Enantioselective total synthesis of (+)-gliocladine C: Convergent construction of cyclotryptamine-fused polyoxopiperazines and a general approach for preparing epidithiodioxopiperazines from trioxopiperazine precursors

Article abstract of DOI:10.1021/ja201789v

A concise second-generation total synthesis of the fungal-derived alkaloid (+)-gliocladin C (11) in 10 steps and 11% overall yield from isatin is reported. In addition, the epipolythiodioxopiperazine (ETP) natural product (+)-gliocladine C (6) has been pr

Full text of DOI:10.1021/ja201789v

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pubs.acs.org/JACS
Enantioselective Total Synthesis of (þ)-Gliocladine C: Convergent
Construction of Cyclotryptamine-Fused Polyoxopiperazines
and a General Approach for Preparing Epidithiodioxopiperazines
from Trioxopiperazine Precursors
John E. DeLorbe, Salman Y. Jabri, Steven M. Mennen,† Larry E. Overman,* and Fang-Li Zhang‡
Department of Chemistry, 1102 Natural Sciences II, University of California, Irvine, California 92697-2025, United States
S Supporting Information
b
ABSTRACT: A concise second-generation total synthesis
of the fungal-derived alkaloid (þ)-gliocladin C (11) in 10
steps and 11% overall yield from isatin is reported. In
addition, the epipolythiodioxopiperazine (ETP) natural
product (þ)-gliocladine C (6) has been prepared in six
steps and 29% yield from the di-(tert-butoxycarbonyl)
precursor of 11. The total synthesis of 6 constitutes the
first total synthesis of an ETP natural product containing a
hydroxyl substituent adjacent to a quaternary carbon stereo-
center in the pyrrolidine ring.
pipolythiodioxopiperazine (ETP) toxins are fungal second-
E
ary metabolites that possess unique molecular structures and
a wide range of biological activities (Figure 1).1 The toxicity of
these amino acid-derived natural products is attributed to the di-
or polysulfide bridge of the dioxopiperazine subunit, which can
either conjugate directly to cysteine residues or generate reactive
oxygen species. A number of recent studies point to the potential
utility of epidithiodioxopiperazines in cancer chemotherapy,2 as
impressive selectivities toward both myeloma3 and solid tumors4
have been demonstrated and novel molecular targets have been
identified.5 The structure and chemical lability of ETPs pose a
number of challenges for chemical synthesis. In a remarkable
accomplishment, Fukuyama and Kishi disclosed the total
synthesis of gliotoxin (1) in 1976,6 and the chemistry developed
in those investigations for incorporation of an epidithiodioxopi-
perazine unit7 was subsequently used for the synthesis of
various other ETP natural products.8 In an incisive total synthesis
of dideoxyverticillin A (2) reported in 2009 by Movassaghi and
co-workers, biosynthetically inspired oxidation of cyclotrypta-
mine-fused dioxopiperazines and sulfidation were employed to
elaborate epidithio bridges onto dimeric dioxopiperazine pre-
cursors.9,10 Shortly thereafter, Sodeoka and co-workers reported
the synthesis of (þ)-chaetocin A (3) using a related strategy for
forging the epidithiodioxopiperazine units.11
Figure 1. Some ETP natural products.
labile hydroxyl substituent,12 which we illustrate by an enantiose-
lective total synthesis of (þ)-gliocladine C (6).13,14 Critical to our
success was the development of a new convergent method for
constructing cyclotryptamine-fused polyoxopiperazines.
Our approach for preparing 6 and congeners is outlined in
Scheme 1. We hypothesized that the simpler alkaloid (þ)-
gliocladin C (11)15 might serve as a synthetic precursor of this
family of ETPs through three potentially straightforward trans-
formations: (i) nucleophilic addition of a C3 substituent16 to the
R-ketoimide carbonyl group, (ii) dihydroxylation of the alkyli-
dene dioxopiperazine double bond, and (iii) formation of the
disulfide bridge.
