Total syntheses of Tardioxopiperazine A, Isoechinulin A, and Variecolorin C

Article abstract of DOI:10.1021/ol2005616

Chemical equations presented. First total syntheses of the isoechinulin-type alkaloids: Tardioxopiperazine A, Isoechinulin A, and Variecolorin C have been achieved from a common key intermediate 5, which was derived from a regiocontrolled Stille cross-coupling reaction of an allylindium reagent.

Full text of DOI:10.1021/ol2005616

ORGANIC
LETTERS
2011
Vol. 13, No. 9
2302–2305
Total Syntheses of Tardioxopiperazine A,
Isoechinulin A, and Variecolorin C
Qipu Dai,† Xingang Xie,† Shiyan Xu,† Donghui Ma,† Shibing Tang,† and
Xuegong She*,†,‡
State Key Laboratory of Applied Organic Chemistry, Department of Chemistry,
Lanzhou University, Lanzhou, 730000, P. R. China, and State Key Laboratory for Oxo
Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese
Academy of Sciences, Lanzhou 730000, P. R. China
shexg@lzu.edu.cn
Received March 2, 2011
ABSTRACT
First total syntheses of the isoechinulin-type alkaloids: Tardioxopiperazine A, Isoechinulin A, and Variecolorin C have been achieved from a
common key intermediate 5, which was derived from a regiocontrolled Stille cross-coupling reaction of an allylindium reagent.
The structurally fascinating and biologically active me-
tabolites Tardioxopiperazine A (1), Isoechinulin A (2), and
Variecolorin C (3), isolated from the Aspergillus species by
Zhu and co-workers in 2007,1 are three new members of
isoechinulin-type alkaloids (Figure 1). These 2,3,5-trisub-
stituted indole alkaloids contain three structural units: an
indole, a 2-methyl-3-buten-2-yl, and a diketopiperazine. A
bioactivity test shows that compounds 1ꢀ3 display radical
scavenging activity, ultraviolet-A protecting activity, im-
munosuppressive activity, and antibacterial activity.1
Herein, we report the first total syntheses of 1ꢀ3 starting
from a common key intermediate 5, which was derived
† Department of Chemistry, Lanzhou University.
‡ Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences.
(1) (a) Wang, W.-L.; Lu, Z.-Y.; Tao, H.-W.; Zhu, T.-J.; Fang, Y.-C.;
Gu, Q.-Q.; Zhu, W.-M. J. Nat. Prod. 2007, 70, 1558–1564. (b) Fujimoto,
H.; Fujimaki, T.; Okuyama, E.; Yamazaki, M. Chem. Pharm. Bull. 1999,
47, 1426–1432. (c) Nagasawa, H.; Isogai, A.; Suzuki, A.; Tamura, S.
Tetrahedron Lett. 1976, 19, 1601–1604. (d) He, J.; Wijeratne, E. M. K.;
Bashyal, B. P.; Zhan, J.; Seliga, C. J.; Liu, M. X.; Pierson, E. E.; Pierson,
L. S.; VanEtten, H. D.; Gunatilaka, A. A. L. J. Nat. Prod. 2004, 67,
1985–1991. (e) Chu, Y.-S.; Niu, X.-M.; Wang, Y.-L.; Guo, J.-P.; Pan,
W.-Z.; Huang, X.-W.; Zhang, K.-Q. Org. Lett. 2010, 12, 4356–4359. (f)
Gugnani, H. C. Frontiers Biosci. 2003, 8, 346–357. (g) Li, Y.; Li, X.; Kim,
S. K.; Kang, J. S.; Choi, H. D.; Rho, J. R.; Son, B. W. Chem. Pharm.
Bull. 2004, 52, 375–376. (h) Li, Y.; Li, X.; Kang, J. S.; Choi, H. D.; Son,
B. W. J. Antibiot. 2004, 57, 337–340. (i) Ravikanth, V.; Niranjan Reddy,
V. L.; Ramesh, P.; Prabhakar Raoa, T.; Diwan, P. V.; Khar, A.;
Venkateswarlu, Y. Phytochemistry 2001, 58, 1263–1266. (j) Naik,
C. G.; Devi, P.; Rodrigues, E. U.S. Patent 2,005,143,392, 2005.
Figure 1. Structures of Tardioxopiperazine A (1), Isoechinulin A
(2), and Variecolorin C (3).
r
10.1021/ol2005616
Published on Web 04/01/2011
2011 American Chemical Society

