Synthetic studies related to MPC1001: Formation of a model epidithiodiketopiperazine

Article abstract of DOI:10.1016/j.tetlet.2012.01.055

A tricyclic epidithiodiketopiperazine was prepared having structural features related to the antitumor antibiotic MPC1001. The method is based on the use of the sulfenylating agent p-MeC₆H₄S(O ₂)SCH₂OSiMe_2<

Full text of DOI:10.1016/j.tetlet.2012.01.055

Tetrahedron Letters 53 (2012) 1504–1506
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Tetrahedron Letters
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Synthetic studies related to MPC1001: formation of a model
epidithiodiketopiperazine
⇑
Lihong Wang, Derrick L.J. Clive
Chemistry Department, University of Alberta, Edmonton, Alberta, Canada T6G 2G2
a r t i c l e i n f o
a b s t r a c t
Article history:
A tricyclic epidithiodiketopiperazine was prepared having structural features related to the antitumor anti-
biotic MPC1001. The method is based on the use of the sulfenylating agent p-MeC6H4S(O2)SCH2OSiMe2Bu-t
to introduce two protected sulfur atoms in a sequential and stereocontrolled manner. Fluoride-induced
deprotection to remove the CH2OSiMe2Bu-t units and release two sulfhydryl groups, followed by in situ
oxidation, then generated the required bridged disulfide.
Received 19 December 2011
Revised 11 January 2012
Accepted 13 January 2012
Available online 21 January 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Epidithiodiketopiperazine
Sulfenylation
Trisulfide
Protection of sulfur
Sulfur deprotection
The epidithiodiketopiperazine 1,1 a fungal metabolite called
MPC1001, which possesses very powerful anticancer activity
against one of the standard prostate cancer cell lines,1a,b presents
a difficult and complex synthetic target. Among the construc-
tional problems that have to be dealt with is the introduction
of two sulfur atoms with stereochemical control. Exploratory
studies in this laboratory have resulted in the conversion of
commercially available 4-hydroxyproline into the models 2a,b2
and 3.3 The former pair illustrate an approach to the dihydrooxe-
pin subunit, while the synthesis of 3 served to test a method for
introducing the first of the two sulfur atoms. One of our plans
was to then introduce a second protected sulfur atom at C(3)
in the proper stereochemical sense. Removal of both S-protecting
groups at an appropriate stage of the synthesis should then pro-
vide an opportunity to generate the disulfide bridge that is a fea-
ture of the natural product and one that is probably essential4
for biological activity. Our route to 3 was by way of the cycliza-
tion–sulfenylation sequence summarized in Scheme 1.3
We examined several reagents for introducing the first pro-
tected sulfur and initially settled on reagent 63 (see Scheme 1) with
which it was possible to obtain the desired sulfenylation product 7
in a 55% yield. However, later in the sequence that was used to
elaborate 7 into 3, and after the C(6) stereochemistry had been in-
verted to the natural configuration, we found that the (trimethyl-
silyl)ethyl group could not be removed under sufficiently mild
conditions, using either n-Bu4NF5 or 2-O2NC6H4SCl,6 and so an
alternative protecting group had to be found. We examined several
candidates and eventually developed reagent 8.7 With this sulfeny-
lating agent it was possible to convert 4 into 9a,b in a 43% yield as a
2.5:1 mixture of 8aa and 8ab epimers (see Eq. (1)), via the interme-
diacy of ketone 5.7 This result, as well as others involving different
sulfenylating agents, indicated that the bulk of the t-BuPh2SiOCH2-
group at C(6) exerts only a modest influence on the stereochemical
course of the sulfenylation, which also varies with the nature of the
sulfenylating agent. We decided to accept the present result in or-
der to explore some of the additional challenges posed by
MPC1001, and at this point, the next tasks were to establish if
the protecting group could indeed be removed and if a second
⇑
Corresponding author.
E-mail address: derrick.clive@ualberta.ca (D.L.J. Clive).
sulfur unit could be attached at C(3) of 9a with the required
a
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doi:10.1016/j.tetlet.2012.01.055

L. Wang, D.L.J. Clive / Tetrahedron Letters 53 (2012) 1504–1506
1505
Scheme 1. Introduction of sulfur protected with a 2-(trimethylsilyl)ethyl group.
Scheme 2. Deprotection of sulfur group with Ph3CSSCl.
stereochemistry. The stereochemistry of both 9a and 9b was estab-
lished by observation of the Noe effects summarized in Figure 1.
Scheme 3. Deprotection of sulfur group with Ph3CSSCl.
