Copper-catalyzed arylation of o-bromoanilides: Highly flexible synthesis of hexahydropyrroloindole alkaloids

Article abstract of DOI:10.1021/ol3012056

In the presence of catalytic amount of copper iodide, a remote amide-assisted intramolecular arylation followed by alkylation leads to a general and flexible synthetic method toward the synthesis of medicinally interesting hexahydropyrroloindole alkaloids.

Full text of DOI:10.1021/ol3012056

ORGANIC
LETTERS
2012
Vol. 14, No. 12
3116–3119
Copper-Catalyzed Arylation of
o-Bromoanilides: Highly Flexible Synthesis
of Hexahydropyrroloindole Alkaloids
Yongyun Zhou, Yongkai Xi, Jingfeng Zhao, Xianfu Sheng, Shuqin Zhang, and
Hongbin Zhang*
Key Laboratory of Medicinal Chemistry for Natural Resource (Yunnan University),
Ministry of Education, School of Chemical Science and Technology, Yunnan University,
Kunming 650091, P. R. China
zhanghb@ynu.edu.cn; zhang_hongbin@hotmail.com
Received May 2, 2012
ABSTRACT
In the presence of catalytic amount of copper iodide, a remote amide-assisted intramolecular arylation followed by alkylation leads to a general
and flexible synthetic method toward the synthesis of medicinally interesting hexahydropyrroloindole alkaloids.
The hexahydropyrrolo[2,3-b]indole ring system appears
in a wide selection of natural alkaloids and a number of
marketed drugs and drug candidates.2 Among them, the
efficient and enantioselective construction of the prenyl
substituted quaternary carbon center at the C3a position
offers an interesting synthetic problem.3 Recently, we
disclosed a new synthesis of esermothole and its analogues
through a palladium-mediated sequential arylationꢀ
alkylation.4 We envisioned that a metal mediated “one-
pot” arylationꢀalkylation of the o-bromoanilide bearing a
certain chiral auxiliary might lead to the required C3a all-
carbon quaternary center in a diastereoselective manner.
Herein we report the first stereocontrolled copper-
catalyzed arylation-alkylation of o-bromoanilides and
the flexible synthesis of hexahydropyrrolo[2,3-b]indole
alkaloids based on this new methodology.
C3a all-carbon quaternary center containing members are
especially attractive because of their important biological
activities.1e,f As a unique family of the hexahydropyrrolo-
[2,3-b]indole alkaloids, natural products shown in Figure 1
are characterized by a sterically congested all-carbon
quaternary center containing prenyl substitutent.2 The
(1) For selected reviews and books, see:(a) Hino, T.; Nakagawa, M.
In The Alkaloids: Chemistry and Pharmacology; Brossi, A., Ed.; Academic
Press: New York, 1989; Vol. 34, pp 1ꢀ75. (b) Anthoni, U.; Christophersen,
C.; Nielsen, P. H. in Alkaloids: Chemical and Biological Perspectives;
Pelletier, S. W., Ed.; Pergamon: London, 1999; Vol. 13, pp 163ꢀ236. (c)
Crich, D.; Banerjee, A. Acc. Chem. Res. 2007, 40, 151. (d) Ruiz-Sanchis,
The retrosynthetic analysis is outlined in Scheme 1. The
metal-mediated arylation of o-bromoanilide 7 bearing a
chiral sulfinyl amide unit followed by alkylation would
ꢀ
P.; Savina, S. A.; Albericio, F.; Alvarez, M. Chem.;Eur. J. 2011, 17, 1388
and references cited therein. (d) Santos, P. E.; Almeida, P. S.; Lobo, A. M.;
Prabhakar, S. Heterocycles 2001, 55, 1029. (e) Greig, N. H.; Pei, X.-F.;
Soncrant, T. T.; Ingram, D. K.; Brossi, A. Med. Res. Rev. 1995, 15, 3. (f)
Sorbera, L. A.; Castaner, J. Drugs Future 2003, 28, 18.
(2) For alkaloids in Figure 1, see: (a) Holst, P. B.; Anthoni, U.;
Christophersen, C.; Nielsen, P. H. J. Nat. Prod. 1994, 57, 997. (b) Badio,
B.; Garraffo, H. M.; Padgett, W. L.; Greig, N. H.; Daly, J. W. Biochem.
Pharmacol. 1997, 53, 671. (c) Smith, B. P.; Tyler, M. J.; Kaneko, T.;
Garraffo, H. M.; Spande, T. F.; Daly, J. W. J. Nat. Prod. 2002, 65, 439.
(d) Raju, R.; Piggott, A. M.; Huang, X.-C.; Capon, R. J. Org. Lett. 2011,
13, 2770.
(3) (a) 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. (b) Peterson,
E. A.; Overman, L. E. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 11943. (c)
Douglas, C. J.; Overman, L. E. Proc. Natl. Acad. Sci. U.S.A. 2004, 101,
5363. (d) Steven, A.; Overman, L. E. Angew. Chem., Int. Ed. 2007, 46,
5488.
(4) Zhou, Y.; Zhao, Y.; Dai, X.; Liu, J.; Li, L.; Zhang, H. Org.
Biomol. Chem. 2011, 9, 4091.
r
10.1021/ol3012056
Published on Web 06/05/2012
2012 American Chemical Society