The opening phase of this endeavor was the development of
an efficient second-generation total synthesis of 11, the first total
synthesis of which was reported by our laboratory in 2007.12 Our
plan was to assemble the tetracyclic core of 11 from the union of
enantioenriched dielectrophile 12 and dinucleophile 13,17 with
The largest group of ETP natural products is derived from
tryptophan and contains an ETP ring fused to a cyclotryptamine
fragment (Figure 1).1 In many of these structures, the carbon of
the pyrrolidine ringadjacent to the quaternary carbon stereocenter
bears a hydroxyl substituent (e.g., 4ꢀ10 in Figure 1). Herein we
disclose a general approach for preparing ETPs having this highly
Received: February 26, 2011
Published: April 07, 2011
r
2011 American Chemical Society
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Scheme 1. Retrosynthetic Analysis of ETPs 6ꢀ10
Scheme 2. Preparation of Enantioenriched Dielectrophile
20a
the quaternary carbon stereocenter of the former arising from a
catalytic enantioselective Steglich-type rearrangement of indolyl
carbonate 14.18,19
a Reaction conditions: (a) TFA, Et3SiH, CH2Cl2, rt. (b) (i) (Boc)2O,
15 mol % DMAP, CH2Cl2, rt; (ii) MeOH (68% from 15). (c) 2,2,
2-Trichloro-1,1-dimethylethyl chloroformate, Et3N, THF, 0 °C (97%). (d)
(S)-(ꢀ)-4-Pyrrolidinopyrindinyl(pentamethylcyclopentadienyl)iron, THF,
rt (96%, 98:2 er). (e) 2,2,2-Trichloro-1,1-dimethylethyl chloroformate,
Et3N, (S)-(ꢀ)-4-pyrrolidinopyrindinyl(pentamethylcyclopentadienyl)iron,
THF, 40 °C (88%, 98:2 er). (f) NaBH4, MeOH, 0 °C (81%). (g)
HC(OMe)3, 10 mol % PPTS, MeOH, 65 °C (83%; 1.2:1.0 dr). (h)
LiBH4ꢀMeOH, Et2O, rt to 40 °C (84%). (i) DessꢀMartin periodinane,
pyridine, CH2Cl2, rt (95%).
The synthesis of 11 commenced with acid-promoted ionic
reduction of readily available 3-hydroxy-3,30-biindolin-2-one
(15)20 followed by Boc protection to give intermediate 16
(Scheme 2).21 Reaction of oxindole 16 with 2,2,2-trichloro-1,
1-dimethylethyl chloroformate and Et3N delivered prochiral indolyl
carbonate 17 in 66% overall yield from biindolinone 15. Catalytic
rearrangement of 17 took place efficiently and with high
enantioselectivity at room temperature in the presence of a
5 mol % loading of Fu’s (S)-(ꢀ)-4-pyrrolidinopyrindinyl(pentame-
thylcyclopentadienyl)iron catalyst19a to give 3,3-disubstituted
oxindole 18 in 96% yield and a 98:2 enantiomer ratio (er) on
scales of up to 15 g. In addition, direct reaction of oxindole 16
with 2,2,2-trichloro-1,1-dimethylethyl chloroformate, Et3N, and
10 mol % of Fu’s catalyst at 40 °C provided oxindole ester 18 in
88% yield and identical high enantioselectivity (98:2 er).
After several shorter approaches proved inefficient or resulted
in partial racemization,22 oxindole 18 was elaborated to indoline
20 in good yield as follows. The oxindole carbonyl group of 18
was reduced selectively with NaBH4 at 0 °C, and the resulting
2-hydroxyindoline intermediate was exposed to a methanolic
solution of trimethyl orthoformate and a catalytic amount of
pyridinium p-toluenesulfonate (PPTS) at 65 °C to afford indo-
line N,O-acetal 19, a 1.2:1.0 mixture of the R- and β-N,O-acetal
epimers, in 67% overall yield. Sequential Soai reduction23 and
DessꢀMartin oxidation24 provided enantioenriched dielectro-
phile 20 in 80% yield from 19.
Scheme 3. Second-Generation Synthesis of (þ)-Gliocladin
C (11)a
In two additional steps, indoline aldehyde 20 was united with
trioxopiperazine derivative 21 to provide 11 (Scheme 3). Aldol
condensation of aldehyde 20 with the lithium enolate of piperazi-
nedione 2125 in THF at ꢀ78 °C followed by quenching of the
reaction with excess acetic acid and warming to room temperature
delivered condensation product 22 exclusively as the Z stereoiso-
a Reaction conditions: (a) (i) LDA, 21, THF, ꢀ78 °C; (ii) 20, ꢀ78 °C;
(iii) AcOH, ꢀ78 °C to rt (75% from 20). (b) BF3 OEt2, CH2Cl2, ꢀ78
3
to ꢀ40 °C (80%). (c) Neat, 175 °C (89%). (d) Sc(OTf)3, MeCN, 0 °C
to rt (60%).
mer in 75% yield. Exposure of 22 to BF3 OEt2 at ꢀ40 °C
3
promoted cyclization and concomitant demethylation to provide
trioxopiperazine-fused cyclotryptamine 23 in 80% yield. The Boc
protecting groups of 23 were then removed thermolytically26 to
afford crystalline (þ)-gliocladin C (11) in 89% yield. Alternatively,
coupled intermediate 22 could be transformed directly to 11
{[R]2D3 þ127 (c 0.23, pyridine)}27 in 60% yield upon reaction
with excess Sc(OTf)3 in acetonitrile from 0 °C to room tempera-
ture. Single-crystal X-ray diffraction of the synthetic 11 confirmed
the constitution and relative configuration of this natural product.28
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Scheme 4. Synthesis of (þ)-Gliocladine C (6)a
face opposite both the angular indolyl substituent and the
adjacent acetate.