ð1Þ
found that it was necessary to add LDA (2.5 equiv) to a cooled
(ꢀ78 °C) mixture of 11 and EtOCOCl (20 equiv). Under these condi-
tions the C(3) carbanion that is generated by deprotonation is
trapped by the chloroformate before the carbanion decomposes.
Experiments in which the chloroformate was added after deproto-
nation always gave complex mixtures containing little, if any, of
the desired product. After workup, the material was isolated as a
separable mixture of the C(3) epimers 13 and 14, but only the b-
The keto group of the major isomer (9a) was reduced
stereoselectively with NaBH4 (94%), and silylation (100%) of the
resulting alcohol gave 11 (Scheme 2). In a single experiment
(Scheme 2), when 11 was treated with Ph3CSSCl8 the trisulfide
12 was produced in a 50% yield. Related experiments in which
the sulfur was protected by other groups (methoxymethyl,
p-methoxybenzyl) revealed a tendency for sulfur to be ejected by
the adjacent nitrogen and replaced by an oxygen nucleophile (after
workup), but that evidently does not occur in the present case, and
the usefulness of the deprotection was confirmed by another series
of experiments (Scheme 3) in which 11 was acylated with EtOCOCl
to the C(3)-substituted derivatives 13 (30%) and 14 (57%). Treat-
ment of 13 with Ph3CSSCl again gave the desired product 15. The
acylation 11 ? 13 + 14 required very specific conditions and we
epimer 13 reacted with Ph3CSSCl. We assume that the
a-epimer
is inert because steric factors obstruct approach of the reagent to
the target sulfur atom. Our experiments verified that deprotection
was indeed possible in compounds that are relevant to our syn-
thetic studies on MPC1001, and so we next dealt with the problem
of generating9 the bridging disulfide unit.
Our choice of Ph3CSSCl as the deprotection reagent was based
on the expectation that deprotonation of 12 (see Scheme 2) or 15
(see Scheme 3) with a hindered base would afford a C(3) carbanion
that could undergo intramolecular sulfenylation, but our experi-
ments to this end, which would have generated the bridging disul-
fide, were unsuccessful. Therefore, we examined an approach in
which not only C(8a) but also C(3) (see 9a for numbering) would
be independently sulfenylated in an intermolecular fashion. Of
course, for such a route to be viable, control of the C(3) stereo-
chemistry is crucial, and we were able to exercise such control as
follows.
Compound 11 was deprotonated with LDA (1.2 equiv) at ꢀ78 °C
and reagent 8 (1.2 equiv) was added (Scheme 4). In generating the
carbanion from 11, the LDA solution was added rapidly (over ca
10 s) and the solution was stirred for 1 min. Then 8 was added
rapidly in one portion and stirring was continued for 10 min.
Under these conditions, which must be followed closely, it is
Figure 1. Noe effects observed for 9a and 9b.

1506
L. Wang, D.L.J. Clive / Tetrahedron Letters 53 (2012) 1504–1506
cle can be found, in the online version, at doi:10.1016/j.tetlet.2012.
01.055.
References and notes
1. (a) Tsumagari, N.; Nakai, R.; Onodera, H.; Hasegawa, A.; Rahayu, E. S.; Ando, K.;
Yamashita, Y. J. Antibiot. 2004, 57, 532–534; (b) Onodera, H.; Hasegawa, A.;
Tsumagari, N.; Nakai, R.; Ogawa, T.; Kanda, Y. Org. Lett. 2004, 6, 4101–4104; The
compound is also an antagonist of the CCR2 receptor: (c) Herath, K. B.;
Jayasuriya, H.; Ondeyka, J. G.; Polishook, J. D.; Bills, G. F.; Dombrowski, A. W.;
Cabello, A.; Vicario, P. P.; Zweerink, H.; Guan, Z.; Singh, S. B. J. Antibiot. 2005, 58,
686–694.
2. Peng, J.; Clive, D. L. J. Org. Lett. 2007, 9, 2939–2941.
3. Peng, J.; Clive, D. L. J. J. Org. Chem. 2009, 74, 513–519.
4. Cf. Chai, C. L. L.; Elix, J. A.; Huleatt, P. B.; Waring, P. Bioorg. Med. Chem. 2004, 12,
5991–5995.
5. Cf. (a) Koreeda, M.; Yang, W. J. Am. Chem. Soc. 1994, 116, 10793–10794; (b)
Wang, Y.; Koreeda, M.; Chatterji, T.; Gates, K. S. J. Org. Chem. 1998, 63, 8644–
8645; (c) Hamm, M. L.; Cholera, R.; Hoey, C. L.; Gill, T. J. Org. Lett. 2004, 6, 3817–
3820.
Scheme 4. Formation of bridged disulfide.
