Construction of epidithiodioxopiperazines by directed oxidation of hydroxyproline-derived dioxopiperazines

Article abstract of DOI:10.1021/ol702518t

(Chemical Equation Presented) Functionalization of the angular methine carbon of hydroxyproline-derived dioxopiperazines by a radical-promoted C-H bond oxidation, which is directed by a proximal (bromomethyl)silyl group, is described. This regioselective

Full text of DOI:10.1021/ol702518t

ORGANIC
LETTERS
2007
Vol. 9, No. 25
5267-5270
Construction of
Epidithiodioxopiperazines by Directed
Oxidation of Hydroxyproline-Derived
Dioxopiperazines
Larry E. Overman* and Takaaki Sato
Department of Chemistry, 1102 Natural Sciences II, UniVersity of California, IrVine,
California 92687-2025
leoVerma@uci.edu
Received October 15, 2007
ABSTRACT
Functionalization of the angular methine carbon of hydroxyproline-derived dioxopiperazines by a radical-promoted C−H bond oxidation, which
is directed by a proximal (bromomethyl)silyl group, is described. This regioselective oxidation is the key step in a new synthesis of
epidithiodioxopiperazines.
Epipolythiodioxopiperazines (ETPs) are toxic secondary
metabolites made by fungi.1 The varied biological effects
of ETP natural products are attributed to the bridged
disulfide, which can directly conjugate to cysteine residues
or generate reactive oxygen species by redox cycling.1 The
largest number of natural ETPs are derived from tryptophan
and contain an ETP ring fused to a cyclotryptamine fragment.
Leptosins D (1) and K (2), which were isolated by Numata
and co-workers, are exemplary of this subclass of ETP
natural products (Figure 1).2,3
The synthesis of ETP compounds received much attention
in the 1970s and 1980s,4 culminating in the landmark total
synthesis of (+)-gliotoxin by Kishi and co-workers.4i As a
Figure 1. Representative ETP natural products containing cyclo-
tryptophan fragments.
step toward developing total syntheses of the cyclotryptophan
group of ETP metabolites, we report a method for con-
structing tricyclic epidithiodioxopiperazines from dioxo-
piperazines containing a hydroxyproline unit. The develop-
ment of a protecting-group-directed, regioselective C-H
bond oxidation was critical to implementing this se-
quence.
(1) For reviews, see: (a) Waring, P.; Eichner, R. D.; Mu¨llbacher, A.
Med. Res. ReV. 1988, 8, 499-524. (b) Gardiner, D. M.; Waring, P.; Howlett,
B. J. Microbiology 2005, 151, 1021-1032.
(2) Takahashi, C.; Numata, A.; Ito, Y.; Matsumura, E.; Araki, H.; Iwaki,
H.; Kushida, K. J. Chem. Soc., Perkin Trans. 1 1994, 1859-1864.
(3) Takahashi, C.; Minoura, K.; Yamada, T.; Numata, A.; Kushida, K.;
Shingu, T.; Hagishita, S.; Nakai, H.; Sato, T.; Harada, H. Tetrahedron 1995,
51, 3483-3498.
10.1021/ol702518t CCC: $37.00
© 2007 American Chemical Society
Published on Web 11/15/2007

