Access to the pyrroloindoline core via [3 + 2] annulation as well as the application in the synthetic approach to (±)-minfiensine

Article abstract of DOI:10.1021/acs.orglett.5b03421

A [3 + 2] formal cycloaddition reaction using aza-oxyallyl cation as a synthetic synthon was developed to construct the pyrroloindololine core. With this novel method, a variety of C3-substituted indoles were readily converted into the corresponding pyrroloindoline analogues at room temperature in the mixed solvents. To further demonstrate the utility of this method, a synthetic approach to the total synthesis of (±)-minfiensine was developed in quite concise fashion.

Full text of DOI:10.1021/acs.orglett.5b03421

Letter
pubs.acs.org/OrgLett
Access to the Pyrroloindoline Core via [3 + 2] Annulation as well as
the Application in the Synthetic Approach to ( )-Minfiensine
Wenzhi Ji, Licheng Yao, and Xuebin Liao*
Department of Pharmacology and Pharmaceutical Sciences, School of Medicine, Collaborative Innovation Center for Diagnosis and
Treatment of Infectious Diseases, Tsinghua University, Beijing 100084, China
S
* Supporting Information
ABSTRACT: A [3 + 2] formal cycloaddition reaction using
aza-oxyallyl cation as a synthetic synthon was developed to
construct the pyrroloindololine core. With this novel method, a
variety of C3-substituted indoles were readily converted into
the corresponding pyrroloindoline analogues at room temper-
ature in the mixed solvents. To further demonstrate the utility
of this method, a synthetic approach to the total synthesis of
( )-minfiensine was developed in quite concise fashion.
ndole alkaloids containing a pyrroloindoline motif are
present in a variety of natural products (Figure 1).1 Their
alkylindoles as the reaction partners.6 Soon after this report, the
Chai and Wang groups disclosed a kinetic resolution approach
to pyrroloindoline cores by copper(I) catalyzed asymmetric [3
+ 2] annulations of indoles with racemic 2-arylaziridines.7
Along with this approach, we decided to develop another 1,3-
dipolar synthon coupled with C3-substitued indoles to furnish
[3 + 2] annulations.
I
Due to their unique chemical features of aza-oxyallyl cations,
this chemistry immediately drew our attention when we started
our investigations. In 1960s, the aza-oxyallyl cation was
suggested as the reaction intermediate when Sheehan studied
α-lactam chemistry.8 In 1993, the Sakamoto group showed the
most convincing evidence for aza-oxyally cation intermediates.9
However, only until 2011, Jeffrey group reported the first
example involving aza-oxyally cations in his pioneering work on
[4 + 3]-cycloaddition reaction.10 Inspired by his elegant and
original studies, we embarked on the exploration of the
possibilities regarding [3 + 2] annulation involving aza-oxyally
cations with C3-substituted indoles to construct pyrroloindo-
lines while applying this reaction in the synthesis of related
indole alkaloids. Unsurprisingly, the Jeffrey group and Wu
group very recently realized a similar strategy to construct
pyrroloindoline scaffolds.11
Figure 1. Some natural products containing hexahydropyrrolo[2,3-
b]indole core.
unique structural features and versatile biological activities
make them very special synthetic targets for organic chemists.
Consequently, lots of new methods for the construction of
pyrroloindoline scaffold were developed during the past decade.