Scheme 2. Synthesis of o-Bromoanilide Bearing a Chiral
tert-Butanesulfinamide Unit
Figure 1. Representative hexahydropyrroloindole alkaloids.
give precursors (8) for the synthesis of debromoflustra-
mines B and E and pseudophrynamine alkaloids (see
Scheme 1).
We began our research by preparing amide 7a bearing a
chiral sulfinyl amide unit. Treatment of 2-bromoaniline
with butenolide in the presence of trimethylaluminum in
toluene afforded amide 10 in 96% yield. Protection of
amide 10 followed by oxidation afforded aldehyde 12
(87%, two steps). Heating aldehyde 12 with (S)-(ꢀ)-tert-
butanesulfinamide5 in toluene, followed by reduction with
sodium borohydride, led to amide 13 in 88% yields in two
steps. The amide (7a, 95% ee, Scheme 2) was finally
obtained by treatment of compound 13 with methyl iodide
in the presence of sodium hydride.
Next, we came to the key stage of our research, the
metal-mediated arylation of o-bromoanilide and the sub-
sequent asymmetric alkylation. Inspired by recent reports
that copper salts could mediate the formation of oxindoles,6
we decided to explore the copper-mediated arylation of
o-bromoanilides in the hope that an efficient and asymmetric
“one-pot” process could be developed for the synthesis of
oxindoles bearing a C3a all-carbon quaternary center.
Table 1. Studies on the Copper-Catalyzed ArylationꢀAlkyla-
tion of o-Bromoanilide Bearing a tert-Butanesulfinamide Unita
Scheme 1. Retrosynthetic Analysis of HPI Alkaloids 1ꢀ4
eeb yielda
entry
metal salts
CuCl2
R, R1 and R2
(%)
(%)
1
2
3
4
5
6
7
8
8a: R = R1 = R2 = H
0c
Cu(OAc)2 H2O 8a: R = R1 = R2 = H
0d
3
CuCl2
CuI
CuI
CuI
CuI
CuI
8a: R = R1 = R2 = H
8a: R = R1 = R2 = H
8a: R = R1 = R2 = H
8b: R = R1 = H, R2 = Me
8c: R = R1 = Me, R2 = H
8d: R = Me,
0d
0e
71
71
66
72
,72f,g
71g
84g
74g
R2 = H R1 =CH2OTBS
8e: R = R1 = H, R2 = CO2Me
8f: R = R1 = H, R2 = Br
9
CuI
CuI
80g
57g
10
80
a Yields represent isolated yields; see the Supporting Information for
detailed reaction conditions. b The ee values were determined after
removal of the tert-butanesulfinamide. c CuCl2 (2.0 equiv), t-BuONa
(5.0 equiv), and DMF, 110 °C. d Copper salts (1.0 equiv), t-BuOK (2.0 equiv),
DMF, 110 °C. e CuI (1.0 equiv), t-BuOK (2.0 equiv), THF (80 °C oil bath).
f CuI (1.0 equiv), LiN(SiMe3)2 (2.0 equiv), THF (80 °C). g CuI (0.1 equiv),
LiN(SiMe3)2 (2.0 equiv), THF (80 °C).
(5) Huang, Z.; Zhang, M.; Wang, Y.; Qin, Y. Synlett 2005, 1334.
(6) For the synthesis of racemic C3a all-carbon oxindoles by copper-
mediated intramolecular coupling of anilides, substrates are limited to
phenylacetanilide derivatives or β-keto acetanilides; see: (a) Jia, Y.-X.;
€
Kundig, E. P. Angew. Chem., Int. Ed. 2009, 48, 1636. (b) Perry, A.;
Taylor, R. J. K. Chem. Commun. 2009, 3249. (c) Pugh, D. S.; Klein, J. E.
M. N.; Perry, A.; Taylor, R. J. K. Synlett 2010, 934. (d) Klein, J. E. M.
N.; Perry, A.; Pugh, D. S.; Taylor, R. J. K. Org. Lett. 2010, 12, 3446.
Org. Lett., Vol. 14, No. 12, 2012
3117

