Enantioselective total synthesis of (+)-gliocladin C

Article abstract of DOI:10.1021/ol062801y

(Chemical Equation Presented) The first total synthesis of gliocladin C, a fungal-derived marine alkaloid containing a rare trioxopiperazine fragment, is reported. This asymmetric synthesis establishes the absolute configuration of this structurally novel

Full text of DOI:10.1021/ol062801y

ORGANIC
LETTERS
2007
Vol. 9, No. 2
339-341
Enantioselective Total Synthesis of
)-Gliocladin C
(+
Larry E. Overman* and Youseung Shin
Department of Chemistry, 1102 Natural Sciences II, UniVersity of California,
IrVine, California 92697-2025
leoVerma@uci.edu
Received November 17, 2006
ABSTRACT
The first total synthesis of gliocladin C, a fungal-derived marine alkaloid containing a rare trioxopiperazine fragment, is reported. This asymmetric
synthesis establishes the absolute configuration of this structurally novel natural product.
Fungi found in marine organisms have proven to be a rich
source of architecturally novel and biologically active natural
products.1 In 2004, Usami and co-workers reported the
isolation of the indole alkaloid gliocladin C (1) from a strain
of Gliocladium roseum, originally obtained from the sea hare
Aplysia kurodai (Figure 1).2 Coisolated with gliocladin C
epidithiodiketopiperazine congeners leptosin D,3 gliocladine
A,4 and T988A.5 Gliocladins A-C exhibited cytotoxic
activity against P388 lymphocytic leukemia in cell culture,
with gliocladin C (1) being most potent (2.4 µg/mL).2
The proposed gross structure and relative configuration
of gliocladin C (1) was based on mass spectrometric and
spectroscopic data, with the absolute configuration being
undefined.2 The most novel structural feature of gliocladin
C is the trioxopiperazine ring, which is an extremely rare
feature of natural products, never before seen in conjunction
with a pyrrolidinoindoline fragment.6,7 We report in this
disclosure the first total synthesis of gliocladin C (1) and
proof that its absolute configuration is as depicted in Figure
1.
Oxindoles having a â-aminoethyl substituent at C3 are
time-tested precursors of pyrrolidinoindolines.8 We recently
(2) Usami, Y.; Yamaguchi, J.; Numata, A. Heterocycles 2004, 63, 1123-
1129.
(3) Takahashi, C.; Numata, A.; Ito, Y.; Matsumura, E.; Araki, H.; Iwaki,
H.; Kushida, K. J. Chem. Soc., Perkin Trans. 1 1994, 1859-1864.
(4) Dong, J.-Y.; He, H.-P.; Shen, Y.-M; Zhang, K.-Q. J. Nat. Prod.
2005, 68, 1510-1513.
Figure 1. Gliocladins A (2), B (3), and C (1).
(5) Feng, Y.; Blunt, J. W.; Cole, A. L. J.; Munro, M. H. G. J. Nat. Prod.
2004, 67, 2090-2092.
were the sulfur-containing analogues gliocladins A (2) and
B (3), the former being related closely in structure to
(6) A trioxopiperazine ring is found in dithiosecoemestrin7a and
neoechinulin.7b
(7) (a) Seya, H.; Nozawa, K.; Udagawa, S.; Nakajima, S.; Kawai, K.
Chem. Pharm. Bull. 1986, 34, 2411-2416. (b) Casnati, G.; Pochini, A.;
Ungaro, R. Gazz. Chim. Ital. 1973, 103, 141-151.
(1) Blunt, J. W.; Copp, B. R.; Munro, M. H. G.; Northcote, P. T.; Prinsep,
M. R. Nat. Prod. Rep. 2006, 23, 26-78 and earlier reviews in this series.
10.1021/ol062801y CCC: $37.00
© 2007 American Chemical Society
Published on Web 12/22/2006