In particular, the methods using tryptamine or its derivatives as
the starting materials were intensively explored.2 However, the
direct utilization of indole or C3-substituted indoles to
construct pyrroloindoline scaffold remains to be extensively
investigated.3 Recently, the Reisman group reported a highly
enantioselective [3 + 2]-cycloaddition reaction employing C3-
substitued indoles and 2-aminoacrylate to construct pyrroloin-
doline analogues.4 Later on, the Davis group developed a
rhodium(II) catalyzed [3 + 2]-cycloaddition reaction to prepare
enantioenriched pyrroloindolines.5 More recently, the Wang
group reported a method to construct pyrroloindolines with
excellent enantioselectivities by using meso-aziridine and C3-
We explored the model reaction using N-benzyl-3-methyl-
indole and N−H or substituted α-haloamides as the reaction
substrates. Initially, the model reaction was attempted under
the Fohlisch conditions.12 However, when both starting
̈
materials were subjected to the standard conditions using
TFE (trifluoroethanol) as the single solvent, we encountered a
problem related to the solubilities. Thus, we quickly switched to
use the mixed solvents (TFE/DCM, 10/1) to run the model
reaction. To our delight, the desired product was obtained in
38% yield in the mixed solvents and with Et3N as base (Table 1,
Received: December 3, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03421
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of Reaction Conditions
Scheme 1. Substrate Scope of the [3 + 2] Annulation with
C3-Substituted Indoles
a
b
entry
R
base
solvent
yield (%)
1
OBn
OBn
OBn
OBn
OBn
OBn
OBn
OBn
OBn
H
Et3N
CF3CH2OH/DCM (10/1)
HFIP/DCM (10/1)
HFIP/DCM (10/1)
DCM
38
76
96
0
2
Et3N
3
K2CO3
Et3N
4
5
Et3N
THF
0
6
Et3N
dioxane
0
7
Et3N
toluene
0
8
Et3N
DMF
0
9
Et3N
CH3CN
0
10
11
K2CO3
K2CO3
HFIP/DCM (10/1)
HFIP/DCM (10/1)
0
Bn
0
a
Conditions: 7 (1.0 equiv), α-haloamides (1.5 equiv), base (2.0
b
equiv), and solvent (1.0 M) at room temperature. Isolated yield.
entry 1). Changing the solvent from TFE to HFIP
(hexafluoroisopropanol) further improved the yield to 76%
(Table 1, entry 2). When we replaced organic base Et3N with
inorganic base K2CO3, excellent yield was achieved in the
mixed solvents (Table 1, entry 3). As anticipated, when R was a
hydrogen or benzyl group, the corresponding product could
not be obtained (Table 1, entry 10 or 11). In addition, the
reaction was attempted in different solvents, no desired product
was observed (Table 1, entry 4−9).
With the optimized conditions in hand, we began to explore
the scope of this cycloaddition reaction (Scheme 1). Different
3-substituted N-methylindoles were first investigated. The
different functional groups including ester, nitrile, ether, olefin,
protected amine, and fluorophenyl are all tolerated in the
reaction conditions. Good to high yields were obtained
(Scheme 1, 10a and 10c−g). When R1 was a hydrogen or
isopropyl group, the reaction proceeded smoothly to afford the
corresponding product in good yield (Scheme 1, 10b or 10h).
When 2,3-substituted N-methylindole was used as a substrate,
the desired product was formed in 87% yield (Scheme 1, 10i).
This result inspired us to apply this method later on in the total
synthesis of the complex natural products. When indole ring
contains an electron-donating or electron-withdrawing group,
the reaction with 2-bromo-2-methyl-N-(phenylmethoxy)-
propanamide occurred in good yield (Scheme 1, 10j−o).
When N-(benzyloxy)-2,2,2-trichloroacetamide was used as a
precursor of the aza-oxyallyl cation, the reaction still occurred
in 83% yield (Scheme 1, 10p). Then when N-(benzyloxy)-2,2-
dichloroacetamide was subjected to the reaction conditions, the
reaction also occurred in good yield to provide a 1:1
diastereomeric ratio of the mixed compounds (Scheme 1,
10q). As anticipated, when other monomethyl substituted α-
haloamides were utilized as starting materials, the mixture of
diastereomers with 1:1 ratio was obtained in moderate to good
yield (Scheme 1, 10r and 10s). Notably, product 10s was
obtained just in moderate yield because the reaction occurred
to afford a small amount of oxindole byproducts via an
intramolecular pathway except the desired product.
a
Conditions: 9 (0.20 mmol), α-haloamides (0.30 mmol), K2CO3 (0.40
mmol) in HFIP/DCM (2.0 mL/0.20 mL) at room temperature.