The high reactivity of the disulfide bridge is a critical
consideration in designing synthetic routes to ETP natural
products. The disulfide bridge is known to be extremely
labile under reductive, basic, and strongly acidic conditions.1,4i
Accordingly, we plan to install the disulfide bridge at a late
stage in the synthesis of cyclotryptophan-containing ETPs
from precursors such as dioxopiperazine diacetate 4 (Scheme
1).5,6 Most ETP natural products of this type contain a
place at carbons R or δ to the hydroxyl group.8,9 Some
transformations of radicals translocated to the â-carbon of
an alcohol derivative have been documented; however,
oxidation of such translocated radicals apparently has not
been reported previously.10
Our investigation commenced with the coupling of 3-hy-
droxyproline derivative 611 and acetylglycolic acid 7 (Scheme
2). After hydrolytic cleavage of the acetate of diamide 8,
Scheme 1
Scheme 2
hydroxyl substituent adjacent to the disulfide bridge (e.g., 1
and 2). Thus, we hoped to engage this substituent to direct
selective, late-stage oxidation of the adjacent angular carbon
of a hexahydropyrrolo[1,2-a]pyrazine-1,4-dione fragment.
The sequence we ultimately developed employs a silyl
group on the secondary alcohol to initiate a radical chain
oxidation reaction (3 f 4, Scheme 1).7 The (bromomethyl)-
dimethylsilyl-protecting/radical-translocating group was cho-
sen because it should be possible to introduce it into complex
molecules under mild conditions, and the resulting trimeth-
ylsiloxy product should be easily transformed to the parent
alcohol. Radical-promoted C-H bond oxidation is appreci-
ated as a technique for remote functionalization of alcohol
derivatives; however, these directed oxidations typically take
Parikh-Doering oxidation12 and attendant cyclization gave
a mixture of dioxopiperazines 10a and 10b (12:1 ratio, 64%
yield), from which the crystalline epimer 10a was isolated
in 59% overall yield from aminoamide 6. After acetylating
the hydroxyl group of 10a, the TBS group was removed at
(4) (a) Trown, P. W. Biochem. Biophys. Res. Commun. 1968, 33, 402-
407. (b) Hino, T.; Sato, T. Tetrahedron Lett. 1971, 12, 3127-3129. (c)
O¨ hler, E.; Poisel, H.; Tataruch, F.; Schmidt, U. Chem. Ber. 1972, 105, 635-
641. (d) O¨ hler, E.; Tataruch, F.; Schmidt, U. Chem. Ber. 1973, 106, 165-
176. (e) Yoshimura, J.; Nakamura, H.; Matsunari, K.; Sugiyama, Y. Chem.
Lett. 1974, 559-560. (f) Kishi, Y.; Fukuyama, T.; Nakatsuka, S. J. Am.
Chem. Soc. 1973, 95, 6490-6492. (g) Kishi, Y.; Fukuyama, T.; Nakatsuka,
S. J. Am. Chem. Soc. 1973, 95, 6492-6493. (h) Kishi, Y.; Nakatsuka, S.;
Fukuyama, T.; Havel, M. J. Am. Chem. Soc. 1973, 95, 6493-6495. (i)
Fukuyama, T.; Nakatsuka, S.; Kishi, Y. Tetrahedron 1981, 37, 2045-2078.
(j) Strunz, G. M.; Kakushima, M. Experientia 1974, 30, 719-720. (k)
Ottenheijm, H. C. J.; Herscheid, J. D. M.; Kerkhoff, G. P. C.; Spande, T.
F. J. Org. Chem. 1976, 41, 3433-3438. (l) Herscheid, J. D. M.; Nivard, R.
J. F.; Tijhuis, M. W.; Ottenheijm, H. C. J. J. Org. Chem. 1980, 45, 1885-
1888. (m) Williams, R. M.; Rastetter, W. H. J. Org. Chem. 1980, 45, 2625-
2631. (n) Srinivasan, A.; Kolar, A. J.; Olsen, R. K. J. Heterocycl. Chem.
1981, 18, 1545-1548. (o) Shimazaki, N.; Shima, I.; Hemmi, K.; Tsurumi,
Y.; Hashimoto, M. Chem. Pharm. Bull. 1987, 35, 3527-3530. (p) Jiang,
H.; Newcombe, N.; Sutton, P.; Lin, Q. H.; Mu¨llbacher, A.; Waring, P. Aust.
J. Chem. 1993, 46, 1743-1754. (q) Wu, Z.; Williams, L. J.; Danishefsky,
S. J. Angew. Chem., Int. Ed. 2000, 39, 3866-3868. (r) Aliev, A. E.; Hilton,
S. T.; Motherwell, W. B.; Selwood, D. L. Tetrahedron Lett. 2006, 47, 2387-
2390.
(5) For synthetic studies toward cyclotryptophan-containing ETPs by
other groups, see: (a) Crich, D.; Fredette, E.; Flosi, W. J. Heterocycles
1998, 48, 545-547. (b) Yamada, F.; Goto, A.; Somei, M. Heterocycles
2000, 53, 1255-1258.
(6) For the recent total synthesis of a related, structurally simpler
cyclotryptophan alkaloid, see: Overman, L. E.; Shin, Y. Org. Lett. 2007,
9, 339-341.
(7) For an early example of 1,5-radical translocation from a protecting
group, see: Curran, D. P.; Kim, D.; Liu, H. T.; Shen, W. J. Am. Chem.
Soc. 1988, 110, 5900-5902.
(8) For examples of C-H bond oxidation R to oxygen of alcohol
derivatives, see: (a) Lewin, A. H.; Dinwoodie, A. H.; Cohen, T. Tetrahedron
1966, 22, 1527-1537. (b) Curran, D. P.; Yu, H. Synthesis 1992, 123-127.
(c) Han, G.; McIntosh, M. C.; Weinreb, S. M. Tetrahedron Lett. 1994, 35,
5813-5816.
(9) For examples of C-H bond oxidation δ to oxygen of alcohol
derivatives, see: (a) Barton, D. H. R.; Beaton, J. M.; Geller, L. E.; Pechet,
M. M. J. Am. Chem. Soc. 1960, 82, 2640-2641. For recent reviews, see:
(b) Majetich, G.; Wheless, K. Tetrahedron 1995, 51, 7095-7129. (c) Reese,
P. B. Steroids 2001, 66, 481-497. (d) Togo, H.; Katohgi, M. Synlett 2001,
565-581. (e) Cˇ ekovic´, Zˇ. Tetrahedron 2003, 59, 8073-8090.
(10) Intramolecular hydrogen atom abstraction â to a protected alcohol,
followed by C-C bond formation or trapping with hydrogen has been
described; see: (a) Brunckova, J.; Crich, D.; Yao, Q. Tetrahedron Lett.
1994, 35, 6619-6622. (b) Yamazaki, N.; Eichenberger, E.; Curran, D. P.
Tetrahedron Lett. 1994, 35, 6623-6626. (c) Curran, D. P.; Xu, J. J. Am.
Chem. Soc. 1996, 118, 3142-3147. (d) Moenius, T.; Andres, H.; Acemoglu,
M.; Kohler, B.; Schnelli, P.; Zueger, C. J. Labelled Compd. Radiopharm.
2000, 43, 113-120. (e) Sukeda, M.; Matsuda, A.; Shuto, S. Tetrahedron
2005, 61, 7865-7873. (f) Sakaguchi, N.; Hirano, S.; Matsuda, A.; Shuto,
S. Org. Lett. 2006, 8, 3291-3294.
(11) Synthesis of 3-hydroxyproline derivative 6 is described in the
Supporting Information.
(12) Parikh, J. R.; Doering, W. E. J. Am. Chem. Soc. 1967, 89, 5505-
5507.
5268
Org. Lett., Vol. 9, No. 25, 2007

