, 7, 41. (f) Ley,
S. V.; Cleator, E.; Hewitt, P. R. Org. Biomol. Chem. 2003, 1, 3492–3494.
(g) Yamada, F.; Fukui, Y.; Iwaki, T.; Ogasawara, S.; Okigawa, M.; Tanaka,
S.; Somei, M. Heterocycles 2006, 67, 129–134. (h) Hong, W.-X.; Chen,
L.-J.; Zhong, C.-L.; Yao, Z.-J. Org. Lett. 2006, 8, 4919–4922.
References
(1) (a) Brewer, D.; McInnes, A. G.; Smith, D. G.; Taylor, A.; Walter, J. A.;
Loosli, H. R.; Kis, Z. L. J. Chem. Soc., Perkin Trans. 1 1978, 1248–1251.
(b) Geiger, W. B.; Conn, J. E.; Waksman, S. A. J. Bacteriol. 1944, 48,
531–536. (c) Waksman, S. A.; Bugie, E. J. Bacteriol. 1944, 48, 527–530.
(2) Varoglu, M.; Corbett, T. H.; Valeriote, F. A.; Crews, P. J. Org. Chem.
1997, 62, 7078–7079.
(3) Tuntiwachwuttikul, P.; Taechowisan, T.; Wanbanjob, A.; Thadaniti, S.;
Taylor, W. C. Tetrahedron 2008, 64, 7583–7586.
(4) For recent examples of biological studies of quaternary-substituted indolines,
see: (a) Cook, K. M.; Hilton, S. T.; Mecinovic, J.; Motherwell, W. B.;
Figg, W. D.; Schofield, C. J. J. Biol. Chem. 2009, 284, 26831–26838. (b)
(10) Hall, H. K., Jr. Macromolecules 1971, 4, 139–142.
(11) A bicyclo[2.1.0]pyrrolidine analogue has been isolated from the fermentation
of Streptomyces azomyceticus. See: Kodama, Y.; Ito, T. Agric. Biol. Chem.
1980, 44, 73–76.
(12) For reviews of the synthesis and reactivity of donor-acceptor cyclopro-
panes, see: (a) Reissig, H.-U.; Zimmer, R. Chem. ReV. 2003, 103, 1151–
1196. (b) Yu, M.; Pagenkopf, B. L. Tetrahedron 2005, 61, 321–347.
´
Rivera-Becerril, E.; Joseph-Nathan, P.; Pe´rez-Alvarez, V. M.; Morales-
R´ıos, M. S. J. Med. Chem. 2008, 51, 5271–5284. (c) Philippe, G.; Angenot,
L.; Tits, M.; Fre´de´rich, M. Toxicon 2004, 44, 405–416.
(13) Kometain, M.; Ihara, K.; Kimura, R.; Kinoshita, H. Bull. Chem. Soc. Jpn.
(5) For reviews that discuss quaternary-substituted indolines, see: (a) Steven,
A.; Overman, L. E. Angew. Chem., Int. Ed. 2007, 46, 5488–5508. (b) Cozzi,
P. G.; Hilgraf, R.; Zimmerman, N. Eur. J. Org. Chem. 2007, 5969–5994.
(c) Ramon, D. J.; Yus, M. Curr. Org. Chem. 2004, 8, 149–183. (d)
Denissova, I.; Barriault, L. Tetrahedron 2003, 59, 10105–10146. (e)
Dounay, A. B.; Overman, L. E. Chem. ReV. 2003, 103, 2945–2963.
(6) For recent examples, see ref 5 and: (a) Eastman, K.; Baran, P. S.
Tetrahedron 2009, 65, 3149–3154. (b) Kim, J.; Ashenhurst, J. A.;
Movassaghi, M. Science 2009, 324, 238–241. (c) Newhouse, T.; Baran,
P. S. J. Am. Chem. Soc. 2008, 130, 10886–10887. (d) Marsden, S. P.;
Watson, E. L.; Raw, S. A. Org. Lett. 2008, 10, 2905–2908. (e) Matsuda,
Y.; Kitajima, M.; Takayama, H. Org. Lett. 2008, 10, 125–128. (f) Govek,
S. P.; Overman, L. E. Tetrahedron 2007, 63, 8499–8513. (g) Austin, J. F.;
Kim, S.-G.; Sinz, C. J.; Xiao, W.-J.; MacMillan, D. W. C. Proc. Natl.
Acad. Sci. U.S.A. 2004, 101, 5482–5487.
2009, 82, 364–380.
(14) Density functional theory (DFT)-calculated bond lengths for 5 matched
the observed reactivity pattern (see Table 2 for the numbering scheme):
C(2)-C(4) ) 1.57 Å, C(3)-C(4) ) 1.48 Å, and C(2)-C(3) ) 1.51 Å.
See the Supporting Information for details.
(15) Although we cannot rule out an SN1 mechanism in which nucleophilic
addition to an intermediate like C (Scheme 3) results in the observed
products, an examination of the C(2)-C(4) bond in the minimized structure
leads us to speculate that an SN2 addition to the cyclopropane leads to
product formation. A more detailed mechanistic investigation is a subject
for future work. For a discussion of related cyclopropane ring-opening
reactions in the CC-1065 and duocarmycin families, see: Boger, D. L.;
Turnbull, P. J. Org. Chem. 1997, 62, 5849–5863.
(16) (a) Jobst, J.; Hesse, O. Justus Liebigs Ann. Chem. 1864, 129, 115–118. (b)
´
Stedman, E.; Barger, G. J. Chem. Soc., Trans. 1925, 127, 247–258.
(7) Lo´pez, C. S.; Pe´rez-Balado, C.; Rodr´ıguez-Gran˜a, P.; de Lera, A. R. Org.
Lett. 2008, 10, 77–80.
(17) (a) Kulkarni, M. G.; Dhondge, A. P.; Borhade, A. S.; Gaikwad, D. D.;
Chavhan, S. W.; Shaikh, Y. B.; Ningdale, V. B.; Desai, M. P.; Birhade,
D. R.; Shinde, M. P. Tetrahedron Lett. 2009, 50, 2411–2413. (b) Node,
M.; Itoh, A.; Masaki, Y.; Fuji, K. Heterocycles 1991, 32, 1705–1707.
(8) (a) Espejo, V. R.; Rainier, J. D. J. Am. Chem. Soc. 2008, 130, 12894–
12895. (b) Espejo, V. R.; Rainier, J. D. Org. Lett. 2010, 12, 2154–2157.
(9) For representative examples, see ref 6b and: (a) Marsden, S. P.; Depew,
K. M.; Danishefsky, S. J. J. Am. Chem. Soc. 1994, 116, 11143–11144. (b)
Depew, K. M.; Marsden, S. P.; Zatorska, D.; Zatorski, A.; Bornmann,
JA103428Y
9
8284 J. AM. CHEM. SOC. VOL. 132, NO. 24, 2010