6. Cf. Gerland, B.; Désiré, J.; Lepoivre, M.; Décout, J.-L. Org. Lett. 2007, 9, 3021–
3023.
7. Wang, L.; Clive, D. L. J. Org. Lett. 2011, 13, 1734–1737.
possible to isolate the sulfenylated product 16 as a mixture of C(3)
epimers. This material was then deprotonated with LDA (4 equiv)
in the same manner (fast addition of the base, followed by a 1-
min stirring period). The resulting carbanion was then quenched
by addition of a mixture of THF and 1 M hydrochloric acid at
ꢀ78 °C. Workup then gave the bis sulfenylated product 1710 as a
single isomer in a 73% overall yield from 11, bringing us to the crit-
ical point of having to remove the sulfur protecting groups and link
the two sulfur atoms that are thereby released. Reaction with n-
Bu4NF alone proved unsatisfactory, but use of n-Bu4NF (5 equiv)
in the presence of AcOH (5 equiv) was very effective, and the
resulting intermediate was easily oxidized by addition of I2 to af-
ford the desired disulfide 18 in a 74% overall yield. As expected,
the triethylsilyl group is also removed in the first part of the proce-
dure. Compound 17 was inert to I2 alone in THF–CH2Cl2. In devel-
oping the t-BuMe2SiOCH2 protecting group for sulfur7 we did not
establish if the action of n-Bu4NF generates a thiol (or thiolate) di-
rectly, or whether only the silicon is removed (t-BuMe2SiOCH2 ? -
HOCH2) and the subsequent loss of formaldehyde occurs on
addition of iodine11; in the present case also, we did not identify
the nature of the intermediate, but characterized only the final
disulfide 18.
8. Williams, C. R.; Britten, J. F.; Harpp, D. N. J. Org. Chem. 1994, 59, 806–812.
9. Review of epidithiodiketopiperazine synthesis including methods of attaching
sulfur to diketopiperazines: Iwasa, E.; Hamashima, Y.; Sodeoka, M. Isr. J. Chem.
2011, 51, 420–433. Methods relevant to the present work, that specifically
involve reaction of carbanions and/or enolic starting materials with sulfur
‘‘electrophiles’’:; (a) Hino, T.; Sato, T. Tetrahedron Lett. 1971, 12, 3127–3129; (b)
Öhler, E.; Poisel, H.; Tataruch, F.; Schmidt, U. Chem. Ber. 1972, 105, 635–641; (c)
Hino, T.; Sato, T. Chem. Pharm. Bull. 1974, 22, 2866–2874; (d) Sato, T.; Hino, T.
Chem. Pharm. Bull. 1976, 24, 285–293; (e) Coffen, D. L.; Katonak, D. A.; Nelson,
N. R.; Sancilio, F. D. J. Org. Chem. 1977, 42, 948–952; (f) Williams, R. M.;
Rastetter, W. H. J. Org. Chem. 1980, 45, 2625–2631; (g) Kirby, G. W.; Robins, D.
J.; Stark, W. M. J. Chem. Soc. Chem. Commun. 1983, 812–813; (h) Williams, R.
M.; Dung, J.-S.; Josey, J.; Armstrong, R. W.; Meyers, H. J. Am. Chem. Soc. 1983,
105, 3214–3220; (i) Friedrich, A.; Jainta, M.; Nieger, M.; Bräse, S. Synlett 2007,
2127–2129; (j) Dubey, R.; Polaske, N. W.; Nichol, G. S.; Olenyuk, B. Tetrahedron
Lett. 2009, 50, 4310–4313; (k) Nicolaou, K. C.; Totokotsopoulos, S.; Giguère, D.;
Sun, Y.-P.; Sarlah, D. J. Am. Chem. Soc. 2011, 133, 8150–8153; (l) Codelli, J. A.;
Puchlopek, A. L. A.; Reisman, S. E. J. Am. Chem. Soc. 2011, ASAP, doi: 10.1021/
ja209354e.; Methods involving replacement of halogen by sulfur nucleophiles:
(m) Trown, P. W. Biochem. Biophys. Res. Commun. 1968, 33, 402–407; (n) Poisel,
H.; Schmidt, U. Angew. Chem., Int. Ed. Engl. 1971, 10, 130–131; (o) Kishi, Y.;
Fukuyama, T.; Nakatsuka, S. J. Am. Chem. Soc. 1973, 95, 6492–6493; (p) Kishi, Y.;
Nakatsuka, S.; Fukuyama, T.; Havel, M. J. Am. Chem. Soc. 1973, 95, 6493–6495;
(q) Ottenheijm, H. C. J.; Kerkhoff, G. P. C.; Bijen, J. W. H. A. J. Chem. Soc., Chem.
