Formal synthesis of (+)-gliocladin C

Article abstract of DOI:10.1016/j.tetlet.2012.12.007

An asymmetric synthesis of chiral intermediate 15 for (+)-gliocladin C has been accomplished from N-phthaloyl l-tryptophan methyl ester.

Full text of DOI:10.1016/j.tetlet.2012.12.007

Tetrahedron Letters 54 (2013) 692–694
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Formal synthesis of (+)-gliocladin C
Mao Sun a,b, Xiao-Yan Hao b, Sheng Liu a, , Xiao-Jiang Hao a,
⇑
⇑
a The Key Laboratory of Chemistry for Natural Products of Guizhou Province, Chinese Academy of Sciences, Guiyang 550002, PR China
b Guiyang Medical Univesity, Guiyang 550002, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
An asymmetric synthesis of chiral intermediate 15 for (+)-gliocladin C has been accomplished from
Received 30 October 2012
Revised 28 November 2012
Accepted 4 December 2012
Available online 12 December 2012
N-phthaloyl L-tryptophan methyl ester.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Indole alkaloids
Gliocladin C
Formal synthesis
Secondary metabolites produced by marine organisms are the
source of architecturally complex and pharmacologically
important compounds. Gliocladins A–B (1–2, Fig. 1), two epidithi-
odi-ketopiperazines and gliocladin C (3), a non-thiolated triketo-
piperazine, were first isolated from a strain of Gliocladium roseum
by Usami et al.1a Notably, among these three alkaloids, gliocladin
C exhibited the most potent cytotoxic activity against P388 lym-
synthesis in 2011.2b Shortly after, Stephenson’s synthesis high-
lighted a photoredox catalysis to install the indolyl group as a
key step.2c The most recent synthesis of (+)-gliocladin C adopted
a novel regioselective Friedel–Crafts strategy to introduce the key
indolyl substructure, reported by Movassaghi and Boyer.2d
Our interest for syntheses of this class of alkaloids was initially
aroused by studies toward the synthesis of trigololiimine C based
on an oxidative rearrangement biogenetic hypothesis,3 we ob-
served that treatment of the hydroxyindolenine 4 with Sc(OTf)3
in refluxed toluene provided a novel bistryptamine derivative 5
in 70% yield (Scheme 1).3c We considered that the migration of
the indolyl group might be very significant for the synthesis of
phocytic leukemia in cell culture (ED50 = 2.4 lg/mL). Interestingly,
gliocladin C was also recently found in the terrestrial fungus
Gliocladium catenulatum.1b
The structural complexity and high biological activities of glio-
cladin C, have attracted the attention of several research groups.2
The first total synthesis was reported by Overman and Shin in
2007.2a Subsequently, they reported the second generation
NPhth
NPhth
NPhth
N
Sc(OTf)3
Me
S
HN
HN
O
O
O
O
N
H
N
H
PhMe, 110°C
R
OH
Me
O
Me
Ref. 3c
O
N
N
N
H
NPhth
N
4
5
70%
N
Me
S
N
H
H
N
H
H
O
O
3:(+)-gliocladin C
1:R=OH, (+)-gliocladin A
2:R=H, (+)-gliocladin B
N15
N15
13C
13C
H
H
(S)
(S)
Aspergilus
versicolor
H
H
13C
13C
N
N
Figure 1. Gliocladins A–C.
(S)
O
O
H
H
O
8.4% incorp
Ref. 4
N
H
N
H
HO
HO
⇑
7: notoamide J
Corresponding authors. Tel./fax: +86 851 5416876 (S.L.); tel.: +86 871 5223263;
fax: +86 871 5219684 (X.-J.H.).
6: 6-hydroxydeoxybrevianamide E
Scheme 1. Initial inspiration.
E-mail addresses: lsheng@126.com (S. Liu), haoxj@mail.kib.ac.cn (X.-J. Hao).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.12.007