Table 1. Regioselective of Intermediate 5
Scheme 1. Retrosynthetic Analysis
Scheme 2. Synthesis of Key Intermediate 5
Scheme 3. Completion of the Synthesis of Tardioxopiperazine A
from a regiocontrolled Stille cross-coupling reaction of an
allylindium reagent.
We envisioned that these 2,3,5-trisubstituted indole alka-
loids could be synthesized by an efficient regioselective stra-
tegy due to the common subunit they shared. Variecolorin
C (3) was chosen as a representive example, and its retro-
synthetic analysis is outlined in Scheme 1. We planned to
construct Variecolorin C (3) by a direct dehydrogenation
(2) Baran, P. S.; Hafensteiner, B. D.; Ambhaikar, N. B.; Guerrero,
C. A.; Gallagher, J. D. J. Am. Chem. Soc. 2006, 128, 8678–8693.
(3) (a) Ugi, I.; Meyr, R.; Fetzer, U.; Steinbruckner, C. Angew. Chem.
1959, 71, 386. (b) Hulme, C.; Peng, J.; Morton, G.; SalvinG, J. M.;
Herpin, T.; Labaudiniere, R. Tetrahedron Lett. 1998, 39, 7227–7230. (c)
Isaacson, J.; Kobayashi, Y. Angew. Chem., Int. Ed. 2009, 48, 1845–1848.
(d) Obrecht, R.; Herrmann, R.; Ugi, I. Synthesis 1985, 4, 400–402.
(4) Schkeryantz, J. M.; Woo, J.C. G.; Siliphaivanh, P.; Depew,
K. M.; Danishefsky, S. J. J. Am. Chem. Soc. 1999, 121, 11964–11975.
reaction,2 a multicomponent Ugi reaction,3 and an SN20
reaction4 from 4. The chiral secondary hydroxyl group of 4
Org. Lett., Vol. 13, No. 9, 2011
2303

Scheme 4. Unsuccessful Route towards Isoechinulin A
Scheme 6. Completion of the Synthesis of Variecolorin C
Scheme 5. Completion of the Synthesis of Isoechinulin A
could be installed by Sharpless asymmetric dihydro-
xylation,5 and the C5 branch chain could be constructed
from the commercially available L-5-hydroxytryptophane
(6) via a Stille cross-coupling reaction.6
tested such as organomagnesium,7 organozinc,8 organo-
lithium,9 and organoboron;10 however the same results
were obtained (Tables 1). Fortunately, when the allylin-
dium reagent generated in situ was utilized in this reac-
tion, we found that 5 and Boc-deprotected product 10
with heat in DMF were obtained in 60% and 20% yields
respectively.
With key intermediate 5 in hand, removal of the Boc
group with heat in DMF gave 10 in 90% yield (Scheme 3).
Treatment of 10 with tert-butyl-hypochlorite4 led to the
formation of an unstable 3-chloroindolenine intermediate
11 which was directly coupled with freshly prepared pre-
nyl-9-BBN11 to give 2,3-disubstituted indole 12 in 90%
yield. Changing the protecting group at N-Phth and
followed by hydrolysis of methyl ester gave the Ugi
A concise synthesis of Tardioxopiperazine A (1) was
outlined in Scheme 2. According to the retrosynthetic
analysis, our synthesis started from the commercially
available L-5-hydroxy-tryptophane (6). Esterification of
6 followed by protection of the primary amino group
gave 7. Sequential treatment of 7 with triflic anhydride
followed by protection of indole’s amino group with
(Boc)2O afforded 8, which was subjected to the Stille
coupling reaction; however, two isomers 5 and 9 were
obtained under the classic Stille coupling reaction con-
ditions (Scheme 2), and the separation was very difficult.
To solve this problem, many coupling partners were
(5) (a) Hentges, S. G.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102,
4263–4265. (b) Jacobsen, E. N.; Marko, I.; Mungall, W. S.; Schroeder,
G.; Sharpless, K. B. J. Am. Chem. Soc. 1988, 110, 1968–1970.
(6) (a) Milstein, D.; Stille, J. K. J. Am. Chem. Soc. 1978, 100, 3636–
3638. (b) Echavarren, A. M.; Stille, J. K. J. Am. Chem. Soc. 1987, 109,
5478–5486. (c) Lee, K.; Lee, J.; Lee, P. H. J. Org. Chem. 2002, 67, 8265–
8268.
(7) (a) Corriu, R. J. P.; Masse, J.-P. J. Chem. Soc., Chem. Commun.
1972, 144. (b) Furstner, A.; Leitner, A. Angew. Chem., Int. Ed. 2002, 41,
609–612.
(8) (a) Baba, S.; Negishi, E. J. Am. Chem. Soc. 1976, 98, 6729–6731.
(b) Zhou, J.; Fu, G.-C. J. Am. Chem. Soc. 2003, 125, 12527–12530.
(9) (a) Yamamura, M.; Moritani, I.; Murahashi, S. I. J. Organomet.
Chem. 1975, 91, 39–42. (b) Murahashi, S.; Yamamura, M.; Yanagisawa,
K.; Mita, N.; Kondo, K. J. Org. Chem. 1979, 44, 2408–2417.
(10) Miyaura, N.; Suzuki, A. J. Chem. Soc., Chem. Commun. 1979,
866–867.
(11) Kramer, G. W.; Brown, H. C. J. Organomet. Chem. 1977, 132, 9.
2304
Org. Lett., Vol. 13, No. 9, 2011