reported9 that elaborate, enantiopure structures of this type
containing an aryl or heteroaryl substituent at the quaternary
C3 stereocenter could be quickly assembled by the Mu-
kaiyama aldol reaction10 of 2-siloxyindoles and the serine-
derived aldehyde 5 (eq 1, DTBMP ) 2,6-di-tert-butyl-4-
methylpyridine).11 (+)-Oxindole 6, which can be prepared
in this fashion on a large scale in five steps from isatin, was
the starting point for our construction of (+)-gliocladin C
(1).
Scheme 1. Conversion of Aldol Product 6 to
Pyrrolidinoindoline Alcohol 11
The conversion of Mukaiyama aldol adduct 6 to hy-
droxymethyl pyrrolidinoindoline 11 is summarized in Scheme
1. This seemingly straightforward elaboration was rendered
challenging by the propensity of oxindole 6 to undergo retro-
aldol fragmentation under basic conditions9 and the acid
sensitivity of pyrrolidinolindolines having a hydroxyl sub-
stituent at C3.12,13 The sequence that ultimately proved
successful began by cleavage of the oxazoline and Boc
substituents of aldol adduct 6 with 3 M HCl in MeOH,
followed by reaction of the resulting amino diol with 2,2-
dimethoxypropane, a sequence that delivered 1,3-dioxane 7
in 85% overall yield. The use of formic acid in the first step9
resulted in partial retroaldolization in large-scale reactions
when this less volatile acid was removed by evaporation.
Reaction of amino oxindole 7 with excess LiAlH4 at room
temperature, followed by exposure of the crude product to a
slurry of silica gel in MeOH provided pyrrolidinoindoline 8
in 93% yield.
We first became aware of the extreme acid sensitivity of
pyrrolidinoindolines containing hydroxyl sustituents at C3
when all standard conditions we surveyed for cleaving the
acetonide substituent of intermediate 8 resulted in extensive
decomposition. However, using the method developed by
Rychnovsky,14 this group was transformed to silyloxy
propenyl ether 9 in high yield by exposure to excess
TMSOTf and diisopropylethylamine. After introducing a Boc
group to protect the pyrrolidine nitrogen, reaction at room
temperature with a catalytic amount of oxalic acid in MeOH
delivered diol 10 in 71% yield for the two steps. As this
intermediate was quite sensitive, all attempts to selectively
oxidize the primary alcohol substituent were unsuccessful.
Thus, diol 10 was transformed to methoxy derivative 11 by
selective protection of the primary alcohol with a TBDMS
group, followed by sequential reaction with excess NaH and
MeI and then TBAF (1 equiv). This series of three reactions
provided intermediate 11 in 68% overall yield from diol
precursor 10.15 All steps of this sequence take place under
basic conditions, which is likely key to its success.
The trioxopiperazine ring of (+)-gliocladin C was as-
sembled, and the ∆11,12-unsaturation introduced by the series
of transformations summarized in Scheme 2. The primary
alcohol substituent of alcohol 11 was first oxidized to give
the corresponding acid without effecting the indole substitu-
ent by a two-step sequence involving initial reaction with
Dess-Martin periodinane16 to give the corresponding alde-
hyde, followed by sodium chlorite oxidation.17 Coupling of
the crude acid product with methylamine using the BOP
reagent18 then delivered amide 12 in 60% overall yield form
(8) Julian, P. L.; Pikl, J.; Boggess, D. J. Am. Chem. Soc. 1934, 56, 1797-
1801.
(9) Adhikari, S.; Caille´, S.; Hanbauer, M.; Ngo, V. X.; Overman, L. E.
Org. Lett. 2005, 7, 2795-2798.
(10) Mukaiyama, T.; Banno, K.; Narasaka, K. J. Am. Chem. Soc. 1974,
96, 7503-7509.
(11) Garner, P.; Park, J. M. Organic Syntheses; Wiley: New York, 1998;
Collect. Vol. IX, pp 300-305.
(12) (a) The acid sensitivity of 3-hydroxypyrrolidinoindolines is believed
to derive from acid-catalyzed ring opening of the aminal functionality.
Iminium species generated in this way could degrade by multiple pathways,
for example, by retroaldol-type cleavage. (b) Degradative studies of
verticillin A13a and leptosin B13b demonstrated the instability of the
3-hydroxypyrrolidinoindoline subunit under strongly basic conditions or
upon reaction with triphenylphosphine.
(14) (a) Rychnovsky, S. D.; Hoye, R. C. J. Am. Chem. Soc. 1994, 116,
1753-1765. (b) Rychnovsky, S. D.; Kim, J. Tetrahedron Lett. 1991, 32,
7219-7222.
(15) The use of excess TBAF resulted in lower yields.
(16) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155-4156.
(b) Meyer, S. D.; Schreiber, S. L. J. Org. Chem. 1994, 59, 7549-7552.
(13) (a) Minato, H.; Matsumoto, M.; Katayama, T. J. Chem. Soc., Perkin
Trans. 1 1973, 1819-1825. (b) Takahashi, C.; Numata, A.; Ito, Y.;
Matsumura, E.; Araki, H.; Iwaki, H.; Kushida, K. J. Chem. Soc., Perkin
Trans. 1 1994, 1859-1864.
340
Org. Lett., Vol. 9, No. 2, 2007