At this stage, all that remained was the removal of the acetate, and
this transformation was accomplished by heating ETP intermediate
27 in a methanolic solution of La(OTf)3 at 40 °C,35 which gave
(þ)-gliocladine C (6) as a colorless amorphous solid in 75% yield.
The optical rotation of synthetic 6 {[R]2D3 þ505 (c 0.47 pyridine)}
compared well with the value reported for the natural sample
{[R]1D8.7 þ513 (c 0.33, pyridine)}, as did spectroscopic data.
In conclusion, the total synthesis of (þ)-gliocladine C (6)
constitutes the first total synthesis of an ETP natural product
containing hydroxy substitution in the pyrrolidine ring. More-
over, the total syntheses of (þ)-gliocladin C (11) and 6 disclosed
herein showcase two short synthetic sequences that we expect
will find broader utility. First, the assembly of 11 from enan-
tioenriched aminal aldehyde 20 and dioxopiperazine derivative
21 illustrates a convergent construction of oxopiperazine-fused
pyrrolidinoindolines that can be employed to access more widely
distributed dioxopiperazine variants. Second, the construction of
epidithiodioxopiperazine alkaloid 6 from trioxopiperazine pre-
cursor 23 illustrates a sequence wherein diversity in the dioxo-
piperazine unit of an ETP product can be introduced at a late
stage in a synthetic sequence.
’ ASSOCIATED CONTENT
S
Supporting Information. Complete ref 4b, experimental
b
details, characterization data, copies of 1H and 13C NMR spectra of
new compounds, and crystallographic data (CIF). This material is
available free of charge via the Internet at http://pubs.acs.org.
a Reaction conditions: (a) MeMgCl, THF, ꢀ78 °C (86%, 9:1 dr). (b)
TBSOTf, DMAP, Et3N, DMF, rt (94%, 3:2 dr). (c) Mixture of 24a and
’ AUTHOR INFORMATION
24b (3:2), AD-Mix-R, H2NSO2Me, K2OsO4 2H2O, (DHQ)2PHAL,
3
t-BuOH/H2O/acetone, rt (82%, >14:1 dr). (d) Ac2O, DMAP, CH2Cl2,
Corresponding Author
leoverma@uci.edu
rt (93%). (e) (i) H2S, BF3 OEt2, CH2Cl2, ꢀ78 °C to rt; (ii) O2,
3
MeOH/EtOAc, rt (62%). (f) La(OTf)3, MeOH, 40 °C (75%).
Present Addresses
†Chemical Process R&D, Amgen, Inc., 360 Binney Street, Cam-
bridge, MA 02142.
With substantial quantities of trioxopiperazine-fused pyrroli-
dinoindoline 23 in hand, we turned to its transformation into 6
(Scheme 4). Chemoselective addition29 of methylmagnesium
chloride to trioxopiperazine 23 at ꢀ78 °C provided a 9:1 mixture
of epimeric tertiary alcohols, which was silylated to give dioxo-
piperazine 24 as a 3:2 mixture of siloxy epimers in 81% overall
yield. Although it was most convenient to prepare ETP product
27 directly from this mixture of stereoisomers (see below),
insight into the dihydroxylation step was obtained when epimers
24a and 24b were separated and individually examined. As
summarized in Scheme 4, catalytic dihydroxylation of the minor
siloxy epimer was highly substrate-controlled, yielding R-diol 25
with 20:1 diasteroselectivity when OsO4/NMO, AD-Mix-R, or
AD-Mix-β was used.30 Although no diasteroselectivity was ob-
served in the dihydroxylation of the major epimer 24a with
OsO4, diastereoselection in forming the R-diol product was
improved to 14:1 using AD-Mix-R. With this oxidant, the initially
produced 3:2 mixture of siloxy epimers 24 was dihydroxylated,
and the crude diol products were acetylated to provide diacetates
26 in 76% yield over the two steps.30b,31 Reaction of this mixture
‡Suzhou Novartis Pharma Technology Co., Ltd., 18 Tonglian
Road, Riverside Industrial Park, Changsu 215537, China.
’ ACKNOWLEDGMENT
Support from the NIH National Institute of General Medical
Sciences (GM-30859) and postdoctoral fellowship support to J.
E.D. (GM090473), S.M.M. (GM082113), and F.-L.Z. (Swiss
NSF) is gratefully acknowledged. NMR and mass spectra were
determined at UC Irvine using instruments purchased with the
assistance of NSF and NIH shared instrumentation grants. We
thank Dr. Joseph Ziller and Dr. John Greaves, Department of
Chemistry, UC Irvine, for their assistance with X-ray and mass
spectrometric analyses.
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