the synthesis of complex indole alkaloids. An indole alkaloid,
minfiensine, has received lots of attention from the synthetic
community due to its unique structural features.13 Different
synthetic pathways were applied in the total synthesis of
minfiensine.14 Herein, we reported our synthetic approach to
minfiensine based on this novel [3 + 2]-cycloaddition reaction
(Scheme 2). Our synthesis began with this [3 + 2] annulation
between N-(benzyloxy)-2,2,2-trichloroacetamide and com-
pound 11, which is commercially available. The reaction
occurred in 72% yield to afford compound 12. To reductively
cleave both C−Cl and N−OBn bonds, different reaction
conditions were attempted. SmI2 was initially found to cleave
both C−Cl and N−OBn bonds to afford the desired product
13. Although SmI2 in THF solution is commercially available, it
is quite expensive. This stopped us from large scale of
preparation of amide 13. Fortunately, we found the mixture
of RuCl3 with Zn−Cu couple also could reductively cleave both
C−Cl and N−OBn bonds in excellent yield but with much less
cost. Then amide 13 was treated with LiAlH4 to afford amine
14 in moderate yield. Amine 14 was readily converted into
aniline 16 through the alkylation and hydrolysis process in very
good yield. Undoubtedly, the advanced intermediate, aniline 16
could be rather easily manipulated in three steps by following
the similar reported reactions to afford ( )-minfiensine.14b,e,f
The whole synthetic strategy could potentially complete the
To further demonstrate the utility of this novel method, we
decided to apply this [3 + 2] formal cycloaddition reaction in
B
DOI: 10.1021/acs.orglett.5b03421
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(2) For some examples using tryptamine or its derivatives as the
starting materials to construct pyrroloindoline core, see: (a) Austin, J.
F.; Kim, S.; Sinz, C. J.; Xiao, W.; MacMillan, D. W. C. Proc. Natl. Acad.
Sci. U. S. A. 2004, 101, 5482. (b) Trost, B. M.; Quancard, J. J. Am.
Chem. Soc. 2006, 128, 6314. (c) Newhouse, T.; Lewis, C. A.; Eastman,
K. J.; Baran, P. S. J. Am. Chem. Soc. 2010, 132, 7119. (d) Jones, S. B.;
Simmons, B.; Mastracchio, A.; MacMillan, D. W. C. Nature 2011, 475,
183. (e) Lozano, O.; Blessley, G.; Martinez del Campo, T.; Thompson,
A. L.; Giuffredi, G. T.; Bettati, M.; Walker, M.; Borman, R.;
Gouverneur, V. Angew. Chem., Int. Ed. 2011, 50, 8105. (f) Zhang,
Z.; Antilla, J. C. Angew. Chem., Int. Ed. 2012, 51, 11778. (g) Cai, Q.;
Liu, C.; Liang, X.; You, S. Org. Lett. 2012, 14, 4588. (h) Xie, W.; Jiang,
G.; Liu, H.; Hu, J.; Pan, X.; Zhang, H.; Wan, X.; Lai, Y.; Ma, D. Angew.
Chem., Int. Ed. 2013, 52, 12924. (i) Nelson, H. M.; Reisberg, S. H.;
Shunatona, H. P.; Patel, J. S.; Toste, F. D. Angew. Chem., Int. Ed. 2014,
53, 5600. (j) Li, Q.; Xia, T.; Yao, L.; Deng, H.; Liao, X. Chem. Sci.
2015, 6, 3599.
Scheme 2. Application of [3 + 2] Formal Cycloaddition
Reaction in the Synthetic Approach to ( )-Minfiensine
(3) For some related [3 + 2]-cycloaddition reaction using indoles or
C3-substituted indoles as starting materials, but not affordiing
pyrroloindoline core, see: (a) Mithani, S.; Drew, D. M.; Rydberg, E.
H.; Taylor, N. J.; Mooibroek, S.; Dmitrienko, G. I. J. Am. Chem. Soc.
́
1997, 119, 1159. (b) Barluenga, J.; Tudela, E.; Ballesteros, A.; Tomas,
M. J. Am. Chem. Soc. 2009, 131, 2096. (c) Lian, Y.; Davies, H. M. L. J.
Am. Chem. Soc. 2010, 132, 440. (d) Zhang, J.; Chen, Z.; Wu, H.-H.;
Zhang, J. Chem. Commun. 2012, 48, 1817. (e) Xiong, H.; Xu, H.; Liao,
S.; Xie, Z.; Tang, Y. J. Am. Chem. Soc. 2013, 135, 7851. (f) Li, H.;
Hughes, R. P.; Wu, J. J. Am. Chem. Soc. 2014, 136, 6288.
(4) (a) Repka, L. M.; Ni, J.; Reisman, S. E. J. Am. Chem. Soc. 2010,
132, 14418. (b) Ni, J.; Wang, H.; Reisman, S. E. Tetrahedron 2013, 69,
5622. (c) Wang, H.; Reisman, S. E. Angew. Chem., Int. Ed. 2014, 53,
6206.
total synthesis of ( )-minfiensine in eight steps from the
commercially available compound 11.