Commun. 1975, 8, 768–769; (r) Yoshimura, J.; Nakamura, H.; Matsunari, K. Bull.
Chem. Soc. Jpn. 1975, 48, 605–609; (s) Ottenheijm, H. C. J.; Herscheid, J. D. M.;
Kerkhoff, G. P. C.; Spande, T. F. J. Org. Chem. 1976, 41, 3433–3438; (t) Fukuyama,
T.; Nakatsuka, S.-I.; Kishi, Y. Tetrahedron 1981, 37, 2045–2078; (u) Kirby, G. W.;
Lösel, W.; Rao, P. S.; Robins, D. J.; Sefton, M. A.; Talekar, R. R. J. Chem. Soc., Chem.
Commun. 1983, 8, 810–812; (v) Williams, R. M.; Armstrong, R. W.; Maruyama,
L. K.; Dung, J.-S.; Anderson, O. P. J. Am. Chem. Soc. 1985, 107, 3246–3253; (w)
Shimazaki, N.; Shima, I.; Hemmi, K.; Tsurumi, Y.; Hashimoto, M. Chem. Pharm.
Bull. 1987, 35, 3527–3539; (x) Jiang, H.; Newcombe, N.; Sutton, P.; Lin, Q. H.;
Müllbacher, A.; Waring, P. Aust. J. Chem. 1993, 46, 1743–1754; (y) Miknis, G. F.;
Williams, R. M. J. Am. Chem. Soc. 1993, 115, 536–547; (z) Badran, T. W.; Chai, C.
L. L.; Easton, C. J.; Harper, J. B.; Page, D. M. Aust. J. Chem. 1995, 48, 1379–1384;
Methods involving replacement of hydroxyl or acyloxy groups by sulfur
nucleophiles: (aa) Öhler, E.; Schmidt, U. Chem. Ber. 1975, 108, 2907–2916; (bb)
Overman, L. E.; Sato, T. Org. Lett. 2007, 9, 5267–5270; (cc) Kim, J.; Ashenhurst, J.
A.; Movassaghi, M. Science 2009, 324, 238–241; (dd) Iwasa, E.; Hamashima, Y.;
Fujishiro, S.; Higuchi, E.; Ito, A.; Yoshida, M.; Sodeoka, M. J. Am. Chem. Soc. 2010,
132, 4078–4079; (ee) Kim, J.; Movassaghi, M. J. Am. Chem. Soc. 2010, 132,
14376–14378; (ff) DeLorbe, J. E.; Jabri, S. Y.; Mennen, S. M.; Overman, L. E.;
Zhang, F.-L. J. Am. Chem. Soc. 2011, 133, 6549–6552; Other methods (gg)
Herscheid, J. D. M.; Nivard, R. J. F.; Tijhuis, M. W.; Ottenheijm, H. C. J. J. Org.
Chem. 1980, 45, 1885–1888; (hh) Aliev, A. E.; Hilton, S. T.; Motherwell, W. B.;
Selwood, D. L. Tetrahedron Lett. 2006, 47, 2387–2390; (ii) Hilton, S. T.;
Motherwell, W. B.; Selwood, D. L. Synlett 2004, 2609–2611.
The formation of 18 concludes this model study to identify one
approach to the construction of the bridged disulfide substructure
of MPC1001 and illustrates an application of the CH2OSiMe2Bu-t
group to protect sulfur in a complex setting. A useful characteristic
of the sulfur protecting group is its compatibility with LDA, and it is
this feature that allows the adjustment of the stereochemistry of
16 by a simple deprotonation–reprotonation sequence.
Acknowledgements
We thank the Natural Sciences and Engineering Research Coun-
cil of Canada for financial support. LW held a Marie Arnold Cancer
Research Graduate Scholarship and an Alberta Heritage Foundation
for Medical Research Graduate Studentship.
Supplementary data
10. An Noe effect was observed between C(8)-H and the tert-butyl methyl
hydrogens of the C(5) protecting group, establishing the C(8) stereochemistry.
11. Cf. (a) Harpp, D. N.; Kobayashi, M. Tetrahedron Lett. 1986, 27, 3975–3978; (b)
Schwartz, B.; Vogel, K. W.; Drueckhammer, D. G. J. Org. Chem. 1996, 61, 9356–
9361; (c) Gong, Y.; Ma, M.; Luo, Y.; Bong, D. J. Am. Chem. Soc. 2008, 130, 6196–
6205; (d) Horner, L.; Jürgens, E. Liebigs Ann. Chem. 1957, 602, 135–153.
Supplementary data (experimental procedures and copies of 1H
and 13C NMR spectra for new compounds) associated with this arti-