M. Sun et al. / Tetrahedron Letters 54 (2013) 692–694
NHCbz
693
BnO
COOMe
NPhth
COOMe
COOMe
10:
HO
O
b
NPhth
NH
NPhth
NH
O
OH
a
N
H
N
H
N
8
9
11
90%(BRSM)
96%
HN
CbzN
COOMe
CONHMe
c
e
d
NPhth
O
NHBoc
O
N
H
N
Cbz
12
13
60%
80 %
CbzN
HN
CbzN
O
O
2 steps
CONHMe
NH
f
CONHMe
Me
O
N
N
N
Ref. 2c
N
H
N
H
H
N
H
Cbz
Cbz
14
85 %
15
98 %
3
Scheme 2. Reagents and conditions: (a) t-BuOCl, Et3N, THF, then indole, BF3ꢁEt2O; (b) 10, 30% H2O2, DIC, DMAP, DCM, 0 °C; (c) Sc(OTf)3, toluene, 110 °C; (d) (i) MeNH2, MeOH,
(ii) Boc2O, satd NaHCO3, (iii) CbzCl, Et3N, DMAP, DCM; (e) (i) NaBH4, MeOH, (ii) TFA, DCM; (f) NBS, DBU, DCM.
PhthN(S)
(S)COOMe
NPhth
O
HO
O
(R)
Cu(OTf)2
NH
(R)
NH
Toluene
50%
N
N
16
Scheme 3. Derivatization and stereochemical assignment of 11.
11
dimeric indole alkaloids. Particularly, it provided a novel strategy
to assemble gliocladin C. On the other hand, the leading study by
Williams and co-workers (Scheme 1),4 indicated the biogenesis of
3-prenylated indole alkaloid notoamide J should incorporate an
oxidative rearrangement, enabled us to investigate whether a sim-
ilar biomimetic step could be achieved in the synthesis of the class
of 3-(30-indolyl) indole alkaloids.5 Intrigued by these consider-
ations, we set out to develop a new approach to the chiral tetracy-
clic core of gliocladin C.
for oxidation in related derivatives,7,8 we focused our attention on
the use of aspartic peracids generated in situ. It was gratifying that
the employment of a simple precatalyst 10 (Cbz-L-Asp-OBn) in the
presence of 30% aqueous H2O2 and 1,3-diisopropylcarbodiimide
(DIC) would lead the desired oxidative transformation. Under this
favorable condition, our key intermediate 11 was obtained as the
only diastereoisomer in 90% yield after recovering 5–10% of staring
material 9 on a multigram scale, with no detectable amount of its
epimer.
The synthetic work started from phthaloyl protected
L
-trypto-
The absolute stereochemistry of hydroxybisindole 11 was con-
firmed by its chemical derivatization to lactone 16 (Scheme 3).
Treatment of 11 with Cu(OTf)2 led to the intramolecular esterifica-
tion thus afforded the spirocycle 16. The 3-(R) assignment of 16
was secured by X-ray crystallography.
With tertiary alcohol 11 in hand, using Sc(OTf)3 mediated con-
dition smoothly led to the desired rearrangement product 12 in
60% yield. Unveiling the amino group of imide 12 by MeNH2 in
MeOH with concurrent ammonolysis as a one pot two-step proce-
dure provided the desired N-methyl amide. To avoid intramolecu-
lar transamidation, crude released amines were immediately
blocked by Boc and Cbz groups, respectively, to afford 13 in 80%
yield over three steps from 12, without further purification. Subse-
quent selective reduction of the oxindole carbonyl moiety of 13
phan methyl ester 8 (Scheme 2). It was reacted with t-butyl
hypochloride in tetrahydrofuran at ꢀ78 °C to cleanly produce a
3-chloroindolenine intermediate, which could be nucleophilically
attacked by indole in the presence of BF3ꢁEt2O thus leading to
N-phthaloyl-2-indolyl tryptophan methyl ester 9 in high yield.6
As our plan is to provide a platform for the asymmetric synthesis
of gliocladin C, the oxidative transformation of 9 should be realized
with a high chemoselectivity and stereoselectivity. Although it was
well precedented that good chemoselectivity and stereoselectivity
of oxidation of indoles could be achieved in the bisindole system
toward the synthetic studies of trigololiimine alkaloids3 and
Movassaghi’s pioneer work,7 it seemed risky to implement this
particular transformation. Given the developed optimal conditions