The proposed arylation of compound 7a was initially
attempted with copper chloride and copper acetate in the
presence of sodium tert-butoxide in DMF at 110 °C under
argon6a or under air6b as reported in the literature (Table 1,
entries 1ꢀ4). Unfortunately, these reaction conditions
afforded no desired product, with starting material being
recovered. We next attempted copper(I) iodide in combi-
nation with a number of bases. To our delight, copper(I)
iodide was found to effect the transformation in the
presence of lithium bis(trimethylsilyl)amide. After some
experimentation, the optimal reaction conditions were
established, and this transformation could be effected in
only a catalytic amount (10%) of CuI (Table 1, entry 6) to
afford the C3a-S and C3a-R products as an inseparable
mixture of diastereoisomers. To the best of our knowledge,
this is the first example of copper-catalyzed intramolecular
arylationꢀalkylation of an o-bromoanilide, a cost-effec-
tive process for the asymmetric synthesis of oxindoles
bearing a C3a all-carbon quaternary center.7
Scheme 3. Further Experiments for Copper-Catalyzed Aryla-
tion of o-Bromoanilide
In order to get some insight toward this copper-cata-
lyzed process, we carried out the reaction with a number
of o-bromoanilides (7bꢀg, Scheme 3). Arylation of o-
bromoanilides (7bꢀd) without the neighboring tert-butane-
sulfinamide unit did not yield the desired arylationꢀ
alkylation products. It was noteworthy that substrates 7e
and 7f bearing a carbamate group underwent the arylation
efficiently in the presence of copper(I) iodide and unpre-
cedentedly led to spiro-oxindoles 14 and 15 in excellent
yields. The remote aza-assistance of a tert-butanesulfina-
mide or a carbamate unit was critical to this copper-catalyzed
arylation. Arylation of the optically active substrate 7g
(derived from L-glutamic acid) provided spirooxindole 16
in high yield with excellent diastereoselectivity (Scheme 3,
16, dr >99:1, based on NMR). Attempts made to isolate
the arylation intermediate, namely oxindole 8i, were fruit-
less, and a complex mixture was formed after workup, with
the major product being identified as oxindole 8j, an air
oxidized product (similar results see ref 10b).
Although the mechanism for this copper-catalyzed ar-
ylation needs further elaboration,8 we favor the concerted
single-electron-transfer pathway.6 We conducted the reac-
tion in the presence of a radical inhibitor, 2,2-diphenyl-1-
picrylhydrazyl (DPPH, 3.0 equiv),9 as well as p-dinitro-
benzene (5.0 equiv)10 and found that the arylation process
was totally inhibited with starting material being recovered.
To demonstrate the usefulness of our new method, we next
turned to the synthesis of selective butyrylcholinesterase
inhibitor debromoflustramine B11 and antibacterial agent
debromoflustramine E.12Amide 7a was subjected to the
sequential arylationꢀalkylation reaction on a gram scale
under our optimized conditions, and compound 8c was
obtained in 84% yield. Treatment of the key intermediate
8c with HCl in methanol and 1,4-dioxane provided amine
17 (C3aS/C3aR = 6:1). Formation of the HPI ring with a
reductive amination and deprotection of the benzyl group
with a Birch reduction afforded debromoflustramine E
(7) The C3a absolute configurations for 8c and 8d were established by
the total synthesis of (ꢀ)-debromoflustramine B and (ꢀ)-pseudophry-
naminol. (S)-(ꢀ)-tert-butanesulfinamide results in C3a-S configuration,
while (R)-(þ)-tert-butanesulfinamide leads to C3a-R configuration. The
C3a absolute configurations (might require further experiments to
confirm its absolute configurations) for compounds 8a, 8b, and 8eꢀh
were deduced by comparing with the sign of the specific rotations of 8c
and 8d.
(11) For enantioselective syntheses of debromoflustramine B, see: (a)
Bruncko, M.; Crich, D.; Samy, R. J. Org. Chem. 1994, 59, 5543. (b)
Cardoso, A. S.; Srinivasan, N.; Lobo, A. M.; Prabhakar, S. Tetrahedron
´
Lett. 2001, 42, 6663. (c) Morales-Rıos, M. S.; Rivera-Becerril, E.;
Joseph-Nathan, P. Tetrahedron: Asymmetry 2005, 16, 2493. (d) Cardoso,
A. S. P.; Marques, M. M. B.; Srinivasan, N.; Prabhakara, S.; Lobo,
(8) We proposed
Information.
a working hypotheses in the Supporting
A. M. Tetrahedron 2007, 63, 10211. (e) Rivera-Becerril, E.; Joseph-
ꢀ
Nathan, P.; Perez-Alvarez, V. M.; Morales-Rı
ꢀ
´
os, M. S. J. Med. Chem.
(9) Hristea, E. N.; Caproiu, M. T.; Pencu, G.; Hillebrand, M.;
Constantinescu, T.; Balaban, A. T. Int. J. Mol. Sci. 2006, 7, 130.
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Fang, C.-L.; Horne, S.; Taylor, N.; Rodrigo, R. J. Am. Chem. Soc. 1994,
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2916.
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Bioorg. Med. Chem. Lett. 2006, 16, 2522. (b) Miyamoto, H.; Okawa, Y.;
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3118
Org. Lett., Vol. 14, No. 12, 2012