reaction precursor 13, which underwent a four-component
reaction with NH3/MeOH, CH3CHO, and 1-(benzyloxy)-
2-isocyanobenzene to afford 14 in 70% yield (dr 2:1). After
deprotection and acid-promoted cyclization, we success-
fully obtained Tardioxopiperazine A (1).
As the structure of Isoechinulin A (2) was close to
Tardioxopiperazine A (1), we proposed 2 could be derived
from the direct dehydrogenation2 of 1; however, that was
proven to be unsuccessful (Scheme 4). Therefore, we
modified the synthetic sequence and conducted the direct
dehydrogenation of 12 first to provide the corresponding
product 15 in 85% yield as a single isomer (Scheme 5).
Then hydrolysis of 15 provided 16 that was coupled with
(S)-methyl 2-aminopropanoate hydrochloride in the pre-
sence of HOBT and EDCI to afford 17.12 Deprotection
and acid-promoted cyclization12 afforded Isoechinulin A
(2) in 85% yield.
Selective protection of the secondary hydroxyl group
followed by dehydration gave ester 19. Using the same
synthetic schemes employed before, Variecolorin C (3) was
obtained in high yield.
In conclusion, the concise total syntheses of Tardioxo-
piperazine A (1), Isoechinulin A (2), and Variecolorin C (3)
were achieved. Our synthetic route features three high-
lights: (1) application of a key intermediate for three
molecules; (2) application of allylindium reagents; (3)
construction of the diketopiperazine core with the reagent
1-(benzyloxy)-2-isocyanobenzene. The application of this
route paves the way for the total syntheses of other
isoechinulin-type alkaloids which are underway in our
laboratory and will be reported in due course.
Acknowledgment. We are grateful for the generous
financial support by the NSFC (21072086, 20872054,
20732002).
The total synthesis of Variecolorin C (3) was shown in
Scheme 6. Asymmetric dihydroxylation of the olefin 5 with
AD-mix-β afforded the diol 18 in 95% yield (dr 8:1).
Supporting Information Available. Complete experi-
mental procedures and spectral data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(12) Movassaghi, M.; Schmidt, M. A.; Ashenhurst, J. A. Angew.
Chem., Int. Ed. 2008, 47, 1485–1487.
Org. Lett., Vol. 13, No. 9, 2011
2305