694
M. Sun et al. / Tetrahedron Letters 54 (2013) 692–694
was achieved with NaBH4 (4.0 equiv) in MeOH at 25 °C for 15 min,9
followed by treatment of the resulting hemiaminal with excess TFA
in DCM to form the five-membered ring and deprotect the Boc
group in one pot, thus gave desired secondary amine 14 in 85%
yield (2 steps). Finally, the oxidation of 14 by sequential treatment
with N-bromosuccinimide (NBS) and 1,8-diazabicyclo[5.4.0]undec-
7-ene (DBU) provided a known imine 15, whose analytical and
spectral data10 were in good agreement with the literature re-
port.2c Having 15 been previously converted into (+)-gliocladin C
in two steps,2c its obtainment constitutes a formal diastereoselec-
tive synthesis of the latter.
In conclusion, a formal synthesis of (+)-gliocladin C was accom-
plished and intermediate 15 was obtained in a 34.5% total yield in
nine steps. A good efficiency combined with the fact that only
cheap reagents and popular conditions were adopted in our proce-
dures made the present synthesis practically and easily to handle,
thus provided a useful starting point for the synthesis of gliocladin
C-like library. Moreover, since epipolythiodiketo-piperazines with
30-indolyl substitution at the C3 position of a cyclotryptophan con-
stitute an intriguing subset of this alkaloid family,5 the methodol-
ogy described herein may be applied to these natural targets.
References and notes
1. (a) Usami, Y.; Yamaguchi, J.; Numata, A. Heterocycles 2004, 63, 1123–1129; (b)
Bertinetti, B. V.; Rodriguez, M. A.; Godeas, A. M.; Cabrera, G. M. J. Antibiot. 2010,
63, 681–683.
2. (a) Overman, L. E.; Shin, Y. Org. Lett. 2007, 9, 339–341; (b) DeLorbe, J. E.; Jabri, S.
Y.; Mennen, S. M.; Overman, L. E.; Zhang, F.-L. J. Am. Chem. Soc. 2011, 133, 6549;
(c) Furst, L.; Narayanam, J. M. R.; Stephenson, C. R. J. Angew. Chem., Int. Ed. 2011,
50, 9655–9659; (d) Boyer, N.; Movassaghi, M. Chem. Sci. 2012, 3, 1798.
3. (a) Qi, X.; Bao, H.; Tambar, U. K. J. Am. Chem. Soc. 2011, 133, 10050–10053; (b)
Han, S.; Movassaghi, M. J. Am. Chem. Soc. 2011, 133, 10768–10771; (c) Liu, S.;
Hao, X.-J. Tetrahedron Lett. 2011, 52, 5640–5642.
4. Finefield, J. M.; Sherman, D. H.; Tsukamoto, S.; Williams, R. M. J. Org. Chem.
2011, 76, 5954–5958.
5. For more C3–C30 bisindole alkaloids can see: Jiang, C.-S.; Guo, Y.-W. Mini-Rev.
Med. Chem. 2011, 11, 728–745.
6. Schkeryantz, J. M.; Woo, J. C. G.; Siliphaivanh, P.; Depew, K. M.; Danishefsky, S.
J. J. Am. Chem. Soc. 1999, 121, 11964–11975.
7. (a) Movassaghi, M.; Schmidt, M. A.; Ashenhurst, J. A. Org. Lett. 2008, 10, 4009–
4012; (b) Kolundzic, F.; Noshi, M. N.; Tjandra, M.; Movassaghi, M.; Miller, S. J. J.
Am. Chem. Soc. 2011, 133, 9104–9111.
8. Peris, G.; Jakobsche, C. E.; Miller, S. J. J. Am. Chem. Soc. 2007, 129, 8710–8711.
9. Govek, S. P.; Overman, L. E. Tetrahedron 2007, 63, 8499–8513.
10. ½ ꢂ ꢀ38.9 (c 0.7, CHCl3); IR (KBr) 3420, 3401, 3033, 2937, 1716, 1684, 1482,
a 2D5
1455, 1396, 1361, 1308, 1282, 1235, 1153, 1096, 1049, 1022, 752; 1H NMR
(500 MHz, CDCl3): d 8.19 (br s, 1H), 7.98 (br s, 0.5H), 7.52–7.32 (br m, 12.5H),
7.26–7.10 (br m, 5H), 6.74 (br s, 0.5H), 6.63 (br s, 0.5H), 5.45–5.36 (m, 4H), 3.91
(dd, J = 17.5, 1.0 Hz, 1H), 3.71 (br d, J = 23.3 Hz, 1H), 2.89 (d, J = 5.3 Hz, 3H); 13
C
NMR (125 MHz, CDCl3): 171.7, 171.6, 161.9, 155.4, 152.3, 150.6, 140.3, 139.2,
136.4, 136.1, 135.5, 134.9, 134.7, 134.0, 129.5, 128.8, 128.5, 128.1, 127.9, 127.8,
125.3, 125.2, 124.9, 124.2, 123.3, 122.6, 119.2, 116.1, 115.9, 96.4, 96.1, 68.8,
68.5, 67.4, 52.8, 52.8, 48.0, 25.9; HRMS Calcd for [C36H30N4O5+Na+]: 621.2108.
Found: 621.2129.
Acknowledgment
The work was financially supported by NSFC (No. 21102026).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
12.007.