Scheme 4. Total Synthesis of Debromoflustramine B and E
Scheme 5. Synthesis of Pseudophrynamine Alkaloids
and revealed a remote aza-assisted effect. These sequential
reactions lead to the medicinally interesting oxindoles
bearing a C3a full quaternary carbon center in a flexible
and practical way.16 Currently, we are investigating the
synthesis of other HPI alkaloids based on this new process
and the utilization of other substrates (such as δ-amino
o-bromoanilide and other less-activated alkylating reagents)
in this copper-catalyzed reaction; the results will be reported
in due course.
(2, nine steps, 41% overall yield). Debromoflustramine B
(1) was obtained by Birch reduction of compound 18
followed by N-alkylation with prenyl bromide11b (Scheme4,
nine steps, 29% overall yield).
Finally, the enantiomerically enriched pseudophryna-
mine alkaloid, namely pseudophrynaminol (3),13 was
synthesized from 8d in 52% yield in three steps, and the
pseudophrynamine (4) was thus synthesized in a formal
sense (Scheme 5).14
In conclusion, we have developed a highly useful
copper catalyzed intramolecular arylation-alkylation of
o-bromoanilides.15 On the basis of this method, a general
synthetic strategy has been established for the synthesis of
(ꢀ)-debromoflustramines B and E and pseudophrynamine
alkaloids. We have also developed a ligand-free copper-
catalyzed process for the synthesis of spirocyclic oxindoles
Acknowledgment. This work was supported by grants
from the Natural Science Foundation of China (20925205,
20832005), National Basic Research Program of China
(973 Program 2009CB522300), and Yunnan Provincial
Science & Technology Department (2010GA014).
Supporting Information Available. Experimental pro-
cedures and spectral data for new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
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R-arylation of o-bromoanilides, substrates are limited to N-(2-
bromophenyl)-2-phenylacetamide derivatives. Only two examples with-
out additional aromatic groups at the newly formed C3a full quaternary
carbon centers were reported, with 40% (see ref 15d) and 70% (see ref
15e) ee values being observed, respectively; see: (a) Arao, T.; Kondo, K.;
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The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 12, 2012
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