led to extensive decomposition. Fortunately, a method
developed by Mulliez to form peptide-derived trioxopipera-
zines proved successful.23 Thus, when a solution of 15 and
1,1,1,3,3,3-hexamethyldisilazane was heated at 140 °C in a
sealed tube, cyclization to form the trioxopiperazine and
elimination of the methoxy group both took place to give
(+)-gliocladin C (1), a pale yellow solid, in 73% yield.
Comparison of 1H and 13C NMR data24,25 of synthetic 1 with
those of the natural product confirmed their identity. The
optical rotation of synthetic 1, [R]23D +116 (c 0.02 CHCl3),
compared well with that reported for the natural sample, [R]D
+131 (c 0.07 CHCl3). Because the relative and absolute
configuration of the Fmoc derivative of synthetic precursor
7 had been determined by single-crystal X-ray analysis,9 this
comparison establishes the absolute configuration of (+)-
gliocladin C (1) to be as depicted.
Scheme 2. Construction of the Trioxopiperazine Ring To
Form (+)-Gliocladin C (1)
In summary, the first total synthesis of the structurally
novel marine alkaloid (+)-gliocladin C (1) was completed
in ∼4% overall yield and 21 steps from isatin. A central
step in this sequence is asymmetric construction of the
quaternary carbon stereocenter by a Mukaiyama aldol
reaction of siloxyindole 4 and enantiopure aldehyde 5.9
Knowledge gained during the latter stages of this synthesis
could potentially allow the synthetic sequence to be stream-
lined. Of more importance, a better appreciation of the acid
sensitivity of pyrrolidinoindolines containing oxygen sub-
stituents at C3 should assist in the design of synthetic
approaches to related, more complex, and biologically more
potent alkaloids.26
Acknowledgment. This research was supported by Grant
No. GM-30859 from the National Institutes of General
Medical Sciences. We also thank Amgen, Merck, Pfizer, and
Roche Palo Alto for unrestricted support. We particularly
thank Professor Y. Usami (Osaka University of Pharmaceuti-
cal Sciences) for providing copies of NMR spectra of natural
gliocladin C and for useful discussions. We also thank Dr.
Young Ho Rhee for optimizing the synthesis of 7 and Dr.
Se´bastien Caille´ for first preparing compounds 8 and 9. NMR
and mass spectra were determined at UC Irvine with
instruments purchased with the assistance of the NSF and
NIH shared instrumentation programs.
hydroxymethylpyrrolidinoindoline 11. To set the stage for
assembling the trioxopiperazine ring, the Boc group was
cleaved by reaction of 12 with TMSI to give secondary amine
13 in 65% yield.19,20 A preliminary survey of the reactivity
of the pyrrolidine nitrogen of congeners of 1321 had shown
that acylation of the hindered and inductively deactivated
secondary amine was problematic; thus, the benzyl protecting
group of the adjacent nitrogen and that of the indole
substituent were removed at this stage by the reaction of 13
at -78 °C with excess Na and t-BuOH in THF-NH3. This
deprotection was remarkably clean, providing the secondary
triamine 14 in 87% yield. Although several potential ap-
proaches for fashioning the trioxopiperazine ring in one step
were unsuccessful,22 reaction of 14 with ethyl chlorooxo-
acetate in the presence of Et3N took place cleanly at N5 to
give oxalyl half-ester half-amide 15 in 87% yield. To our
initial dismay, attempts to cyclize this intermdiate by reaction
with a variety of bases (e.g., DBU, i-Pr2EtN, Et3N, or NaH)
Supporting Information Available: Experimental pro-
1
cedures, tabulated H and 13C NMR spectra of natural and
1
synthetic (+)-gliocladin C, copies of H and 13C NMR
spectra of new compounds, and the X-ray model of the C3
acetate analogue of 13. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL062801Y
(17) (a) Bal, B. S.; Childers, W. E., Jr.; Pinnick, H. W. Tetrahedron
1981, 37, 2091-2096. (b) Kraus, G. A.; Taschner, M. J. J. Org. Chem.
1980, 45, 1175-1176.
(23) Mulliez, M.; Royer, J. Tetrahedron 1984, 40, 5143-5151.
(24) The small signal for the quaternary carbon C3′ at 116.7 ppm, which
is seen in the 13C NMR spectrum of natural gliocladin C, was not reported
in ref 2. Assignments reported in this paper for signals at 122.7 and 120.11/
120.13 ppm should be changed to C6′ and C4′/C5′.25 A summary of peak
assignments for synthetic gliocladin C, which were established by HMQC
and HMBC experiments, can be found in the Supporting Information.
(25) Usami, Y. Personal communication, Aug 8, 2006.
(18) BOP ) benzotriazole-1-yloxy-tris(dimethylamino)phosphonium
hexafluorophosphate.
(19) Depew, K. M.; Marsden, S. P.; Zatorska, D.; Zatorski, A.; Bornmann,
W. G.; Danishefsky, S. J. J. Am. Chem. Soc. 1999, 121, 11953-11963.
(20) The C3 acetate analogue of 13 provided single crystals allowing
the relative configuration of this intermediate to be confirmed by X-ray
crystallography.
(21) The substituent was OAc or OTIPS instead of OMe.
(22) (a) Makino, S.; Nakanishi, E.; Tsuji, T. Synlett 2003, 6, 817-820.
(b) Bailey, P. D.; Bannister, N.; Bernad, M.; Blanchard, S.; Boa, A. N. J.
Chem. Soc., Perkin Trans. 1 2001, 3245-3251.
(26) Anthoni, U.; Christophersen, C.; Nielsen, P. H. Naturally Occurring
Cyclotryptophans and Cyclotryptamines. In Alkaloids: Chemical and
Biological PerspectiVes; Pelletier, S. W., Ed.; Pergamon: New York, 1999;
Vol. 13, pp 163-236.
Org. Lett., Vol. 9, No. 2, 2007
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