60 °C with TBAF buffered with acetic acid to provide
dioxopiperazine alcohol 11 in 73% yield (over two steps).13
To allow selective oxidation at the angular position, this
secondary alcohol was transformed in high yield to (bro-
momethyl)dimethylsiloxy ether 12 by reaction at room
temperature with (bromomethyl)chlorodimethylsilane and
Et3N.14
The crucial radical-promoted functionalization of the
angular carbon was initially developed with the more readily
available bromomethylsilyl acetal 13 (Table 1).15 Conditions
However, when the weaker reducing agent tributylgerma-
nium hydride was employed, the desired acetate 14 was
isolated in 16% yield, together with recovered starting
material (entry 2). Tris(trimethylsilyl)silane proved to be the
best radical mediator, providing 14 in 29% yield (entry 3).
The nature of the solvent had some effect on reaction
efficiency (entries 3-6). Best results were obtained in (CH2-
Cl)2, wherein acetate 14 (37% yield) and alcohol 15 (27%
yield) were the major products produced (entry 6), corre-
sponding to 64% efficiency in selectively oxidizing the
angular carbon. A large excess of Cu(OAc)2 and excess
AIBN and tris(trimethylsilyl)silane are required because of
competing redox side reactions between these reagents.
Encouraged by the success in selectively oxidizing the
angular carbon of model substrate 13, we turned our attention
to 3-acetoxyhydropyrrolopyrazine-1,4-dione 12 (Scheme 3).
Table 1. Radical-Promoted Selective Oxidation of
Bromomethylsilyl Ether 13a,b
Scheme 3
yield (%)
entry
mediator
solvent
14
15
13
1
2
3
4
5
6
Bu3SnH
Bu3GeH
(TMS)3SiH
(TMS)3SiH
(TMS)3SiH
(TMS)3SiH
benzene
benzene
benzene
MeCN
DME
(CH2Cl)2
0
16
29
15
30
37
0
0
0
0
0
53
40
0
0
38
23
27
a Conditions: 40 µmol of 13, 3 equiv of mediator, 3 equiv of AIBN, 10
equiv of Cu(OAc)2, solvent (0.02 M), 80 °C. b The relative configurations
of 14 and 15 were not determined.
that favor oxidative termination were examined, on the
assumption that single-electron transfer from the primary
radical derived from 13 would be slower than oxidation of
the more electron-rich captodative radical produced upon 1,5-
hydrogen atom transfer.16 Attempted reaction of 13 with 3
equiv of Bu3SnH and 3 equiv of AIBN in benzene at 80 °C
in the presence of a large excess of Cu(OAc)2 led only to
recovered starting material, as tributyltin hydride and Cu-
(OAc)2 reacted rapidly under these conditions (entry 1).
(13) Attempted cleavage of the TBS group under several other conditions
(TBAF, HF/pyridine, or MeOH in HCl) led to significant decomposition.
(14) For pioneering studies of the use of (bromomethyl)dimethylsiloxy
ethers in free radical chain reactions, see: (a) Nishiyama, H.; Kitajima, T.;
Matsumoto, M.; Itoh, K. J. Org. Chem. 1984, 49, 2298-2300. (b) Stork,
G.; Kahn, M. J. Am. Chem. Soc. 1985, 107, 500-501.
(15) The synthesis of R-bromomethylsilyl 13 is described in the
Supporting Information.
(16) In an early calibration experiment, the reaction of iodoacetal i with
tributyltin hydride, AIBN, and TEMPO in benzene at 85 °C resulted only
in substitution at the acetal substituent to provide TEMPO adduct ii. This
result showed that the primary radical derived from i was trapped with
TEMPO faster than it underwent 1,5-hydrogen atom transfer.
Radical-promoted oxidation of this substrate using the
conditions optimized with bromide 13 (Table 1, entry 6)
provided acetate 16 and alcohols 17 and 18 as major
products. Also produced in significant amounts was the
reduced product 19. Modifying the procedure slightly by
adding a solution of tris(trimethylsilyl)silane and AIBN to
acetoxy substrate 12 and incorporating a trace amount of
water17 led to products of selective oxidation of the angular
Org. Lett., Vol. 9, No. 25, 2007
5269