In conclusion, we reported a [3 + 2] formal cycloaddition
reaction using aza-oxyallyl cation as a synthetic synthon to
construct the pyrroloindololine core. Different functional
groups are well-tolerated in such reaction conditions. With
this novel method, a variety of C3-substituted indoles were
readily converted into the corresponding pyrroloindoline
analogues at room temperature in the mixed solvents. To
further demonstrate the application of this method, a synthetic
approach to ( )-minfiensine was developed in very concise
fashion. This reaction provides a rapid synthetic approach to
the related indole alkaloids. The investigations of asymmetric
version of this [3 + 2] annulation are underway.
(5) Spangler, J. E.; Davies, H. M. L. J. Am. Chem. Soc. 2013, 135,
6802.
(6) Wang, L.; Yang, D.; Han, F.; Li, D.; Zhao, D.; Wang, R. Org. Lett.
2015, 17, 176.
(7) Chai, Z.; Zhu, Y.-M.; Yang, P.-J.; Wang, S.; Wang, S.; Liu, Z.;
Yang, G. J. Am. Chem. Soc. 2015, 137, 10088.
(8) Lengyel, I.; Sheehan, J. C. Angew. Chem., Int. Ed. Engl. 1968, 7, 25.
(9) Kikugawa, Y.; Shimada, M.; Kato, M.; Sakamoto, T. Chem. Pharm.
Bull. 1993, 41, 2192.
(10) (a) Jeffrey, C. S.; Barnes, K. L.; Eickhoff, J. A.; Carson, C. R. J.
Am. Chem. Soc. 2011, 133, 7688. (b) Acharya, A.; Eickhoff, J. A.;
Jeffrey, C. S. Synthesis 2013, 45, 1825. (c) Barnes, K. L.; Koster, A. K.;
Jeffrey, C. S. Tetrahedron Lett. 2014, 55, 4690.
(11) (a) Acharya, A.; Anumandla, D.; Jeffrey, C. S. J. Am. Chem. Soc.
2015, 137, 14858. (b) DiPoto, M. C.; Hughes, R. P.; Wu, J. J. Am.
Chem. Soc. 2015, 137, 14861.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b03421.
■
S
Detailed experimental procedures, and spectral data
(PDF)
(12) Fohlisch, B.; Gehrlach, E.; Herter, R. Angew. Chem., Int. Ed. Engl.
̈
1982, 21, 137.
́
(13) Massiot, G.; Thepenier, P.; Jacquier, M.; Le Men-Olivier, L.;
Delaude, C. Heterocycles 1989, 29, 1435.
AUTHOR INFORMATION
■
(14) For examples of total synthesis, see: (a) Dounay, A. B.;
Overman, L. E.; Wrobleski, A. D. J. Am. Chem. Soc. 2005, 127, 10186.
(b) Dounay, A. B.; Humphreys, P. G.; Overman, L. E.; Wrobleski, A.
D. J. Am. Chem. Soc. 2008, 130, 5368. (c) Shen, L.; Zhang, M.; Wu, Y.;
Qin, Y. Angew. Chem., Int. Ed. 2008, 47, 3618. (d) Jones, S. B.;
Simmons, B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2009, 131, 13606.
(e) Li, G.; Padwa, A. Org. Lett. 2011, 13, 3767. (f) Liu, P.; Wang, J.;
Zhang, J.; Qiu, F. G. Org. Lett. 2011, 13, 6426.
Corresponding Author
*E-mail: liaoxuebin@mail.tsinghua.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Collaborative Innovation
Center for Diagnosis and Treatment of Infectious Diseases,
Tsinghua-Peking Centre for Life Sciences, and “1000 Talents
Recruitment Program”.
REFERENCES
■
(1) Anthoni, U.; Christophersen, C.; Nielsen, P. H. Naturally
Occuring Cyclotryptophans and Cyclotryptamins. In Alkaloids:
Chemical & Biological Perspective; Pelletier, S. W., Ed.; Pergamon:
Oxford, 1999; Vol. 13, p 163.
C
DOI: 10.1021/acs.orglett.5b03421
Org. Lett. XXXX, XXX, XXX−XXX