carbon being isolated in 73% combined yield: â-acetate 16
(42%), â-alcohol 17 (25%), and R-alcohol 18 (6%).18,19
The major products of angular oxidation were transformed
to epidithiodioxopiperazine congeners 22 and 23 as follows.
First, alcohol 17 was converged with acetate 16 by reaction
with acetic anhydride in the presence of DMAP (Scheme
3). Next, the trimethylsiloxy group of intermediate 16 was
converted to an acetate in two standard steps in high yield.
Finally, reaction of triacetate 20 with excess hydrogen sulfide
and a catalytic amount of scandium triflate in acetonitrile
provided dithiol 21, which upon exposure to oxygen gave a
single epidithiodioxopiperazine product 22 in 37% yield.20
The success of this transformation was highly dependent
upon the choice of solvent for the first step; the desired
dithiol was not isolated when CH2Cl2, benzene, Et2O, or
MeNO2 were substituted for acetonitrile. Extensive NMR
analysis failed to conclusively establish the relative config-
uration of the disulfide bridge. Therefore, the acetyl group
of epidithiodioxopiperazine 22 was removed by reaction with
1 equiv of scandium triflate in MeOH/MeCN at room
temperature to give the crystalline alcohol 23, mp 198-199
°C (dec), in quantitative yield.21 Single-crystal X-ray analysis
of this product established that the hydroxyl substituent and
the disulfide bridge are cis,22 indicating the absence of acetate
participation in the addition of H2S to the angular carbon.
The observed 1,2-cis stereoselectivity in this addition step
is in accord with the Woerpel model for stereoselection in
the addition of nucleophiles to five-membered oxocarbenium
ions (and related N-acyliminium ions) containing oxygen
substituents adjacent to the electrophilic carbon.23
In summary, a procedure for selective oxidation of the
angular methine carbon of hydroxyproline-derived dioxopip-
erazines to allow a dithio bridge to be introduced into such
heterocyclic frameworks is reported. The protecting-group-
directed C-H bond oxidation that is a key step in this
sequence likely will be useful for the regioselective oxidative
elaboration of other polyfunctional organic molecules.
Acknowledgment. Support from the NIH National In-
stitutes of General Medical Sciences (GM-30859) and
postdoctoral fellowship support to T.S. by the JSPS 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, Depart-
ment of Chemistry, UC Irvine, for their assistance with X-ray
and mass spectrometric analyses.
(17) These modifications were developed during contemporaneous studies
of the oxidation of an analogue of 12 having an isopropylidene substituent
at C3.
Supporting Information Available: Experimental pro-
1
cedures and copies of H and 13C NMR spectra of new
(18) The relative configuration of these products was determined by
NOESY NMR experiments; see the Supporting Information for details.
(19) Experiments aimed at decreasing the excess of reagents employed
showed that the amount of Cu(OAc)2 could be reduced to 7 equiv; however,
yields of angular oxidation were maximized by using an equal excess of
the silane.
(20) The construction of epidithiodioxopiperazines from dioxopiperazines
that contain two leaving groups by ZnCl2-promoted reaction of H2S has
been reported; see refs 4d, 4e, 4k, and 4l.
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL702518T
(22) CCDC 663428. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
(21) More conventional conditions for removing the acetate group were
not compatible with the disulfide bridge.
(23) Larsen, C. H.; Ridgway, B. H.; Shaw, J. T.; Smith, D. M.; Woerpel,
K. A. J. Am. Chem. Soc. 2005, 127, 10879-10884.
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